JPWO2011142359A1 - Spiro compounds and adiponectin receptor activators - Google Patents

Abstract

It is an object of the present invention to provide a novel medicament having affinity for adiponectin receptor and agonistic activity and useful for the prevention or treatment of metabolic syndrome, particularly metabolic syndrome associated with obesity and diabetes, and arteriosclerosis. Novel spiro compound represented by formula (I) (wherein Z1, X, L1, L2, E, R6, R7, m, n and T are defined in the text), tautomerism of the compound It is intended to provide a sex substance, or a pharmaceutically acceptable salt thereof. (Chemical formula 1)

Description

  The present invention relates to a preventive / therapeutic / ameliorating agent for diseases in which an adiponectin receptor activation action is effective, which has an adiponectin receptor affinity and / or agonist action. Furthermore, the present invention relates to a metabolic syndrome containing a drug having an adiponectin receptor agonistic action as an active ingredient, particularly a metabolic syndrome associated with obesity or diabetes, and a prophylactic or therapeutic agent for arteriosclerosis.

Adiponectin is a kind of adipocytokine that is a physiologically active substance secreted from adipocytes. Various possibilities have been suggested for the role of adiponectin, but the most important role is to prevent tissues from acquiring insulin resistance and to act as a protective factor for diabetes. It has been reported that the resistance index is inversely correlated with the blood adiponectin concentration (see, for example, Non-Patent Document 1).
In addition, as its detailed action, by directly stimulating sugar uptake in adipose tissue and muscle tissue, increasing fatty acid oxidation in liver and muscle tissue, reducing intracellular fatty acid and triglyceride content, The possibility of improving insulin resistance is considered (for example, see Non-Patent Documents 2, 3, and 4). Considering such effects, adiponectin may improve obesity through improvement of insulin resistance, and it has been reported that the degree of obesity actually decreases in inverse proportion to the blood adiponectin concentration (for example, Non-patent document 5). Furthermore, adiponectin may be effective in treating metabolic syndrome, which is a complex pathological condition involving them, by improving diabetes and obesity.

It has been clarified that the action of adiponectin is mediated by an adiponectin receptor (hereinafter sometimes referred to as AdipoR). In addition, AdipoR has two subtypes, AdipoR1 and AdipoR2, AdipoR1 is distributed in systemic tissues, and its stimulation mainly exhibits AMP kinase activation (gluconeogenesis suppression) action, while AdipoR2 is the main It is reported that the stimulation is mainly exerted on the enhancement of β-oxidation of fatty acids through the activation of PPARα. AMP kinase is a kinase whose substrate is an enzyme important for glycolipid metabolism such as ACC and HMG-CoA, and regulates various metabolic pathways such as sugar transport, glycolysis and lipid metabolism. Β-oxidation of activated AMP kinase and activated fatty acid enhances metabolic pathways such as fatty acid degradation and glycolysis, and exerts an insulin resistance improving action by suppressing lipid biosynthesis and the like.
In addition, adiponectin has been reported to reduce glycogen content by reducing liver glycogen synthase activity. In addition, it has been reported that adiponectin exerts a protective action against inflammation, coronary artery disease, non-alcoholic steatohepatitis, liver fibrosis or malignant tumor (for example, Non-Patent Documents 6 and 7, and 8).

  As described above, a compound having an affinity for an adiponectin receptor and / or an agonistic action exhibits an adiponectin-like action, whereby a disease in which the adiponectin receptor activating action is effective, such as diabetes, obesity, metabolic It may be effective in the prevention, treatment and improvement of syndrome, arteriosclerosis, coronary artery disease, nonalcoholic steatohepatitis, liver fibrosis or malignant tumors, especially diabetes.

  As a low molecular weight compound exhibiting an adiponectin receptor agonist activity, a report from Rigel has been made (see Patent Documents 1 to 4), but further drug development is desired.

International Publication No. 2008/083124 International Publication No. 2009/066511 International Publication No. 2009/076631 International Publication No. 2009/132136

Circ J. 2004, 68 (11), 975-981. Adiponectin as a biomarker of the metabolic syndrome. Nat. Med. 2002, 8 (11), 1288-1295. Adiponectin stimulates glucose utilization and fatty-acid oxidation by activating AMP-activated protein kinase. Proc. Natl. Acad. Sci. USA. 2002, 99 (25), 16309-16313. Enhanced muscle fat oxidation and glucose transport by ACRP30 globular domain: acetyl-CoA carboxylase inhibition and AMP-activated protein kinase activation. Diabetes. 2003, 52 (6), 1355-1363. Involvement of AMP-activated protein kinase in glucose uptake stimulated by the globular domain of adiponectin in primary rat adipocytes. Arterioscler.Thromb.Vasc.Biol.2000, 20 (6), 1595-1599.Plasma concentrations of a novel, adipose-specific protein, adiponectin, in type 2 diabetic patients. Arterioscler. Thromb. Vasc. Biol. 2003, 23 (1), 85-89. Coronary artery disease. Association of hypoadiponectinemia with coronary artery disease in men. Hepatology. 2008, 47 (4), 1167-77. Adiponectin gene polymorphisms modulate acute adiponectin response to dietary fat: Possible pathogenetic role in NASH. Proc. Natl. Acad. Sci. USA. 2004, 101 (8), 2476-2481. Adiponectin-induced antiangiogenesis and antitumor activity involve caspase-mediated endothelial cell apoptosis.

  It is an object of the present invention to provide a novel pharmaceutical having excellent adiponectin receptor affinity and agonistic activity and useful for the prevention or treatment of metabolic syndrome, particularly metabolic syndrome associated with obesity and diabetes, and arteriosclerosis. And

As a result of intensive studies on the above problems, the present inventors have found that the compound represented by the general formula (I) exhibits an excellent adiponectin receptor agonistic action, and completed the present invention.
That is, the present invention relates to the following.
(1)
Formula (I)

［式（Ｉ）中、
Ｅは、酸素原子又は硫黄原子を意味し、
Ｌ^１は、単結合、Ｃ_１−３アルキレン基、Ｃ_２−３アルケニレン基又はＣ_２−３アルキニレン基（該Ｃ_１−３アルキレン基、Ｃ_２−３アルケニレン基及びＣ_２−３アルキニレン基は、無置換であるか又はシクロプロピル基によって置換されている。）を意味し、
Ｌ^２は、単結合、Ｃ_１−３アルキレン基、Ｃ_２−３アルケニレン基又はＣ_２−３アルキニレン基（該Ｃ_１−３アルキレン基、Ｃ_２−３アルケニレン基及びＣ_２−３アルキニレン基は、無置換であるか又はシクロプロピル基によって置換されている。）を意味し、
Ｘは、Ｃ_３−１１シクロアルキレン基、Ｃ_３−１１シクロアルケニレン基（該Ｃ_３−１１シクロアルキレン基及びＣ_３−１１シクロアルケニレン基は、無置換であるか又は、Ｃ_１−３アルキル基、Ｃ_２−３アルケニル基、−ＯＲ^１６及びシアノ基からなる群より独立して選ばれる１つ以上の置換基によって置換されている。）、Ｃ_６−１０アリーレン基又は５〜１０員ヘテロアリーレン基（該Ｃ_６−１０アリーレン基及び５〜１０員ヘテロアリーレン基は、無置換であるか又は、ハロゲン原子、ニトロ基、シアノ基、Ｃ_１−３アルキル基（該Ｃ_１−３アルキル基は無置換であるか又は、ハロゲン原子及び−ＯＲ^１６からなる群より独立して選ばれる１つ以上の置換基によって置換されている。）、Ｃ_２−３アルケニル基、Ｃ_２−３アルキニル基、−ＯＲ^１６、−Ｏ（Ｃ_２−３アルケニル基）、−Ｏ（Ｃ_３−４シクロアルキル基）、−Ｎ（Ｒ^１６）Ｃ（＝Ｏ）ＯＲ^１７、−Ｎ（Ｒ^１６）Ｃ（＝Ｏ）Ｒ^１７、−Ｎ（Ｒ^１６）Ｃ（＝Ｏ）Ｈ、−Ｎ（Ｒ^１６）Ｒ^１７、−ＮＨ_２、−Ｎ（Ｒ^１６）Ｓ（＝Ｏ）_２Ｒ^１７、−Ｃ（＝Ｏ）ＮＲ^１６Ｒ^１７、−Ｃ（＝Ｏ）ＮＨ_２、−Ｃ（＝Ｏ）Ｒ^１６、−Ｓ（＝Ｏ）_２Ｒ^１７、−Ｓ（＝Ｏ）_２ＮＲ^１６Ｒ^１７、−Ｓ（＝Ｏ）_２ＮＨ_２からなる群より独立して選ばれる１つ以上の置換基によって置換されている。）を意味し、
Ｚ^１は、式（ＩＩ−１）乃至（ＩＩ−８）

[In the formula (I),
E means an oxygen atom or a sulfur atom;
L 1 is a single bond, a C 1-3 alkylene group, a C 2-3 alkenylene group or a C 2-3 alkynylene group (the C 1-3 alkylene group, C 2-3 alkenylene group and C 2-3 alkynylene group are , Unsubstituted or substituted by a cyclopropyl group)
L 2 is a single bond, a C 1-3 alkylene group, a C 2-3 alkenylene group or a C 2-3 alkynylene group (the C 1-3 alkylene group, C 2-3 alkenylene group and C 2-3 alkynylene group are , Unsubstituted or substituted by a cyclopropyl group)
X is a C 3-11 cycloalkylene group, a C 3-11 cycloalkenylene group (the C 3-11 cycloalkylene group and the C 3-11 cycloalkenylene group are unsubstituted or a C 1-3 alkyl group Substituted with one or more substituents independently selected from the group consisting of C 2-3 alkenyl group, —OR 16 and cyano group.), C 6-10 arylene group or 5-10 membered heteroarylene. Group (the C 6-10 arylene group and the 5- to 10-membered heteroarylene group are unsubstituted or a halogen atom, a nitro group, a cyano group, a C 1-3 alkyl group (the C 1-3 alkyl group is or an unsubstituted, substituted by one or more substituents independently selected from the group consisting of a halogen atom and -OR 16.), C 2-3 alkenyl, C 2-3 Rukiniru group, -OR 16, -O (C 2-3 alkenyl group), - O (C 3-4 cycloalkyl group), - N (R 16) C (= O) OR 17, -N (R 16) C (═O) R 17 , —N (R 16 ) C (═O) H, —N (R 16 ) R 17 , —NH 2 , —N (R 16 ) S (═O) 2 R 17 , — C (= O) NR 16 R 17, -C (= O) NH 2, -C (= O) R 16, -S (= O) 2 R 17, -S (= O) 2 NR 16 R 17, -S (= O) substituted by one or more substituents independently selected from the group consisting of 2 NH 2.) I mean,
Z 1 represents the formulas (II-1) to (II-8)

（式中、
Ｊ^１は、それぞれ独立して酸素原子又は硫黄原子を意味し、
Ｇ^１は、単結合、酸素原子又は硫黄原子を意味し、
Ｒ^１とＲ^３は、
Ｒ^１が、水素原子、ＯＲ^１１、ＮＲ^１１Ｒ^１２、Ｃ_１−９アルキル基（該Ｃ_１−９アルキル基は、無置換であるか又は置換基群Ａ_３より独立して選ばれる１つ以上の置換基によって置換されている。）、Ｃ_３−１１シクロアルキル基又は４〜１１員ヘテロシクロアルキル基（該Ｃ_３−１１シクロアルキル基及び４〜１１員ヘテロシクロアルキル基は、Ｃ_６−１０アリール又は５〜１０員ヘテロアリール（該Ｃ_６−１０アリール及び５〜１０員ヘテロアリールは無置換であるか又は置換基群Ａ_２及びＣ_４−６アルキル基からなる群より独立して選ばれる１つ以上の置換基によって置換されている。）と縮環していても良く、且つ該Ｃ_３−１１シクロアルキル基及び４〜１１員ヘテロシクロアルキル基は、無置換であるか又は置換基群Ａ_１及びＣ_４−６アルキル基からなる群より独立して選ばれる１つ以上の置換基によって置換されている。）を意味し、Ｒ^３が水素原子若しくはＣ_１−３アルキル基を意味するか、
又は、Ｒ^１とＲ^３が、それらが結合している窒素原子と一緒になって４〜１１員ヘテロシクロアルキル基（該４〜１１員ヘテロシクロアルキル基は、無置換であるか又は置換基群Ａ_１及びＣ_４−６アルキル基からなる群より独立して選ばれる１つ以上の置換基によって置換されている。）を意味し、
Ｒ^２は、Ｃ_１−９アルキル基（該Ｃ_１−９アルキル基は、無置換であるか又は置換基群Ａ_３より独立して選ばれる１つ以上の置換基によって置換されている。）、Ｃ_３−１１シクロアルキル基又は４〜１１員ヘテロシクロアルキル基（該Ｃ_３−１１シクロアルキル基及び４〜１１員ヘテロシクロアルキル基は、Ｃ_６−１０アリール又は５〜１０員ヘテロアリール（該Ｃ_６−１０アリール及び５〜１０員ヘテロアリールは無置換であるか又は置換基群Ａ_２及びＣ_４−６アルキル基からなる群より独立して選ばれる１つ以上の置換基によって置換されている。）と縮環していても良く、且つ該Ｃ_３−１１シクロアルキル基及び４〜１１員ヘテロシクロアルキル基は、無置換であるか又は置換基群Ａ_１及びＣ_４−６アルキル基からなる群より独立して選ばれる１つ以上の置換基によって置換されている。）を意味し、
Ｒ^４及びＲ^５は、それぞれ独立して水素原子又はＣ_１−３アルキル基を意味する。）
の何れかを意味し、
ｍは、１又は２の整数を意味し、
Ｒ^６は、それぞれ独立して、水素原子、Ｃ_１−３アルキル基若しくはシクロプロピル基を意味するか、又は、同一炭素原子上に存在する二つのＲ^６が、それらが結合している炭素原子と一緒になってＣ_３−６シクロアルカンを形成し、
ｎは、０乃至４の整数を意味し、
Ｒ^７は、それぞれ独立してＣ_１−３アルキル基を意味し、
Ｔは、式（ＶＩ−１）乃至（ＶＩ−３）

(Where
J ¹ each independently represents an oxygen atom or a sulfur atom;
G ¹ means a single bond, an oxygen atom or a sulfur atom,
R ¹ and R ³ are
R ¹ is a hydrogen atom, OR ¹¹ , NR ¹¹ R ¹² , C _1-9 alkyl group (the C _1-9 alkyl group is unsubstituted or one independently selected from substituent group A ₃ Substituted with the above substituents), a C _3-11 cycloalkyl group or a 4-11 membered heterocycloalkyl group (the C _3-11 cycloalkyl group and 4-11 membered heterocycloalkyl group are C _{6 -10} aryl or 5-10 membered heteroaryl (wherein the C _6-10 aryl and 5-10 membered heteroaryl are unsubstituted or independently of the group consisting of substituent groups A ₂ and C _4-6 alkyl groups) The C _3-11 cycloalkyl group and the 4-11 membered heterocycloalkyl group may be unsubstituted or substituted with one or more selected substituents). Substituent Which is substituted by one or more substituents independently selected from the group consisting of A ₁ and C _4-6 alkyl groups.) Means, R ³ means a hydrogen atom or a C _1-3 alkyl group Or
Or R ¹ and R ³ , together with the nitrogen atom to which they are attached, are a 4-11 membered heterocycloalkyl group (the 4-11 membered heterocycloalkyl group is unsubstituted or substituted) Substituted with one or more substituents independently selected from the group consisting of group A ₁ and a C _4-6 alkyl group.
R ² represents a C _1-9 alkyl group (the C _1-9 alkyl group is unsubstituted or substituted with one or more substituents independently selected from Substituent Group A ₃ ). , A C _3-11 cycloalkyl group or a 4-11 membered heterocycloalkyl group (the C _3-11 cycloalkyl group and 4-11 membered heterocycloalkyl group are C _6-10 aryl or 5-10 membered heteroaryl ( The C _6-10 aryl and 5-10 membered heteroaryl are unsubstituted or substituted by one or more substituents independently selected from the group consisting of the substituent groups A ₂ and C _4-6 alkyl groups. And the C _3-11 cycloalkyl group and the 4-11 membered heterocycloalkyl group may be unsubstituted or substituted with the substituent groups A ₁ and C _4-6 alkyl. A group of groups Substituted by one or more substituents independently selected),
R ⁴ and R ⁵ each independently represent a hydrogen atom or a C _1-3 alkyl group. )
Means either
m means an integer of 1 or 2,
R ⁶ independently represents a hydrogen atom, a C _1-3 alkyl group or a cyclopropyl group, or two R ⁶ existing on the same carbon atom are bonded to the carbon atom to which they are bonded. Together with C to form a C _3-6 cycloalkane,
n means an integer of 0 to 4,
R ⁷ each independently represents a C _1-3 alkyl group;
T represents formulas (VI-1) to (VI-3)

（式中、
Ｌ^４は、Ｃ_１−３アルキレン基を意味し、
Ｌ^５は、単結合、酸素原子、硫黄原子、Ｓ（＝Ｏ）、Ｓ（＝Ｏ）_２、Ｃ＝Ｏ又はＣ＝ＮＯＲ^１２を意味し、
Ｒ^８は、Ｃ_６−１０アリール基又は５〜１０員ヘテロアリール基（該Ｃ_６−１０アリール基及び５〜１０員ヘテロアリール基は、無置換であるか又は置換基群Ａ_２及びＣ_４−６アルキル基からなる群より独立して選ばれる１つ以上の置換基によって置換されている。）を意味し、
Ｊ^２は、酸素原子又は硫黄原子を意味し、
Ｇ^２は、酸素原子、硫黄原子又はＮＲ^１１を意味し、
Ｒ^９は、Ｃ_１−９アルキル基（該Ｃ_１−９アルキル基は、無置換であるか又は置換基群Ａ_４より独立して選ばれる１つ以上の置換基によって置換されている。）、Ｃ_６−１０アリール基（該Ｃ_６−１０アリール基は、無置換であるか又は置換基群Ａ_２及びＣ_４−６アルキル基からなる群より独立して選ばれる１つ以上の置換基によって置換されている。）、Ｃ_３−１１シクロアルキル基（該Ｃ_３−１１シクロアルキル基は、Ｃ_６−１０アリールもしくは５〜１０員ヘテロアリール（該Ｃ_６−１０アリール及び５〜１０員ヘテロアリールは無置換であるか又は置換基群Ａ_２及びＣ_４−６アルキル基からなる群より独立して選ばれる１つ以上の置換基によって置換されている。）と縮環していても良く、且つ該Ｃ_３−１１シクロアルキル基は、無置換であるか又は置換基群Ａ_２より独立して選ばれる１つ以上の置換基によって置換されている。）、又は、Ｃ_１−３アルキル基（該Ｃ_１−３アルキル基は、Ｃ_６−１０アリール基もしくはＣ_３−１１シクロアルキル基（該Ｃ_６−１０アリール基及びＣ_３−１１シクロアルキル基は、無置換であるか又は置換基群Ａ_２及びＣ_４−６アルキル基からなる群より独立して選ばれる１つ以上の置換基によって置換されている。）で置換されている。）を意味し、
Ｒ^１０は、Ｃ_１−９アルキル基（該Ｃ_１−９アルキル基は、無置換であるか又は置換基群Ａ_４より独立して選ばれる１つ以上の置換基によって置換されている。）、Ｃ_６−１０アリール基、５〜１０員ヘテロアリール基（該Ｃ_６−１０アリール基及び５〜１０員ヘテロアリール基は、無置換であるか又は置換基群Ａ_２及びＣ_４−６アルキル基からなる群より独立して選ばれる１つ以上の置換基によって置換されている。）、Ｃ_３−１１シクロアルキル基（該Ｃ_３−１１シクロアルキル基は、Ｃ_６−１０アリールもしくは５〜１０員ヘテロアリール（該Ｃ_６−１０アリール及び５〜１０員ヘテロアリールは無置換であるか又は置換基群Ａ_２及びＣ_４−６アルキル基からなる群より独立して選ばれる１つ以上の置換基によって置換されている。）と縮環していても良く、且つ該Ｃ_３−１１シクロアルキル基は、無置換であるか又は置換基群Ａ_２より独立して選ばれる１つ以上の置換基によって置換されている。）、又はＣ_１−３アルキル基（該Ｃ_１−３アルキル基はＣ_３−１１シクロアルキル基（該Ｃ_３−１１シクロアルキル基は、無置換であるか又は置換基群Ａ_２より独立して選ばれる１つ以上の置換基によって置換されている。）で置換されている。）を意味する。）
の何れかを意味し、
置換基群Ａ_１は、Ｃ_１−３アルキル基（該Ｃ_１−３アルキル基は無置換であるか又は置換基群Ａ_３より独立して選ばれる１つ以上の置換基によって置換されている。）及び置換基群Ａ_３で構成される置換基群を意味し、
置換基群Ａ_３は、
Ｃ_３−１１シクロアルキル基、４〜１１員ヘテロシクロアルキル基（該Ｃ_３−１１シクロアルキル基及び４〜１１員ヘテロシクロアルキル基は、Ｃ_６−１０アリールもしくは５〜１０員ヘテロアリール（該Ｃ_６−１０アリール及び５〜１０員ヘテロアリールは無置換であるか又は置換基群Ａ_２及びＣ_４−６アルキル基からなる群より独立して選ばれる１つ以上の置換基によって置換されている。）と縮環していても良く、且つ該Ｃ_３−１１シクロアルキル基及び４〜１１員ヘテロシクロアルキル基は、無置換であるか又は置換基群Ａ_２及びＣ_４−６アルキル基からなる群より独立して選ばれる１つ以上の置換基によって置換されている。）、Ｃ_６−１０アリール基、５〜１０員ヘテロアリール基（該Ｃ_６−１０アリール基及び５〜１０員ヘテロアリール基は、４〜１１員ヘテロシクロアルカン（該４〜１１員ヘテロシクロアルカンは無置換であるか又は置換基群Ａ_２より独立して選ばれる１つ以上の置換基によって置換されている。）と縮環していても良く、且つ該Ｃ_６−１０アリール基及び５〜１０員ヘテロアリール基は無置換であるか又は置換基群Ａ_２及びＣ_４−６アルキル基からなる群より独立して選ばれる１つ以上の置換基によって置換されている。）、−Ｃ（＝Ｏ）ＯＲ^１３、−Ｃ（＝Ｏ）ＮＲ^１２Ｒ^１３、−Ｃ（＝Ｏ）Ｒ^１３、−Ｃ（＝ＮＯＲ^１２）Ｒ^１３、−Ｓ（＝Ｏ）Ｒ^１３、−Ｓ（＝Ｏ）_２Ｒ^１３、−ＯＲ^１３、−ＳＲ^１３、−Ｎ（Ｒ^１２）Ｃ（＝Ｏ）ＯＲ^１３、−Ｎ（Ｒ^１２）Ｃ（＝Ｏ）Ｒ^１３、−Ｎ（Ｒ^１２）Ｒ^１３、ハロゲン原子、シアノ基、ニトロ基、ホルミル基、−Ｃ（＝ＮＯＲ^１２）Ｈ、−Ｎ（Ｒ^１２）Ｃ（＝Ｏ）Ｈ、又は水酸基で構成される置換基群を意味し、
置換基群Ａ_２は、
Ｃ_１−３アルキル基（該Ｃ_１−３アルキル基は無置換であるか又は１つ以上のハロゲン原子によって置換されている。）及び置換基群Ａ_４で構成される置換基群を意味し、
置換基群Ａ_４は、
ハロゲン原子、ニトロ基、シアノ基、−ＯＲ^１４、−ＳＲ^１４、−Ｃ（＝Ｏ）ＯＲ^１４、−Ｃ（＝Ｏ）ＮＲ^１４Ｒ^１５、−Ｃ（＝Ｏ）Ｒ^１５、−Ｃ（＝ＮＯＲ^１５）Ｒ^１４、−Ｃ（＝ＮＯＲ^１５）Ｈ、−Ｓ（＝Ｏ）Ｒ^１４、−Ｓ（＝Ｏ）_２Ｒ^１４、−Ｎ（Ｒ^１５）Ｃ（＝Ｏ）ＯＲ^１４、−Ｎ（Ｒ^１５）Ｃ（＝Ｏ）Ｒ^１４、又は−Ｎ（Ｒ^１５）Ｃ（＝Ｏ）Ｈで構成される置換基群を意味し、
Ｒ^１１は、それぞれ独立して、水素原子又はＣ_１−６アルキル基を意味し、
Ｒ^１２は、それぞれ独立して、水素原子又はＣ_１−３アルキル基を意味し、
Ｒ^１３は、それぞれ独立して、
Ｃ_１−６アルキル基（該Ｃ_１−６アルキル基は、無置換であるか又は置換基群Ａ_４より独立して選ばれる１つ以上の置換基によって置換されている。）、
Ｃ_３−１１シクロアルキル基、４〜１１員ヘテロシクロアルキル基、Ｃ_６−１０アリール基、又は５〜１０員ヘテロアリール基（該Ｃ_３−１１シクロアルキル基、４〜１１員ヘテロシクロアルキル基、Ｃ_６−１０アリール基及び５〜１０員ヘテロアリール基は、無置換であるか又は置換基群Ａ_２及びＣ_４−６アルキル基からなる群より独立して選ばれる１つ以上の置換基によって置換されている。）を意味し、
Ｒ^１４は、Ｃ_１−３アルキル基（該Ｃ_１−３アルキル基は無置換であるか又は１つ以上のハロゲン原子によって置換されている。）を意味し、
Ｒ^１５は、水素原子又はＣ_１−３アルキル基（該Ｃ_１−３アルキル基は無置換であるか又は１つ以上のハロゲン原子によって置換されている。）を意味し、
Ｒ^１６は、水素原子又はＣ_１−３アルキル基を意味し、
Ｒ^１７は、Ｃ_１−３アルキル基を意味する。］
で表されるスピロ化合物、該化合物の互変異性体、若しくはその医薬的に許容され得る塩。

（２）
式（Ｉ）

(Where
L ⁴ means a C _1-3 alkylene group,
L ⁵ represents a single bond, an oxygen atom, a sulfur atom, S (═O), S (═O) ₂ , C═O or C═NOR ¹² ;
R ⁸ represents a C _6-10 aryl group or a 5- to 10-membered heteroaryl group (the C _6-10 aryl group and the 5- to 10-membered heteroaryl group are unsubstituted or substituted by the substituent groups A ₂ and C _4. Substituted with one or more substituents independently selected from the group consisting of _-6 alkyl groups).
J ² means an oxygen atom or a sulfur atom,
G ² means an oxygen atom, a sulfur atom or NR ¹¹ ,
R ⁹ represents a C _1-9 alkyl group (the C _1-9 alkyl group is unsubstituted or substituted with one or more substituents independently selected from substituent group A ₄ ). , A C _6-10 aryl group (wherein the C _6-10 aryl group is unsubstituted or one or more substituents independently selected from the group consisting of the substituent group A ₂ and the C _4-6 alkyl group) A C _3-11 cycloalkyl group (wherein the C _3-11 cycloalkyl group is a C _6-10 aryl or 5-10 membered heteroaryl (the C _6-10 aryl and 5-10 membered). Heteroaryl is unsubstituted or substituted by one or more substituents independently selected from the group consisting of substituent groups A ₂ and C _4-6 alkyl groups. well, and the _{C 3-11} cycloalkyl Group is substituted by one or more substituents selected as or independently from Substituent group A ₂ unsubstituted.), Or, a C _1-3 alkyl group (the C _1-3 alkyl group Is a C _6-10 aryl group or a C _3-11 cycloalkyl group (the C _6-10 aryl group and the C _3-11 cycloalkyl group are unsubstituted or substituted with the substituent groups A ₂ and C _4-6. Substituted with one or more substituents independently selected from the group consisting of alkyl groups).
R ¹⁰ represents a C _1-9 alkyl group (the C _1-9 alkyl group is unsubstituted or substituted with one or more substituents independently selected from substituent group A ₄ ). A C _6-10 aryl group, a 5-10 membered heteroaryl group (the C _6-10 aryl group and the 5-10 membered heteroaryl group are unsubstituted or substituted with a substituent group A ₂ and a C _4-6 alkyl). Substituted with one or more substituents independently selected from the group consisting of groups), a C _3-11 cycloalkyl group (wherein the C _3-11 cycloalkyl group is C _6-10 aryl or 5- 10-membered heteroaryl (wherein the C _6-10 aryl and the 5-10 membered heteroaryl are unsubstituted or selected from the group consisting of the substituent groups A ₂ and C _4-6 alkyl group independently) Substituted by substituents It is.) And may be a condensed ring, and the C _3-11 cycloalkyl group, optionally substituted by one or more substituents selected as or independently from Substituent group A ₂ unsubstituted Or a C _1-3 alkyl group (the C _1-3 alkyl group is a C _3-11 cycloalkyl group (the C _3-11 cycloalkyl group is unsubstituted or from substituent group A ₂₎ . Substituted with one or more independently selected substituents)). )
Means either
Substituent group A ₁ is a C _1-3 alkyl group (the C _1-3 alkyl group is unsubstituted or substituted by one or more substituents independently selected from substituent group A ₃ ). .) and means a substituent group consisting of substituent group a _3,
Substituent group A ₃ is
A C _3-11 cycloalkyl group, a 4-11 membered heterocycloalkyl group (the C _3-11 cycloalkyl group and 4-11 membered heterocycloalkyl group are C _6-10 aryl or 5-10 membered heteroaryl (the C _6-10 aryl and 5-10 membered heteroaryl are unsubstituted or substituted by one or more substituents independently selected from the group consisting of substituent groups A ₂ and C _4-6 alkyl groups. The C _3-11 cycloalkyl group and the 4- to 11-membered heterocycloalkyl group may be unsubstituted or substituted with a substituent group A ₂ and a C _4-6 alkyl group. which is substituted by one or more substituents independently selected from the group consisting _{of.), C 6-10} aryl group, 5-10-membered heteroaryl group (the _{C 6-10} aryl and 5 to 1 Membered heteroaryl group, 4-11-membered heterocycloalkyl alkane (said 4-11 membered heterocycloalkyl cycloalkane is substituted by one or more substituents selected as or independently from Substituent group A ₂ unsubstituted And the C _6-10 aryl group and the 5- to 10-membered heteroaryl group are unsubstituted or a group consisting of the substituent group A ₂ and the C _4-6 alkyl group. Substituted with one or more substituents selected more independently.), —C (═O) OR ¹³ , —C (═O) NR ¹² R ¹³ , —C (═O) R ¹³ , — _{^{C (= NOR 12) R 13}} , -S (= O) R 13, -S (= O) 2 R 13, -OR 13, -SR 13, -N (R 12) C (= O) OR 13, ^{-N (R 12) C (=} O) R 13, -N (R 12) R 13, C Gen atom, a cyano group, a nitro group, means a formyl ^{group, -C (= NOR 12) H} , -N (R 12) C (= O) H, or a substituent group consisting of a hydroxyl group,
Substituent group A ₂ is
Means a substituent group composed of a C _1-3 alkyl group (the C _1-3 alkyl group is unsubstituted or substituted by one or more halogen atoms) and a substituent group A ₄ ,
Substituent group A ₄ is
A halogen atom, a nitro group, a cyano group, —OR ¹⁴ , —SR ¹⁴ , —C (═O) OR ¹⁴ , —C (═O) NR ¹⁴ R ¹⁵ , —C (═O) R ¹⁵ , —C (= ^{NOR 15) R 14, -C (} = NOR 15) H, -S (= O) R 14, -S (= O) 2 R 14, -N (R 15) C (= O) OR 14, -N Means a group of substituents composed of (R ¹⁵ ) C (═O) R ¹⁴ or —N (R ¹⁵ ) C (═O) H;
Each of R ¹¹ independently represents a hydrogen atom or a C _1-6 alkyl group;
R ¹² each independently represents a hydrogen atom or a C _1-3 alkyl group;
Each R ¹³ is independently
A C _1-6 alkyl group (the C _1-6 alkyl group is unsubstituted or substituted by one or more substituents independently selected from Substituent Group A ₄ );
A C _3-11 cycloalkyl group, a 4-11 membered heterocycloalkyl group, a C _6-10 aryl group, or a 5-10 membered heteroaryl group (the C _3-11 cycloalkyl group, 4-11 membered heterocycloalkyl group; , The C _6-10 aryl group and the 5-10 membered heteroaryl group are one or more substituents which are unsubstituted or independently selected from the group consisting of the substituent groups A ₂ and C _4-6 alkyl groups Is replaced by
R ¹⁴ represents a C _1-3 alkyl group (the C _1-3 alkyl group is unsubstituted or substituted by one or more halogen atoms);
R ¹⁵ represents a hydrogen atom or a C _1-3 alkyl group (the C _1-3 alkyl group is unsubstituted or substituted by one or more halogen atoms);
R ¹⁶ represents a hydrogen atom or a C _1-3 alkyl group,
R ¹⁷ means a C _1-3 alkyl group. ]
Or a tautomer of the compound, or a pharmaceutically acceptable salt thereof.

(2)
Formula (I)

［式（Ｉ）中、
Ｅは、酸素原子又は硫黄原子を意味し、
Ｌ^１は、単結合、Ｃ_１−３アルキレン基、Ｃ_２−３アルケニレン基又はＣ_２−３アルキニレン基（該Ｃ_１−３アルキレン基、Ｃ_２−３アルケニレン基及びＣ_２−３アルキニレン基は、無置換であるか又はシクロプロピル基によって置換されている。）を意味し、
Ｌ^２は、単結合、Ｃ_１−３アルキレン基、Ｃ_２−３アルケニレン基又はＣ_２−３アルキニレン基（該Ｃ_１−３アルキレン基、Ｃ_２−３アルケニレン基及びＣ_２−３アルキニレン基は、無置換であるか又はシクロプロピル基によって置換されている。）を意味し、
Ｘは、Ｃ_３−１１シクロアルキレン基、Ｃ_３−１１シクロアルケニレン基（該Ｃ_３−１１シクロアルキレン基及びＣ_３−１１シクロアルケニレン基は、無置換であるか又は、Ｃ_１−３アルキル基、Ｃ_２−３アルケニル基、−ＯＲ^１６及びシアノ基からなる群より独立して選ばれる１つ以上の置換基によって置換されている。）、Ｃ_６−１０アリーレン基又は５〜１０員ヘテロアリーレン基（該Ｃ_６−１０アリーレン基及び５〜１０員ヘテロアリーレン基は、無置換であるか又は、ハロゲン原子、ニトロ基、シアノ基、Ｃ_１−３アルキル基（該Ｃ_１−３アルキル基は無置換であるか又は、ハロゲン原子及び−ＯＲ^１６からなる群より独立して選ばれる１つ以上の置換基によって置換されている。）、Ｃ_２−３アルケニル基、Ｃ_２−３アルキニル基、−ＯＲ^１６、−Ｏ（Ｃ_２−３アルケニル基）、−Ｏ（Ｃ_３−４シクロアルキル基）、−Ｎ（Ｒ^１６）Ｃ（＝Ｏ）ＯＲ^１７、−Ｎ（Ｒ^１６）Ｃ（＝Ｏ）Ｒ^１７、−Ｎ（Ｒ^１６）Ｃ（＝Ｏ）Ｈ、−Ｎ（Ｒ^１６）Ｒ^１７、−ＮＨ_２、−Ｎ（Ｒ^１６）Ｓ（＝Ｏ）_２Ｒ^１７、−Ｃ（＝Ｏ）ＮＲ^１６Ｒ^１７、−Ｃ（＝Ｏ）ＮＨ_２、−Ｃ（＝Ｏ）Ｒ^１６、−Ｓ（＝Ｏ）_２Ｒ^１７、−Ｓ（＝Ｏ）_２ＮＲ^１６Ｒ^１７、−Ｓ（＝Ｏ）_２ＮＨ_２からなる群より独立して選ばれる１つ以上の置換基によって置換されている。）を意味し、
Ｚ^１は、式（ＩＩ−１）乃至（ＩＩ−８）

[In the formula (I),
E means an oxygen atom or a sulfur atom;
L 1 is a single bond, a C 1-3 alkylene group, a C 2-3 alkenylene group or a C 2-3 alkynylene group (the C 1-3 alkylene group, C 2-3 alkenylene group and C 2-3 alkynylene group are , Unsubstituted or substituted by a cyclopropyl group)
L 2 is a single bond, a C 1-3 alkylene group, a C 2-3 alkenylene group or a C 2-3 alkynylene group (the C 1-3 alkylene group, C 2-3 alkenylene group and C 2-3 alkynylene group are , Unsubstituted or substituted by a cyclopropyl group)
X is a C 3-11 cycloalkylene group, a C 3-11 cycloalkenylene group (the C 3-11 cycloalkylene group and the C 3-11 cycloalkenylene group are unsubstituted or a C 1-3 alkyl group Substituted with one or more substituents independently selected from the group consisting of C 2-3 alkenyl group, —OR 16 and cyano group.), C 6-10 arylene group or 5-10 membered heteroarylene. Group (the C 6-10 arylene group and the 5- to 10-membered heteroarylene group are unsubstituted or a halogen atom, a nitro group, a cyano group, a C 1-3 alkyl group (the C 1-3 alkyl group is or an unsubstituted, substituted by one or more substituents independently selected from the group consisting of a halogen atom and -OR 16.), C 2-3 alkenyl, C 2-3 Rukiniru group, -OR 16, -O (C 2-3 alkenyl group), - O (C 3-4 cycloalkyl group), - N (R 16) C (= O) OR 17, -N (R 16) C (═O) R 17 , —N (R 16 ) C (═O) H, —N (R 16 ) R 17 , —NH 2 , —N (R 16 ) S (═O) 2 R 17 , — C (= O) NR 16 R 17, -C (= O) NH 2, -C (= O) R 16, -S (= O) 2 R 17, -S (= O) 2 NR 16 R 17, -S (= O) substituted by one or more substituents independently selected from the group consisting of 2 NH 2.) I mean,
Z 1 represents the formulas (II-1) to (II-8)

（式中、
Ｊ^１は、それぞれ独立して酸素原子又は硫黄原子を意味し、
Ｇ^１は、単結合、酸素原子又は硫黄原子を意味し、
Ｒ^１とＲ^３は、
Ｒ^１が、水素原子、ＯＲ^１１、ＮＲ^１１Ｒ^１２、Ｃ_１−９アルキル基（該Ｃ_１−９アルキル基は、無置換であるか又は置換基群Ａ_３より独立して選ばれる１つ以上の置換基によって置換されている。）、Ｃ_３−１１シクロアルキル基又は４〜１１員ヘテロシクロアルキル基（該Ｃ_３−１１シクロアルキル基及び４〜１１員ヘテロシクロアルキル基は、Ｃ_６−１０アリール又は５〜１０員ヘテロアリール（該Ｃ_６−１０アリール及び５〜１０員ヘテロアリールは無置換であるか又は置換基群Ａ_２より独立して選ばれる１つ以上の置換基によって置換されている。）と縮環していても良く、且つ該Ｃ_３−１１シクロアルキル基及び４〜１１員ヘテロシクロアルキル基は、無置換であるか又は置換基群Ａ_１より独立して選ばれる１つ以上の置換基によって置換されている。）を意味し、Ｒ^３が水素原子若しくはＣ_１−３アルキル基を意味するか、
又は、Ｒ^１とＲ^３が、それらが結合している窒素原子と一緒になって４〜１１員ヘテロシクロアルキル基（該４〜１１員ヘテロシクロアルキル基は、無置換であるか又は置換基群Ａ_１より独立して選ばれる１つ以上の置換基によって置換されている。）を意味し、
Ｒ^２は、Ｃ_１−９アルキル基（該Ｃ_１−９アルキル基は、無置換であるか又は置換基群Ａ_３より独立して選ばれる１つ以上の置換基によって置換されている。）、Ｃ_３−１１シクロアルキル基又は４〜１１員ヘテロシクロアルキル基（該Ｃ_３−１１シクロアルキル基及び４〜１１員ヘテロシクロアルキル基は、Ｃ_６−１０アリール又は５〜１０員ヘテロアリール（該Ｃ_６−１０アリール及び５〜１０員ヘテロアリールは無置換であるか又は置換基群Ａ_２より独立して選ばれる１つ以上の置換基によって置換されている。）と縮環していても良く、且つ該Ｃ_３−１１シクロアルキル基及び４〜１１員ヘテロシクロアルキル基は、無置換であるか又は置換基群Ａ_１より独立して選ばれる１つ以上の置換基によって置換されている。）を意味し、
Ｒ^４及びＲ^５は、それぞれ独立して水素原子又はＣ_１−３アルキル基を意味する。）
の何れかを意味し、
ｍは、１又は２の整数を意味し、
Ｒ^６は、それぞれ独立して、水素原子、Ｃ_１−３アルキル基若しくはシクロプロピル基を意味するか、又は、同一炭素原子上に存在する二つのＲ^６が、それらが結合している炭素原子と一緒になってＣ_３−６シクロアルカンを形成し、
ｎは、０乃至４の整数を意味し、
Ｒ^７は、それぞれ独立してＣ_１−３アルキル基を意味し、
Ｔは、式（ＶＩ−１）乃至（ＶＩ−３）

(Where
J ¹ each independently represents an oxygen atom or a sulfur atom;
G ¹ means a single bond, an oxygen atom or a sulfur atom,
R ¹ and R ³ are
R ¹ is a hydrogen atom, OR ¹¹ , NR ¹¹ R ¹² , C _1-9 alkyl group (the C _1-9 alkyl group is unsubstituted or one independently selected from substituent group A ₃ Substituted with the above substituents), a C _3-11 cycloalkyl group or a 4-11 membered heterocycloalkyl group (the C _3-11 cycloalkyl group and 4-11 membered heterocycloalkyl group are C _{6 -10} aryl or 5-10 membered heteroaryl (wherein the C _6-10 aryl and 5-10 membered heteroaryl are unsubstituted or substituted by one or more substituents independently selected from substituent group A ₂₎ It is.) and may be a condensed ring, and the C _3-11 cycloalkyl group and 4-11 membered heterocycloalkyl group chosen as or independently from substituent group a ₁ unsubstituted One or more Which is substituted by substituents.) I mean, or R ³ means a hydrogen atom or a C _1-3 alkyl group,
Or R ¹ and R ³ , together with the nitrogen atom to which they are attached, are a 4-11 membered heterocycloalkyl group (the 4-11 membered heterocycloalkyl group is unsubstituted or substituted) which is substituted by one or more substituents independently selected from the group a _1.) means,
R ² represents a C _1-9 alkyl group (the C _1-9 alkyl group is unsubstituted or substituted with one or more substituents independently selected from Substituent Group A ₃ ). , A C _3-11 cycloalkyl group or a 4-11 membered heterocycloalkyl group (the C _3-11 cycloalkyl group and 4-11 membered heterocycloalkyl group are C _6-10 aryl or 5-10 membered heteroaryl ( The C _6-10 aryl and the 5-10 membered heteroaryl are unsubstituted or substituted with one or more substituents independently selected from substituent group A ₂ ). And the C _3-11 cycloalkyl group and the 4- to 11-membered heterocycloalkyl group are unsubstituted or substituted with one or more substituents independently selected from Substituent Group A ₁ ) And,
R ⁴ and R ⁵ each independently represent a hydrogen atom or a C _1-3 alkyl group. )
Means either
m means an integer of 1 or 2,
R ⁶ independently represents a hydrogen atom, a C _1-3 alkyl group or a cyclopropyl group, or two R ⁶ existing on the same carbon atom are bonded to the carbon atom to which they are bonded. Together with C to form a C _3-6 cycloalkane,
n means an integer of 0 to 4,
R ⁷ each independently represents a C _1-3 alkyl group;
T represents formulas (VI-1) to (VI-3)

（式中、
Ｌ^４は、Ｃ_１−３アルキレン基を意味し、
Ｌ^５は、単結合、酸素原子、硫黄原子、Ｓ（＝Ｏ）、Ｓ（＝Ｏ）_２、Ｃ＝Ｏ又はＣ＝ＮＯＲ^１２を意味し、
Ｒ^８は、Ｃ_６−１０アリール基又は５〜１０員ヘテロアリール基（該Ｃ_６−１０アリール基及び５〜１０員ヘテロアリール基は、無置換であるか又は置換基群Ａ_２より独立して選ばれる１つ以上の置換基によって置換されている。）を意味し、
Ｊ^２は、酸素原子又は硫黄原子を意味し、
Ｇ^２は、酸素原子、硫黄原子又はＮＲ^１１を意味し、
Ｒ^９は、Ｃ_１−９アルキル基（該Ｃ_１−９アルキル基は、無置換であるか又は置換基群Ａ_４より独立して選ばれる１つ以上の置換基によって置換されている。）、Ｃ_６−１０アリール基（該Ｃ_６−１０アリール基は、無置換であるか又は置換基群Ａ_２より独立して選ばれる１つ以上の置換基によって置換されている。）、Ｃ_３−１１シクロアルキル基（該Ｃ_３−１１シクロアルキル基は、Ｃ_６−１０アリールもしくは５〜１０員ヘテロアリール（該Ｃ_６−１０アリール及び５〜１０員ヘテロアリールは無置換であるか又は置換基群Ａ_２より独立して選ばれる１つ以上の置換基によって置換されている。）と縮環していても良く、且つ該Ｃ_３−１１シクロアルキル基は、無置換であるか又は置換基群Ａ_２より独立して選ばれる１つ以上の置換基によって置換されている。）、又は、Ｃ_１−３アルキル基（該Ｃ_１−３アルキル基は、Ｃ_６−１０アリール基もしくはＣ_３−１１シクロアルキル基（該Ｃ_６−１０アリール基及びＣ_３−１１シクロアルキル基は、無置換であるか又は置換基群Ａ_２より独立して選ばれる１つ以上の置換基によって置換されている。）で置換されている。）を意味し、
Ｒ^１０は、Ｃ_１−９アルキル基（該Ｃ_１−９アルキル基は、無置換であるか又は置換基群Ａ_４より独立して選ばれる１つ以上の置換基によって置換されている。）、Ｃ_６−１０アリール基、５〜１０員ヘテロアリール基（該Ｃ_６−１０アリール基及び５〜１０員ヘテロアリール基は、無置換であるか又は置換基群Ａ_２より独立して選ばれる１つ以上の置換基によって置換されている。）、Ｃ_３−１１シクロアルキル基（該Ｃ_３−１１シクロアルキル基は、Ｃ_６−１０アリールもしくは５〜１０員ヘテロアリール（該Ｃ_６−１０アリール及び５〜１０員ヘテロアリールは無置換であるか又は置換基群Ａ_２より独立して選ばれる１つ以上の置換基によって置換されている。）と縮環していても良く、且つ該Ｃ_３−１１シクロアルキル基は、無置換であるか又は置換基群Ａ_２より独立して選ばれる１つ以上の置換基によって置換されている。）、又はＣ_１−３アルキル基（該Ｃ_１−３アルキル基はＣ_３−１１シクロアルキル基（該Ｃ_３−１１シクロアルキル基は、無置換であるか又は置換基群Ａ_２より独立して選ばれる１つ以上の置換基によって置換されている。）で置換されている。）を意味する。）
の何れかを意味し、
置換基群Ａ_１は、Ｃ_１−３アルキル基（該Ｃ_１−３アルキル基は無置換であるか又は置換基群Ａ_３より独立して選ばれる１つ以上の置換基によって置換されている。）及び置換基群Ａ_３で構成される置換基群を意味し、
置換基群Ａ_３は、
Ｃ_３−１１シクロアルキル基、４〜１１員ヘテロシクロアルキル基（該Ｃ_３−１１シクロアルキル基及び４〜１１員ヘテロシクロアルキル基は、Ｃ_６−１０アリールもしくは５〜１０員ヘテロアリール（該Ｃ_６−１０アリール及び５〜１０員ヘテロアリールは無置換であるか又は置換基群Ａ_２より独立して選ばれる１つ以上の置換基によって置換されている。）と縮環していても良く、且つ該Ｃ_３−１１シクロアルキル基及び４〜１１員ヘテロシクロアルキル基は、無置換であるか又は置換基群Ａ_２より独立して選ばれる１つ以上の置換基によって置換されている。）、Ｃ_６−１０アリール基、５〜１０員ヘテロアリール基（該Ｃ_６−１０アリール基及び５〜１０員ヘテロアリール基は、４〜１１員ヘテロシクロアルカン（該４〜１１員ヘテロシクロアルカンは無置換であるか又は置換基群Ａ_２より独立して選ばれる１つ以上の置換基によって置換されている。）と縮環していても良く、且つ該Ｃ_６−１０アリール基及び５〜１０員ヘテロアリール基は無置換であるか又は置換基群Ａ_２より独立して選ばれる１つ以上の置換基によって置換されている。）、−Ｃ（＝Ｏ）ＯＲ^１３、−Ｃ（＝Ｏ）ＮＲ^１２Ｒ^１３、−Ｃ（＝Ｏ）Ｒ^１３、−Ｃ（＝ＮＯＲ^１２）Ｒ^１３、−Ｓ（＝Ｏ）Ｒ^１３、−Ｓ（＝Ｏ）_２Ｒ^１３、−ＯＲ^１３、−ＳＲ^１３、−Ｎ（Ｒ^１２）Ｃ（＝Ｏ）ＯＲ^１３、−Ｎ（Ｒ^１２）Ｃ（＝Ｏ）Ｒ^１３、−Ｎ（Ｒ^１２）Ｒ^１３、ハロゲン原子、シアノ基、ニトロ基、ホルミル基、−Ｃ（＝ＮＯＲ^１２）Ｈ、−Ｎ（Ｒ^１２）Ｃ（＝Ｏ）Ｈ、又は水酸基で構成される置換基群を意味し、
置換基群Ａ_２は、
Ｃ_１−３アルキル基（該Ｃ_１−３アルキル基は無置換であるか又は１つ以上のハロゲン原子によって置換されている。）及び置換基群Ａ_４で構成される置換基群を意味し、
置換基群Ａ_４は、
ハロゲン原子、ニトロ基、シアノ基、−ＯＲ^１４、−ＳＲ^１４、−Ｃ（＝Ｏ）ＯＲ^１４、−Ｃ（＝Ｏ）ＮＲ^１４Ｒ^１５、−Ｃ（＝Ｏ）Ｒ^１５、−Ｃ（＝ＮＯＲ^１５）Ｒ^１４、−Ｃ（＝ＮＯＲ^１５）Ｈ、−Ｓ（＝Ｏ）Ｒ^１４、−Ｓ（＝Ｏ）_２Ｒ^１４、−Ｎ（Ｒ^１５）Ｃ（＝Ｏ）ＯＲ^１４、−Ｎ（Ｒ^１５）Ｃ（＝Ｏ）Ｒ^１４、又は−Ｎ（Ｒ^１５）Ｃ（＝Ｏ）Ｈで構成される置換基群を意味し、
Ｒ^１１は、それぞれ独立して、水素原子又はＣ_１−６アルキル基を意味し、
Ｒ^１２は、それぞれ独立して、水素原子又はＣ_１−３アルキル基を意味し、
Ｒ^１３は、それぞれ独立して、
Ｃ_１−６アルキル基（該Ｃ_１−６アルキル基は、無置換であるか又は置換基群Ａ_４より独立して選ばれる１つ以上の置換基によって置換されている。）、
Ｃ_３−１１シクロアルキル基、４〜１１員ヘテロシクロアルキル基、Ｃ_６−１０アリール基、又は５〜１０員ヘテロアリール基（該Ｃ_３−１１シクロアルキル基、４〜１１員ヘテロシクロアルキル基、Ｃ_６−１０アリール基及び５〜１０員ヘテロアリール基は、無置換であるか又は置換基群Ａ_２より独立して選ばれる１つ以上の置換基によって置換されている。）を意味し、
Ｒ^１４は、Ｃ_１−３アルキル基（該Ｃ_１−３アルキル基は無置換であるか又は１つ以上のハロゲン原子によって置換されている。）を意味し、
Ｒ^１５は、水素原子又はＣ_１−３アルキル基（該Ｃ_１−３アルキル基は無置換であるか又は１つ以上のハロゲン原子によって置換されている。）を意味し、
Ｒ^１６は、水素原子又はＣ_１−３アルキル基を意味し、
Ｒ^１７は、Ｃ_１−３アルキル基を意味する。］
で表される上記（１）に記載のスピロ化合物、該化合物の互変異性体、若しくはその医薬的に許容され得る塩。

（３）
Ｘが、Ｃ_３−１１シクロアルキレン基又はＣ_３−１１シクロアルケニレン基（該Ｃ_３−１１シクロアルキレン基及びＣ_３−１１シクロアルケニレン基は、無置換であるか又は、Ｃ_１−３アルキル基、Ｃ_２−３アルケニル基、−ＯＲ^１６及びシアノ基からなる群より独立して選ばれる１つ以上の置換基によって置換されている。）
である上記（２）に記載のスピロ化合物、該化合物の互変異性体、若しくはその医薬的に許容され得る塩。

（４）
Ｘが、Ｃ_６−１０アリーレン基又は５〜１０員ヘテロアリーレン基（該Ｃ_６−１０アリーレン基及び５〜１０員ヘテロアリーレン基は、無置換であるか又は、ハロゲン原子、ニトロ基、シアノ基、Ｃ_１−３アルキル基（該Ｃ_１−３アルキル基は無置換であるか又は、ハロゲン原子及び−ＯＲ^１６からなる群より独立して選ばれる１つ以上の置換基によって置換されている。）、Ｃ_２−３アルケニル基、Ｃ_２−３アルキニル基、−ＯＲ^１６、−Ｏ（Ｃ_２−３アルケニル基）、−Ｏ（Ｃ_３−４シクロアルキル基）、−Ｎ（Ｒ^１６）Ｃ（＝Ｏ）ＯＲ^１７、−Ｎ（Ｒ^１６）Ｃ（＝Ｏ）Ｒ^１７、−Ｎ（Ｒ^１６）Ｃ（＝Ｏ）Ｈ、−Ｎ（Ｒ^１６）Ｒ^１７、−ＮＨ_２、−Ｎ（Ｒ^１６）Ｓ（＝Ｏ）_２Ｒ^１７、−Ｃ（＝Ｏ）ＮＲ^１６Ｒ^１７、−Ｃ（＝Ｏ）ＮＨ_２、−Ｃ（＝Ｏ）Ｒ^１６、−Ｓ（＝Ｏ）_２Ｒ^１７、−Ｓ（＝Ｏ）_２ＮＲ^１６Ｒ^１７、−Ｓ（＝Ｏ）_２ＮＨ_２からなる群より独立して選ばれる１つ以上の置換基によって置換されている。）
である上記（２）に記載のスピロ化合物、該化合物の互変異性体、若しくはその医薬的に許容され得る塩。

（５）
Ｌ^１が、Ｃ_１−３アルキレン基、Ｃ_２−３アルケニレン基又はＣ_２−３アルキニレン基（該Ｃ_１−３アルキレン基、Ｃ_２−３アルケニレン基及びＣ_２−３アルキニレン基は、無置換であるか又はシクロプロピル基によって置換されている。）
である上記（４）に記載のスピロ化合物、該化合物の互変異性体、若しくはその医薬的に許容され得る塩。

（６）
Ｚ^１が、式（ＩＩ−１）乃至（ＩＩ−８）

(Where
L ⁴ means a C _1-3 alkylene group,
L ⁵ represents a single bond, an oxygen atom, a sulfur atom, S (═O), S (═O) ₂ , C═O or C═NOR ¹² ;
R ⁸ represents a C _6-10 aryl group or a 5-10 membered heteroaryl group (the C _6-10 aryl group and the 5-10 membered heteroaryl group are unsubstituted or independent of substituent group A _2). Substituted with one or more substituents selected from
J ² means an oxygen atom or a sulfur atom,
G ² means an oxygen atom, a sulfur atom or NR ¹¹ ,
R ⁹ represents a C _1-9 alkyl group (the C _1-9 alkyl group is unsubstituted or substituted with one or more substituents independently selected from substituent group A ₄ ). , C _6-10 aryl group (the C _6-10 aryl group is unsubstituted or substituted by one or more substituents independently selected from substituent group A ₂ ), C _{3. -11} cycloalkyl group (wherein the C _3-11 cycloalkyl group is C _6-10 aryl or 5-10 membered heteroaryl (the C _6-10 aryl and 5-10 membered heteroaryl are unsubstituted or substituted) Substituted with one or more substituents independently selected from group A ₂ ), and the C _3-11 cycloalkyl group may be unsubstituted or substituted. one or more independently selected from the group & A ₂ Which is substituted by a substituent.), _{Or, a C 1-3} alkyl group (the _{C 1-3} alkyl _{group, C 6-10} aryl group or _{C 3-11} cycloalkyl group (the _{C 6-10} aryl Group and C _3-11 cycloalkyl group are unsubstituted or substituted by one or more substituents independently selected from substituent group A ₂ ). And
R ¹⁰ represents a C _1-9 alkyl group (the C _1-9 alkyl group is unsubstituted or substituted with one or more substituents independently selected from substituent group A ₄ ). , C _6-10 aryl group, 5-10 membered heteroaryl group (the C _6-10 aryl group and 5-10 membered heteroaryl group are unsubstituted or independently selected from substituent group A ₂ Substituted with one or more substituents), a C _3-11 cycloalkyl group (wherein the C _3-11 cycloalkyl group is C _6-10 aryl or 5-10 membered heteroaryl (the C _6-10 aryl and 5-10 membered heteroaryl is substituted by one or more substituents selected as or independently from substituent group a ₂ unsubstituted.) and may be a condensed ring, and the The C _3-11 cycloalkyl group is , Unsubstituted or substituted by one or more substituents independently selected from substituent group A ₂ ), or a C _1-3 alkyl group (the C _1-3 alkyl group is C _3). Substituted with an _-11 cycloalkyl group (the C _3-11 cycloalkyl group is unsubstituted or substituted by one or more substituents independently selected from substituent group A ₂ ). Means). )
Means either
Substituent group A ₁ is a C _1-3 alkyl group (the C _1-3 alkyl group is unsubstituted or substituted by one or more substituents independently selected from substituent group A ₃ ). .) and means a substituent group consisting of substituent group a _3,
Substituent group A ₃ is
A C _3-11 cycloalkyl group, a 4-11 membered heterocycloalkyl group (the C _3-11 cycloalkyl group and 4-11 membered heterocycloalkyl group are C _6-10 aryl or 5-10 membered heteroaryl (the C _6-10 aryl and 5-10 membered heteroaryl may be unsubstituted or substituted with one or more substituents independently selected from substituent group A ₂ ). well, and the C _3-11 cycloalkyl group and 4-11 membered heterocycloalkyl group is substituted by one or more substituents selected as or independently from substituent group a ₂ unsubstituted _{.), C 6-10} aryl group, 5-10-membered heteroaryl group (the _{C 6-10} aryl and 5-10 membered heteroaryl groups, 4-11 membered heterocycloalkyl alkane (said 4-11 Heterocycloalkane may be condensed with unsubstituted or substituted with or independently from the substituent group A ₂ is substituted by one or more substituents selected.), And the C _6-10 aryl groups and 5-10 membered heteroaryl group is substituted by one or more substituents selected as or independently from substituent group a ₂ unsubstituted), -. C (= O ) oR 13, ^{-C (= O) NR 12 R} 13, -C (= O) R 13, -C (= NOR 12) R 13, -S (= O) R 13, -S (= O) 2 R 13, - OR ¹³ , —SR ¹³ , —N (R ¹² ) C (═O) OR ¹³ , —N (R ¹² ) C (═O) R ¹³ , —N (R ¹² ) R ¹³ , halogen atom, cyano group, nitro group, formyl ^{group, -C (= NOR 12) H} , -N (R 12) C (= O) H, Or a group of substituents composed of hydroxyl groups,
Substituent group A ₂ is
Means a substituent group composed of a C _1-3 alkyl group (the C _1-3 alkyl group is unsubstituted or substituted by one or more halogen atoms) and a substituent group A ₄ ,
Substituent group A ₄ is
A halogen atom, a nitro group, a cyano group, —OR ¹⁴ , —SR ¹⁴ , —C (═O) OR ¹⁴ , —C (═O) NR ¹⁴ R ¹⁵ , —C (═O) R ¹⁵ , —C (= ^{NOR 15) R 14, -C (} = NOR 15) H, -S (= O) R 14, -S (= O) 2 R 14, -N (R 15) C (= O) OR 14, -N Means a group of substituents composed of (R ¹⁵ ) C (═O) R ¹⁴ or —N (R ¹⁵ ) C (═O) H;
Each of R ¹¹ independently represents a hydrogen atom or a C _1-6 alkyl group;
R ¹² each independently represents a hydrogen atom or a C _1-3 alkyl group;
Each R ¹³ is independently
A C _1-6 alkyl group (the C _1-6 alkyl group is unsubstituted or substituted by one or more substituents independently selected from Substituent Group A ₄ );
A C _3-11 cycloalkyl group, a 4-11 membered heterocycloalkyl group, a C _6-10 aryl group, or a 5-10 membered heteroaryl group (the C _3-11 cycloalkyl group, 4-11 membered heterocycloalkyl group; , C _6-10 aryl and 5-10 membered heteroaryl group is substituted by one or more substituents selected as or independently from substituent group a ₂ unsubstituted.) means ,
R ¹⁴ represents a C _1-3 alkyl group (the C _1-3 alkyl group is unsubstituted or substituted by one or more halogen atoms);
R ¹⁵ represents a hydrogen atom or a C _1-3 alkyl group (the C _1-3 alkyl group is unsubstituted or substituted by one or more halogen atoms);
R ¹⁶ represents a hydrogen atom or a C _1-3 alkyl group,
R ¹⁷ means a C _1-3 alkyl group. ]
A spiro compound according to the above (1), a tautomer of the compound, or a pharmaceutically acceptable salt thereof.

(3)
X is a C _3-11 cycloalkylene group or a C _3-11 cycloalkenylene group (the C _3-11 cycloalkylene group and the C _3-11 cycloalkenylene group are unsubstituted or a C _1-3 alkyl group) Substituted with one or more substituents independently selected from the group consisting of C _{2 -3} alkenyl groups, —OR ¹⁶ and cyano groups.)
The spiro compound according to the above (2), a tautomer of the compound, or a pharmaceutically acceptable salt thereof.

(4)
X is a C _6-10 arylene group or a 5- to 10-membered heteroarylene group (the C _6-10 arylene group and the 5- to 10-membered heteroarylene group are unsubstituted, a halogen atom, a nitro group, or a cyano group A C _1-3 alkyl group (the C _1-3 alkyl group is unsubstituted or substituted by one or more substituents independently selected from the group consisting of a halogen atom and —OR ¹⁶ ). ), C _2-3 alkenyl group, C _2-3 alkynyl group, —OR ¹⁶ , —O (C _2-3 alkenyl group), —O (C _3-4 cycloalkyl group), —N (R ¹⁶ ) C (═O) OR ¹⁷ , —N (R ¹⁶ ) C (═O) R ¹⁷ , —N (R ¹⁶ ) C (═O) H, —N (R ¹⁶ ) R ¹⁷ , —NH ₂ , —N ( _{^{R 16) S (= O)}} 2 R 17, -C (= O) NR 16 R 1 _{^{, -C (= O) NH 2}} , -C (= O) R 16, -S (= O) 2 R 17, -S (= O) 2 NR 16 R 17, -S (= O) 2 NH 2 Substituted with one or more substituents independently selected from the group consisting of
The spiro compound according to the above (2), a tautomer of the compound, or a pharmaceutically acceptable salt thereof.

(5)
L ¹ is a C _1-3 alkylene group, a C _2-3 alkenylene group or a C _2-3 alkynylene group (the C _1-3 alkylene group, C _2-3 alkenylene group and C _2-3 alkynylene group are unsubstituted) Or is substituted by a cyclopropyl group.)
The spiro compound according to the above (4), a tautomer of the compound, or a pharmaceutically acceptable salt thereof.

(6)
Z ¹ is represented by formulas (II-1) to (II-8).

（式中、
Ｊ^１は、それぞれ独立して酸素原子又は硫黄原子を意味し、
Ｇ^１は、単結合、酸素原子又は硫黄原子を意味し、
Ｒ^１とＲ^３は、
Ｒ^１が、水素原子、ＯＲ^１１、ＮＲ^１１Ｒ^１２、Ｃ_１−５アルキル基（該Ｃ_１−５アルキル基は、無置換であるか又は置換基群Ａ_３より独立して選ばれる１つ以上の置換基によって置換されている。ただし、ｍが１を意味し、二つのＲ^６がともに水素原子を意味する場合、該Ｃ_１−５アルキル基は置換基群Ａ_３より独立して選ばれる１つ以上の置換基によって置換されている。）、Ｃ_６−９アルキル基（該Ｃ_６−９アルキル基は、無置換であるか又は置換基群Ａ_３より独立して選ばれる１つ以上の置換基によって置換されている。）、Ｃ_３−１１シクロアルキル基又は４〜１１員ヘテロシクロアルキル基（該Ｃ_３−１１シクロアルキル基及び４〜１１員ヘテロシクロアルキル基は、Ｃ_６−１０アリール又は５〜１０員ヘテロアリール（該Ｃ_６−１０アリール及び５〜１０員ヘテロアリールは無置換であるか又は置換基群Ａ_２より独立して選ばれる１つ以上の置換基によって置換されている。）と縮環していても良く、且つ該Ｃ_３−１１シクロアルキル基及び４〜１１員ヘテロシクロアルキル基は、無置換であるか又は置換基群Ａ_１より独立して選ばれる１つ以上の置換基によって置換されている。）を意味し、Ｒ^３が水素原子若しくはＣ_１−３アルキル基を意味するか、
又は、Ｒ^１とＲ^３が、それらが結合している窒素原子と一緒になって４〜１１員ヘテロシクロアルキル基（該４〜１１員ヘテロシクロアルキル基は、無置換であるか又は置換基群Ａ_１より独立して選ばれる１つ以上の置換基によって置換されている。）を意味し、
Ｒ^２は、Ｃ_１−５アルキル基（該Ｃ_１−５アルキル基は、無置換であるか又は置換基群Ａ_３より独立して選ばれる１つ以上の置換基によって置換されている。ただし、ｍが１を意味し、二つのＲ^６がともに水素原子を意味する場合、該Ｃ_１−５アルキル基は置換基群Ａ_３より独立して選ばれる１つ以上の置換基によって置換されている。）、Ｃ_６−９アルキル基（該Ｃ_６−９アルキル基は、無置換であるか又は置換基群Ａ_３より独立して選ばれる１つ以上の置換基によって置換されている。）、Ｃ_３−１１シクロアルキル基又は４〜１１員ヘテロシクロアルキル基（該Ｃ_３−１１シクロアルキル基及び４〜１１員ヘテロシクロアルキル基は、Ｃ_６−１０アリール又は５〜１０員ヘテロアリール（該Ｃ_６−１０アリール及び５〜１０員ヘテロアリールは無置換であるか又は置換基群Ａ_２より独立して選ばれる１つ以上の置換基によって置換されている。）と縮環していても良く、且つ該Ｃ_３−１１シクロアルキル基及び４〜１１員ヘテロシクロアルキル基は、無置換であるか又は置換基群Ａ_１より独立して選ばれる１つ以上の置換基によって置換されている。）を意味し、
Ｒ^４及びＲ^５は、それぞれ独立して、水素原子又はＣ_１−３アルキル基を意味する。）
の何れかである上記（５）に記載のスピロ化合物、該化合物の互変異性体、若しくはその医薬的に許容され得る塩。

（７）
Ｌ^１が、Ｃ_１−３アルキレン基であり、
Ｌ^２が、単結合であり、
Ｚ^１が、式（ＩＩ−１）、（ＩＩ−４）又は（ＩＩ−７）

(Where
J ¹ each independently represents an oxygen atom or a sulfur atom;
G ¹ means a single bond, an oxygen atom or a sulfur atom,
R ¹ and R ³ are
R ¹ is a hydrogen atom, OR ¹¹ , NR ¹¹ R ¹² , C _1-5 alkyl group (the C _1-5 alkyl group is unsubstituted or one selected independently from substituent group A ₃ Substituted by the above substituents, provided that when m is 1 and both R ⁶ are hydrogen atoms, the C _1-5 alkyl group is independently selected from the substituent group A ₃ A C _6-9 alkyl group (the C _6-9 alkyl group is unsubstituted or independently selected from Substituent Group A ₃ ). Substituted with the above substituents), a C _3-11 cycloalkyl group or a 4-11 membered heterocycloalkyl group (the C _3-11 cycloalkyl group and 4-11 membered heterocycloalkyl group are C _{6 -10} aryl or 5-10 membered hetero ants (The C _6-10 aryl and 5-10 membered heteroaryl are unsubstituted or substituted by one or more substituents independently selected from substituent group A ₂ ) and fused rings. And the C _3-11 cycloalkyl group and the 4-11 membered heterocycloalkyl group may be unsubstituted or substituted by one or more substituents independently selected from the substituent group A ₁ Substituted, and R ³ represents a hydrogen atom or a C _1-3 alkyl group,
Or R ¹ and R ³ , together with the nitrogen atom to which they are attached, are a 4-11 membered heterocycloalkyl group (the 4-11 membered heterocycloalkyl group is unsubstituted or substituted) which is substituted by one or more substituents independently selected from the group a _1.) means,
R ² represents a C _1-5 alkyl group (the C _1-5 alkyl group is unsubstituted or substituted with one or more substituents independently selected from Substituent Group A ₃ . , M represents 1 and two R ⁶ both represent a hydrogen atom, the C _1-5 alkyl group is substituted with one or more substituents independently selected from substituent group A ₃ C _6-9 alkyl group (the C _6-9 alkyl group is unsubstituted or substituted by one or more substituents independently selected from substituent group A ₃ ). , A C _3-11 cycloalkyl group or a 4-11 membered heterocycloalkyl group (the C _3-11 cycloalkyl group and 4-11 membered heterocycloalkyl group are C _6-10 aryl or 5-10 membered heteroaryl ( the _{C 6-10} aryl and 5-10 Heteroaryl may be condensed one or more are replaced by a substituent.) And selected as or independently from Substituent group A ₂ unsubstituted, and the C _3-11 cycloalkyl groups and 4-11 membered heterocycloalkyl group is substituted by one or more substituents selected as or independently from substituent group a ₁ unsubstituted.) I mean,
R ⁴ and R ⁵ each independently represents a hydrogen atom or a C _1-3 alkyl group. )
The spiro compound according to (5), a tautomer of the compound, or a pharmaceutically acceptable salt thereof.

(7)
L ¹ is a C _1-3 alkylene group,
L ² is a single bond,
Z ¹ is represented by formula (II-1), (II-4) or (II-7)

（式中、Ｒ^１、Ｒ^２、Ｒ^３、Ｒ^４、Ｊ^１及びＧ^１は上記（２）に記載の定義と同じ意味を示す。）の何れかである上記（２）又は（３）に記載のスピロ化合物、該化合物の互変異性体、若しくはその医薬的に許容され得る塩。

（８）
Ｌ^１が、Ｃ_１−３アルキレン基であり、
Ｌ^２が、単結合であり、
Ｚ^１が、式（ＩＩ−１）、（ＩＩ−４）又は（ＩＩ−７）

(Wherein R ¹ , R ² , R ³ , R ⁴ , J ¹ and G ¹ have the same meaning as defined in (2) above), (2) or (3) Or a tautomer of the compound, or a pharmaceutically acceptable salt thereof.

(8)
L ¹ is a C _1-3 alkylene group,
L ² is a single bond,
Z ¹ is represented by formula (II-1), (II-4) or (II-7)

（式中、Ｒ^１、Ｒ^２、Ｒ^３、Ｒ^４、Ｊ^１及びＧ^１は上記（６）に記載の定義と同じ意味を示す。）の何れかである上記（６）に記載のスピロ化合物、該化合物の互変異性体、若しくはその医薬的に許容され得る塩。

（９）
Ｅが酸素原子であり、ｍが１であり、ｎが０である上記（２）乃至（８）の何れか１項に記載のスピロ化合物、該化合物の互変異性体、若しくはその医薬的に許容され得る塩。

（１０）
Ｅが酸素原子であり、ｍが２であり、ｎが０である上記（２）乃至（８）の何れか１項に記載のスピロ化合物、該化合物の互変異性体、若しくはその医薬的に許容され得る塩。

（１１）
Ｔが、式（ＶＩ−１）又は（ＶＩ−２）

(Wherein R ¹ , R ² , R ³ , R ⁴ , J ¹ and G ¹ have the same meaning as defined in (6) above), and the spiro described in (6) above A compound, a tautomer of the compound, or a pharmaceutically acceptable salt thereof.

(9)
The spiro compound according to any one of the above (2) to (8), wherein E is an oxygen atom, m is 1, and n is 0, a tautomer of the compound, or a pharmaceutically acceptable salt thereof An acceptable salt.

(10)
The spiro compound according to any one of (2) to (8) above, wherein E is an oxygen atom, m is 2, and n is 0, a tautomer of the compound, or a pharmaceutically acceptable salt thereof An acceptable salt.

(11)
T is the formula (VI-1) or (VI-2)

（式中、Ｌ^４はＣ_１−３アルキレン基を意味し、Ｌ^５は単結合を意味し、Ｒ^８及びＲ^１０は、上記（２）に記載の定義と同じ意味を示す。）の何れかである上記（２）乃至（１０）の何れか１項に記載のスピロ化合物、該化合物の互変異性体、若しくはその医薬的に許容され得る塩。

（１２）
Ｚ^１が、
式（ＩＩ−１）、（ＩＩ−４）又は（ＩＩ−７）

(Wherein L ⁴ represents a C _1-3 alkylene group, L ⁵ represents a single bond, and R ⁸ and R ¹⁰ have the same meaning as defined in (2) above). The spiro compound according to any one of (2) to (10) above, a tautomer of the compound, or a pharmaceutically acceptable salt thereof.

(12)
Z ¹ is
Formula (II-1), (II-4) or (II-7)

（式中、Ｒ^１とＲ^３は、
Ｒ^１が、Ｃ_１−６アルキル基（該Ｃ_１−６アルキル基は、４〜７員含酸素ヘテロシクロアルキル基又は−ＮＨＣ（＝Ｏ）Ｏ（Ｃ_１−６アルキル）で置換されている。）を意味し、Ｒ^３が水素原子を意味するか、
Ｒ^１が、Ｃ_１−６アルキル基（該Ｃ_１−６アルキル基は、Ｃ_６−１０アリール基又は５〜１０員ヘテロアリール基（該Ｃ_６−１０アリール基及び５〜１０員ヘテロアリール基は、４〜１１員ヘテロシクロアルカン（該４〜１１員ヘテロシクロアルカンは無置換であるか又は置換基群Ａ_２より独立して選ばれる１つ以上の置換基によって置換されている。）と縮環していても良く、且つ該Ｃ_６−１０アリール基及び５〜１０員ヘテロアリール基は無置換であるか又は置換基群Ａ_２より独立して選ばれる１つ以上の置換基によって置換されている。）の何れかで置換されており、且つ該Ｃ_１−６アルキル基は水酸基、ハロゲン原子及びシアノ基からなる群より独立して選ばれる１つ以上の置換基で置換されていても良い。）を意味し、Ｒ^３が水素原子を意味するか、
Ｒ^１が、４〜１１員含窒素ヘテロシクロアルキル基（該４〜１１員含窒素ヘテロシクロアルキル基は、Ｃ_１−３アルキル基（該Ｃ_１−３アルキル基はフェニル基（該フェニル基は無置換であるか又は−Ｃ（＝Ｏ）ＯＣＨ_３、シアノ基、ニトロ基、−ＳＣＨ_３、−ＯＣＦ_３、−ＯＣＨ_３、塩素原子、−ＣＦ_３及び−ＣＨ_３からなる群より独立して選ばれる１つ以上の置換基によって置換されている。）又はシアノ基の何れかで置換されている。）又は−Ｃ（＝Ｏ）Ｏ（Ｃ_１−６アルキル）の何れかで置換されている。）を意味し、Ｒ^３が水素原子を意味するか、又は、
Ｒ^１とＲ^３が、それらが結合している窒素原子と一緒になって４〜１１員含窒素ヘテロシクロアルキル基（該４〜１１員含窒素ヘテロシクロアルキル基は、置換基群Ａ_１より独立して選ばれる１つ以上の置換基によって置換されている。）を意味し、
Ｒ^２が、Ｃ_１−６アルキル基（該Ｃ_１−６アルキル基は、４〜７員含酸素ヘテロシクロアルキル基又は−ＮＨＣ（＝Ｏ）Ｏ（Ｃ_１−６アルキル）で置換されている。）を意味し、
Ｒ^４が、水素原子を意味し、
Ｊ^１が、酸素原子を意味し、
Ｇ^１が、単結合又は酸素原子を意味する。）
の何れかである上記（２）乃至（１１）の何れか１項に記載のスピロ化合物、該化合物の互変異性体、若しくはその医薬的に許容され得る塩。

（１３）
Ｚ^１が、
式（ＩＩ−１）、（ＩＩ−４）又は（ＩＩ−７）

(Wherein R ¹ and R ³ are
R ¹ is substituted with a C _1-6 alkyl group (the C _1-6 alkyl group is a 4- to 7-membered oxygen-containing heterocycloalkyl group or —NHC (═O) O (C _1-6 alkyl)). Or R ³ represents a hydrogen atom,
R ¹ is a C _1-6 alkyl group (the C _1-6 alkyl group is a C _6-10 aryl group or a 5-10 membered heteroaryl group (the C _6-10 aryl group and a 5-10 membered heteroaryl group). is 4-11 membered heterocycloalkyl alkane (said 4-11 membered heterocycloalkyl alkanes are substituted by one or more substituents selected as or independently from substituent group a ₂ unsubstituted.) and The C _6-10 aryl group and the 5- to 10-membered heteroaryl group may be condensed or substituted with one or more substituents independently selected from substituent group A ₂ And the C _1-6 alkyl group is substituted with one or more substituents independently selected from the group consisting of a hydroxyl group, a halogen atom and a cyano group. means may be.), ^{R 3} Means a hydrogen atom,
R ¹ is a 4- to 11-membered nitrogen-containing heterocycloalkyl group (the 4- to 11-membered nitrogen-containing heterocycloalkyl group is a C _1-3 alkyl group (the C _1-3 alkyl group is a phenyl group (the phenyl group is Is unsubstituted or independently of the group consisting of —C (═O) OCH ₃ , cyano group, nitro group, —SCH ₃ , —OCF ₃ , —OCH ₃ , chlorine atom, —CF ₃ and —CH _3. Substituted with one or more selected substituents)) or substituted with either a cyano group) or substituted with either —C (═O) O (C _1-6 alkyl). R ³ represents a hydrogen atom, or
R ¹ and R ³ , together with the nitrogen atom to which they are bonded, form a 4- to 11-membered nitrogen-containing heterocycloalkyl group (the 4- to 11-membered nitrogen-containing heterocycloalkyl group is represented by substituent group A ₁ Substituted by one or more independently selected substituents),
R ² is substituted with a C _1-6 alkyl group (the C _1-6 alkyl group is a 4- to 7-membered oxygen-containing heterocycloalkyl group or —NHC (═O) O (C _1-6 alkyl)). .)
R ⁴ represents a hydrogen atom,
J ¹ means an oxygen atom,
G ¹ means a single bond or an oxygen atom. )
The spiro compound according to any one of the above (2) to (11), a tautomer of the compound, or a pharmaceutically acceptable salt thereof.

(13)
Z ¹ is
Formula (II-1), (II-4) or (II-7)

（式中、Ｒ^１とＲ^３は、
Ｒ^１が、Ｃ_１−６アルキル基（該Ｃ_１−６アルキル基は、４〜７員含酸素ヘテロシクロアルキル基又は−ＮＨＣ（＝Ｏ）Ｏ（Ｃ_１−６アルキル）で置換されている。）を意味し、Ｒ^３が水素原子を意味するか、
Ｒ^１が、５〜７員含窒素ヘテロシクロアルキル基（該５〜７員含窒素ヘテロシクロアルキル基は、Ｃ_１−３アルキル基（該Ｃ_１−３アルキル基はフェニル基（該フェニル基は無置換であるか又は−Ｃ（＝Ｏ）ＯＣＨ_３、シアノ基、ニトロ基、−ＳＣＨ_３、−ＯＣＦ_３、−ＯＣＨ_３、塩素原子、−ＣＦ_３及び−ＣＨ_３からなる群より独立して選ばれる１つ以上の置換基によって置換されている。）で置換されている。）で置換されている。）を意味し、Ｒ^３が水素原子を意味するか、又は
Ｒ^１とＲ^３が、それらが結合している窒素原子と一緒になって５〜７員含窒素ヘテロシクロアルキル基（該５〜７員含窒素ヘテロシクロアルキル基は、置換基群Ａ_１より独立して選ばれる１つ以上の置換基によって置換されている。）を意味し、
Ｒ^２が、Ｃ_１−６アルキル基（該Ｃ_１−６アルキル基は、４〜７員含酸素ヘテロシクロアルキル基又は−ＮＨＣ（＝Ｏ）Ｏ（Ｃ_１−６アルキル）で置換されている。）を意味し、
Ｒ^４が、水素原子を意味し、
Ｊ^１が、酸素原子を意味し、
Ｇ^１が、単結合又は酸素原子を意味する。）
の何れかである上記（２）乃至（１２）の何れか１項に記載のスピロ化合物、該化合物の互変異性体、若しくはその医薬的に許容され得る塩。

（１４）
Ｚ^１が、
式（ＩＩ−１）又は（ＩＩ−４）

(Wherein R ¹ and R ³ are
R ¹ is substituted with a C _1-6 alkyl group (the C _1-6 alkyl group is a 4- to 7-membered oxygen-containing heterocycloalkyl group or —NHC (═O) O (C _1-6 alkyl)). Or R ³ represents a hydrogen atom,
R ¹ is a 5- to 7-membered nitrogen-containing heterocycloalkyl group (the 5- to 7-membered nitrogen-containing heterocycloalkyl group is a C _1-3 alkyl group (the C _1-3 alkyl group is a phenyl group (the phenyl group is Is unsubstituted or independently of the group consisting of —C (═O) OCH ₃ , cyano group, nitro group, —SCH ₃ , —OCF ₃ , —OCH ₃ , chlorine atom, —CF ₃ and —CH _3. Substituted with one or more selected substituents)), substituted with), and R ³ represents a hydrogen atom, or R ¹ and R ³ are , 1 they are attached a 5- to 7-membered nitrogen-containing heterocycloalkyl group together with the nitrogen atom to which (the 5- to 7-membered nitrogen-containing heterocycloalkyl group is independently selected from substituent group a ₁ Substituted with one or more substituents.
R ² is substituted with a C _1-6 alkyl group (the C _1-6 alkyl group is a 4- to 7-membered oxygen-containing heterocycloalkyl group or —NHC (═O) O (C _1-6 alkyl)). .)
R ⁴ represents a hydrogen atom,
J ¹ means an oxygen atom,
G ¹ means a single bond or an oxygen atom. )
The spiro compound according to any one of (2) to (12), a tautomer of the compound, or a pharmaceutically acceptable salt thereof.

(14)
Z ¹ is
Formula (II-1) or (II-4)

（式中、Ｒ^１とＲ^３は、
Ｒ^１が、Ｃ_１−６アルキル基（該Ｃ_１−６アルキル基は、Ｃ_６−１０アリール基又は５〜１０員ヘテロアリール基（該Ｃ_６−１０アリール基及び５〜１０員ヘテロアリール基は、４〜７員含酸素ヘテロシクロアルカン（該４〜７員含酸素ヘテロシクロアルカンは無置換であるか又は置換基群Ａ_２より独立して選ばれる１つ以上の置換基によって置換されている。）と縮環していても良く、且つ該Ｃ_６−１０アリール基及び５〜１０員ヘテロアリール基は無置換であるか又は置換基群Ａ_２より独立して選ばれる１つ以上の置換基によって置換されている。）で置換されており、且つ該Ｃ_１−６アルキル基は、水酸基、ハロゲン原子及びシアノ基からなる群より独立して選ばれる１つ以上の置換基で置換されていても良い。）を意味し、Ｒ^３が水素原子を意味するか、
Ｒ^１が、４−１１員含窒素ヘテロシクロアルキル基（該４−１１員含窒素ヘテロシクロアルキル基は−Ｃ（＝Ｏ）Ｏ（Ｃ_１−６アルキル）によって置換されている。）を意味し、Ｒ^３が水素原子を意味するか、又は
Ｒ^１とＲ^３が、それらが結合している窒素原子と一緒になってアゼチジニル基（該アゼチジニル基は、置換基群Ａ_１より独立して選ばれる１つ以上の置換基によって置換されている。）を意味し、
Ｒ^４が、水素原子を意味し、
Ｊ^１が、酸素原子を意味する。）
の何れかである上記（２）乃至（１２）の何れか１項に記載のスピロ化合物、該化合物の互変異性体、若しくはその医薬的に許容され得る塩。

（１５）
Ｔが、式（ＶＩ−１）又は（ＶＩ−２）

(Wherein R ¹ and R ³ are
R ¹ is a C _1-6 alkyl group (the C _1-6 alkyl group is a C _6-10 aryl group or a 5-10 membered heteroaryl group (the C _6-10 aryl group and a 5-10 membered heteroaryl group). Is a 4- to 7-membered oxygen-containing heterocycloalkane (the 4- to 7-membered oxygen-containing heterocycloalkane is unsubstituted or substituted by one or more substituents independently selected from Substituent Group A ₂₎ And the C _6-10 aryl group and the 5- to 10-membered heteroaryl group are unsubstituted or independently selected from Substituent Group A ₂ The C _1-6 alkyl group is substituted with one or more substituents independently selected from the group consisting of a hydroxyl group, a halogen atom and a cyano group. Meaning R) ³ means a hydrogen atom,
R ¹ represents a 4-11 membered nitrogen-containing heterocycloalkyl group (the 4-11 membered nitrogen-containing heterocycloalkyl group is substituted by —C (═O) O (C _1-6 alkyl)). R ³ represents a hydrogen atom, or R ¹ and R ³ together with the nitrogen atom to which they are bonded are an azetidinyl group (the azetidinyl group is independently of the substituent group A ₁ Substituted with one or more selected substituents),
R ⁴ represents a hydrogen atom,
J ¹ is, means an oxygen atom. )
The spiro compound according to any one of (2) to (12), a tautomer of the compound, or a pharmaceutically acceptable salt thereof.

(15)
T is the formula (VI-1) or (VI-2)

（式中、Ｌ^４はＣ_１−３アルキレン基を意味し、Ｌ^５は単結合を意味し、Ｒ^８及びＲ^１０は、それぞれ独立してＣ_６−１０アリール基又は５−１０員含窒素ヘテロアリール基（Ｃ_６−１０アリール基及び５−１０員含窒素ヘテロアリール基は、無置換であるか又はフッ素原子、Ｃ_１−３アルキル基（該Ｃ_１−３アルキル基は１つ以上のフッ素原子によって置換されている。）及びシアノ基からなる群より独立して選ばれる１つ以上の置換基によって置換されている。）の何れかを意味する。）の何れかである上記（２）乃至（１４）の何れか１項に記載のスピロ化合物、該化合物の互変異性体、若しくはその医薬的に許容され得る塩。

（１６）
Ｔが、式（ＶＩ−１）又は（ＶＩ−２）

(In the formula, L ⁴ represents a C _1-3 alkylene group, L ⁵ represents a single bond, and R ⁸ and R ¹⁰ each independently represents a C _6-10 aryl group or a 5-10 membered nitrogen-containing group. A heteroaryl group (a C _6-10 aryl group and a 5-10 membered nitrogen-containing heteroaryl group are unsubstituted or a fluorine atom, a C _1-3 alkyl group (the C _1-3 alkyl group is one or more Or substituted with one or more substituents independently selected from the group consisting of a cyano group.)) And (2) above. The spiro compound according to any one of (1) to (14), a tautomer of the compound, or a pharmaceutically acceptable salt thereof.

(16)
T is the formula (VI-1) or (VI-2)

（式中、Ｌ^４はＣ_１−３アルキレン基を意味し、Ｌ^５は単結合を意味し、Ｒ^８及びＲ^１０は、それぞれ独立してフェニル基又はピリジル基（該フェニル基及びピリジル基は、無置換であるか又はフッ素原子、Ｃ_１−３アルキル基（該Ｃ_１−３アルキル基は１つ以上のフッ素原子によって置換されている。）及びシアノ基からなる群より独立して選ばれる１つ以上の置換基によって置換されている。）を意味する。）の何れかである上記（２）乃至（１５）の何れか１項に記載のスピロ化合物、該化合物の互変異性体、若しくはその医薬的に許容され得る塩。

（１７）
Ｔが、式（ＶＩ−１）又は（ＶＩ−２）

(In the formula, L ⁴ represents a C _1-3 alkylene group, L ⁵ represents a single bond, R ⁸ and R ¹⁰ are each independently a phenyl group or a pyridyl group (the phenyl group and the pyridyl group are , Unsubstituted or independently selected from the group consisting of a fluorine atom, a C _1-3 alkyl group (wherein the C _1-3 alkyl group is substituted by one or more fluorine atoms) and a cyano group. The spiro compound according to any one of (2) to (15) above, which is substituted by one or more substituents, and a tautomer of the compound, Or a pharmaceutically acceptable salt thereof.

(17)
T is the formula (VI-1) or (VI-2)

（式中、Ｌ^４はＣ_１−３アルキレン基を意味し、Ｌ^５は単結合を意味し、Ｒ^８及びＲ^１０は、それぞれ独立してフェニル基（該フェニル基は、１つ又は２つのＣ_１−３アルキル基（該Ｃ_１−３アルキル基は１つ以上のフッ素原子によって置換されている。）又は１つのシアノ基で置換されている。）を意味する。）の何れかである上記（２）乃至（１６）の何れか１項に記載のスピロ化合物、該化合物の互変異性体、若しくはその医薬的に許容され得る塩。

（１８）
Ｔが、式（ＶＩ−１）又は（ＶＩ−２）

(In the formula, L ⁴ represents a C _1-3 alkylene group, L ⁵ represents a single bond, R ⁸ and R ¹⁰ are each independently a phenyl group (the phenyl group represents one or two Or a C _1-3 alkyl group (the C _1-3 alkyl group is substituted with one or more fluorine atoms) or a cyano group). The spiro compound according to any one of (2) to (16) above, a tautomer of the compound, or a pharmaceutically acceptable salt thereof.

(18)
T is the formula (VI-1) or (VI-2)

（式中、Ｌ^４はＣ_１−３アルキレン基を意味し、Ｌ^５は単結合を意味し、Ｒ^８及びＲ^１０は、それぞれ独立してフェニル基（該フェニル基は、一つ以上のフッ素原子によって置換されており、且つ該フェニル基はＣ_１−３アルキル基（該Ｃ_１−３アルキル基は１つ以上のフッ素原子によって置換されている。）又はシアノ基の何れかによって置換されている。）を意味する。）の何れかである上記（２）乃至（１６）の何れか１項に記載のスピロ化合物、該化合物の互変異性体、若しくはその医薬的に許容され得る塩。

（１９）
Ｚ^１が、
式（ＩＩ−１）又は（ＩＩ−４）

(Wherein L ⁴ represents a C _1-3 alkylene group, L ⁵ represents a single bond, R ⁸ and R ¹⁰ are each independently a phenyl group (the phenyl group is one or more fluorine atoms) Substituted by an atom and the phenyl group is substituted by either a C _1-3 alkyl group (the C _1-3 alkyl group is substituted by one or more fluorine atoms) or a cyano group The spiro compound according to any one of the above (2) to (16), a tautomer of the compound, or a pharmaceutically acceptable salt thereof.

(19)
Z ¹ is
Formula (II-1) or (II-4)

（式中、Ｒ^１とＲ^３は、
Ｒ^１とＲ^３が、それらが結合している窒素原子と一緒になって５〜７員含窒素ヘテロシクロアルキル基（該５〜７員含窒素ヘテロシクロアルキル基は、フェニル基、５−１０員ヘテロアリール基（該フェニル基及び５−１０員ヘテロアリール基は、無置換であるか、又はＣ_１−３アルキル基（該Ｃ_１−３アルキル基は無置換であるか又は一つ以上のフッ素原子により置換されている。）、ハロゲン原子及びシアノ基からなる群より独立して選ばれる一つ以上の置換基によって置換されている。）、−Ｃ（＝Ｏ）ＯＲ^１３、−Ｃ（＝Ｏ）Ｒ^１３、−ＯＲ^１３、−ＮＲ^１２Ｒ^１３、ハロゲン原子及びシアノ基からなる群より独立して選ばれる１つ以上の置換基によって置換されている。）を意味し、
Ｒ^１２が、水素原子を意味し、
Ｒ^１３が、Ｃ_１−６アルキル基（該Ｃ_１−６アルキル基は無置換であるか又は一つ以上のフッ素原子により置換されている。）、Ｃ_６−１０アリール基又は５〜１０員ヘテロアリール基（該Ｃ_６−１０アリール基及び５〜１０員ヘテロアリール基は、無置換であるか又はＣ_１−３アルキル基（該Ｃ_１−３アルキル基は無置換であるか又は一つ以上のフッ素原子により置換されている。）、ハロゲン原子、シアノ基及び−ＯＲ^１４からなる群より独立して選ばれる一つ以上の置換基によって置換されている。）の何れかを意味し、
Ｒ^１４が、Ｃ_１−３アルキル基（該Ｃ_１−３アルキル基は無置換であるか又は１つ以上のハロゲン原子によって置換されている。）を意味し、
Ｒ^４が、水素原子を意味し、
Ｊ^１が、酸素原子を意味する。）
の何れかである上記（２）乃至（１３）、又は（１５）乃至（１８）の何れか１項に記載のスピロ化合物、該化合物の互変異性体、若しくはその医薬的に許容され得る塩。

（２０）
Ｚ^１が、
式（ＩＩ−１）又は（ＩＩ−４）

(Wherein R ¹ and R ³ are
R ¹ and R ³ are combined with the nitrogen atom to which they are bonded to form a 5- to 7-membered nitrogen-containing heterocycloalkyl group (the 5- to 7-membered nitrogen-containing heterocycloalkyl group is a phenyl group, 5-10 A member heteroaryl group (the phenyl group and the 5-10 membered heteroaryl group are unsubstituted or a C _1-3 alkyl group (the C _1-3 alkyl group is unsubstituted or one or more Substituted with one or more substituents independently selected from the group consisting of halogen atoms and cyano groups.), -C (= O) OR ¹³ , -C ( = O) R ¹³ , —OR ¹³ , —NR ¹² R ¹³ , substituted with one or more substituents independently selected from the group consisting of halogen atoms and cyano groups.
R ¹² represents a hydrogen atom,
R ¹³ is a C _1-6 alkyl group (the C _1-6 alkyl group is unsubstituted or substituted by one or more fluorine atoms), a C _6-10 aryl group, or 5 to 10 members. A heteroaryl group (the C _6-10 aryl group and the 5-10 membered heteroaryl group are unsubstituted or a C _1-3 alkyl group (the C _1-3 alkyl group is unsubstituted or Substituted with one or more substituents independently selected from the group consisting of a halogen atom, a cyano group, and —OR ¹⁴ ).
R ¹⁴ represents a C _1-3 alkyl group (the C _1-3 alkyl group is unsubstituted or substituted by one or more halogen atoms);
R ⁴ represents a hydrogen atom,
J ¹ is, means an oxygen atom. )
The spiro compound according to any one of (2) to (13) or (15) to (18), a tautomer of the compound, or a pharmaceutically acceptable salt thereof .

(20)
Z ¹ is
Formula (II-1) or (II-4)

（式中、Ｒ^１とＲ^３は、
Ｒ^１が、Ｃ_１−３アルキル基（該Ｃ_１−３アルキル基は、フェニル基、ピリジル基、フリル基又はイソオキサゾリル基（該フェニル基、ピリジル基、フリル基及びイソオキサゾリル基は、４〜７員含酸素ヘテロシクロアルカンと縮環していても良く、且つ該フェニル基、ピリジル基、フリル基及びイソオキサゾリル基は、無置換であるか又はハロゲン原子、シアノ基、Ｃ_１−３アルキル基（該Ｃ_１−３アルキル基は一つ以上のフッ素原子によって置換されている。）及び−Ｏ（Ｃ_１−３アルキル）からなる群より独立して選ばれる１つ以上の置換基によって置換されている。）の何れか一つにより置換されている。）を意味し、Ｒ^３が水素原子を意味するか、又は
Ｒ^１が、Ｃ_１−３アルキル基（該Ｃ_１−３アルキル基は、フェニル基、ピリジル基又はフリル基（該フェニル基、ピリジル基及びフリル基は、４〜７員含酸素ヘテロシクロアルカンと縮環していても良く、且つ該フェニル基、ピリジル基及びフリル基は、無置換であるか又はハロゲン原子、シアノ基及びＣ_１−３アルキル基（該Ｃ_１−３アルキル基は一つ以上のフッ素原子によって置換されている。）からなる群より独立して選ばれる１つ以上の置換基によって置換されている。）の何れか一つにより置換されており、且つ該Ｃ_１−３アルキル基は、水酸基、ハロゲン原子及びシアノ基からなる群より独立して選ばれる１つ以上の置換基で置換されている。）を意味し、Ｒ^３が水素原子を意味し、
Ｒ^４が、水素原子を意味し、
Ｊ^１が、酸素原子を意味する。）
の何れかである上記（２）乃至（１２）、又は（１４）乃至（１８）の何れか１項に記載のスピロ化合物、該化合物の互変異性体、若しくはその医薬的に許容され得る塩。

（２１）
Ｚ^１が、
式（ＩＩ−１）又は（ＩＩ−４）

(Wherein R ¹ and R ³ are
R ¹ is a C _1-3 alkyl group (the C _1-3 alkyl group is a phenyl group, a pyridyl group, a furyl group or an isoxazolyl group (the phenyl group, pyridyl group, furyl group and isoxazolyl group are 4 to 7 members It may be condensed with an oxygen-containing heterocycloalkane, and the phenyl group, pyridyl group, furyl group and isoxazolyl group may be unsubstituted, halogen atoms, cyano groups, C _1-3 alkyl groups (the C _1-3 alkyl groups are substituted by one or more fluorine atoms.) And one or more substituents independently selected from the group consisting of —O (C _1-3 alkyl). And R ³ is a hydrogen atom, or R ¹ is a C _1-3 alkyl group (the C _1-3 alkyl group is a phenyl group). , Pyridyl group or furyl group (the phenyl group, pyridyl group and furyl group may be condensed with a 4- to 7-membered oxygen-containing heterocycloalkane, and the phenyl group, pyridyl group and furyl group are unsubstituted. Or one or more independently selected from the group consisting of a halogen atom, a cyano group and a C _1-3 alkyl group (wherein the C _1-3 alkyl group is substituted by one or more fluorine atoms). And the C _1-3 alkyl group is one or more independently selected from the group consisting of a hydroxyl group, a halogen atom, and a cyano group. Substituted with a substituent group), R ³ represents a hydrogen atom,
R ⁴ represents a hydrogen atom,
J ¹ is, means an oxygen atom. )
The spiro compound according to any one of (2) to (12) or (14) to (18), a tautomer of the compound, or a pharmaceutically acceptable salt thereof .

(21)
Z ¹ is
Formula (II-1) or (II-4)

（式中、Ｒ^１とＲ^３は、
Ｒ^１とＲ^３が、それらが結合している窒素原子と一緒になってピペリジル基、ピペラジニル基、ホモピペリジル基又はホモピペラジニル基（該ピペリジル基、ピペラジニル基、ホモピペリジル基及びホモピペラジニル基は、−Ｃ（＝Ｏ）ＯＲ^１３、−Ｃ（＝Ｏ）Ｒ^１３、−ＯＲ^１３、−ＮＲ^１２Ｒ^１３、ハロゲン原子及びシアノ基からなる群より独立して選ばれる１つ以上の置換基によって置換されている。）を意味し、
Ｒ^１２が、水素原子を意味し、
Ｒ^１３が、Ｃ_１−６アルキル基（該Ｃ_１−６アルキル基は無置換であるか又は一つ以上のフッ素原子により置換されている。）、フェニル基又はピリジル基（該フェニル基及びピリジル基は、無置換であるか又はＣ_１−３アルキル基（該Ｃ_１−３アルキル基は無置換であるか又は一つ以上のフッ素原子により置換されている。）、ハロゲン原子、シアノ基及び−Ｏ（Ｃ_１−３アルキル）からなる群より独立して選ばれる一つ以上の置換基によって置換されている。）の何れかを意味し、
Ｒ^４が、水素原子を意味し、
Ｊ^１が、酸素原子を意味する。）
の何れかである上記（１９）に記載のスピロ化合物、該化合物の互変異性体、若しくはその医薬的に許容され得る塩。

（２２）
Ｚ^１が、
式（ＩＩ−１）又は（ＩＩ−４）

(Wherein R ¹ and R ³ are
R ¹ and R ³ together with the nitrogen atom to which they are attached are piperidyl, piperazinyl, homopiperidyl or homopiperazinyl (the piperidyl, piperazinyl, homopiperidyl and homopiperazinyl groups are -C (═O) OR ¹³ , —C (═O) R ¹³ , —OR ¹³ , —NR ¹² R ¹³ , substituted by one or more substituents independently selected from the group consisting of a halogen atom and a cyano group Means)
R ¹² represents a hydrogen atom,
R ¹³ is a C _1-6 alkyl group (the C _1-6 alkyl group is unsubstituted or substituted by one or more fluorine atoms), a phenyl group or a pyridyl group (the phenyl group and pyridyl group). The group may be unsubstituted or a C _1-3 alkyl group (the C _1-3 alkyl group is unsubstituted or substituted by one or more fluorine atoms), a halogen atom, a cyano group, and Substituted with one or more substituents independently selected from the group consisting of —O (C _1-3 alkyl).
R ⁴ represents a hydrogen atom,
J ¹ is, means an oxygen atom. )
The spiro compound according to the above (19), a tautomer of the compound, or a pharmaceutically acceptable salt thereof.

(22)
Z ¹ is
Formula (II-1) or (II-4)

（式中、Ｒ^１とＲ^３は、
Ｒ^１とＲ^３が、それらが結合している窒素原子と一緒になってピペリジル基、ピペラジニル基、ホモピペリジル基又はホモピペラジニル基（該ピペリジル基、ピペラジニル基、ホモピペリジル基及びホモピペラジニル基は、フェニル基、ピリジル基、オキサジアゾリル基、ベンズイミダゾリル基、ベンゾイソキサゾリル基又はキノリル基（該フェニル基、ピリジル基、オキサジアゾリル基、ベンズイミダゾリル基、ベンゾイソキサゾリル基及びキノリル基は、無置換であるか又はＣ_１−３アルキル基（該Ｃ_１−３アルキル基は無置換であるか又は一つ以上のフッ素原子により置換されている。）、ハロゲン原子及びシアノ基からなる群より独立して選ばれる一つ以上の置換基によって置換されている。）で置換されている。）の何れかを意味し、
Ｒ^４が、水素原子を意味し、
Ｊ^１が、酸素原子を意味する。）
の何れかである上記（１９）に記載のスピロ化合物、該化合物の互変異性体、若しくはその医薬的に許容され得る塩。

（２３）
Ｚ^１が、
式（ＩＩ−１）又は（ＩＩ−４）

(Wherein R ¹ and R ³ are
R ¹ and R ³ together with the nitrogen atom to which they are bonded are piperidyl, piperazinyl, homopiperidyl or homopiperazinyl (the piperidyl, piperazinyl, homopiperidyl and homopiperazinyl groups are phenyl groups , Pyridyl group, oxadiazolyl group, benzimidazolyl group, benzisoxazolyl group or quinolyl group (the phenyl group, pyridyl group, oxadiazolyl group, benzimidazolyl group, benzisoxazolyl group and quinolyl group are unsubstituted) Or a C _1-3 alkyl group (the C _1-3 alkyl group is unsubstituted or substituted by one or more fluorine atoms), a halogen atom and a cyano group independently. Substituted by one or more substituents)). Taste,
R ⁴ represents a hydrogen atom,
J ¹ is, means an oxygen atom. )
The spiro compound according to the above (19), a tautomer of the compound, or a pharmaceutically acceptable salt thereof.

(23)
Z ¹ is
Formula (II-1) or (II-4)

（式中、Ｒ^１とＲ^３は、
Ｒ^１とＲ^３が、それらが結合している窒素原子と一緒になってアゼチジニル基（該アゼチジニル基は、無置換であるか、又は−Ｃ（＝Ｏ）ＯＲ^１３、−Ｃ（＝Ｏ）Ｒ^１３、−ＯＲ^１３、−ＮＲ^１２Ｒ^１３、ハロゲン原子及びシアノ基からなる群より独立して選ばれる１つ以上の置換基によって置換されている。）を意味し、
Ｒ^１２が、水素原子を意味し、
Ｒ^１３が、Ｃ_１−６アルキル基、フェニル基又はピリジル基（該フェニル基及びピリジル基は、無置換であるか又はＣ_１−３アルキル基（該Ｃ_１−３アルキル基は無置換であるか又は一つ以上のフッ素原子により置換されている。）、ハロゲン原子、シアノ基及び−Ｏ（Ｃ_１−３アルキル）からなる群より独立して選ばれる一つ以上の置換基によって置換されている。）の何れかを意味し、
Ｒ^４が、水素原子を意味し、
Ｊ^１が、酸素原子を意味する。）
の何れかである上記（２）乃至（１２）、（１４）の何れか１項に記載のスピロ化合物、該化合物の互変異性体、若しくはその医薬的に許容され得る塩。

（２４）
Ｌ^１が、Ｃ_１−３アルキレン基であり、
Ｌ^２が、単結合であり、
Ｅが酸素原子であり、
ｍが１又は２の整数であり、
Ｒ^６が水素原子であり、
ｎが０であり、
Ｔが、式（ＶＩ−１）又は（ＶＩ−２）

(Wherein R ¹ and R ³ are
R ¹ and R ³ together with the nitrogen atom to which they are attached are azetidinyl groups (the azetidinyl group is unsubstituted or —C (═O) OR ¹³ , —C (═O) R ¹³ , —OR ¹³ , —NR ¹² R ¹³ , substituted with one or more substituents independently selected from the group consisting of a halogen atom and a cyano group.
R ¹² represents a hydrogen atom,
R ¹³ represents a C _1-6 alkyl group, a phenyl group or a pyridyl group (the phenyl group and the pyridyl group are unsubstituted or a C _1-3 alkyl group (the C _1-3 alkyl group is unsubstituted). Or substituted by one or more fluorine atoms.), Substituted by one or more substituents independently selected from the group consisting of halogen atoms, cyano groups and —O (C _1-3 alkyl). Means either)
R ⁴ represents a hydrogen atom,
J ¹ is, means an oxygen atom. )
The spiro compound according to any one of (2) to (12) and (14), a tautomer of the compound, or a pharmaceutically acceptable salt thereof.

(24)
L ¹ is a C _1-3 alkylene group,
L ² is a single bond,
E is an oxygen atom,
m is an integer of 1 or 2,
R ⁶ is a hydrogen atom,
n is 0,
T is the formula (VI-1) or (VI-2)

（式中、Ｌ^４はＣ_１−３アルキレン基を意味し、Ｌ^５は単結合を意味し、Ｒ^８及びＲ^１０は、上記（１）に記載の定義と同じ意味を示す。）の何れかである上記（１）に記載のスピロ化合物、該化合物の互変異性体、若しくはその医薬的に許容され得る塩。

（２５）
Ｚ^１が、
式（ＩＩ−１）又は（ＩＩ−４）

(Wherein L ⁴ represents a C _1-3 alkylene group, L ⁵ represents a single bond, and R ⁸ and R ¹⁰ have the same meaning as defined in (1) above). The spiro compound according to (1) above, a tautomer of the compound, or a pharmaceutically acceptable salt thereof.

(25)
Z ¹ is
Formula (II-1) or (II-4)

（式中、Ｒ^１とＲ^３は、
Ｒ^１が、Ｃ_１−３アルキル基（該Ｃ_１−３アルキル基は、フェニル基又はピリジル基（該フェニル基及びピリジル基は、Ｃ_４−６アルキル基によって置換されている。）の何れかにより置換されている。）を意味し、Ｒ^３が水素原子を意味するか、
Ｒ^１が、ピペリジル基（該ピペリジル基は、Ｃ_４−６アルキル基によって置換されている。）を意味し、Ｒ^３が水素原子を意味するか、又は
Ｒ^１とＲ^３が、それらが結合している窒素原子と一緒になってピペリジル基（該ピペリジル基は、−Ｃ（＝Ｏ）Ｒ^１３、−ＯＲ^１３及び−ＮＲ^１２Ｒ^１３からなる群より独立して選ばれる１つ以上の置換基によって置換されている。）を意味し、
Ｒ^１２が、水素原子を意味し、
Ｒ^１３が、フェニル基又はピリジル基（該フェニル基及びピリジル基は、無置換であるか又はＣ_４−６アルキル基によって置換されている。）の何れかを意味し、
Ｒ^４が、水素原子を意味し、
Ｊ^１が、酸素原子を意味する。）
の何れかである上記（１）又は（２４）に記載のスピロ化合物、該化合物の互変異性体、若しくはその医薬的に許容され得る塩。

（２６）
Ｚ^１が、
式（ＩＩ−１）又は（ＩＩ−４）

(Wherein R ¹ and R ³ are
R ¹ is either a C _1-3 alkyl group (the C _1-3 alkyl group is a phenyl group or a pyridyl group (the phenyl group and the pyridyl group are substituted by a C _4-6 alkyl group)). Or R ³ represents a hydrogen atom, or
R ¹ represents a piperidyl group (the piperidyl group is substituted by a C _4-6 alkyl group), and R ³ represents a hydrogen atom, or R ¹ and R ³ are bonded to each other. A piperidyl group together with the nitrogen atom in which the piperidyl group is independently selected from the group consisting of —C (═O) R ¹³ , —OR ¹³ and —NR ¹² R ¹³ Substituted by a group)
R ¹² represents a hydrogen atom,
R ¹³ represents either a phenyl group or a pyridyl group (the phenyl group and the pyridyl group are unsubstituted or substituted by a C _4-6 alkyl group);
R ⁴ represents a hydrogen atom,
J ¹ is, means an oxygen atom. )
The spiro compound according to (1) or (24), a tautomer of the compound, or a pharmaceutically acceptable salt thereof.

(26)
Z ¹ is
Formula (II-1) or (II-4)

（式中、Ｒ^１とＲ^３は、
Ｒ^１が、Ｃ_１−６アルキル基（該Ｃ_１−６アルキル基は、４〜７員含酸素ヘテロシクロアルキル基又は−ＮＨＣ（＝Ｏ）Ｏ（Ｃ_１−６アルキル）で置換されている。）を意味し、Ｒ^３が水素原子を意味するか、
Ｒ^１が、Ｃ_１−６アルキル基（該Ｃ_１−６アルキル基は、Ｃ_６−１０アリール基又は５〜１０員ヘテロアリール基（該Ｃ_６−１０アリール基及び５〜１０員ヘテロアリール基は、４〜７員含酸素ヘテロシクロアルカンと縮環していても良く、且つ該Ｃ_６−１０アリール基及び５〜１０員ヘテロアリール基は無置換であるか又はハロゲン原子、シアノ基、Ｃ_１−３アルキル基（該Ｃ_１−３アルキル基は無置換であるか又は一つ以上のフッ素原子によって置換されている。）、−Ｏ（Ｃ_１−３アルキル）及びＣ_４−６アルキル基からなる群より独立して選ばれる１つ以上の置換基によって置換されている。）の何れか一つで置換されており、且つ該Ｃ_１−６アルキル基は水酸基、ハロゲン原子及びシアノ基からなる群より独立して選ばれる１つ以上の置換基で置換されていても良い。）を意味し、Ｒ^３が水素原子を意味するか、
Ｒ^１が、４−１１員含窒素ヘテロシクロアルキル基（該４−１１員含窒素ヘテロシクロアルキル基は−Ｃ（＝Ｏ）Ｏ（Ｃ_１−６アルキル）によって置換されている。）を意味し、Ｒ^３が水素原子を意味するか、又は
Ｒ^１とＲ^３が、それらが結合している窒素原子と一緒になってアゼチジニル基又は５〜７員含窒素ヘテロシクロアルキル基（該アゼチジニル基及び５〜７員含窒素ヘテロシクロアルキル基は、フェニル基、５−１０員ヘテロアリール基（該フェニル基及び５−１０員ヘテロアリール基は、無置換であるか、又はＣ_１−３アルキル基（該Ｃ_１−３アルキル基は無置換であるか又は一つ以上のフッ素原子により置換されている。）、ハロゲン原子及びシアノ基からなる群より独立して選ばれる一つ以上の置換基によって置換されている。）、−Ｃ（＝Ｏ）ＯＲ^１３、−Ｃ（＝Ｏ）Ｒ^１３、−ＯＲ^１３、−ＮＲ^１２Ｒ^１３、ハロゲン原子及びシアノ基からなる群より独立して選ばれる１つ以上の置換基によって置換されている。）を意味し、
Ｒ^１２が、水素原子を意味し、
Ｒ^１３が、Ｃ_１−６アルキル基（該Ｃ_１−６アルキル基は無置換であるか又は一つ以上のフッ素原子により置換されている。）、フェニル基又はピリジル基（該フェニル基及びピリジル基は、無置換であるか又はＣ_１−３アルキル基（該Ｃ_１−３アルキル基は無置換であるか又は一つ以上のフッ素原子により置換されている。）、ハロゲン原子、シアノ基及び−Ｏ（Ｃ_１−３アルキル）からなる群より独立して選ばれる一つ以上の置換基によって置換されている。）の何れかを意味し、
Ｒ^４が、水素原子を意味し、
Ｊ^１が、酸素原子を意味する。）の何れかである上記（１）又は（２４）に記載のスピロ化合物、該化合物の互変異性体、若しくはその医薬的に許容され得る塩。

（２７）
Ｔが、式（ＶＩ−１）又は（ＶＩ−２）

(Wherein R ¹ and R ³ are
R ¹ is substituted with a C _1-6 alkyl group (the C _1-6 alkyl group is a 4- to 7-membered oxygen-containing heterocycloalkyl group or —NHC (═O) O (C _1-6 alkyl)). Or R ³ represents a hydrogen atom,
R ¹ is a C _1-6 alkyl group (the C _1-6 alkyl group is a C _6-10 aryl group or a 5-10 membered heteroaryl group (the C _6-10 aryl group and a 5-10 membered heteroaryl group). May be condensed with a 4- to 7-membered oxygen-containing heterocycloalkane, and the C _6-10 aryl group and the 5- to 10-membered heteroaryl group are unsubstituted or a halogen atom, a cyano group, C _1-3 alkyl groups (the C _1-3 alkyl groups are unsubstituted or substituted by one or more fluorine atoms), —O (C _1-3 alkyl) and C _4-6 alkyl groups And the C _1-6 alkyl group is substituted with a hydroxyl group, a halogen atom and a cyano group, each of which is substituted with one or more substituents independently selected from the group consisting of Chosen independently from the group May be substituted with one or more substituents.) Means, or R ³ means a hydrogen atom,
R ¹ represents a 4-11 membered nitrogen-containing heterocycloalkyl group (the 4-11 membered nitrogen-containing heterocycloalkyl group is substituted by —C (═O) O (C _1-6 alkyl)). R ³ represents a hydrogen atom, or R ¹ and R ³ together with the nitrogen atom to which they are bonded are an azetidinyl group or a 5- to 7-membered nitrogen-containing heterocycloalkyl group (the azetidinyl group). And a 5- to 7-membered nitrogen-containing heterocycloalkyl group is a phenyl group, a 5-10-membered heteroaryl group (the phenyl group and the 5-10-membered heteroaryl group are unsubstituted, or a C _1-3 alkyl group (The C _1-3 alkyl group is unsubstituted or substituted by one or more fluorine atoms), by one or more substituents independently selected from the group consisting of halogen atoms and cyano groups Replaced One or more independently selected from the group consisting of —C (═O) OR ¹³ , —C (═O) R ¹³ , —OR ¹³ , —NR ¹² R ¹³ , a halogen atom and a cyano group. Substituted with a substituent of
R ¹² represents a hydrogen atom,
R ¹³ is a C _1-6 alkyl group (the C _1-6 alkyl group is unsubstituted or substituted by one or more fluorine atoms), a phenyl group or a pyridyl group (the phenyl group and pyridyl group). The group may be unsubstituted or a C _1-3 alkyl group (the C _1-3 alkyl group is unsubstituted or substituted by one or more fluorine atoms), a halogen atom, a cyano group, and Substituted with one or more substituents independently selected from the group consisting of —O (C _1-3 alkyl).
R ⁴ represents a hydrogen atom,
J ¹ is, means an oxygen atom. The spiro compound according to (1) or (24), a tautomer of the compound, or a pharmaceutically acceptable salt thereof.

(27)
T is the formula (VI-1) or (VI-2)

（式中、Ｌ^４はＣ_１−３アルキレン基を意味し、Ｌ^５は単結合を意味し、Ｒ^８及びＲ^１０は、それぞれ独立してフェニル基又はピリジル基（該フェニル基及びピリジル基は、無置換であるか又はフッ素原子、Ｃ_１−３アルキル基（該Ｃ_１−３アルキル基は１つ以上のフッ素原子によって置換されている。）及びシアノ基からなる群より独立して選ばれる１つ以上の置換基によって置換されている。）を意味する。）の何れかである上記（１）、（２４）乃至（２６）の何れか１項に記載のスピロ化合物、該化合物の互変異性体、若しくはその医薬的に許容され得る塩。

（２８）
Ｔが、式（ＶＩ−１）又は（ＶＩ−２）

(In the formula, L ⁴ represents a C _1-3 alkylene group, L ⁵ represents a single bond, R ⁸ and R ¹⁰ are each independently a phenyl group or a pyridyl group (the phenyl group and the pyridyl group are , Unsubstituted or independently selected from the group consisting of a fluorine atom, a C _1-3 alkyl group (wherein the C _1-3 alkyl group is substituted by one or more fluorine atoms) and a cyano group. The spiro compound according to any one of (1), (24) to (26) above, which is substituted with one or more substituents) Mutant, or a pharmaceutically acceptable salt thereof.

(28)
T is the formula (VI-1) or (VI-2)

（式中、Ｌ^４はＣ_１−３アルキレン基を意味し、Ｌ^５は単結合を意味し、Ｒ^８及びＲ^１０は、それぞれ独立してフェニル基（該フェニル基は、Ｃ_４−６アルキル基で置換されている。）を意味する。）の何れかである上記（１）、（２４）乃至（２６）の何れか１項に記載のスピロ化合物、該化合物の互変異性体、若しくはその医薬的に許容され得る塩。

（２９）
Ｒ^６が水素原子である上記（２）乃至（２３）の何れか１項に記載のスピロ化合物、該化合物の互変異性体、若しくはその医薬的に許容され得る塩。

（３０）
Ｘがシクロヘキシレンである上記（１）乃至（３）、（７）、（９）乃至（２９）の何れか１項に記載のスピロ化合物、該化合物の互変異性体、若しくはその医薬的に許容され得る塩。

（３１）
Ｘがフェニレン基、ピリジンジイル基、ピラジンジイル基、チオフェンジイル基又はチアゾールジイル基である上記（１）又は（２）、（４）乃至（６）、（８）乃至（２９）の何れか１項に記載のスピロ化合物、該化合物の互変異性体、若しくはその医薬的に許容され得る塩。

（３２）
上記（１）乃至（３１）の何れか１項に記載のスピロ化合物、該化合物の互変異性体、若しくはその医薬的に許容され得る塩を有効成分として含有するアディポネクチン受容体活性化薬。

（３３）
上記（３２）に記載のアディポネクチン受容体活性化薬を有効成分として含有するアディポネクチン受容体活性化作用が有効な疾患の予防・治療・改善薬。

（３４）
上記（３２）に記載のアディポネクチン受容体活性化薬を有効成分として含有するメタボリックシンドローム及び動脈硬化の予防又は治療薬。

（３５）
上記（１）乃至（３１）の何れか１項に記載のスピロ化合物、該化合物の互変異性体、若しくはその医薬的に許容され得る塩を有効成分として含有する医薬。

(Wherein L ⁴ represents a C _1-3 alkylene group, L ⁵ represents a single bond, R ⁸ and R ¹⁰ are each independently a phenyl group (the phenyl group is a C _4-6 alkyl group). The spiro compound according to any one of (1), (24) to (26), a tautomer of the compound, or Its pharmaceutically acceptable salt.

(29)
The spiro compound according to any one of (2) to (23), wherein R ⁶ is a hydrogen atom, a tautomer of the compound, or a pharmaceutically acceptable salt thereof.

(30)
The spiro compound according to any one of (1) to (3), (7), (9) to (29), wherein X is cyclohexylene, a tautomer of the compound, or a pharmaceutically acceptable salt thereof An acceptable salt.

(31)
Any one of the above (1) or (2), (4) to (6), (8) to (29), wherein X is a phenylene group, a pyridinediyl group, a pyrazinediyl group, a thiophenediyl group, or a thiazolediyl group Or a tautomer of the compound, or a pharmaceutically acceptable salt thereof.

(32)
An adiponectin receptor activator comprising the spiro compound according to any one of (1) to (31) above, a tautomer of the compound, or a pharmaceutically acceptable salt thereof as an active ingredient.

(33)
A prophylactic / therapeutic / ameliorating agent for a disease having an effective adiponectin receptor activating action, comprising the adiponectin receptor activating drug according to (32) as an active ingredient.

(34)
Metabolic syndrome and prophylactic or therapeutic agent for arteriosclerosis comprising the adiponectin receptor activator according to (32) as an active ingredient.

(35)
The pharmaceutical which contains the spiro compound of any one of said (1) thru | or (31), the tautomer of this compound, or its pharmaceutically acceptable salt as an active ingredient.

Hereinafter, the present invention will be described in more detail.
In this specification, “n-” is normal, “s-” and “sec-” are secondary, “t-” and “tert-” are tertiary, “o-” is ortho, “m-” Means meta, “p-” means para, “rac-” means racemate, “Ph” means phenyl, “Py” means pyridyl, “Me” means methyl, “Et” means ethyl, “Pr” means propyl , “Bu” means butyl, “Boc” means tert-butoxycarbonyl, “Ms” means methanesulfonyl, “Ts” means p-toluenesulfonyl, and “Tf” means trifluoromethanesulfonyl.

  “Halogen atom” means a fluorine atom, a chlorine atom, a bromine atom or an iodine atom.

In the present specification, “4 to 11-membered heterocycloalkane” means
1) The number of atoms constituting the ring is 4 to 11,
2) The atoms constituting the ring contain at least one heteroatom selected from the group consisting of a nitrogen atom, a sulfur atom and an oxygen atom,
3) the ring is saturated or partially unsaturated,
4) The ring may contain 1 to 3 carbonyl groups or thiocarbonyl groups,
5) When a sulfur atom is contained in the atoms constituting the ring, the sulfur atom may be a sulfinyl group or a sulfone group. 6) An aromatic heterocycle is meant. Specific examples of this “4-11 membered heterocycloalkane” include, for example:

などが挙げられる。

Etc.

  The “4- to 11-membered heterocycloalkyl group” means a monovalent substituent obtained by removing one hydrogen atom from the “4- to 11-membered heterocycloalkane”.

“4- to 11-membered oxygen-containing heterocycloalkyl group” is the above-mentioned definition of “4- to 11-membered heterocycloalkyl group” wherein the hetero atom contained in the atoms constituting the ring is one kind of oxygen atom Means.
Specific examples of the group include:

などが挙げられる。

Etc.

  The “4 to 7-membered oxygen-containing heterocycloalkyl group” means the above-mentioned definition “4 to 11-membered oxygen-containing heterocycloalkyl group” having 4 to 7 atoms constituting the ring.

"4- to 11-membered nitrogen-containing heterocycloalkyl group" means that in the definition "4- to 11-membered heterocycloalkyl group", the hetero atom contained in the atoms constituting the ring is one kind of nitrogen atom Means.
Specific examples of the group include:

などが挙げられる。

Etc.

  The “5 to 7-membered nitrogen-containing heterocycloalkyl group” means the above-mentioned definition “4 to 11-membered nitrogen-containing heterocycloalkyl group” having 5 to 7 atoms constituting the ring.

The “4 to 11-membered oxygen-containing nitrogen-containing heterocycloalkyl group” means that the hetero atom contained in the atoms constituting the ring in the above-mentioned definition “4 to 11-membered heterocycloalkyl group” is an oxygen atom and a nitrogen atom. Means two types.
Specific examples of the group include:

などが挙げられる。

Etc.

The “4 to 11-membered sulfur-containing nitrogen-containing heterocycloalkyl group” means that the hetero atom contained in the atoms constituting the ring in the above-mentioned definition “4 to 11-membered heterocycloalkyl group” is a sulfur atom and a nitrogen atom. Means two types. Further, the “4- to 11-membered sulfur-containing nitrogen-containing heterocycloalkyl group” includes a monooxide and a dioxide of a sulfur atom.
Specific examples of the group include:

などが挙げられる。

Etc.

"5-10 membered heteroaryl"
1) There are 5 to 10 atoms constituting the ring,
2) The atoms constituting the ring contain at least one heteroatom selected from the group consisting of a nitrogen atom, a sulfur atom and an oxygen atom,
3) A monocyclic or bicyclic aromatic heterocycle.
Specific examples of the “5- to 10-membered heteroaryl” include, for example, pyrrole, pyridine, pyridazine, pyrimidine, pyrazine, triazole, tetrazole, benzotriazole, pyrazole, imidazole, benzimidazole, indole, isoindole, and India. Lysine, purine, indazole, quinoline, isoquinoline, quinolidine, phthalazine, quinoxaline, quinazoline, cinnoline, pteridine, imidazo [1,5-a] [1,3,5] triazine, pyrazino [2,3-d] pyridazine, imidazo [4,5-b] pyridine, imidazo [1,2-a] pyrimidine, pyrazolo [1,5-a] pyrimidine, furan, pyran, benzofuran, isobenzofuran, thiophene, benzothiophene, thiazole, isothiazole, benzothiazole , Benzothiadiazole, isoxazole Oxazole, benzoxazole, oxadiazole, pyrazolo [3,4-d] oxazole, imidazo [4,5-d] thiazole, thieno [3,2-b] furan, thieno [2,3-c] pyrazole, [ 1,4] dioxino [2,3-b] pyridine and the like.
Further, when the “5- to 10-membered heteroaryl” has a C═N double bond, the N-oxide form thereof is also included.

"5- to 10-membered heteroaryl group"
The monovalent substituent which remove | eliminated one hydrogen atom from the said definition "5-10 membered heteroaryl" is meant.

“C _6-10 aryl” means
1) 6-10 atoms constituting the ring,
2) It means a monocyclic or bicyclic aromatic hydrocarbon ring in which all atoms constituting the ring are carbon atoms.
Specific examples of the “C _6-10 aryl” include benzene, pentalene, naphthalene, azulene and the like.

The “C _6-10 aryl group” means a monovalent substituent obtained by removing one hydrogen atom from the definition “C _6-10 aryl”.

In the present specification, the “C _1-3 alkyl group” means a methyl group, an ethyl group, a propyl group, or an isopropyl group.

“C _1-6 alkyl group” means
The monovalent substituent which removed one hydrogen atom from the linear or branched saturated hydrocarbon which has 1-6 carbon atoms is meant.
Specific examples of the group include, for example, methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl group, s-butyl group, t-butyl group, pentyl group, isopentyl group, neopentyl group, t-pentyl group, 1-methylbutyl group, 2-methylbutyl group, 1,2-dimethylpropyl group, hexyl group, 1-methylpentyl group, 2-methylpentyl group, 3-methylpentyl group, 4-methylpentyl group, 1,1-dimethylbutyl group, 1,2-dimethylbutyl group, 1,3-dimethylbutyl group, 2,2-dimethylbutyl group, 2,3-dimethylbutyl group, 3,3-dimethylbutyl group, 1, Examples include 1,2-trimethylpropyl group, 1,2,2-trimethylpropyl group, 1-ethyl-1-methylpropyl group, 1-ethyl-2-methylpropyl group, and the like.

“C _1-9 alkyl group” means
The monovalent substituent which removed one hydrogen atom from the linear or branched saturated hydrocarbon which has 1-9 carbon atoms is meant.

“C _1-5 alkyl group” means
The monovalent substituent which remove | eliminated one hydrogen atom from the linear or branched saturated hydrocarbon which has 1-5 carbon atoms is meant.
“C _4-6 alkyl group” means
It means a monovalent substituent obtained by removing one hydrogen atom from a linear or branched saturated hydrocarbon having 4 to 6 carbon atoms.

“C _6-9 alkyl group” means
It means a monovalent substituent obtained by removing one hydrogen atom from a linear or branched saturated hydrocarbon having 6 to 9 carbon atoms.

“C _3-6 cycloalkane” means
1) 3 to 6 atoms constituting the ring,
2) An aromatic hydrocarbon ring of “monocyclic system” or “bridged ring system” in which all atoms constituting the ring are carbon atoms.
Specific examples of the “C _3-6 cycloalkane” include cyclopropane, cyclobutane, cyclopentane, cyclohexane and the like.

“C _3-11 cycloalkane” means
1) The number of atoms constituting the ring is 3 to 11,
2) The atoms constituting the ring are all carbon atoms. 3) An aliphatic hydrocarbon ring of “monocyclic system”, “fused ring system”, “bridged ring system” or “spiro ring system”.
Specific examples of this “C _3-11 cycloalkane” include, for example, cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, cyclooctane, adamantane, bicyclo [3.1.0] octane, bicyclo [2.2. 1] heptane, spiro [5.5] undecane, etc.

The “C _3-11 cycloalkyl group” means a monovalent substituent obtained by removing one hydrogen atom from the above-mentioned definition “C _3-11 cycloalkane”.

The “C _3-4 cycloalkyl group” means a group having 3 to 4 atoms constituting the ring in the above-mentioned definition “C _3-11 cycloalkyl group”.

The “C _2-3 alkenyl group” refers to an ethenyl group, a prop-1-en-1-yl group, a prop-2-en-1-yl group, or a prop-1-en-2-yl group.

“C _2-6 alkenyl group” means
1) 2 to 6 carbon atoms,
2) A monovalent substituent obtained by removing one hydrogen atom from a linear or branched unsaturated hydrocarbon having one or more double bonds.
Specific examples of the group include, for example, ethenyl group, prop-1-en-1-yl group, prop-2-en-1-yl group, prop-1-en-2-yl group, butane -1-en-1-yl group, but-2-en-1-yl group, but-3-en-1-yl group, penta-1-en-1-yl group, penta-4-en-1 -Yl group, hexa-1-en-1-yl group, hexa-5-en-1-yl group, 4-methylpent-3-en-1-yl group penta-2,4-dien-1-yl group Etc.

“C _3-11 cycloalkene” means
1) The number of atoms constituting the ring is 3 to 11,
2) The atoms constituting the ring are all carbon atoms,
3) means a “monocyclic”, “fused ring”, “bridged ring” or “spiro ring” aliphatic hydrocarbon ring having one or more double bonds.
Specific examples of this “C _3-11 cycloalkene” include, for example, cyclopropene, cyclobutene, cyclopentene, cyclohexene, 1,3-cyclohexadiene, 1,4-cyclohexadiene, cycloheptene, cyclooctene, 1 , 4-cyclooctadiene, 1,2,3,3a, 4,6a-hexahydropentalene, (1R, 4S) -bicyclo [2.2.1] hept-2-ene, spiro [5.5] undec-2- En.

The “C _3-11 cycloalkenyl group” means a monovalent substituent obtained by removing one hydrogen atom from the above-mentioned definition “C _3-11 cycloalkene”.

The “C _2-3 alkynyl group” means an ethynyl group, a prop-1-in-1-yl group, or a prop-2-in-1-yl group.

The “C _1-3 alkylene group” means a divalent substituent obtained by further removing one hydrogen atom at an arbitrary position from the above-mentioned definition “C _1-3 alkyl group”.
Specific examples of the group include a methylene group, an ethylene group, a propane-1,3-diyl group, and a propane-2,2-diyl group.

The “C _1-6 alkylene group” means a divalent substituent obtained by further removing one hydrogen atom at any position from the above-defined “C _1-6 alkyl group”.
Specific examples of the group include methylene group, ethylene group, propane-1,3-diyl group, propane-2,2-diyl group, 2,2-dimethyl-propane-1,3-diyl group, Hexane-1,6-diyl group, 3-methylbutane-1,2-diyl group and the like can be mentioned.

The “C _3-11 cycloalkylene group” means a divalent substituent obtained by further removing one hydrogen atom at an arbitrary position from the above-mentioned definition “C _3-11 cycloalkyl group”.
Specific examples of the group include cyclopropane-1,1-diyl group, cyclopropane-1,2-diyl group, cyclopentane-1,3-diyl group, cyclohexane-1,4-diyl group, Cyclohexane-1,1-diyl group, bicyclo [2.2.1] heptane-2,5-diyl group, bicyclo [3.3.0] octane-2,5-diyl group, spiro [5.5] undecane-3,9-diyl Group and the like.

The “C _3-11 cycloalkenylene group” means a divalent substituent obtained by further removing one hydrogen atom at an arbitrary position from the definition “C _3-11 cycloalkenyl group”.

The “C _6-10 arylene group” means a divalent substituent obtained by further removing one hydrogen atom at an arbitrary position from the above-mentioned definition “C _6-10 aryl group”.
Specific examples of the group include a phenylene group and a naphthalene-2,6-diyl group.

The “5- to 10-membered heteroarylene group” means a divalent substituent obtained by further removing one hydrogen atom at an arbitrary position from the above-described definition of “5- to 10-membered heteroaryl group”.
Specific examples of the group include a pyridine-2,5-diyl group, a pyrimidine-2,4-diyl group, and a pyridazine-3,6-diyl group.

The “C _2-3 alkenylene group” means a divalent substituent obtained by further removing one hydrogen atom at an arbitrary position from the above-mentioned definition “C _2-3 alkenyl group”.

The “C _2-3 alkynylene group” means a divalent substituent obtained by further removing one hydrogen atom at an arbitrary position from the definition “C _2-3 alkynyl group”.

  Next, a preferred structure of each substituent in the present invention is listed.

  E is preferably an oxygen atom.

L ¹ is preferably a C _1-3 alkylene group, a C _2-3 alkenylene group or a C _2-3 alkynylene group (the C _1-3 alkylene group, C _2-3 alkenylene group and C _2-3 alkynylene group are It is unsubstituted or substituted by a cyclopropyl group.), More preferably a C _1-3 alkylene group, and still more preferably a methylene group.

L ² is preferably a single bond or a C _1-3 alkylene group, more preferably a single bond or a methylene group, and still more preferably a single bond.

Preferable examples of X include a C _3-11 cycloalkylene group, more preferably a cyclohexanediyl group, and still more preferably a cyclohexane-1,4-diyl group.
Other preferable examples of X include a C _6-10 arylene group (the C _6-10 arylene group is unsubstituted or substituted with a methoxy group) or a 5- to 10-membered heteroarylene group. More preferably, it is a phenylene group, a thiophenediyl group or a pyridinediyl group, and more preferably a phenylene group.

R ⁴ is preferably a hydrogen atom.

R ⁶ is preferably each independently a hydrogen atom or a C _1-3 alkyl group, more preferably a hydrogen atom or a methyl group, and still more preferably a hydrogen atom.

R ⁷ is preferably each independently a methyl group.

  Preferred examples of T include formula (VI-1) or (VI-2)

（式中、Ｌ^４はＣ_１−３アルキレン基を意味し、Ｌ^５は単結合を意味し、Ｒ^８はフェニル基又はピリジル基（該フェニル基及びピリジル基は、無置換であるか又はＣ_１−６アルキル基、フッ素原子、Ｃ_１−３アルキル基（該Ｃ_１−３アルキル基は１つ以上のフッ素原子によって置換されている。）及びシアノ基からなる群より独立して選ばれる１つ以上の置換基によって置換されている。）を意味し、Ｒ^１０はフェニル基、ピリジル基（該フェニル基及びピリジル基は、無置換であるか又はＣ_１−６アルキル基、フッ素原子、Ｃ_１−３アルキル基（該Ｃ_１−３アルキル基は１つ以上のフッ素原子によって置換されている。）及びシアノ基からなる群より独立して選ばれる１つ以上の置換基によって置換されている。）又はＣ_６−１０アリールと縮環しているＣ_３−１１シクロアルキル基を意味する。）の何れかである。

(In the formula, L ⁴ represents a C _1-3 alkylene group, L ⁵ represents a single bond, R ⁸ represents a phenyl group or a pyridyl group (the phenyl group and the pyridyl group are unsubstituted or C 1 independently selected from the group consisting of a _1-6 alkyl group, a fluorine atom, a C _1-3 alkyl group (the C _1-3 alkyl group is substituted by one or more fluorine atoms) and a cyano group. R ¹⁰ is a phenyl group or a pyridyl group (the phenyl group and the pyridyl group are unsubstituted or a C _1-6 alkyl group, a fluorine atom, a C atom). _1-3 alkyl group (the C _1-3 alkyl group is substituted with one or more fluorine atoms) and one or more substituents independently selected from the group consisting of cyano groups .) or _{C 6-10} It means a C _3-11 cycloalkyl group which is fused with the reel.) Is either.

Preferred examples of Z ¹ include those represented by the formula (III-1), (III-2) or (III-3)

（式中、Ｒ^１とＲ^３は、
Ｒ^１が、Ｃ_１−６アルキル基（該Ｃ_１−６アルキル基は、４〜１１員へテロシクロアルキル基又は−ＮＨＣ（＝Ｏ）Ｏ（Ｃ_１−６アルキル）で置換されている。）を意味し、Ｒ^３が水素原子を意味し、Ｇ^１が単結合又は酸素原子を意味する。）の何れかである。より好ましくは、式（ＩＩＩ−１）、（ＩＩＩ−２）又は（ＩＩＩ−３）

(Wherein R ¹ and R ³ are
R ¹ is substituted with a C _1-6 alkyl group (the C _1-6 alkyl group is a 4- to 11-membered heterocycloalkyl group or —NHC (═O) O (C _1-6 alkyl)). ), R ³ represents a hydrogen atom, and G ¹ represents a single bond or an oxygen atom. ) More preferably, the formula (III-1), (III-2) or (III-3)

（式中、Ｒ^１とＲ^３は、
Ｒ^１が、Ｃ_１−６アルキル基（該Ｃ_１−６アルキル基は、４〜７員含酸素ヘテロシクロアルキル基又は−ＮＨＣ（＝Ｏ）Ｏ（Ｃ_１−６アルキル）で置換されている。）を意味し、Ｒ^３が水素原子を意味し、Ｇ^１が単結合又は酸素原子を意味する。）の何れかである。

(Wherein R ¹ and R ³ are
R ¹ is substituted with a C _1-6 alkyl group (the C _1-6 alkyl group is a 4- to 7-membered oxygen-containing heterocycloalkyl group or —NHC (═O) O (C _1-6 alkyl)). .), R ³ represents a hydrogen atom, and G ¹ represents a single bond or an oxygen atom. )

Other preferred examples of Z ¹ include compounds of formula (III-1), (III-2) or (III-3)

（式中、Ｒ^１とＲ^３は、
Ｒ^１が、４〜１１員へテロシクロアルキル基（該４〜１１員へテロシクロアルキル基は、Ｃ_１−３アルキル基（該Ｃ_１−３アルキル基はフェニル基（該フェニル基は無置換であるか又は−Ｃ（＝Ｏ）ＯＣＨ_３、シアノ基、ニトロ基、−ＳＣＨ_３、−ＯＣＦ_３、−ＯＣＨ_３、塩素原子、−ＣＦ_３及び−ＣＨ_３からなる群より独立して選ばれる１つ以上の置換基によって置換されている。）で置換されている。）で置換されている。）を意味し、Ｒ^３が水素原子を意味し、Ｇ^１が単結合又は酸素原子を意味する。)の何れかである。より好ましくは、式（ＩＩＩ−１）、（ＩＩＩ−２）又は（ＩＩＩ−３）

(Wherein R ¹ and R ³ are
R ¹ is a 4- to 11-membered heterocycloalkyl group (the 4- to 11-membered heterocycloalkyl group is a C _1-3 alkyl group (the C _1-3 alkyl group is a phenyl group (the phenyl group is unsubstituted) Or independently selected from the group consisting of —C (═O) OCH ₃ , cyano group, nitro group, —SCH ₃ , —OCF ₃ , —OCH ₃ , chlorine atom, —CF ₃ and —CH _3. Substituted with one or more substituents)), substituted with)), R ³ represents a hydrogen atom, and G ¹ represents a single bond or an oxygen atom. To do. ) More preferably, the formula (III-1), (III-2) or (III-3)

（式中、Ｒ^１とＲ^３は、
Ｒ^１が、５〜７員含窒素ヘテロシクロアルキル基（該５〜７員含窒素ヘテロシクロアルキル基は、Ｃ_１−３アルキル基（該Ｃ_１−３アルキル基はフェニル基（該フェニル基は無置換であるか又は−Ｃ（＝Ｏ）ＯＣＨ_３、シアノ基、ニトロ基、−ＳＣＨ_３、−ＯＣＦ_３、−ＯＣＨ_３、塩素原子、−ＣＦ_３及び−ＣＨ_３からなる群より独立して選ばれる１つ以上の置換基によって置換されている。）で置換されている。）で置換されている。）を意味し、Ｒ^３が水素原子を意味し、Ｇ^１が単結合又は酸素原子を意味する。)の何れかである。さらに好ましい５〜７員含窒素ヘテロシクロアルキル基の具体例としては、ピペリジル基、ピペラジニル基、ホモピペリジル基又はホモピペラジニル基が挙げられる。

(Wherein R ¹ and R ³ are
R ¹ is a 5- to 7-membered nitrogen-containing heterocycloalkyl group (the 5- to 7-membered nitrogen-containing heterocycloalkyl group is a C _1-3 alkyl group (the C _1-3 alkyl group is a phenyl group (the phenyl group is Is unsubstituted or independently of the group consisting of —C (═O) OCH ₃ , cyano group, nitro group, —SCH ₃ , —OCF ₃ , —OCH ₃ , chlorine atom, —CF ₃ and —CH _3. Substituted with one or more selected substituents)), substituted with), R ³ represents a hydrogen atom, and G ¹ represents a single bond or an oxygen atom. Means. ) More specific examples of the 5- to 7-membered nitrogen-containing heterocycloalkyl group include a piperidyl group, a piperazinyl group, a homopiperidyl group, and a homopiperazinyl group.

Other preferred examples of Z ¹ include compounds of formula (III-1) or (III-2)

（式中、Ｒ^１とＲ^３は、
Ｒ^１とＲ^３が、それらが結合している窒素原子と一緒になって４〜１１員へテロシクロアルキル基（該４〜１１員へテロシクロアルキル基は、Ｃ_１−６アルキル基、フェニル基、５−１０員ヘテロアリール基（該フェニル基及び５−１０員ヘテロアリール基は、無置換であるか、又はＣ_１−３アルキル基（該Ｃ_１−３アルキル基は無置換であるか又は一つ以上のフッ素原子により置換されている。）、ハロゲン原子及びシアノ基からなる群より独立して選ばれる一つ以上の置換基によって置換されている。）、−Ｃ（＝Ｏ）ＯＲ^１３、−Ｃ（＝Ｏ）Ｒ^１３、−ＯＲ^１３、−ＮＲ^１２Ｒ^１３、ハロゲン原子及びシアノ基からなる群より独立して選ばれる１つ以上の置換基によって置換されている。）を意味し、Ｒ^１２が、水素原子を意味し、Ｒ^１３が、Ｃ_６−１０アリール基又は５〜１０員ヘテロアリール基（該Ｃ_６−１０アリール基及び５〜１０員ヘテロアリール基は、無置換であるか又はＣ_１−３アルキル基（該Ｃ_１−３アルキル基は一つ以上のフッ素原子により置換されている。）、Ｃ_１−６アルキル基、ハロゲン原子及びシアノ基からなる群より独立して選ばれる一つ以上の置換基によって置換されている。）の何れかを意味する。）の何れかである。より好ましくは、式（ＩＩＩ−１）又は（ＩＩＩ−２）

(Wherein R ¹ and R ³ are
R ¹ and R ³ together with the nitrogen atom to which they are attached are 4- to 11-membered heterocycloalkyl groups (the 4- to 11-membered heterocycloalkyl group is a C _1-6 alkyl group, phenyl A group, a 5- to 10-membered heteroaryl group (the phenyl group and the 5- to 10-membered heteroaryl group are unsubstituted, or a C _1-3 alkyl group (the C _1-3 alkyl group is unsubstituted) Or substituted by one or more substituents independently selected from the group consisting of a halogen atom and a cyano group.), -C (= O) OR ¹³ , —C (═O) R ¹³ , —OR ¹³ , —NR ¹² R ¹³ , substituted with one or more substituents independently selected from the group consisting of a halogen atom and a cyano group. R ¹² represents a hydrogen atom Means that R ¹³ is a C _6-10 aryl group or a 5- to 10-membered heteroaryl group (the C _6-10 aryl group and 5- to 10-membered heteroaryl group are unsubstituted or C _1-3 alkyl One or more substituents independently selected from the group consisting of a group (wherein the C _1-3 alkyl group is substituted by one or more fluorine atoms), a C _1-6 alkyl group, a halogen atom and a cyano group; Substituted with a group). ) More preferably, the formula (III-1) or (III-2)

（式中、Ｒ^１とＲ^３は、
Ｒ^１とＲ^３が、それらが結合している窒素原子と一緒になってアゼチジニル基、５〜７員含窒素ヘテロシクロアルキル基又は４〜１１員含酸素含窒素へテロシクロアルキル基（該アゼチジニル基、５〜７員含窒素ヘテロシクロアルキル基及び４〜１１員含酸素含窒素へテロシクロアルキル基は、Ｃ_１−６アルキル基、フェニル基、５−１０員ヘテロアリール基（該フェニル基及び５−１０員ヘテロアリール基は、無置換であるか、又はＣ_１−３アルキル基（該Ｃ_１−３アルキル基は無置換であるか又は一つ以上のフッ素原子により置換されている。）、ハロゲン原子及びシアノ基からなる群より独立して選ばれる一つ以上の置換基によって置換されている。）、−Ｃ（＝Ｏ）ＯＲ^１３、−Ｃ（＝Ｏ）Ｒ^１３、−ＯＲ^１３、−ＮＲ^１２Ｒ^１３、ハロゲン原子及びシアノ基からなる群より独立して選ばれる１つ以上の置換基によって置換されている。）を意味し、Ｒ^１２が、水素原子を意味し、Ｒ^１３が、Ｃ_６−１０アリール基又は５〜１０員ヘテロアリール基（該Ｃ_６−１０アリール基及び５〜１０員ヘテロアリール基は、無置換であるか又はＣ_１−３アルキル基（該Ｃ_１−３アルキル基は一つ以上のフッ素原子により置換されている。）、Ｃ_１−６アルキル基、ハロゲン原子及びシアノ基からなる群より独立して選ばれる一つ以上の置換基によって置換されている。）の何れかを意味する。）の何れかである。さらに好ましくは、式（ＩＩＩ−１）又は（ＩＩＩ−２）

(Wherein R ¹ and R ³ are
R ¹ and R ³ together with the nitrogen atom to which they are attached, an azetidinyl group, a 5- to 7-membered nitrogen-containing heterocycloalkyl group, or a 4- to 11-membered oxygen-containing nitrogen-containing heterocycloalkyl group (the azetidinyl Group, a 5- to 7-membered nitrogen-containing heterocycloalkyl group and a 4- to 11-membered oxygen-containing nitrogen-containing heterocycloalkyl group include a C _1-6 alkyl group, a phenyl group, a 5-10-membered heteroaryl group (the phenyl group and The 5-10 membered heteroaryl group is unsubstituted or a C _1-3 alkyl group (the C _1-3 alkyl group is unsubstituted or substituted by one or more fluorine atoms). Substituted with one or more substituents independently selected from the group consisting of a halogen atom and a cyano group.), —C (═O) OR ¹³ , —C (═O) R ¹³ , —OR ¹³ , -NR ¹² R ¹³ is substituted with one or more substituents independently selected from the group consisting of a halogen atom and a cyano group.), R ¹² represents a hydrogen atom, and R ¹³ represents C _{6. A -10} aryl group or a 5- to 10-membered heteroaryl group (the C _6-10 aryl group and a 5- to 10-membered heteroaryl group are unsubstituted or a C _1-3 alkyl group (the C _1-3 alkyl group); Is substituted by one or more fluorine atoms), and is substituted by one or more substituents independently selected from the group consisting of C _1-6 alkyl groups, halogen atoms and cyano groups. It means either. ) More preferably, the formula (III-1) or (III-2)

（式中、Ｒ^１とＲ^３は、
Ｒ^１とＲ^３が、それらが結合している窒素原子と一緒になってアゼチジニル基又は５〜７員含窒素ヘテロシクロアルキル基（該アゼチジニル基及び５〜７員含窒素ヘテロシクロアルキル基は、Ｃ_１−６アルキル基、フェニル基、５−１０員ヘテロアリール基（該フェニル基及び５−１０員ヘテロアリール基は、無置換であるか、又はＣ_１−３アルキル基（該Ｃ_１−３アルキル基は無置換であるか又は一つ以上のフッ素原子により置換されている。）、ハロゲン原子及びシアノ基からなる群より独立して選ばれる一つ以上の置換基によって置換されている。）、−Ｃ（＝Ｏ）ＯＲ^１３、−Ｃ（＝Ｏ）Ｒ^１３、−ＯＲ^１３、−ＮＲ^１２Ｒ^１３、ハロゲン原子及びシアノ基からなる群より独立して選ばれる１つ以上の置換基によって置換されている。）を意味し、Ｒ^１２が、水素原子を意味し、Ｒ^１３が、Ｃ_１−３アルキル基（該Ｃ_１−３アルキル基は無置換であるか又は一つ以上のフッ素原子により置換されている。）、Ｃ_６−１０アリール基又は５〜１０員ヘテロアリール基（該Ｃ_６−１０アリール基及び５〜１０員ヘテロアリール基は、無置換であるか又はＣ_１−３アルキル基（該Ｃ_１−３アルキル基は一つ以上のフッ素原子により置換されている。）、Ｃ_１−６アルキル基、ハロゲン原子及びシアノ基からなる群より独立して選ばれる一つ以上の置換基によって置換されている。）の何れかを意味する。）の何れかである。特に好ましい５〜７員含窒素ヘテロシクロアルキル基の具体例としては、ピペリジル基、ピペラジニル基、ホモピペリジル基又はホモピペラジニル基が挙げられる。

(Wherein R ¹ and R ³ are
R ¹ and R ³ together with the nitrogen atom to which they are bonded are an azetidinyl group or a 5- to 7-membered nitrogen-containing heterocycloalkyl group (the azetidinyl group and a 5- to 7-membered nitrogen-containing heterocycloalkyl group are A C _1-6 alkyl group, a phenyl group, a 5-10-membered heteroaryl group (the phenyl group and the 5-10-membered heteroaryl group are unsubstituted or a C _1-3 alkyl group (the C _1-3 The alkyl group is unsubstituted or substituted by one or more fluorine atoms), and is substituted by one or more substituents independently selected from the group consisting of halogen atoms and cyano groups. -C (= O) OR ¹³ , -C (= O) R ¹³ , -OR ¹³ , -NR ¹² R ¹³ , one or more substituents independently selected from the group consisting of halogen atoms and cyano groups Replace Is.) ^{Means, R 12} is, represents a hydrogen ^{atom, R 13} _{is C 1-3} alkyl group (the _{C 1-3} alkyl group is either unsubstituted or one or more fluorine atoms A C _6-10 aryl group or a 5-10 membered heteroaryl group (the C _6-10 aryl group and 5-10 membered heteroaryl group are unsubstituted or C _1-3). One or more independently selected from the group consisting of an alkyl group (the C _1-3 alkyl group is substituted by one or more fluorine atoms), a C _1-6 alkyl group, a halogen atom and a cyano group; It is substituted by a substituent. ) Specific examples of particularly preferred 5- to 7-membered nitrogen-containing heterocycloalkyl groups include piperidyl group, piperazinyl group, homopiperidyl group and homopiperazinyl group.

Other preferred examples of Z ¹ include compounds of formula (III-1) or (III-2)

（式中、Ｒ^１とＲ^３は、
Ｒ^１が、Ｃ_１−６アルキル基（該Ｃ_１−６アルキル基は、Ｃ_６−１０アリール基又は５〜１０員ヘテロアリール基（該Ｃ_６−１０アリール基及び５〜１０員ヘテロアリール基は、４〜７員含酸素ヘテロシクロアルカンと縮環していても良く、且つ該Ｃ_６−１０アリール基及び５〜１０員ヘテロアリール基は無置換であるか又はＣ_４−６アルキル基、ハロゲン原子、シアノ基、Ｃ_１−３アルキル基（該Ｃ_１−３アルキル基は無置換であるか又は一つ以上のフッ素原子によって置換されている。）及び−Ｏ（Ｃ_１−３アルキル）からなる群より独立して選ばれる１つ以上の置換基によって置換されている。）で置換されており、且つ該Ｃ_１−６アルキル基は、水酸基、ハロゲン原子及びシアノ基からなる群より独立して選ばれる１つ以上の置換基で置換されていても良い。）を意味し、Ｒ^３が水素原子を意味する。）の何れかである。より好ましくは、式（ＩＩＩ−１）又は（ＩＩＩ−２）

(Wherein R ¹ and R ³ are
R ¹ is a C _1-6 alkyl group (the C _1-6 alkyl group is a C _6-10 aryl group or a 5-10 membered heteroaryl group (the C _6-10 aryl group and a 5-10 membered heteroaryl group). May be condensed with a 4-7 membered oxygen-containing heterocycloalkane, and the C _6-10 aryl group and the 5-10 membered heteroaryl group are unsubstituted or a C _4-6 alkyl group, A halogen atom, a cyano group, a C _1-3 alkyl group (the C _1-3 alkyl group is unsubstituted or substituted by one or more fluorine atoms) and —O (C _1-3 alkyl) Substituted with one or more substituents independently selected from the group consisting of: and the C _1-6 alkyl group is independent of the group consisting of a hydroxyl group, a halogen atom and a cyano group. One or more selected May be substituted with a substituent.) Means, R ³ means a hydrogen atom. ) More preferably, the formula (III-1) or (III-2)

（式中、Ｒ^１とＲ^３は、
Ｒ^１が、Ｃ_１−３アルキル基（該Ｃ_１−３アルキル基は、フェニル基、ピリジル基、フリル基又はイソオキサゾリル基（該フェニル基、ピリジル基、フリル基及びイソオキサゾリル基は、４〜７員含酸素ヘテロシクロアルカンと縮環していても良く、且つ該フェニル基、ピリジル基、フリル基及びイソオキサゾリル基は無置換であるか又はＣ_４−６アルキル基、ハロゲン原子、シアノ基、Ｃ_１−３アルキル基（該Ｃ_１−３アルキル基は無置換であるか又は一つ以上のフッ素原子によって置換されている。）及び−Ｏ（Ｃ_１−３アルキル）からなる群より独立して選ばれる１つ以上の置換基によって置換されている。）の何れかにより置換されており、且つ該Ｃ_１−３アルキル基は、水酸基、ハロゲン原子及びシアノ基からなる群より独立して選ばれる１つ以上の置換基で置換されていても良い。）を意味し、Ｒ^３が水素原子を意味する。）の何れかである。

(Wherein R ¹ and R ³ are
R ¹ is a C _1-3 alkyl group (the C _1-3 alkyl group is a phenyl group, a pyridyl group, a furyl group or an isoxazolyl group (the phenyl group, the pyridyl group, the furyl group and the isoxazolyl group are 4 to 7 members) It may be condensed with an oxygen-containing heterocycloalkane, and the phenyl group, pyridyl group, furyl group and isoxazolyl group are unsubstituted or a C _4-6 alkyl group, a halogen atom, a cyano group, C _1- Independently selected from the group consisting of ₃ alkyl groups (wherein the C _1-3 alkyl group is unsubstituted or substituted by one or more fluorine atoms) and —O (C _1-3 alkyl) which is substituted by one or more substituents. is substituted by any of the), and the C _1-3 alkyl group, Germany from the group consisting hydroxyl, a halogen atom, and a cyano group To one or more substituents selected may be substituted.) Means, R ³ means a hydrogen atom. )

Other preferred examples of Z ¹ include compounds of formula (III-1) or (III-2)

（式中、Ｒ^１とＲ^３は、
Ｒ^１が、４〜１１員へテロシクロアルキル基（該４〜１１員へテロシクロアルキル基は−Ｃ（＝Ｏ）Ｏ（Ｃ_１−６アルキル）によって置換されている。）を意味し、Ｒ^３が水素原子を意味する。）の何れかである。より好ましくは、式（ＩＩＩ−１）又は（ＩＩＩ−２）

(Wherein R ¹ and R ³ are
R ¹ represents a 4-11 membered heterocycloalkyl group (the 4-11 membered heterocycloalkyl group is substituted by —C (═O) O (C _1-6 alkyl)); R ³ represents a hydrogen atom. ) More preferably, the formula (III-1) or (III-2)

（式中、Ｒ^１とＲ^３は、
Ｒ^１が、４−１１員含窒素ヘテロシクロアルキル基（該４−１１員含窒素ヘテロシクロアルキル基は−Ｃ（＝Ｏ）Ｏ（Ｃ_１−６アルキル）によって置換されている。）を意味し、Ｒ^３が水素原子を意味する。）の何れかである。さらに好ましい４−１１員含窒素ヘテロシクロアルキル基の具体例としては、アゼチジニル基、ピロリジニル基、ピペリジル基、ピペラジニル基、ホモピペリジル基又はホモピペラジニル基が挙げられる。

(Wherein R ¹ and R ³ are
R ¹ represents a 4-11 membered nitrogen-containing heterocycloalkyl group (the 4-11 membered nitrogen-containing heterocycloalkyl group is substituted by —C (═O) O (C _1-6 alkyl)). R ³ represents a hydrogen atom. ) More specific examples of the 4-11 membered nitrogen-containing heterocycloalkyl group include azetidinyl group, pyrrolidinyl group, piperidyl group, piperazinyl group, homopiperidyl group and homopiperazinyl group.

Examples of preferred compounds of the spiro compound of the present invention include the structures shown below.
(1) Formula (I)

［式（Ｉ）中、
Ｅは、酸素原子を意味し、
Ｌ^１は、Ｃ_１−３アルキレン基、Ｃ_２−３アルケニレン基又はＣ_２−３アルキニレン基を意味し、
Ｌ^２は、単結合又はＣ_１−３アルキレン基を意味し、
ＸがＣ_３−１１シクロアルキレン基、Ｃ_６−１０アリーレン基（該Ｃ_６−１０アリーレン基は、無置換であるか又はメトキシ基で置換されている。）又は５〜１０員ヘテロアリーレン基を意味し、
Ｚ^１が、
式（ＩＩＩ−１）、（ＩＩＩ−２）又は（ＩＩＩ−３）

[In the formula (I),
E means an oxygen atom,
L ¹ means a C _1-3 alkylene group, a C _2-3 alkenylene group or a C _2-3 alkynylene group,
L ² represents a single bond or a C _1-3 alkylene group,
X represents a C _3-11 cycloalkylene group, a C _6-10 arylene group (the C _6-10 arylene group is unsubstituted or substituted with a methoxy group) or a 5- to 10-membered heteroarylene group. Means
Z ¹ is
Formula (III-1), (III-2) or (III-3)

（式中、Ｒ^１とＲ^３は、
Ｒ^１が、Ｃ_１−６アルキル基（該Ｃ_１−６アルキル基は、４〜７員含酸素ヘテロシクロアルキル基、Ｃ_６−１０アリール基、５〜１０員ヘテロアリール基（該Ｃ_６−１０アリール基及び５〜１０員ヘテロアリール基は、４〜７員含酸素ヘテロシクロアルカンと縮環していても良く、且つ該Ｃ_６−１０アリール基及び５〜１０員ヘテロアリール基は無置換であるか又はＣ_４−６アルキル基、ハロゲン原子、シアノ基、Ｃ_１−３アルキル基（該Ｃ_１−３アルキル基は無置換であるか又は一つ以上のフッ素原子によって置換されている。）及び−Ｏ（Ｃ_１−３アルキル）からなる群より独立して選ばれる１つ以上の置換基によって置換されている。）又は−ＮＨＣ（＝Ｏ）Ｏ（Ｃ_１−６アルキル）の何れかで置換されており、且つ該Ｃ_１−６アルキル基は水酸基、ハロゲン原子及びシアノ基からなる群より独立して選ばれる１つ以上の置換基で置換されていても良い。）を意味し、Ｒ^３が水素原子を意味するか、
Ｒ^１が、４〜１１員含窒素ヘテロシクロアルキル基（該４〜１１員含窒素ヘテロシクロアルキル基は、Ｃ_１−３アルキル基（該Ｃ_１−３アルキル基はフェニル基（該フェニル基は無置換であるか又は−Ｃ（＝Ｏ）ＯＣＨ_３、シアノ基、ニトロ基、−ＳＣＨ_３、−ＯＣＦ_３、−ＯＣＨ_３、塩素原子、−ＣＦ_３及び−ＣＨ_３からなる群より独立して選ばれる１つ以上の置換基によって置換されている。）又はシアノ基の何れかで置換されている。）又は−Ｃ（＝Ｏ）Ｏ（Ｃ_１−６アルキル）の何れかで置換されている。）を意味し、Ｒ^３が水素原子を意味するか、又は、
Ｒ^１とＲ^３が、それらが結合している窒素原子と一緒になって４〜１１員含窒素ヘテロシクロアルキル基（該４〜１１員含窒素ヘテロシクロアルキル基は、Ｃ_１−６アルキル基、フェニル基、５−１０員ヘテロアリール基（該フェニル基及び５−１０員ヘテロアリール基は、無置換であるか、又はＣ_１−３アルキル基（該Ｃ_１−３アルキル基は無置換であるか又は一つ以上のフッ素原子により置換されている。）、ハロゲン原子及びシアノ基からなる群より独立して選ばれる一つ以上の置換基によって置換されている。）、−Ｃ（＝Ｏ）ＯＲ^１３、−Ｃ（＝Ｏ）Ｒ^１３、−ＯＲ^１３、−ＮＲ^１２Ｒ^１３、ハロゲン原子及びシアノ基からなる群より独立して選ばれる１つ以上の置換基によって置換されている。）を意味し、Ｒ^１２が、水素原子を意味し、Ｒ^１３が、Ｃ_６−１０アリール基又は５〜１０員ヘテロアリール基（該Ｃ_６−１０アリール基及び５〜１０員ヘテロアリール基は、無置換であるか又はＣ_１−３アルキル基（該Ｃ_１−３アルキル基は一つ以上のフッ素原子により置換されている。）、Ｃ_１−６アルキル基、ハロゲン原子及びシアノ基からなる群より独立して選ばれる一つ以上の置換基によって置換されている。）の何れかを意味し、
Ｇ^１が、単結合又は酸素原子を意味する。）を意味し、
ｍは、１を意味し、
Ｒ^６は、水素原子を意味し、
ｎは、０を意味し、
Ｔは、式（ＶＩ−１）又は（ＶＩ−２）

(Wherein R ¹ and R ³ are
R ¹ is a C _1-6 alkyl group (the C _1-6 alkyl group is a 4-7 membered oxygen-containing heterocycloalkyl group, a C _6-10 aryl group, a 5-10 membered heteroaryl group (the C _{6-6 The 10} aryl group and the 5-10 membered heteroaryl group may be condensed with a 4-7 membered oxygen-containing heterocycloalkane, and the C _6-10 aryl group and the 5-10 membered heteroaryl group are unsubstituted. Or a C _4-6 alkyl group, a halogen atom, a cyano group, a C _1-3 alkyl group (the C _1-3 alkyl group is unsubstituted or substituted by one or more fluorine atoms. ) And —O (C _1-3 alkyl) are substituted by one or more substituents independently selected from the group consisting of :) or —NHC (═O) O (C _1-6 alkyl) It is substituted with one, and the C _1- Alkyl group means a hydroxyl group, with one or more substituents independently selected from the group consisting of a halogen atom and a cyano group may be substituted.), R ³ means a hydrogen atom or,
R ¹ is a 4- to 11-membered nitrogen-containing heterocycloalkyl group (the 4- to 11-membered nitrogen-containing heterocycloalkyl group is a C _1-3 alkyl group (the C _1-3 alkyl group is a phenyl group (the phenyl group is Is unsubstituted or independently of the group consisting of —C (═O) OCH ₃ , cyano group, nitro group, —SCH ₃ , —OCF ₃ , —OCH ₃ , chlorine atom, —CF ₃ and —CH _3. Substituted with one or more selected substituents)) or substituted with either a cyano group) or substituted with either —C (═O) O (C _1-6 alkyl). R ³ represents a hydrogen atom, or
R ¹ and R ³ , together with the nitrogen atom to which they are attached, are a 4-11 membered nitrogen-containing heterocycloalkyl group (the 4-11 membered nitrogen-containing heterocycloalkyl group is a C _1-6 alkyl group). , Phenyl group, 5-10 membered heteroaryl group (the phenyl group and 5-10 membered heteroaryl group are unsubstituted or C _1-3 alkyl group (the C _1-3 alkyl group is unsubstituted) Or substituted by one or more substituents independently selected from the group consisting of halogen atoms and cyano groups), -C (= O And substituted with one or more substituents independently selected from the group consisting of OR ¹³ , —C (═O) R ¹³ , —OR ¹³ , —NR ¹² R ¹³ , a halogen atom and a cyano group. And R ¹² is Represents a hydrogen atom, and R ¹³ represents a C _6-10 aryl group or a 5- to 10-membered heteroaryl group (the C _6-10 aryl group and 5- to 10-membered heteroaryl group are unsubstituted or C _{A 1-3} alkyl group (the C _1-3 alkyl group is substituted with one or more fluorine atoms), a C _1-6 alkyl group, a halogen atom, and a cyano group; Substituted with one or more substituents)
G ¹ means a single bond or an oxygen atom. )
m means 1;
R ⁶ represents a hydrogen atom,
n means 0,
T represents the formula (VI-1) or (VI-2)

（式中、Ｌ^４はＣ_１−３アルキレン基を意味し、Ｌ^５は単結合を意味し、Ｒ^８はフェニル基又はピリジル基（該フェニル基及びピリジル基は、無置換であるか又はＣ_１−６アルキル基、フッ素原子、Ｃ_１−３アルキル基（該Ｃ_１−３アルキル基は１つ以上のフッ素原子によって置換されている。）及びシアノ基からなる群より独立して選ばれる１つ以上の置換基によって置換されている。）を意味し、Ｒ^１０はフェニル基、ピリジル基（該フェニル基及びピリジル基は、無置換であるか又はＣ_１−６アルキル基、フッ素原子、Ｃ_１−３アルキル基（該Ｃ_１−３アルキル基は１つ以上のフッ素原子によって置換されている。）及びシアノ基からなる群より独立して選ばれる１つ以上の置換基によって置換されている。）又はＣ_６−１０アリールと縮環しているＣ_３−１１シクロアルキル基を意味する。）を意味する。］
で表されるスピロ化合物。
（２）Ｌ^１が、Ｃ_１−３アルキレン基である前記（１）に記載のスピロ化合物。
（３）Ｌ^１がメチレン基である前記（１）に記載のスピロ化合物。
（４）Ｌ^２が単結合又はメチレン基である前記（１）乃至（３）の何れか１項に記載のスピロ化合物。
（５）Ｌ^２が単結合である前記（１）乃至（３）の何れか１項に記載のスピロ化合物。
（６）Ｘがシクロヘキサンジイル基である前記（１）乃至（５）の何れか１項に記載のスピロ化合物。
（７）Ｘがシクロヘキサン−１，４−ジイル基である前記（１）乃至（５）の何れか１項に記載のスピロ化合物。
（８）Ｘがピリジンジイル基である前記（１）乃至（５）の何れか１項に記載のスピロ化合物。
（９）Ｘがチオフェンジイル基である前記（１）乃至（５）の何れか１項に記載のスピロ化合物。
（１０）Ｘがフェニレン基である前記（１）乃至（５）の何れか１項に記載のスピロ化合物。
（１１）Ｒ^６が水素原子又はメチル基である前記（１）乃至（１０）の何れか１項に記載のスピロ化合物。
（１２）Ｒ^６が水素原子である前記（１）乃至（１０）の何れか１項に記載のスピロ化合物。
（１３）Ｔが、以下に示す構造の何れかである、前記（１）乃至（１２）の何れか１項に記載のスピロ化合物。

(In the formula, L ⁴ represents a C _1-3 alkylene group, L ⁵ represents a single bond, R ⁸ represents a phenyl group or a pyridyl group (the phenyl group and the pyridyl group are unsubstituted or C 1 independently selected from the group consisting of a _1-6 alkyl group, a fluorine atom, a C _1-3 alkyl group (the C _1-3 alkyl group is substituted by one or more fluorine atoms) and a cyano group. R ¹⁰ is a phenyl group or a pyridyl group (the phenyl group and the pyridyl group are unsubstituted or a C _1-6 alkyl group, a fluorine atom, a C atom). _1-3 alkyl group (the C _1-3 alkyl group is substituted with one or more fluorine atoms) and one or more substituents independently selected from the group consisting of cyano groups .) or _{C 6-10} Means a C _3-11 cycloalkyl group which is fused with the reel.) Means. ]
A spiro compound represented by:
(2) The spiro compound according to (1), wherein L ¹ is a C _1-3 alkylene group.
(3) The spiro compound according to (1), wherein L ¹ is a methylene group.
(4) The spiro compound according to any one of (1) to (3), wherein L ² is a single bond or a methylene group.
(5) The spiro compound according to any one of (1) to (3), wherein L ² is a single bond.
(6) The spiro compound according to any one of (1) to (5), wherein X is a cyclohexanediyl group.
(7) The spiro compound according to any one of (1) to (5), wherein X is a cyclohexane-1,4-diyl group.
(8) The spiro compound according to any one of (1) to (5), wherein X is a pyridinediyl group.
(9) The spiro compound according to any one of (1) to (5), wherein X is a thiophenediyl group.
(10) The spiro compound according to any one of (1) to (5), wherein X is a phenylene group.
(11) The spiro compound according to any one of (1) to (10), wherein R ⁶ is a hydrogen atom or a methyl group.
(12) The spiro compound according to any one of (1) to (10), wherein R ⁶ is a hydrogen atom.
(13) The spiro compound according to any one of (1) to (12), wherein T is any one of the structures shown below.

（１４） Ｚ^１が、式（ＩＩＩ−１）、（ＩＩＩ−２）又は（ＩＩＩ−３）

(14) Z ¹ is represented by formula (III-1), (III-2) or (III-3)

（式中、Ｒ^１とＲ^３は、
Ｒ^１が、Ｃ_１−６アルキル基（該Ｃ_１−６アルキル基は、４〜７員含酸素ヘテロシクロアルキル基又は−ＮＨＣ（＝Ｏ）Ｏ（Ｃ_１−６アルキル）で置換されている。）を意味し、Ｒ^３が水素原子を意味し、Ｇ^１が単結合又は酸素原子を意味する。）である前記（１）乃至（１３）の何れか１項に記載のスピロ化合物。
（１５）Ｚ^１が、以下に示す構造の何れかである、前記（１４）に記載のスピロ化合物。

(Wherein R ¹ and R ³ are
R ¹ is substituted with a C _1-6 alkyl group (the C _1-6 alkyl group is a 4- to 7-membered oxygen-containing heterocycloalkyl group or —NHC (═O) O (C _1-6 alkyl)). .), R ³ represents a hydrogen atom, and G ¹ represents a single bond or an oxygen atom. The spiro compound according to any one of (1) to (13), wherein
(15) The spiro compound according to (14), wherein Z ¹ is any of the structures shown below.

（１６）Ｚ^１が、式（ＩＩＩ−１）、（ＩＩＩ−２）又は（ＩＩＩ−３）

(16) Z ¹ is represented by formula (III-1), (III-2) or (III-3)

（式中、Ｒ^１とＲ^３は、
Ｒ^１が、５〜７員含窒素ヘテロシクロアルキル基（該５〜７員含窒素ヘテロシクロアルキル基は、Ｃ_１−３アルキル基（該Ｃ_１−３アルキル基はフェニル基（該フェニル基は無置換であるか又は−Ｃ（＝Ｏ）ＯＣＨ_３、シアノ基、ニトロ基、−ＳＣＨ_３、−ＯＣＦ_３、−ＯＣＨ_３、塩素原子、−ＣＦ_３及び−ＣＨ_３からなる群より独立して選ばれる１つ以上の置換基によって置換されている。）で置換されている。）で置換されている。）を意味し、Ｒ^３が水素原子を意味し、Ｇ^１が単結合又は酸素原子を意味する。)である、前記（１）乃至（１３）の何れか１項に記載のスピロ化合物。
（１７）５〜７員含窒素ヘテロシクロアルキル基がピペリジル基、ピペラジニル基、ホモピペリジル基又はホモピペラジニル基である前記（１６）に記載のスピロ化合物。
（１８）Ｚ^１が、以下に示す構造の何れかである、前記（１６）に記載のスピロ化合物。

(Wherein R ¹ and R ³ are
R ¹ is a 5- to 7-membered nitrogen-containing heterocycloalkyl group (the 5- to 7-membered nitrogen-containing heterocycloalkyl group is a C _1-3 alkyl group (the C _1-3 alkyl group is a phenyl group (the phenyl group is Is unsubstituted or independently of the group consisting of —C (═O) OCH ₃ , cyano group, nitro group, —SCH ₃ , —OCF ₃ , —OCH ₃ , chlorine atom, —CF ₃ and —CH _3. Substituted with one or more selected substituents)), substituted with), R ³ represents a hydrogen atom, and G ¹ represents a single bond or an oxygen atom. Means. The spiro compound according to any one of (1) to (13), wherein
(17) The spiro compound according to (16), wherein the 5- to 7-membered nitrogen-containing heterocycloalkyl group is a piperidyl group, piperazinyl group, homopiperidyl group, or homopiperazinyl group.
(18) The spiro compound according to (16), wherein Z ¹ is any of the structures shown below.

（１９）Ｚ^１が、式（ＩＩＩ−１）又は（ＩＩＩ−２）

(19) Z ¹ is represented by formula (III-1) or (III-2)

（式中、Ｒ^１とＲ^３は、
Ｒ^１とＲ^３が、それらが結合している窒素原子と一緒になってアゼチジニル基又は５〜７員含窒素ヘテロシクロアルキル基（該アゼチジニル基及び５〜７員含窒素ヘテロシクロアルキル基は、Ｃ_１−６アルキル基、フェニル基、５−１０員ヘテロアリール基（該フェニル基及び５−１０員ヘテロアリール基は、無置換であるか、又はＣ_１−３アルキル基（該Ｃ_１−３アルキル基は無置換であるか又は一つ以上のフッ素原子により置換されている。）、ハロゲン原子及びシアノ基からなる群より独立して選ばれる一つ以上の置換基によって置換されている。）、−Ｃ（＝Ｏ）ＯＲ^１３、−Ｃ（＝Ｏ）Ｒ^１３、−ＯＲ^１３、−ＮＲ^１２Ｒ^１３、ハロゲン原子及びシアノ基からなる群より独立して選ばれる１つ以上の置換基によって置換されている。）を意味し、Ｒ^１２が、水素原子を意味し、Ｒ^１３が、Ｃ_１−３アルキル基（該Ｃ_１−３アルキル基は無置換であるか又は一つ以上のフッ素原子により置換されている。）、Ｃ_６−１０アリール基又は５〜１０員ヘテロアリール基（該Ｃ_６−１０アリール基及び５〜１０員ヘテロアリール基は、無置換であるか又はＣ_１−３アルキル基（該Ｃ_１−３アルキル基は一つ以上のフッ素原子により置換されている。）、Ｃ_１−６アルキル基、ハロゲン原子及びシアノ基からなる群より独立して選ばれる一つ以上の置換基によって置換されている。）の何れかを意味する。）の何れかである、前記（１）乃至（１３）の何れか１項に記載のスピロ化合物。
（２０）５〜７員含窒素ヘテロシクロアルキル基がピロリジニル基、ピペリジル基、ピペラジニル基、ホモピペリジル基又はホモピペラジニル基である前記（１９）に記載のスピロ化合物。
（２１）Ｚ^１が、以下に示す構造の何れかである、前記（１９）記載のスピロ化合物。

(Wherein R ¹ and R ³ are
R ¹ and R ³ together with the nitrogen atom to which they are bonded are an azetidinyl group or a 5- to 7-membered nitrogen-containing heterocycloalkyl group (the azetidinyl group and a 5- to 7-membered nitrogen-containing heterocycloalkyl group are A C _1-6 alkyl group, a phenyl group, a 5-10-membered heteroaryl group (the phenyl group and the 5-10-membered heteroaryl group are unsubstituted or a C _1-3 alkyl group (the C _1-3 The alkyl group is unsubstituted or substituted by one or more fluorine atoms), and is substituted by one or more substituents independently selected from the group consisting of halogen atoms and cyano groups. -C (= O) OR ¹³ , -C (= O) R ¹³ , -OR ¹³ , -NR ¹² R ¹³ , one or more substituents independently selected from the group consisting of halogen atoms and cyano groups Replace Is.) ^{Means, R 12} is, represents a hydrogen ^{atom, R 13} _{is C 1-3} alkyl group (the _{C 1-3} alkyl group is either unsubstituted or one or more fluorine atoms A C _6-10 aryl group or a 5-10 membered heteroaryl group (the C _6-10 aryl group and 5-10 membered heteroaryl group are unsubstituted or C _1-3). One or more independently selected from the group consisting of an alkyl group (the C _1-3 alkyl group is substituted by one or more fluorine atoms), a C _1-6 alkyl group, a halogen atom and a cyano group; It is substituted by a substituent. The spiro compound according to any one of (1) to (13), which is any one of
(20) The spiro compound according to (19), wherein the 5- to 7-membered nitrogen-containing heterocycloalkyl group is a pyrrolidinyl group, piperidyl group, piperazinyl group, homopiperidyl group or homopiperazinyl group.
(21) The spiro compound according to (19), wherein Z ¹ is any of the structures shown below.

（２２）Ｚ^１が、式（ＩＩＩ−１）又は（ＩＩＩ−２）

(22) Z ¹ is represented by formula (III-1) or (III-2)

（式中、Ｒ^１とＲ^３は、
Ｒ^１が、Ｃ_１−６アルキル基（該Ｃ_１−６アルキル基は、Ｃ_６−１０アリール基又は５〜１０員ヘテロアリール基（該Ｃ_６−１０アリール基及び５〜１０員ヘテロアリール基は、４〜７員含酸素ヘテロシクロアルカンと縮環していても良く、且つ該Ｃ_６−１０アリール基及び５〜１０員ヘテロアリール基は無置換であるか又はＣ_４−６アルキル基、ハロゲン原子、シアノ基、Ｃ_１−３アルキル基（該Ｃ_１−３アルキル基は無置換であるか又は一つ以上のフッ素原子によって置換されている。）及び−Ｏ（Ｃ_１−３アルキル）からなる群より独立して選ばれる１つ以上の置換基によって置換されている。）で置換されており、且つ該Ｃ_１−６アルキル基は、水酸基、ハロゲン原子及びシアノ基からなる群より独立して選ばれる１つ以上の置換基で置換されていても良い。）を意味し、Ｒ^３が水素原子を意味する。）である、前記（１）乃至（１３）の何れか１項に記載のスピロ化合物。
（２３）Ｒ^１が、Ｃ_１−３アルキル基（該Ｃ_１−３アルキル基は、フェニル基、ピリジル基、フリル基又はイソオキサゾリル基（該フェニル基、ピリジル基、フリル基及びイソオキサゾリル基は、４〜７員含酸素ヘテロシクロアルカンと縮環していても良く、且つ該フェニル基、ピリジル基、フリル基及びイソオキサゾリル基は無置換であるか又はＣ_４−６アルキル基、ハロゲン原子、シアノ基、Ｃ_１−３アルキル基（該Ｃ_１−３アルキル基は無置換であるか又は一つ以上のフッ素原子によって置換されている。）及び−Ｏ（Ｃ_１−３アルキル）からなる群より独立して選ばれる１つ以上の置換基によって置換されている。）の何れかにより置換されており、且つ該Ｃ_１−３アルキル基は、水酸基、ハロゲン原子及びシアノ基からなる群より独立して選ばれる１つ以上の置換基で置換されていても良い。）である、前記（２２）記載のスピロ化合物。
（２４）Ｚ^１が、以下に示す構造の何れかである、前記（２２）記載のスピロ化合物。

(Wherein R ¹ and R ³ are
R ¹ is a C _1-6 alkyl group (the C _1-6 alkyl group is a C _6-10 aryl group or a 5-10 membered heteroaryl group (the C _6-10 aryl group and a 5-10 membered heteroaryl group). May be condensed with a 4-7 membered oxygen-containing heterocycloalkane, and the C _6-10 aryl group and the 5-10 membered heteroaryl group are unsubstituted or a C _4-6 alkyl group, A halogen atom, a cyano group, a C _1-3 alkyl group (the C _1-3 alkyl group is unsubstituted or substituted by one or more fluorine atoms) and —O (C _1-3 alkyl) Substituted with one or more substituents independently selected from the group consisting of: and the C _1-6 alkyl group is independent of the group consisting of a hydroxyl group, a halogen atom and a cyano group. One or more selected May be substituted with a substituent.) Means, R ³ means a hydrogen atom. The spiro compound according to any one of (1) to (13), wherein
(23) R ¹ is a C _1-3 alkyl group (the C _1-3 alkyl group is a phenyl group, a pyridyl group, a furyl group, or an isoxazolyl group (the phenyl group, the pyridyl group, the furyl group, and the isoxazolyl group are 4 May be condensed with a 7-membered oxygen-containing heterocycloalkane, and the phenyl group, pyridyl group, furyl group and isoxazolyl group are unsubstituted or a C _4-6 alkyl group, a halogen atom, a cyano group, Independently from the group consisting of C _1-3 alkyl groups (wherein the C _1-3 alkyl groups are unsubstituted or substituted by one or more fluorine atoms) and —O (C _1-3 alkyl). is substituted by one or more substituents selected Te. which is substituted by one of), and the C _1-3 alkyl group, comprising a hydroxyl group, a halogen atom, and a cyano group May be substituted with one or more substituents selected more independently.) Is the (22) spiro compound as claimed.
(24) The spiro compound according to the above (22), wherein Z ¹ is any one of the structures shown below.

（２５）Ｚ^１が、式（ＩＩＩ−１）又は（ＩＩＩ−２）

(25) Z ¹ is represented by formula (III-1) or (III-2)

（式中、Ｒ^１とＲ^３は、
Ｒ^１が、４−１１員含窒素ヘテロシクロアルキル基（該４−１１員含窒素ヘテロシクロアルキル基は−Ｃ（＝Ｏ）Ｏ（Ｃ_１−６アルキル）によって置換されている。）を意味し、Ｒ^３が水素原子を意味する。）である、前記（１）乃至（１３）の何れか１項に記載のスピロ化合物。
（２６）４−１１員含窒素ヘテロシクロアルキル基がアゼチジニル基、ピロリジニル基、ピペリジル基、ピペラジニル基、ホモピペリジル基又はホモピペラジニル基である前記（２５）記載のスピロ化合物。
（２７）Ｚ^１が、以下に示す構造の何れかである、前記（２５）記載のスピロ化合物。

(Wherein R ¹ and R ³ are
R ¹ represents a 4-11 membered nitrogen-containing heterocycloalkyl group (the 4-11 membered nitrogen-containing heterocycloalkyl group is substituted by —C (═O) O (C _1-6 alkyl)). R ³ represents a hydrogen atom. The spiro compound according to any one of (1) to (13), wherein
(26) The spiro compound according to the above (25), wherein the 4-11 membered nitrogen-containing heterocycloalkyl group is an azetidinyl group, a pyrrolidinyl group, a piperidyl group, a piperazinyl group, a homopiperidyl group or a homopiperazinyl group.
(27) The spiro compound according to (25), wherein Z ¹ is any one of the structures shown below.

  In the present invention, the compound represented by the formula (I) of the present invention exists, for example, via the tautomerism and geometric isomerism, both inside and outside the ring, in addition to a mixture thereof, It also exists as a mixture of isomers. Further, when an asymmetric center is present, or when an asymmetric center is formed as a result of isomerization, it includes the presence of each optical isomer and a mixture in any ratio. In addition, in the case of a compound having two or more asymmetric centers, diastereomers by respective optical isomerism also exist. The compounds of the present invention also include those containing all these types in any proportion. For example, diastereomers can be separated by methods well known to those skilled in the art, such as fractional crystallization, and optically active forms can be obtained by organic chemistry techniques well known for this purpose. it can.

  The compound represented by the formula (I) of the present invention or a pharmaceutically acceptable salt thereof can exist as any crystal form depending on the production conditions, and can exist as any hydrate. Forms and hydrates and mixtures thereof are also included within the scope of the present invention. Moreover, although it may exist as a solvate containing organic solvents, such as acetone, ethanol, and tetrahydrofuran, all of these forms are contained in the scope of the present invention.

  The compound represented by the formula (I) of the present invention can be converted into a pharmaceutically acceptable salt or released from the formed salt, if necessary. Examples of the pharmaceutically acceptable salt of the present invention include salts with alkali metals (lithium, sodium, potassium, etc.), alkaline earth metals (magnesium, calcium, etc.), ammonium, organic bases and amino acids. It is done. In addition, inorganic acids (hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, etc.) and organic acids (acetic acid, citric acid, maleic acid, fumaric acid, tartaric acid, benzenesulfonic acid, methanesulfonic acid, p-toluenesulfonic acid, etc.) Other salts are also possible.

  The prophylactic / therapeutic / ameliorating agent for “disease with an effective adiponectin receptor activation effect” containing the “adiponectin receptor activator” of the present invention as an active ingredient is usually a tablet, capsule, powder, granule, It can be administered as an oral administration agent such as a pill or syrup, a rectal administration agent, a transdermal absorption agent or an injection. The agent can be administered as a single therapeutic agent or as a mixture with other therapeutic agents. They may be administered alone, but are generally administered in the form of a pharmaceutical composition. These preparations can be produced by a conventional method with addition of pharmacologically and pharmaceutically acceptable additives. That is, additives such as ordinary excipients, lubricants, binders, disintegrants, wetting agents, plasticizers, and coating agents can be used for oral preparations. Oral solutions may be in the form of aqueous or oily suspensions, solutions, emulsions, syrups, elixirs, etc., or provided as dry syrups prepared with water or other suitable solvent prior to use. Good. The liquid preparation may contain conventional additives such as suspending agents, fragrances, diluents or emulsifiers. When administered rectally, it can be administered as a suppository. Suppositories are based on suitable substances such as cacao butter, lauric fat, macrogol, glycerogelatin, witepsol, sodium stearate or mixtures thereof, and emulsifiers, suspending agents, preservatives, etc. as necessary Can be added. Injections include aqueous or injectable distilled water, physiological saline, 5% glucose solution, propylene glycol and other solubilizers or solubilizers, pH adjusters, isotonic agents, Pharmaceutical ingredients such as stabilizers are used.

  When the drug of the present invention is administered to humans, the dosage is determined depending on the age and condition of the patient. In general, in the case of an adult, 0.1 to 1000 mg / human / day for oral administration or rectal administration is injected. The dosage is about 0.05 mg to 500 mg / human / day. These numerical values are merely examples, and the dosage is determined according to the symptoms of the patient.

  The scene where the present invention is used includes a scene where improvement of a disease state can be expected by using a compound having an adiponectin receptor activating action. Specifically, prevention and treatment of metabolic syndrome, particularly metabolic syndrome with obesity, diabetes, hypertension, etc., and arteriosclerosis; prevention and treatment of cardiovascular diseases such as myocardial infarction and myocardial hypertrophy; non-alcoholic fatty Prevention and treatment of liver diseases such as hepatitis and liver fibrosis; prevention and treatment of malignant tumors such as gastric cancer, rectal cancer, breast cancer and myeloblastic leukemia; other systemic lupus erythematosus due to anti-inflammatory action, renal failure, A scene of performing prevention / treatment of acute lung injury is assumed, but is not limited thereto.

  The compound of the present invention can be synthesized by the method shown below, but the following production method is an example of a general production method and does not limit the production method.

  The compound of the present invention can usually be purified by column chromatography, thin layer chromatography, high performance liquid chromatography (HPLC), etc., and if necessary, it has a high purity by recrystallization or washing with a solvent. Can be obtained.

Examples of the base in the description of the general production method of the compound of the present invention include sodium acetate, potassium acetate, sodium bicarbonate, sodium carbonate, potassium carbonate, cesium carbonate, potassium hydroxide, sodium hydroxide, potassium t-butoxide, Alkali metal salts such as sodium t-butoxide, sodium amide, sodium hydride, lithium hydride, lithium diisopropylamide, lithium bis (trimethylsilyl) amide, n-butyllithium, pyridine, triethylamine, diisopropylethylamine, N-methylmorpholine, Examples include amines such as N-methylpiperidine and bis (trimethylsilyl) amine.
The solvent in the description of the general production method of the compound of the present invention is not particularly limited as long as it is stable under the reaction conditions and is inert and does not hinder the reaction. For example, a sulfoxide solvent represented by dimethyl sulfoxide; an amide solvent represented by N, N-dimethylformamide or N, N-dimethylacetamide; diethyl ether, dimethoxyethane, tetrahydrofuran, 1,4-dioxane or cyclopentyl methyl ether Ether solvents typified by: halogen solvents typified by dichloromethane, chloroform or 1,2-dichloroethane; nitrile solvents typified by acetonitrile or propionitrile; aromatic hydrocarbon systems typified by benzene or toluene Solvent; hydrocarbon solvent represented by n-hexane, n-heptane or cyclohexane; ester solvent represented by ethyl acetate or n-butyl acetate; methanol, ethanol, 1-propanol, Alcohol solvents represented by 2-propanol or ethylene glycol; or water. In addition, the reaction can be carried out under conditions where the above-mentioned solvents are arbitrarily mixed or without solvent.

  The reaction temperature in the general production method of the compound of the present invention can be selected from −78 ° C. within the range of the boiling point of the solvent used in the reaction. It can be carried out under irradiation or the like.

  In the general method for producing the compound of the present invention shown below, general formulas of intermediates and final products in each step are shown, and these intermediates and final products also include their precursors. Here, a precursor means a compound that can be derived into a target product by performing deprotection, hydrolysis, reduction, oxidation, alkylation, etc., if necessary. Protected with various protecting groups. Protection and deprotection are generally known protection reactions / deprotection reactions [eg, Protective Groups in Organic Synthesis, Fourth Edition, Green (TWGreene ), John Wiley & Sons Inc. (2006), etc.].

  Among the compounds included in the compound (I) according to the present invention, the compound represented by the formula (I-1) can be produced, for example, by the following method.

[式中、Ｐ^１はアミノ基の保護基を示し、Ｐ^２はカルボキシル基の保護基を示し、Ｖ^１ａ、Ｖ^１ｂおよびＶ^２はそれぞれ独立して脱離基を示し、その他の記号は前記定義に同じである。]

[Wherein P ¹ represents an amino-protecting group, P ² represents a carboxyl-protecting group, V ^1a , V ^1b and V ² each independently represent a leaving group, Same as definition. ]

(Step 1) This step is a so-called Corey-Chaykovsky reaction in which the compound (2) is produced by converting the carbonyl group of the compound (1) into an epoxide by reaction with sulfur ylide. . The compound (1) used in this step can be obtained as a compound synthesized by using various organic synthesis methods known to those skilled in the art from commercially available compounds, known compounds, or readily available compounds.
The reaction in this step is performed by reacting a sulfur ylide generated by reacting a base with a sulfonium ion such as trimethylsulfonium iodide or a sulfoxonium ion such as trimethylsulfoxonium iodide and the compound (1). Can be done. The amount of trimethylsulfonium iodide, trimethylsulfoxonium iodide, etc. used in this step is usually 1 to 5 equivalents, preferably 1 to 3 equivalents, relative to 1 equivalent of compound (1).
Examples of the base used in this step include sodium hydroxide, potassium hydroxide, sodium hydride, lithium hexamethyldisilazide and the like, preferably sodium hydroxide. The amount of the base is usually 1 to 10 equivalents, preferably 1 to 5 equivalents, relative to 1 equivalent of compound (1).
The reaction solvent is not particularly limited as long as it does not hinder the reaction, and examples thereof include tetrahydrofuran, acetonitrile, methanol, ethanol, tert-butanol, water, dimethyl sulfoxide, N, N-dimethylformamide, and the like. Methanol, acetonitrile, water.
The reaction temperature is usually 0 ° C. to the reflux temperature of the reaction solvent, preferably 0 to 30 ° C.
The reaction time is usually 0.1 to 240 hours, preferably 0.1 to 120 hours.

(Step 2) This step is a method for producing an amino alcohol compound (4) by reacting the epoxide moiety of the compound (2) obtained in the step 1 with the amino group of the compound (3). The compound (3) used in this step can be obtained as a compound synthesized by using various organic synthesis methods known to those skilled in the art from commercially available compounds, known compounds, or readily available compounds.
The reaction solvent is not particularly limited as long as it does not hinder the reaction, and examples thereof include tetrahydrofuran, 1,4-dioxane, methanol, ethanol, water, and the like, preferably methanol and water.
The reaction temperature is usually 0 ° C. to the reflux temperature of the reaction solvent, preferably 0 to 30 ° C.
The reaction time is usually 0.1 to 240 hours, preferably 0.1 to 120 hours.

(Step 3) In this step, compound (6) is produced by reacting compound (4) obtained in step 2 above with the carbonylating agent or thiocarbonylating agent represented by compound (5). It is a method to do. Examples of the compound (5) used include 1,1′-carbonyldiimidazole, p-nitrophenyl chloroformate, 1,1′-thiocarbonyldiimidazole, triphosgene, thiophosgene, and preferably 1,1′-carbonyl. Carbonyldiimidazole, p-nitrophenyl chloroformate, 1,1′-thiocarbonyldiimidazole. The amount of the compound (5) is usually 1 to 20 equivalents, preferably 1 to 6 equivalents, relative to 1 equivalent of the compound (4).
The reaction solvent is not particularly limited as long as it does not interfere with the reaction, and examples thereof include tetrahydrofuran, 1,4-dioxane, dichloromethane, chloroform and the like, and preferably 1,4-dioxane and chloroform.
The reaction temperature is usually 0 ° C. to the reflux temperature of the reaction solvent, preferably 0 to 120 ° C.
The reaction time is usually 0.1 to 100 hours, preferably 0.1 to 72 hours.

(Step 4) This step is a method for producing the compound (7) by hydrolyzing the ester group of the compound (6) obtained in the step 3 with a base.
Examples of the base used in this step include sodium hydroxide and potassium hydroxide. The amount of the base is usually 1 to 100 equivalents, preferably 1 to 10 equivalents, relative to 1 equivalent of compound (6).
The reaction solvent is not particularly limited as long as it does not hinder the reaction, and examples thereof include methanol, ethanol, tetrahydrofuran, 1,4-dioxane, N, N-dimethylformamide, and preferably methanol.
The reaction temperature is usually 0 ° C. to the reflux temperature of the reaction solvent, preferably 0 to 180 ° C.
The reaction time is usually 0.1 to 240 hours, preferably 0.1 to 24 hours.

(Step 5) In this step, compound (9) is produced by reacting the carboxyl group of compound (7) obtained in step 4 with the amine moiety of compound (8) to produce an amide bond. Is the method. The compound (8) used in this step can be obtained as a compound synthesized by using various organic synthesis techniques known to those skilled in the art from commercially available compounds, known compounds, or readily available compounds. The amide bond forming reaction in this step is performed using a carboxylic acid represented by compound (7) or a reactive derivative thereof. Examples of the reactive derivative of the compound (7) include mixed acid anhydrides, active esters, active amides, acid halides and the like.・ Transformations 2nd Edition (Comprehensive Organic Transformations, Second Edition), by Richard C. Larock, John Wiley & Sons Inc. (1999) 1941-1949). In the above reaction, when the carboxylic acid represented by the compound (7) is used, for example, 1,1′-carbonyldiimidazole, N, N′-dicyclohexylcarbodiimide, 1-ethyl-3- (3- Dimethylaminopropyl) carbodiimide, diphenylphosphoryl azide, dipyridyl disulfide-triphenylphosphine, O- (7-azabenzotriazol-1-yl) -N, N, N ′, N′-tetramethyluronium hexafluorophosphate, The reaction can be carried out in the presence of a condensing agent such as PyBOP (registered trademark) or PyBroP (registered trademark). The amount of the condensing agent is 1 to 5 equivalents, preferably 1 to 2 equivalents, relative to 1 equivalent of compound (7).
The amount of compound (8) used is 0.5 to 5 equivalents, preferably 1 to 2 equivalents, relative to 1 equivalent of compound (7).
The reaction solvent is not particularly limited as long as it does not hinder the reaction, and examples thereof include dichloromethane, chloroform, acetonitrile, N, N-dimethylformamide, and preferably chloroform.
The reaction temperature is usually 0 ° C. to the reflux temperature of the reaction solvent, preferably 0 to 60 ° C.
The reaction time is usually 0.1 to 240 hours, preferably 0.1 to 100 hours.

(Step 6) This step is a method for producing the compound (10) by removing the amino-protecting group of the compound (9) obtained in the step 5. The reaction in this step is a reaction for removing the protecting group of the amino group, and a method described in the literature [for example, Protective Groups in Organic Synthesis, Fourth Edition, Green, (TWGreene), John Wiley & Sons Inc. (2006), etc.], a method according to it, or a combination of these and conventional methods Can do.

(Step 7) This step is a method for producing compound (I-1) or a precursor thereof by reacting compound (10) obtained in step 6 with compound (11) in the presence of a base. is there. The compound (11) used in this step can be obtained as a compound synthesized from a commercially available compound, a known compound, or an easily available compound using various organic synthesis methods known to those skilled in the art.
Examples of the base used in this step include potassium carbonate, sodium carbonate, cesium carbonate, triethylamine, N, N-diisopropylethylamine, and preferably potassium carbonate. The amount of the base is usually 1 to 10 equivalents, preferably 1 to 3 equivalents, relative to 1 equivalent of compound (10).
The reaction solvent is not particularly limited as long as it does not hinder the reaction, and examples thereof include acetonitrile, tetrahydrofuran, 1,4-dioxane, N, N-dimethylformamide and the like, preferably tetrahydrofuran, N, N-dimethyl. Formamide.
The reaction temperature is usually 0 ° C. to the reflux temperature of the reaction solvent, preferably 0 to 180 ° C.
The reaction time is usually 0.1 to 240 hours, preferably 0.1 to 48 hours.
In the compound (11) used in this step, when the carbon atom to which V ² is bonded is substituted with 1 to ² hydrogen atoms, V ² and one hydrogen atom are combined to form carbonyl. Compound (I-1) can also be produced by reductive amination with a base aldehyde compound or ketone compound.
Examples of the reducing agent used in this step include sodium triacetoxyborohydride, zinc chloride-sodium cyanoborohydride complex, and the like, preferably sodium triacetoxyborohydride. The amount of the reducing agent is usually 1 to 30 equivalents, preferably 1 to 10 equivalents, relative to 1 equivalent of compound (10).
The reaction solvent is not particularly limited as long as it does not hinder the reaction, and examples thereof include chloroform, methanol, ethanol, tetrahydrofuran, 1,4-dioxane, acetic acid, and the like, preferably chloroform and methanol.
The reaction temperature is usually 0 ° C. to the reflux temperature of the reaction solvent, preferably 0 to 30 ° C.
The reaction time is usually 0.1 to 100 hours, preferably 0.1 to 48 hours.

  Moreover, among the compounds included in the compound (I) according to the present invention, the compound represented by the formula (I-2) can be produced, for example, by the following method.

[式中、Ｖ^３は脱離基を示し、その他の記号は前記定義に同じである。]

[Wherein V ³ represents a leaving group, and other symbols are the same as defined above. ]

(Step 8) In this step, compound (I-2) or a precursor thereof is prepared by reacting the amine moiety of compound (10) obtained in step 6 with compound (12) or compound (13). It is a method of manufacturing. The compound (12) or compound (13) used in this step can be obtained as a compound synthesized by using various organic synthesis methods known to those skilled in the art from commercially available compounds, known compounds, or readily available compounds.

  Moreover, among the compounds included in the compound (I) according to the present invention, the compound represented by the formula (I-3) can be produced, for example, by the following method.

[式中、Ｖ^４ａはハロゲン原子またはハロゲン原子等価体を示し、Ｒ^１０ａはＣ_６−１０アリール基、５〜１０員ヘテロアリール基（該Ｃ_６−１０アリール基及び５〜１０員ヘテロアリール基は、無置換であるか又は置換基群Ａ_２より独立して選ばれる１つ以上の置換基によって置換されている。）を示し、その他の記号は前記定義に同じである。]

[Wherein, V ^4a represents a halogen atom or a halogen atom equivalent, and R ^10a represents a C _6-10 aryl group, a 5- to 10-membered heteroaryl group (the C _6-10 aryl group and a 5- to 10-membered heteroaryl group) Is unsubstituted or substituted by one or more substituents independently selected from Substituent Group A _{2. The} other symbols are the same as defined above. ]

(Step 9) In this step, compound (I-3) or a precursor thereof is produced by reacting compound (10) obtained in step 6 with compound (14) in the presence of a transition metal catalyst. This is the so-called Buchwald-Hartwig reaction. The compound (14) used in this step can be obtained as a compound synthesized from a commercially available compound, a known compound, or an easily available compound using various organic synthesis methods known to those skilled in the art. The reaction in this step is carried out according to a method described in the literature (for example, Angew. Chem. Int. Ed., 1998, 37, 2046-2067, Accounts of Chemical Research ( Acc. Chem. Res.), 1998, Vol. 31, pp. 805-818).
Examples of combinations of transition metal catalysts used in this step include palladium acetate and tris (dibenzylideneacetone) palladium as a transition metal complex, and 2,2′-bis (diphenylphosphino) as a ligand. ) -1,1'-binaphthalene and the like. Examples of the base include cesium carbonate, potassium phosphate, sodium tert-butoxide and the like. The amount of the base is usually 1 to 100 equivalents, preferably 1 to 10 equivalents, relative to 1 equivalent of compound (10).
The reaction solvent is not particularly limited as long as it does not hinder the reaction, and examples thereof include toluene, tetrahydrofuran, 1,4-dioxane, N, N-dimethylformamide, N-methylpyrrolidone and the like, preferably toluene, 1,4-dioxane.
The reaction temperature is usually 20 ° C. to the reflux temperature of the reaction solvent, preferably 50 to 180 ° C.
The reaction time is usually 0.1 to 48 hours, preferably 0.1 to 24 hours.

In this step, compound (I-3) can also be produced without using a transition metal catalyst in some cases. In this case, examples of the base used in this step include potassium carbonate, sodium carbonate, cesium carbonate, triethylamine, N, N-diisopropylethylamine, and preferably potassium carbonate. The amount of the base is usually 1 to 10 equivalents, preferably 1 to 3 equivalents, relative to 1 equivalent of compound (10).
The reaction solvent is not particularly limited as long as it does not hinder the reaction, and examples thereof include acetonitrile, tetrahydrofuran, 1,4-dioxane, N, N-dimethylformamide and the like, preferably tetrahydrofuran, N, N-dimethyl. Formamide.
The reaction temperature is usually 0 ° C. to the reflux temperature of the reaction solvent, preferably 0 to 180 ° C.
The reaction time is usually 0.1 to 240 hours, preferably 0.1 to 48 hours.

  Moreover, among the compounds included in the compound (I) according to the present invention, the compound represented by the formula (I-4) can be produced, for example, by the following method.

[式中、Ｖ^４ｂは脱離基を示し、Ｒ^１０ｂは、Ｃ_１−９アルキル基（該Ｃ_１−９アルキル基は、無置換であるか又は置換基群Ａ_４より独立して選ばれる１つ以上の置換基によって置換されている。）、Ｃ_３−１１シクロアルキル基（該Ｃ_３−１１シクロアルキル基は、Ｃ_６−１０アリールもしくは５〜１０員ヘテロアリール（該Ｃ_６−１０アリール及び５〜１０員ヘテロアリールは無置換であるか又は置換基群Ａ_２より独立して選ばれる１つ以上の置換基によって置換されている。）と縮環していても良く、且つ該Ｃ_３−１１シクロアルキル基は、無置換であるか又は置換基群Ａ_２より独立して選ばれる１つ以上の置換基によって置換されている。）、又は、Ｃ_１−３アルキル基（該Ｃ_１−３アルキル基はＣ_３−１１シクロアルキル基（該Ｃ_３−１１シクロアルキル基は、無置換であるか又は置換基群Ａ_２より独立して選ばれる１つ以上の置換基によって置換されている。）で置換されている。）を示し、その他の記号は前記定義に同じである。]

[Wherein, V ^4b represents a leaving group, R ^10b represents a C _1-9 alkyl group (the C _1-9 alkyl group is unsubstituted or independently selected from substituent group A ₄ ) Substituted with one or more substituents), a C _3-11 cycloalkyl group (wherein the C _3-11 cycloalkyl group is C _6-10 aryl or 5-10 membered heteroaryl (the C _6-10 aryl and 5-10 membered heteroaryl is substituted by one or more substituents selected as or independently from substituent group a ₂ unsubstituted.) and may be a condensed ring, and the The C _3-11 cycloalkyl group is unsubstituted or substituted by one or more substituents independently selected from substituent group A ₂ ), or a C _1-3 alkyl group C _1-3 alkyl group is C _3-11 cycloalkyl A group (the C _3-11 cycloalkyl group is unsubstituted or substituted by one or more substituents independently selected from substituent group A ₂ ). The other symbols are the same as defined above. ]

(Step 10) This step is a method for producing compound (I-4) or a precursor thereof by reacting compound (10) obtained in step 6 with compound (15) in the presence of a base. is there.
Examples of the base used in this step include potassium carbonate, sodium carbonate, triethylamine, N, N-diisopropylethylamine, and preferably potassium carbonate. The amount of the base is usually 1 to 10 equivalents, preferably 1 to 3 equivalents, relative to 1 equivalent of compound (10).
The reaction solvent is not particularly limited as long as it does not hinder the reaction, and examples thereof include acetonitrile, tetrahydrofuran, 1,4-dioxane, N, N-dimethylformamide and the like, preferably tetrahydrofuran, N, N-dimethyl. Formamide.
The reaction temperature is usually 0 ° C. to the reflux temperature of the reaction solvent, preferably 0 to 180 ° C.
The reaction time is usually 0.1 to 240 hours, preferably 0.1 to 48 hours.
In the compound (15) used in this step, when the carbon atom to which V ^4b is bonded is substituted with 1 to 2 hydrogen atoms, V ^4b and one hydrogen atom are combined to form carbonyl. Compound (I-4) can also be produced by reductive amination with a base aldehyde compound or ketone compound.
Examples of the reducing agent used in this step include sodium triacetoxyborohydride, zinc chloride-sodium cyanoborohydride complex, 2-picoline borane complex, and preferably sodium triacetoxyborohydride. The amount of the reducing agent is usually 1 to 30 equivalents, preferably 1 to 10 equivalents, relative to 1 equivalent of compound (10).
The reaction solvent is not particularly limited as long as it does not hinder the reaction, and examples thereof include chloroform, methanol, ethanol, tetrahydrofuran, 1,4-dioxane, acetic acid, and the like, preferably chloroform and methanol.
The reaction temperature is usually 0 ° C. to the reflux temperature of the reaction solvent, preferably 0 to 30 ° C.
The reaction time is usually 0.1 to 100 hours, preferably 0.1 to 48 hours.

  The compound represented by the formula (I-1) can also be produced from the compound (6) by the following method.

[式中、記号は前記定義に同じである。]

[Wherein the symbols are as defined above. ]

(Step 11) This step is a method for producing the compound (16) by removing the amino-protecting group of the compound (6) obtained in the step 3. The reaction in this step is a reaction for removing the protecting group of the amino group, and a method described in the literature (for example, Protective Groups in Organic Synthesis, Fourth Edition, Green Edition) (TWGreene), John Wiley & Sons Inc. (2006), etc.), a method according to it, or a combination of these with conventional methods Can do.

(Step 12) This step is a method for producing the compound (17) by reacting the compound (16) obtained in the step 11 with the compound (11) in the presence of a base. The compound (11) used in this step can be obtained as a compound synthesized from a commercially available compound, a known compound, or an easily available compound using various organic synthesis methods known to those skilled in the art.
Examples of the base used in this step include potassium carbonate, sodium carbonate, triethylamine, N, N-diisopropylethylamine, and preferably potassium carbonate. The amount of the base is usually 1 to 10 equivalents, preferably 1 to 3 equivalents, relative to 1 equivalent of compound (16).
The reaction solvent is not particularly limited as long as it does not hinder the reaction, and examples thereof include acetonitrile, tetrahydrofuran, 1,4-dioxane, N, N-dimethylformamide and the like, preferably tetrahydrofuran, N, N-dimethyl. Formamide.
The reaction temperature is usually 0 ° C. to the reflux temperature of the reaction solvent, preferably 0 to 180 ° C.
The reaction time is usually 0.1 to 240 hours, preferably 0.1 to 48 hours.
In the compound (11) used in this step, when the carbon atom to which V ² is bonded is substituted with 1 to ² hydrogen atoms, V ² and one hydrogen atom are combined to form carbonyl. Compound (17) can also be produced by reductive amination with a base aldehyde compound or ketone compound.
Examples of the reducing agent used in this step include sodium triacetoxyborohydride, zinc chloride-sodium cyanoborohydride complex, 2-picoline borane complex, and preferably sodium triacetoxyborohydride. The amount of the reducing agent is usually 1 to 30 equivalents, preferably 1 to 10 equivalents, relative to 1 equivalent of compound (16).
The reaction solvent is not particularly limited as long as it does not hinder the reaction, and examples thereof include chloroform, methanol, ethanol, tetrahydrofuran, 1,4-dioxane, acetic acid, and the like, preferably chloroform and methanol.
The reaction temperature is usually 0 ° C. to the reflux temperature of the reaction solvent, preferably 0 to 30 ° C.
The reaction time is usually 0.1 to 100 hours, preferably 0.1 to 48 hours.

(Step 13) This step is a method for producing the compound (18) by hydrolyzing the ester group of the compound (17) obtained in the step 12 with a base.
Examples of the base used in this step include sodium hydroxide and potassium hydroxide. The amount of the base is usually 1 to 100 equivalents, preferably 1 to 10 equivalents, relative to 1 equivalent of compound (17).
The reaction solvent is not particularly limited as long as it does not hinder the reaction, and examples thereof include methanol, ethanol, tetrahydrofuran, 1,4-dioxane, N, N-dimethylformamide, and preferably methanol.
The reaction temperature is usually 0 ° C. to the reflux temperature of the reaction solvent, preferably 0 to 180 ° C.
The reaction time is usually 0.1 to 240 hours, preferably 0.1 to 24 hours.

(Step 14) In this step, an amide bond is formed by reacting the carboxyl group of compound (18) obtained in Step 13 with the amine moiety of compound (8) to produce compound (I-1) or It is a method for producing these precursors. The compound (8) used in this step can be obtained as a compound synthesized by using various organic synthesis techniques known to those skilled in the art from commercially available compounds, known compounds, or readily available compounds. The amide bond forming reaction in this step is performed using a carboxylic acid represented by compound (18) or a reactive derivative thereof. Examples of the reactive derivative of the compound (18) include mixed acid anhydrides, active esters, active amides, acid halides, etc., and these include, for example, methods described in the literature (for example, comprehensive organic compounds).・ Transformations 2nd Edition (Comprehensive Organic Transformations, Second Edition), by Richard C. Larock, John Wiley & Sons Inc. (1999) 1941-1949). In the above reaction, when the carboxylic acid represented by the compound (18) is used, for example, 1,1′-carbonyldiimidazole, N, N′-dicyclohexylcarbodiimide, 1-ethyl-3- (3- Dimethylaminopropyl) carbodiimide, diphenylphosphoryl azide, dipyridyl disulfide-triphenylphosphine, O- (7-azabenzotriazol-1-yl) -N, N, N ′, N′-tetramethyluronium hexafluorophosphate, The reaction can be performed in the presence of a condensing agent such as PyBOP (registered trademark) or PyBroP (registered trademark).
The reaction solvent is not particularly limited as long as it does not hinder the reaction, and examples thereof include dichloromethane, chloroform, acetonitrile, N, N-dimethylformamide, and preferably chloroform.
The reaction temperature is usually 0 ° C. to the reflux temperature of the reaction solvent, preferably 0 to 60 ° C.
The reaction time is usually 0.1 to 240 hours, preferably 0.1 to 100 hours.

  The compound represented by the formula (I-2) can also be produced from the compound (16) by the following method.

[式中、記号は前記定義に同じである。]

[Wherein the symbols are as defined above. ]

(Step 15) This step is a method for producing a compound (19) by reacting the amine moiety of the compound (16) obtained in the step 11 with the compound (12) or the compound (13). The compound (12) or compound (13) used in this step can be obtained as a compound synthesized by using various organic synthesis methods known to those skilled in the art from commercially available compounds, known compounds, or readily available compounds.

(Step 16) This step is a method for producing the compound (20) by hydrolyzing the ester group of the compound (19) obtained in the step 15 with a base.
Examples of the base used in this step include sodium hydroxide and potassium hydroxide. The amount of the base is generally 1 to 100 equivalents, preferably 1 to 10 equivalents, relative to 1 equivalent of compound (19).
The reaction solvent is not particularly limited as long as it does not hinder the reaction, and examples thereof include methanol, ethanol, tetrahydrofuran, 1,4-dioxane, N, N-dimethylformamide, and preferably methanol.
The reaction temperature is usually 0 ° C. to the reflux temperature of the reaction solvent, preferably 0 to 180 ° C.
The reaction time is usually 0.1 to 240 hours, preferably 0.1 to 24 hours.

(Step 17) In this step, an amide bond is produced by reacting the carboxyl group of the compound (20) obtained in the above step 16 with the amine moiety of the compound (8), and the compound (I-2) or It is a method for producing these precursors. The compound (8) used in this step can be obtained as a compound synthesized by using various organic synthesis techniques known to those skilled in the art from commercially available compounds, known compounds, or readily available compounds. The amide bond forming reaction in this step is performed using a carboxylic acid represented by compound (20) or a reactive derivative thereof. Examples of the reactive derivative of the compound (20) include mixed acid anhydrides, active esters, active amides, acid halides, etc., and these include, for example, methods described in the literature (for example, comprehensive organic compounds).・ Transformations 2nd Edition (Comprehensive Organic Transformations, Second Edition), by Richard C. Larock, John Wiley & Sons Inc. (1999) 1941-1949). In the above reaction, when the carboxylic acid represented by the compound (20) is used, for example, 1,1′-carbonyldiimidazole, N, N′-dicyclohexylcarbodiimide, 1-ethyl-3- (3- Dimethylaminopropyl) carbodiimide, diphenylphosphoryl azide, dipyridyl disulfide-triphenylphosphine, O- (7-azabenzotriazol-1-yl) -N, N, N ′, N′-tetramethyluronium hexafluorophosphate, The reaction can be carried out in the presence of a condensing agent such as PyBOP (registered trademark) or PyBroP (registered trademark). The amount of the condensing agent is 1 to 5 equivalents, preferably 1 to 2 equivalents, relative to 1 equivalent of compound (20).
In addition, the amount of compound (8) to be used is 0.5 to 5 equivalents, preferably 1 to 2 equivalents, relative to 1 equivalent of compound (20).
The reaction solvent is not particularly limited as long as it does not hinder the reaction, and examples thereof include dichloromethane, chloroform, acetonitrile, N, N-dimethylformamide, and preferably chloroform.
The reaction temperature is usually 0 ° C. to the reflux temperature of the reaction solvent, preferably 0 to 60 ° C.
The reaction time is usually 0.1 to 240 hours, preferably 0.1 to 100 hours.

  In addition, the compound represented by the formula (I-3) can also be produced from the compound (16) by the following method.

[式中、記号は前記定義に同じである。]

[Wherein the symbols are as defined above. ]

(Step 18) This step is a method for producing the compound (21) by reacting the compound (16) obtained in the step 11 with the compound (14) in the presence of a transition metal catalyst. Buchwald-Hartwig reaction. The compound (14) used in this step can be obtained as a compound synthesized from a commercially available compound, a known compound, or an easily available compound using various organic synthesis methods known to those skilled in the art. The reaction in this step is carried out according to a method described in the literature (for example, Angew. Chem. Int. Ed., 1998, 37, 2046-2067, Accounts of Chemical Research ( Acc. Chem. Res.), 1998, Vol. 31, pp. 805-818).
Examples of combinations of transition metal catalysts used in this step include palladium acetate and tris (dibenzylideneacetone) palladium as a transition metal complex, and 2,2′-bis (diphenylphosphino) as a ligand. ) -1,1'-binaphthalene and the like. Examples of the base include cesium carbonate, potassium phosphate, sodium tert-butoxide and the like. The amount of the base is usually 1 to 100 equivalents, preferably 1 to 10 equivalents, relative to 1 equivalent of compound (16).
The reaction solvent is not particularly limited as long as it does not hinder the reaction, and examples thereof include toluene, tetrahydrofuran, 1,4-dioxane, N, N-dimethylformamide, N-methylpyrrolidone and the like, preferably toluene, 1,4-dioxane.
The reaction temperature is usually 20 ° C. to the reflux temperature of the reaction solvent, preferably 50 ° C. to 180 ° C.
The reaction time is usually 0.1 to 48 hours, preferably 0.1 to 24 hours.

In this step, compound (21) can also be produced without using a transition metal catalyst. In this case, examples of the base used in this step include potassium carbonate, sodium carbonate, cesium carbonate, triethylamine, N, N-diisopropylethylamine, and preferably potassium carbonate. The amount of the base is usually 1 to 10 equivalents, preferably 1 to 3 equivalents, relative to 1 equivalent of compound (16).
The reaction solvent is not particularly limited as long as it does not hinder the reaction, and examples thereof include acetonitrile, tetrahydrofuran, 1,4-dioxane, N, N-dimethylformamide and the like, preferably tetrahydrofuran, N, N-dimethyl. Formamide.
The reaction temperature is usually 0 ° C. to the reflux temperature of the reaction solvent, preferably 0 to 180 ° C.
The reaction time is usually 0.1 to 240 hours, preferably 0.1 to 48 hours.

(Step 19) This step is a method for producing the compound (22) by hydrolyzing the ester group of the compound (21) obtained in the step 18.
Examples of the base used in this step include sodium hydroxide and potassium hydroxide. The amount of the base is generally 1 to 100 equivalents, preferably 1 to 10 equivalents, relative to 1 equivalent of compound (21).
The reaction solvent is not particularly limited as long as it does not hinder the reaction, and examples thereof include methanol, ethanol, tetrahydrofuran, 1,4-dioxane, N, N-dimethylformamide, and preferably methanol.
The reaction temperature is usually 0 ° C. to the reflux temperature of the reaction solvent, preferably 0 to 180 ° C.
The reaction time is usually 0.1 to 240 hours, preferably 0.1 to 24 hours.

(Step 20) In this step, an amide bond is produced by reacting the carboxyl group of compound (22) obtained in Step 15 with the amine moiety of compound (8) to produce compound (I-3) or It is a method for producing these precursors. The compound (8) used in this step can be obtained as a compound synthesized by using various organic synthesis techniques known to those skilled in the art from commercially available compounds, known compounds, or readily available compounds. The amide bond forming reaction in this step is performed using a carboxylic acid represented by compound (22) or a reactive derivative thereof. Examples of the reactive derivative of the compound (22) include mixed acid anhydrides, active esters, active amides, acid halides, and the like.・ Transformations 2nd Edition (Comprehensive Organic Transformations, Second Edition), by Richard C. Larock, John Wiley & Sons Inc. (1999) 1941-1949). In the above reaction, when the carboxylic acid represented by the compound (22) is used, for example, 1,1′-carbonyldiimidazole, N, N′-dicyclohexylcarbodiimide, 1-ethyl-3- (3- Dimethylaminopropyl) carbodiimide, diphenylphosphoryl azide, dipyridyl disulfide-triphenylphosphine, O- (7-azabenzotriazol-1-yl) -N, N, N ′, N′-tetramethyluronium hexafluorophosphate, The reaction can be carried out in the presence of a condensing agent such as PyBOP (registered trademark) or PyBroP (registered trademark). The amount of the condensing agent is 1 to 5 equivalents, preferably 1 to 2 equivalents, relative to 1 equivalent of compound (22).
The amount of compound (8) used is 0.5 to 5 equivalents, preferably 1 to 2 equivalents, relative to 1 equivalent of compound (22).
The reaction solvent is not particularly limited as long as it does not hinder the reaction, and examples thereof include dichloromethane, chloroform, acetonitrile, N, N-dimethylformamide, and preferably chloroform.
The reaction temperature is usually 0 ° C. to the reflux temperature of the reaction solvent, preferably 0 to 60 ° C.
The reaction time is usually 0.1 to 240 hours, preferably 0.1 to 100 hours.

  In addition, the compound represented by the formula (I-4) can also be produced from the compound (16) by the following method.

[式中、記号は前記定義に同じである。]

[Wherein the symbols are as defined above. ]

(Step 21) This step is a method for producing a compound (23) by reacting the compound (16) obtained in the step 11 with a compound (15) in the presence of a base.
Examples of the base used in this step include potassium carbonate, sodium carbonate, triethylamine, N, N-diisopropylethylamine, and preferably potassium carbonate. The amount of the base is usually 1 to 10 equivalents, preferably 1 to 3 equivalents, relative to 1 equivalent of compound (16).
The reaction solvent is not particularly limited as long as it does not hinder the reaction, and examples thereof include acetonitrile, tetrahydrofuran, 1,4-dioxane, N, N-dimethylformamide and the like, preferably tetrahydrofuran, N, N-dimethyl. Formamide.
The reaction temperature is usually 0 ° C. to the reflux temperature of the reaction solvent, preferably 0 to 180 ° C.
The reaction time is usually 0.1 to 240 hours, preferably 0.1 to 48 hours.
In the compound (13) used in this step, when the carbon atom to which V ^4b is bonded is substituted with 1 to 2 hydrogen atoms, V ^4b and one hydrogen atom are combined to form carbonyl. Compound (23) can also be produced by reductive amination with a base aldehyde compound or ketone compound. Examples of the reducing agent used in this step include sodium triacetoxyborohydride, zinc chloride-sodium cyanoborohydride complex, 2-picoline borane complex, and preferably sodium triacetoxyborohydride. The amount of the reducing agent is usually 1 to 30 equivalents, preferably 1 to 10 equivalents, relative to 1 equivalent of compound (16).
The reaction solvent is not particularly limited as long as it does not hinder the reaction, and examples thereof include chloroform, methanol, ethanol, tetrahydrofuran, 1,4-dioxane, acetic acid, and the like, preferably chloroform and methanol.
The reaction temperature is usually 0 ° C. to the reflux temperature of the reaction solvent, preferably 0 to 30 ° C.
The reaction time is usually 0.1 to 100 hours, preferably 0.1 to 48 hours.

(Step 22) This step is a method for producing the compound (24) by hydrolyzing the ester group of the compound (23) obtained in the step 21.
Examples of the base used in this step include sodium hydroxide and potassium hydroxide. The amount of the base is generally 1 to 100 equivalents, preferably 1 to 10 equivalents, relative to 1 equivalent of compound (23).
The reaction solvent is not particularly limited as long as it does not hinder the reaction, and examples thereof include methanol, ethanol, tetrahydrofuran, 1,4-dioxane, N, N-dimethylformamide, and preferably methanol.
The reaction temperature is usually 0 ° C. to the reflux temperature of the reaction solvent, preferably 0 to 180 ° C.
The reaction time is usually 0.1 to 240 hours, preferably 0.1 to 24 hours.

(Step 23) In this step, an amide bond is produced by reacting the carboxyl group of the compound (24) obtained in the step 22 with the amine moiety of the compound (8) to produce a compound (I-4) or It is a method for producing these precursors. The compound (8) used in this step can be obtained as a compound synthesized by using various organic synthesis techniques known to those skilled in the art from commercially available compounds, known compounds, or readily available compounds. The amide bond forming reaction in this step is performed using a carboxylic acid represented by compound (24) or a reactive derivative thereof. Examples of the reactive derivative of the compound (24) include mixed acid anhydrides, active esters, active amides, acid halides, etc., and these include, for example, methods described in the literature (for example, comprehensive organic compounds).・ Transformations 2nd Edition (Comprehensive Organic Transformations, Second Edition), by Richard C. Larock, John Wiley & Sons Inc. (1999) 1941-1949). In the above reaction, when the carboxylic acid represented by the compound (24) is used, for example, 1,1′-carbonyldiimidazole, N, N′-dicyclohexylcarbodiimide, 1-ethyl-3- (3- Dimethylaminopropyl) carbodiimide, diphenylphosphoryl azide, dipyridyl disulfide-triphenylphosphine, O- (7-azabenzotriazol-1-yl) -N, N, N ′, N′-tetramethyluronium hexafluorophosphate, The reaction can be carried out in the presence of a condensing agent such as PyBOP (registered trademark) or PyBroP (registered trademark).
The reaction solvent is not particularly limited as long as it does not hinder the reaction, and examples thereof include dichloromethane, chloroform, acetonitrile, N, N-dimethylformamide, and preferably chloroform.
The reaction temperature is usually 0 ° C. to the reflux temperature of the reaction solvent, preferably 0 to 60 ° C.
The reaction time is usually 0.1 to 240 hours, preferably 0.1 to 100 hours.

  Moreover, among the compounds included in the compound (I) according to the present invention, the compound represented by the formula (I-5) can be produced, for example, by the following method.

[式中、記号は前記定義に同じである。]

[Wherein the symbols are as defined above. ]

(Step 24) This step is performed by using Compound (I-1), Compound (I-2), Compound (I-3) or Compound (I-2) obtained in Step 7, 8, 9, 10, 14, 17, 20, or 23. In this method, compound (I-5) is produced by converting a carbonyl group of compound (I-4) to a thiocarbonyl group. The reaction in this step can be carried out by using a Lawesson reagent or diphosphorus pentasulfide.
The amount of Lawesson's reagent or diphosphorus pentasulfide used in this step is 1 to 100 equivalents, preferably 1 to 1 with respect to 1 equivalent of any of compounds (I-1) to (I-4). 10 equivalents.
The reaction solvent is not particularly limited as long as it does not hinder the reaction, and examples thereof include tetrahydrofuran.
The reaction temperature is usually 20 to 200 ° C., preferably 50 ° C. to the reflux temperature of the reaction solvent.
The reaction time is usually 0.1 to 48 hours, preferably 1 to 24 hours.

  Moreover, among the compounds included in the compound (I) according to the present invention, the compound represented by the formula (I-6) can be produced, for example, by the following method.

[式中、Ｖ^５は脱離基を示し、その他の記号は前記定義に同じである。]

[Wherein V ⁵ represents a leaving group, and other symbols are the same as defined above. ]

(Step 25) In this step, an anion is produced at the α-position of the ester group of the compound (25) in the presence of a base, and this is allowed to act on the carbonyl group of the compound (1), whereby the compound (26) is produced. It is a manufacturing method. The compound (1) and compound (25) used in this step can be obtained as commercially available compounds, known compounds, or compounds synthesized by various organic synthesis methods known to those skilled in the art from readily available compounds. Examples of the base used in this step include lithium diisopropylamide and lithium hexamethyldisilazide.
The amount of the base used in this step is usually 0.9 to 2 equivalents, preferably 1 to 1.5 equivalents, relative to 1 equivalent of compound (25).
The reaction solvent is not particularly limited as long as it does not hinder the reaction, and examples thereof include tetrahydrofuran.
The reaction temperature is usually −78 to 100 ° C., preferably −78 to 30 ° C.
The reaction time is usually 0.1 to 48 hours, preferably 1 to 24 hours.

(Step 26) This step is a method for producing the compound (27) by hydrolyzing the ester group of the compound (26) obtained in the step 25.
Examples of the base used in this step include sodium hydroxide and potassium hydroxide. The amount of the base is usually 1 to 100 equivalents, preferably 1 to 10 equivalents, relative to 1 equivalent of compound (26).
The reaction solvent is not particularly limited as long as it does not hinder the reaction, and examples thereof include methanol, ethanol, tetrahydrofuran, 1,4-dioxane, N, N-dimethylformamide, and preferably methanol.
The reaction temperature is usually 0 ° C. to the reflux temperature of the reaction solvent, preferably 0 to 180 ° C.
The reaction time is usually 0.1 to 240 hours, preferably 0.1 to 24 hours.

(Step 27) This step is a method for producing the compound (28) by converting the carboxyl group of the compound (27) obtained in the step 26 into an isocyanate by a rearrangement reaction and cyclizing it as it is in the molecule. is there. The reaction in this step is performed according to a method described in the literature (for example, Comprehensive Organic Transformations, Second Edition, by Richard C. Larock, John Wiley and It can be carried out by a method according to Sands Incorporated (John Wiley & Sons Inc. (1999) pp. 868-869, etc.), or a combination thereof with a conventional method.

(Step 28) This step is a method for producing a compound (30) by reacting the compound (28) obtained in the step 27 with a compound part (29) in the presence of a base. The compound (29) used in this step can be obtained as a compound synthesized from commercially available compounds, known compounds, or readily available compounds using various organic synthesis techniques known to those skilled in the art.
Examples of the base used in this step include sodium hydride, potassium hydride, potassium t-butoxide, cesium fluoride, lithium diisopropylamide, lithium hexamethyldisilazide, sodium hexamethyldisilazide, and the like. Is sodium hydride, potassium t-butoxide. The amount of the base is usually 1 to 10 equivalents, preferably 1 to 2 equivalents, relative to 1 equivalent of compound (28).
The reaction solvent is not particularly limited as long as it does not hinder the reaction. For example, acetonitrile, tetrahydrofuran, 1,4-dioxane, N, N-dimethylformamide, N, N-dimethylacetamide, N-methylpyrrolidone, tert -Butanol and the like, and tetrahydrofuran, N, N-dimethylformamide are preferable.
The reaction temperature is usually 0 ° C. to the reflux temperature of the reaction solvent, preferably 0 to 180 ° C.
The reaction time is usually 0.1 to 240 hours, preferably 0.1 to 48 hours.

  Conversion from the compound (30) to the compound represented by the formula (I-6) is performed by the above steps 4-7, 8, 9, 10, 11-14, 15-17, 18-20, 21-23, And 24 can be carried out by a method combining any of the methods similar to those described above, a method according to this, or a method combining these with conventional methods.

  Moreover, among the compounds included in the compound (I) according to the present invention, the compound represented by the formula (I-7) can be produced, for example, by the following method.

[式中、記号は前記定義に同じである。]

[Wherein the symbols are as defined above. ]

(Step 29) In this step, an anion is generated at the α-position of the cyano group of the compound (31) in the presence of a base, and this is allowed to act on the carbonyl group of the compound (1), whereby the compound (32) It is a manufacturing method. The compound (1) and compound (31) used in this step can be obtained as commercially available compounds, known compounds, or compounds synthesized from readily available compounds using various organic synthesis techniques known to those skilled in the art. Examples of the base used in this step include lithium diisopropylamide and lithium hexamethyldisilazide.
The amount of the base used in this step is usually 0.9 to 2 equivalents, preferably 1 to 1.5 equivalents, relative to 1 equivalent of compound (31).
The reaction solvent is not particularly limited as long as it does not hinder the reaction, and examples thereof include tetrahydrofuran.
The reaction temperature is usually −78 to 100 ° C., preferably −78 to 30 ° C.
The reaction time is usually 0.1 to 48 hours, preferably 1 to 24 hours.

(Step 30) This step is a method for producing a compound (33) by reducing the cyano group of the compound (32) obtained in the step 29 and converting it to an aminomethyl group in the presence of a base. The reaction in this step is performed according to a method described in the literature (for example, Comprehensive Organic Transformations, Second Edition, by Richard C. Larock, John Wiley and It can be carried out by a method according to Sands Incorporated (John Wiley & Sons Inc. (1999) pp. 875-878, etc.) or a combination thereof with a conventional method.

(Step 31) In this step, compound (34) is produced by reacting compound (33) obtained in step 30 with the carbonylating agent or thiocarbonylating agent represented by compound (5). It is a method to do. Examples of the compound (5) used include 1,1′-carbonyldiimidazole, p-nitrophenyl chloroformate, 1,1′-thiocarbonyldiimidazole, triphosgene, thiophosgene and the like. The amount of the compound (5) is usually 1 to 20 equivalents, preferably 1 to 6 equivalents, relative to 1 equivalent of the compound (33).
The reaction solvent is not particularly limited as long as it does not hinder the reaction, and examples thereof include tetrahydrofuran, 1,4-dioxane, dichloromethane, chloroform and the like, and preferably 1,4-dioxane and chloroform.
The reaction temperature is usually 0 ° C. to the reflux temperature of the reaction solvent, preferably 0 to 120 ° C.
The reaction time is usually 0.1 to 100 hours, preferably 0.1 to 72 hours.

(Step 32) This step is a method for producing a compound (35) by reacting the compound (34) obtained in the step 31 with a compound part (29) in the presence of a base. The compound (29) used in this step can be obtained as a compound synthesized from commercially available compounds, known compounds, or readily available compounds using various organic synthesis techniques known to those skilled in the art. Examples of the base used in this step include sodium hydride and potassium t-butoxide.
Examples of the base used in this step include sodium hydride, potassium hydride, potassium t-butoxide, cesium fluoride, lithium diisopropylamide, lithium hexamethyldisilazide, sodium hexamethyldisilazide, and the like. Is sodium hydride, potassium t-butoxide. The amount of the base is generally 1 to 10 equivalents, preferably 1 to 2 equivalents, relative to 1 equivalent of compound (34).
The reaction solvent is not particularly limited as long as it does not hinder the reaction. For example, acetonitrile, tetrahydrofuran, 1,4-dioxane, N, N-dimethylformamide, N, N-dimethylacetamide, N-methylpyrrolidone, tert -Butanol and the like, and tetrahydrofuran, N, N-dimethylformamide are preferable.
The reaction temperature is usually 0 ° C. to the reflux temperature of the reaction solvent, preferably 0 to 180 ° C.
The reaction time is usually 0.1 to 240 hours, preferably 0.1 to 48 hours.

  Conversion from the compound (35) to the compound represented by the formula (I-7) is performed by the above steps 4-7, 8, 9, 10, 11-14, 15-17, 18-20, 21-23, And 24 can be carried out by a method combining any of the methods similar to those described above, a method according to this, or a method combining these with conventional methods.

  Moreover, among the compounds included in the compound (I) according to the present invention, the compound represented by the formula (I-8) can be produced, for example, by the following method.

[式中、Ｐ^１およびＰ^３はアミノ基の保護基を示し、Ｐ^２はカルボキシル基の保護基を示し、Ｖ^６は脱離基を示し、その他の記号は前記定義に同じである。]

[Wherein P ¹ and P ³ represent an amino-protecting group, P ² represents a carboxyl-protecting group, V ⁶ represents a leaving group, and other symbols are the same as defined above. ]

(Step 33) This step is a method for producing a compound (37) by hydrolyzing the ester group of the compound (36) obtained in the step 3, 28 or 32.
Examples of the base used in this step include sodium hydroxide and potassium hydroxide. The amount of the base is generally 1 to 100 equivalents, preferably 1 to 10 equivalents, relative to 1 equivalent of compound (36).
The reaction solvent is not particularly limited as long as it does not hinder the reaction, and examples thereof include methanol, ethanol, tetrahydrofuran, 1,4-dioxane, N, N-dimethylformamide, and preferably methanol.
The reaction temperature is usually 0 ° C. to the reflux temperature of the reaction solvent, preferably 0 to 180 ° C.
The reaction time is usually 0.1 to 240 hours, preferably 0.1 to 24 hours.

(Step 34) In this step, a hydrazide bond is generated by reacting the carboxyl group of the compound (37) obtained in Step 33 with the amine moiety of the compound (38) to produce the compound (39). Is the method. The compound (37) used in this step can be obtained as a compound synthesized from a commercially available compound, a known compound, or an easily available compound using various organic synthesis techniques known to those skilled in the art. The hydrazide bond forming reaction in this step is performed using a carboxylic acid represented by compound (37) or a reactive derivative thereof. Examples of the reactive derivative of the compound (37) include mixed acid anhydrides, active esters, active amides, acid halides, etc., and these include, for example, methods described in the literature (for example, comprehensive organic compounds).・ Transformations 2nd edition (Comprehensive Organic Transformations, Second Edition), by Richard C. Larock, John Wiley & Sons Inc. (1999) 1941-1949). In the above reaction, when the carboxylic acid represented by the compound (37) is used, for example, 1,1′-carbonyldiimidazole, N, N′-dicyclohexylcarbodiimide, 1-ethyl-3- (3- Dimethylaminopropyl) carbodiimide, diphenylphosphoryl azide, dipyridyl disulfide-triphenylphosphine, O- (7-azabenzotriazol-1-yl) -N, N, N ′, N′-tetramethyluronium hexafluorophosphate, The reaction can be carried out in the presence of a condensing agent such as PyBOP (registered trademark) or PyBroP (registered trademark). The amount of the condensing agent is 1 to 5 equivalents, preferably 1 to 2 equivalents, relative to 1 equivalent of the compound (37).
The amount of compound (38) to be used is 0.5 to 5 equivalents, preferably 1 to 2 equivalents, relative to 1 equivalent of compound (37).
The reaction solvent is not particularly limited as long as it does not hinder the reaction, and examples thereof include dichloromethane, chloroform, acetonitrile, N, N-dimethylformamide, and preferably chloroform.
The reaction temperature is usually 0 ° C. to the reflux temperature of the reaction solvent, preferably 0 to 60 ° C.
The reaction time is usually 0.1 to 240 hours, preferably 0.1 to 100 hours.

(Step 35) In this step, compound (40) is obtained by selectively removing the group (P ³ : amino-protecting group) protecting the hydrazide group of compound (39) obtained in Step 34. It is a method of manufacturing. The reaction in this step is a reaction for removing the protecting group of the amino group, and a method described in the literature (for example, Protective Groups in Organic Synthesis, Fourth Edition, Green Edition) (TWGreene), John Wiley & Sons Inc. (2006), etc.), a method according to it, or a combination of these with conventional methods it can.

(Step 36) This step is a method for producing the compound (42) by reacting the hydrazide moiety of the compound (40) obtained in the step 35 with the compound (41). The compound (41) used in this step can be obtained as a compound synthesized by using various organic synthesis methods known to those skilled in the art from commercially available compounds, known compounds, or readily available compounds.

(Step 37) This step is a method for producing the compound (43) by removing the amino-protecting group of the compound (42) obtained in the step 36. The reaction in this step is a reaction for removing the protecting group of the amino group, and a method described in the literature (for example, Protective Groups in Organic Synthesis, Fourth Edition, Green Edition) (TWGreene), John Wiley & Sons Inc. (2006), etc.), a method according to it, or a combination of these with conventional methods Can do.

  The conversion from the compound (43) to the compound represented by the formula (I-8) was carried out in the same manner as in Step 7, 8, 9 or 10, the method according to this, or a combination thereof with a conventional method. It can be done by the method.

  Moreover, the compound represented by the said Formula (I-8) can be manufactured also with the following method, for example.

[式中、Ｐ^１およびＰ^３はアミノ基の保護基を示し、Ｐ^２はカルボキシル基の保護基を示し、Ｖ^６は脱離基を示し、その他の記号は前記定義に同じである。]

[Wherein P ¹ and P ³ represent an amino-protecting group, P ² represents a carboxyl-protecting group, V ⁶ represents a leaving group, and other symbols are the same as defined above. ]

(Step 38) This step is a method for producing the compound (44) by removing the amino-protecting group (P ¹ ) of the compound (36) obtained in the step 3, 28 or 32. The reaction in this step is a reaction for removing the protecting group of the amino group, and a method described in the literature (for example, Protective Groups in Organic Synthesis, Fourth Edition, Green Edition) (TWGreene), John Wiley & Sons Inc. (2006), etc.), a method according to it, or a combination of these with conventional methods it can.

  Conversion from the compound (44) to the compound (45) can be carried out by the same method as in Step 12, 15, 18 or 23, a method according to this, or a method combining these with conventional methods.

(Step 39) This step is a method for producing a compound (46) by hydrolyzing the ester group of the compound (45).
Examples of the base used in this step include sodium hydroxide and potassium hydroxide. The amount of the base is usually 1 to 100 equivalents, preferably 1 to 10 equivalents, relative to 1 equivalent of compound (45).
The reaction solvent is not particularly limited as long as it does not hinder the reaction, and examples thereof include methanol, ethanol, tetrahydrofuran, 1,4-dioxane, N, N-dimethylformamide, and preferably methanol.
The reaction temperature is usually 0 ° C. to the reflux temperature of the reaction solvent, preferably 0 to 180 ° C.
The reaction time is usually 0.1 to 240 hours, preferably 0.1 to 24 hours.

(Step 40) In this step, a hydrazide bond is generated by reacting the carboxyl group of compound (46) obtained in Step 39 with the amine moiety of compound (38) to produce compound (47). Is the method. The compound (38) used in this step can be obtained as a compound synthesized by using various organic synthesis methods known to those skilled in the art from commercially available compounds, known compounds, or readily available compounds. The hydrazide bond forming reaction in this step is performed using a carboxylic acid represented by compound (46) or a reactive derivative thereof. Examples of the reactive derivative of the compound (46) include mixed acid anhydrides, active esters, active amides, acid halides, etc., and these include, for example, methods described in the literature (for example, comprehensive organic compounds).・ Transformations 2nd Edition (Comprehensive Organic Transformations, Second Edition), by Richard C. Larock, John Wiley & Sons Inc. (1999) 1941-1949). In the above reaction, when the carboxylic acid represented by the compound (46) is used, for example, 1,1′-carbonyldiimidazole, N, N′-dicyclohexylcarbodiimide, 1-ethyl-3- (3- Dimethylaminopropyl) carbodiimide, diphenylphosphoryl azide, dipyridyldisulfide-triphenylphosphine, O- (7-azabenzotriazol-1-yl) -N, N, N ′, N′-tetramethyluronium hexafluorophosphate, The reaction can be carried out in the presence of a condensing agent such as PyBOP (registered trademark) or PyBroP (registered trademark).
The reaction solvent is not particularly limited as long as it does not hinder the reaction, and examples thereof include dichloromethane, chloroform, acetonitrile, N, N-dimethylformamide, and preferably chloroform.
The reaction temperature is usually 0 ° C. to the reflux temperature of the reaction solvent, preferably 0 to 60 ° C.
The reaction time is usually 0.1 to 240 hours, preferably 0.1 to 100 hours.

(Step 41) In this step, compound (48) is produced by removing the group (P ³ : protecting group for amino group) protecting the hydrazide group of compound (47) obtained in Step 40. Is the method. The reaction in this step is a reaction for removing the protecting group of the amino group, and a method described in the literature (for example, Protective Groups in Organic Synthesis, Fourth Edition, Green Edition) (TWGreene), John Wiley & Sons Inc. (2006), etc.), a method according to it, or a combination of these with conventional methods it can.

(Step 42) This step is a method for producing compound (I-8) or a precursor thereof by reacting the hydrazide moiety of compound (48) obtained in step 41 with compound (41). is there. The compound (41) used in this step can be obtained as a compound synthesized by using various organic synthesis methods known to those skilled in the art from commercially available compounds, known compounds, or readily available compounds.

  Moreover, among the compounds included in the compound (I) according to the present invention, the compound represented by the formula (I-9) can be produced, for example, by the following method.

[式中、Ｐ^１はアミノ基の保護基を示し、Ｖ^７は脱離基を示し、その他の記号は前記定義に同じである。]

[Wherein P ¹ represents an amino-protecting group, V ⁷ represents a leaving group, and other symbols are the same as defined above. ]

(Step 43) This step is a method for producing compound (51) by reacting the hydrazide moiety of compound (40) obtained in step 35 with compound (49) or compound (50). The compound (49) or compound (50) used in this step can be obtained as a compound synthesized from a commercially available compound, a known compound, or an easily available compound using various organic synthesis methods known to those skilled in the art.

(Step 44) This step is a method for producing the compound (52) by removing the amino-protecting group of the compound (51) obtained in the step 43. The reaction in this step is a reaction for removing the protecting group of the amino group, and a method described in the literature (for example, Protective Groups in Organic Synthesis, Fourth Edition, Green Edition) (TWGreene), John Wiley & Sons Inc. (2006), etc.), a method according to it, or a combination of these with conventional methods Can do.

  The conversion from the compound (52) to the compound represented by the formula (I-8) was carried out in the same manner as in Step 7, 8, 9 or 10, the method according to this, or a combination thereof with a conventional method. It can be done by the method.

  In addition, the compound represented by the formula (I-9) can also be produced, for example, by the following method.

[式中、Ｖ^７は脱離基を示し、その他の記号は前記定義に同じである。]

[Wherein V ⁷ represents a leaving group, and other symbols are the same as defined above. ]

(Step 45) In this step, compound (I-9) or a precursor thereof is reacted by reacting the hydrazide moiety of compound (48) obtained in step 41 with compound (49) or compound (50). It is a method of manufacturing. The compound (49) or compound (50) used in this step can be obtained as a compound synthesized from a commercially available compound, a known compound, or an easily available compound using various organic synthesis methods known to those skilled in the art.

  Of the compounds included in the compound (I) according to the present invention, compounds represented by the formula (I-10), the formula (I-11), the formula (I-12) and the formula (I-13) Can be produced, for example, by the following method.

[式中、Ｖ^８およびＶ^９は脱離基を示し、その他の記号は前記定義に同じである。]

[Wherein V ⁸ and V ⁹ represent a leaving group, and other symbols are the same as defined above. ]

(Step 46) This step is a method for producing a compound (53) by converting the carboxyl group of the compound (46) obtained in the step 39 into an amino group by a rearrangement reaction. Rearrangement reactions that can be used in this process include rearrangement reactions via acyl azides (so-called Curtius rearrangement and Schmidt rearrangement), rearrangement reactions via primary amides (so-called Hofmann rearrangement) and hydroxams. Examples include a rearrangement reaction via an acid (so-called Lossen rearrangement). These reactions are described in literature (for example, Comprehensive Organic Transformations, Second Edition, by Richard C. Larock, John Wiley and Sons). -Incorporated (John Wiley & Sons Inc.) (1999) 868-869 etc.), it can carry out by the method according to it, or combining these and a conventional method.

(Step 47) This step is a method for producing compound (I-10) or a precursor thereof by reacting the amine moiety of compound (53) obtained in step 46 with compound (41). is there. The compound (41) used in this step can be obtained as a compound synthesized by using various organic synthesis methods known to those skilled in the art from commercially available compounds, known compounds, or readily available compounds.

(Step 48) In this step, compound (I-11) or a precursor thereof is prepared by reacting the amine moiety of compound (53) obtained in step 46 with compound (49) or compound (50). It is a method of manufacturing. The compound (49) or compound (50) used in this step can be obtained as a compound synthesized from a commercially available compound, a known compound, or an easily available compound using various organic synthesis methods known to those skilled in the art.

(Step 49) This step is a method for producing a compound (I-12) or a precursor thereof by reacting the amine moiety of the compound (53) obtained in the step 46 with the compound (54). is there. The compound (54) used in this step can be obtained from a commercially available compound, a known compound, or a compound synthesized by various organic synthesis methods known to those skilled in the art from a readily available compound.

(Step 50) This step is a method for producing compound (I-13) or a precursor thereof by reacting the amine moiety of compound (53) obtained in step 46 with compound (55). is there. The compound (55) used in this step can be obtained from a commercially available compound, a known compound, or a compound synthesized from various readily available organic synthesis methods known to those skilled in the art.

  Moreover, the compound represented by the said Formula (I-10) can be manufactured also with the following method, for example.

[式中、記号は前記定義に同じである。]

[Wherein the symbols are as defined above. ]

(Step 51) This step is a method for producing a compound (56) by converting the carboxyl group of the compound (37) obtained in the step 33 to an amino group by a rearrangement reaction. Rearrangement reactions that can be used in this process include rearrangement reactions via acyl azides (so-called Curtius rearrangement and Schmidt rearrangement), rearrangement reactions via primary amides (so-called Hofmann rearrangement) and hydroxams. Examples include a rearrangement reaction via an acid (so-called Lossen rearrangement). These reactions are described in literature (for example, Comprehensive Organic Transformations, Second Edition, by Richard C. Larock, John Wiley and Sons). -Incorporated (John Wiley & Sons Inc.) (1999) 868-869 etc.), it can carry out by the method according to it, or combining these and a conventional method.

(Step 52) This step is a method for producing a compound (57) by reacting the amine moiety of the compound (56) obtained in the step 51 with the compound (41). The compound (41) used in this step can be obtained as a compound synthesized by using various organic synthesis methods known to those skilled in the art from commercially available compounds, known compounds, or readily available compounds.

(Step 53) This step is a method for producing the compound (58) by removing the amino-protecting group of the compound (57) obtained in the step 52. The reaction in this step is a reaction for removing the protecting group of the amino group, and a method described in the literature (for example, Protective Groups in Organic Synthesis, Fourth Edition, Green Edition) (TWGreene), John Wiley & Sons Inc. (2006), etc.), a method according to it, or a combination of these with conventional methods Can do.

  The conversion from the compound (58) to the compound represented by the formula (I-10) was carried out in the same manner as in Step 7, 8, 9 or 10, a method analogous thereto, or a combination of these and a conventional method. It can be done by the method.

  Moreover, the compound represented by the said formula (I-11) can be manufactured also with the following method, for example.

[式中、記号は前記定義に同じである。]

[Wherein the symbols are as defined above. ]

(Step 54) This step is a method for producing the compound (59) by reacting the amine moiety of the compound (56) obtained in the step 51 with the compound (49) or the compound (50). The compound (49) or compound (50) used in this step can be obtained as a compound synthesized from a commercially available compound, a known compound, or an easily available compound using various organic synthesis methods known to those skilled in the art.

(Step 55) This step is a method for producing the compound (60) by removing the amino-protecting group of the compound (59) obtained in the step 54. The reaction in this step is a reaction for removing the protecting group of the amino group, and a method described in the literature (for example, Protective Groups in Organic Synthesis, Fourth Edition, Green Edition) (TWGreene), John Wiley & Sons Inc. (2006), etc.), a method according to it, or a combination of these with conventional methods Can do.

  The conversion from the compound (60) to the compound represented by the formula (I-11) was carried out by the same method as in Step 7, 8, 9 or 10, the method according to this, or a combination of these and a conventional method. It can be done by the method.

  Moreover, the compound represented by the said formula (I-12) can be manufactured also with the following method, for example.

[式中、記号は前記定義に同じである。]

[Wherein the symbols are as defined above. ]

(Step 56) This step is a method for producing the compound (61) by reacting the amine moiety of the compound (56) obtained in the step 51 with the compound (54). The compound (54) used in this step can be obtained from a commercially available compound, a known compound, or a compound synthesized by various organic synthesis methods known to those skilled in the art from a readily available compound.

(Step 57) This step is a method for producing the compound (62) by removing the amino-protecting group of the compound (61) obtained in the step 56. The reaction in this step is a reaction for removing the protecting group of the amino group, and a method described in the literature (for example, Protective Groups in Organic Synthesis, Fourth Edition, Green Edition) (TWGreene), John Wiley & Sons Inc. (2006), etc.), a method according to it, or a combination of these with conventional methods Can do.

  The conversion from the compound (62) to the compound represented by the formula (I-12) was carried out in the same manner as in Step 7, 8, 9 or 10 above, a method analogous thereto, or a combination thereof with a conventional method. It can be done by the method.

  Moreover, the compound represented by the said formula (I-13) can be manufactured also with the following method, for example.

[式中、記号は前記定義に同じである。]

[Wherein the symbols are as defined above. ]

(Step 58) This step is a method for producing a compound (63) by reacting the amine moiety of the compound (56) obtained in the step 51 with the compound (55). The compound (55) used in this step can be obtained from a commercially available compound, a known compound, or a compound synthesized from various readily available organic synthesis methods known to those skilled in the art.

(Step 59) This step is a method for producing the compound (64) by removing the amino-protecting group of the compound (63) obtained in the step 58. The reaction in this step is a reaction for removing the protecting group of the amino group, and a method described in the literature (for example, Protective Groups in Organic Synthesis, Fourth Edition, Green Edition) (TWGreene), John Wiley & Sons Inc. (2006), etc.), a method according to it, or a combination of these with conventional methods Can do.

  The conversion from the compound (64) to the compound represented by the formula (I-13) was carried out in the same manner as in Step 7, 8, 9 or 10, the method according to this, or a combination of these and the usual method. It can be done by the method.

The present invention will be described in more detail with reference synthesis examples, synthesis examples, test examples, and formulation examples below, but the present invention is not limited to these examples.
The NMR (nuclear magnetic resonance) spectrum was measured at room temperature using a 300 MHz (JNM-ECP300; manufactured by JEOL Ltd. or JNM-ECX300; manufactured by JEOL Ltd.) type spectrometer. The chemical shift value in this specification uses tetramethylsilane as an internal standard substance when any of deuterated chloroform (CDCl ₃ ), deuterated dimethyl sulfoxide (DMSO-d ₆ ), and deuterated methanol (CD ₃ OD) is used. All δ values are shown in ppm (parts per million). In the description of the NMR spectrum, s is a singlet, d is a doublet, dd is a doublet of doublet, dt is a doublet of triplet, dq is a doublet of quartet, ddd is a doublet of doublet of Doublet, t is a triplet, tt is a triplet of triplet, q is a quartet, sep is a septet, quint is a quintet, m is a multiplet, br is broad, J is a coupling constant, and Hz is hertz.
LC-MS (liquid chromatograph-mass spectrometry) spectrum was measured using the following conditions and apparatus.
Condition 1:
Device: Waters micromass ZQ
Column: Waters SunFire C18 (3.5 μm, 4.6 × 30 mm)
Column temperature: 40 ° C
Eluent composition: acetonitrile / 0.1 mass% formic acid aqueous solution (volume ratio: 10/90 → 85/15)

Condition 2
Device: Waters micromass ZQ
Column: Waters SunFire C18 (3.5 μm, 2.1 × 20 mm)
Column temperature: 40 ° C
Eluent composition: acetonitrile / 0.1 mass% formic acid aqueous solution (volume ratio: 15/85 → 85/15)

When purified by HPLC, the following conditions and equipment were used.
Device: Waters micromass ZQ
Column: WatersSunFireC18 (5.0 μm, 19 × 100 mm)
Column temperature: 23 ± 2 ° C
Eluent composition: acetonitrile / 0.1 wt% formic acid aqueous solution (volume ratio: 20/80 → 95/5)
Flow rate: 20 mL / min

In addition, when there exists description regarding the mixing ratio of a mixed solvent in an Example, when there is no description in particular, a mixing ratio means volume ratio.

参考例１−１
１−オキサ−６−アザスピロ［２．５］オクタン−６−カルボン酸ｔ−ブチルの製造
１−（ｔ−ブトキシカルボニル）−４−ピペリドン（和光純薬工業（株）より購入）（５．１ｇ、２６ｍｍｏｌ）をアセトニトリル（５０ｍＬ）に溶解し、ヨウ化トリメチルスルホキソニウム（６．６ｇ、３０ｍｍｏｌ）、水酸化カリウム（２．１ｇ、３８ｍｍｏｌ）を加えて、室温にて３日間激しくかき混ぜた。反応終了後、得られた反応混合物中の不溶物を取り除き、ヘキサン／酢酸エチル（２／１、７５ｍＬ）、水（２５ｍＬ）を加えて、振とう、静置して、上澄み液を分離した。得られた有機層を無水硫酸ナトリウムで乾燥、減圧下濃縮乾固し、１−オキサ−６−アザスピロ［２．５］オクタン−６−カルボン酸ｔ−ブチル（４．３ｇ、収率 ７８％）を無色固体として得た。

^１Ｈ−ＮＭＲ（３００ＭＨｚ，ＣＤＣｌ_３）δ：１．４１−１．５０（２Ｈ，ｍ），１．４８（９Ｈ，ｓ），１．８０（２Ｈ，ｄｄｄ，Ｊ＝１３．１，９．４，３．３Ｈｚ），２．６９（２Ｈ，ｓ），３．４３（２Ｈ，ｄｄｄ，Ｊ＝１３．１，９．４，３．３Ｈｚ），３．６３−３．８０（２Ｈ，ｍ）．

Reference Example 1-1
Preparation of 1-oxa-6-azaspiro [2.5] octane-6-carboxylate t-butyl 1- (t-butoxycarbonyl) -4-piperidone (purchased from Wako Pure Chemical Industries, Ltd.) (5.1 g 26 mmol) was dissolved in acetonitrile (50 mL), trimethylsulfoxonium iodide (6.6 g, 30 mmol) and potassium hydroxide (2.1 g, 38 mmol) were added, and the mixture was vigorously stirred at room temperature for 3 days. After completion of the reaction, insoluble matters in the obtained reaction mixture were removed, hexane / ethyl acetate (2/1, 75 mL) and water (25 mL) were added, and the mixture was shaken and allowed to stand to separate the supernatant. The resulting organic layer was dried over anhydrous sodium sulfate and concentrated to dryness under reduced pressure to give t-butyl 1-oxa-6-azaspiro [2.5] octane-6-carboxylate (4.3 g, yield 78%). Was obtained as a colorless solid.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.41-1.50 (2H, m), 1.48 (9H, s), 1.80 (2H, ddd, J = 13.1, 9 .. 4, 3.3 Hz), 2.69 (2H, s), 3.43 (2H, ddd, J = 13.1, 9.4, 3.3 Hz), 3.63-3.80 (2H, m ).

参考例１−２
３−［４−（メトキシカルボニル）ベンジル］−２−オキソ−１−オキサ−３，８−ジアザスピロ［４．５］デカン−８−カルボン酸ｔ−ブチルの製造
参考例１−１で得られた１−オキサ−６−アザスピロ［２．５］オクタン−６−カルボン酸ｔ−ブチル（１７ｇ、８０ｍｍｏｌ）と４−アミノメチル安息香酸メチル（アルドリッチ（株）より購入）（１７ｇ、８６ｍｍｏｌ）をメタノール（３４０ｍＬ）に懸濁し、水（３０ｍＬ）と１Ｍ水酸化ナトリウム水溶液（８６ｍＬ、８６ｍｏｌ）を加え、室温で３日間かき混ぜた後、減圧下メタノールを留去した。得られた反応混合物に水（２００ｍＬ）を加えクロロホルム（３４０ｍＬ）で抽出した。有機層を無水硫酸ナトリウムで乾燥した後、減圧下濃縮乾固し、４−ヒドロキシ−４−｛［４−（メトキシカルボニル）ベンジルアミノ］メチル｝ピペリジン−１−カルボン酸ｔ−ブチル（３７ｇ、収率 定量的）を黄色油状物として得た。精製せずに次の反応に用いた。
得られた４−ヒドロキシ−４−｛［４−（メトキシカルボニル）ベンジルアミノ］メチル｝ピペリジン−１−カルボン酸ｔ−ブチル（３４ｇ、７５ｍｍｏｌ）を１，４−ジオキサン（３００ｍＬ）に溶解し、１，１’−カルボニルジイミダゾール（４６ｇ、３００ｍｍｏｌ）を加え、９０℃で２日間かき混ぜた。反応混合物を冷却し減圧下濃縮後、氷冷下、酢酸エチル（１００ｍＬ）と水（２０ｍＬ）を加え減圧下濃縮した。これに酢酸エチル（３００ｍＬ）と水（２００ｍＬ）を加え、有機層を分離した後、減圧下濃縮した。得られた残留物をシリカゲルカラムクロマトグラフィー［充填剤：Ｍｅｒｃｋ ＧＭＢＨ製シリカゲル６０（０．０４０−０．０６３ｍｍ）、展開溶媒：クロロホルム／酢酸エチル＝１０／１］にて精製し、クロロホルム／酢酸エチル／ヘキサンで再結晶することにより、３−［４−（メトキシカルボニル）ベンジル］−２−オキソ−１−オキサ−３，８−ジアザスピロ［４．５］デカン−８−カルボン酸ｔ−ブチル（１１ｇ、２９％）を白色固体として得た。

^１Ｈ−ＮＭＲ（３００ＭＨｚ，ＣＤＣｌ_３）δ：１．４４（９Ｈ，ｓ），１．５４−１．６７（２Ｈ，ｍ），１．８６（２Ｈ，ｄ，Ｊ＝１３．０Ｈｚ），３．１３（２Ｈ，ｓ），３．２８（２Ｈ，ｔ，Ｊ＝１１．６Ｈｚ），３．８１（２Ｈ，ｄ，Ｊ＝１１．６Ｈｚ），３．９２（３Ｈ，ｓ），４．４９（２Ｈ，ｓ），７．３４（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ），８．０４（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ）．

ＬＣ／ＭＳ［条件１］：保持時間４．１４分；ｍ／ｚ４２６．９［Ｍ＋Ｎａ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ４４８．９［Ｍ＋ＨＣＯＯ］^―（ＥＳＩ負イオンモード）

Reference Example 1-2
Production of t-butyl 3- [4- (methoxycarbonyl) benzyl] -2-oxo-1-oxa-3,8-diazaspiro [4.5] decane-8-carboxylate Obtained in Reference Example 1-1 1-oxa-6-azaspiro [2.5] octane-6-carboxylate t-butyl (17 g, 80 mmol) and methyl 4-aminomethylbenzoate (purchased from Aldrich Co.) (17 g, 86 mmol) were added to methanol ( 340 mL), water (30 mL) and 1M aqueous sodium hydroxide solution (86 mL, 86 mol) were added, and the mixture was stirred at room temperature for 3 days, and methanol was evaporated under reduced pressure. Water (200 mL) was added to the resulting reaction mixture, and the mixture was extracted with chloroform (340 mL). The organic layer was dried over anhydrous sodium sulfate and then concentrated to dryness under reduced pressure to give t-butyl 4-hydroxy-4-{[4- (methoxycarbonyl) benzylamino] methyl} piperidine-1-carboxylate (37 g, yield). (Quantitative) was obtained as a yellow oil. Used in the next reaction without purification.
The obtained 4-hydroxy-4-{[4- (methoxycarbonyl) benzylamino] methyl} piperidine-1-carboxylate t-butyl (34 g, 75 mmol) was dissolved in 1,4-dioxane (300 mL). , 1′-carbonyldiimidazole (46 g, 300 mmol) was added, and the mixture was stirred at 90 ° C. for 2 days. The reaction mixture was cooled and concentrated under reduced pressure, ethyl acetate (100 mL) and water (20 mL) were added under ice cooling, and the mixture was concentrated under reduced pressure. Ethyl acetate (300 mL) and water (200 mL) were added thereto, the organic layer was separated, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography [filler: silica gel 60 (0.040-0.063 mm) manufactured by Merck GMBH, developing solvent: chloroform / ethyl acetate = 10/1], and chloroform / ethyl acetate. By recrystallization from hexane / hexane to give t-butyl 3- [4- (methoxycarbonyl) benzyl] -2-oxo-1-oxa-3,8-diazaspiro [4.5] decane-8-carboxylate (11 g 29%) as a white solid.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.44 (9H, s), 1.54-1.67 (2H, m), 1.86 (2H, d, J = 13.0 Hz), 3 .13 (2H, s), 3.28 (2H, t, J = 11.6 Hz), 3.81 (2H, d, J = 11.6 Hz), 3.92 (3H, s), 4.49 (2H, s), 7.34 (2H, d, J = 8.2 Hz), 8.04 (2H, d, J = 8.2 Hz).

LC / MS [Condition 1]: Retention time 4.14 minutes; m / z 426.9 [M + Na] ⁺ (ESI positive ion mode), m / z 448.9 [M + HCOO] ⁻ (ESI negative ion mode)

参考例１−３
４−［（２−オキソ−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル）メチル］安息香酸メチル塩酸塩の製造
参考例１−２で得られた、３−［４−（メトキシカルボニル）ベンジル］−２−オキソ−１−オキサ−３，８−ジアザスピロ［４．５］デカン−８−カルボン酸ｔ−ブチル（５．０ｇ、１２ｍｍｏｌ）をメタノール（７０ｍＬ）に溶解し、４Ｍ塩化水素−ジオキサン溶液（３１ｍＬ、１２０ｍｍｏｌ）を加え、室温にて１６時間かき混ぜた。析出した固体をろ取し、減圧下５０℃で乾燥させ、４−［（２−オキソ−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル）メチル］安息香酸メチル塩酸塩（４．０ｇ、収率９５％）を白色固体として得た。

^１Ｈ−ＮＭＲ（３００ＭＨｚ，ＤＭＳＯ−ｄ_６）δ：１．８５−２．０７（４Ｈ，ｍ），２．９７−３．２５（４Ｈ，ｍ），３．３１（２Ｈ，ｓ），３．８４（３Ｈ，ｓ），４．４４（２Ｈ，ｓ），７．４１（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ），７．９５（２Ｈ，ｄ，Ｊ＝７．８Ｈｚ），８．８２（２Ｈ，ｂｒｓ）．

ＬＣ／ＭＳ［条件１］：保持時間０．８８分；ｍ／ｚ３０５．０［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）

Reference Example 1-3
4-[(2-Oxo-1-oxa-3,8-diazaspiro [4.5] decan-3-yl) methyl] benzoic acid methyl hydrochloride 3- [obtained in Reference Example 1-2 4- (Methoxycarbonyl) benzyl] -2-oxo-1-oxa-3,8-diazaspiro [4.5] decane-8-carboxylate t-butyl (5.0 g, 12 mmol) dissolved in methanol (70 mL) 4M hydrogen chloride-dioxane solution (31 mL, 120 mmol) was added, and the mixture was stirred at room temperature for 16 hours. The precipitated solid was collected by filtration, dried at 50 ° C. under reduced pressure, and methyl 4-[(2-oxo-1-oxa-3,8-diazaspiro [4.5] decan-3-yl) methyl] benzoate. The salt (4.0 g, 95% yield) was obtained as a white solid.

¹ H-NMR (300 MHz, DMSO-d ₆ ) δ: 1.85-2.07 (4H, m), 2.97-3.25 (4H, m), 3.31 (2H, s), 3 .84 (3H, s), 4.44 (2H, s), 7.41 (2H, d, J = 8.2 Hz), 7.95 (2H, d, J = 7.8 Hz), 8.82 (2H, brs).

LC / MS [Condition 1]: Retention time 0.88 min; m / z 305.0 [M + H] ⁺ (ESI positive ion mode)

実施例１
４−（｛２−オキソ−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）安息香酸メチル（化合物番号１）の製造
参考例１−３で得られた、４−［（２−オキソ−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル）メチル］安息香酸メチル塩酸塩（４．０ｇ、１１ｍｍｏｌ）をＮ，Ｎ−ジメチルホルムアミド（４０ｍＬ）に溶解し、トリエチルアミン（４．９ｍＬ、３５ｍｍｏｌ）、４−（トリフルオロメチル）ベンジルブロミド（東京化成工業（株）より購入）（３．４ｇ、１４ｍｍｏｌ）を室温にて加えたのち、３時間かき混ぜた。反応混合物を水（２００ｍＬ）に滴下し、析出した固体をろ取した後、水で洗浄した。得られた固体を５０℃で減圧下乾燥し、４−（｛２−オキソ−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）安息香酸メチル（５．２ｇ、収率９５％）を白色固体として得た。

^１Ｈ−ＮＭＲ（３００ＭＨｚ，ＣＤＣｌ_３）δ：１．７３（２Ｈ，ｄｄｄ，Ｊ＝１４．０，７．２，７．４Ｈｚ），１．９２（２Ｈ，ｄｔ，Ｊ＝１２．９，４．７Ｈｚ），２．６２−２．４７（４Ｈ，ｍ），３．１３（２Ｈ，ｓ），３．５６（２Ｈ，ｓ），３．９２（３Ｈ，ｓ），４．４８（２Ｈ，ｓ），７．３３（２Ｈ，ｄ，Ｊ＝８．３Ｈｚ），７．４２（２Ｈ，ｄ，Ｊ＝８．３Ｈｚ），７．５６（２Ｈ，ｄ，Ｊ＝８．３Ｈｚ），８．０３（２Ｈ，ｄ，Ｊ＝８．３Ｈｚ）．

ＬＣ／ＭＳ［条件１］：保持時間３．２５分；ｍ／ｚ４６２．９［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ５０７．１［Ｍ＋ＨＣＯＯ］^―（ＥＳＩ負イオンモード）

Example 1
4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl) benzoic acid methyl ester (Compound No. 1 ) 4-[(2-oxo-1-oxa-3,8-diazaspiro [4.5] decan-3-yl) methyl] benzoic acid methyl hydrochloride (4) obtained in Reference Example 1-3 0.0 g, 11 mmol) in N, N-dimethylformamide (40 mL), triethylamine (4.9 mL, 35 mmol), 4- (trifluoromethyl) benzyl bromide (purchased from Tokyo Chemical Industry Co., Ltd.) (3. 4 g, 14 mmol) was added at room temperature, followed by stirring for 3 hours. The reaction mixture was added dropwise to water (200 mL), and the precipitated solid was collected by filtration and washed with water. The obtained solid was dried at 50 ° C. under reduced pressure, and 4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decane- Methyl 3-yl} methyl) benzoate (5.2 g, 95% yield) was obtained as a white solid.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.73 (2H, ddd, J = 14.0, 7.2, 7.4 Hz), 1.92 (2H, dt, J = 12.9, 4 .7 Hz), 2.62-2.47 (4H, m), 3.13 (2H, s), 3.56 (2H, s), 3.92 (3H, s), 4.48 (2H, s), 7.33 (2H, d, J = 8.3 Hz), 7.42 (2H, d, J = 8.3 Hz), 7.56 (2H, d, J = 8.3 Hz), 8. 03 (2H, d, J = 8.3 Hz).

LC / MS [Condition 1]: Retention time 3.25 minutes; m / z 462.9 [M + H] ⁺ (ESI positive ion mode), m / z 507.1 [M + HCOO] ⁻ (ESI negative ion mode)

参考例２−１
（１ｒ，４ｒ）−４−（アミノメチル）シクロヘキサンカルボン酸メチル塩酸塩の製造
ｔｒａｎｓ−４−アミノメチル−１−シクロヘキサンカルボン酸（東京化成工業（株）より購入）（３．９ｇ、２５ｍｍｏｌ）をメタノール（６０ｍＬ）に溶解し、１Ｍ塩化水素−メタノール（３９ｍＬ、７５ｍｍｏｌ）を加えて、室温にて７時間かき混ぜた。反応終了後、反応溶媒を減圧留去した。析出した固体をクロロホルムにて溶解させた後、シクロペンチルメチルエーテル（２０ｍＬ）を加え、再度析出した固体をろ取して、（１ｒ，４ｒ）−４−（アミノメチル）シクロヘキサンカルボン酸メチル塩酸塩（５．５ｇ、定量的）を無色固体として得た。

^１Ｈ−ＮＭＲ（３００ＭＨｚ，ＣＤＣｌ_３）δ：１．０８（２Ｈ，ｑ，Ｊ＝１１．９Ｈｚ），１．４８（２Ｈ，ｑ，Ｊ＝１２．７Ｈｚ），１．６８−１．８７（１Ｈ，ｍ），１．８８−２．１２（４Ｈ，ｍ），２．２６（１Ｈ，ｔｔ，Ｊ＝１２．３，３．３Ｈｚ），２．７６−２．９５（２Ｈ，ｂｒｍ），３．６６（３Ｈ，ｓ），８．３６（２Ｈ，ｂｒｓ）．

Reference Example 2-1
Preparation of methyl (1r, 4r) -4- (aminomethyl) cyclohexanecarboxylic acid hydrochloride trans-4-aminomethyl-1-cyclohexanecarboxylic acid (purchased from Tokyo Chemical Industry Co., Ltd.) (3.9 g, 25 mmol) It melt | dissolved in methanol (60 mL), 1M hydrogen chloride-methanol (39 mL, 75 mmol) was added, and it stirred at room temperature for 7 hours. After completion of the reaction, the reaction solvent was distilled off under reduced pressure. After the precipitated solid was dissolved in chloroform, cyclopentyl methyl ether (20 mL) was added, and the precipitated solid was again collected by filtration to obtain (1r, 4r) -4- (aminomethyl) cyclohexanecarboxylic acid methyl hydrochloride ( 5.5 g, quantitative) was obtained as a colorless solid.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.08 (2H, q, J = 11.9 Hz), 1.48 (2H, q, J = 12.7 Hz), 1.68-1.87 ( 1H, m), 1.88-2.12 (4H, m), 2.26 (1H, tt, J = 12.3, 3.3 Hz), 2.76-2.95 (2H, brm), 3.66 (3H, s), 8.36 (2H, brs).

参考例２−２
３−｛［（１ｒ，４ｒ）−４−（メトキシカルボニル）シクロヘキシル］メチル｝−２−オキソ−１−オキサ−３，８−ジアザスピロ［４．５］デカン−８−カルボン酸ｔ−ブチルの製造
参考例１−１で得られた、１−オキサ−６−アザスピロ［２．５］オクタン−６−カルボン酸ｔ−ブチル（３．２ｇ、１５ｍｍｏｌ）、参考例２−１で得られた（１ｒ，４ｒ）−４−（アミノメチル）シクロヘキサンカルボン酸メチル塩酸塩（３．４ｇ、１７ｍｍｏｌ）をメタノール−水混合溶媒（１：１、９６ｍＬ）に溶解し、１Ｍ水酸化ナトリウム水溶液（１５ｍＬ、１５ｍｍｏｌ）を加え、室温にて６日間かき混ぜた。反応終了後、メタノールを減圧留去後、クロロホルム（８０ｍＬ）と水（２０ｍＬ）を加えて、振とう、静置して、有機層を分離した。得られた有機層を無水硫酸ナトリウムで乾燥、減圧下濃縮して、反応中間体である４−ヒドロキシ−４−（｛［（１ｒ，４ｒ）−４−（メトキシカルボニル）シクロヘキシル］メチルアミノ｝メチル）ピペリジン−１−カルボン酸ｔ−ブチルを淡黄色油状物として得た。得られた４−ヒドロキシ−４−（｛［（１ｒ，４ｒ）−４−（メトキシカルボニル）シクロヘキシル］メチルアミノ｝メチル）ピペリジン−１−カルボン酸ｔ−ブチルを１，４−ジオキサン（２０ｍＬ）に溶解し、１，１’−カルボニルジイミダゾール（１．１ｇ、６６ｍｍｏｌ）を加えて、９０℃にて２日間攪拌した。反応終了後、反応溶媒を減圧留去して得られた残留物に水（５０ｍＬ）、１Ｍ塩酸（１００ｍＬ）及びクロロホルム（２００ｍＬ）を加えて、振とう、静置して、有機層を分離した。得られた有機層を無水硫酸ナトリウムにて乾燥、減圧下濃縮乾固し、３−｛［（１ｒ，４ｒ）−４−（メトキシカルボニル）シクロヘキシル］メチル｝−２−オキソ−１−オキサ−３，８−ジアザスピロ［４．５］デカン−８−カルボン酸ｔ−ブチル（３．３ｇ、収率５４％）を淡黄色無定形物として得た。

^１Ｈ−ＮＭＲ（３００ＭＨｚ，ＣＤＣｌ_３）δ：１．０３（２Ｈ，ｄｑ，Ｊ＝３．３，１２．９Ｈｚ），１．４２（２Ｈ，ｄｑ，Ｊ＝３．６，１２．９Ｈｚ），１．４６（９Ｈ，ｓ），１．５２−１．６２（１Ｈ，ｍ），１．６６（２Ｈ，ｄｄｄ，Ｊ＝１１．９，１２．２，４．６Ｈｚ），１．７７（２Ｈ，ｂｒｄ，Ｊ＝１３．２Ｈｚ），１．８８（２Ｈ，ｂｒｄ，Ｊ＝１３．２Ｈｚ），２．０２（２Ｈ，ｂｒｄ，Ｊ＝１３．５Ｈｚ），２．２６（１Ｈ，ｔｔ，Ｊ＝１２．２，３．３Ｈｚ），３．１０（２Ｈ，ｄ，Ｊ＝７．３Ｈｚ），３．２６（２Ｈ，ｓ），３．２７（２Ｈ，ｂｒｔ，Ｊ＝１１．６Ｈｚ），３．６７（３Ｈ，ｓ），３．７５−３．９７（２Ｈ，ｂｒｍ）．

Reference Example 2-2
Preparation of tert-butyl 3-{[(1r, 4r) -4- (methoxycarbonyl) cyclohexyl] methyl} -2-oxo-1-oxa-3,8-diazaspiro [4.5] decane-8-carboxylate 1-oxa-6-azaspiro [2.5] octane-6-carboxylate t-butyl obtained in Reference Example 1-1 (3.2 g, 15 mmol), obtained in Reference Example 2-1 (1r , 4r) -4- (aminomethyl) cyclohexanecarboxylic acid methyl hydrochloride (3.4 g, 17 mmol) was dissolved in a methanol-water mixed solvent (1: 1, 96 mL), and 1M aqueous sodium hydroxide solution (15 mL, 15 mmol) was dissolved. And stirred for 6 days at room temperature. After completion of the reaction, methanol was distilled off under reduced pressure, chloroform (80 mL) and water (20 mL) were added, and the mixture was shaken and allowed to stand to separate the organic layer. The obtained organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give 4-hydroxy-4-({[(1r, 4r) -4- (methoxycarbonyl) cyclohexyl] methylamino} methyl as a reaction intermediate. ) Piperidine-1-carboxylate t-butyl was obtained as a pale yellow oil. The resulting 4-hydroxy-4-({[(1r, 4r) -4- (methoxycarbonyl) cyclohexyl] methylamino} methyl) piperidine-1-carboxylate in 1,4-dioxane (20 mL) After dissolution, 1,1′-carbonyldiimidazole (1.1 g, 66 mmol) was added and stirred at 90 ° C. for 2 days. After completion of the reaction, the reaction solvent was distilled off under reduced pressure, water (50 mL), 1M hydrochloric acid (100 mL) and chloroform (200 mL) were added to the residue, shaken and allowed to stand, and the organic layer was separated. . The obtained organic layer was dried over anhydrous sodium sulfate and concentrated to dryness under reduced pressure to give 3-{[(1r, 4r) -4- (methoxycarbonyl) cyclohexyl] methyl} -2-oxo-1-oxa-3. , 8-diazaspiro [4.5] decane-8-carboxylate t-butyl (3.3 g, yield 54%) was obtained as a pale yellow amorphous product.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.03 (2H, dq, J = 3.3, 12.9 Hz), 1.42 (2H, dq, J = 3.6, 12.9 Hz), 1.46 (9H, s), 1.52-1.62 (1H, m), 1.66 (2H, ddd, J = 11.9, 12.2, 4.6 Hz), 1.77 (2H , Brd, J = 13.2 Hz), 1.88 (2H, brd, J = 13.2 Hz), 2.02 (2H, brd, J = 13.5 Hz), 2.26 (1H, tt, J = 12.2, 3.3 Hz), 3.10 (2H, d, J = 7.3 Hz), 3.26 (2H, s), 3.27 (2H, brt, J = 11.6 Hz), 3. 67 (3H, s), 3.75-3.97 (2H, brm).

参考例２−３
（１ｒ，４ｒ）−４−｛［８−（ｔ−ブトキシカルボニル）−２−オキソ−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル］メチル｝シクロヘキサンカルボン酸の製造
参考例２−２で得られた、３−｛［（１ｒ，４ｒ）−４−（メトキシカルボニル）シクロヘキシル］メチル｝−２−オキソ−１−オキサ−３，８−ジアザスピロ［４．５］デカン−８−カルボン酸ｔ−ブチル（１．９ｇ、４．５ｍｍｏｌ）を１，４−ジオキサン（４０ｍＬ）に溶解し、１Ｍ水酸化ナトリウム水溶液（６．８ｍＬ、６．８ｍｍｏｌ）を加えて、室温にて３時間かき混ぜた。反応終了後、減圧下濃縮して１，４−ジオキサンを留去した後、残留反応混合物に１Ｍ塩酸（６．８ｍＬ）と酢酸エチル（４０ｍＬ）を加えて、有機層を分離した。得られた有機層を減圧下濃縮乾固して、（１ｒ，４ｒ）−４−｛［８−（ｔ−ブトキシカルボニル）−２−オキソ−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル］メチル｝シクロヘキサンカルボン酸（１．９ｇ、定量的）を無色無定形物として得た。

^１Ｈ−ＮＭＲ（３００ＭＨｚ，ＣＤＣｌ_３）δ：１．０３（２Ｈ，ｄｑ，Ｊ＝３．３，１２．９Ｈｚ），１．４２（２Ｈ，ｄｑ，Ｊ＝３．６，１２．９Ｈｚ），１．４６（９Ｈ，ｓ），１．５２−１．６２（１Ｈ，ｍ），１．６６（２Ｈ，ｄｄｄ，Ｊ＝１１．９，１２．２，４．６Ｈｚ），１．７７（２Ｈ，ｂｒｄ，Ｊ＝１３．２Ｈｚ），１．８８（２Ｈ，ｂｒｄ，Ｊ＝１３．２Ｈｚ），２．０２（２Ｈ，ｂｒｄ，Ｊ＝１３．５Ｈｚ），２．２６（１Ｈ，ｔｔ，Ｊ＝１２．２，３．３Ｈｚ），３．１０（２Ｈ，ｄ，Ｊ＝７．３Ｈｚ），３．２６（２Ｈ，ｓ），３．２７（２Ｈ，ｂｒｔ，Ｊ＝１１．６Ｈｚ），３．７５−３．９７（２Ｈ，ｂｒｍ）．

ＬＣ／ＭＳ［条件１］：保持時間３．６５分；ｍ／ｚ３９５［Ｍ−Ｈ］⁻（ＥＳＩ負イオンモード）

Reference Example 2-3
Preparation of (1r, 4r) -4-{[8- (t-butoxycarbonyl) -2-oxo-1-oxa-3,8-diazaspiro [4.5] decan-3-yl] methyl} cyclohexanecarboxylic acid 3-{[(1r, 4r) -4- (methoxycarbonyl) cyclohexyl] methyl} -2-oxo-1-oxa-3,8-diazaspiro [4.5] decane obtained in Reference Example 2-2 Dissolve t-butyl-8-carboxylate (1.9 g, 4.5 mmol) in 1,4-dioxane (40 mL), add 1 M aqueous sodium hydroxide solution (6.8 mL, 6.8 mmol), and bring to room temperature. Stir for 3 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to distill off 1,4-dioxane, and then 1M hydrochloric acid (6.8 mL) and ethyl acetate (40 mL) were added to the residual reaction mixture to separate the organic layer. The obtained organic layer was concentrated to dryness under reduced pressure, and (1r, 4r) -4-{[8- (t-butoxycarbonyl) -2-oxo-1-oxa-3,8-diazaspiro [4.5 ] Decan-3-yl] methyl} cyclohexanecarboxylic acid (1.9 g, quantitative) was obtained as a colorless amorphous product.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.03 (2H, dq, J = 3.3, 12.9 Hz), 1.42 (2H, dq, J = 3.6, 12.9 Hz), 1.46 (9H, s), 1.52-1.62 (1H, m), 1.66 (2H, ddd, J = 11.9, 12.2, 4.6 Hz), 1.77 (2H , Brd, J = 13.2 Hz), 1.88 (2H, brd, J = 13.2 Hz), 2.02 (2H, brd, J = 13.5 Hz), 2.26 (1H, tt, J = 12.2, 3.3 Hz), 3.10 (2H, d, J = 7.3 Hz), 3.26 (2H, s), 3.27 (2H, brt, J = 11.6 Hz), 3. 75-3.97 (2H, brm).

LC / MS [Condition 1]: Retention time 3.65 minutes; m / z 395 [MH] ⁻ (ESI negative ion mode)

実施例２
２−オキソ−３−［（（１ｒ，４ｒ）−４−｛［（テトラヒドロフラン−２−イル）メチル］カルバモイル｝シクロヘキシル）メチル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−８−カルボン酸ｔ−ブチル（化合物番号２）の製造
参考例２−３で得られた、（１ｒ，４ｒ）−４−｛［８−（ｔ−ブトキシカルボニル）−２−オキソ−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル］メチル｝シクロヘキサンカルボン酸（７００ｍｇ、１．７ｍｍｏｌ）をクロロホルム（１４ｍＬ）に溶解し、テトラヒドロフルフリルアミン（０．２６ｍＬ、２．５ｍｍｏｌ）、１−ヒドロキシベンゾトリアゾール（２３０ｍｇ、１．７ｍｏｌ）及び１−エチル−３−（３−ジメチルアミノプロピル）カルボジイミド塩酸塩（４８０ｍｇ、２．５ｍｍｏｌ）を加え、室温にて４日間かき混ぜた。反応終了後、反応混合物を減圧下濃縮してクロロホルムを留去し、残留物に酢酸エチルと飽和炭酸水素ナトリウム水溶液を加え有機層を分離した。有機層を減圧下濃縮乾固して２−オキソ−３−［（（１ｒ，４ｒ）−４−｛［（テトラヒドロフラン−２−イル）メチル］カルバモイル｝シクロヘキシル）メチル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−８−カルボン酸ｔ−ブチル（８７０ｍｇ、定量的）を無色無定形物として得た。

^１Ｈ−ＮＭＲ（３００ＭＨｚ，ＣＤＣｌ_３）δ：１．０２（２Ｈ，ｍ），１．４６（９Ｈ，ｓ），１．４３−１．７９（７Ｈ），１．８７−２．０９（９Ｈ，ｍ），３．０８（２Ｈ，ｄ，Ｊ＝５．４Ｈｚ），３．０８−３．１６（１Ｈ，ｍ），３．２６（２Ｈ，ｓ），３．２６−３．３２（２Ｈ，ｍ），３．５４−３．６２（１Ｈ，ｍ），３．７２−３．７８（１Ｈ，ｍ），３．８２−３．９８（４Ｈ，ｍ）．

Example 2
2-Oxo-3-[((1r, 4r) -4-{[(tetrahydrofuran-2-yl) methyl] carbamoyl} cyclohexyl) methyl] -1-oxa-3,8-diazaspiro [4.5] decane- Production of t-butyl 8-carboxylate (Compound No. 2) (1r, 4r) -4-{[8- (t-butoxycarbonyl) -2-oxo-1-oxaxamine obtained in Reference Example 2-3 -3,8-diazaspiro [4.5] decan-3-yl] methyl} cyclohexanecarboxylic acid (700 mg, 1.7 mmol) was dissolved in chloroform (14 mL) and tetrahydrofurfurylamine (0.26 mL, 2.5 mmol) was dissolved. , 1-hydroxybenzotriazole (230 mg, 1.7 mol) and 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (4 0 mg, 2.5 mmol) and the mixture was stirred at room temperature for 4 days. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to distill off chloroform, and ethyl acetate and saturated aqueous sodium hydrogen carbonate solution were added to the residue to separate the organic layer. The organic layer was concentrated to dryness under reduced pressure to give 2-oxo-3-[((1r, 4r) -4-{[(tetrahydrofuran-2-yl) methyl] carbamoyl} cyclohexyl) methyl] -1-oxa-3, T-butyl 8-diazaspiro [4.5] decane-8-carboxylate (870 mg, quantitative) was obtained as a colorless amorphous product.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.02 (2H, m), 1.46 (9H, s), 1.43-1.79 (7H), 1.87-2.09 (9H M), 3.08 (2H, d, J = 5.4 Hz), 3.08-3.16 (1H, m), 3.26 (2H, s), 3.26-3.32 (2H M), 3.54-3.62 (1H, m), 3.72-3.78 (1H, m), 3.82-3.98 (4H, m).

実施例３
（１ｒ，４ｒ）−４−［（２−オキソ−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル）メチル］−Ｎ−［（テトラヒドロフラン−２−イル）メチル］シクロヘキサンカルボキサミド塩酸塩（化合物番号３）の製造
実施例２で得られた、２−オキソ−３−［（（１ｒ，４ｒ）−４−｛［（テトラヒドロフラン−２−イル）メチル］カルバモイル｝シクロヘキシル）メチル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−８−カルボン酸ｔ−ブチル（１．２ｇ、２．４ｍｍｏｌ）をメタノール（２０ｍＬ）に溶解し、室温にて４Ｍ塩化水素−ジオキサン溶液（３．０ｍＬ、１２ｍｍｏｌ）を加えて、５０℃にて１日間かき混ぜた。反応終了後、減圧下濃縮乾固して（１ｒ，４ｒ）−４−［（２−オキソ−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル）メチル］−Ｎ−［（テトラヒドロフラン−２−イル）メチル］シクロヘキサンカルボキサミド塩酸塩（１．０ｇ、定量的）を無色無定形物として得た。

^１Ｈ−ＮＭＲ（３００ＭＨｚ，ＤＭＳＯ−ｄ_６）δ：０．８２−０．９３（２Ｈ，ｍ），１．２７−１．３９（２Ｈ，ｍ），１．４４−１．５２（２Ｈ，ｍ），１．６４−１．８８（７Ｈ），１．９９−２．１３（５Ｈ，ｍ），２．９７（２Ｈ，ｄ，Ｊ＝６．６Ｈｚ），３．０８−３．１６（６Ｈ，ｍ），３．４０（２Ｈ，ｓ），３．４５−３．６２（３Ｈ，ｍ），７．８１（１Ｈ，ｂｒｓ），９．２３−９．３２（２Ｈ，ｂｒｍ）．

Example 3
(1r, 4r) -4-[(2-oxo-1-oxa-3,8-diazaspiro [4.5] decan-3-yl) methyl] -N-[(tetrahydrofuran-2-yl) methyl] cyclohexane Preparation of carboxamide hydrochloride (Compound No. 3) 2-oxo-3-[((1r, 4r) -4-{[(tetrahydrofuran-2-yl) methyl] carbamoyl} cyclohexyl) methyl obtained in Example 2 ] 1-Oxa-3,8-diazaspiro [4.5] t-butyl decane-8-carboxylate (1.2 g, 2.4 mmol) was dissolved in methanol (20 mL), and 4M hydrogen chloride- Dioxane solution (3.0 mL, 12 mmol) was added and stirred at 50 ° C. for 1 day. After completion of the reaction, the reaction mixture was concentrated to dryness under reduced pressure to give (1r, 4r) -4-[(2-oxo-1-oxa-3,8-diazaspiro [4.5] decan-3-yl) methyl] -N- [(Tetrahydrofuran-2-yl) methyl] cyclohexanecarboxamide hydrochloride (1.0 g, quantitative) was obtained as a colorless amorphous product.

¹ H-NMR (300 MHz, DMSO-d ₆ ) δ: 0.82-0.93 (2H, m), 1.27-1.39 (2H, m), 1.44-1.52 (2H, m), 1.64-1.88 (7H), 1.99-2.13 (5H, m), 2.97 (2H, d, J = 6.6 Hz), 3.08-3.16 ( 6H, m), 3.40 (2H, s), 3.45-3.62 (3H, m), 7.81 (1H, brs), 9.23-9.32 (2H, brm).

実施例４
（１ｒ，４ｒ）−４−｛［２−オキソ−８−（ピリジン−３−イルメチル）−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル］メチル｝−Ｎ−［（テトラヒドロフラン−２−イル）メチル］シクロヘキサンカルボキサミド（化合物番号４）の製造
実施例３で得られた、（１ｒ，４ｒ）−４−［（２−オキソ−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル）メチル］−Ｎ−［（テトラヒドロフラン−２−イル）メチル］シクロヘキサンカルボキサミド塩酸塩（５０ｍｇ、０．１３ｍｍｏｌ）をＮ，Ｎ−ジメチルホルムアミド（１．０ｍＬ）に溶解し、室温にてトリエチルアミン（０．０５５ｍＬ、０．３３ｍｍｏｌ）と３−（ブロモメチル）ピリジン臭化水素酸塩（４９ｍｇ、０．１７ｍｍｏｌ）を加えて、室温で１日間かき混ぜた。反応終了後、酢酸エチルを加え、水で洗浄し、無水硫酸ナトリウムで乾燥、減圧留去した。得られた反応残渣をシリカゲルカラムクロマトグラフィー［充填剤：富士シリシア製ＦＬ１００Ｄ、展開溶媒：クロロホルム／メタノール＝３０／１］にて精製し、（１ｒ，４ｒ）−４−｛［２−オキソ−８−（ピリジン−３−イルメチル）−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル］メチル｝−Ｎ−［（テトラヒドロフラン−２−イル）メチル］シクロヘキサンカルボキサミド（２．９ｍｇ、収率４％）を無色無定形物として得た。

^１Ｈ−ＮＭＲ（３００ＭＨｚ，ＣＤＣｌ_３）δ：１．００−１．０４（２Ｈ，ｍ），１．４７−１．５８（４Ｈ，ｍ），１．６９−１．７９（５Ｈ，ｍ），１．８７−２．０５（７Ｈ，ｍ），２．５７（４Ｈ，ｂｒｍ），３．０９（２Ｈ，ｄ，Ｊ＝７．４Ｈｚ），３．２５（２Ｈ，ｓ），３．５４（２Ｈ，ｓ），３．５６−３．６２（１Ｈ，ｍ），３．７３−３．７８（１Ｈ，ｍ），３．８４−３．８６（１Ｈ，ｍ），３．９２−３．９４（１Ｈ，ｍ），５．８１（１Ｈ，ｂｒｓ），７．２５（１Ｈ，ｄｄ，Ｊ＝７．７，５．１Ｈｚ），７．６４（１Ｈ，ｄ，Ｊ＝７．７Ｈｚ），８．５１（１Ｈ，ｄ，Ｊ＝５．１Ｈｚ），８．５６（１Ｈ，ｓ）．

Example 4
(1r, 4r) -4-{[2-oxo-8- (pyridin-3-ylmethyl) -1-oxa-3,8-diazaspiro [4.5] decan-3-yl] methyl} -N- [ Preparation of (tetrahydrofuran-2-yl) methyl] cyclohexanecarboxamide (Compound No. 4) (1r, 4r) -4-[(2-oxo-1-oxa-3,8-diazaspiro [3] obtained in Example 3 4.5] decan-3-yl) methyl] -N-[(tetrahydrofuran-2-yl) methyl] cyclohexanecarboxamide hydrochloride (50 mg, 0.13 mmol) dissolved in N, N-dimethylformamide (1.0 mL) At room temperature, triethylamine (0.055 mL, 0.33 mmol) and 3- (bromomethyl) pyridine hydrobromide (49 mg, 0.17 mmol) were added. And the mixture was stirred at room temperature for 1 day. After completion of the reaction, ethyl acetate was added, washed with water, dried over anhydrous sodium sulfate and evaporated under reduced pressure. The obtained reaction residue was purified by silica gel column chromatography [filler: FL100D manufactured by Fuji Silysia, developing solvent: chloroform / methanol = 30/1], and (1r, 4r) -4-{[2-oxo-8 -(Pyridin-3-ylmethyl) -1-oxa-3,8-diazaspiro [4.5] decan-3-yl] methyl} -N-[(tetrahydrofuran-2-yl) methyl] cyclohexanecarboxamide (2.9 mg Yield 4%) as a colorless amorphous product.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.00-1.04 (2H, m), 1.47-1.58 (4H, m), 1.69-1.79 (5H, m) , 1.87-2.05 (7H, m), 2.57 (4H, brm), 3.09 (2H, d, J = 7.4 Hz), 3.25 (2H, s), 3.54 (2H, s), 3.56-3.62 (1H, m), 3.73-3.78 (1H, m), 3.84-3.86 (1H, m), 3.92-3 .94 (1H, m), 5.81 (1H, brs), 7.25 (1H, dd, J = 7.7, 5.1 Hz), 7.64 (1H, d, J = 7.7 Hz) 8.51 (1H, d, J = 5.1 Hz), 8.56 (1H, s).

実施例５
（１ｒ，４ｒ）−４−（｛８−［２−（エチルチオ）エチル］−２−オキソ−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）−Ｎ−［（テトラヒドロフラン−２−イル）メチル］シクロヘキサンカルボキサミド（化合物番号５）の製造
３−（ブロモメチル）ピリジン臭化水素酸塩の代わりに、２−ブロモエチルエチルスルフィドを用いること以外は実質的に実施例４と同様に反応を行なって、表題化合物（３．１ｍｇ、収率７％）を無色粉末として得た。

^１Ｈ−ＮＭＲ（３００ＭＨｚ，ＣＤＣｌ_３）δ：０．９６−１．０８（２Ｈ，ｍ），１．２７（３Ｈ，ｔ，Ｊ＝７．２Ｈｚ）１．４３−１．６０（４Ｈ，ｍ），１．７５−２．０８（１２Ｈ，ｍ），２．５３−２．６５（８Ｈ，ｍ），２．５７（２Ｈ，ｑ，Ｊ＝７．２Ｈｚ），３．０９（２Ｈ，ｄ，Ｊ＝７．８Ｈｚ），３．０７−３．１５（１Ｈ，ｍ），３．２５（２Ｈ，ｓ），３．５５−３．６３（１Ｈ，ｍ），３．７１−３．９８（３Ｈ，ｍ），５．８１（１Ｈ，ｂｒｓ）．

Example 5
(1r, 4r) -4-({8- [2- (ethylthio) ethyl] -2-oxo-1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl) -N- Preparation of [(Tetrahydrofuran-2-yl) methyl] cyclohexanecarboxamide (Compound No. 5) Substantially Examples except using 2-bromoethylethyl sulfide instead of 3- (bromomethyl) pyridine hydrobromide The reaction was performed in the same manner as in 4 to obtain the title compound (3.1 mg, yield 7%) as a colorless powder.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 0.96-1.08 (2H, m), 1.27 (3H, t, J = 7.2 Hz) 1.43-1.60 (4H, m ), 1.75-2.08 (12H, m), 2.53-2.65 (8H, m), 2.57 (2H, q, J = 7.2 Hz), 3.09 (2H, d) , J = 7.8 Hz), 3.07-3.15 (1H, m), 3.25 (2H, s), 3.55-3.63 (1H, m), 3.71-3.98. (3H, m), 5.81 (1H, brs).

参考例６−１
（１ｒ，４ｒ）−４−［（２−オキソ−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル）メチル］シクロヘキサンカルボン酸メチル塩酸塩の製造
参考例２−２で得られた、３−｛［（１ｒ，４ｒ）−４−（メトキシカルボニル）シクロヘキシル］メチル｝−２−オキソ−１−オキサ−３，８−ジアザスピロ［４．５］デカン−８−カルボン酸ｔ−ブチル（２．４ｇ、５．８ｍｍｏｌ）をメタノール（３０ｍＬ）に溶解し、０℃にて４Ｍ塩化水素−ジオキサン溶液（１５ｍＬ、５８ｍｍｏｌ）を加えて、室温まで昇温して１日間かき混ぜた。その後、減圧下濃縮乾固して（１ｒ，４ｒ）−４−［（２−オキソ−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル）メチル］シクロヘキサンカルボン酸メチル塩酸塩（２．１ｇ、定量的）を白色粉末として得た。

^１Ｈ−ＮＭＲ（３００ＭＨｚ，ＣＤＣｌ_３）δ：１．０２（２Ｈ，ｑ，Ｊ＝１２．３Ｈｚ），１．４２（２Ｈ，ｑ，Ｊ＝１２．７Ｈｚ），１．５１−１．６６（１Ｈ，ｍ），１．７６（２Ｈ，ｄ，Ｊ＝１１．５Ｈｚ），１．９７−２．１５（４Ｈ，ｍ），２．１９−２．４１（３Ｈ，ｍ），３．１１（２Ｈ，ｄ，Ｊ＝７．４Ｈｚ），３．２１−３．４０（４Ｈ，ｍ），３．４１−３．５５（２Ｈ，ｍ），３．６７（３Ｈ，ｓ），９．７５（２Ｈ，ｂｒｓ）．

ＬＣ／ＭＳ［条件１］：保持時間０．８２分；ｍ／ｚ３１１．０［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）

Reference Example 6-1
Preparation of (1r, 4r) -4-[(2-oxo-1-oxa-3,8-diazaspiro [4.5] decan-3-yl) methyl] cyclohexanecarboxylic acid methyl hydrochloride In Reference Example 2-2 The resulting 3-{[(1r, 4r) -4- (methoxycarbonyl) cyclohexyl] methyl} -2-oxo-1-oxa-3,8-diazaspiro [4.5] decane-8-carboxylic acid t -Butyl (2.4 g, 5.8 mmol) was dissolved in methanol (30 mL), 4 M hydrogen chloride-dioxane solution (15 mL, 58 mmol) was added at 0 ° C., and the mixture was warmed to room temperature and stirred for 1 day. Thereafter, the solution was concentrated to dryness under reduced pressure, and (1r, 4r) -4-[(2-oxo-1-oxa-3,8-diazaspiro [4.5] decan-3-yl) methyl] cyclohexanecarboxylate methyl hydrochloride The salt (2.1 g, quantitative) was obtained as a white powder.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.02 (2H, q, J = 12.3 Hz), 1.42 (2H, q, J = 12.7 Hz), 1.51-1.66 ( 1H, m), 1.76 (2H, d, J = 11.5 Hz), 1.97-2.15 (4H, m), 2.19-2.41 (3H, m), 3.11 ( 2H, d, J = 7.4 Hz), 3.21-3.40 (4H, m), 3.41-3.55 (2H, m), 3.67 (3H, s), 9.75 ( 2H, brs).

LC / MS [Condition 1]: Retention time 0.82 minutes; m / z 311.0 [M + H] ⁺ (ESI positive ion mode)

参考例６−２
（１ｒ，４ｒ）−４−（｛２−オキソ−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）シクロヘキサンカルボン酸メチルの製造
参考合成例６−１で得られた、（１ｒ，４ｒ）−４−［（２−オキソ−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル）メチル］シクロヘキサンカルボン酸メチル塩酸塩（２．１ｇ、５．９ｍｍｏｌ）をＮ，Ｎ−ジメチルホルムアミド（２２ｍＬ）に溶解した後、室温にて４−（トリフルオロメチル）ベンジルブロミド（１．６ｇ、６．５ｍｍｏｌ）、トリエチルアミン（２．５ｍＬ、１８ｍｍｏｌ）を加えて、室温で１日間かき混ぜた。その後、水８０ｍＬを加え、析出した固体をろ取して、（１ｒ，４ｒ）−４−（｛２−オキソ−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）シクロヘキサンカルボン酸メチル（２．６ｇ、収率９４％）を白色粉末として得た。

^１Ｈ−ＮＭＲ（３００ＭＨｚ，ＣＤＣｌ_３）δ：０．９３−１．１１（２Ｈ，ｍ），１．３３−１．４９（２Ｈ，ｍ），１．５０−１．６６（１Ｈ，ｍ），１．７０−１．８６（４Ｈ，ｍ），１．８８−２．０８（４Ｈ，ｍ），２．２５（１Ｈ，ｔｔ，Ｊ＝１２．１，３．５Ｈｚ），２．５７（４Ｈ，ｂｒｓ），３．０９（２Ｈ，ｄ，Ｊ＝７．４Ｈｚ），３．２７（２Ｈ，ｓ），３．５８（２Ｈ，ｂｒｓ），３．６６（３Ｈ，ｓ），７．３３−７．７２（４Ｈ，ｂｒｍ）．

ＬＣ／ＭＳ［条件１］：保持時間３．２６分；ｍ／ｚ４６９．２［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ５１２．９［Ｍ＋ＨＣＯＯ］^―（ＥＳＩ負イオンモード）

Reference Example 6-2
(1r, 4r) -4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl) cyclohexane Production of methyl carboxylate (1r, 4r) -4-[(2-oxo-1-oxa-3,8-diazaspiro [4.5] decan-3-yl) obtained in Reference Synthesis Example 6-1 Methyl] cyclohexanecarboxylic acid methyl hydrochloride (2.1 g, 5.9 mmol) was dissolved in N, N-dimethylformamide (22 mL) and then 4- (trifluoromethyl) benzyl bromide (1.6 g, 6) at room temperature. 0.5 mmol) and triethylamine (2.5 mL, 18 mmol) were added, and the mixture was stirred at room temperature for 1 day. Thereafter, 80 mL of water was added, and the precipitated solid was collected by filtration, and (1r, 4r) -4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8 -Diazaspiro [4.5] decan-3-yl} methyl) methyl cyclohexanecarboxylate (2.6 g, 94% yield) was obtained as a white powder.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 0.93-1.11 (2H, m), 1.33-1.49 (2H, m), 1.50-1.66 (1H, m) , 1.70-1.86 (4H, m), 1.88-2.08 (4H, m), 2.25 (1H, tt, J = 12.1, 3.5 Hz), 2.57 ( 4H, brs), 3.09 (2H, d, J = 7.4 Hz), 3.27 (2H, s), 3.58 (2H, brs), 3.66 (3H, s), 7.33 -7.72 (4H, brm).

LC / MS [Condition 1]: Retention time 3.26 minutes; m / z 469.2 [M + H] ⁺ (ESI positive ion mode), m / z 512.9 [M + HCOO] ⁻ (ESI negative ion mode)

参考例６−３
（１ｒ，４ｒ）−４−（｛２−オキソ−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）シクロヘキサンカルボン酸の製造
参考例６−２で得られた、（１ｒ，４ｒ）−４−（｛２−オキソ−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）シクロヘキサンカルボン酸メチル（２．６ｇ、５．６ｍｍｏｌ）をメタノール（２８ｍＬ）に溶解した後、室温にて１Ｍ水酸化ナトリウム水溶液（８．４ｍＬ、８４ｍｍｏｌ）を加えて、６０℃で１時間かき混ぜた。その後、減圧下濃縮してメタノールを留去し、水（２５ｍＬ）を加えた。１Ｍ塩酸をｐＨ６になるまで加え、析出した固体をろ取して（１ｒ，４ｒ）−４−（｛２−オキソ−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）シクロヘキサンカルボン酸（２．３ｇ、収率９０％）を白色粉末として得た。

^１Ｈ−ＮＭＲ（３００ＭＨｚ，ＣＤＣｌ_３）δ：０．９４−１．１３（２Ｈ，ｍ），１．３３−１．５１（２Ｈ，ｍ），１．５１−１．６８（１Ｈ，ｍ），１．７２−２．１４（８Ｈ，ｍ），２．２０−２．３５（１Ｈ，ｍ），２．６１（４Ｈ，ｂｒｓ），３．１０（２Ｈ，ｄ，Ｊ＝７．４Ｈｚ），３．２７（２Ｈ，ｓ），３．６１（２Ｈ，ｂｒｓ），７．４５（２Ｈ，ｄ，Ｊ＝７．４Ｈｚ），７．５９（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ）．

ＬＣ／ＭＳ［条件１］：保持時間２．９０分；ｍ／ｚ４５４．８［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ４５２．９［Ｍ−Ｈ］^―（ＥＳＩ負イオンモード）

Reference Example 6-3
(1r, 4r) -4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl) cyclohexane Production of carboxylic acid (1r, 4r) -4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro obtained in Reference Example 6-2 [4.5] Methyl [decane-3-yl} methyl) cyclohexanecarboxylate (2.6 g, 5.6 mmol) was dissolved in methanol (28 mL), and then 1 M aqueous sodium hydroxide solution (8.4 mL, 84 mmol) at room temperature. ) And stirred at 60 ° C. for 1 hour. Then, it concentrated under pressure reduction, methanol was distilled off, and water (25 mL) was added. 1M hydrochloric acid was added until the pH reached 6, and the precipitated solid was collected by filtration to give (1r, 4r) -4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3, 8-Diazaspiro [4.5] decan-3-yl} methyl) cyclohexanecarboxylic acid (2.3 g, 90% yield) was obtained as a white powder.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 0.94-1.13 (2H, m), 1.33-1.51 (2H, m), 1.51-1.68 (1H, m) , 1.72-2.14 (8H, m), 2.20-2.35 (1H, m), 2.61 (4H, brs), 3.10 (2H, d, J = 7.4 Hz) 3.27 (2H, s), 3.61 (2H, brs), 7.45 (2H, d, J = 7.4 Hz), 7.59 (2H, d, J = 8.2 Hz).

LC / MS [Condition 1]: Retention time 2.90 minutes; m / z 454.8 [M + H] ⁺ (ESI positive ion mode), m / z 452.9 [M−H] ⁻ (ESI negative ion mode)

実施例６
４−［（１ｒ，４ｒ）−４−（｛２−オキソ−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）シクロヘキサンカルボキサミド］ピペリジン−１−カルボン酸ｔ−ブチル（化合物番号６）の製造
参考例６−３で得られた、（１ｒ，４ｒ）−４−（｛２−オキソ−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）シクロヘキサンカルボン酸（９２ｍｇ、０．２０ｍｍｏｌ）と４−アミノピペリジン−１−カルボン酸ｔ−ブチル（４５ｍｇ、０．２２ｍｍｏｌ）、そして１−ヒドロキシベンゾトリアゾール（２７ｍｇ、０．２０ｍｏｌ）をクロロホルム（１．０ｍｌ）に溶解した後、室温にて、１−エチル−３−（３−ジメチルアミノプロピル）カルボジイミド塩酸塩（４６ｍｇ、０．２２ｍｍｏｌ）を加え、室温で３日間かき混ぜた。その後、反応混合物を減圧下濃縮してクロロホルムを留去し、残留物に酢酸エチルと飽和炭酸水素ナトリウム水溶液を加え有機層を分離した。有機層を無水硫酸ナトリウムで乾燥した後、減圧下濃縮乾固して４−［（１ｒ，４ｒ）−４−（｛２−オキソ−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）シクロヘキサンカルボキサミド］ピペリジン−１−カルボン酸ｔ−ブチル（１２０ｍｇ、収率８９％）を白色粉末として得た。

^１Ｈ−ＮＭＲ（３００ＭＨｚ，ＣＤＣｌ_３）δ：１．０１（２Ｈ，ｑｄ，Ｊ＝１３．１，３．３Ｈｚ），１．２７（２Ｈ，ｑｄ，Ｊ＝１１．９，４．１Ｈｚ），１．３９−１．６７（１３Ｈ，ｍ），１．７０−２．０６（１０Ｈ，ｍ），２．５６（４Ｈ，ｂｒｓ），２．８４（２Ｈ，ｔ，Ｊ＝１１．９Ｈｚ），３．０９（２Ｈ，ｄ，Ｊ＝７．４Ｈｚ），３．２５（２Ｈ，ｓ），３．５７（２Ｈ，ｓ），３．８１−３．９８（１Ｈ，ｍ），３．９７−４．１２（２Ｈ，ｂｒｍ），５．４２（１Ｈ，ｄ，Ｊ＝７．４Ｈｚ），７．４４（２Ｈ，ｄ，Ｊ＝７．８Ｈｚ），７．５７（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ）．

ＬＣ／ＭＳ［条件１］：保持時間３．４６分；ｍ／ｚ６３６．９［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード））、ｍ／ｚ６８１．０［Ｍ＋ＨＣＯＯ］^―（ＥＳＩ負イオンモード）

Example 6
4-[(1r, 4r) -4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} (Methyl) cyclohexanecarboxamide] piperidine-1-carboxylate t-butyl (Compound No. 6) (1r, 4r) -4-({2-oxo-8- [4- (Trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl) cyclohexanecarboxylic acid (92 mg, 0.20 mmol) and 4-aminopiperidine-1-carboxylic acid After dissolving t-butyl (45 mg, 0.22 mmol) and 1-hydroxybenzotriazole (27 mg, 0.20 mol) in chloroform (1.0 ml), at room temperature, - ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (46 mg, 0.22 mmol) and the mixture was stirred at room temperature for 3 days. Thereafter, the reaction mixture was concentrated under reduced pressure to distill off chloroform, and ethyl acetate and saturated aqueous sodium hydrogen carbonate solution were added to the residue to separate the organic layer. The organic layer was dried over anhydrous sodium sulfate and then concentrated to dryness under reduced pressure to give 4-[(1r, 4r) -4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1- Oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl) cyclohexanecarboxamide] piperidine-1-carboxylate (120 mg, 89% yield) was obtained as a white powder.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.01 (2H, qd, J = 13.1, 3.3 Hz), 1.27 (2H, qd, J = 11.9, 4.1 Hz), 1.39-1.67 (13H, m), 1.70-2.06 (10H, m), 2.56 (4H, brs), 2.84 (2H, t, J = 11.9 Hz), 3.09 (2H, d, J = 7.4 Hz), 3.25 (2H, s), 3.57 (2H, s), 3.81-3.98 (1H, m), 3.97- 4.12 (2H, brm), 5.42 (1H, d, J = 7.4 Hz), 7.44 (2H, d, J = 7.8 Hz), 7.57 (2H, d, J = 8) .2 Hz).

LC / MS [Condition 1]: Retention time 3.46 minutes; m / z 636.9 [M + H] ⁺ (ESI positive ion mode)), m / z 681.0 [M + HCOO] ⁻ (ESI negative ion mode)

実施例７
（１ｒ，４ｒ）−４−（｛２−オキソ−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）−Ｎ−（ピペリジン−４−イル）シクロヘキサンカルボキサミド２塩酸塩（化合物番号７）の製造
実施例６で得られた、４−［（１ｒ，４ｒ）−４−（｛２−オキソ−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）シクロヘキサンカルボキサミド］ピペリジン−１−カルボン酸ｔ−ブチル（４９ｍｇ、０．０７７ｍｍｏｌ）をメタノール（０．５０ｍＬ）に溶解し、室温にて４Ｍ塩化水素−ジオキサン溶液（０．１９ｍＬ、０．７７ｍｍｏｌ）を加えて、室温で１日間かき混ぜた。その後、減圧下濃縮乾固して（１ｒ，４ｒ）−４−（｛２−オキソ−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）−Ｎ−（ピペリジン−４−イル）シクロヘキサンカルボキサミド２塩酸塩（４７ｍｇ、定量的）を白色粉末として得た。

ＬＣ／ＭＳ［条件１］：保持時間１．１０分；ｍ／ｚ５３６．８［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ５８１．０［Ｍ＋ＨＣＯＯ］^―（ＥＳＩ負イオンモード）

Example 7
(1r, 4r) -4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl)- Preparation of N- (piperidin-4-yl) cyclohexanecarboxamide dihydrochloride (Compound No. 7) 4-[(1r, 4r) -4-({2-oxo-8- [4] obtained in Example 6 -(Trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl) cyclohexanecarboxamide] piperidine-1-carboxylate (49 mg, 0.077 mmol) Was dissolved in methanol (0.50 mL), 4M hydrogen chloride-dioxane solution (0.19 mL, 0.77 mmol) was added at room temperature, and the mixture was stirred at room temperature for 1 day. Then, it was concentrated to dryness under reduced pressure to give (1r, 4r) -4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5]. Decan-3-yl} methyl) -N- (piperidin-4-yl) cyclohexanecarboxamide dihydrochloride (47 mg, quantitative) was obtained as a white powder.

LC / MS [Condition 1]: Retention time 1.10 minutes; m / z 536.8 [M + H] ⁺ (ESI positive ion mode), m / z 581.0 [M + HCOO] ⁻ (ESI negative ion mode)

実施例８
４−［（１ｒ，４ｒ）−４−（｛２−オキソ−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）シクロヘキサンカルボキサミド］ピペリジン−１−カルボン酸メチル（化合物番号８）の製造
実施例７で得られた、（１ｒ，４ｒ）−４−（｛２−オキソ−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）−Ｎ−（ピペリジン−４−イル）シクロヘキサンカルボキサミド２塩酸塩（２０ｍｇ、０．０３３ｍｍｏｌ）を酢酸エチル（１．０ｍＬ）に溶解し、室温にてトリエチルアミン（０．０２３ｍＬ、０．１７ｍｍｏｌ）とクロロギ酸メチル（０．０３８ｍＬ、０．０５０ｍｍｏｌ）を加えて、室温で１日間かき混ぜた。その後、水を加えて有機層を分離し、有機層を無水硫酸ナトリウムで乾燥した後、減圧下濃縮乾固して４−［（１ｒ，４ｒ）−４−（｛２−オキソ−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）シクロヘキサンカルボキサミド］ピペリジン−１−カルボン酸メチル（４．３ｍｇ、収率２２％）を白色粉末として得た。

^１Ｈ−ＮＭＲ（３００ＭＨｚ，ＣＤＣｌ_３）δ：１．００（２Ｈ，ｑｄ，Ｊ＝１２．７，２．５Ｈｚ），１．２０−１．３８（２Ｈ，ｍ），１．３９−１．６７（３Ｈ，ｍ），１．７０−２．０６（１１Ｈ，ｍ），２．５６（４Ｈ，ｂｒｓ），２．９０（２Ｈ，ｔ，Ｊ＝１１．９Ｈｚ），３．０９（２Ｈ，ｄ，Ｊ＝７．４Ｈｚ），３．２５（２Ｈ，ｓ），３．５７（２Ｈ，ｓ），３．６９（３Ｈ，ｓ），３．８２−４．００（１Ｈ，ｍ），４．００−４．２４（２Ｈ，ｍ），５．４６（１Ｈ，ｄ，Ｊ＝７．８Ｈｚ），７．４４（２Ｈ，ｄ，Ｊ＝７．８Ｈｚ），７．５７（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ）．

ＬＣ／ＭＳ［条件１］：保持時間３．１６分；ｍ／ｚ５９５．０［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、

Example 8
4-[(1r, 4r) -4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} Preparation of methyl) cyclohexanecarboxamide] piperidine-1-carboxylate (Compound No. 8) (1r, 4r) -4-({2-oxo-8- [4- (trifluoromethyl) obtained in Example 7 )] Benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl) -N- (piperidin-4-yl) cyclohexanecarboxamide dihydrochloride (20 mg, 0.033 mmol) Dissolve in ethyl (1.0 mL), add triethylamine (0.023 mL, 0.17 mmol) and methyl chloroformate (0.038 mL, 0.050 mmol) at room temperature, And the mixture was stirred for 1 day with warm. Thereafter, water was added to separate the organic layer, and the organic layer was dried over anhydrous sodium sulfate and then concentrated to dryness under reduced pressure to give 4-[(1r, 4r) -4-({2-oxo-8- [ 4- (Trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl) cyclohexanecarboxamide] piperidine-1-carboxylate methyl (4.3 mg, yield 22 %) As a white powder.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.00 (2H, qd, J = 12.7, 2.5 Hz), 1.20-1.38 (2H, m), 1.39-1. 67 (3H, m), 1.70-2.06 (11H, m), 2.56 (4H, brs), 2.90 (2H, t, J = 11.9 Hz), 3.09 (2H, d, J = 7.4 Hz), 3.25 (2H, s), 3.57 (2H, s), 3.69 (3H, s), 3.82-4.00 (1H, m), 4 .00-4.24 (2H, m), 5.46 (1H, d, J = 7.8 Hz), 7.44 (2H, d, J = 7.8 Hz), 7.57 (2H, d, J = 8.2 Hz).

LC / MS [Condition 1]: retention time 3.16 minutes; m / z 595.0 [M + H] ⁺ (ESI positive ion mode),

実施例９
（１ｒ，４ｒ）−Ｎ−［１−（シアノメチル）ピペリジン−４−イル］−４−（｛２−オキソ−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）シクロヘキサンカルボキサミド（化合物番号９）の製造
実施例７で得られた、（１ｒ，４ｒ）−４−（｛２−オキソ−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）−Ｎ−（ピペリジン−４−イル）シクロヘキサンカルボキサミド２塩酸塩（１５ｍｇ、０．０２４ｍｍｏｌ）を酢酸エチル（１．０ｍＬ）に懸濁させて、室温にてトリエチルアミン（０．０１７ｍＬ、０．１２ｍｍｏｌ）とブロモアセトニトリル（０．０２０ｍＬ、０．０２９ｍｍｏｌ）を加えて、室温で１日間かき混ぜた。その後、反応混合物を減圧下濃縮乾固して、得られた残渣をシリカゲルカラムクロマトグラフィー［充填剤：富士シリシア製ＦＬ１００Ｄ、展開溶媒：クロロホルム／メタノール＝１０／１］にて精製し、（１ｒ，４ｒ）−Ｎ−［１−（シアノメチル）ピペリジン−４−イル］−４−（｛２−オキソ−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）シクロヘキサンカルボキサミド（１．８ｍｇ、収率１３％）を白色粉末として得た。

^１Ｈ−ＮＭＲ（３００ＭＨｚ，ＣＤＣｌ_３）δ：１．０１（２Ｈ，ｑ，Ｊ＝１２．７Ｈｚ），１．３８−１．６７（６Ｈ，ｍ），１．７１−１．８４（４Ｈ，ｍ），１．８４−２．０６（６Ｈ，ｍ），２．４５（２Ｈ，ｔｄ，Ｊ＝１１．２，２．５Ｈｚ），２．６１（４Ｈ，ｂｒｓ），２．７２−２．８２（２Ｈ，ｍ），３．０９（２Ｈ，ｄ，Ｊ＝７．４Ｈｚ），３．２５（２Ｈ，ｓ），３．５０（２Ｈ，ｓ），３．５７（２Ｈ，ｓ），３．７２−３．９０（１Ｈ，ｍ），５．３０（１Ｈ，ｄ，Ｊ＝７．８Ｈｚ），７．４３（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ），７．５６（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ）．

ＬＣ／ＭＳ［条件１］：保持時間２．９２分；ｍ／ｚ５７５．９［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ６２０．０［Ｍ＋ＨＣＯＯ］^―（ＥＳＩ負イオンモード）

Example 9
(1r, 4r) -N- [1- (cyanomethyl) piperidin-4-yl] -4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8- Preparation of diazaspiro [4.5] decan-3-yl} methyl) cyclohexanecarboxamide (Compound No. 9) (1r, 4r) -4-({2-oxo-8- [4- (Trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl) -N- (piperidin-4-yl) cyclohexanecarboxamide dihydrochloride (15 mg, .0. 024 mmol) was suspended in ethyl acetate (1.0 mL) and triethylamine (0.017 mL, 0.12 mmol) and bromoacetonitrile (0.020 mL, 0.029 m) at room temperature. ol) were added and stirred at room temperature for 1 day. Thereafter, the reaction mixture was concentrated to dryness under reduced pressure, and the resulting residue was purified by silica gel column chromatography [filler: FL100D manufactured by Fuji Silysia, developing solvent: chloroform / methanol = 10/1] (1r, 4r) -N- [1- (cyanomethyl) piperidin-4-yl] -4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4 .5] decan-3-yl} methyl) cyclohexanecarboxamide (1.8 mg, 13% yield) was obtained as a white powder.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.01 (2H, q, J = 12.7 Hz), 1.38-1.67 (6H, m), 1.71-1.84 (4H, m), 1.84 to 2.06 (6H, m), 2.45 (2H, td, J = 11.2, 2.5 Hz), 2.61 (4H, brs), 2.72-2. 82 (2H, m), 3.09 (2H, d, J = 7.4 Hz), 3.25 (2H, s), 3.50 (2H, s), 3.57 (2H, s), 3 .72-3.90 (1H, m), 5.30 (1H, d, J = 7.8 Hz), 7.43 (2H, d, J = 8.2 Hz), 7.56 (2H, d, J = 8.2 Hz).

LC / MS [Condition 1]: Retention time 2.92 minutes; m / z 575.9 [M + H] ⁺ (ESI positive ion mode), m / z 620.0 [M + HCOO] ⁻ (ESI negative ion mode)

実施例１０
（１ｒ，４ｒ）−４−（｛２−オキソ−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）−Ｎ−［（テトラヒドロフラン−２−イル）メチル］シクロヘキサンカルボキサミド（化合物番号１０）の製造
参考例６−３で得られた、（１ｒ，４ｒ）−４−（｛２−オキソ−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）シクロヘキサンカルボン酸（４１ｍｇ、０．０９０ｍｍｏｌ）とテトラヒドロフルフリルアミン（０．００９０ｍＬ、０．０９０ｍｍｏｌ）、そして１−ヒドロキシベンゾトリアゾール（１２ｍｇ、０．０９０ｍｏｌ）をクロロホルム（１．０ｍｌ）に溶解した後、室温にて、１−エチル−３−（３−ジメチルアミノプロピル）カルボジイミド塩酸塩（２１ｍｇ、０．１１ｍｍｏｌ）を加え、室温で１日間かき混ぜた。その後、反応混合物を減圧下濃縮してクロロホルムを留去し、残留物に酢酸エチルと飽和炭酸水素ナトリウム水溶液を加え有機層を分離した。有機層を無水硫酸ナトリウムで乾燥した後、減圧下濃縮乾固して（１ｒ，４ｒ）−４−（｛２−オキソ−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）−Ｎ−［（テトラヒドロフラン−２−イル）メチル］シクロヘキサンカルボキサミド（４１ｍｇ、収率８５％）を白色粉末として得た。

^１Ｈ−ＮＭＲ（３００ＭＨｚ，ＣＤＣｌ_３）δ：１．０２（２Ｈ，ｑｄ，Ｊ＝１１．５，２．０Ｈｚ），１．４０−１．６６（４Ｈ，ｍ），１．７１−１．８５（４Ｈ，ｍ），１．８６−２．１０（８Ｈ，ｍ），２．５６（４Ｈ，ｂｒｓ），３．０５−３．１６（３Ｈ，ｍ），３．２５（２Ｈ，ｓ），３．５２−３．６３（３Ｈ，ｍ），３．６９−３．８０（１Ｈ，ｍ），３．８８−３．８０（１Ｈ，ｍ），３．９９−３．８９（１Ｈ，ｍ），５．８１（１Ｈ，ｓ），７．４４（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ），７．５７（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ）．

ＬＣ／ＭＳ［条件１］：保持時間２．９８分；ｍ／ｚ５３７．８［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ５８２．０［Ｍ＋ＨＣＯＯ］^―（ＥＳＩ負イオンモード）

Example 10
(1r, 4r) -4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl)- Production of N-[(tetrahydrofuran-2-yl) methyl] cyclohexanecarboxamide (Compound No. 10) (1r, 4r) -4-({2-oxo-8- [4- (Trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl) cyclohexanecarboxylic acid (41 mg, 0.090 mmol) and tetrahydrofurfurylamine (0.0090 mL, 0 .090 mmol) and 1-hydroxybenzotriazole (12 mg, 0.090 mol) in chloroform (1.0 ml), and then at room temperature. 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (21 mg, 0.11 mmol) and the mixture was stirred at room temperature for 1 day. Thereafter, the reaction mixture was concentrated under reduced pressure to distill off chloroform, and ethyl acetate and saturated aqueous sodium hydrogen carbonate solution were added to the residue to separate the organic layer. The organic layer was dried over anhydrous sodium sulfate and then concentrated to dryness under reduced pressure to give (1r, 4r) -4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3. , 8-diazaspiro [4.5] decan-3-yl} methyl) -N-[(tetrahydrofuran-2-yl) methyl] cyclohexanecarboxamide (41 mg, 85% yield) was obtained as a white powder.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.02 (2H, qd, J = 11.5, 2.0 Hz), 1.40-1.66 (4H, m), 1.71-1. 85 (4H, m), 1.86-2.10 (8H, m), 2.56 (4H, brs), 3.05-3.16 (3H, m), 3.25 (2H, s) , 3.52-3.63 (3H, m), 3.69-3.80 (1H, m), 3.88-3.80 (1H, m), 3.99-3.89 (1H, m), 5.81 (1H, s), 7.44 (2H, d, J = 8.2 Hz), 7.57 (2H, d, J = 8.2 Hz).

LC / MS [Condition 1]: Retention time 2.98 minutes; m / z 537.8 [M + H] ⁺ (ESI positive ion mode), m / z 582.0 [M + HCOO] ⁻ (ESI negative ion mode)

実施例１１
（１ｒ，４ｒ）−Ｎ−（１−メトキシブタン−２−イル）−４−（｛２−オキソ−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）シクロヘキサンカロボキサミド（化合物番号１１）の製造
テトラヒドロフルフリルアミンの代わりに、２−アミノ−１−メトキシブタンを用いること以外は実質的に実施例１０と同様に反応を行なって、表題化合物（２０ｍｇ、収率７８％）を白色粉末として得た。

^１Ｈ−ＮＭＲ（３００ＭＨｚ，ＣＤＣｌ_３）δ：０．９０（３Ｈ，ｔ，Ｊ＝７．８Ｈｚ），１．０２（２Ｈ，ｑ，Ｊ＝１２．７Ｈｚ），１．４０−１．６７（５Ｈ，ｍ），１．７１−１．８４（４Ｈ，ｍ），１．８６−２．０８（５Ｈ，ｍ），２．５６（４Ｈ，ｂｒｓ），３．０９（２Ｈ，ｄ，Ｊ＝７．４Ｈｚ），３．２５（２Ｈ，ｓ），３．３１−３．４４（５Ｈ，ｍ），３．５７（２Ｈ，ｓ），３．８９−４．０１（１Ｈ，ｍ），５．６０（１Ｈ，ｄ，Ｊ＝９．０Ｈｚ），７．４４（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ），７．５７（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ）．

ＬＣ／ＭＳ［条件１］：保持時間３．１６分；ｍ／ｚ５３９．８［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ５８４．０［Ｍ＋ＨＣＯＯ］^―（ＥＳＩ負イオンモード）

Example 11
(1r, 4r) -N- (1-methoxybutan-2-yl) -4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [ 4.5] Preparation of decan-3-yl} methyl) cyclohexane carboxamide (Compound No. 11) Substantially Example 10 except that 2-amino-1-methoxybutane was used instead of tetrahydrofurfurylamine. The title compound (20 mg, yield 78%) was obtained as a white powder.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 0.90 (3H, t, J = 7.8 Hz), 1.02 (2H, q, J = 12.7 Hz), 1.40-1.67 ( 5H, m), 1.71-1.84 (4H, m), 1.86-2.08 (5H, m), 2.56 (4H, brs), 3.09 (2H, d, J = 7.4 Hz), 3.25 (2H, s), 3.31-3.44 (5 H, m), 3.57 (2H, s), 3.89-4.01 (1 H, m), 5 .60 (1H, d, J = 9.0 Hz), 7.44 (2H, d, J = 8.2 Hz), 7.57 (2H, d, J = 8.2 Hz).

LC / MS [Condition 1]: Retention time 3.16 minutes; m / z 539.8 [M + H] ⁺ (ESI positive ion mode), m / z 584.0 [M + HCOO] ⁻ (ESI negative ion mode)

実施例１２
２−［（１ｒ，４ｒ）−４−（｛２−オキソ−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）シクロヘキサンカルボニル］ヒドラジンカルボン酸ｔ−ブチル（化合物番号１２）の製造
テトラヒドロフルフリルアミンの代わりに、カルバジン酸ｔ−ブチルを用いること以外は実質的に実施例１０と同様に反応を行なって、表題化合物（１４０ｍｇ、収率９５％）を白色粉末として得た。

^１Ｈ−ＮＭＲ（３００ＭＨｚ，ＣＤＣｌ_３）δ：１．０３（２Ｈ，ｑ，Ｊ＝１２．７Ｈｚ），１．４２−１．６４（１２Ｈ，ｍ），１．７２−１．８４（４Ｈ，ｍ），１．８９−２．０１（４Ｈ，ｍ），２．０２−２．１６（１Ｈ，ｍ），２．５６（４Ｈ，ｂｒｓ），３．１０（２Ｈ，ｄ，Ｊ＝７．４Ｈｚ），３．２５（２Ｈ，ｓ），３．５７（２Ｈ，ｓ），６．４４（１Ｈ，ｓ），７．１８（１Ｈ，ｓ），７．４４（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ），７．５７（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ）．

ＬＣ／ＭＳ［条件１］：保持時間３．１６分；ｍ／ｚ５６８．８［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ５６７．０［Ｍ−Ｈ］^―（ＥＳＩ負イオンモード）

Example 12
2-[(1r, 4r) -4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} Preparation of t-butyl (methyl) cyclohexanecarbonyl] hydrazinecarboxylate (Compound No. 12) The reaction was conducted in substantially the same manner as in Example 10 except that t-butyl carbazate was used instead of tetrahydrofurfurylamine. The compound (140 mg, yield 95%) was obtained as a white powder.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.03 (2H, q, J = 12.7 Hz), 1.42-1.64 (12H, m), 1.72-1.84 (4H, m), 1.89-2.01 (4H, m), 2.02-2.16 (1H, m), 2.56 (4H, brs), 3.10 (2H, d, J = 7. 4Hz), 3.25 (2H, s), 3.57 (2H, s), 6.44 (1H, s), 7.18 (1H, s), 7.44 (2H, d, J = 8) .2 Hz), 7.57 (2H, d, J = 8.2 Hz).

LC / MS [Condition 1]: Retention time 3.16 minutes; m / z 568.8 [M + H] ⁺ (ESI positive ion mode), m / z 567.0 [M−H] ⁻ (ESI negative ion mode)

実施例１３
（１ｒ，４ｒ）−４−（｛２−オキソ−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）シクロヘキサンカルボヒドラジド２塩酸塩（化合物番号１３）の製造
実施例１２で得られた、２−［（１ｒ，４ｒ）−４−（｛２−オキソ−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）シクロヘキサンカルボニル］ヒドラジンカルボン酸ｔ−ブチル（６３ｍｇ、０．１１ｍｍｏｌ）をメタノール（０．５０ｍＬ）に溶解し、室温にて４Ｍ塩化水素−ジオキサン溶液（０．２８ｍＬ、１．１ｍｍｏｌ）を加えて、室温で１日間かき混ぜた。その後、減圧下濃縮乾固して（１ｒ，４ｒ）−４−（｛２−オキソ−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）シクロヘキサンカルボヒドラジド２塩酸塩（６０ｍｇ、定量的）を白色粉末として得た。

ＬＣ／ＭＳ［条件１］：保持時間３．２４分；ｍ／ｚ４６８．８［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）

Example 13
(1r, 4r) -4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl) cyclohexane Preparation of carbohydrazide dihydrochloride (Compound No. 13) 2-[(1r, 4r) -4-({2-oxo-8- [4- (trifluoromethyl) benzyl]-] obtained in Example 12 1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl) cyclohexanecarbonyl] hydrazine carboxylate t-butyl (63 mg, 0.11 mmol) was dissolved in methanol (0.50 mL) at room temperature. 4M hydrogen chloride-dioxane solution (0.28 mL, 1.1 mmol) was added and stirred at room temperature for 1 day. Then, it was concentrated to dryness under reduced pressure to give (1r, 4r) -4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5]. Decan-3-yl} methyl) cyclohexanecarbohydrazide dihydrochloride (60 mg, quantitative) was obtained as a white powder.

LC / MS [Condition 1]: Retention time 3.24 minutes; m / z 468.8 [M + H] ⁺ (ESI positive ion mode)

参考例１４
２−（テトラヒドロフラン−２−イル）酢酸の製造
２−（テトラヒドロフラン−２−イル）酢酸エチル（東京化成工業（株）より購入）（０．９４ｇ、６．０ｍｍｏｌ）をメタノール（６．０ｍＬ）に溶解し、１Ｍ水酸化ナトリウム水溶液（９．０ｍＬ、９．０ｍｍｏｌ）を加えて室温で３．５時間かき混ぜた。反応混合物に１Ｍ塩酸（９．０ｍＬ）を加えて中和した後、減圧下メタノールを留去した。残留物に水（１０ｍＬ）とクロロホルム（１０ｍＬ）を加え、有機層を分離した。有機層を無水硫酸マグネシウムで乾燥した後、減圧下濃縮し、２−（テトラヒドロフラン−２−イル）酢酸（０．５５ｇ、収率７０％）を無色油状物として得た。

^１Ｈ−ＮＭＲ（３００ＭＨｚ，ＣＤＣｌ_３）δ：１．５８（１Ｈ，ｄｑ，Ｊ＝１２．３，７．８Ｈｚ），２．０２−１．８４（２Ｈ，ｍ），２．１１（１Ｈ，ｄｔｔ，Ｊ＝１１．９，７．４，６．１Ｈｚ），２．５６（１Ｈ，ｄｄ，Ｊ＝１５．６，５．７Ｈｚ），２．６２（１Ｈ，ｄｄ，Ｊ＝１５．６，７．４Ｈｚ），３．８０（１Ｈ，ｄｔ，Ｊ＝８．６，７．０Ｈｚ），３．９２（１Ｈ，ｄｔ，Ｊ＝８．２，７．０Ｈｚ），４．２６（１Ｈ，ｔｔ，Ｊ＝６．５，６．５Ｈｚ）．

ＬＣ／ＭＳ［条件１］：保持時間０．７３分；ｍ／ｚ１３０．９［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）

Reference Example 14
Preparation of 2- (tetrahydrofuran-2-yl) acetic acid Ethyl 2- (tetrahydrofuran-2-yl) acetate (purchased from Tokyo Chemical Industry Co., Ltd.) (0.94 g, 6.0 mmol) in methanol (6.0 mL) Dissolved, 1M aqueous sodium hydroxide solution (9.0 mL, 9.0 mmol) was added, and the mixture was stirred at room temperature for 3.5 hr. The reaction mixture was neutralized with 1M hydrochloric acid (9.0 mL), and methanol was distilled off under reduced pressure. Water (10 mL) and chloroform (10 mL) were added to the residue, and the organic layer was separated. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give 2- (tetrahydrofuran-2-yl) acetic acid (0.55 g, yield 70%) as a colorless oil.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.58 (1H, dq, J = 12.3, 7.8 Hz), 2.02-1.84 (2H, m), 2.11 (1H, dtt, J = 11.9, 7.4, 6.1 Hz), 2.56 (1H, dd, J = 15.6, 5.7 Hz), 2.62 (1H, dd, J = 15.6, 7.4 Hz), 3.80 (1H, dt, J = 8.6, 7.0 Hz), 3.92 (1H, dt, J = 8.2, 7.0 Hz), 4.26 (1H, tt , J = 6.5, 6.5 Hz).

LC / MS [Condition 1]: retention time 0.73 minutes; m / z 130.9 [M + H] ⁺ (ESI positive ion mode)

実施例１４
（１ｒ，４ｒ）−４−（｛２−オキソ−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）−Ｎ’−［２−（テトラヒドロフラン−２−イル）アセチル］シクロヘキサンカルボヒドラジド（化合物番号１４）の製造
実施例１３で得られた、（１ｒ，４ｒ）−４−（｛２−オキソ−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）シクロヘキサンカルボヒドラジド２塩酸塩（４２ｍｇ、０．０７７ｍｍｏｌ）と参考例１４で得られた、２−（テトラヒドロフラン−２−イル）酢酸（１５ｍｇ、０．１２ｍｍｏｌ）、及び１−ヒドロキシベンゾトリアゾール（１０ｍｇ、０．０７７ｍｍｏｌ）をクロロホルム（１．０ｍＬ）に溶解し、室温にてトリエチルアミン（０．０５４ｍＬ、０．３９ｍｍｏｌ）と１−エチル−３−（３−ジメチルアミノプロピル）カルボジイミド塩酸塩（１６ｍｇ、０．０８５ｍｍｏｌ）を加えて、室温にて１日間かき混ぜた。反応混合物を減圧下濃縮してクロロホルムを留去し、酢酸エチルと飽和炭酸水素ナトリウム水溶液を加えて有機層を分離した。その後、有機層を無水硫酸ナトリウムで乾燥した後、減圧下濃縮乾固して（１ｒ，４ｒ）−４−（｛２−オキソ−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）−Ｎ’−［２−（テトラヒドロフラン−２−イル）アセチル］シクロヘキサンカルボヒドラジド（２５ｍｇ、収率５５％）を白色粉末として得た。

^１Ｈ−ＮＭＲ（３００ＭＨｚ，ＣＤＣｌ_３）δ：１．０２（２Ｈ，ｑ，Ｊ＝１２．７Ｈｚ），１．４３−１．６７（４Ｈ，ｍ），１．７１−１．８５（４Ｈ，ｍ），２．１７−１．８６（８Ｈ，ｍ），２．４１−２．６２（６Ｈ，ｍ），３．０９（２Ｈ，ｄ，Ｊ＝７．４Ｈｚ），３．２５（２Ｈ，ｓ），３．５７（２Ｈ，ｓ），３．８１（１Ｈ，ｑ，Ｊ＝６．５Ｈｚ），３．９６（１Ｈ，ｑ，Ｊ＝７．０Ｈｚ），４．１０−４．２２（１Ｈ，ｍ），７．４３（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ），７．５６（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ），８．０５（１Ｈ，ｄ，Ｊ＝４．５Ｈｚ），９．０８（１Ｈ，ｄ，Ｊ＝４．５Ｈｚ）．

ＬＣ／ＭＳ［条件１］：保持時間２．８１分；ｍ／ｚ５８０．９［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ５７９．１［Ｍ−Ｈ］^―（ＥＳＩ負イオンモード）

Example 14
(1r, 4r) -4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl)- Preparation of N ′-[2- (tetrahydrofuran-2-yl) acetyl] cyclohexanecarbohydrazide (Compound No. 14) (1r, 4r) -4-({2-oxo-8- [ 4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl) cyclohexanecarbohydrazide dihydrochloride (42 mg, 0.077 mmol) and Reference Example 14 The obtained 2- (tetrahydrofuran-2-yl) acetic acid (15 mg, 0.12 mmol) and 1-hydroxybenzotriazole (10 mg, 0.077 mmol) were mixed together. Dissolve in chloroform (1.0 mL) and add triethylamine (0.054 mL, 0.39 mmol) and 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (16 mg, 0.085 mmol) at room temperature. Stir at room temperature for 1 day. The reaction mixture was concentrated under reduced pressure to remove chloroform, and ethyl acetate and saturated aqueous sodium hydrogen carbonate solution were added to separate the organic layer. Thereafter, the organic layer was dried over anhydrous sodium sulfate and then concentrated to dryness under reduced pressure to give (1r, 4r) -4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa. -3,8-diazaspiro [4.5] decan-3-yl} methyl) -N ′-[2- (tetrahydrofuran-2-yl) acetyl] cyclohexanecarbohydrazide (25 mg, 55% yield) as a white powder Obtained.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.02 (2H, q, J = 12.7 Hz), 1.43-1.67 (4H, m), 1.71-1.85 (4H, m), 2.17-1.86 (8H, m), 2.41-2.62 (6H, m), 3.09 (2H, d, J = 7.4 Hz), 3.25 (2H, s), 3.57 (2H, s), 3.81 (1H, q, J = 6.5 Hz), 3.96 (1H, q, J = 7.0 Hz), 4.10-4.22 ( 1H, m), 7.43 (2H, d, J = 8.2 Hz), 7.56 (2H, d, J = 8.2 Hz), 8.05 (1H, d, J = 4.5 Hz), 9.08 (1H, d, J = 4.5 Hz).

LC / MS [Condition 1]: Retention time 2.81 minutes; m / z 580.9 [M + H] ⁺ (ESI positive ion mode), m / z 579.1 [M−H] ⁻ (ESI negative ion mode)

実施例１６
３−｛［（１ｒ，４ｒ）−４−（ピペリジン−１−カルボニル）シクロヘキシル］メチル｝−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−２−オン（化合物番号１６）の製造
参考例６−３で得られた、（１ｒ，４ｒ）−４−（｛２−オキソ−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）シクロヘキサンカルボン酸（６６ｍｇ、０．１５ｍｍｏｌ）とピペリジン（０．０１６ｍＬ、０．１６ｍｍｏｌ）、そして１−ヒドロキシベンゾトリアゾール（２０ｍｇ、０．１５ｍｏｌ）をクロロホルム（１．０ｍｌ）に溶解した後、室温にて、１−エチル−３−（３−ジメチルアミノプロピル）カルボジイミド塩酸塩（３１ｍｇ、０．１６ｍｍｏｌ）を加え、室温で３日間かき混ぜた。その後、反応混合物を減圧下濃縮してクロロホルムを留去し、残留物に酢酸エチルと飽和炭酸水素ナトリウム水溶液を加え有機層を分離した。有機層を無水硫酸ナトリウムで乾燥した後、減圧下濃縮し、得られた残留物をシリカゲルカラムクロマトグラフィー［充填剤：富士シリシア製ＦＬ１００Ｄ、展開溶媒：クロロホルム／メタノール＝１０／１］で精製し、３−｛［（１ｒ，４ｒ）−４−（ピペリジン−１−カルボニル）シクロヘキシル］メチル｝−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−２−オン（４４ｍｇ、収率５７％）を白色粉末として得た。

^１Ｈ−ＮＭＲ（３００ＭＨｚ，ＣＤＣｌ_３）δ：１．０４（２Ｈ，ｑ，Ｊ＝１１．９Ｈｚ），１．４６−１．７０（９Ｈ，ｍ），１．７０−１．８６（６Ｈ，ｍ），１．８８−２．００（２Ｈ，ｍ），２．３８−２．５１（１Ｈ，ｍ），２．５６（４Ｈ，ｂｒｓ），３．１０（２Ｈ，ｄ，Ｊ＝７．４Ｈｚ），３．２５（２Ｈ，ｓ），３．４１（２Ｈ，ｔ，Ｊ＝５．１Ｈｚ），３．４９−３．６２（４Ｈ，ｍ），７．４３（２Ｈ，ｄ，Ｊ＝７．８Ｈｚ），７．５６（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ）．

ＬＣ／ＭＳ［条件１］：保持時間３．３０分；ｍ／ｚ５２１．９［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ５６６．０［Ｍ＋ＨＣＯＯ］^―（ＥＳＩ負イオンモード）

Example 16
3-{[(1r, 4r) -4- (piperidine-1-carbonyl) cyclohexyl] methyl} -8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5 Production of decan-2-one (Compound No. 16) (1r, 4r) -4-({2-oxo-8- [4- (trifluoromethyl) benzyl]-obtained in Reference Example 6-3 1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl) cyclohexanecarboxylic acid (66 mg, 0.15 mmol) and piperidine (0.016 mL, 0.16 mmol), and 1-hydroxybenzotriazole (20 mg, 0.15 mol) was dissolved in chloroform (1.0 ml) and then 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide salt at room temperature. Salt (31 mg, 0.16 mmol) and the mixture was stirred at room temperature for 3 days. Thereafter, the reaction mixture was concentrated under reduced pressure to distill off chloroform, and ethyl acetate and saturated aqueous sodium hydrogen carbonate solution were added to the residue to separate the organic layer. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography [filler: FL100D manufactured by Fuji Silysia, developing solvent: chloroform / methanol = 10/1], 3-{[(1r, 4r) -4- (piperidine-1-carbonyl) cyclohexyl] methyl} -8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5 ] Decan-2-one (44 mg, 57% yield) was obtained as a white powder.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.04 (2H, q, J = 11.9 Hz), 1.46-1.70 (9H, m), 1.70-1.86 (6H, m), 1.88-2.00 (2H, m), 2.38-2.51 (1H, m), 2.56 (4H, brs), 3.10 (2H, d, J = 7. 4Hz), 3.25 (2H, s), 3.41 (2H, t, J = 5.1 Hz), 3.49-3.62 (4H, m), 7.43 (2H, d, J = 7.8 Hz), 7.56 (2H, d, J = 8.2 Hz).

LC / MS [Condition 1]: Retention time 3.30 minutes; m / z 521.9 [M + H] ⁺ (ESI positive ion mode), m / z 566.0 [M + HCOO] ⁻ (ESI negative ion mode)

参考例１７−１
（１ｒ，４ｒ）−４−｛［８−（４−シアノベンジル）−２−オキソ−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル］メチル｝シクロヘキサンカルボン酸メチルの製造
参考例６−１で得られた、（１ｒ，４ｒ）−４−［（２−オキソ−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル）メチル］シクロヘキサンカルボン酸メチル塩酸塩（９１０ｍｇ、２．６ｍｍｏｌ）をＮ，Ｎ−ジメチルホルムアミド（１０ｍＬ）に溶解した後、室温にて４−シアノベンジルブロミド（５７０ｍｇ、２．９ｍｍｏｌ）、トリエチルアミン（１．１ｍＬ、７．９ｍｍｏｌ）を加えて、室温で１日間かき混ぜた。その後、水１００ｍＬを加え、析出した固体をろ取して、（１ｒ，４ｒ）−４−｛［８−（４−シアノベンジル）−２−オキソ−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル］メチル｝シクロヘキサンカルボン酸メチル（１．０ｇ、収率９２％）を白色粉末として得た。

^１Ｈ−ＮＭＲ（３００ＭＨｚ，ＣＤＣｌ_３）δ：１．０２（２Ｈ，ｑ，Ｊ＝１２．３Ｈｚ），１．４１（２Ｈ，ｑ，Ｊ＝１２．３Ｈｚ），１．４９−１．６６（１Ｈ，ｍ），１．７０−１．８５（４Ｈ，ｍ），１．８８−２．０７（４Ｈ，ｍ），２．２５（１Ｈ，ｔｔ，Ｊ＝１２．３，４．５Ｈｚ），２．５０−２．６１（４Ｈ，ｂｒｍ），３．０９（２Ｈ，ｄ，Ｊ＝７．４Ｈｚ），３．２６（２Ｈ，ｓ），３．５７（２Ｈ，ｓ），３．６６（３Ｈ，ｓ），７．４４（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ），７．６１（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ）．

ＬＣ／ＭＳ［条件１］：保持時間２．６１分；ｍ／ｚ４２５．９［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ４７０．１［Ｍ＋ＨＣＯＯ］^―（ＥＳＩ負イオンモード）

Reference Example 17-1
(1r, 4r) -4-{[8- (4-Cyanobenzyl) -2-oxo-1-oxa-3,8-diazaspiro [4.5] decan-3-yl] methyl} of methyl cyclohexanecarboxylate (1r, 4r) -4-[(2-oxo-1-oxa-3,8-diazaspiro [4.5] decan-3-yl) methyl] cyclohexanecarboxylic acid obtained in Preparation Reference Example 6-1 Methyl hydrochloride (910 mg, 2.6 mmol) was dissolved in N, N-dimethylformamide (10 mL), then 4-cyanobenzyl bromide (570 mg, 2.9 mmol), triethylamine (1.1 mL, 7.9 mmol) at room temperature. ) And stirred at room temperature for 1 day. Thereafter, 100 mL of water was added, and the precipitated solid was collected by filtration, and (1r, 4r) -4-{[8- (4-cyanobenzyl) -2-oxo-1-oxa-3,8-diazaspiro [4 .5] Decan-3-yl] methyl} cyclohexanecarboxylate (1.0 g, 92% yield) was obtained as a white powder.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.02 (2H, q, J = 12.3 Hz), 1.41 (2H, q, J = 12.3 Hz), 1.49-1.66 ( 1H, m), 1.70-1.85 (4H, m), 1.88-2.07 (4H, m), 2.25 (1H, tt, J = 12.3, 4.5 Hz), 2.50-2.61 (4H, brm), 3.09 (2H, d, J = 7.4 Hz), 3.26 (2H, s), 3.57 (2H, s), 3.66 ( 3H, s), 7.44 (2H, d, J = 8.2 Hz), 7.61 (2H, d, J = 8.2 Hz).

LC / MS [Condition 1]: Retention time 2.61 minutes; m / z 425.9 [M + H] ⁺ (ESI positive ion mode), m / z 470.1 [M + HCOO] ⁻ (ESI negative ion mode)

参考例１７−２
（１ｒ，４ｒ）−４−｛［８−（４−シアノベンジル）−２−オキソ−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル］メチル｝シクロヘキサンカルボン酸の製造
参考例１７−１で得られた、（１ｒ，４ｒ）−４−｛［８−（４−シアノベンジル）−２−オキソ−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル］メチル｝シクロヘキサンカルボン酸メチル（１．０ｇ、２．４ｍｍｏｌ）をメタノール（１０ｍＬ）に溶解し、室温にて１Ｍ水酸化ナトリウム水溶液（３．６ｍＬ、３．６ｍｍｏｌ）を加え、６０℃で３時間かき混ぜた。反応混合物を減圧下濃縮してメタノールを留去し、水（４．０ｍＬ）を加えた。１Ｍ塩酸をｐＨ６になるまで加え、析出した固体をろ取して、（１ｒ，４ｒ）−４−｛［８−（４−シアノベンジル）−２−オキソ−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル］メチル｝シクロヘキサンカルボン酸（１．０ｇ、定量的）を白色粉末として得た。

^１Ｈ−ＮＭＲ（３００ＭＨｚ，ＤＭＳＯ−ｄ_６）δ：０．９２（２Ｈ，ｑ，Ｊ＝１３．１Ｈｚ），１．２７（２Ｈ，ｑ，Ｊ＝１２．７Ｈｚ），１．４２−２．２０（１０Ｈ，ｍ），２．３０−２．５９（６Ｈ，ｂｒｍ），２．９７（２Ｈ，ｄ，Ｊ＝７．０Ｈｚ），３．３４（２Ｈ，ｓ），７．３３−８．１２（４Ｈ，ｍ），１２．０２（１Ｈ，ｓ）．

ＬＣ／ＭＳ［条件１］：保持時間１．０４分；ｍ／ｚ４１１．９［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）

Reference Example 17-2
Preparation of (1r, 4r) -4-{[8- (4-cyanobenzyl) -2-oxo-1-oxa-3,8-diazaspiro [4.5] decan-3-yl] methyl} cyclohexanecarboxylic acid (1r, 4r) -4-{[8- (4-Cyanobenzyl) -2-oxo-1-oxa-3,8-diazaspiro [4.5] decane-3 obtained in Reference Example 17-1 -Il] methyl} methyl cyclohexanecarboxylate (1.0 g, 2.4 mmol) was dissolved in methanol (10 mL), 1 M aqueous sodium hydroxide solution (3.6 mL, 3.6 mmol) was added at room temperature, and the mixture was heated at 60 ° C. Stir for 3 hours. The reaction mixture was concentrated under reduced pressure to distill off methanol, and water (4.0 mL) was added. 1M hydrochloric acid was added until the pH reached 6, and the precipitated solid was collected by filtration to give (1r, 4r) -4-{[8- (4-cyanobenzyl) -2-oxo-1-oxa-3,8-diazaspiro. [4.5] Decan-3-yl] methyl} cyclohexanecarboxylic acid (1.0 g, quantitative) was obtained as a white powder.

¹ H-NMR (300 MHz, DMSO-d ₆ ) δ: 0.92 (2H, q, J = 13.1 Hz), 1.27 (2H, q, J = 12.7 Hz), 1.42-2. 20 (10H, m), 2.30-2.59 (6H, brm), 2.97 (2H, d, J = 7.0 Hz), 3.34 (2H, s), 7.33-8. 12 (4H, m), 12.02 (1H, s).

LC / MS [Condition 1]: Retention time 1.04 minutes; m / z 411.9 [M + H] ⁺ (ESI positive ion mode)

実施例１７
４−（（１ｒ，４ｒ）−４−｛［８−（４−シアノベンジル）−２−オキソ−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル］メチル｝シクロヘキサンカルボキサミド）ピペリジン−１−カルボン酸ｔ−ブチル（化合物番号１７）の製造
参考例１７−２で得られた、（１ｒ，４ｒ）−４−｛［８−（４−シアノベンジル）−２−オキソ−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル］メチル｝シクロヘキサンカルボン酸（１１０ｍｇ、０．２６ｍｍｏｌ）と、４−アミノピペリジン−１−カルボン酸ｔ−ブチル（５８ｍｇ、０．２９ｍｍｏｌ）、そして１−ヒドロキシベンゾトリアゾール（３５ｍｇ、０．２６ｍｏｌ）をＮ，Ｎ−ジメチルホルムアミド（１．０ｍｌ）に溶解した後、室温にて、１−エチル−３−（３−ジメチルアミノプロピル）カルボジイミド塩酸塩（５５ｍｇ、０．２９ｍｍｏｌ）を加えたのち１日間かき混ぜた。その後、反応混合物にクロロホルムと飽和炭酸水素ナトリウム水溶液を加え、有機層を分離した。有機層を無水硫酸ナトリウムで乾燥した後、減圧下濃縮乾固して、４−（（１ｒ，４ｒ）−４−｛［８−（４−シアノベンジル）−２−オキソ−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル］メチル｝シクロヘキサンカルボキサミド）ピペリジン−１−カルボン酸ｔ−ブチル（７０ｍｇ、収率４５％）を白色固体として得た。

^１Ｈ−ＮＭＲ（３００ＭＨｚ，ＣＤＣｌ_３）δ：１．０１（２Ｈ，ｑ，Ｊ＝１１．５Ｈｚ），１．１９−１．３６（２Ｈ，ｍ），１．３８−１．６８（１３Ｈ，ｍ），１．６９−２．０６（１０Ｈ，ｍ），２．５６（４Ｈ，ｂｒｓ），２．８４（２Ｈ，ｔ，Ｊ＝１２．９Ｈｚ），３．０９（２Ｈ，ｄ，Ｊ＝７．４Ｈｚ），３．２５（２Ｈ，ｓ），３．５７（２Ｈ，ｓ），３．８２−４．１３（３Ｈ，ｍ），５．２９（１Ｈ，ｄ，Ｊ＝８．２Ｈｚ），７．４４（２Ｈ，ｄ，Ｊ＝７．４Ｈｚ），７．６１（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ）．

ＬＣ／ＭＳ［条件１］：保持時間３．１６分；ｍ／ｚ５９４．０［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ６３８．２［Ｍ＋ＨＣＯＯ］^―（ＥＳＩ負イオンモード）

Example 17
4-((1r, 4r) -4-{[8- (4-cyanobenzyl) -2-oxo-1-oxa-3,8-diazaspiro [4.5] decan-3-yl] methyl} cyclohexanecarboxamide ) Preparation of t-butyl piperidine-1-carboxylate (Compound No. 17) (1r, 4r) -4-{[8- (4-cyanobenzyl) -2-oxo-] obtained in Reference Example 17-2 1-oxa-3,8-diazaspiro [4.5] decan-3-yl] methyl} cyclohexanecarboxylic acid (110 mg, 0.26 mmol) and t-butyl 4-aminopiperidine-1-carboxylate (58 mg, 0 .29 mmol) and 1-hydroxybenzotriazole (35 mg, 0.26 mol) in N, N-dimethylformamide (1.0 ml), 3- (3-dimethylaminopropyl) carbodiimide hydrochloride (55 mg, 0.29 mmol) was stirred for 1 day after the addition of. Then, chloroform and saturated sodium hydrogencarbonate aqueous solution were added to the reaction mixture, and the organic layer was isolate | separated. The organic layer was dried over anhydrous sodium sulfate and then concentrated to dryness under reduced pressure to give 4-((1r, 4r) -4-{[8- (4-cyanobenzyl) -2-oxo-1-oxa-3]. , 8-diazaspiro [4.5] decan-3-yl] methyl} cyclohexanecarboxamido) piperidine-1-carboxylate (70 mg, 45% yield) was obtained as a white solid.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.01 (2H, q, J = 11.5 Hz), 1.19-1.36 (2H, m), 1.38-1.68 (13H, m), 1.69-2.06 (10H, m), 2.56 (4H, brs), 2.84 (2H, t, J = 12.9 Hz), 3.09 (2H, d, J = 7.4 Hz), 3.25 (2H, s), 3.57 (2H, s), 3.82-4.13 (3H, m), 5.29 (1 H, d, J = 8.2 Hz) 7.44 (2H, d, J = 7.4 Hz), 7.61 (2H, d, J = 8.2 Hz).

LC / MS [condition 1]: retention time 3.16 minutes; m / z 594.0 [M + H] ⁺ (ESI positive ion mode), m / z 638.2 [M + HCOO] ⁻ (ESI negative ion mode)

参考例１８
（１ｒ，４ｒ）−４−｛［８−（４−シアノベンジル）−２−オキソ−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル］メチル｝−Ｎ−（ピペリジン−４−イル）シクロヘキサンカルボキサミド２塩酸塩の製造
実施例１７で得られた、４−（（１ｒ，４ｒ）−４−｛［８−（４−シアノベンジル）−２−オキソ−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル］メチル｝シクロヘキサンカルボキサミド）ピペリジン−１−カルボン酸ｔ−ブチル（６４ｍｇ、０．１１ｍｍｏｌ）をメタノールに溶解して、室温にて４Ｍ塩化水素−ジオキサン溶液（０．２８ｍＬ、１．１ｍｍｏｌ）を加え、６０℃で１時間かき混ぜた。その後、減圧下濃縮乾固させ（１ｒ，４ｒ）−４−｛［８−（４−シアノベンジル）−２−オキソ−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル］メチル｝−Ｎ−（ピペリジン−４−イル）シクロヘキサンカルボキサミド２塩酸塩（６４ｍｇ、定量的）を緑色固体として得た。

ＬＣ／ＭＳ［条件１］：保持時間０．５３分；ｍ／ｚ４９３．９［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ５２８．１［Ｍ＋Ｃｌ］^―（ＥＳＩ負イオンモード）

Reference Example 18
(1r, 4r) -4-{[8- (4-Cyanobenzyl) -2-oxo-1-oxa-3,8-diazaspiro [4.5] decan-3-yl] methyl} -N- (piperidine Preparation of 4-yl) cyclohexanecarboxamide dihydrochloride 4-((1r, 4r) -4-{[8- (4-cyanobenzyl) -2-oxo-1-oxa-] obtained in Example 17 3,8-diazaspiro [4.5] decan-3-yl] methyl} cyclohexanecarboxamide) piperidine-1-carboxylate (64 mg, 0.11 mmol) dissolved in methanol and 4M hydrogen chloride at room temperature -Dioxane solution (0.28 mL, 1.1 mmol) was added and stirred at 60 ° C for 1 hour. Then, it was concentrated to dryness under reduced pressure, and (1r, 4r) -4-{[8- (4-cyanobenzyl) -2-oxo-1-oxa-3,8-diazaspiro [4.5] decan-3-yl. ] Methyl} -N- (piperidin-4-yl) cyclohexanecarboxamide dihydrochloride (64 mg, quantitative) was obtained as a green solid.

LC / MS [Condition 1]: retention time 0.53 minutes; m / z 493.9 [M + H] ⁺ (ESI positive ion mode), m / z 528.1 [M + Cl] ⁻ (ESI negative ion mode)

実施例１８
４−（（１ｒ，４ｒ）−４−｛［８−（４−シアノベンジル）−２−オキソ−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル］メチル｝シクロヘキサンカルボキサミド）ピペリジン−１−カルボン酸メチル（化合物番号１８）の製造
参考例１８で得られた、（１ｒ，４ｒ）−４−｛［８−（４−シアノベンジル）−２−オキソ−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル］メチル｝−Ｎ−（ピペリジン−４−イル）シクロヘキサンカルボキサミド２塩酸塩（１７ｍｇ、０．０３０ｍｍｏｌ）をＮ，Ｎ−ジメチルホルムアミド（０．５０ｍＬ）に溶解し、室温にてトリエチルアミン（０．０２１ｍＬ、０．１５ｍｍｏｌ）、及びクロロギ酸メチル（０．００４０ｍＬ、０．０４５ｍｍｏｌ）を加え、６０℃で３時間かき混ぜた。反応混合物にクロロホルムと水を加え、有機層を分離した。有機層を無水硫酸ナトリウムで乾燥した後、減圧下濃縮乾固して４−（（１ｒ，４ｒ）−４−｛［８−（４−シアノベンジル）−２−オキソ−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル］メチル｝シクロヘキサンカルボキサミド）ピペリジン−１−カルボン酸メチル（６．２ｍｇ、収率３６％）を白色固体として得た。

^１Ｈ−ＮＭＲ（３００ＭＨｚ，ＣＤＣｌ_３）δ：１．０１（２Ｈ，ｑ，Ｊ＝１１．９Ｈｚ），１．１８−１．３７（２Ｈ，ｍ），１．３７−１．６６（３Ｈ，ｍ），１．６９−１．８３（４Ｈ，ｍ），１．８３−２．０５（７Ｈ，ｍ），２．５５（４Ｈ，ｂｒｓ），２．８９（２Ｈ，ｔ，Ｊ＝１１．９Ｈｚ），３．０９（２Ｈ，ｄ，Ｊ＝７．４Ｈｚ），３．２５（２Ｈ，ｓ），３．５６（２Ｈ，ｓ），３．６８（３Ｈ，ｓ），３．８３−３．９９（１Ｈ，ｍ），４．０８（２Ｈ，ｂｒｓ），５．３０（１Ｈ，ｄ，Ｊ＝７．８Ｈｚ），７．４４（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ），７．６０（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ）．

ＬＣ／ＭＳ［条件１］：保持時間２．６９分；ｍ／ｚ５５１．９［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）

Example 18
4-((1r, 4r) -4-{[8- (4-cyanobenzyl) -2-oxo-1-oxa-3,8-diazaspiro [4.5] decan-3-yl] methyl} cyclohexanecarboxamide ) Preparation of methyl piperidine-1-carboxylate (Compound No. 18) (1r, 4r) -4-{[8- (4-cyanobenzyl) -2-oxo-1-oxa-] obtained in Reference Example 18 3,8-Diazaspiro [4.5] decan-3-yl] methyl} -N- (piperidin-4-yl) cyclohexanecarboxamide dihydrochloride (17 mg, 0.030 mmol) was added to N, N-dimethylformamide (0. 50 mL), and triethylamine (0.021 mL, 0.15 mmol) and methyl chloroformate (0.0040 mL, 0.045 mmol) were added at room temperature. And the mixture was stirred in 3 hours. Chloroform and water were added to the reaction mixture, and the organic layer was separated. The organic layer was dried over anhydrous sodium sulfate and then concentrated to dryness under reduced pressure to give 4-((1r, 4r) -4-{[8- (4-cyanobenzyl) -2-oxo-1-oxa-3, Methyl 8-diazaspiro [4.5] decan-3-yl] methyl} cyclohexanecarboxamide) piperidine-1-carboxylate (6.2 mg, 36% yield) was obtained as a white solid.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.01 (2H, q, J = 11.9 Hz), 1.18-1.37 (2H, m), 1.37-1.66 (3H, m), 1.69-1.83 (4H, m), 1.83 to 2.05 (7H, m), 2.55 (4H, brs), 2.89 (2H, t, J = 1.11. 9 Hz), 3.09 (2H, d, J = 7.4 Hz), 3.25 (2H, s), 3.56 (2H, s), 3.68 (3H, s), 3.83-3 .99 (1H, m), 4.08 (2H, brs), 5.30 (1H, d, J = 7.8 Hz), 7.44 (2H, d, J = 8.2 Hz), 7.60 (2H, d, J = 8.2 Hz).

LC / MS [Condition 1]: Retention time 2.69 minutes; m / z 551.9 [M + H] ⁺ (ESI positive ion mode)

実施例１９
（１ｒ，４ｒ）−４−｛［８−（４−シアノベンジル）−２−オキソ−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル］メチル｝−Ｎ−［１−（シアノメチル）ピペリジン−４−イル］シクロヘキサンカルボキサミド（化合物番号１９）の製造
クロロギ酸メチルの代わりに、ブロモアセトニトリルを用いること以外は実質的に実施例１８と同様に反応を行なって、表題化合物（２．４ｍｇ、収率１３％）を白色固体として得た。

^１Ｈ−ＮＭＲ（３００ＭＨｚ，ＣＤＣｌ_３）δ：１．０１（２Ｈ，ｑ，Ｊ＝１３．１Ｈｚ），１．３８−１．６５（５Ｈ，ｍ），１．７０−１．８４（４Ｈ，ｍ），１．８４−２．０６（７Ｈ，ｍ），２．４５（２Ｈ，ｔ，Ｊ＝１１．０Ｈｚ），２．５６（４Ｈ，ｂｒｓ），２．７１−２．８２（２Ｈ，ｍ），３．０９（２Ｈ，ｄ，Ｊ＝７．４Ｈｚ），３．２５（２Ｈ，ｓ），３．５０（２Ｈ，ｓ），３．５６（２Ｈ，ｓ），３．７４−３．８９（１Ｈ，ｍ），５．２７（１Ｈ，ｄ，Ｊ＝７．８Ｈｚ），７．４３（２Ｈ，ｄ，Ｊ＝７．８Ｈｚ），７．６０（２Ｈ，ｄ，Ｊ＝７．８Ｈｚ）．

ＬＣ／ＭＳ［条件１］：保持時間１．０８分；ｍ／ｚ５３２．７［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ５６７．０［Ｍ＋Ｃｌ］^―（ＥＳＩ負イオンモード）

Example 19
(1r, 4r) -4-{[8- (4-Cyanobenzyl) -2-oxo-1-oxa-3,8-diazaspiro [4.5] decan-3-yl] methyl} -N- [1 Preparation of-(cyanomethyl) piperidin-4-yl] cyclohexanecarboxamide (Compound No. 19) The reaction was conducted in substantially the same manner as in Example 18 except that bromoacetonitrile was used instead of methyl chloroformate to give the title compound ( 2.4 mg, 13% yield) was obtained as a white solid.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.01 (2H, q, J = 13.1 Hz), 1.38-1.65 (5H, m), 1.70-1.84 (4H, m), 1.84-2.06 (7H, m), 2.45 (2H, t, J = 11.0 Hz), 2.56 (4H, brs), 2.71-2.82 (2H, m), 3.09 (2H, d, J = 7.4 Hz), 3.25 (2H, s), 3.50 (2H, s), 3.56 (2H, s), 3.74-3 .89 (1H, m), 5.27 (1H, d, J = 7.8 Hz), 7.43 (2H, d, J = 7.8 Hz), 7.60 (2H, d, J = 7. 8 Hz).

LC / MS [Condition 1]: Retention time 1.08 minutes; m / z 532.7 [M + H] ⁺ (ESI positive ion mode), m / z 567.0 [M + Cl] ⁻ (ESI negative ion mode)

実施例２０
（１ｒ，４ｒ）−４−｛［８−（４−シアノベンジル）−２−オキソ−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル］メチル｝−Ｎ−［（テトラヒドロフラン−２−イル）メチル］シクロヘキサンカルボキサミド（化合物番号２０）の製造
４−アミノピペリジン−１−カルボン酸ｔ−ブチルの代わりに、テトラヒドロフルフリルアミンを用いること以外は実質的に実施例１７と同様に反応を行って、表題化合物（１３ｍｇ、収率３２％）を白色固体として得た。

^１Ｈ−ＮＭＲ（３００ＭＨｚ，ＣＤＣｌ_３）δ：１．０２（２Ｈ，ｑ，Ｊ＝１１．６Ｈｚ），１．６６−１．３９（４Ｈ，ｍ），１．７１−２．１０（１２Ｈ，ｍ），２．４９−２．６１（４Ｈ，ｂｒｍ），３．０３−３．１７（３Ｈ，ｍ），３．２５（２Ｈ，ｓ），３．５３−３．６４（３Ｈ，ｍ），３．７０−３．７９（１Ｈ，ｍ），３．８０−３．８９（１Ｈ，ｍ），３．８９−３．９９（１Ｈ，ｍ），５．７９（１Ｈ，ｔ，Ｊ＝５．３Ｈｚ），７．４４（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ），７．６１（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ）．

ＬＣ／ＭＳ［条件１］：保持時間１．４２分；ｍ／ｚ４９４．９［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ５３９．０［Ｍ＋ＨＣＯＯ］^―（ＥＳＩ負イオンモード）

Example 20
(1r, 4r) -4-{[8- (4-Cyanobenzyl) -2-oxo-1-oxa-3,8-diazaspiro [4.5] decan-3-yl] methyl} -N-[( Tetrahydrofuran-2-yl) methyl] cyclohexanecarboxamide (Compound No. 20) Substantially the same as Example 17 except that tetrahydrofurfurylamine was used in place of t-butyl 4-aminopiperidine-1-carboxylate. Reaction was performed to obtain the title compound (13 mg, yield 32%) as a white solid.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.02 (2H, q, J = 11.6 Hz), 1.6-1.39 (4H, m), 1.71-2.10 (12H, m), 2.49-2.61 (4H, brm), 3.03-3.17 (3H, m), 3.25 (2H, s), 3.53-3.64 (3H, m) , 3.70-3.79 (1H, m), 3.80-3.89 (1H, m), 3.89-3.99 (1H, m), 5.79 (1H, t, J = 5.3 Hz), 7.44 (2H, d, J = 8.2 Hz), 7.61 (2H, d, J = 8.2 Hz).

LC / MS [Condition 1]: Retention time 1.42 minutes; m / z 494.9 [M + H] ⁺ (ESI positive ion mode), m / z 539.0 [M + HCOO] ⁻ (ESI negative ion mode)

参考例２１
４−（｛２−オキソ−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）安息香酸の製造
実施例１で得られた、４−（｛２−オキソ−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）安息香酸メチル（５．２ｇ、１１ｍｍｏｌ）をメタノール−テトラヒドロフラン（２５ｍＬ−２５ｍＬ）混合溶媒に溶解し、１Ｍ水酸化ナトリウム水溶液（５６ｍＬ、５６ｍｍｏｌ）を加えて、６０℃で、３０分間かき混ぜた。反応混合物を冷却し、１，４−ジオキサン（１００ｍＬ）を加えて減圧下濃縮した。得られた淡黄色液体に水（２０ｍＬ）、１Ｍ塩酸（５６ｍＬ、５６ｍｍｏｌ）を加えた。析出した固体をろ取した後、減圧下５０℃で乾燥し、４−（｛２−オキソ−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）安息香酸（４．７ｇ、収率９４％）を白色固体として得た。

^１Ｈ−ＮＭＲ（３００ＭＨｚ，ＤＭＳＯ−ｄ_６）δ：１．６７−１．８５（４Ｈ，ｍ），２．３６−２．４６（４Ｈ，ｍ），３．２０（２Ｈ，ｓ），３．５６（２Ｈ，ｓ），４．４１（２Ｈ，ｓ），７．３６（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ），７．５１（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ），７．６７（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ），７．９２（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ）．

ＬＣ／ＭＳ［条件１］：保持時間２．８９分；ｍ／ｚ４４８．８［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ４４６．９［Ｍ−Ｈ］^―（ＥＳＩ負イオンモード）

Reference Example 21
Preparation of 4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl) benzoic acid Example 1 4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl) benzoic acid obtained in Methyl (5.2 g, 11 mmol) was dissolved in a mixed solvent of methanol-tetrahydrofuran (25 mL-25 mL), 1M aqueous sodium hydroxide solution (56 mL, 56 mmol) was added, and the mixture was stirred at 60 ° C. for 30 min. The reaction mixture was cooled, 1,4-dioxane (100 mL) was added, and the mixture was concentrated under reduced pressure. Water (20 mL) and 1M hydrochloric acid (56 mL, 56 mmol) were added to the obtained pale yellow liquid. The precipitated solid was collected by filtration, dried at 50 ° C. under reduced pressure, and 4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4. 5] Decan-3-yl} methyl) benzoic acid (4.7 g, 94% yield) was obtained as a white solid.

¹ H-NMR (300 MHz, DMSO-d ₆ ) δ: 1.67-1.85 (4H, m), 2.36-2.46 (4H, m), 3.20 (2H, s), 3 .56 (2H, s), 4.41 (2H, s), 7.36 (2H, d, J = 8.2 Hz), 7.51 (2H, d, J = 8.2 Hz), 7.67 (2H, d, J = 8.2 Hz), 7.92 (2H, d, J = 8.2 Hz).

LC / MS [Condition 1]: Retention time 2.89 minutes; m / z 448.8 [M + H] ⁺ (ESI positive ion mode), m / z 446.9 [M−H] ⁻ (ESI negative ion mode)

実施例２１
４−［４−（｛２−オキソ−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）ベンズアミド］ピペリジン−１−カルボン酸ｔ−ブチル（化合物番号２１）の製造
参考例２１で得られた、４−（｛２−オキソ−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）安息香酸（５００ｍｇ、１．１ｍｍｏｌ）と、４−アミノピペリジン−１−カルボン酸ｔ−ブチル（２５０ｍｇ、１．２ｍｍｏｌ）、そして１−ヒドロキシベンゾトリアゾール（１５０ｍｇ、１．１ｍｏｌ）をクロロホルム（６．０ｍｌ）に溶解した後、室温にて、１−エチル−３−（３−ジメチルアミノプロピル）カルボジイミド塩酸塩（２３０ｍｇ、１．２ｍｍｏｌ）を加えたのち１日間かき混ぜた。その後、反応混合物を減圧下濃縮してクロロホルムを留去し、残留物に酢酸エチル（２０ｍＬ）と飽和炭酸水素ナトリウム水溶液を加え有機層を分離した。有機層を無水硫酸ナトリウムで乾燥した後、減圧下濃縮乾固して、４−［４−（｛２−オキソ−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）ベンズアミド］ピペリジン−１−カルボン酸ｔ−ブチル（６８０ｍｇ、収率９７％）を白色粉末として得た。

^１Ｈ−ＮＭＲ（３００ＭＨｚ，ＣＤＣｌ_３）δ：１．５１−１．３３（１１Ｈ，ｍ），１．６５−１．７８（２Ｈ，ｍ），１．８４−１．９５（２Ｈ，ｍ），１．９７−２．０７（２Ｈ，ｍ），２．４４−２．５９（４Ｈ，ｂｒｍ），２．９１（２Ｈ，ｔ，Ｊ＝１２．１Ｈｚ），３．１１（２Ｈ，ｓ），３．５５（２Ｈ，ｓ），４．０２−４．２１（３Ｈ，ｍ），４．４６（２Ｈ，ｓ），６．００（１Ｈ，ｄ，Ｊ＝７．８Ｈｚ），７．３２（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ），７．４１（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ），７．５５（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ），７．７４（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ）．

ＬＣ／ＭＳ［条件１］：保持時間３．４６分；ｍ／ｚ６３１．０［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ６７５．２［Ｍ＋ＨＣＯＯ］^―（ＥＳＩ負イオンモード）

Example 21
4- [4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl) benzamide] piperidine- Production of t-butyl 1-carboxylate (Compound No. 21) 4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8 obtained in Reference Example 21 -Diazaspiro [4.5] decan-3-yl} methyl) benzoic acid (500 mg, 1.1 mmol), t-butyl 4-aminopiperidine-1-carboxylate (250 mg, 1.2 mmol), and 1-hydroxy 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide salt was dissolved in chloroform (6.0 ml) after dissolving benzotriazole (150 mg, 1.1 mol) at room temperature. It was stirred for 1 day after the addition of salt (230mg, 1.2mmol). Thereafter, the reaction mixture was concentrated under reduced pressure to distill off chloroform, and ethyl acetate (20 mL) and saturated aqueous sodium hydrogen carbonate solution were added to the residue to separate the organic layer. The organic layer was dried over anhydrous sodium sulfate and then concentrated to dryness under reduced pressure to give 4- [4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8. -Diazaspiro [4.5] decan-3-yl} methyl) benzamide] piperidine-1-carboxylate t-butyl (680 mg, 97% yield) was obtained as a white powder.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.51-1.33 (11H, m), 1.65-1.78 (2H, m), 1.84-1.95 (2H, m) 1.97-2.07 (2H, m), 2.44-2.59 (4H, brm), 2.91 (2H, t, J = 12.1 Hz), 3.11 (2H, s) , 3.55 (2H, s), 4.02-4.21 (3H, m), 4.46 (2H, s), 6.00 (1H, d, J = 7.8 Hz), 7.32 (2H, d, J = 8.2 Hz), 7.41 (2H, d, J = 8.2 Hz), 7.55 (2H, d, J = 8.2 Hz), 7.74 (2H, d, J = 8.2 Hz).

LC / MS [Condition 1]: Retention time 3.46 minutes; m / z 631.0 [M + H] ⁺ (ESI positive ion mode), m / z 675.2 [M + HCOO] ⁻ (ESI negative ion mode)

参考例２２
４−（｛２−オキソ−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）−Ｎ−（ピペリジン−４−イル）ベンズアミド２塩酸塩の製造
実施例２１で得られた、４−［４−（｛２−オキソ−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）ベンズアミド］ピペリジン−１−カルボン酸ｔ−ブチル（６８０ｍｇ、１．１ｍｍｏｌ）をメタノール（５．０ｍＬ）に溶解し、室温にて４Ｍ塩化水素−ジオキサン溶液（２．７ｍＬ、１１ｍｍｏｌ）を加えて、室温で１日間かき混ぜた。その後、減圧下濃縮乾固して４−（｛２−オキソ−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）−Ｎ−（ピペリジン−４−イル）ベンズアミド２塩酸塩（６５０ｍｇ、定量的）を白色粉末として得た。

ＬＣ／ＭＳ［条件１］：保持時間０．９４分；ｍ／ｚ５３０．９［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ５７５．１［Ｍ＋ＨＣＯＯ］^―（ＥＳＩ負イオンモード）

Reference Example 22
4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl) -N- (piperidine-4 Preparation of 4- yl) benzamide dihydrochloride 4- [4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro obtained in Example 21 [4.5] decan-3-yl} methyl) benzamide] t-butyl piperidine-1-carboxylate (680 mg, 1.1 mmol) was dissolved in methanol (5.0 mL) and 4 M hydrogen chloride-dioxane at room temperature. The solution (2.7 mL, 11 mmol) was added and stirred at room temperature for 1 day. Then, it was concentrated to dryness under reduced pressure, and 4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} Methyl) -N- (piperidin-4-yl) benzamide dihydrochloride (650 mg, quantitative) was obtained as a white powder.

LC / MS [Condition 1]: retention time 0.94 min; m / z 530.9 [M + H] ⁺ (ESI positive ion mode), m / z 575.1 [M + HCOO] ⁻ (ESI negative ion mode)

実施例２２
４−［４−（｛２−オキソ−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）ベンズアミド］ピペリジン−１−カルボン酸メチル（化合物番号２２）の製造
参考例２２で得られた、４−（｛２−オキソ−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）−Ｎ−（ピペリジン−４−イル）ベンズアミド２塩酸塩（２１３ｍｇ、０．３５ｍｍｏｌ）をＮ，Ｎ−ジメチルホルムアミド（１．０ｍＬ）に溶解し、室温にてトリエチルアミン（０．２５ｍＬ、１．８ｍｍｏｌ）、及びクロロギ酸メチル（０．０５４ｍＬ、０．７１ｍｍｏｌ）を加え、室温で１日間かき混ぜた。その後、反応混合物に酢酸エチルと水を加え、有機層を分離した。有機層を無水硫酸ナトリウムで乾燥した後、減圧下濃縮乾固して４−［４−（｛２−オキソ−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）ベンズアミド］ピペリジン−１−カルボン酸メチル（１５０ｍｇ、収率７１％）を白色固体として得た。

^１Ｈ−ＮＭＲ（３００ＭＨｚ，ＣＤＣｌ_３）δ：１．３３−１．５１（２Ｈ，ｍ），１．６５−１．７９（２Ｈ，ｍ），１．８４−１．９６（２Ｈ，ｂｒｍ），１．９９−２．１０（２Ｈ，ｂｒｍ），２．４２−２．６１（４Ｈ，ｂｒｍ），２．９７（２Ｈ，ｔ，Ｊ＝１１．９Ｈｚ），３．１１（２Ｈ，ｓ），３．５５（２Ｈ，ｓ），３．７０（３Ｈ，ｓ），４．０４−４．２７（３Ｈ，ｍ），４．４６（２Ｈ，ｓ），５．９７（１Ｈ，ｄ，Ｊ＝７．８Ｈｚ），７．３３（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ），７．４１（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ），７．５５（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ），７．７３（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ）．

ＬＣ／ＭＳ［条件１］：保持時間３．２０分；ｍ／ｚ５８８．９［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ６３３．１［Ｍ＋ＨＣＯＯ］^―（ＥＳＩ負イオンモード）

Example 22
4- [4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl) benzamide] piperidine- Production of methyl 1-carboxylate (Compound No. 22) 4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro obtained in Reference Example 22 [4.5] decan-3-yl} methyl) -N- (piperidin-4-yl) benzamide dihydrochloride (213 mg, 0.35 mmol) was dissolved in N, N-dimethylformamide (1.0 mL), Triethylamine (0.25 mL, 1.8 mmol) and methyl chloroformate (0.054 mL, 0.71 mmol) were added at room temperature, and the mixture was stirred at room temperature for 1 day. Thereafter, ethyl acetate and water were added to the reaction mixture, and the organic layer was separated. The organic layer was dried over anhydrous sodium sulfate and then concentrated to dryness under reduced pressure to give 4- [4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8- Diazaspiro [4.5] decan-3-yl} methyl) benzamide] piperidine-1-carboxylate (150 mg, 71% yield) was obtained as a white solid.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.33-1.51 (2H, m), 1.65-1.79 (2H, m), 1.84-1.96 (2H, brm) 1.99-2.10 (2H, brm), 2.42-2.61 (4H, brm), 2.97 (2H, t, J = 11.9 Hz), 3.11 (2H, s) , 3.55 (2H, s), 3.70 (3H, s), 4.04-4.27 (3H, m), 4.46 (2H, s), 5.97 (1H, d, J = 7.8 Hz), 7.33 (2H, d, J = 8.2 Hz), 7.41 (2H, d, J = 8.2 Hz), 7.55 (2H, d, J = 8.2 Hz) , 7.73 (2H, d, J = 8.2 Hz).

LC / MS [Condition 1]: Retention time 3.20 minutes; m / z 588.9 [M + H] ⁺ (ESI positive ion mode), m / z 633.1 [M + HCOO] ⁻ (ESI negative ion mode)

実施例２３
Ｎ−［１−（シアノメチル）ピペリジン−４−イル］−４−（｛２−オキソ−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）ベンズアミド（化合物番号２３）の製造
クロロギ酸メチルの代わりに、ブロモアセトニトリルを用いること以外は実質的に実施例２２と同様に反応を行なって、表題化合物（３０ｍｇ、収率８０％）を白色固体として得た。

ＬＣ／ＭＳ［条件１］：保持時間２．９２分；ｍ／ｚ５６９．９［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ６１４．０［Ｍ＋ＨＣＯＯ］^―（ＥＳＩ負イオンモード）

Example 23
N- [1- (cyanomethyl) piperidin-4-yl] -4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] Preparation of decan-3-yl} methyl) benzamide (Compound No. 23) The reaction was conducted in substantially the same manner as in Example 22 except that bromoacetonitrile was used instead of methyl chloroformate to give the title compound (30 mg, yield). 80%) was obtained as a white solid.

LC / MS [Condition 1]: Retention time 2.92 minutes; m / z 569.9 [M + H] ⁺ (ESI positive ion mode), m / z 614.0 [M + HCOO] ⁻ (ESI negative ion mode)

実施例２４
Ｎ−（１−アセチルピペリジン−４−イル）−４−（｛２−オキソ−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）ベンズアミド（化合物番号２４）の製造
クロロギ酸メチルの代わりに、塩化アセチルを用いること以外は実質的に実施例２２と同様に反応を行なって、表題化合物（３１ｍｇ、収率８２％）を白色固体として得た。

ＬＣ／ＭＳ［条件１］：保持時間２．９０分；ｍ／ｚ５７２．８［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ６１６．９［Ｍ＋ＨＣＯＯ］^―（ＥＳＩ負イオンモード）

Example 24
N- (1-acetylpiperidin-4-yl) -4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decane- Preparation of 3-yl} methyl) benzamide (Compound No. 24) The reaction was conducted in substantially the same manner as in Example 22 except that acetyl chloride was used instead of methyl chloroformate to give the title compound (31 mg, yield 82). %) As a white solid.

LC / MS [Condition 1]: Retention time 2.90 minutes; m / z 572.8 [M + H] ⁺ (ESI positive ion mode), m / z 616.9 [M + HCOO] ⁻ (ESI negative ion mode)

実施例２５
Ｎ−［１−（メチルスルホニル）ピペリジン−４−イル］−４−（｛２−オキソ−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）ベンズアミド（化合物番号２５）の製造
クロロギ酸メチルの代わりに、塩化メタンスルホニルを用いること以外は実質的に実施例２２と同様に反応を行なって、表題化合物（３０ｍｇ、収率７５％）を白色固体として得た。

ＬＣ／ＭＳ［条件１］：保持時間３．０８分；ｍ／ｚ６０８．８［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ６５２．９［Ｍ＋ＨＣＯＯ］^―（ＥＳＩ負イオンモード）

Example 25
N- [1- (methylsulfonyl) piperidin-4-yl] -4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5 ] Preparation of decan-3-yl} methyl) benzamide (Compound No. 25) The reaction was conducted in substantially the same manner as in Example 22 except that methanesulfonyl chloride was used in place of methyl chloroformate to give the title compound (30 mg Yield 75%) as a white solid.

LC / MS [Condition 1]: Retention time 3.08 minutes; m / z 608.8 [M + H] ⁺ (ESI positive ion mode), m / z 652.9 [M + HCOO] ⁻ (ESI negative ion mode)

実施例２６
Ｎ−［１−（４−クロロベンジル）ピペリジン−４−イル］−４−（｛２−オキソ−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）ベンズアミド（化合物番号２６）の製造
クロロギ酸メチルの代わりに、４−クロロベンジルブロミドを用いること以外は実質的に実施例２２と同様に反応を行なって、表題化合物（１８ｍｇ、収率４１％）を白色固体として得た。

ＬＣ／ＭＳ［条件１］：保持時間３．０８分；ｍ／ｚ６５４．９［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ６９９．０［Ｍ＋ＨＣＯＯ］^―（ＥＳＩ負イオンモード）

Example 26
N- [1- (4-Chlorobenzyl) piperidin-4-yl] -4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4 .5] Preparation of decan-3-yl} methyl) benzamide (Compound No. 26) The reaction was carried out in substantially the same manner as in Example 22 except that 4-chlorobenzyl bromide was used instead of methyl chloroformate. The title compound (18 mg, 41% yield) was obtained as a white solid.

LC / MS [Condition 1]: Retention time 3.08 minutes; m / z 654.9 [M + H] ⁺ (ESI positive ion mode), m / z 699.0 [M + HCOO] ⁻ (ESI negative ion mode)

実施例２７
４−（｛２−オキソ−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）−Ｎ−｛１−［４−（トリフルオロメチル）ベンジル］ピペリジン−４−イル｝ベンズアミド（化合物番号２７）の製造
クロロギ酸メチルの代わりに、４−（トリフルオロメチル）ベンジルブロミドを用いること以外は実質的に実施例２２と同様に反応を行なって、表題化合物（２７ｍｇ、収率６０％）を白色固体として得た。

ＬＣ／ＭＳ［条件１］：保持時間３．１４分；ｍ／ｚ６８９．０［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ７３３．０［Ｍ＋ＨＣＯＯ］^―（ＥＳＩ負イオンモード）

Example 27
4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl) -N- {1- [ Preparation of 4- (trifluoromethyl) benzyl] piperidin-4-yl} benzamide (Compound No. 27) Substantially Example 22 except that 4- (trifluoromethyl) benzyl bromide was used instead of methyl chloroformate. The title compound (27 mg, yield 60%) was obtained as a white solid.

LC / MS [Condition 1]: Retention time 3.14 minutes; m / z 689.0 [M + H] ⁺ (ESI positive ion mode), m / z 733.0 [M + HCOO] ⁻ (ESI negative ion mode)

実施例２８
Ｎ−［１−（３−メチルベンジル）ピペリジン−４−イル］−４−（｛２−オキソ−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）ベンズアミド（化合物番号２８）の製造
クロロギ酸メチルの代わりに、α−ブロモ−ｍ−キシレンを用いること以外は実質的に実施例２２と同様に反応を行なって、表題化合物（２２ｍｇ、収率５１％）を白色固体として得た。

ＬＣ／ＭＳ［条件１］：保持時間３．０２分；ｍ／ｚ６３５．０［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ６７９．１［Ｍ＋ＨＣＯＯ］^―（ＥＳＩ負イオンモード）

Example 28
N- [1- (3-Methylbenzyl) piperidin-4-yl] -4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4 .5] Preparation of decan-3-yl} methyl) benzamide (Compound No. 28) The reaction was carried out in substantially the same manner as in Example 22 except that α-bromo-m-xylene was used instead of methyl chloroformate. To give the title compound (22 mg, 51% yield) as a white solid.

LC / MS [Condition 1]: Retention time 3.02 minutes; m / z 635.0 [M + H] ⁺ (ESI positive ion mode), m / z 679.1 [M + HCOO] ⁻ (ESI negative ion mode)

実施例２９
Ｎ−（１−エチルピペリジン−４−イル）−４−（｛２−オキソ−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）ベンズアミド（化合物番号２９）の製造
クロロギ酸メチルの代わりに、ブロモエタンを用いること以外は実質的に実施例２２と同様に反応を行なって、表題化合物（７．４ｍｇ、収率２０％）を白色固体として得た。

ＬＣ／ＭＳ［条件１］：保持時間１．１６分；ｍ／ｚ５５８．９［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）

Example 29
N- (1-ethylpiperidin-4-yl) -4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decane- Preparation of 3-yl} methyl) benzamide (Compound No. 29) The reaction was conducted in substantially the same manner as in Example 22 except that bromoethane was used instead of methyl chloroformate to give the title compound (7.4 mg, yield). 20%) as a white solid.

LC / MS [Condition 1]: Retention time 1.16 minutes; m / z 558.9 [M + H] ⁺ (ESI positive ion mode)

実施例３０
４−（｛２−オキソ−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）−Ｎ−｛１−［４−（トリフルオロメトキシ）ベンジル］ピペリジン−４−イル｝ベンズアミド（化合物番号３０）の製造
クロロギ酸メチルの代わりに、４−（トリフルオロメトキシ）ベンジルブロミド用いること以外は実質的に実施例２２と同様に反応を行なって、表題化合物（３０ｍｇ、収率６６％）を白色固体として得た。

ＬＣ／ＭＳ［条件１］：保持時間３．３０分；ｍ／ｚ７０５．３［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ７４９．１［Ｍ＋ＨＣＯＯ］^―（ＥＳＩ負イオンモード）

Example 30
4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl) -N- {1- [ Preparation of 4- (trifluoromethoxy) benzyl] piperidin-4-yl} benzamide (Compound No. 30) Substantially the same as in Example 22 except that 4- (trifluoromethoxy) benzyl bromide was used instead of methyl chloroformate. The reaction was performed in the same manner to obtain the title compound (30 mg, yield 66%) as a white solid.

LC / MS [Condition 1]: Retention time 3.30 minutes; m / z 705.3 [M + H] ⁺ (ESI positive ion mode), m / z 749.1 [M + HCOO] ⁻ (ESI negative ion mode)

実施例３１
Ｎ−｛１−［２−（ジエチルアミノ）−２−オキソエチル］ピペリジン−４−イル｝−４−（｛２−オキソ−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）ベンズアミド（化合物番号３１）の製造
参考例２２で得られた、４−（｛２−オキソ−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）−Ｎ−（ピペリジン−４−イル）ベンズアミド２塩酸塩（４０ｍｇ、０．０６６ｍｍｏｌ）をＮ，Ｎ−ジメチルホルムアミド（４．０ｍＬ）に溶解し、室温にてトリエチルアミン（０．０４６ｍＬ、０．３３ｍｍｏｌ）、及びＮ，Ｎ−ジエチルクロロアセトアミド（０．０１８ｍＬ、０．１３ｍｍｏｌ）を加え、４０℃で１日間かき混ぜた。反応混合物を減圧下濃縮してＮ，Ｎ−ジメチルホルムアミドを留去した。得られた残留物をＨＰＬＣにて精製し、Ｎ−｛１−［２−（ジエチルアミノ）−２−オキソエチル］ピペリジン−４−イル｝−４−（｛２−オキソ−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）ベンズアミド（１７ｍｇ、収率４０％）を黄色固体として得た。

ＬＣ／ＭＳ［条件１］：保持時間２．７３分；ｍ／ｚ６４３．９［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ６８８．１［Ｍ＋ＨＣＯＯ］^―（ＥＳＩ負イオンモード）

Example 31
N- {1- [2- (diethylamino) -2-oxoethyl] piperidin-4-yl} -4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3, Preparation of 8-diazaspiro [4.5] decan-3-yl} methyl) benzamide (Compound No. 31) 4-({2-oxo-8- [4- (trifluoromethyl)) obtained in Reference Example 22 [Benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl) -N- (piperidin-4-yl) benzamide dihydrochloride (40 mg, 0.066 mmol) is added to N, N -Dissolved in dimethylformamide (4.0 mL), triethylamine (0.046 mL, 0.33 mmol) and N, N-diethylchloroacetamide (0.018 mL, 0.13 mm) at room temperature. l) and the mixture was stirred for 1 day at 40 ° C.. The reaction mixture was concentrated under reduced pressure to distill off N, N-dimethylformamide. The obtained residue was purified by HPLC, and N- {1- [2- (diethylamino) -2-oxoethyl] piperidin-4-yl} -4-({2-oxo-8- [4- (tri Fluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl) benzamide (17 mg, 40% yield) was obtained as a yellow solid.

LC / MS [Condition 1]: Retention time 2.73 minutes; m / z 643.9 [M + H] ⁺ (ESI positive ion mode), m / z 688.1 [M + HCOO] ⁻ (ESI negative ion mode)

実施例３２
Ｎ−｛１−［４−（メチルチオ）ベンジル］ピペリジン−４−イル｝−４−（｛２−オキソ−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）ベンズアミド（化合物番号３２）の製造
Ｎ，Ｎ−ジエチルクロロアセトアミドの代わりに４−（メチルチオ）ベンジルブロミドを用いること以外は実質的に実施例３１と同様に反応を行って、表題化合物（１３ｍｇ、収率３０％）を黄色固体として得た。

ＬＣ／ＭＳ［条件１］：保持時間３．２０分；ｍ／ｚ６６６．９［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ７１０．９［Ｍ＋ＨＣＯＯ］^―（ＥＳＩ負イオンモード）

Example 32
N- {1- [4- (methylthio) benzyl] piperidin-4-yl} -4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro Preparation of [4.5] decan-3-yl} methyl) benzamide (Compound No. 32) Substantially the same as in Example 31 except that 4- (methylthio) benzyl bromide was used instead of N, N-diethylchloroacetamide. The reaction was performed in the same manner to obtain the title compound (13 mg, yield 30%) as a yellow solid.

LC / MS [Condition 1]: Retention time 3.20 minutes; m / z 666.9 [M + H] ⁺ (ESI positive ion mode), m / z 710.9 [M + HCOO] ⁻ (ESI negative ion mode)

実施例３３
Ｎ−［１−（ナフタレン−２−イルメチル）ピペリジン−４−イル］−４−（｛２−オキソ−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）ベンズアミド（化合物番号３３）の製造
Ｎ，Ｎ−ジエチルクロロアセトアミドの代わりに２−（ブロモメチル）ナフタレンを用いること以外は実質的に実施例３１と同様に反応を行って、表題化合物（１６ｍｇ、収率３６％）を黄色固体として得た。

ＬＣ／ＭＳ［条件１］：保持時間３．３４分；ｍ／ｚ６７１．１［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ７１５．０［Ｍ＋ＨＣＯＯ］^―（ＥＳＩ負イオンモード）

Example 33
N- [1- (Naphthalen-2-ylmethyl) piperidin-4-yl] -4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [ 4.5] Preparation of decan-3-yl} methyl) benzamide (Compound No. 33) Substantially the same as Example 31 except that 2- (bromomethyl) naphthalene was used in place of N, N-diethylchloroacetamide. Reaction was performed to obtain the title compound (16 mg, yield 36%) as a yellow solid.

LC / MS [Condition 1]: Retention time 3.34 minutes; m / z 671.1 [M + H] ⁺ (ESI positive ion mode), m / z 715.0 [M + HCOO] ⁻ (ESI negative ion mode)

実施例３４
Ｎ−［１−（３−ニトロベンジル）ピペリジン−４−イル］−４−（｛２−オキソ−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）ベンズアミド（化合物番号３４）の製造
Ｎ，Ｎ−ジエチルクロロアセトアミドの代わりに３−ニトロベンジルブロミドを用いること以外は実質的に実施例３１と同様に反応を行って、表題化合物（１４ｍｇ、収率３２％）を黄色固体として得た。

ＬＣ／ＭＳ［条件１］：保持時間３．０２分；ｍ／ｚ６６６．０［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ７１０．０［Ｍ＋ＨＣＯＯ］^―（ＥＳＩ負イオンモード）

Example 34
N- [1- (3-nitrobenzyl) piperidin-4-yl] -4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4 .5] Preparation of decan-3-yl} methyl) benzamide (Compound No. 34) The reaction was carried out in substantially the same manner as in Example 31 except that 3-nitrobenzyl bromide was used instead of N, N-diethylchloroacetamide. Performed to give the title compound (14 mg, 32% yield) as a yellow solid.

LC / MS [Condition 1]: Retention time 3.02 minutes; m / z 666.0 [M + H] ⁺ (ESI positive ion mode), m / z 710.0 [M + HCOO] ⁻ (ESI negative ion mode)

実施例３５
Ｎ−［１−（３−クロロベンジル）ピペリジン−４−イル］−４−（｛２−オキソ−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）ベンズアミド（化合物番号３５）の製造
Ｎ，Ｎ−ジエチルクロロアセトアミドの代わりに３−クロロベンジルブロミドを用いること以外は実質的に実施例３１と同様に反応を行って、表題化合物（１３ｍｇ、収率３０％）を黄色固体として得た。

ＬＣ／ＭＳ［条件１］：保持時間３．１８分；ｍ／ｚ６５４．９［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ６９９．０［Ｍ＋ＨＣＯＯ］^―（ＥＳＩ負イオンモード）

Example 35
N- [1- (3-Chlorobenzyl) piperidin-4-yl] -4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4 .5] Preparation of decan-3-yl} methyl) benzamide (Compound No. 35) The reaction was carried out in substantially the same manner as in Example 31 except that 3-chlorobenzyl bromide was used instead of N, N-diethylchloroacetamide. Performed to give the title compound (13 mg, 30% yield) as a yellow solid.

LC / MS [Condition 1]: Retention time 3.18 minutes; m / z 654.9 [M + H] ⁺ (ESI positive ion mode), m / z 699.0 [M + HCOO] ⁻ (ESI negative ion mode)

実施例３６
Ｎ−［１−（３−メトキシベンジル）ピペリジン−４−イル］−４−（｛２−オキソ−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）ベンズアミド（化合物番号３６）の製造
Ｎ，Ｎ−ジエチルクロロアセトアミドの代わりに３−メトキシベンジルブロミドを用いること以外は実質的に実施例３１と同様に反応を行って、表題化合物（１４ｍｇ、収率３３％）を黄色固体として得た。

ＬＣ／ＭＳ［条件１］：保持時間３．０２分；ｍ／ｚ６５０．９［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ６９５．１［Ｍ＋ＨＣＯＯ］^―（ＥＳＩ負イオンモード）

Example 36
N- [1- (3-methoxybenzyl) piperidin-4-yl] -4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4 .5] Preparation of decan-3-yl} methyl) benzamide (Compound No. 36) The reaction was carried out in substantially the same manner as in Example 31 except that 3-methoxybenzyl bromide was used instead of N, N-diethylchloroacetamide. Performed to give the title compound (14 mg, 33% yield) as a yellow solid.

LC / MS [Condition 1]: Retention time 3.02 minutes; m / z 650.9 [M + H] ⁺ (ESI positive ion mode), m / z 695.1 [M + HCOO] ⁻ (ESI negative ion mode)

実施例３７
Ｎ−［１−（３−シアノベンジル）ピペリジン−４−イル］−４−（｛２−オキソ−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）ベンズアミド（化合物番号３７）の製造
Ｎ，Ｎ−ジエチルクロロアセトアミドの代わりに３−ブロモメチルベンゾニトリルを用いること以外は実質的に実施例３１と同様に反応を行って、表題化合物（１２ｍｇ、収率２８％）を黄色固体として得た。

ＬＣ／ＭＳ［条件１］：保持時間２．９０分；ｍ／ｚ６４６．０［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ６９０．２［Ｍ＋ＨＣＯＯ］^―（ＥＳＩ負イオンモード）

Example 37
N- [1- (3-cyanobenzyl) piperidin-4-yl] -4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4 .5] Preparation of decan-3-yl} methyl) benzamide (Compound No. 37) Reaction was substantially the same as Example 31 except that 3-bromomethylbenzonitrile was used instead of N, N-diethylchloroacetamide. To give the title compound (12 mg, 28% yield) as a yellow solid.

LC / MS [Condition 1]: Retention time 2.90 minutes; m / z 646.0 [M + H] ⁺ (ESI positive ion mode), m / z 690.2 [M + HCOO] ⁻ (ESI negative ion mode)

実施例３８
４−（４−［４−（｛２−オキソ−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）ベンズアミド］ピペリジン−１−イル）ブタン酸エチル（化合物番号３８）の製造
Ｎ，Ｎ−ジエチルクロロアセトアミドの代わりに４−ブロモ酪酸エチルを用いること以外は実質的に実施例３１と同様に反応を行って、表題化合物（６３ｍｇ、収率６１％）を白色固体として得た。

ＬＣ／ＭＳ［条件１］：保持時間２．７９分；ｍ／ｚ６４５．０［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ６８９．２［Ｍ＋ＨＣＯＯ］^―（ＥＳＩ負イオンモード）

Example 38
4- (4- [4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl) benzamide ] Preparation of piperidin-1-yl) ethyl butanoate (Compound No. 38) The reaction was carried out in substantially the same manner as in Example 31 except that ethyl 4-bromobutyrate was used in place of N, N-diethylchloroacetamide. The title compound (63 mg, 61% yield) was obtained as a white solid.

LC / MS [Condition 1]: Retention time 2.79 minutes; m / z 645.0 [M + H] ⁺ (ESI positive ion mode), m / z 689.2 [M + HCOO] ⁻ (ESI negative ion mode)

実施例３９
３−（｛４−［４−（｛２−オキソ−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）ベンズアミド］ピペリジン−１−イル｝メチル）安息香酸メチル（化合物番号３９）の製造
Ｎ，Ｎ−ジエチルクロロアセトアミドの代わりに３−（ブロモメチル）安息香酸メチルを用いること以外は実質的に実施例３１と同様に反応を行って、表題化合物（７３ｍｇ、収率６７％）を白色固体として得た。

ＬＣ／ＭＳ［条件１］：保持時間２．９８分；ｍ／ｚ６７９．１［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ７２３．１［Ｍ＋ＨＣＯＯ］^―（ＥＳＩ負イオンモード）

Example 39
3-({4- [4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl) Benzamido] piperidin-1-yl} methyl) Preparation of methyl benzoate (Compound No. 39) Substantially as in Example 31 except that methyl 3- (bromomethyl) benzoate is used in place of N, N-diethylchloroacetamide. The reaction was performed in the same manner to obtain the title compound (73 mg, yield 67%) as a white solid.

LC / MS [Condition 1]: Retention time 2.98 minutes; m / z 679.1 [M + H] ⁺ (ESI positive ion mode), m / z 723.1 [M + HCOO] ⁻ (ESI negative ion mode)

実施例４０
４−（｛４−［４−（｛２−オキソ−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）ベンズアミド］ピペリジン−１−イル｝メチル）安息香酸メチル（化合物番号４０）の製造
Ｎ，Ｎ−ジエチルクロロアセトアミドの代わりに４−（ブロモメチル）安息香酸メチルを用いること以外は実質的に実施例３１と同様に反応を行って、表題化合物（８４ｍｇ、収率７７％）を黄色固体として得た。

ＬＣ／ＭＳ［条件１］：保持時間２．９８分；ｍ／ｚ６７９．１［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ７２３．２［Ｍ＋ＨＣＯＯ］^―（ＥＳＩ負イオンモード）

Example 40
4-({4- [4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl) Preparation of benzamido] piperidin-1-yl} methyl) methyl benzoate (Compound No. 40) Substantially Example 31 except that methyl 4- (bromomethyl) benzoate is used in place of N, N-diethylchloroacetamide The same reaction was performed to obtain the title compound (84 mg, yield 77%) as a yellow solid.

LC / MS [Condition 1]: Retention time 2.98 minutes; m / z 679.1 [M + H] ⁺ (ESI positive ion mode), m / z 723.2 [M + HCOO] ⁻ (ESI negative ion mode)

実施例４１
４−（｛４−［４−（｛２−オキソ−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）ベンズアミド］ピペリジン−１−イル｝メチル）安息香酸（化合物番号４１）の製造
実施例４０で得られた、４−（｛４−［４−（｛２−オキソ−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）ベンズアミド］ピペリジン−１−イル｝メチル）安息香酸メチル（３３ｍｇ、０．０４８ｍｍｏｌ）をメタノールに溶解し、室温にて１Ｍ水酸化ナトリウム水溶液（０．０８８ｍＭ、０．４８ｍｍｏｌ）を加え、６０℃で１０時間かき混ぜた。反応混合物を減圧下濃縮してメタノールを留去し、ｐＨ７になるまで１Ｍ塩酸を加えた。その後、クロロホルムを加えて有機層を分離し、得られた有機層を無水硫酸ナトリウムで乾燥した後、減圧下濃縮乾固して４−（｛４−［４−（｛２−オキソ−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）ベンズアミド］ピペリジン−１−イル｝メチル）安息香酸（５．２ｍｇ、収率１６％）を白色固体として得た。

ＬＣ／ＭＳ［条件１］：保持時間２．６１分；ｍ／ｚ６６５．１［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ６６３．１［Ｍ−Ｈ］^―（ＥＳＩ負イオンモード）

Example 41
4-({4- [4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl) Preparation of benzamido] piperidin-1-yl} methyl) benzoic acid (Compound No. 41) 4-({4- [4-({2-oxo-8- [4- (trifluoro )] obtained in Example 40. Methyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl) benzamido] piperidin-1-yl} methyl) methyl benzoate (33 mg, 0.048 mmol) in methanol After dissolution, 1 M aqueous sodium hydroxide solution (0.088 mM, 0.48 mmol) was added at room temperature, and the mixture was stirred at 60 ° C. for 10 hr. The reaction mixture was concentrated under reduced pressure to distill off methanol, and 1M hydrochloric acid was added until pH 7 was reached. Thereafter, chloroform was added to separate the organic layer, and the obtained organic layer was dried over anhydrous sodium sulfate and then concentrated to dryness under reduced pressure to give 4-({4- [4-({2-oxo-8- [4- (Trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl) benzamido] piperidin-1-yl} methyl) benzoic acid (5.2 mg, Yield 16%) was obtained as a white solid.

LC / MS [Condition 1]: Retention time 2.61 minutes; m / z 665.1 [M + H] ⁺ (ESI positive ion mode), m / z 663.1 [M−H] ⁻ (ESI negative ion mode)

実施例４２
Ｎ−（１−（２−エチルブチル）ピペリジン−４−イル）−４−（（２−オキソ−８−（４−（トリフルオロメチル）ベンジル）−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル）メチル）ベンズアミド（化合物番号４２）の製造
参考例２２で得られた、４−（｛２−オキソ−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）−Ｎ−（ピペリジン−４−イル）ベンズアミド２塩酸塩（３８ｍｇ、０．０６３ｍｍｏｌ）をメタノールに溶解し、室温にて酢酸（０．０１１ｍＬ、０．１９ｍｍｏｌ）と２−エチルブチルアルデヒド（０．０４５ｍＬ、０．３８ｍｍｏｌ）を加えて、室温で３時間かき混ぜた。そして、反応混合物にトリアセトキシ水素化ホウ素ナトリウム（７０ｍｇ、０．３２ｍｍｏｌ）を加えて、３日間かき混ぜた。その後、反応混合物にクロロホルムと飽和炭酸水素ナトリウム水溶液を加えて有機層を分離し、有機層を無水硫酸ナトリウムで乾燥した後、減圧下濃縮してクロロホルムを留去した。得られた残留物をシリカゲルカラムクロマトグラフィー［充填剤：富士シリシア製ＮＨ−ＤＭ１０２０、展開溶媒：ヘキサン／酢酸エチル＝１／４］にて精製し、Ｎ−［１−（２−エチルブチル）ピペリジン−４−イル］−４−（｛２−オキソ−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）ベンズアミド（２４ｍｇ、収率６２％）を白色固体として得た。

^１Ｈ−ＮＭＲ（３００ＭＨｚ，ＣＤＣｌ_３）δ：０．８６（６Ｈ，ｔ，Ｊ＝７．４Ｈｚ），１．２１−１．４５（５Ｈ，ｍ），１．４７−１．６２（２Ｈ，ｍ），１．６５−１．７８（２Ｈ，ｍ），１．８３−２．１９（８Ｈ，ｍ），２．４５−２．６０（４Ｈ，ｂｒｍ），２．８０（２Ｈ，ｄ，Ｊ＝１１．９Ｈｚ），３．１１（２Ｈ，ｓ），３．５５（２Ｈ，ｓ），３．９０−４．０６（１Ｈ，ｍ），４．４５（２Ｈ，ｓ），５．９７（１Ｈ，ｄ，Ｊ＝７．８Ｈｚ），７．３２（２Ｈ，ｄ，Ｊ＝８．６Ｈｚ），７．４１（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ），７．５５（２Ｈ，ｄ，Ｊ＝７．８Ｈｚ），７．７３（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ）．

ＬＣ／ＭＳ［条件１］：保持時間３．００分；ｍ／ｚ６１５．０［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ６５９．２［Ｍ＋ＨＣＯＯ］^―（ＥＳＩ負イオンモード）

Example 42
N- (1- (2-ethylbutyl) piperidin-4-yl) -4-((2-oxo-8- (4- (trifluoromethyl) benzyl) -1-oxa-3,8-diazaspiro [4. 5] Preparation of decan-3-yl) methyl) benzamide (Compound No. 42) 4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa obtained in Reference Example 22 -3,8-diazaspiro [4.5] decan-3-yl} methyl) -N- (piperidin-4-yl) benzamide dihydrochloride (38 mg, 0.063 mmol) dissolved in methanol and acetic acid at room temperature (0.011 mL, 0.19 mmol) and 2-ethylbutyraldehyde (0.045 mL, 0.38 mmol) were added, and the mixture was stirred at room temperature for 3 hours. Then, sodium triacetoxyborohydride (70 mg, 0.32 mmol) was added to the reaction mixture and stirred for 3 days. Thereafter, chloroform and saturated aqueous sodium hydrogen carbonate solution were added to the reaction mixture to separate the organic layer. The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure to distill off chloroform. The obtained residue was purified by silica gel column chromatography [filler: NH-DM1020 manufactured by Fuji Silysia, developing solvent: hexane / ethyl acetate = 1/4], and N- [1- (2-ethylbutyl) piperidine- 4-yl] -4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl) benzamide ( 24 mg, 62% yield) was obtained as a white solid.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 0.86 (6H, t, J = 7.4 Hz), 1.21-1.45 (5H, m), 1.47-1.62 (2H, m), 1.65-1.78 (2H, m), 1.83-2.19 (8H, m), 2.45-2.60 (4H, brm), 2.80 (2H, d, J = 11.9 Hz), 3.11 (2H, s), 3.55 (2H, s), 3.90-4.06 (1H, m), 4.45 (2H, s), 5.97. (1H, d, J = 7.8 Hz), 7.32 (2H, d, J = 8.6 Hz), 7.41 (2H, d, J = 8.2 Hz), 7.55 (2H, d, J = 7.8 Hz), 7.73 (2H, d, J = 8.2 Hz).

LC / MS [Condition 1]: Retention time 3.00 minutes; m / z 615.0 [M + H] ⁺ (ESI positive ion mode), m / z 659.2 [M + HCOO] ⁻ (ESI negative ion mode)

実施例４３
Ｎ−［１−（シクロヘキシルメチル）ピペリジン−４−イル］−４−（｛２−オキソ−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）ベンズアミド（化合物番号４３）の製造
２−エチルブチルアルデヒドの代わりにシクロヘキサンカルボキシアルデヒドを用いること以外は実質的に実施例４２と同様に反応を行って、表題化合物（２．８ｍｇ、収率１１％）を黄色固体として得た。

ＬＣ／ＭＳ［条件１］：保持時間３．１２分；ｍ／ｚ６２７．０［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ６７１．２［Ｍ＋ＨＣＯＯ］^―（ＥＳＩ負イオンモード）

Example 43
N- [1- (cyclohexylmethyl) piperidin-4-yl] -4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5 ] Decan-3-yl} methyl) benzamide (Compound No. 43) The reaction was conducted in substantially the same manner as in Example 42 except that cyclohexanecarboxaldehyde was used instead of 2-ethylbutyraldehyde to give the title compound ( 2.8 mg, 11% yield) was obtained as a yellow solid.

LC / MS [Condition 1]: Retention time 3.12 minutes; m / z 627.0 [M + H] ⁺ (ESI positive ion mode), m / z 671.2 [M + HCOO] ⁻ (ESI negative ion mode)

実施例４４
Ｎ−（２−モルホリノエチル）−４−（｛２−オキソ−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）ベンズアミド（化合物番号４４）の製造
参考例２１で得られた、４−（｛２−オキソ−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）安息香酸（４０ｍｇ、０．０８９ｍｍｏｌ）と、４−（２−アミノエチル）モルホリン（０．０２３ｍＬ、０．１８ｍｍｏｌ）、そして１−ヒドロキシベンゾトリアゾール（１２ｍｇ、０．０８９ｍｏｌ）をＮ，Ｎ−ジメチルホルムアミド（４．０ｍＬ）に溶解し、室温にて１−エチル−３−（３−ジメチルアミノプロピル）カルボジイミド（０．０３２ｍＬ、０．１８ｍｍｏｌ）を加えた後、４０℃で１日間かき混ぜた。反応混合物を減圧下濃縮してＮ，Ｎ−ジメチルホルムアミドを留去し、クロロホルムと飽和炭酸水素ナトリウム水溶液を加え、有機層を分離した。得られた有機層を無水硫酸ナトリウムで乾燥した後、減圧下濃縮してクロロホルムを留去し、残留物をＨＰＬＣにて精製し、Ｎ−（２−モルホリノエチル）−４−（｛２−オキソ−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）ベンズアミド（３８ｍｇ、収率９５％）を黄色固体として得た。

ＬＣ／ＭＳ［条件１］：保持時間１．０４分；ｍ／ｚ５６１．２［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ６０５．０［Ｍ＋ＨＣＯＯ］^―（ＥＳＩ負イオンモード）

Example 44
N- (2-morpholinoethyl) -4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} Production of methyl) benzamide (Compound No. 44) 4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4] obtained in Reference Example 21 .5] decan-3-yl} methyl) benzoic acid (40 mg, 0.089 mmol), 4- (2-aminoethyl) morpholine (0.023 mL, 0.18 mmol), and 1-hydroxybenzotriazole (12 mg, 0.089 mol) was dissolved in N, N-dimethylformamide (4.0 mL) and 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide (0.0 2 mL, 0.18 mmol) was added, which was stirred for 1 day at 40 ° C.. The reaction mixture was concentrated under reduced pressure to distill off N, N-dimethylformamide, chloroform and saturated aqueous sodium hydrogen carbonate solution were added, and the organic layer was separated. The obtained organic layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure to distill off chloroform, the residue was purified by HPLC, and N- (2-morpholinoethyl) -4-({2-oxo -8- [4- (Trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl) benzamide (38 mg, 95% yield) was obtained as a yellow solid. It was.

LC / MS [Condition 1]: Retention time 1.04 minutes; m / z 561.2 [M + H] ⁺ (ESI positive ion mode), m / z 605.0 [M + HCOO] ⁻ (ESI negative ion mode)

実施例４５
４−（｛２−オキソ−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）−Ｎ−［３−（２−オキソピロリジン−１−イル）プロピル］ベンズアミド（化合物番号４５）の製造
４−（２−アミノエチル）モルホリンの代わりに１−（３−アミノプロピル）−２−ピロリドンを用いること以外は実質的に実施例４４と同様に反応を行って、表題化合物（４１ｍｇ、定量的）を茶色油状物として得た。

ＬＣ／ＭＳ［条件１］：保持時間２．９４分；ｍ／ｚ５７２．９［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ６１７．０［Ｍ＋ＨＣＯＯ］^―（ＥＳＩ負イオンモード）

Example 45
4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl) -N- [3- ( Preparation of 2-oxopyrrolidin-1-yl) propyl] benzamide (Compound No. 45) Substantially except that 1- (3-aminopropyl) -2-pyrrolidone is used instead of 4- (2-aminoethyl) morpholine Was reacted in the same manner as in Example 44 to give the title compound (41 mg, quantitative) as a brown oil.

LC / MS [Condition 1]: Retention time 2.94 minutes; m / z 572.9 [M + H] ⁺ (ESI positive ion mode), m / z 617.0 [M + HCOO] ⁻ (ESI negative ion mode)

実施例４６
Ｎ−（１−メトキシブタン−２−イル）−４−（｛２−オキソ−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）ベンズアミド（化合物番号４６）の製造
４−（２−アミノエチル）モルホリンの代わりに２−アミノ−１−メトキシブタンを用いること以外は実質的に実施例４４と同様に反応を行って、表題化合物（３５ｍｇ、定量的）を黄色固体として得た。

ＬＣ／ＭＳ［条件１］：保持時間３．１８分；ｍ／ｚ５３３．９［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ５７８．０［Ｍ＋ＨＣＯＯ］^―（ＥＳＩ負イオンモード）

Example 46
N- (1-methoxybutan-2-yl) -4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decane- Preparation of 3-yl} methyl) benzamide (Compound No. 46) The reaction was carried out in substantially the same manner as in Example 44, except that 2-amino-1-methoxybutane was used instead of 4- (2-aminoethyl) morpholine. Performed to give the title compound (35 mg, quantitative) as a yellow solid.

LC / MS [Condition 1]: Retention time 3.18 minutes; m / z 533.9 [M + H] ⁺ (ESI positive ion mode), m / z 578.0 [M + HCOO] ⁻ (ESI negative ion mode)

実施例４７
４−（｛２−オキソ−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）−Ｎ−［（テトラヒドロフラン−２−イル）メチル］ベンズアミド（化合物番号４７）の製造
４−（２−アミノエチル）モルホリンの代わりにテトラヒドロフルフリルアミンを用いること以外は実質的に実施例４４と同様に反応を行って、表題化合物（３５ｍｇ、定量的）を白色固体として得た。

ＬＣ／ＭＳ［条件１］：保持時間３．０４分；ｍ／ｚ５３１．８［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ５７５．９［Ｍ＋ＨＣＯＯ］^―（ＥＳＩ負イオンモード）

Example 47
4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl) -N-[(tetrahydrofuran- Preparation of 2-yl) methyl] benzamide (Compound No. 47) The title compound was reacted in substantially the same manner as in Example 44 except that tetrahydrofurfurylamine was used instead of 4- (2-aminoethyl) morpholine. (35 mg, quantitative) was obtained as a white solid.

LC / MS [Condition 1]: Retention time 3.04 minutes; m / z 531.8 [M + H] ⁺ (ESI positive ion mode), m / z 575.9 [M + HCOO] ⁻ (ESI negative ion mode)

実施例４８
Ｎ−シクロオクチル−４−（｛２−オキソ−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）ベンズアミド（化合物番号４８）の製造
４−（２−アミノエチル）モルホリンの代わりにシクロオクチルアミンを用いること以外は実質的に実施例４４と同様に反応を行って、表題化合物（３７ｍｇ、定量的）を黄色固体として得た。

ＬＣ／ＭＳ［条件１］：保持時間３．６２分；ｍ／ｚ５５７．９［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ６０２．０［Ｍ＋ＨＣＯＯ］^―（ＥＳＩ負イオンモード）

Example 48
N-cyclooctyl-4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl) benzamide ( Preparation of Compound No. 48) The reaction was conducted in substantially the same manner as in Example 44 except that cyclooctylamine was used in place of 4- (2-aminoethyl) morpholine to give the title compound (37 mg, quantitative) as yellow Obtained as a solid.

LC / MS [Condition 1]: retention time 3.62 minutes; m / z 557.9 [M + H] ⁺ (ESI positive ion mode), m / z 602.0 [M + HCOO] ⁻ (ESI negative ion mode)

実施例４９
（Ｓ）−Ｎ−（１−ヒドロキシ−４−メチルペンタン−２−イル）−４−（｛２−オキソ−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）ベンズアミド（化合物番号４９）の製造
４−（２−アミノエチル）モルホリンの代わりにＬ−（＋）−ロイシノールを用いること以外は実質的に実施例４４と同様に反応を行って、表題化合物（３３ｍｇ、収率９４％）を白色固体として得た。

ＬＣ／ＭＳ［条件１］：保持時間３．２２分；ｍ／ｚ５４７．８［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ５９２．０［Ｍ＋ＨＣＯＯ］^―（ＥＳＩ負イオンモード）

Example 49
(S) -N- (1-hydroxy-4-methylpentan-2-yl) -4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8- Preparation of diazaspiro [4.5] decan-3-yl} methyl) benzamide (Compound No. 49) Substantially carried out except that L-(+)-leucinol is used instead of 4- (2-aminoethyl) morpholine The reaction was carried out in the same manner as in Example 44 to obtain the title compound (33 mg, yield 94%) as a white solid.

LC / MS [Condition 1]: Retention time 3.22 min; m / z 547.8 [M + H] ⁺ (ESI positive ion mode), m / z 592.0 [M + HCOO] ⁻ (ESI negative ion mode)

実施例５０
Ｎ−（１−アダマンチルメチル）−４−（｛２−オキソ−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）ベンズアミド（化合物番号５０）の製造
４−（２−アミノエチル）モルホリンの代わりに１−アダマンタンメチルアミンを用いること以外は実質的に実施例４４と同様に反応を行って、表題化合物（３９ｍｇ、定量的）を黄色固体として得た。

ＬＣ／ＭＳ［条件１］：保持時間３．７８分；ｍ／ｚ５９５．８［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ６４０．０［Ｍ＋ＨＣＯＯ］^―（ＥＳＩ負イオンモード）

Example 50
N- (1-adamantylmethyl) -4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} Preparation of methyl) benzamide (Compound No. 50) The reaction was conducted in substantially the same manner as in Example 44 except that 1-adamantanemethylamine was used instead of 4- (2-aminoethyl) morpholine to give the title compound (39 mg , Quantitative) was obtained as a yellow solid.

LC / MS [Condition 1]: Retention time 3.78 minutes; m / z 595.8 [M + H] ⁺ (ESI positive ion mode), m / z 640.0 [M + HCOO] ⁻ (ESI negative ion mode)

実施例５１
ｔ−ブチル ５−［４−（｛２−オキソ−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）ベンズアミド］ペンチルカルバメート（化合物番号５１）の製造
４−（２−アミノエチル）モルホリンの代わりにＮ−（ｔ−ブトキシカルボニル）−１，５−ジアミノペンタンを用いること以外は実質的に実施例４４と同様に反応を行って、表題化合物（４１ｍｇ、定量的）を茶色油状物として得た。

ＬＣ／ＭＳ［条件１］：保持時間３．４４分；ｍ／ｚ６３２．８［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ６７７．０［Ｍ＋ＨＣＯＯ］^―（ＥＳＩ負イオンモード）

Example 51
t-butyl 5- [4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl) benzamide Preparation of pentylcarbamate (Compound No. 51) Substantially the same as Example 44, except that N- (t-butoxycarbonyl) -1,5-diaminopentane was used instead of 4- (2-aminoethyl) morpholine. The title compound (41 mg, quantitative) was obtained as a brown oil.

LC / MS [Condition 1]: Retention time 3.44 minutes; m / z 632.8 [M + H] ⁺ (ESI positive ion mode), m / z 677.0 [M + HCOO] ⁻ (ESI negative ion mode)

実施例５２
ｔ−ブチル ６−［４−（｛２−オキソ−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）ベンズアミド］ヘキシルカルバメート（化合物番号５２）の製造
４−（２−アミノエチル）モルホリンの代わりにＮ−（ｔ−ブトキシカルボニル）−１，６−ジアミノヘキサンを用いること以外は実質的に実施例４４と同様に反応を行って、表題化合物（４３ｍｇ、定量的）を白色固体として得た。

ＬＣ／ＭＳ［条件１］：保持時間３．５４分；ｍ／ｚ６４６．９［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ６９１．０［Ｍ＋ＨＣＯＯ］^―（ＥＳＩ負イオンモード）

Example 52
t-butyl 6- [4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl) benzamide Preparation of hexyl carbamate (Compound No. 52) Substantially the same as Example 44, except that N- (t-butoxycarbonyl) -1,6-diaminohexane was used instead of 4- (2-aminoethyl) morpholine. The title compound (43 mg, quantitative) was obtained as a white solid.

LC / MS [Condition 1]: Retention time 3.54 minutes; m / z 646.9 [M + H] ⁺ (ESI positive ion mode), m / z 691.0 [M + HCOO] ⁻ (ESI negative ion mode)

実施例５３
３−［４−（チオモルホリン−４−カルボニル）ベンジル］−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−２−オン（化合物番号５３）の製造
４−（２−アミノエチル）モルホリンの代わりにチオモルホリンを用いること以外は実質的に実施例４４と同様に反応を行って、表題化合物（３５ｍｇ、定量的）を白色固体として得た。

ＬＣ／ＭＳ［条件１］：保持時間３．１８分；ｍ／ｚ５３３．７［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ５７８．０［Ｍ＋ＨＣＯＯ］^―（ＥＳＩ負イオンモード）

Example 53
3- [4- (Thiomorpholine-4-carbonyl) benzyl] -8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-2-one (compound Preparation of No. 53) The reaction was carried out in substantially the same manner as in Example 44 except that thiomorpholine was used instead of 4- (2-aminoethyl) morpholine to give the title compound (35 mg, quantitative) as a white solid Obtained.

LC / MS [Condition 1]: Retention time 3.18 minutes; m / z 533.7 [M + H] ⁺ (ESI positive ion mode), m / z 578.0 [M + HCOO] ⁻ (ESI negative ion mode)

実施例５４
３−｛４−［４−（ピロリジン−１−イル）ピペリジン−１−カルボニル］ベンジル｝−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−２−オン（化合物番号５４）の製造
４−（２−アミノエチル）モルホリンの代わりに４−（ピロリジン−１−イル）ピペリジンを用いること以外は実質的に実施例４４と同様に反応を行って、表題化合物（２８ｍｇ、収率７２％）を黄色固体として得た。

ＬＣ／ＭＳ［条件１］：保持時間１．１２分；ｍ／ｚ５８４．７［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ６２９．０［Ｍ＋ＨＣＯＯ］^―（ＥＳＩ負イオンモード）

Example 54
3- {4- [4- (Pyrrolidin-1-yl) piperidin-1-carbonyl] benzyl} -8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5 Preparation of decan-2-one (Compound No. 54) Reaction substantially in the same manner as in Example 44 except that 4- (pyrrolidin-1-yl) piperidine was used instead of 4- (2-aminoethyl) morpholine. To give the title compound (28 mg, 72% yield) as a yellow solid.

LC / MS [Condition 1]: Retention time 1.12 minutes; m / z 584.7 [M + H] ⁺ (ESI positive ion mode), m / z 629.0 [M + HCOO] ⁻ (ESI negative ion mode)

実施例５５
３−［４−（４−ベンゾイルピペリジン−１−カルボニル）ベンジル］−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−２−オン（化合物番号５５）の製造
４−（２−アミノエチル）モルホリンの代わりに４−ベンゾイルピペリジン塩酸塩とトリエチルアミンを用いること以外は実質的に実施例４４と同様に反応を行って、表題化合物（４１ｍｇ、定量的）を白色固体として得た。

ＬＣ／ＭＳ［条件１］：保持時間３．４６分；ｍ／ｚ６１９．８［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ６６４．０［Ｍ＋ＨＣＯＯ］^―（ＥＳＩ負イオンモード）

Example 55
3- [4- (4-Benzoylpiperidin-1-carbonyl) benzyl] -8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-2-one Preparation of (Compound No. 55) The reaction was conducted in substantially the same manner as in Example 44 except that 4-benzoylpiperidine hydrochloride and triethylamine were used instead of 4- (2-aminoethyl) morpholine to give the title compound (41 mg , Quantitative) was obtained as a white solid.

LC / MS [Condition 1]: Retention time 3.46 min; m / z 619.8 [M + H] ⁺ (ESI positive ion mode), m / z 664.0 [M + HCOO] ⁻ (ESI negative ion mode)

実施例５６
Ｎ−（ベンゾ［ｄ］［１，３］ジオキソール−５−イルメチル）−４−（｛２−オキソ−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）ベンズアミド（化合物番号５６）の製造
４−（２−アミノエチル）モルホリンの代わりにピペロニルアミンを用いること以外は実質的に実施例４４と同様に反応を行って、表題化合物（３８ｍｇ、定量的）を黄色固体として得た。

ＬＣ／ＭＳ［条件１］：保持時間３．３２分；ｍ／ｚ５８１．８［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ６２５．９［Ｍ＋ＨＣＯＯ］^―（ＥＳＩ負イオンモード）

Example 56
N- (benzo [d] [1,3] dioxol-5-ylmethyl) -4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [ 4.5] Preparation of decan-3-yl} methyl) benzamide (Compound No. 56) The reaction was carried out in substantially the same manner as in Example 44, except that piperonylamine was used instead of 4- (2-aminoethyl) morpholine. To give the title compound (38 mg, quantitative) as a yellow solid.

LC / MS [Condition 1]: Retention time 3.32 minutes; m / z 581.8 [M + H] ⁺ (ESI positive ion mode), m / z 625.9 [M + HCOO] ⁻ (ESI negative ion mode)

実施例５７
Ｎ−（２，３−ジヒドロ−１Ｈ−インデン−１−イル）−４−（｛２−オキソ−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）ベンズアミド（化合物番号５７）の製造
４−（２−アミノエチル）モルホリンの代わりに１−アミノインダンを用いること以外は実質的に実施例４４と同様に反応を行って、表題化合物（３７ｍｇ、定量的）を黄色固体として得た。

ＬＣ／ＭＳ［条件１］：保持時間３．５０分；ｍ／ｚ５６３．８［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ６０７．９［Ｍ＋ＨＣＯＯ］^―（ＥＳＩ負イオンモード）

Example 57
N- (2,3-dihydro-1H-inden-1-yl) -4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4 .5] Preparation of decan-3-yl} methyl) benzamide (Compound No. 57) Reaction substantially in the same manner as in Example 44 except that 1-aminoindan was used instead of 4- (2-aminoethyl) morpholine To give the title compound (37 mg, quantitative) as a yellow solid.

LC / MS [Condition 1]: Retention time 3.50 minutes; m / z 563.8 [M + H] ⁺ (ESI positive ion mode), m / z 607.9 [M + HCOO] ⁻ (ESI negative ion mode)

実施例５８
Ｎ−（ナフタレン−１−イルメチル）−４−（｛２−オキソ−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）ベンズアミド（化合物番号５８）の製造
４−（２−アミノエチル）モルホリンの代わりに１−ナフチルメチルアミンを用いること以外は実質的に実施例４４と同様に反応を行って、表題化合物（３８ｍｇ、定量的）を黄色固体として得た。

ＬＣ／ＭＳ［条件１］：保持時間３．５６分；ｍ／ｚ５８７．８［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ６３２．０［Ｍ＋ＨＣＯＯ］^―（ＥＳＩ負イオンモード）

Example 58
N- (naphthalen-1-ylmethyl) -4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl } Preparation of methyl) benzamide (Compound No. 58) The reaction was conducted in substantially the same manner as in Example 44 except that 1-naphthylmethylamine was used instead of 4- (2-aminoethyl) morpholine to give the title compound ( 38 mg, quantitative) was obtained as a yellow solid.

LC / MS [Condition 1]: retention time 3.56 minutes; m / z 587.8 [M + H] ⁺ (ESI positive ion mode), m / z 632.0 [M + HCOO] ⁻ (ESI negative ion mode)

実施例５９
Ｎ−（２，３−ジヒドロ−１Ｈ−インデン−２−イル）−４−（｛２−オキソ−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）ベンズアミド（化合物番号５９）の製造
４−（２−アミノエチル）モルホリンの代わりに２−アミノインダンを用いること以外は実質的に実施例４４と同様に反応を行って、表題化合物（１０ｍｇ、収率２７％）を黄色固体として得た。

ＬＣ／ＭＳ［条件１］：保持時間３．５０分；ｍ／ｚ５６３．８［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ６０７．９［Ｍ＋ＨＣＯＯ］^―（ＥＳＩ負イオンモード）

Example 59
N- (2,3-dihydro-1H-inden-2-yl) -4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4 .5] Preparation of decan-3-yl} methyl) benzamide (Compound No. 59) Reaction substantially in the same manner as in Example 44 except that 2-aminoindane was used instead of 4- (2-aminoethyl) morpholine To give the title compound (10 mg, 27% yield) as a yellow solid.

LC / MS [Condition 1]: Retention time 3.50 minutes; m / z 563.8 [M + H] ⁺ (ESI positive ion mode), m / z 607.9 [M + HCOO] ⁻ (ESI negative ion mode)

実施例６０
４−（｛２−オキソ−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）−Ｎ−フェネチルベンズアミド（化合物番号６０）の製造
４−（２−アミノエチル）モルホリンの代わりにフェネチルアミンを用いること以外は実質的に実施例４４と同様に反応を行って、表題化合物（３０ｍｇ、収率８１％）を白色固体として得た。

ＬＣ／ＭＳ［条件１］：保持時間３．４０分；ｍ／ｚ５５１．８［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ５９６．０［Ｍ＋ＨＣＯＯ］^―（ＥＳＩ負イオンモード）

Example 60
4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl) -N-phenethylbenzamide (compound Preparation of No. 60) The reaction was conducted in substantially the same manner as in Example 44 except that phenethylamine was used instead of 4- (2-aminoethyl) morpholine to give the title compound (30 mg, yield 81%) as a white solid Got as.

LC / MS [Condition 1]: Retention time 3.40 minutes; m / z 551.8 [M + H] ⁺ (ESI positive ion mode), m / z 596.0 [M + HCOO] ⁻ (ESI negative ion mode)

実施例６１
Ｎ−イソプロピル−４−（｛２−オキソ−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）ベンズアミド（化合物番号６１）の製造
４−（２−アミノエチル）モルホリンの代わりにイソプロピルアミンを用いること以外は実質的に実施例４４と同様に反応を行って、表題化合物（３９ｍｇ、収率８８％）を白色固体として得た。

ＬＣ／ＭＳ［条件１］：保持時間３．０８分；ｍ／ｚ４８９．７［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ５３３．９［Ｍ＋ＨＣＯＯ］^―（ＥＳＩ負イオンモード）

Example 61
N-isopropyl-4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl) benzamide (compound Preparation of No. 61) The reaction was conducted in substantially the same manner as in Example 44 except that isopropylamine was used instead of 4- (2-aminoethyl) morpholine to give the title compound (39 mg, yield 88%) as white Obtained as a solid.

LC / MS [Condition 1]: Retention time 3.08 minutes; m / z 489.7 [M + H] ⁺ (ESI positive ion mode), m / z 533.9 [M + HCOO] ⁻ (ESI negative ion mode)

実施例６２
Ｎ−シクロヘキシル−４−（｛２−オキソ−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）ベンズアミド（化合物番号６２）の製造
４−（２−アミノエチル）モルホリンの代わりにシクロヘキシルアミンを用いること以外は実質的に実施例４４と同様に反応を行って、表題化合物（４７ｍｇ、定量的）を白色固体として得た。

ＬＣ／ＭＳ［条件１］：保持時間３．４２分；ｍ／ｚ５２９．７［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ５７３．９［Ｍ＋ＨＣＯＯ］^―（ＥＳＩ負イオンモード）

Example 62
N-cyclohexyl-4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl) benzamide (compound Preparation of No. 62) The reaction was carried out in substantially the same manner as in Example 44 except that cyclohexylamine was used instead of 4- (2-aminoethyl) morpholine to give the title compound (47 mg, quantitative) as a white solid Obtained.

LC / MS [Condition 1]: Retention time 3.42 minutes; m / z 529.7 [M + H] ⁺ (ESI positive ion mode), m / z 573.9 [M + HCOO] ⁻ (ESI negative ion mode)

実施例６３
４−（｛２−オキソ−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）−Ｎ−［１−（ピリジン−４−イル）ピペリジン−４−イル］ベンズアミド（化合物番号６３）の製造
４−（２−アミノエチル）モルホリンの代わりに４−（４−アミノピペリジノ）ピリジンを用いること以外は実質的に実施例４４と同様に反応を行って、表題化合物（５１ｍｇ、収率７９％）を白色固体として得た。

^１Ｈ−ＮＭＲ（３００ＭＨｚ，ＣＤＣｌ_３）δ：１．４９−１．６５（２Ｈ，ｍ），１．６５−１．７８（２Ｈ，ｍ），１．８５−１．９６（２Ｈ，ｂｒｍ），２．１０−２．２１（２Ｈ，ｂｒｍ），２．６２−２．４２（４Ｈ，ｂｒｍ），２．９８−３．１５（４Ｈ，ｍ），３．５５（２Ｈ，ｓ），３．８６−３．９７（２Ｈ，ｂｒｍ），４．１８−４．３３（１Ｈ，ｍ），４．４６（２Ｈ，ｓ），６．０１（１Ｈ，ｄ，Ｊ＝７．８Ｈｚ），６．６９（２Ｈ，ｄｄ，Ｊ＝５．３，１．６Ｈｚ），７．３４（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ），７．４２（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ），７．５６（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ），７．７４（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ），８．２８（２Ｈ，ｄｄ，Ｊ＝５．３，１．６Ｈｚ）．

Example 63
4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl) -N- [1- ( Preparation of Pyridin-4-yl) piperidin-4-yl] benzamide (Compound No. 63) Essentially except that 4- (4-aminopiperidino) pyridine was used instead of 4- (2-aminoethyl) morpholine The reaction was conducted in the same manner as for 44 to give the title compound (51 mg, yield 79%) as a white solid.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.49-1.65 (2H, m), 1.65-1.78 (2H, m), 1.85-1.96 (2H, brm) 2.10-2.21 (2H, brm), 2.62-2.42 (4H, brm), 2.98-3.15 (4H, m), 3.55 (2H, s), 3 .86-3.97 (2H, brm), 4.18-4.33 (1H, m), 4.46 (2H, s), 6.01 (1H, d, J = 7.8 Hz), 6 .69 (2H, dd, J = 5.3, 1.6 Hz), 7.34 (2H, d, J = 8.2 Hz), 7.42 (2H, d, J = 8.2 Hz), 7. 56 (2H, d, J = 8.2 Hz), 7.74 (2H, d, J = 8.2 Hz), 8.28 (2H, dd, J = 5.3, 1.6 Hz).

参考例６４
４−アミノ−１−（ピリジン−３−イルメチル）ピペリジン三塩酸塩の製造
ニコチンアルデヒド（東京化成工業（株）より購入）（１．３ｇ、１２ｍｍｏｌ）をクロロホルム（５０ｍｌ）に溶解し、室温にて４−（ｔ−ブトキシカルボニルアミノ）ピペリジン（シグマアルドリッチ（株）より購入）（２．４ｇ，１２ｍｍｏｌ）を加えたのち、２分間かき混ぜた。反応混合物にトリアセトキシ水素化ホウ素ナトリウム（３．２ｇ、１５ｍｍｏｌ）をゆっくり加えたのち、室温にて４時間かき混ぜた。反応混合物に１Ｍ水酸化ナトリウム水溶液を加えたのち、有機層を分離した。有機層を飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥させたのち、減圧下濃縮乾固して、１−（ピリジン−３−イルメチル）−４−（ｔ−ブトキシカルボニルアミノ）ピペリジンを白色固体として得た。さらに精製することなく、この化合物をメタノール（５．０ｍｌ）に溶解し、室温にて４Ｍ塩化水素−ジオキサン溶液（２５ｍｌ）を加えて３時間かき混ぜた。反応混合物を減圧下濃縮乾固して、得られた残留物にメタノールと酢酸エチルを加えたのち、終夜静置した。析出した固体をろ取し、減圧下５０℃で１時間乾燥することで、４−アミノ−１−（ピリジン−３−イルメチル）ピペリジン三塩酸塩（２．９ｇ、収率８１％）を白色固体として得た。

^１Ｈ−ＮＭＲ（３００ＭＨｚ，ＣＤ_３ＯＤ）δ：２．０３−２．２２（２Ｈ，ｍ），２．２８（２Ｈ，ｄ，Ｊ＝１３．０Ｈｚ），３．２５−３．４５（２Ｈ，ｍ），３．４９−３．６２（１Ｈ，ｍ），３．６７（２Ｈ，ｄ，Ｊ＝１２．６Ｈｚ），４．６８（２Ｈ，ｓ），８．１９（１Ｈ，ｄｄ，Ｊ＝８．２，５．８Ｈｚ），８．９４（１Ｈ，ｄｔ，Ｊ＝８．２，１．７Ｈｚ），８．９８（１Ｈ，ｄ，Ｊ＝５．８Ｈｚ），９．２６（１Ｈ，ｄ，Ｊ＝１．７Ｈｚ）．

Reference Example 64
Preparation of 4-amino-1- (pyridin-3-ylmethyl) piperidine trihydrochloride Nicotinaldehyde (purchased from Tokyo Chemical Industry Co., Ltd.) (1.3 g, 12 mmol) was dissolved in chloroform (50 ml) at room temperature. 4- (t-Butoxycarbonylamino) piperidine (purchased from Sigma-Aldrich Co.) (2.4 g, 12 mmol) was added, and the mixture was stirred for 2 minutes. Sodium triacetoxyborohydride (3.2 g, 15 mmol) was slowly added to the reaction mixture, and then stirred at room temperature for 4 hours. After adding 1M aqueous sodium hydroxide solution to the reaction mixture, the organic layer was separated. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to dryness under reduced pressure to give 1- (pyridin-3-ylmethyl) -4- (t-butoxycarbonylamino) piperidine as a white solid Got as. Without further purification, this compound was dissolved in methanol (5.0 ml), a 4M hydrogen chloride-dioxane solution (25 ml) was added at room temperature, and the mixture was stirred for 3 hours. The reaction mixture was concentrated to dryness under reduced pressure, methanol and ethyl acetate were added to the obtained residue, and the mixture was allowed to stand overnight. The precipitated solid was collected by filtration and dried at 50 ° C. under reduced pressure for 1 hour to give 4-amino-1- (pyridin-3-ylmethyl) piperidine trihydrochloride (2.9 g, yield 81%) as a white solid. Got as.

¹ H-NMR (300 MHz, CD ₃ OD) δ: 2.03-2.22 (2H, m), 2.28 (2H, d, J = 13.0 Hz), 3.25-3.45 (2H M), 3.49-3.62 (1H, m), 3.67 (2H, d, J = 12.6 Hz), 4.68 (2H, s), 8.19 (1H, dd, J = 8.2, 5.8 Hz), 8.94 (1H, dt, J = 8.2, 1.7 Hz), 8.98 (1H, d, J = 5.8 Hz), 9.26 (1H, d, J = 1.7 Hz).

実施例６４
４−（｛２−オキソ−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）−Ｎ−［１−（ピリジン−３−イルメチル）ピペリジン−４−イル］ベンズアミド（化合物番号６４）の製造
参考例２１で得た４−（｛２−オキソ−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）安息香酸（２３ｍｇ、０．０５１ｍｍｏｌ）、参考例６４で得られた、４−アミノ−１−（ピリジン−３−イルメチル）ピペリジン三塩酸塩（１８ｍｇ、０．０６２ｍｍｏｌ）およびトリエチルアミン（０．０３５ｍＬ、０．２６ｍｍｏｌ）をクロロホルム（１．５ｍＬ）に懸濁し、１−ヒドロキシベンゾトリアゾール（６．８ｍｇ、０．０５１ｍｍｏｌ）および１−エチル−３−（３−ジメチルアミノプロピル）カルボジイミド塩酸塩（１４ｍｇ、０．０７６ｍｍｏｌ）を加えたのち室温にて１６時間かき混ぜた。反応混合物にクロロホルム（１．０ｍＬ）と飽和炭酸水素ナトリウム水溶液（２．０ｍＬ）を加え、有機層を分離した後、水層をクロロホルム（２．０ｍＬ）で抽出した。合わせた有機層を無水硫酸マグネシウムで乾燥した後、減圧下濃縮し、得られた残留物をシリカゲルカラムクロマトグラフィー［充填剤：富士シリシア製ＮＨ−ＤＭ１０２０、展開溶媒：酢酸エチル］にて精製し、表題化合物（２５ｍｇ、収率８０％）を白色固体として得た。

^１Ｈ−ＮＭＲ（３００ＭＨｚ，ＣＤＣｌ_３）δ：１．５６（２Ｈ，ｄｑ，Ｊ＝３．９，１１．６Ｈｚ），１．６６−１．７９（２Ｈ，ｍ），１．８５−１．９６（２Ｈ，ｍ），２．２１（２Ｈ，ｄｔ，Ｊ＝２．８，１１．６Ｈｚ），２．４３−２．６２（４Ｈ，ｍ），２．８５（２Ｈ，ｄ，Ｊ＝１１．８Ｈｚ），３．１１（２Ｈ，ｓ），３．５４（４Ｈ，ｄ，Ｊ＝５．８Ｈｚ），３．９３−４．１０（１Ｈ，ｍ），４．４６（２Ｈ，ｓ），６．０１（１Ｈ，ｄ，Ｊ＝７．４Ｈｚ），７．２６（３Ｈ，ｄｄ，Ｊ＝７．４，５．０Ｈｚ），７．３３（２Ｈ，ｄ，Ｊ＝８．３Ｈｚ），７．４２（２Ｈ，ｄ，Ｊ＝８．３Ｈｚ），７．５６（２Ｈ，ｄ，Ｊ＝８．０Ｈｚ），７．６６（１Ｈ，ｄｔ，Ｊ＝７．７，１．９Ｈｚ），７．７４（２Ｈ，ｄ，Ｊ＝８．３Ｈｚ），８．５１（１Ｈ，ｄｄ，Ｊ＝４．７，１．７Ｈｚ），８．５６（１Ｈ，ｄ，Ｊ＝１．９Ｈｚ）．

ＬＣ／ＭＳ［条件１］：保持時間１．１９分；ｍ／ｚ６２１．８［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ６２０．０［Ｍ−Ｈ］^―（ＥＳＩ負イオンモード）

Example 64
4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl) -N- [1- ( Preparation of Pyridin-3-ylmethyl) piperidin-4-yl] benzamide (Compound No. 64) 4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa obtained in Reference Example 21 -3,8-diazaspiro [4.5] decan-3-yl} methyl) benzoic acid (23 mg, 0.051 mmol), 4-amino-1- (pyridin-3-ylmethyl) obtained in Reference Example 64 Piperidine trihydrochloride (18 mg, 0.062 mmol) and triethylamine (0.035 mL, 0.26 mmol) are suspended in chloroform (1.5 mL) and 1-hydroxybenzotriazole ( .8Mg, stirred 16 hours at room temperature After addition of 0.051 mmol) and 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (14 mg, 0.076 mmol). Chloroform (1.0 mL) and saturated aqueous sodium hydrogen carbonate solution (2.0 mL) were added to the reaction mixture, the organic layer was separated, and the aqueous layer was extracted with chloroform (2.0 mL). The combined organic layers were dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography [filler: NH-DM1020 manufactured by Fuji Silysia, developing solvent: ethyl acetate] The title compound (25 mg, 80% yield) was obtained as a white solid.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.56 (2H, dq, J = 3.9, 11.6 Hz), 1.66-1.79 (2H, m), 1.85-1. 96 (2H, m), 2.21 (2H, dt, J = 2.8, 11.6 Hz), 2.44-2.62 (4H, m), 2.85 (2H, d, J = 11) .8 Hz), 3.11 (2H, s), 3.54 (4 H, d, J = 5.8 Hz), 3.93-4.10 (1 H, m), 4.46 (2 H, s), 6.01 (1H, d, J = 7.4 Hz), 7.26 (3H, dd, J = 7.4, 5.0 Hz), 7.33 (2H, d, J = 8.3 Hz), 7 .42 (2H, d, J = 8.3 Hz), 7.56 (2H, d, J = 8.0 Hz), 7.66 (1H, dt, J = 7.7, 1.9 Hz), 7. 74 (2H, d, J 8.3Hz), 8.51 (1H, dd, J = 4.7,1.7Hz), 8.56 (1H, d, J = 1.9Hz).

LC / MS [Condition 1]: Retention time 1.19 minutes; m / z 621.8 [M + H] ⁺ (ESI positive ion mode), m / z 620.0 [M−H] ⁻ (ESI negative ion mode)

実施例６５
Ｎ−［３−（ジメチルアミノ）プロピル］−４−（｛２−オキソ−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）ベンズアミドギ酸塩（化合物番号６５）の製造
４−（２−アミノエチル）モルホリンの代わりにＮ，Ｎ−ジメチルプロパンジアミン（東京化成工業（株）より購入）を用いること以外は実質的に実施例４４と同様に反応を行って、表題化合物（４３ｍｇ、収率７９％）を淡黄色油状物として得た。

^１Ｈ−ＮＭＲ（３００ＭＨｚ，ＣＤＣｌ_３）δ：１．７８−１．９９（４Ｈ，ｍ），２．１１（２Ｈ，ｔｔ，Ｊ＝６．１，６．５Ｈｚ），２．５７−２．７４（４Ｈ，ｍ），２．７６（６Ｈ，ｓ），３．０９（２Ｈ，ｔ，Ｊ＝６．８Ｈｚ），３．１５（２Ｈ，ｓ），３．５８（２Ｈ，ｑ，Ｊ＝６．１Ｈｚ），３．６９（２Ｈ，ｓ），４．４５（２Ｈ，ｓ），７．３４（２Ｈ，ｄ，Ｊ＝８．５Ｈｚ），７．４６（２Ｈ，ｄ，Ｊ＝７．２Ｈｚ），７．５９（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ），７．９３（２Ｈ，ｄ，Ｊ＝８．５Ｈｚ），８．１９（１Ｈ，ｔ，Ｊ＝５．５Ｈｚ），８．４０（２Ｈ，ｓ）．

ＬＣ／ＭＳ［条件１］：保持時間１．０７分；ｍ／ｚ５３２．８［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ５７７．０［Ｍ＋ＨＣＯＯ］^―（ＥＳＩ負イオンモード）

Example 65
N- [3- (dimethylamino) propyl] -4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decane-3 -Il} methyl) Preparation of benzamidoformate (Compound No. 65) Substantially except that N, N-dimethylpropanediamine (purchased from Tokyo Chemical Industry Co., Ltd.) was used instead of 4- (2-aminoethyl) morpholine. The reaction was carried out as in Example 44 to give the title compound (43 mg, 79% yield) as a pale yellow oil.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.78-1.99 (4H, m), 2.11 (2H, tt, J = 6.1, 6.5 Hz), 2.57-2. 74 (4H, m), 2.76 (6H, s), 3.09 (2H, t, J = 6.8 Hz), 3.15 (2H, s), 3.58 (2H, q, J = 6.1 Hz), 3.69 (2H, s), 4.45 (2H, s), 7.34 (2H, d, J = 8.5 Hz), 7.46 (2H, d, J = 7. 2 Hz), 7.59 (2H, d, J = 8.2 Hz), 7.93 (2H, d, J = 8.5 Hz), 8.19 (1H, t, J = 5.5 Hz), 8. 40 (2H, s).

LC / MS [Condition 1]: Retention time 1.07 minutes; m / z 532.8 [M + H] ⁺ (ESI positive ion mode), m / z 577.0 [M + HCOO] ⁻ (ESI negative ion mode)

実施例６６
３−［４−（モルホリン−４−カルボニル）ベンジル］−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−２−オンギ酸塩（化合物番号６６）の製造
４−（２−アミノエチル）モルホリンの代わりにモルホリン（純正化学（株）より購入）を用いること以外は実質的に実施例４４と同様に反応を行って、表題化合物（３８ｍｇ、収率７６％）を淡黄色油状物として得た。

^１Ｈ−ＮＭＲ（３００ＭＨｚ，ＣＤＣｌ_３）δ：１．８３−１．９９（４Ｈ，ｍ），２．６１−２．９０（４Ｈ，ｍ），３．１６（２Ｈ，ｓ），３．２４−３．９５（１０Ｈ，ｂｒｍ），４．４４（２Ｈ，ｓ），７．３１（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ），７．４１（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ），７．４７（３Ｈ，ｄ，Ｊ＝８．２Ｈｚ），７．６０（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ），８．２２（１Ｈ，ｓ）．

ＬＣ／ＭＳ［条件１］：保持時間２．９１分；ｍ／ｚ５１７．８［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ５６１．９［Ｍ＋ＨＣＯＯ］^―（ＥＳＩ負イオンモード）

Example 66
3- [4- (morpholine-4-carbonyl) benzyl] -8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-2-one formate ( Preparation of Compound No. 66) The reaction was conducted in substantially the same manner as in Example 44 except that morpholine (purchased from Junsei Kagaku Co., Ltd.) was used instead of 4- (2-aminoethyl) morpholine to give the title compound ( 38 mg, yield 76%) was obtained as a pale yellow oil.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.83-1.99 (4H, m), 2.61-2.90 (4H, m), 3.16 (2H, s), 3.24 -3.95 (10H, brm), 4.44 (2H, s), 7.31 (2H, d, J = 8.2 Hz), 7.41 (2H, d, J = 8.2 Hz), 7 .47 (3H, d, J = 8.2 Hz), 7.60 (2H, d, J = 8.2 Hz), 8.22 (1H, s).

LC / MS [Condition 1]: Retention time 2.91 minutes; m / z 517.8 [M + H] ⁺ (ESI positive ion mode), m / z 561.9 [M + HCOO] ⁻ (ESI negative ion mode)

実施例６７
Ｎ−ベンジル−４−（｛２−オキソ−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）ベンズアミドギ酸塩（化合物番号６７）の製造
４−（２−アミノエチル）モルホリンの代わりにベンジルアミン（東京化成工業（株）より購入）を用いること以外は実質的に実施例４４と同様に反応を行って、表題化合物（１０ｍｇ、収率２１％）を白色固体として得た。

^１Ｈ−ＮＭＲ（３００ＭＨｚ，ＤＭＳＯ−ｄ_６）δ：１．６４−１．９０（３Ｈ，ｂｒｍ），２．３３−２．５６（２Ｈ，ｂｒｍ），３．２１（２Ｈ，ｓ），３．７５−３．３８（５Ｈ，ｍ），４．３９（２Ｈ，ｓ），４．４６（２Ｈ，ｄ，Ｊ＝５．８Ｈｚ），７．１８−７．３３（５Ｈ，ｍ），７．３４（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ），７．４７−７．６１（２Ｈ，ｍ），７．６３−７．７６（２Ｈ，ｍ），７．８８（３Ｈ，ｄ，Ｊ＝８．２Ｈｚ），９．０４（１Ｈ，ｔ，Ｊ＝５．５Ｈｚ）．

ＬＣ／ＭＳ［条件１］：保持時間３．３７分；ｍ／ｚ５３７．８［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ５３５．９［Ｍ−Ｈ］^―（ＥＳＩ負イオンモード）

Example 67
N-benzyl-4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl) benzamidoformate Production of (Compound No. 67) The reaction was carried out in substantially the same manner as in Example 44 except that benzylamine (purchased from Tokyo Chemical Industry Co., Ltd.) was used instead of 4- (2-aminoethyl) morpholine, The title compound (10 mg, 21% yield) was obtained as a white solid.

¹ H-NMR (300 MHz, DMSO-d ₆ ) δ: 1.64-1.90 (3H, brm), 2.33-2.56 (2H, brm), 3.21 (2H, s), 3 .75-3.38 (5H, m), 4.39 (2H, s), 4.46 (2H, d, J = 5.8 Hz), 7.18-7.33 (5H, m), 7 .34 (2H, d, J = 8.2 Hz), 7.47-7.61 (2H, m), 7.63-7.76 (2H, m), 7.88 (3H, d, J = 8.2 Hz), 9.04 (1H, t, J = 5.5 Hz).

LC / MS [Condition 1]: Retention time 3.37 minutes; m / z 537.8 [M + H] ⁺ (ESI positive ion mode), m / z 535.9 [M−H] ⁻ (ESI negative ion mode)

実施例６８
４−（｛２−オキソ−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）−Ｎ−（ピリジン−３−イルメチル）ベンズアミド（化合物番号６８）の製造
４−アミノ−１−（ピリジン−３−イルメチル）ピペリジン三塩酸塩の代わりに３−ピコリルアミン（東京化成工業（株）より購入）を用いること以外は実質的に実施例６４と同様に反応を行なって、表題化合物（１７ｍｇ、収率７０％）を白色固体として得た。

^１Ｈ−ＮＭＲ（３００ＭＨｚ，ＣＤＣｌ_３）δ：１．６５−１．７８（２Ｈ，ｍ），１．８４−１．９６（２Ｈ，ｍ），２．４２−２．６２（４Ｈ，ｂｒｍ），３．１２（２Ｈ，ｓ），３．５５（２Ｈ，ｓ），４．４６（２Ｈ，ｓ），４．６７（２Ｈ，ｄ，Ｊ＝６．１Ｈｚ），６．５４（１Ｈ，ｔ，Ｊ＝５．５Ｈｚ），７．２９（１Ｈ，ｄｄ，Ｊ＝８．２，５．１Ｈｚ），７．３４（２Ｈ，ｄ，Ｊ＝８．５Ｈｚ），７．４２（２Ｈ，ｄ，Ｊ＝７．８Ｈｚ），７．５６（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ），７．７２（１Ｈ，ｄｔ，Ｊ＝７．８，２．０Ｈｚ），７．７９（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ），８．５５（１Ｈ，ｄｄ，Ｊ＝４．８，１．７Ｈｚ），８．６１（１Ｈ，ｄ，Ｊ＝２．０Ｈｚ）．

ＬＣ／ＭＳ［条件１］：保持時間１．２１分；ｍ／ｚ５３６．９［Ｍ−Ｈ］^―（ＥＳＩ負イオンモード）

Example 68
4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl) -N- (pyridine-3 -Preparation of ylmethyl) benzamide (Compound No. 68) Except for using 3-picolylamine (purchased from Tokyo Chemical Industry Co., Ltd.) instead of 4-amino-1- (pyridin-3-ylmethyl) piperidine trihydrochloride The reaction was carried out substantially in the same manner as in Example 64 to obtain the title compound (17 mg, yield 70%) as a white solid.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.65-1.78 (2H, m), 1.84-1.96 (2H, m), 2.42-2.62 (4H, brm) , 3.12 (2H, s), 3.55 (2H, s), 4.46 (2H, s), 4.67 (2H, d, J = 6.1 Hz), 6.54 (1H, t , J = 5.5 Hz), 7.29 (1H, dd, J = 8.2, 5.1 Hz), 7.34 (2H, d, J = 8.5 Hz), 7.42 (2H, d, J = 7.8 Hz), 7.56 (2H, d, J = 8.2 Hz), 7.72 (1H, dt, J = 7.8, 2.0 Hz), 7.79 (2H, d, J = 8.2 Hz), 8.55 (1H, dd, J = 4.8, 1.7 Hz), 8.61 (1H, d, J = 2.0 Hz).

LC / MS [Condition 1]: Retention time 1.21 minutes; m / z 536.9 [M−H] ⁻ (ESI negative ion mode)

実施例６９
４−（［４−（｛２−オキソ−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）ベンズアミド］メチル）安息香酸メチル（化合物番号６９）の製造
４−アミノ−１−（ピリジン−３−イルメチル）ピペリジン三塩酸塩の代わりに４−（アミノメチル）安息香酸メチル塩酸塩（アルドリッチ（株）より購入）を用いること以外は実質的に実施例６４と同様に反応を行なって、表題化合物（１４０ｍｇ、定量的）を白色固体として得た。

^１Ｈ−ＮＭＲ（３００ＭＨｚ，ＣＤＣｌ_３）δ：１．７２（２Ｈ，ｄｄｄ，Ｊ＝１３．６，６．８，７．２Ｈｚ），１．９０（２Ｈ，ｄｔ，Ｊ＝１３．３，３．４Ｈｚ），２．４２−２．６０（４Ｈ，ｍ），３．１２（２Ｈ，ｓ），３．５５（２Ｈ，ｓ），３．９１（３Ｈ，ｓ），４．４６（２Ｈ，ｓ），４．７１（２Ｈ，ｄ，Ｊ＝６．１Ｈｚ），６．５２（１Ｈ，ｔ，Ｊ＝５．８Ｈｚ），７．３４（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ），７．４２（４Ｈ，ｄ，Ｊ＝８．５Ｈｚ），７．５６（２Ｈ，ｄ，Ｊ＝７．８Ｈｚ），７．８０（２Ｈ，ｄ，Ｊ＝８．５Ｈｚ），８．０２（２Ｈ，ｄ，Ｊ＝８．４Ｈｚ）．

ＬＣ／ＭＳ［条件１］：保持時間３．４１分；ｍ／ｚ５９５．８１［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ５９３．９［Ｍ−Ｈ］^―（ＥＳＩ負イオンモード）

Example 69
4-([4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl) benzamido] methyl ) Preparation of methyl benzoate (Compound No. 69) 4- (Aminomethyl) benzoic acid methyl hydrochloride instead of 4-amino-1- (pyridin-3-ylmethyl) piperidine trihydrochloride (purchased from Aldrich) The reaction was carried out substantially in the same manner as in Example 64 except that was used to obtain the title compound (140 mg, quantitative) as a white solid.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.72 (2H, ddd, J = 13.6, 6.8, 7.2 Hz), 1.90 (2H, dt, J = 13.3, 3 .4 Hz), 2.42-2.60 (4H, m), 3.12 (2H, s), 3.55 (2H, s), 3.91 (3H, s), 4.46 (2H, s), 4.71 (2H, d, J = 6.1 Hz), 6.52 (1H, t, J = 5.8 Hz), 7.34 (2H, d, J = 8.2 Hz), 7. 42 (4H, d, J = 8.5 Hz), 7.56 (2H, d, J = 7.8 Hz), 7.80 (2H, d, J = 8.5 Hz), 8.02 (2H, d , J = 8.4 Hz).

LC / MS [Condition 1]: Retention time 3.41 min; m / z 595.81 [M + H] ⁺ (ESI positive ion mode), m / z 593.9 [M−H] ⁻ (ESI negative ion mode)

実施例７０
ｔ−ブチル ２−［４−（｛２−オキソ−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）ベンズアミド］エチルカルバメート（化合物番号７０）の製造
４−アミノ−１−（ピリジン−３−イルメチル）ピペリジン三塩酸塩の代わりに２−アミノエチルカルバミン酸ｔ−ブチル（東京化成工業（株）より購入）を用いること以外は実質的に実施例６４と同様に反応を行なって、表題化合物（１１ｍｇ、収率４３％）を白色固体として得た。

^１Ｈ−ＮＭＲ（３００ＭＨｚ，ＣＤＣｌ_３）δ：１．４３（９Ｈ，ｓ），１．７１（２Ｈ，ｄｄｄ，Ｊ＝１４．０，６．５，５．８Ｈｚ），１．８４−１．９７（２Ｈ，ｍ），２．４２−２．６１（４Ｈ，ｍ），３．１１（２Ｈ，ｓ），３．４１（２Ｈ，ｑ，Ｊ＝５．５Ｈｚ），３．５５−３．５７（４Ｈ，ｍ），４．４６（２Ｈ，ｓ），４．９６（１Ｈ，ｂｒｓ），７．３２（３Ｈ，ｄ，Ｊ＝８．２Ｈｚ），７．４２（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ），７．５６（２Ｈ，ｄ，Ｊ＝７．８Ｈｚ），７．８１（２Ｈ，ｄ，Ｊ＝７．８Ｈｚ）．

ＬＣ／ＭＳ［条件１］：保持時間３．２７分；ｍ／ｚ５９０．９［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ６３４．９［Ｍ＋ＨＣＯＯ］^―（ＥＳＩ負イオンモード）

Example 70
t-butyl 2- [4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl) benzamide Preparation of ethyl carbamate (Compound No. 70) Instead of 4-amino-1- (pyridin-3-ylmethyl) piperidine trihydrochloride, t-butyl 2-aminoethylcarbamate (purchased from Tokyo Chemical Industry Co., Ltd.) The reaction was carried out substantially in the same manner as in Example 64 except for using, and the title compound (11 mg, yield 43%) was obtained as a white solid.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.43 (9H, s), 1.71 (2H, ddd, J = 14.0, 6.5, 5.8 Hz), 1.84-1. 97 (2H, m), 2.42-2.61 (4H, m), 3.11 (2H, s), 3.41 (2H, q, J = 5.5 Hz), 3.55-3. 57 (4H, m), 4.46 (2H, s), 4.96 (1H, brs), 7.32 (3H, d, J = 8.2 Hz), 7.42 (2H, d, J = 8.2 Hz), 7.56 (2H, d, J = 7.8 Hz), 7.81 (2H, d, J = 7.8 Hz).

LC / MS [Condition 1]: Retention time 3.27 minutes; m / z 590.9 [M + H] ⁺ (ESI positive ion mode), m / z 634.9 [M + HCOO] ⁻ (ESI negative ion mode)

実施例７１
ｔ−ブチル ４−［４−（｛２−オキソ−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）ベンズアミド］ブチルカルバメート（化合物番号７１）の製造
４−アミノ−１−（ピリジン−３−イルメチル）ピペリジン三塩酸塩の代わりに４−アミノブチルカルバミン酸ｔ−ブチル（東京化成工業（株）より購入）を用いること以外は実質的に実施例６４と同様に反応を行なって、表題化合物（２５ｍｇ、収率８０％）を白色固体として得た。

^１Ｈ−ＮＭＲ（３００ＭＨｚ，ＣＤＣｌ_３）δ：１．４４（９Ｈ，ｓ），１．５４−１．６７（４Ｈ，ｍ），１．７２（２Ｈ，ｄｄｄ，Ｊ＝１４．０，７．２，６．８Ｈｚ），１．９１（２Ｈ，ｄｔ，Ｊ＝１３．０，４．１Ｈｚ），２．４６−２．５９（４Ｈ，ｍ），３．１２（２Ｈ，ｓ），３．１７（２Ｈ，ｑ，Ｊ＝６．１Ｈｚ），３．５０（２Ｈ，ｑ，Ｊ＝６．５Ｈｚ），３．５５（２Ｈ，ｓ），４．４６（２Ｈ，ｓ），４．６５（１Ｈ，ｂｒｓ），６．５７（１Ｈ，ｂｒｓ），７．３２（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ），７．４２（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ），７．５６（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ），７．７９（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ）．

ＬＣ／ＭＳ［条件１］：保持時間３．４１分；ｍ／ｚ６１８．９［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ６６３．０［Ｍ＋ＨＣＯＯ］^―（ＥＳＩ負イオンモード）

Example 71
t-butyl 4- [4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl) benzamide Preparation of Butylcarbamate (Compound No. 71) Instead of 4-amino-1- (pyridin-3-ylmethyl) piperidine trihydrochloride, t-butyl 4-aminobutylcarbamate (purchased from Tokyo Chemical Industry Co., Ltd.) The reaction was carried out substantially in the same manner as in Example 64 except for using, and the title compound (25 mg, yield 80%) was obtained as a white solid.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.44 (9H, s), 1.54-1.67 (4H, m), 1.72 (2H, ddd, J = 14.0, 7. 2,6.8 Hz), 1.91 (2H, dt, J = 13.0, 4.1 Hz), 2.46-2.59 (4H, m), 3.12 (2H, s), 3. 17 (2H, q, J = 6.1 Hz), 3.50 (2H, q, J = 6.5 Hz), 3.55 (2H, s), 4.46 (2H, s), 4.65 ( 1H, brs), 6.57 (1H, brs), 7.32 (2H, d, J = 8.2 Hz), 7.42 (2H, d, J = 8.2 Hz), 7.56 (2H, d, J = 8.2 Hz), 7.79 (2H, d, J = 8.2 Hz).

LC / MS [Condition 1]: retention time 3.41 min; m / z 618.9 [M + H] ⁺ (ESI positive ion mode), m / z 663.0 [M + HCOO] ⁻ (ESI negative ion mode)

実施例７２
Ｎ−ブチル−４−（｛２−オキソ−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）ベンズアミド（化合物番号７２）の製造
４−アミノ−１−（ピリジン−３−イルメチル）ピペリジン三塩酸塩の代わりにブチルアミン（和光純薬工業（株）より購入）を用いること以外は実質的に実施例６４と同様に反応を行なって、表題化合物（１７ｍｇ、収率７６％）を白色固体として得た。

^１Ｈ−ＮＭＲ（３００ＭＨｚ，ＣＤＣｌ_３）δ：０．９６（３Ｈ，ｔ，Ｊ＝７．２Ｈｚ），１．４３（２Ｈ，ｔｔ，Ｊ＝１０．０，５．０Ｈｚ），１．６６−１．５４（２Ｈ，ｍ），１．７２（２Ｈ，ｄｄｄ，Ｊ＝１３．８，７．０，６．５Ｈｚ），１．９１（２Ｈ，ｄｔ，Ｊ＝１３．３，３．７Ｈｚ），２．４４−２．６２（４Ｈ，ｍ），３．１２（２Ｈ，ｓ），３．４６（２Ｈ，ｑ，Ｊ＝６．５Ｈｚ），３．５５（２Ｈ，ｓ），４．４６（２Ｈ，ｓ），６．１０（１Ｈ，ｔ，Ｊ＝５．８Ｈｚ），７．３３（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ），７．４２（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ），７．５６（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ），７．７４（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ）．

ＬＣ／ＭＳ［条件１］：保持時間３．３１分；ｍ／ｚ５０３．９［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ５４７．９［Ｍ＋ＨＣＯＯ］^―（ＥＳＩ負イオンモード）

Example 72
N-butyl-4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl) benzamide (compound Preparation of No. 72) Substantially the same as in Example 64 except that butylamine (purchased from Wako Pure Chemical Industries, Ltd.) was used instead of 4-amino-1- (pyridin-3-ylmethyl) piperidine trihydrochloride The title compound (17 mg, 76% yield) was obtained as a white solid.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 0.96 (3H, t, J = 7.2 Hz), 1.43 (2H, tt, J = 10.0, 5.0 Hz), 1.66 1.54 (2H, m), 1.72 (2H, ddd, J = 13.8, 7.0, 6.5 Hz), 1.91 (2H, dt, J = 13.3, 3.7 Hz) , 2.44-2.62 (4H, m), 3.12 (2H, s), 3.46 (2H, q, J = 6.5 Hz), 3.55 (2H, s), 4.46. (2H, s), 6.10 (1H, t, J = 5.8 Hz), 7.33 (2H, d, J = 8.2 Hz), 7.42 (2H, d, J = 8.2 Hz) 7.56 (2H, d, J = 8.2 Hz), 7.74 (2H, d, J = 8.2 Hz).

LC / MS [Condition 1]: Retention time 3.31 min; m / z 503.9 [M + H] ⁺ (ESI positive ion mode), m / z 547.9 [M + HCOO] ⁻ (ESI negative ion mode)

実施例７３
Ｎ−（２−メトキシエチル）−４−（｛２−オキソ−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）ベンズアミド（化合物番号７３）の製造
４−アミノ−１−（ピリジン−３−イルメチル）ピペリジン三塩酸塩の代わりに２−メトキシエチルアミン（和光純薬工業（株）より購入）を用いること以外は実質的に実施例６４と同様に反応を行なって、表題化合物（１５ｍｇ、収率６４％）を白色固体として得た。

^１Ｈ−ＮＭＲ（３００ＭＨｚ，ＣＤＣｌ_３）δ：１．７２（２Ｈ，ｄｄｄ，Ｊ＝１４．３，６．９，６．１Ｈｚ），１．９１（２Ｈ，ｄ，Ｊ＝１２．７Ｈｚ），２．４５−２．６２（４Ｈ，ｍ），３．１２（２Ｈ，ｓ），３．３９（３Ｈ，ｓ），３．５５（２Ｈ，ｓ），３．５７（２Ｈ，ｔ，Ｊ＝５．０Ｈｚ），３．６６（２Ｈ，ｑ，Ｊ＝５．２Ｈｚ），４．４７（２Ｈ，ｓ），６．５１（１Ｈ，ｂｒｓ），７．３３（２Ｈ，ｄ，Ｊ＝８．３Ｈｚ），７．４２（２Ｈ，ｄ，Ｊ＝８．０Ｈｚ），７．５６（２Ｈ，ｄ，Ｊ＝８．３Ｈｚ），７．７７（２Ｈ，ｄ，Ｊ＝８．０Ｈｚ）．

ＬＣ／ＭＳ［条件１］：保持時間２．９５分；ｍ／ｚ５０５．８［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ５０３．９［Ｍ−Ｈ］^―（ＥＳＩ負イオンモード）

Example 73
N- (2-methoxyethyl) -4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} Preparation of methyl) benzamide (Compound No. 73) Except for using 2-methoxyethylamine (purchased from Wako Pure Chemical Industries, Ltd.) instead of 4-amino-1- (pyridin-3-ylmethyl) piperidine trihydrochloride The reaction was carried out substantially in the same manner as in Example 64 to obtain the title compound (15 mg, yield 64%) as a white solid.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.72 (2H, ddd, J = 14.3, 6.9, 6.1 Hz), 1.91 (2H, d, J = 12.7 Hz), 2.45-2.62 (4H, m), 3.12 (2H, s), 3.39 (3H, s), 3.55 (2H, s), 3.57 (2H, t, J = 5.0 Hz), 3.66 (2H, q, J = 5.2 Hz), 4.47 (2H, s), 6.51 (1H, brs), 7.33 (2H, d, J = 8. 3 Hz), 7.42 (2H, d, J = 8.0 Hz), 7.56 (2H, d, J = 8.3 Hz), 7.77 (2H, d, J = 8.0 Hz).

LC / MS [Condition 1]: Retention time 2.95 minutes; m / z 505.8 [M + H] ⁺ (ESI positive ion mode), m / z 503.9 [M−H] ⁻ (ESI negative ion mode)

実施例７４
３−［４−（ピペリジン−１−カルボニル）ベンジル］−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−２−オン（化合物番号７４）の製造
４−アミノ−１−（ピリジン−３−イルメチル）ピペリジン三塩酸塩の代わりにピペリジン（純正化学（株）より購入）を用いること以外は実質的に実施例６４と同様に反応を行なって、表題化合物（１２ｍｇ、収率５２％）を白色固体として得た。

^１Ｈ−ＮＭＲ（３００ＭＨｚ，ＣＤＣｌ_３）δ：１．８０−１．４３（８Ｈ，ｍ），１．９２（２Ｈ，ｄｔ，Ｊ＝１２．９，４．１Ｈｚ），２．４４−２．６１（４Ｈ，ｍ），３．１３（２Ｈ，ｓ），３．２５−３．４３（２Ｈ，ｂｒｍ），３．５６（２Ｈ，ｓ），３．６３−３．７９（２Ｈ，ｂｒｍ），４．４４（２Ｈ，ｓ），７．２９（２Ｈ，ｄ，Ｊ＝８．０Ｈｚ），７．３８（２Ｈ，ｄ，Ｊ＝８．０Ｈｚ），７．４３（２Ｈ，ｄ，Ｊ＝８．０Ｈｚ），７．５７（２Ｈ，ｄ，Ｊ＝８．０Ｈｚ）．

ＬＣ／ＭＳ［条件１］：保持時間３．２９分；ｍ／ｚ５１５．８［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ５５９．９［Ｍ＋ＨＣＯＯ］^―（ＥＳＩ負イオンモード）

Example 74
3- [4- (Piperidin-1-carbonyl) benzyl] -8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-2-one (Compound No. 74) The reaction was carried out in substantially the same manner as in Example 64 except that piperidine (purchased from Junsei Kagaku Co.) was used instead of 4-amino-1- (pyridin-3-ylmethyl) piperidine trihydrochloride. The title compound (12 mg, 52% yield) was obtained as a white solid.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.80-1.43 (8H, m), 1.92 (2H, dt, J = 12.9, 4.1 Hz), 2.44-2. 61 (4H, m), 3.13 (2H, s), 3.25-3.43 (2H, brm), 3.56 (2H, s), 3.63-3.79 (2H, brm) 4.44 (2H, s), 7.29 (2H, d, J = 8.0 Hz), 7.38 (2H, d, J = 8.0 Hz), 7.43 (2H, d, J = 8.0 Hz), 7.57 (2H, d, J = 8.0 Hz).

LC / MS [Condition 1]: Retention time 3.29 minutes; m / z 515.8 [M + H] ⁺ (ESI positive ion mode), m / z 559.9 [M + HCOO] ⁻ (ESI negative ion mode)

実施例７５
（１ｒ，４ｒ）−４−｛［４−（｛２−オキソ−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）ベンズアミド］メチル｝シクロヘキサンカルボン酸メチル（化合物番号７５）の製造
４−アミノ−１−（ピリジン−３−イルメチル）ピペリジン三塩酸塩の代わりに参考例２−１で得られたｔｒａｎｓ−４−アミノメチルシクロヘキサンカルボン酸メチル塩酸塩を用いること以外は実質的に実施例６４と同様に反応を行なって、表題化合物を白色固体（２０ｍｇ、収率７５％）として得た。

^１Ｈ−ＮＭＲ（３００ＭＨｚ，ＣＤＣｌ_３）δ：１．０５（２Ｈ，ｄｑ，Ｊ＝３．４，１２．３Ｈｚ），１．４４（２Ｈ，ｄｑ，Ｊ＝３．４，１３．０Ｈｚ），１．５２−１．７９（３Ｈ，ｍ），１．８４−１．９６（４Ｈ，ｍ），１．９８−２．０８（２Ｈ，ｍ），２．２６（１Ｈ，ｔｔ，Ｊ＝１１．９，３．７Ｈｚ），２．６２−２．４３（４Ｈ，ｍ），３．１２（２Ｈ，ｓ），３．３３（２Ｈ，ｔ，Ｊ＝６．５Ｈｚ），３．５５（２Ｈ，ｓ），３．６６（３Ｈ，ｓ），４．４６（２Ｈ，ｓ），６．１６（１Ｈ，ｔ，Ｊ＝５．８Ｈｚ），７．３３（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ），７．４２（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ），７．５６（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ），７．７５（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ）．

ＬＣ／ＭＳ［条件１］：保持時間３．３７分；ｍ／ｚ６０１．９［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ６００．０［Ｍ−Ｈ］^―（ＥＳＩ負イオンモード）

Example 75
(1r, 4r) -4-{[4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl } Methyl) benzamido] methyl} cyclohexanecarboxylate (Compound No. 75) Preparation of trans-4 obtained in Reference Example 2-1 instead of 4-amino-1- (pyridin-3-ylmethyl) piperidine trihydrochloride Reaction was carried out substantially in the same manner as in Example 64 except that methyl aminomethylcyclohexanecarboxylate hydrochloride was used to obtain the title compound as a white solid (20 mg, yield 75%).

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.05 (2H, dq, J = 3.4, 12.3 Hz), 1.44 (2H, dq, J = 3.4, 13.0 Hz), 1.52-1.79 (3H, m), 1.84-1.96 (4H, m), 1.98-2.08 (2H, m), 2.26 (1H, tt, J = 11) .9, 3.7 Hz), 2.62-2.43 (4H, m), 3.12 (2H, s), 3.33 (2H, t, J = 6.5 Hz), 3.55 (2H) , S), 3.66 (3H, s), 4.46 (2H, s), 6.16 (1H, t, J = 5.8 Hz), 7.33 (2H, d, J = 8.2 Hz). ), 7.42 (2H, d, J = 8.2 Hz), 7.56 (2H, d, J = 8.2 Hz), 7.75 (2H, d, J = 8.2 Hz).

LC / MS [Condition 1]: Retention time 3.37 minutes; m / z 601.9 [M + H] ⁺ (ESI positive ion mode), m / z 600.0 [M−H] ⁻ (ESI negative ion mode)

実施例７６
１−［４−（｛２−オキソ−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）ベンゾイル］ピペリジン−４−カルボン酸メチル（化合物番号７６）の製造
４−アミノ−１−（ピリジン−３−イルメチル）ピペリジン三塩酸塩の代わりにイソニペコチン酸メチル（東京化成工業（株）より購入）を用いること以外は実質的に実施例６４と同様に反応を行なって、表題化合物（２０ｍｇ、収率７５％）を無色油状物として得た。

^１Ｈ−ＮＭＲ（３００ＭＨｚ，ＣＤＣｌ_３）δ：１．５９−２．１２（８Ｈ，ｍ），２．４６−２．５８（４Ｈ，ｍ），２．６０（１Ｈ，ｔｔ，Ｊ＝１０．６，４．３Ｈｚ），２．９８−３．１７（２Ｈ，ｍ），３．１３（２Ｈ，ｓ），３．５６（２Ｈ，ｓ），３．６９−３．７３（１Ｈ，ｍ），３．７１（３Ｈ，ｓ），４．６１−４．３８（１Ｈ，ｍ），４．４５（２Ｈ，ｓ），７．３０（２Ｈ，ｄ，Ｊ＝７．９Ｈｚ），７．３９（２Ｈ，ｄ，Ｊ＝８．３Ｈｚ），７．４３（２Ｈ，ｄ，Ｊ＝７．９Ｈｚ），７．５７（２Ｈ，ｄ，Ｊ＝７．９Ｈｚ）．

ＬＣ／ＭＳ［条件１］：保持時間３．２１分；ｍ／ｚ５７３．８［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ６１７．９［Ｍ＋ＨＣＯＯ］^―（ＥＳＩ負イオンモード）

Example 76
1- [4-({2-Oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl) benzoyl] piperidine- Preparation of methyl 4-carboxylate (Compound No. 76) Except for using methyl isonipecotate (purchased from Tokyo Chemical Industry Co., Ltd.) instead of 4-amino-1- (pyridin-3-ylmethyl) piperidine trihydrochloride The reaction was carried out substantially in the same manner as in Example 64 to give the title compound (20 mg, yield 75%) as a colorless oil.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.59-2.12 (8H, m), 2.46-2.58 (4H, m), 2.60 (1H, tt, J = 10. 6, 4.3 Hz), 2.98-3.17 (2H, m), 3.13 (2H, s), 3.56 (2H, s), 3.69-3.73 (1H, m) 3.71 (3H, s), 4.61-4.38 (1H, m), 4.45 (2H, s), 7.30 (2H, d, J = 7.9 Hz), 7.39. (2H, d, J = 8.3 Hz), 7.43 (2H, d, J = 7.9 Hz), 7.57 (2H, d, J = 7.9 Hz).

LC / MS [Condition 1]: Retention time 3.21 minutes; m / z 573.8 [M + H] ⁺ (ESI positive ion mode), m / z 617.9 [M + HCOO] ⁻ (ESI negative ion mode)

実施例７７
２−［４−（｛２−オキソ−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）ベンズアミド］酢酸エチル（化合物番号７７）の製造
４−アミノ−１−（ピリジン−３−イルメチル）ピペリジン三塩酸塩の代わりにグリシンエチルエステル塩酸塩（東京化成工業（株）より購入）を用いること以外は実質的に実施例６４と同様に反応を行なって、表題化合物を白色固体（２０ｍｇ、収率７５％）として得た。

^１Ｈ−ＮＭＲ（３００ＭＨｚ，ＣＤＣｌ_３）δ：１．３２（３Ｈ，ｔ，Ｊ＝７．４Ｈｚ），１．６５−１．７９（２Ｈ，ｍ），１．９２（２Ｈ，ｄｔ，Ｊ＝１２．７，３．７Ｈｚ），２．４５−２．６２（４Ｈ，ｍ），３．１２（２Ｈ，ｓ），３．５５（２Ｈ，ｓ），４．２４（２Ｈ，ｄ，Ｊ＝４．９Ｈｚ），４．２７（２Ｈ，ｑ，Ｊ＝７．０Ｈｚ），４．４７（２Ｈ，ｓ），６．６２（１Ｈ，ｔ，Ｊ＝４．９Ｈｚ），７．３５（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ），７．４２（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ），７．５６（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ），７．８０（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ）．

ＬＣ／ＭＳ［条件１］：保持時間３．０７分；ｍ／ｚ５３３．７［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ５３２．０［Ｍ−Ｈ］^―（ＥＳＩ負イオンモード）

Example 77
2- [4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl) benzamido] acetic acid ethyl Preparation of (Compound No. 77) Substantially except that glycine ethyl ester hydrochloride (purchased from Tokyo Chemical Industry Co., Ltd.) was used instead of 4-amino-1- (pyridin-3-ylmethyl) piperidine trihydrochloride. The reaction was carried out in the same manner as in Example 64 to obtain the title compound as a white solid (20 mg, yield 75%).

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.32 (3H, t, J = 7.4 Hz), 1.65-1.79 (2H, m), 1.92 (2H, dt, J = 12.7, 3.7 Hz), 2.45-2.62 (4H, m), 3.12 (2H, s), 3.55 (2H, s), 4.24 (2H, d, J = 4.9 Hz), 4.27 (2H, q, J = 7.0 Hz), 4.47 (2H, s), 6.62 (1H, t, J = 4.9 Hz), 7.35 (2H, d, J = 8.2 Hz), 7.42 (2H, d, J = 8.2 Hz), 7.56 (2H, d, J = 8.2 Hz), 7.80 (2H, d, J = 8) .2 Hz).

LC / MS [Condition 1]: Retention time 3.07 minutes; m / z 533.7 [M + H] ⁺ (ESI positive ion mode), m / z 532.0 [M−H] ⁻ (ESI negative ion mode)

実施例７８
（１ｒ，４ｒ）−Ｎ−（２−イソプロポキシエチル）−４−（｛２−オキソ−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）シクロヘキサンカルボキサミド（化合物番号７８）の製造
テトラヒドロフルフリルアミンの代わりに２−アミノエチルイソプロピルエーテルを用いること以外は実質的に実施例１０と同様に反応を行って、表題化合物（３２ｍｇ、収率８８％）を白色固体として得た。

^１Ｈ−ＮＭＲ（３００ＭＨｚ，ＣＤＣｌ_３）δ：１．０３（２Ｈ，ｄｑ，Ｊ＝３．３，１２．３Ｈｚ），１．１６（６Ｈ，ｄ，Ｊ＝６．１Ｈｚ），２．０８−１．３９（１２Ｈ，ｍ），２．５０−２．６１（４Ｈ，ｍ），３．０９（２Ｈ，ｄ，Ｊ＝７．４Ｈｚ），３．２６（２Ｈ，ｓ），３．３８（４Ｈ，ｓ），３．４１（２Ｈ，ｑ，Ｊ＝４．９Ｈｚ），３．４４−３．５１（２Ｈ，ｍ），３．５２−３．６３（３Ｈ，ｍ），５．８５（１Ｈ，ｔ，Ｊ＝４．９Ｈｚ），７．４４（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ），７．５７（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ）．

ＬＣ／ＭＳ［条件１］：保持時間３．１６分；ｍ／ｚ５３９．８［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ５８４．０［Ｍ＋ＨＣＯＯ］^―（ＥＳＩ負イオンモード）

Example 78
(1r, 4r) -N- (2-Isopropoxyethyl) -4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5 ] Decan-3-yl} methyl) cyclohexanecarboxamide (Compound No. 78) The reaction was conducted in substantially the same manner as in Example 10 except that 2-aminoethylisopropyl ether was used instead of tetrahydrofurfurylamine. The compound (32 mg, 88% yield) was obtained as a white solid.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.03 (2H, dq, J = 3.3, 12.3 Hz), 1.16 (6H, d, J = 6.1 Hz), 2.08- 1.39 (12H, m), 2.50-2.61 (4H, m), 3.09 (2H, d, J = 7.4 Hz), 3.26 (2H, s), 3.38 ( 4H, s), 3.41 (2H, q, J = 4.9 Hz), 3.44-3.51 (2H, m), 3.52-3.63 (3H, m), 5.85 ( 1H, t, J = 4.9 Hz), 7.44 (2H, d, J = 8.2 Hz), 7.57 (2H, d, J = 8.2 Hz).

LC / MS [Condition 1]: Retention time 3.16 minutes; m / z 539.8 [M + H] ⁺ (ESI positive ion mode), m / z 584.0 [M + HCOO] ⁻ (ESI negative ion mode)

実施例７９
（１ｒ，４ｒ）−Ｎ−（フラン−２−イルメチル）−４−（｛２−オキソ−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）シクロヘキサンカルボキサミド（化合物番号７９）の製造
テトラヒドロフルフリルアミンの代わりにフルフリルアミンを用いること以外は実質的に実施例１０と同様に反応を行って、表題化合物（３５ｍｇ、収率９６％）を白色固体として得た。

^１Ｈ−ＮＭＲ（３００ＭＨｚ，ＣＤＣｌ_３）δ：１．０１（２Ｈ，ｄｑ，Ｊ＝３．３，１２．７Ｈｚ），１．５０（２Ｈ，ｄｑ，Ｊ＝３．３，１２．３Ｈｚ），１．６０−１．６８（１Ｈ，ｍ），１．７０−１．８５（４Ｈ，ｍ），１．８６−１．９８（４Ｈ，ｍ），２．０４（１Ｈ，ｔｔ，Ｊ＝１１．９，３．７Ｈｚ），２．４８−２．６１（４Ｈ，ｍ），３．０９（２Ｈ，ｄ，Ｊ＝７．４Ｈｚ），３．２５（２Ｈ，ｓ），３．５７（２Ｈ，ｓ），４．４３（２Ｈ，ｄ，Ｊ＝５．７Ｈｚ），５．７３（１Ｈ，ｔ，Ｊ＝５．１Ｈｚ），６．２１（１Ｈ，ｄ，Ｊ＝３．３Ｈｚ），６．３２（１Ｈ，ｄｄ，Ｊ＝３．３，１．６Ｈｚ），７．３５−７．３５（１Ｈ，ｍ），７．４４（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ），７．５７（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ）．

ＬＣ／ＭＳ［条件１］：保持時間３．２１分；ｍ／ｚ５３３．８［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ５７８．１［Ｍ＋ＨＣＯＯ］^―（ＥＳＩ負イオンモード）

Example 79
(1r, 4r) -N- (furan-2-ylmethyl) -4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5 ] Decan-3-yl} methyl) cyclohexanecarboxamide (Compound No. 79) The reaction was conducted in substantially the same manner as in Example 10 except that furfurylamine was used instead of tetrahydrofurfurylamine to give the title compound (35 mg, (96% yield) was obtained as a white solid.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.01 (2H, dq, J = 3.3, 12.7 Hz), 1.50 (2H, dq, J = 3.3, 12.3 Hz), 1.60-1.68 (1H, m), 1.70-1.85 (4H, m), 1.86-1.98 (4H, m), 2.04 (1H, tt, J = 11) .9, 3.7 Hz), 2.48-2.61 (4H, m), 3.09 (2H, d, J = 7.4 Hz), 3.25 (2H, s), 3.57 (2H) , S), 4.43 (2H, d, J = 5.7 Hz), 5.73 (1H, t, J = 5.1 Hz), 6.21 (1H, d, J = 3.3 Hz), 6 .32 (1H, dd, J = 3.3, 1.6 Hz), 7.35-7.35 (1H, m), 7.44 (2H, d, J = 8.2 Hz), 7.57 ( 2H, d, J = 8. Hz).

LC / MS [Condition 1]: Retention time 3.21 minutes; m / z 533.8 [M + H] ⁺ (ESI positive ion mode), m / z 578.1 [M + HCOO] ⁻ (ESI negative ion mode)

実施例８０
（１ｒ，４ｒ）−４−（｛２−オキソ−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）−Ｎ−（テトラヒドロ−２Ｈ−ピラン−４−イル）シクロヘキサンカルボキサミド（化合物番号８０）の製造
テトラヒドロフルフリルアミンの代わりに４−アミノ−テトラヒドロ−２Ｈ−ピラン塩酸塩を用いること以外は実質的に実施例１０と同様に反応を行って、表題化合物（３１ｍｇ、収率８４％）を淡黄色固体として得た。

^１Ｈ−ＮＭＲ（３００ＭＨｚ，ＣＤＣｌ_３）δ：１．０１（２Ｈ，ｄｑ，Ｊ＝３．３，１２．７Ｈｚ），１．３５−２．０６（１６Ｈ，ｍ），２．４９−２．６２（４Ｈ，ｍ），３．０９（２Ｈ，ｄ，Ｊ＝７．４Ｈｚ），３．２５（２Ｈ，ｓ），３．４６（２Ｈ，ｔｄ，Ｊ＝１１．７，２．０Ｈｚ），３．５７（２Ｈ，ｓ），３．８８−４．０６（３Ｈ，ｍ），５．３２（１Ｈ，ｄ，Ｊ＝７．８Ｈｚ），７．４４（２Ｈ，ｄ，Ｊ＝７．８Ｈｚ），７．５７（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ）．

ＬＣ／ＭＳ［条件１］：保持時間２．９７分；ｍ／ｚ５３７．９［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ５８２．０［Ｍ＋ＨＣＯＯ］^―（ＥＳＩ負イオンモード）

Example 80
(1r, 4r) -4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl)- Preparation of N- (tetrahydro-2H-pyran-4-yl) cyclohexanecarboxamide (Compound No. 80) Substantially Example 10 except that 4-amino-tetrahydro-2H-pyran hydrochloride was used instead of tetrahydrofurfurylamine The title compound (31 mg, yield 84%) was obtained as a pale yellow solid.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.01 (2H, dq, J = 3.3, 12.7 Hz), 1.35 to 2.06 (16H, m), 2.49-2. 62 (4H, m), 3.09 (2H, d, J = 7.4 Hz), 3.25 (2H, s), 3.46 (2H, td, J = 11.7, 2.0 Hz), 3.57 (2H, s), 3.88-4.06 (3H, m), 5.32 (1H, d, J = 7.8 Hz), 7.44 (2H, d, J = 7.8 Hz) ), 7.57 (2H, d, J = 8.2 Hz).

LC / MS [Condition 1]: Retention time 2.97 minutes; m / z 537.9 [M + H] ⁺ (ESI positive ion mode), m / z 582.0 [M + HCOO] ⁻ (ESI negative ion mode)

実施例８１
（１ｒ，４ｒ）−４−（｛２−オキソ−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）−Ｎ−［（テトラヒドロ−２Ｈ−ピラン−４−イル）メチル］シクロヘキサンカルボキサミド（化合物番号８１）の製造
テトラヒドロフルフリルアミンの代わりに４−（アミノメチル）テトラヒドロピランを用いること以外は実質的に実施例１０と同様に反応を行って、表題化合物（３１ｍｇ、収率８４％）を淡黄色固体として得た。

^１Ｈ−ＮＭＲ（３００ＭＨｚ，ＣＤＣｌ_３）δ：１．０２（２Ｈ，ｔｄｄ，Ｊ＝１３．１，１３．１，３．０Ｈｚ），１．３０（２Ｈ，ｔｄｄ，Ｊ＝１１．９，１１．９，５．３Ｈｚ），１．４１−１．９９（１４Ｈ，ｍ），２．０２（１Ｈ，ｔｔ，Ｊ＝１１．１，４．１Ｈｚ），２．４７−２．６２（４Ｈ，ｍ），３．０９（２Ｈ，ｄ，Ｊ＝７．４Ｈｚ），３．１５（２Ｈ，ｔ，Ｊ＝６．５Ｈｚ），３．２６（２Ｈ，ｓ），３．３６（２Ｈ，ｔｄ，Ｊ＝１１．８，２．２Ｈｚ），３．５７（２Ｈ，ｓ），３．９２−４．０１（２Ｈ，ｍ），５．５５（１Ｈ，ｔ，Ｊ＝５．７Ｈｚ），７．４４（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ），７．５７（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ）．

ＬＣ／ＭＳ［条件１］：保持時間３．０７分；ｍ／ｚ５５１．８［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ５９６．０［Ｍ−Ｈ］^―（ＥＳＩ負イオンモード）

Example 81
(1r, 4r) -4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl)- Preparation of N-[(tetrahydro-2H-pyran-4-yl) methyl] cyclohexanecarboxamide (Compound No. 81) Substantially Example 10 except that 4- (aminomethyl) tetrahydropyran was used in place of tetrahydrofurfurylamine. The title compound (31 mg, yield 84%) was obtained as a pale yellow solid.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.02 (2H, tdd, J = 13.1, 13.1, 3.0 Hz), 1.30 (2H, tdd, J = 11.9, 11) .9, 5.3 Hz), 1.41-1.99 (14H, m), 2.02 (1H, tt, J = 11.1, 4.1 Hz), 2.47-2.62 (4H, m), 3.09 (2H, d, J = 7.4 Hz), 3.15 (2H, t, J = 6.5 Hz), 3.26 (2H, s), 3.36 (2H, td, J = 11.8, 2.2 Hz), 3.57 (2H, s), 3.92-4.01 (2H, m), 5.55 (1 H, t, J = 5.7 Hz), 7. 44 (2H, d, J = 8.2 Hz), 7.57 (2H, d, J = 8.2 Hz).

LC / MS [Condition 1]: Retention time 3.07 minutes; m / z 551.8 [M + H] ⁺ (ESI positive ion mode), m / z 596.0 [M−H] ⁻ (ESI negative ion mode)

実施例８２
ｔ−ブチル ４−（｛２−オキソ−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）フェニルカルバメート（化合物番号８２）の製造
参考例２１で得られた４−（｛２−オキソ−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）安息香酸（１９０ｍｇ、０．４２ｍｍｏｌ）をｔ−ブチルアルコール（２．０ｍＬ）に懸濁し、トリエチルアミン（０．１５ｍＬ、１．０ｍｍｏｌ）およびジフェニルホスホリルアジド（０．１４ｍＬ、０．６３ｍｍｏｌ）を加え室温で３０分かき混ぜた後、８０℃で６時間かき混ぜた。反応混合物を室温まで冷却し、酢酸エチル（５．０ｍＬ），水（５．０ｍＬ）を加え有機層を分離した。水層を酢酸エチルで抽出したのち、合わせた有機層を無水硫酸マグネシウムで乾燥し、減圧下濃縮した。得られた残留物をシリカゲルカラムクロマトグラフィー［充填剤：富士シリシア製アミンシリカＮＨ−ＤＭ１０２０、展開溶媒：ｎ−ヘキサン／酢酸エチル＝２／１〜１／１］にて精製し、表題化合物（１６０ｍｇ、収率６４％）を白色固体として得た。

^１Ｈ−ＮＭＲ（３００ＭＨｚ，ＣＤＣｌ_３）δ：１．５２（９Ｈ，ｓ），１．６９（２Ｈ，ｄｄｄ，Ｊ＝１４．７，７．２，７．５Ｈｚ），１．８９（２Ｈ，ｄｔ，Ｊ＝１３．０，３．７Ｈｚ），２．４３−２．５９（４Ｈ，ｍ），３．０９（２Ｈ，ｓ），３．５５（２Ｈ，ｓ），４．３６（２Ｈ，ｓ），６．４９（１Ｈ，ｂｒｓ），７．１９（２Ｈ，ｄ，Ｊ＝８．５Ｈｚ），７．３４（２Ｈ，ｄ，Ｊ＝８．５Ｈｚ），７．４２（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ），７．５６（２Ｈ，ｄ，Ｊ＝７．８Ｈｚ）．

ＬＣ／ＭＳ［条件１］：保持時間３．５５分；ｍ／ｚ５１９．８［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ５１８．０［Ｍ−Ｈ］^―（ＥＳＩ負イオンモード）

Example 82
t-butyl 4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl) phenylcarbamate (compound No. 82) 4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decane-3 obtained in Reference Example 21 -Il} methyl) benzoic acid (190 mg, 0.42 mmol) suspended in t-butyl alcohol (2.0 mL), triethylamine (0.15 mL, 1.0 mmol) and diphenylphosphoryl azide (0.14 mL, 0.63 mmol). ) And stirred at room temperature for 30 minutes, and then stirred at 80 ° C. for 6 hours. The reaction mixture was cooled to room temperature, ethyl acetate (5.0 mL) and water (5.0 mL) were added, and the organic layer was separated. The aqueous layer was extracted with ethyl acetate, and the combined organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography [filler: amine silica NH-DM1020 manufactured by Fuji Silysia, developing solvent: n-hexane / ethyl acetate = 2/1 to 1/1], and the title compound (160 mg, Yield 64%) was obtained as a white solid.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.52 (9H, s), 1.69 (2H, ddd, J = 14.7, 7.2, 7.5 Hz), 1.89 (2H, dt, J = 13.0, 3.7 Hz), 2.43-2.59 (4H, m), 3.09 (2H, s), 3.55 (2H, s), 4.36 (2H, s), 6.49 (1H, brs), 7.19 (2H, d, J = 8.5 Hz), 7.34 (2H, d, J = 8.5 Hz), 7.42 (2H, d, J = 8.2 Hz), 7.56 (2H, d, J = 7.8 Hz).

LC / MS [Condition 1]: Retention time 3.55 minutes; m / z 519.8 [M + H] ⁺ (ESI positive ion mode), m / z 518.0 [M−H] ⁻ (ESI negative ion mode)

実施例８３
ｔ−ブチル ３−｛３−［４−（｛２−オキソ−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）フェニル］ウレイド｝プロピルカルバメート（化合物番号８３）の製造
参考例２１で得られた４−（｛２−オキソ−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）安息香酸（４３ｍｇ、０．０９６ｍｍｏｌ）をトルエン（１．０ｍＬ）に懸濁し、トリエチルアミン（０．０３３ｍＬ、０．２４ｍｍｏｌ）およびジフェニルホスホリルアジド（０．０３１ｍＬ、０．１４ｍｍｏｌ）を加え室温で３０分間かき混ぜた後、８０℃で４時間かき混ぜた。そのままＮ−（ｔ−ブトキシカルボニル）−１，３−ジアミノプロパン（東京化成工業（株）より購入）（３３ｍｇ、０．１９ｍｍｏｌ）を加え、８０℃で４時間かき混ぜた。反応混合物を室温まで冷却し、酢酸エチル（３．０）ｍＬ，水（３．０）ｍＬを加え有機層を分離した後、水層を酢酸エチル（３．０）ｍＬで抽出した。合わせた有機層を無水硫酸マグネシウムで乾燥し、減圧下濃縮した。得られた残留物をシリカゲルカラムクロマトグラフィー［充填剤：富士シリシア製アミンシリカＮＨ−ＤＭ１０２０、展開溶媒：酢酸エチル］にて精製し、表題化合物（２３ｍｇ、収率３９％）を無色油状物として得た。

^１Ｈ−ＮＭＲ（３００ＭＨｚ，ＣＤＣｌ_３）δ：１．４４（９Ｈ，ｓ），１．５９−１．７７（４Ｈ，ｍ），１．８９（２Ｈ，ｄｔ，Ｊ＝１３．０，３．４Ｈｚ），２．４３−２．６０（４Ｈ，ｍ），３．１１（２Ｈ，ｓ），３．２１（２Ｈ，ｑ，Ｊ＝６．５Ｈｚ），３．２９（２Ｈ，ｑ，Ｊ＝５．８Ｈｚ），３．５４（２Ｈ，ｓ），４．３６（２Ｈ，ｓ），４．８７（１Ｈ，ｔ，Ｊ＝６．５Ｈｚ），５．５８（１Ｈ，ｔ，Ｊ＝６．５Ｈｚ），６．７１（１Ｈ，ｂｒｓ），７．１６（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ），７．３４（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ），７．４２（２Ｈ，ｄ，Ｊ＝８．５Ｈｚ），７．５６（２Ｈ，ｄ，Ｊ＝８．５Ｈｚ）．

ＬＣ／ＭＳ［条件１］：保持時間３．４３分；ｍ／ｚ６１９．９［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ６１８．０［Ｍ−Ｈ］^―（ＥＳＩ負イオンモード）

Example 83
t-butyl 3- {3- [4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} 4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8] obtained in Reference Example 21 for preparation of methyl) phenyl] ureido} propylcarbamate (Compound No. 83) -Diazaspiro [4.5] decan-3-yl} methyl) benzoic acid (43 mg, 0.096 mmol) suspended in toluene (1.0 mL), triethylamine (0.033 mL, 0.24 mmol) and diphenylphosphoryl azide ( 0.031 mL, 0.14 mmol) was added, and the mixture was stirred at room temperature for 30 minutes, and then stirred at 80 ° C. for 4 hours. N- (t-butoxycarbonyl) -1,3-diaminopropane (purchased from Tokyo Chemical Industry Co., Ltd.) (33 mg, 0.19 mmol) was added as it was, and the mixture was stirred at 80 ° C. for 4 hours. The reaction mixture was cooled to room temperature, ethyl acetate (3.0) mL and water (3.0) mL were added, the organic layer was separated, and the aqueous layer was extracted with ethyl acetate (3.0) mL. The combined organic layers were dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography [filler: amine silica NH-DM1020 manufactured by Fuji Silysia, developing solvent: ethyl acetate] to obtain the title compound (23 mg, yield 39%) as a colorless oil. .

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.44 (9H, s), 1.59-1.77 (4H, m), 1.89 (2H, dt, J = 13.0, 3. 4Hz), 2.43-2.60 (4H, m), 3.11 (2H, s), 3.21 (2H, q, J = 6.5 Hz), 3.29 (2H, q, J = 5.8 Hz), 3.54 (2H, s), 4.36 (2H, s), 4.87 (1H, t, J = 6.5 Hz), 5.58 (1H, t, J = 6. 5 Hz), 6.71 (1H, brs), 7.16 (2H, d, J = 8.2 Hz), 7.34 (2H, d, J = 8.2 Hz), 7.42 (2H, d, J = 8.5 Hz), 7.56 (2H, d, J = 8.5 Hz).

LC / MS [Condition 1]: Retention time 3.43 minutes; m / z 619.9 [M + H] ⁺ (ESI positive ion mode), m / z 618.0 [M−H] ⁻ (ESI negative ion mode)

実施例８４
１−（１−ベンジルピペリジン−４−イル）−３−［４−（｛２−オキソ−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）フェニル］ウレア（化合物番号８４）の製造
Ｎ−（ｔ−ブトキシカルボニル）−１，３−ジアミノプロパンの代わりに４−アミノ−１−ベンジルピペリジン（東京化成工業（株）より購入）を用いること以外は実質的に実施例８３と同様に反応を行って、表題化合物（７．０ｍｇ、収率１１％）を白色固体として得た。

^１Ｈ−ＮＭＲ（３００ＭＨｚ，ＣＤＣｌ_３）δ：１．４６（２Ｈ，ｄｑ，Ｊ＝３．７，１１．６Ｈｚ），１．７９−１．５８（２Ｈ，ｍ），１．８３−２．０２（４Ｈ，ｍ），２．１３（２Ｈ，ｔ，Ｊ＝１０．９Ｈｚ），２．４２−２．５９（４Ｈ，ｍ），２．８１（２Ｈ，ｄ，Ｊ＝１１．６Ｈｚ），３．１２（２Ｈ，ｓ），３．４９（２Ｈ，ｓ），３．５４（２Ｈ，ｓ），３．６１−３．８０（１Ｈ，ｍ），４．３６（２Ｈ，ｓ），４．６８（１Ｈ，ｄ，Ｊ＝７．８Ｈｚ），６．４３（１Ｈ，ｓ），７．１６（２Ｈ，ｄ，Ｊ＝８．５Ｈｚ），７．２２−７．３５（７Ｈ，ｍ），７．４１（２Ｈ，ｄ，Ｊ＝７．８Ｈｚ），７．５６（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ）．

ＬＣ／ＭＳ［条件１］：保持時間３．２７分；ｍ／ｚ６３５．９［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ６３４．０［Ｍ−Ｈ］^―（ＥＳＩ負イオンモード）

Example 84
1- (1-Benzylpiperidin-4-yl) -3- [4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5 ] Decan-3-yl} methyl) phenyl] urea (Compound No. 84) N- (t-butoxycarbonyl) -1,3-diaminopropane instead of 4-amino-1-benzylpiperidine (Tokyo Chemical Industry ( The title compound (7.0 mg, yield 11%) was obtained as a white solid in substantially the same manner as in Example 83, except that the product purchased from KK was used.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.46 (2H, dq, J = 3.7, 11.6 Hz), 1.79-1.58 (2H, m), 1.83-2. 02 (4H, m), 2.13 (2H, t, J = 10.9 Hz), 2.42-2.59 (4H, m), 2.81 (2H, d, J = 11.6 Hz), 3.12 (2H, s), 3.49 (2H, s), 3.54 (2H, s), 3.61-3.80 (1H, m), 4.36 (2H, s), 4 .68 (1H, d, J = 7.8 Hz), 6.43 (1H, s), 7.16 (2H, d, J = 8.5 Hz), 7.22-7.35 (7H, m) , 7.41 (2H, d, J = 7.8 Hz), 7.56 (2H, d, J = 8.2 Hz).

LC / MS [Condition 1]: retention time 3.27 minutes; m / z 635.9 [M + H] ⁺ (ESI positive ion mode), m / z 634.0 [M−H] ⁻ (ESI negative ion mode)

実施例８５
１−ベンジルピペリジン−４−イル ４−（｛２−オキソ−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）フェニルカルバメート（化合物番号８５）の製造
Ｎ−（ｔ−ブトキシカルボニル）−１，３−ジアミノプロパンの代わりに４−ヒドロキシ−１−ベンジルピペリジン（東京化成工業（株）より購入）を用いること以外は実質的に実施例８３と同様に反応を行って、表題化合物（４．９ｍｇ、収率８％）を無色油状物として得た。

^１Ｈ−ＮＭＲ（３００ＭＨｚ，ＣＤＣｌ_３）δ：２．０３−１．６１（８Ｈ，ｍ），２．２８（２Ｈ，ｔ，Ｊ＝９．６Ｈｚ），２．４４−２．５９（４Ｈ，ｍ），２．６６−２．７８（２Ｈ，ｍ），３．１０（２Ｈ，ｓ），３．５２（２Ｈ，ｓ），３．５５（２Ｈ，ｓ），４．３７（２Ｈ，ｓ），４．７２−４．８５（１Ｈ，ｍ），６．６０（１Ｈ，ｓ），７．２０（２Ｈ，ｄ，Ｊ＝８．３Ｈｚ），７．２４−７．４０（７Ｈ，ｍ），７．４２（２Ｈ，ｄ，Ｊ＝８．３Ｈｚ），７．５６（２Ｈ，ｄ，Ｊ＝８．３Ｈｚ）．

ＬＣ／ＭＳ［条件１］：保持時間３．１３分；ｍ／ｚ６３７．０２［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ６３５．０７［Ｍ−Ｈ］^―（ＥＳＩ負イオンモード）

Example 85
1-benzylpiperidin-4-yl 4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl ) Preparation of phenylcarbamate (Compound No. 85) Other than using 4-hydroxy-1-benzylpiperidine (purchased from Tokyo Chemical Industry Co., Ltd.) instead of N- (t-butoxycarbonyl) -1,3-diaminopropane Was carried out in substantially the same manner as in Example 83 to obtain the title compound (4.9 mg, yield 8%) as a colorless oil.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 2.03-1.61 (8H, m), 2.28 (2H, t, J = 9.6 Hz), 2.44-2.59 (4H, m), 2.66-2.78 (2H, m), 3.10 (2H, s), 3.52 (2H, s), 3.55 (2H, s), 4.37 (2H, s) ), 4.72-4.85 (1H, m), 6.60 (1H, s), 7.20 (2H, d, J = 8.3 Hz), 7.24-7.40 (7H, m) ), 7.42 (2H, d, J = 8.3 Hz), 7.56 (2H, d, J = 8.3 Hz).

LC / MS [Condition 1]: Retention time 3.13 minutes; m / z 637.02 [M + H] ⁺ (ESI positive ion mode), m / z 635.07 [M−H] ⁻ (ESI negative ion mode)

実施例８６
３−（ｔ−ブトキシカルボニルアミノ）プロピル ４−（｛２−オキソ−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）フェニルカルバメート（化合物番号８６）の製造
Ｎ−（ｔ−ブトキシカルボニル）−１，３−ジアミノプロパンの代わりにＮ−（３−ヒドロキシプロピル）カルバミン酸ｔ−ブチル（東京化成工業（株）より購入）を用いること以外は実質的に実施例８３と同様に反応を行って、表題化合物（１６ｍｇ、収率２７％）を無色油状物として得た。

^１Ｈ−ＮＭＲ（３００ＭＨｚ，ＣＤＣｌ_３）δ：１．４４（９Ｈ，ｓ），１．５９−１．９５（６Ｈ，ｍ），２．４３−２．６３（４Ｈ，ｍ），３．１０（２Ｈ，ｓ），３．２４（２Ｈ，ｑ，Ｊ＝６．０Ｈｚ），３．５５（２Ｈ，ｓ），４．２３（２Ｈ，ｔ，Ｊ＝６．３Ｈｚ）４．３７（２Ｈ，ｓ），４．６８（１Ｈ，ｂｒｓ），６．７５（１Ｈ，ｂｒｓ），７．２３（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ），７．３７（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ），７．４２（２Ｈ，ｄ，Ｊ＝８．５Ｈｚ），７．５６（２Ｈ，ｄ，Ｊ＝８．５Ｈｚ）．

ＬＣ／ＭＳ［条件１］：保持時間３．５５分；ｍ／ｚ６２１．０［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ６１９．０［Ｍ−Ｈ］^―（ＥＳＩ負イオンモード）

Example 86
3- (t-Butoxycarbonylamino) propyl 4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl } Methyl) Phenylcarbamate (Compound No. 86) Preparation of t-butyl N- (3-hydroxypropyl) carbamate instead of N- (t-butoxycarbonyl) -1,3-diaminopropane (Tokyo Chemical Industry Co., Ltd.) The title compound (16 mg, 27% yield) was obtained as a colorless oil substantially in the same manner as in Example 83 except that the above compound was used.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.44 (9H, s), 1.59-1.95 (6H, m), 2.43-2.63 (4H, m), 3.10 (2H, s), 3.24 (2H, q, J = 6.0 Hz), 3.55 (2H, s), 4.23 (2H, t, J = 6.3 Hz) 4.37 (2H, s), 4.68 (1H, brs), 6.75 (1H, brs), 7.23 (2H, d, J = 8.2 Hz), 7.37 (2H, d, J = 8.2 Hz) , 7.42 (2H, d, J = 8.5 Hz), 7.56 (2H, d, J = 8.5 Hz).

LC / MS [Condition 1]: Retention time 3.55 minutes; m / z 621.0 [M + H] ⁺ (ESI positive ion mode), m / z 619.0 [M−H] ⁻ (ESI negative ion mode)

実施例８７
１−シクロヘキシル−３−［４−（｛２−オキソ−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）フェニル］ウレア（化合物番号８７）の製造
Ｎ−（ｔ−ブトキシカルボニル）−１，３−ジアミノプロパンの代わりにシクロヘキシルアミン（東京化成工業（株）より購入）を用いること以外は実質的に実施例８３と同様に反応を行って、表題化合物（１７ｍｇ、収率３４％）を白色固体として得た。

^１Ｈ−ＮＭＲ（３００ＭＨｚ，ＣＤＣｌ_３）δ：１．０６−１．４７（６Ｈ，ｍ），１．６４−１．８１（４Ｈ，ｍ），１．８３−２．０３（４Ｈ，ｍ），２．４２−２．６１（４Ｈ，ｍ），３．１３（２Ｈ，ｓ），３．５５（２Ｈ，ｓ），３．５８−３．７３（１Ｈ，ｍ），４．３６（２Ｈ，ｓ），４．７２（１Ｈ，ｄ，Ｊ＝７．７Ｈｚ），６．４７（１Ｈ，ｓ），７．１６（２Ｈ，ｄ，Ｊ＝８．３Ｈｚ），７．２９（２Ｈ，ｄ，Ｊ＝８．５Ｈｚ），７．４２（２Ｈ，ｄ，Ｊ＝８．３Ｈｚ），７．５６（２Ｈ，ｄ，Ｊ＝８．３Ｈｚ）．

ＬＣ／ＭＳ［条件１］：保持時間３．４１分；ｍ／ｚ５４４．９［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ５４３．０［Ｍ−Ｈ］^―（ＥＳＩ負イオンモード）

Example 87
1-cyclohexyl-3- [4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl) Preparation of phenyl] urea (Compound No. 87) Substantially Examples except that cyclohexylamine (purchased from Tokyo Chemical Industry Co., Ltd.) was used instead of N- (t-butoxycarbonyl) -1,3-diaminopropane The reaction was performed in the same manner as in 83 to give the title compound (17 mg, yield 34%) as a white solid.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.06-1.47 (6H, m), 1.64-1.81 (4H, m), 1.83 to 2.03 (4H, m) , 2.42-2.61 (4H, m), 3.13 (2H, s), 3.55 (2H, s), 3.58-3.73 (1H, m), 4.36 (2H , S), 4.72 (1H, d, J = 7.7 Hz), 6.47 (1H, s), 7.16 (2H, d, J = 8.3 Hz), 7.29 (2H, d) , J = 8.5 Hz), 7.42 (2H, d, J = 8.3 Hz), 7.56 (2H, d, J = 8.3 Hz).

LC / MS [Condition 1]: Retention time 3.41 minutes; m / z 544.9 [M + H] ⁺ (ESI positive ion mode), m / z 543.0 [M−H] ⁻ (ESI negative ion mode)

実施例８８
シクロヘキシル ４−（｛２−オキソ−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）フェニルカルバメート（化合物番号８８）の製造
Ｎ−（ｔ−ブトキシカルボニル）−１，３−ジアミノプロパンの代わりにシクロヘキサノール（関東化学（株）より購入）を用いること以外は実質的に実施例８３と同様に反応を行って、表題化合物（３．０ｍｇ、収率６％）を無色油状物として得た。

^１Ｈ−ＮＭＲ（３００ＭＨｚ，ＣＤＣｌ_３）δ：１．８１−１．３５（１０Ｈ，ｍ），１．８３−２．００（４Ｈ，ｍ），２．４２−２．６２（４Ｈ，ｍ），３．１０（２Ｈ，ｓ），３．５５（２Ｈ，ｓ），４．３７（２Ｈ，ｓ），４．６９−４．８０（１Ｈ，ｍ），６．５６（１Ｈ，ｓ），７．２０（２Ｈ，ｄ，Ｊ＝８．５Ｈｚ），７．３７（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ），７．４２（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ），７．５６（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ）．

ＬＣ／ＭＳ［条件１］：保持時間３．６７分；ｍ／ｚ５４５．８［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ５４４．０［Ｍ−Ｈ］^―（ＥＳＩ負イオンモード）

Example 88
Cyclohexyl 4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl) phenylcarbamate (Compound No. 88 )Manufacturing of
The title compound was reacted in the same manner as in Example 83 except that cyclohexanol (purchased from Kanto Chemical Co., Inc.) was used instead of N- (t-butoxycarbonyl) -1,3-diaminopropane. (3.0 mg, 6% yield) was obtained as a colorless oil.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.81-1.35 (10H, m), 1.83-2.00 (4H, m), 2.42-2.62 (4H, m) 3.10 (2H, s), 3.55 (2H, s), 4.37 (2H, s), 4.69-4.80 (1H, m), 6.56 (1H, s), 7.20 (2H, d, J = 8.5 Hz), 7.37 (2H, d, J = 8.2 Hz), 7.42 (2H, d, J = 8.2 Hz), 7.56 (2H , D, J = 8.2 Hz).

LC / MS [Condition 1]: Retention time 3.67 minutes; m / z 545.8 [M + H] ⁺ (ESI positive ion mode), m / z 544.0 [M−H] ⁻ (ESI negative ion mode)

実施例８９
１−［４−（｛２−オキソ−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）フェニル］−３−［（テトラヒドロフラン−２−イル）メチル］ウレア（化合物番号８９）の製造
Ｎ−（ｔ−ブトキシカルボニル）−１，３−ジアミノプロパンの代わりにテトラヒドロフルフリルアミン（東京化成工業（株）より購入）を用いること以外は実質的に実施例８３と同様に反応を行って、表題化合物（２０ｍｇ、収率３８％）を無色油状物として得た。

^１Ｈ−ＮＭＲ（３００ＭＨｚ，ＣＤＣｌ_３）δ：１．５９−１．７７（３Ｈ，ｍ），１．８４−２．０４（５Ｈ，ｍ），２．４０−２．６２（４Ｈ，ｍ），３．１１（２Ｈ，ｓ），３．１５（１Ｈ，ｄｄｄ，Ｊ＝１４．３，６．５，５．３Ｈｚ），３．５６（２Ｈ，ｓ），３．５８（１Ｈ，ｄｄｄ，Ｊ＝１４．７，７．０，２．９Ｈｚ），３．７８（１Ｈ，ｄｔ，Ｊ＝８．２，７．０Ｈｚ），３．８８（１Ｈ，ｄｔ，Ｊ＝８．２，６．５Ｈｚ），３．９８−４．０８（１Ｈ，ｍ），４．３６（２Ｈ，ｓ），５．２３（１Ｈ，ｔ，Ｊ＝５．３Ｈｚ），７．１７（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ），７．３０（１Ｈ，ｂｒｓ），７．３２（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ），７．４２（２Ｈ，ｄ，Ｊ＝７．８Ｈｚ），７．５６（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ）．

ＬＣ／ＭＳ［条件１］：保持時間３．１７分；ｍ／ｚ５４６．８［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ５４５．０［Ｍ−Ｈ］^―（ＥＳＩ負イオンモード）

Example 89
1- [4-({2-Oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl) phenyl] -3 -Preparation of [(tetrahydrofuran-2-yl) methyl] urea (Compound No. 89) Tetrahydrofurfurylamine instead of N- (t-butoxycarbonyl) -1,3-diaminopropane (purchased from Tokyo Chemical Industry Co., Ltd.) The title compound (20 mg, 38% yield) was obtained as a colorless oil by substantially reacting in the same manner as in Example 83 except that was used.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.59-1.77 (3H, m), 1.84 to 2.04 (5H, m), 2.40-2.62 (4H, m) , 3.11 (2H, s), 3.15 (1H, ddd, J = 14.3, 6.5, 5.3 Hz), 3.56 (2H, s), 3.58 (1H, ddd, J = 14.7, 7.0, 2.9 Hz), 3.78 (1H, dt, J = 8.2, 7.0 Hz), 3.88 (1H, dt, J = 8.2, 6. 5 Hz), 3.98-4.08 (1 H, m), 4.36 (2 H, s), 5.23 (1 H, t, J = 5.3 Hz), 7.17 (2 H, d, J = 8.2 Hz), 7.30 (1H, brs), 7.32 (2H, d, J = 8.2 Hz), 7.42 (2H, d, J = 7.8 Hz), 7.56 (2H, d, J = 8.2H ).

LC / MS [Condition 1]: Retention time 3.17 minutes; m / z 546.8 [M + H] ⁺ (ESI positive ion mode), m / z 545.0 [M−H] ⁻ (ESI negative ion mode)

実施例９０
（テトラヒドロフラン−２−イル）メチル ４−（｛２−オキソ−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）フェニルカルバメート（化合物番号９０）の製造
Ｎ−（ｔ−ブトキシカルボニル）−１，３−ジアミノプロパンの代わりにテトラヒドロフルフリルアルコール（東京化成工業（株）より購入）を用いること以外は実質的に実施例８３と同様に反応を行って、表題化合物（３０ｍｇ、収率９６％）を無色油状物として得た。

^１Ｈ−ＮＭＲ（３００ＭＨｚ，ＣＤＣｌ_３）δ：１．５７−１．７６（３Ｈ，ｍ），１．８４−２．１０（５Ｈ，ｍ），２．４５−２．６０（４Ｈ，ｍ），３．１０（２Ｈ，ｓ），３．５４（２Ｈ，ｓ），３．８２（１Ｈ，ｄｔ，Ｊ＝８．２，７．０Ｈｚ），３．９１（１Ｈ，ｄｔ，Ｊ＝８．６，６．５Ｈｚ），４．０５（１Ｈ，ｄｄ，Ｊ＝１１．１，７．４Ｈｚ），４．２１−４．１０（１Ｈ，ｍ），４．２９（１Ｈ，ｄｄ，Ｊ＝１１．１，２．９Ｈｚ），４．３７（２Ｈ，ｓ），６．７８（１Ｈ，ｓ），７．２０（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ），７．３６（２Ｈ，ｄ，Ｊ＝８．６Ｈｚ），７．４２（２Ｈ，ｄ，Ｊ＝７．８Ｈｚ），７．５６（２Ｈ，ｄ，Ｊ＝７．８Ｈｚ）．

ＬＣ／ＭＳ［条件１］：保持時間３．２５分；ｍ／ｚ５４７．７［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ５４５．９［Ｍ−Ｈ］^―（ＥＳＩ負イオンモード）

Example 90
(Tetrahydrofuran-2-yl) methyl 4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl ) Preparation of phenylcarbamate (Compound No. 90) Substantially except that tetrahydrofurfuryl alcohol (purchased from Tokyo Chemical Industry Co., Ltd.) was used instead of N- (t-butoxycarbonyl) -1,3-diaminopropane. The reaction was carried out in the same manner as in Example 83 to obtain the title compound (30 mg, yield 96%) as a colorless oil.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.57-1.76 (3H, m), 1.84-2.10 (5H, m), 2.45-2.60 (4H, m) , 3.10 (2H, s), 3.54 (2H, s), 3.82 (1H, dt, J = 8.2, 7.0 Hz), 3.91 (1H, dt, J = 8. 6, 6.5 Hz), 4.05 (1H, dd, J = 11.1, 7.4 Hz), 4.21-4.10 (1H, m), 4.29 (1H, dd, J = 11) .1, 2.9 Hz), 4.37 (2 H, s), 6.78 (1 H, s), 7.20 (2 H, d, J = 8.2 Hz), 7.36 (2 H, d, J = 8.6 Hz), 7.42 (2H, d, J = 7.8 Hz), 7.56 (2H, d, J = 7.8 Hz).

LC / MS [Condition 1]: Retention time 3.25 minutes; m / z 547.7 [M + H] ⁺ (ESI positive ion mode), m / z 545.9 [M−H] ⁻ (ESI negative ion mode)

実施例９１
１−［（１ｒ，４ｒ）−４−（｛２−オキソ−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）シクロヘキシル］−３−［（テトラヒドロフラン−２−イル）メチル］ウレア（化合物番号９１）の製造
Ｎ−（ｔ−ブトキシカルボニル）−１，３−ジアミノプロパンの代わりにテトラヒドロフルフリルアミン（東京化成工業（株）より購入）を、４−（｛２−オキソ−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）安息香酸の代わりに参考例６−３で得られた（１ｒ，４ｒ）−４−（｛２−オキソ−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）シクロヘキサンカルボン酸を用いること以外は、実質的に実施例８３と同様に反応を行って、表題化合物（３９ｍｇ、収率７１％）を淡黄色固体として得た。

^１Ｈ−ＮＭＲ（３００ＭＨｚ，ＣＤＣｌ_３）δ：０．９７−１．１９（４Ｈ，ｍ），１．５０−２．０８（１３Ｈ，ｍ），２．４６−２．６３（４Ｈ，ｍ），３．０３（１Ｈ，ｄｄｄ，Ｊ＝１４．３，７．０，５．３Ｈｚ），３．０８（２Ｈ，ｄ，Ｊ＝７．０Ｈｚ），３．２７（２Ｈ，ｓ），３．４１−３．５２（２Ｈ，ｍ），３．５７（２Ｈ，ｓ），３．７４（１Ｈ，ｄｔ，Ｊ＝８．２，７．０Ｈｚ），３．８３（１Ｈ，ｄｔ，Ｊ＝７．８，６．５Ｈｚ），３．９１−４．０１（１Ｈ，ｍ），４．５３−４．７２（２Ｈ，ｂｒｍ），７．４４（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ），７．５７（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ）．

ＬＣ／ＭＳ［条件１］：保持時間３．０２分；ｍ／ｚ５５２．８［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ５９７．０［Ｍ＋ＨＣＯＯ］^―（ＥＳＩ負イオンモード）

Example 91
1-[(1r, 4r) -4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} Preparation of methyl) cyclohexyl] -3-[(tetrahydrofuran-2-yl) methyl] urea (Compound No. 91) Tetrahydrofurfurylamine (Tokyo Chemical Industry Co., Ltd.) instead of N- (t-butoxycarbonyl) -1,3-diaminopropane 4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl) ) (1r, 4r) -4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-] obtained in Reference Example 6-3 instead of benzoic acid Diazaspiro [4. Except using] decan-3-yl} methyl) cyclohexanecarboxylic acid The reaction was carried out in the same manner as substantially Example 83 to give the title compound (39 mg, 71% yield) as a pale yellow solid.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 0.97-1.19 (4H, m), 1.50-2.08 (13H, m), 2.46-2.63 (4H, m) 3.03 (1H, ddd, J = 14.3, 7.0, 5.3 Hz), 3.08 (2H, d, J = 7.0 Hz), 3.27 (2H, s), 3. 41-3.52 (2H, m), 3.57 (2H, s), 3.74 (1H, dt, J = 8.2, 7.0 Hz), 3.83 (1H, dt, J = 7) .8, 6.5 Hz), 3.91-4.01 (1H, m), 4.53-4.72 (2H, brm), 7.44 (2H, d, J = 8.2 Hz), 7 .57 (2H, d, J = 8.2 Hz).

LC / MS [Condition 1]: Retention time 3.02 minutes; m / z 552.8 [M + H] ⁺ (ESI positive ion mode), m / z 597.0 [M + HCOO] ⁻ (ESI negative ion mode)

実施例９２
（テトラヒドロフラン−２−イル）メチル （１ｒ，４ｒ）−４−（｛２−オキソ−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）シクロヘキシルカルバメート（化合物番号９２）の製造
Ｎ−（ｔ−ブトキシカルボニル）−１，３−ジアミノプロパンの代わりにテトラヒドロフルフリルアルコール（東京化成工業（株）より購入）を、４−（｛２−オキソ−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）安息香酸の代わりに参考例６−３で得られた（１ｒ，４ｒ）−４−（｛２−オキソ−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）シクロヘキサンカルボン酸を用いること以外は、実質的に実施例８３と同様に反応を行って、表題化合物（２４ｍｇ、収率４１％）を白色固体として得た。

^１Ｈ−ＮＭＲ（３００ＭＨｚ，ＣＤＣｌ_３）δ：１．００−１．１９（４Ｈ，ｍ），１．４８−２．０９（１３Ｈ，ｍ），２．４８−２．６４（４Ｈ，ｍ），３．０８（２Ｈ，ｄ，Ｊ＝７．０Ｈｚ），３．２６（２Ｈ，ｓ），３．３５−３．４８（１Ｈ，ｍ），３．５７（２Ｈ，ｓ），３．８０（１Ｈ，ｄｔ，Ｊ＝７．８，６．５Ｈｚ），３．８５−３．９５（２Ｈ，ｍ），４．１４−４．０３（１Ｈ，ｍ），４．１８（１Ｈ，ｄｄ，Ｊ＝１１．１，３．３Ｈｚ），４．６３（１Ｈ，ｄ，Ｊ＝８．２Ｈｚ），７．４４（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ），７．５７（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ）．

ＬＣ／ＭＳ［条件１］：保持時間３．０７分；ｍ／ｚ５５３．４［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ５９７．９［Ｍ＋ＨＣＯＯ］^―（ＥＳＩ負イオンモード）

Example 92
(Tetrahydrofuran-2-yl) methyl (1r, 4r) -4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decane Preparation of -3-yl} methyl) cyclohexyl carbamate (Compound No. 92) Tetrahydrofurfuryl alcohol (purchased from Tokyo Chemical Industry Co., Ltd.) instead of N- (t-butoxycarbonyl) -1,3-diaminopropane, Reference example instead of 4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl) benzoic acid (1r, 4r) -4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] deca Except that n-3-yl} methyl) cyclohexanecarboxylic acid was used, the reaction was carried out in substantially the same manner as in Example 83 to obtain the title compound (24 mg, yield 41%) as a white solid.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.00-1.19 (4H, m), 1.48-2.09 (13H, m), 2.48-2.64 (4H, m) , 3.08 (2H, d, J = 7.0 Hz), 3.26 (2H, s), 3.35-3.48 (1H, m), 3.57 (2H, s), 3.80 (1H, dt, J = 7.8, 6.5 Hz), 3.85-3.95 (2H, m), 4.14-4.03 (1H, m), 4.18 (1H, dd, J = 11.1, 3.3 Hz), 4.63 (1H, d, J = 8.2 Hz), 7.44 (2H, d, J = 8.2 Hz), 7.57 (2H, d, J = 8.2 Hz).

LC / MS [Condition 1]: Retention time 3.07 minutes; m / z 553.4 [M + H] ⁺ (ESI positive ion mode), m / z 597.9 [M + HCOO] ⁻ (ESI negative ion mode)

参考例９３
３−（４−アミノベンジル）−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−２−オン２塩酸塩の製造
実施例８２で得られたｔ−ブチル ４−（｛２−オキソ−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）フェニルカルバメート（１６０ｍｇ、０．３１ｍｍｏｌ）を１，４−ジオキサン（４．０ｍＬ）に溶解し、４Ｍ塩化水素−ジオキサン溶液（３．０ｍｌ）とメタノール（４．０ｍＬ）を加えて５０℃で３時間かき混ぜた。これを減圧下濃縮乾固し、３−（４−アミノベンジル）−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−２−オン２塩酸塩（２００ｍｇ、定量的）を黄色固体として得た。

^１Ｈ−ＮＭＲ（３００ＭＨｚ，ＣＤ_３ＯＤ）δ：２．１３−２．２９（４Ｈ，ｍ），３．４２−３．３１（２Ｈ，ｍ），３．３７（２Ｈ，ｂｒｓ），３．４９（２Ｈ，ｄ，Ｊ＝１２．７Ｈｚ），４．４９（４Ｈ，ｓ），７．４２（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ），７．５０（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ），７．７７−７．８７（４Ｈ，ｍ）．

ＬＣ／ＭＳ［条件１］：保持時間１．０６分；ｍ／ｚ４１９．４［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）

Reference Example 93
Preparation of 3- (4-aminobenzyl) -8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-2-one dihydrochloride In Example 82 The resulting t-butyl 4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl) phenyl Carbamate (160 mg, 0.31 mmol) was dissolved in 1,4-dioxane (4.0 mL), 4M hydrogen chloride-dioxane solution (3.0 ml) and methanol (4.0 mL) were added, and the mixture was stirred at 50 ° C. for 3 hours. It was. This was concentrated to dryness under reduced pressure, and 3- (4-aminobenzyl) -8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-2-one. Dihydrochloride (200 mg, quantitative) was obtained as a yellow solid.

¹ H-NMR (300 MHz, CD ₃ OD) δ: 2.13-2.29 (4H, m), 3.42-3.31 (2H, m), 3.37 (2H, brs), 3. 49 (2H, d, J = 12.7 Hz), 4.49 (4H, s), 7.42 (2H, d, J = 8.2 Hz), 7.50 (2H, d, J = 8.2 Hz) ), 7.77-7.87 (4H, m).

LC / MS [Condition 1]: Retention time 1.06 minutes; m / z 419.4 [M + H] ⁺ (ESI positive ion mode)

実施例９３
Ｎ−［４−（｛２−オキソ−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）フェニル］シクロヘキサンカルボキサミド（化合物番号９３）の製造
参考例９３で得られた３−（４−アミノベンジル）−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−２−オン２塩酸塩（２３ｍｇ、０．０４７ｍｍｏｌ）、トリエチルアミン（０．０１５ｍＬ、０．１１ｍｍｏｌ）をジクロロメタン（２．０ｍＬ）に溶解し、シクロヘキサンカルボニルクロリド（０．０１０ｍＬ，０．０７４ｍｍｏｌ）を加え、４０℃で４時間かき混ぜた。反応混合物にクロロホルム（４．０ｍＬ）、飽和炭酸水素ナトリウム水溶液（４．０ｍＬ）を加え、有機層を分離した後、無水硫酸マグネシウムで乾燥し、減圧下濃縮した。得られた残留物をシリカゲルカラムクロマトグラフィー［充填剤：富士シリシア製アミンシリカＮＨ−ＤＭ１０２０、展開溶媒：酢酸エチル］にて精製し、表題化合物（４．５ｍｇ、収率７７％）を無色油状物として得た。

^１Ｈ−ＮＭＲ（３００ＭＨｚ，ＣＤＣｌ_３）δ：１．２１−２．０１（１４Ｈ，ｍ），２．２３（１Ｈ，ｔｔ，Ｊ＝１１．６，３．３Ｈｚ），２．４３−２．６２（４Ｈ，ｍ），３．１０（２Ｈ，ｓ），３．５５（２Ｈ，ｓ），４．３８（２Ｈ，ｓ），７．１５（１Ｈ，ｓ），７．２２（２Ｈ，ｄ，Ｊ＝８．３Ｈｚ），７．４２（２Ｈ，ｄ，Ｊ＝７．９Ｈｚ），７．５１（２Ｈ，ｄ，Ｊ＝８．３Ｈｚ），７．５６（２Ｈ，ｄ，Ｊ＝７．９Ｈｚ）．

ＬＣ／ＭＳ［条件１］：保持時間３．５１分；ｍ／ｚ５２９．８［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ５２９．７［Ｍ−Ｈ］^―（ＥＳＩ負イオンモード）

Example 93
N- [4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl) phenyl] cyclohexanecarboxamide Production of (Compound No. 93) 3- (4-aminobenzyl) -8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] obtained in Reference Example 93 Decan-2-one dihydrochloride (23 mg, 0.047 mmol), triethylamine (0.015 mL, 0.11 mmol) was dissolved in dichloromethane (2.0 mL), and cyclohexanecarbonyl chloride (0.010 mL, 0.074 mmol) was dissolved. In addition, the mixture was stirred at 40 ° C. for 4 hours. Chloroform (4.0 mL) and saturated aqueous sodium hydrogen carbonate solution (4.0 mL) were added to the reaction mixture, the organic layer was separated, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography [filler: amine silica NH-DM1020 manufactured by Fuji Silysia, developing solvent: ethyl acetate] to give the title compound (4.5 mg, yield 77%) as a colorless oil. Obtained.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.21-2.01 (14H, m), 2.23 (1H, tt, J = 11.6, 3.3 Hz), 2.43-2. 62 (4H, m), 3.10 (2H, s), 3.55 (2H, s), 4.38 (2H, s), 7.15 (1H, s), 7.22 (2H, d , J = 8.3 Hz), 7.42 (2H, d, J = 7.9 Hz), 7.51 (2H, d, J = 8.3 Hz), 7.56 (2H, d, J = 7. 9 Hz).

LC / MS [Condition 1]: Retention time 3.51 minutes; m / z 529.8 [M + H] ⁺ (ESI positive ion mode), m / z 529.7 [M−H] ⁻ (ESI negative ion mode)

実施例９４
ｔ−ブチル ４−オキソ−４−［４−（｛２−オキソ−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）フェニルアミノ］ブチルカルバメート（化合物番号９４）の製造
４−（｛２−オキソ−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）安息香酸の代わりに４−（ｔ−ブトキシカルボニルアミノ）ブチルカルボン酸（アルドリッチ（株）より購入）、４−アミノ−１−（ピリジン−３−イルメチル）ピペリジン三塩酸塩の代わりに参考例９３で得られた３−（４−アミノベンジル）−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−２−オン２塩酸塩を用いること以外は実質的に実施例６４と同様に反応を行って、表題化合物（１６ｍｇ、収率６１％）を無色油状物として得た。

^１Ｈ−ＮＭＲ（３００ＭＨｚ，ＣＤＣｌ_３）δ：１．４６（９Ｈ，ｓ），１．７７−１．６４（２Ｈ，ｍ），１．８２−１．９５（４Ｈ，ｍ），２．３８（２Ｈ，ｔ，Ｊ＝６．３Ｈｚ），２．４４−２．６１（４Ｈ，ｍ），３．０８（２Ｈ，ｓ），３．２６（２Ｈ，ｑ，Ｊ＝５．９Ｈｚ），３．５５（２Ｈ，ｓ），４．３８（２Ｈ，ｓ），４．７９（１Ｈ，ｔ，Ｊ＝５．３Ｈｚ），７．２２（２Ｈ，ｄ，Ｊ＝８．３Ｈｚ），７．４２（２Ｈ，ｄ，Ｊ＝８．３Ｈｚ），７．５６（２Ｈ，ｄ，Ｊ＝７．９Ｈｚ），７．６２（２Ｈ，ｄ，Ｊ＝８．３Ｈｚ），９．００（１Ｈ，ｓ）．

ＬＣ／ＭＳ［条件１］：保持時間３．３９分；ｍ／ｚ６０４．９［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ６０３．０［Ｍ−Ｈ］^―（ＥＳＩ負イオンモード）

Example 94
t-butyl 4-oxo-4- [4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl } Methyl) phenylamino] butylcarbamate (Compound No. 94) 4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] 4- (t-butoxycarbonylamino) butylcarboxylic acid (purchased from Aldrich) instead of decan-3-yl} methyl) benzoic acid, 4-amino-1- (pyridin-3-ylmethyl) piperidine trihydrochloride 3- (4-Aminobenzyl) -8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decane-obtained in Reference Example 93 instead of the salt The reaction was carried out substantially in the same manner as in Example 64 except that 2-one dihydrochloride was used to give the title compound (16 mg, yield 61%) as a colorless oil.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.46 (9H, s), 1.77-1.64 (2H, m), 1.82-1.95 (4H, m), 2.38 (2H, t, J = 6.3 Hz), 2.44-2.61 (4H, m), 3.08 (2H, s), 3.26 (2H, q, J = 5.9 Hz), 3 .55 (2H, s), 4.38 (2H, s), 4.79 (1H, t, J = 5.3 Hz), 7.22 (2H, d, J = 8.3 Hz), 7.42 (2H, d, J = 8.3 Hz), 7.56 (2H, d, J = 7.9 Hz), 7.62 (2H, d, J = 8.3 Hz), 9.00 (1H, s) .

LC / MS [Condition 1]: Retention time 3.39 minutes; m / z 604.9 [M + H] ⁺ (ESI positive ion mode), m / z 603.0 [M−H] ⁻ (ESI negative ion mode)

実施例９５
４−［４−（｛２−オキソ−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）フェニルカルバモイル］ピペリジン−１−カルボン酸ｔ−ブチル（化合物番号９５）の製造
４−（｛２−オキソ−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）安息香酸の代わりに１−（ｔ−ブトキシキカルボニル）ピペリジン−４−カルボン酸（シグマアルドリッチジャパン（株）より購入）、４−アミノ−１−（ピリジン−３−イルメチル）ピペリジン三塩酸塩の代わりに参考例９３で得られた３−（４−アミノベンジル）−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−２−オン２塩酸塩を用いること以外は実質的に実施例６４と同様に反応を行って、表題化合物（１７ｍｇ、収率９３％）を白色固体として得た。

^１Ｈ−ＮＭＲ（３００ＭＨｚ，ＣＤＣｌ_３）δ：１．４７（９Ｈ，ｓ），１．６４−１．８２（４Ｈ，ｍ），１．８３−１．９５（４Ｈ，ｍ），２．３９（１Ｈ，ｔｔ，Ｊ＝１１．５，３．７Ｈｚ），２．４６−２．５８（４Ｈ，ｍ），２．７９（２Ｈ，ｔ，Ｊ＝１１．９Ｈｚ），３．１１（２Ｈ，ｓ），３．５４（２Ｈ，ｓ），４．１９（２Ｈ，ｄ，Ｊ＝１１．９Ｈｚ），４．３８（２Ｈ，ｓ），７．２２（２Ｈ，ｄ，Ｊ＝８．６Ｈｚ），７．２９（１Ｈ，ｓ），７．４２（２Ｈ，ｄ，Ｊ＝７．８Ｈｚ），７．５０（２Ｈ，ｄ，Ｊ＝８．６Ｈｚ），７．５６（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ）．

ＬＣ／ＭＳ［条件１］：保持時間３．５７分；ｍ／ｚ６３０．９［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ６２９．１［Ｍ−Ｈ］^―（ＥＳＩ負イオンモード）

Example 95
4- [4-({2-Oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl) phenylcarbamoyl] piperidine Preparation of t-butyl-1-carboxylate (Compound No. 95) 4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] 1- (t-Butoxycarbonyl) piperidine-4-carboxylic acid (purchased from Sigma-Aldrich Japan Co.) instead of decan-3-yl} methyl) benzoic acid, 4-amino-1- (pyridine-3- 3- (4-Aminobenzyl) -8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazas obtained in Reference Example 93 instead of (ylmethyl) piperidine trihydrochloride B [4.5] Except for using an decan-2-one dihydrochloride The reaction was carried out in the same manner as substantially Example 64 to give the title compound (17 mg, 93% yield) as a white solid.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.47 (9H, s), 1.64-1.82 (4H, m), 1.83-1.95 (4H, m), 2.39 (1H, tt, J = 11.5, 3.7 Hz), 2.46-2.58 (4H, m), 2.79 (2H, t, J = 11.9 Hz), 3.11 (2H, s), 3.54 (2H, s), 4.19 (2H, d, J = 11.9 Hz), 4.38 (2H, s), 7.22 (2H, d, J = 8.6 Hz) 7.29 (1H, s), 7.42 (2H, d, J = 7.8 Hz), 7.50 (2H, d, J = 8.6 Hz), 7.56 (2H, d, J = 8.2 Hz).

LC / MS [Condition 1]: Retention time 3.57 minutes; m / z 630.9 [M + H] ⁺ (ESI positive ion mode), m / z 629.1 [M−H] ⁻ (ESI negative ion mode)

参考例９６−１
ｔ−ブチル （１ｒ，４ｒ）−４−（｛２−オキソ−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）シクロヘキシルカルバメートの製造
４−（｛２−オキソ−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）安息香酸の代わりに参考例６−３で得た、（１ｒ，４ｒ）−４−（｛２−オキソ−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）シクロヘキサンカルボン酸を用いること以外は、実質的に実施例８２と同様に反応を行なって、表題化合物（８．０ｍｇ、収率１０％）を白色固体として得た。

^１Ｈ−ＮＭＲ（３００ＭＨｚ，ＣＤＣｌ_３）δ：０．９８−１．１７（４Ｈ，ｍ），１．４４（９Ｈ，ｓ），１．６３−１．４８（１Ｈ，ｍ），１．６８−１．８３（４Ｈ，ｍ），１．８７−２．０８（４Ｈ，ｍ），２．４８−２．５９（４Ｈ，ｍ），３．０７（２Ｈ，ｄ，Ｊ＝７．０Ｈｚ），３．２６（２Ｈ，ｓ），３．３０−３．４３（１Ｈ，ｍ），３．５７（２Ｈ，ｓ），４．３６（１Ｈ，ｂｒｓ），７．４４（２Ｈ，ｄ，Ｊ＝７．８Ｈｚ），７．５８（２Ｈ，ｔ，Ｊ＝８．０Ｈｚ）．

ＬＣ／ＭＳ［条件１］：保持時間３．４８分；ｍ／ｚ５２５．８［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ５７０．１［Ｍ＋ＨＣＯＯ］^―（ＥＳＩ負イオンモード）

Reference Example 96-1
t-butyl (1r, 4r) -4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} Preparation of methyl) cyclohexyl carbamate 4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl) benzoic acid (1r, 4r) -4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [0] obtained in Reference Example 6-3 instead of the acid 4.5] decan-3-yl} methyl) cyclohexanecarboxylic acid was used except that the reaction was carried out in substantially the same manner as in Example 82 to give the title compound (8.0 mg, yield 10%) as a white solid Got as.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 0.98-1.17 (4H, m), 1.44 (9H, s), 1.63-1.48 (1H, m), 1.68 -1.83 (4H, m), 1.87-2.08 (4H, m), 2.48-2.59 (4H, m), 3.07 (2H, d, J = 7.0Hz) , 3.26 (2H, s), 3.30-3.43 (1H, m), 3.57 (2H, s), 4.36 (1H, brs), 7.44 (2H, d, J = 7.8 Hz), 7.58 (2H, t, J = 8.0 Hz).

LC / MS [condition 1]: retention time 3.48 minutes; m / z 525.8 [M + H] ⁺ (ESI positive ion mode), m / z 570.1 [M + HCOO] ⁻ (ESI negative ion mode)

参考例９６−２
３−｛［（１ｒ，４ｒ）−４−アミノシクロヘキシル］メチル｝−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−２−オン２塩酸塩の製造
参考例９６−１で得られたｔ−ブチル （１ｒ，４ｒ）−４−（｛２−オキソ−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）シクロヘキシルカルバメートをｔ−ブチル ４−（｛２−オキソ−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）フェニルカルバメートの代わりに用いること以外は実質的に参考例９３と同様に反応を行って、表題化合物（５．０ｍｇ、定量的）を淡黄色液体として得た。

^１Ｈ−ＮＭＲ（３００ＭＨｚ，ＣＤ_３ＯＤ）δ：１．１２（２Ｈ，ｑ，Ｊ＝１２．７Ｈｚ），１．２６−１．５１（３Ｈ，ｍ），１．５７−１．７７（１Ｈ，ｍ），１．８４（２Ｈ，ｄ，Ｊ＝１２．３Ｈｚ），２．０６（２Ｈ，ｄ，Ｊ＝１１．１Ｈｚ），２．１４−２．３３（４Ｈ，ｍ），２．９７−３．１２（１Ｈ，ｍ），３．１２（２Ｈ，ｄ，Ｊ＝７．４Ｈｚ），３．７２−３．３５（４Ｈ，ｍ），４．４９（２Ｈ，ｓ），７．８１（４Ｈ，ｓ）．

ＬＣ／ＭＳ［条件１］：保持時間０．８８分；ｍ／ｚ４２６．０［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）

Reference Example 96-2
3-{[(1r, 4r) -4-aminocyclohexyl] methyl} -8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-2-one Production of dihydrochloride t-butyl (1r, 4r) -4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3, obtained in Reference Example 96-1 8-Diazaspiro [4.5] decan-3-yl} methyl) cyclohexyl carbamate is converted to t-butyl 4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8 -Diazaspiro [4.5] decan-3-yl} methyl) phenylcarbamate was used in the same manner as in Reference Example 93 except that the title compound (5.0 mg, quantitative) was obtained lightly. As yellow liquid It was.

¹ H-NMR (300 MHz, CD ₃ OD) δ: 1.12 (2H, q, J = 12.7 Hz), 1.26 to 1.51 (3H, m), 1.57-1.77 (1H M), 1.84 (2H, d, J = 12.3 Hz), 2.06 (2H, d, J = 11.1 Hz), 2.14-2.33 (4H, m), 2.97. −3.12 (1H, m), 3.12 (2H, d, J = 7.4 Hz), 3.72−3.35 (4H, m), 4.49 (2H, s), 7.81 (4H, s).

LC / MS [Condition 1]: Retention time 0.88 min; m / z 426.0 [M + H] ⁺ (ESI positive ion mode)

実施例９６
Ｎ−［（１ｒ，４ｒ）−４−（｛２−オキソ−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）シクロヘキシル］−２−（テトラヒドロフラン−２−イル）アセトアミド（化合物番号９６）の製造
４−（｛２−オキソ−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）安息香酸の代わりに参考例１４で得られた２−（テトラヒドロフラン−２−イル）酢酸、４−アミノ−１−（ピリジン−３−イルメチル）ピペリジン三塩酸塩の代わりに参考例９６−２で得られた３−｛［（１ｒ，４ｒ）−４−アミノシクロヘキシル］メチル｝−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−２−オン２塩酸塩を用いること以外は実質的に実施例６４と同様に反応を行って、表題化合物（４．７ｍｇ、収率８７％）を白色固体として得た。

^１Ｈ−ＮＭＲ（３００ＭＨｚ，ＣＤＣｌ_３）δ：１．０２−１．２１（４Ｈ，ｍ），１．４５−２．１５（１３Ｈ，ｍ），２．３６（１Ｈ，ｄｄ，Ｊ＝１５．１，７．８Ｈｚ），２．４６（１Ｈ，ｄｄ，Ｊ＝１５．１，３．７Ｈｚ），２．４６−２．７３（４Ｈ，ｍ），３．０８（２Ｈ，ｄ，Ｊ＝７．０Ｈｚ），３．２７（２Ｈ，ｓ），３．５７（２Ｈ，ｓ），３．６３−３．８１（１Ｈ，ｍ），３．７７（１Ｈ，ｄｔ，Ｊ＝７．４，７．４Ｈｚ），３．８８（１Ｈ，ｄｔ，Ｊ＝８．６，７．０Ｈｚ），４．０５−４．１５（１Ｈ，ｍ），６．３０（１Ｈ，ｄ，Ｊ＝８．２Ｈｚ），７．４４（２Ｈ，ｄ，Ｊ＝７．８Ｈｚ），７．５７（２Ｈ，ｄ，Ｊ＝７．８Ｈｚ）．

ＬＣ／ＭＳ［条件１］：保持時間３．０５分；ｍ／ｚ５３７．８［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ５８２．０［Ｍ＋ＨＣＯＯ］^―（ＥＳＩ負イオンモード）

Example 96
N-[(1r, 4r) -4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} Preparation of methyl) cyclohexyl] -2- (tetrahydrofuran-2-yl) acetamide (Compound No. 96) 4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8 2- (tetrahydrofuran-2-yl) acetic acid, 4-amino-1- (pyridin-3-ylmethyl) obtained in Reference Example 14 instead of -diazaspiro [4.5] decan-3-yl} methyl) benzoic acid ) 3-{[(1r, 4r) -4-aminocyclohexyl] methyl} -8- [4- (trifluoromethyl) benzyl] -1- obtained in Reference Example 96-2 instead of piperidine trihydrochloride Oxa The reaction was conducted in substantially the same manner as in Example 64 except that 3,8-diazaspiro [4.5] decan-2-one dihydrochloride was used to give the title compound (4.7 mg, yield 87%). Obtained as a white solid.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.02-1.21 (4H, m), 1.45-2.15 (13H, m), 2.36 (1H, dd, J = 15. 1,7.8 Hz), 2.46 (1H, dd, J = 15.1, 3.7 Hz), 2.46-2.73 (4H, m), 3.08 (2H, d, J = 7) .0Hz), 3.27 (2H, s), 3.57 (2H, s), 3.63-3.81 (1H, m), 3.77 (1H, dt, J = 7.4, 7 .4 Hz), 3.88 (1 H, dt, J = 8.6, 7.0 Hz), 4.05-4.15 (1 H, m), 6.30 (1 H, d, J = 8.2 Hz) 7.44 (2H, d, J = 7.8 Hz), 7.57 (2H, d, J = 7.8 Hz).

LC / MS [Condition 1]: Retention time 3.05 minutes; m / z 537.8 [M + H] ⁺ (ESI positive ion mode), m / z 582.0 [M + HCOO] ⁻ (ESI negative ion mode)

実施例９７
（１ｒ，４ｒ）−４−（｛２−オキソ−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）−Ｎ−［（テトラヒドロフラン−２−イル）メチル］シクロヘキサンカルボチオアミド（化合物番号９７）の製造
実施例１０で得られた、（１ｒ，４ｒ）−４−（｛２−オキソ−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）−Ｎ−［（テトラヒドロフラン−２−イル）メチル］シクロヘキサンカルボキサミド（２１ｍｇ、０．０３８ｍｏｌ）をトルエン（２．０ｍＬ）に溶解し、ローソン試薬（１８ｍｇ、０．０４５ｍｏｌ）を加えて１１０℃で２時間かき混ぜた。冷却後、酢酸エチル（５．０ｍＬ）と飽和炭酸水素ナトリウム水溶液（３．０ｍＬ）を加え、有機層を分離した。水層を酢酸エチル（５．０ｍＬ）で抽出した後、合わせた有機層を無水硫酸マグネシウムで乾燥し、減圧下濃縮した。得られた残留物をシリカゲルカラムクロマトグラフィー［充填剤：富士シリシア製アミンシリカＮＨ−ＤＭ１０２０、展開溶媒：ヘキサン／酢酸エチル＝１／１］にて精製し、表題化合物（２．４ｍｇ、収率１７％）を白色固体として得た。

^１Ｈ−ＮＭＲ（３００ＭＨｚ，ＣＤＣｌ_３）δ：１．０７（２Ｈ，ｄｑ，Ｊ＝３．３，１２．７Ｈｚ），１．６２−２．０８（１５Ｈ，ｍ），２．４３（１Ｈ，ｔｔ，Ｊ＝１２．３，３．３Ｈｚ），２．４９−２．６８（４Ｈ，ｍ），３．１０（２Ｈ，ｄ，Ｊ＝７．４Ｈｚ），３．２５（２Ｈ，ｓ），３．４５（１Ｈ，ｄｄｄ，Ｊ＝１４．３，９．０，３．７Ｈｚ），３．５７（２Ｈ，ｓ），３．７８（１Ｈ，ｄｔ，Ｊ＝８．２，６．５Ｈｚ），３．８９（１Ｈ，ｄｔ，Ｊ＝８．６，６．５Ｈｚ），４．０４−４．１４（２Ｈ，ｍ），７．４４（２Ｈ，ｄ，Ｊ＝７．８Ｈｚ），７．５７（２Ｈ，ｄ，Ｊ＝７．８Ｈｚ），７．５８（１Ｈ，ｓ）．

ＬＣ／ＭＳ［条件１］：保持時間３．３８分；ｍ／ｚ５５３．８［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ５５１．９［Ｍ−Ｈ］^―（ＥＳＩ負イオンモード）

Example 97
(1r, 4r) -4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl)- Preparation of N-[(tetrahydrofuran-2-yl) methyl] cyclohexanecarbothioamide (Compound No. 97) (1r, 4r) -4-({2-oxo-8- [4- ( Trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl) -N-[(tetrahydrofuran-2-yl) methyl] cyclohexanecarboxamide (21 mg, 0.038 mol) ) Was dissolved in toluene (2.0 mL), Lawesson's reagent (18 mg, 0.045 mol) was added, and the mixture was stirred at 110 ° C. for 2 hours. After cooling, ethyl acetate (5.0 mL) and saturated aqueous sodium hydrogen carbonate solution (3.0 mL) were added, and the organic layer was separated. The aqueous layer was extracted with ethyl acetate (5.0 mL), and the combined organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography [filler: amine silica NH-DM1020 manufactured by Fuji Silysia, developing solvent: hexane / ethyl acetate = 1/1], and the title compound (2.4 mg, yield 17%). ) Was obtained as a white solid.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.07 (2H, dq, J = 3.3, 12.7 Hz), 1.62-2.08 (15H, m), 2.43 (1H, tt, J = 12.3, 3.3 Hz), 2.49-2.68 (4H, m), 3.10 (2H, d, J = 7.4 Hz), 3.25 (2H, s), 3.45 (1H, ddd, J = 14.3, 9.0, 3.7 Hz), 3.57 (2H, s), 3.78 (1H, dt, J = 8.2, 6.5 Hz) 3.89 (1H, dt, J = 8.6, 6.5 Hz), 4.04-4.14 (2H, m), 7.44 (2H, d, J = 7.8 Hz), 7. 57 (2H, d, J = 7.8 Hz), 7.58 (1 H, s).

LC / MS [Condition 1]: Retention time 3.38 minutes; m / z 553.8 [M + H] ⁺ (ESI positive ion mode), m / z 551.9 [M−H] ⁻ (ESI negative ion mode)

参考例９８
（１ｒ，４ｒ）−Ｎ−（１−ベンジルピペリジン−４−イル）−４−［（２−オキソ−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル）メチル］シクロヘキサンカルボキサミド塩酸塩の製造
実施例１２３で得られた、３−｛［（１ｒ，４ｒ）−４−（１−ベンジルピペリジン−４−イルカルバモイル）シクロヘキシル］メチル｝−２−オキソ−１−オキサ−３，８−ジアザスピロ［４．５］デカン−８−カルボン酸ｔ−ブチル（０．３５ｇ、０．６２ｍｍｏｌ）を１，４−ジオキサン（７．０ｍＬ）とメタノール（４．０ｍＬ）の混合溶媒に溶解し、室温にて４Ｍ塩化水素−ジオキサン溶液（０．６２ｍＬ、２．５ｍｍｏｌ）を加えて、室温にて１日間静置したのち、減圧下濃縮乾固した。残留物にアセトン（５．０ｍＬ）を加えて３日間静置した後に減圧下濃縮乾固して、（１ｒ，４ｒ）−Ｎ−（１−ベンジルピペリジン−４−イル）−４−［（２−オキソ−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル）メチル］シクロヘキサンカルボキサミド塩酸塩（０．３５ｇ、収率定量的）を白色固体として得た。

Reference Example 98
(1r, 4r) -N- (1-Benzylpiperidin-4-yl) -4-[(2-oxo-1-oxa-3,8-diazaspiro [4.5] decan-3-yl) methyl] cyclohexane Preparation of carboxamide hydrochloride 3-{[(1r, 4r) -4- (1-benzylpiperidin-4-ylcarbamoyl) cyclohexyl] methyl} -2-oxo-1-oxa-3 obtained in Example 123 , 8-diazaspiro [4.5] decane-8-carboxylate t-butyl (0.35 g, 0.62 mmol) dissolved in a mixed solvent of 1,4-dioxane (7.0 mL) and methanol (4.0 mL) A 4M hydrogen chloride-dioxane solution (0.62 mL, 2.5 mmol) was added at room temperature, and the mixture was allowed to stand at room temperature for 1 day, and then concentrated to dryness under reduced pressure. Acetone (5.0 mL) was added to the residue, and the mixture was allowed to stand for 3 days and then concentrated to dryness under reduced pressure to give (1r, 4r) -N- (1-benzylpiperidin-4-yl) -4-[(2 -Oxo-1-oxa-3,8-diazaspiro [4.5] decan-3-yl) methyl] cyclohexanecarboxamide hydrochloride (0.35 g, quantitative yield) was obtained as a white solid.

実施例９８
（１ｒ，４ｒ）−４−［（８−ベンジル−２−オキソ−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル）メチル］−Ｎ−（１−ベンジルピペリジン−４−イル）シクロヘキサンカルボキサミド（化合物番号９８）の製造
参考例９８で得られた、（１ｒ，４ｒ）−Ｎ−（１−ベンジルピペリジン−４−イル）−４−［（２−オキソ−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル）メチル］シクロヘキサンカルボキサミド塩酸塩（２０ｍｇ、０．０３７ｍｍｏｌ）をＮ，Ｎ−ジメチルホルムアミド（０．４０ｍＬ）に懸濁し、トリエチルアミン（０．０２１ｍＬ、０．１５ｍｍｏｌ）、ベンジルブロミド（０．００５０ｍＬ、０．０４１ｍｍｏｌ）を加え、室温で３日間かき混ぜた。反応混合物に水（１．０ｍＬ）とクロロホルム（２．０ｍＬ）を加え、有機層を分離した後、水（１．０ｍＬ）で洗浄した。有機層を減圧下濃縮した後、得られた残留物をシリカゲルカラムクロマトグラフィー［充填剤：富士シリシア製アミンシリカＮＨ−ＤＭ１０２０、展開溶媒：クロロホルム／酢酸エチル＝１／１］にて精製し、表題化合物（１５ｍｇ、収率７２％）を白色固体として得た。

^１Ｈ−ＮＭＲ（３００ＭＨｚ，ＣＤＣｌ_３）δ：１．０１（２Ｈ，ｄｑ，Ｊ＝３．７，１１．９Ｈｚ），１．３４−１．５６（５Ｈ，ｍ），１．６９−２．０３（１１Ｈ，ｍ），２．１１（２Ｈ，ｔ，Ｊ＝１１．６Ｈｚ），２．４６−２．６５（４Ｈ，ｍ），２．８０（２Ｈ，ｄ，Ｊ＝１１．６Ｈｚ），３．０８（２Ｈ，ｄ，Ｊ＝７．２Ｈｚ），３．２４（２Ｈ，ｓ），３．４９（２Ｈ，ｓ），３．５３（２Ｈ，ｓ），３．６９−３．８７（１Ｈ，ｍ），５．２８（１Ｈ，ｄ，Ｊ＝７．８Ｈｚ），７．３７−７．２２（１０Ｈ，ｍ）．

ＬＣ／ＭＳ［条件１］：保持時間１．１５分；ｍ／ｚ５５９．１［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ６０３．１［Ｍ＋ＨＣＯＯ］^―（ＥＳＩ負イオンモード）

Example 98
(1r, 4r) -4-[(8-Benzyl-2-oxo-1-oxa-3,8-diazaspiro [4.5] decan-3-yl) methyl] -N- (1-benzylpiperidine-4 -Ill) Preparation of cyclohexanecarboxamide (Compound No. 98) (1r, 4r) -N- (1-benzylpiperidin-4-yl) -4-[(2-oxo-1-oxa) obtained in Reference Example 98 −3,8-diazaspiro [4.5] decan-3-yl) methyl] cyclohexanecarboxamide hydrochloride (20 mg, 0.037 mmol) was suspended in N, N-dimethylformamide (0.40 mL) and triethylamine (0. 021 mL, 0.15 mmol) and benzyl bromide (0.0050 mL, 0.041 mmol) were added, and the mixture was stirred at room temperature for 3 days. Water (1.0 mL) and chloroform (2.0 mL) were added to the reaction mixture, and the organic layer was separated and washed with water (1.0 mL). After the organic layer was concentrated under reduced pressure, the obtained residue was purified by silica gel column chromatography [filler: amine silica NH-DM1020 manufactured by Fuji Silysia, developing solvent: chloroform / ethyl acetate = 1/1] to give the title compound. (15 mg, 72% yield) was obtained as a white solid.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.01 (2H, dq, J = 3.7, 11.9 Hz), 1.34 to 1.56 (5H, m), 1.69-2. 03 (11H, m), 2.11 (2H, t, J = 11.6 Hz), 2.46-2.65 (4H, m), 2.80 (2H, d, J = 11.6 Hz), 3.08 (2H, d, J = 7.2 Hz), 3.24 (2H, s), 3.49 (2H, s), 3.53 (2H, s), 3.69-3.87 ( 1H, m), 5.28 (1H, d, J = 7.8 Hz), 7.37-7.22 (10H, m).

LC / MS [Condition 1]: Retention time 1.15 minutes; m / z 559.1 [M + H] ⁺ (ESI positive ion mode), m / z 603.1 [M + HCOO] ⁻ (ESI negative ion mode)

実施例９９
３−｛［（１ｒ，４ｒ）−４−（１−ベンジルピペリジン−４−イルカルバモイル）シクロヘキシル］メチル｝−２−オキソ−１−オキサ−３，８−ジアザスピロ［４．５］デカン−８−カルボン酸ベンジル（化合物番号９９）の製造
ベンジルブロミドの代わりにクロロギ酸ベンジルを、Ｎ，Ｎ−ジメチルホルムアミドの代わりにクロロホルムを用いること以外は実質的に実施例９８と同様に反応を行って、表題化合物（１５ｍｇ、収率６８％）を白色固体として得た。

^１Ｈ−ＮＭＲ（３００ＭＨｚ，ＣＤＣｌ_３）δ：１．０１（２Ｈ，ｄｑ，Ｊ＝３．０，１２．２Ｈｚ），１．９５−１．３３（１５Ｈ，ｍ），１．９７（１Ｈ，ｔｔ，Ｊ＝１２．９，３．３Ｈｚ），２．１０（２Ｈ，ｔ，Ｊ＝１１．２Ｈｚ），２．８０（２Ｈ，ｄ，Ｊ＝１１．６Ｈｚ），３．１０（２Ｈ，ｄ，Ｊ＝７．３Ｈｚ），３．２５（２Ｈ，ｓ），３．３３（２Ｈ，ｔ，Ｊ＝１１．６Ｈｚ），３．４８（２Ｈ，ｓ），３．７０−３．８６（１Ｈ，ｍ），３．８７−４．０６（２Ｈ，ｍ），５．１３（２Ｈ，ｓ），５．２９（１Ｈ，ｄ，Ｊ＝７．６Ｈｚ），７．３１−７．３６（１０Ｈ，ｍ）．

ＬＣ／ＭＳ［条件１］：保持時間３．３５分；ｍ／ｚ６０３．０［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ６４７．１［Ｍ＋ＨＣＯＯ］^―（ＥＳＩ負イオンモード）

Example 99
3-{[(1r, 4r) -4- (1-Benzylpiperidin-4-ylcarbamoyl) cyclohexyl] methyl} -2-oxo-1-oxa-3,8-diazaspiro [4.5] decane-8- Preparation of benzyl carboxylate (Compound No. 99) The reaction was conducted in substantially the same manner as in Example 98 except that benzyl chloroformate was used instead of benzyl bromide and chloroform was used instead of N, N-dimethylformamide. The compound (15 mg, 68% yield) was obtained as a white solid.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.01 (2H, dq, J = 3.0, 12.2 Hz), 1.95-1.33 (15H, m), 1.97 (1H, tt, J = 12.9, 3.3 Hz), 2.10 (2H, t, J = 111.2 Hz), 2.80 (2H, d, J = 11.6 Hz), 3.10 (2H, d , J = 7.3 Hz), 3.25 (2H, s), 3.33 (2H, t, J = 11.6 Hz), 3.48 (2H, s), 3.70-3.86 (1H) M), 3.87-4.06 (2H, m), 5.13 (2H, s), 5.29 (1H, d, J = 7.6 Hz), 7.31-7.36 (10H). , M).

LC / MS [Condition 1]: Retention time 3.35 minutes; m / z 603.0 [M + H] ⁺ (ESI positive ion mode), m / z 647.1 [M + HCOO] ⁻ (ESI negative ion mode)

実施例１００
（１ｒ，４ｒ）−Ｎ−（１−ベンジルピペリジン−４−イル）−４−｛［８−（４−シアノベンジル）−２−オキソ−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル］メチル｝シクロヘキサンカルボキサミド（化合物番号１００）の製造
ベンジルブロミドの代わりに４−シアノベンジルブロミドを用いること以外は実質的に実施例９８と同様に反応を行って、表題化合物（１１ｍｇ、収率５１％）を白色固体として得た。

^１Ｈ−ＮＭＲ（３００ＭＨｚ，ＣＤＣｌ_３）δ：１．０１（２Ｈ，ｄｑ，Ｊ＝３．６，１２．６Ｈｚ），１．３５−２．０３（１６Ｈ，ｍ），２．１１（２Ｈ，ｔ，Ｊ＝１０．９Ｈｚ），２．４８−２．６３（４Ｈ，ｍ），２．８１（２Ｈ，ｄ，Ｊ＝１１．９Ｈｚ），３．０９（２Ｈ，ｄ，Ｊ＝７．３Ｈｚ），３．２５（２Ｈ，ｓ），３．４９（２Ｈ，ｓ），３．５７（２Ｈ，ｓ），３．７０−３．８６（１Ｈ，ｍ），５．２７（１Ｈ，ｄ，Ｊ＝７．９Ｈｚ），７．３７−７．２３（５Ｈ，ｍ），７．４４（２Ｈ，ｄ，Ｊ＝８．３Ｈｚ），７．６１（２Ｈ，ｄ，Ｊ＝８．３Ｈｚ）．

ＬＣ／ＭＳ［条件１］：保持時間１．０７分；ｍ／ｚ５８３．９［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ６２８．０［Ｍ＋ＨＣＯＯ］^―（ＥＳＩ負イオンモード）

Example 100
(1r, 4r) -N- (1-Benzylpiperidin-4-yl) -4-{[8- (4-cyanobenzyl) -2-oxo-1-oxa-3,8-diazaspiro [4.5] Decan-3-yl] methyl} cyclohexanecarboxamide (Compound No. 100) The reaction was conducted in substantially the same manner as in Example 98 except that 4-cyanobenzylbromide was used instead of benzylbromide to give the title compound (11 mg Yield 51%) as a white solid.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.01 (2H, dq, J = 3.6, 12.6 Hz), 1.35 to 2.03 (16H, m), 2.11 (2H, t, J = 10.9 Hz), 2.48-2.63 (4H, m), 2.81 (2H, d, J = 11.9 Hz), 3.09 (2H, d, J = 7.3 Hz) ), 3.25 (2H, s), 3.49 (2H, s), 3.57 (2H, s), 3.70-3.86 (1H, m), 5.27 (1H, d, J = 7.9 Hz), 7.37-7.23 (5H, m), 7.44 (2H, d, J = 8.3 Hz), 7.61 (2H, d, J = 8.3 Hz).

LC / MS [Condition 1]: Retention time 1.07 minutes; m / z 583.9 [M + H] ⁺ (ESI positive ion mode), m / z 628.0 [M + HCOO] ⁻ (ESI negative ion mode)

実施例１０１
（１ｒ，４ｒ）−Ｎ−（１−ベンジルピペリジン−４−イル）−４−（｛８−［（３，５−ジメチルイソキサゾール−４−イル）メチル］−２−オキソ−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）シクロヘキサンカルボキサミド（化合物番号１０１）の製造
ベンジルブロミドの代わりに４−（クロロメチル）−３，５−ジメチルイソキサゾール（アルドリッチ（株）より購入）を用いること以外は実質的に実施例９８と同様に反応を行って、表題化合物（１８ｍｇ、収率８５％）を白色固体として得た。

^１Ｈ−ＮＭＲ（３００ＭＨｚ，ＣＤＣｌ_３）δ：１．０１（２Ｈ，ｑ，Ｊ＝１３．２Ｈｚ），１．８０−１．９１（１６Ｈ，ｍ），２．１１（２Ｈ，ｔ，Ｊ＝１１．２Ｈｚ），２．２４（３Ｈ，ｓ），２．３３（３Ｈ，ｓ），２．４０−２．６０（４Ｈ，ｍ），２．８０（２Ｈ，ｄ，Ｊ＝１０．６Ｈｚ），３．０９（２Ｈ，ｄ，Ｊ＝７．３Ｈｚ），３．２４（４Ｈ，ｓ），３．４９（２Ｈ，ｓ），３．７１−３．８７（１Ｈ，ｍ），５．２９（１Ｈ，ｄ，Ｊ＝８．３Ｈｚ），７．４３−７．２３（５Ｈ，ｍ）．

ＬＣ／ＭＳ［条件１］：保持時間０．６９分；ｍ／ｚ５７８．０［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ６２２．１［Ｍ＋ＨＣＯＯ］^―（ＥＳＩ負イオンモード）

Example 101
(1r, 4r) -N- (1-Benzylpiperidin-4-yl) -4-({8-[(3,5-dimethylisoxazol-4-yl) methyl] -2-oxo-1-oxa Preparation of 3,8-diazaspiro [4.5] decan-3-yl} methyl) cyclohexanecarboxamide (Compound No. 101) 4- (Chloromethyl) -3,5-dimethylisoxazole (Aldrich) instead of benzyl bromide The title compound (18 mg, 85% yield) was obtained as a white solid in substantially the same manner as in Example 98 except that (purchased from KK) was used.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.01 (2H, q, J = 13.2 Hz), 1.80-1.91 (16H, m), 2.11 (2H, t, J = 11.2 Hz), 2.24 (3 H, s), 2.33 (3 H, s), 2.40-2.60 (4 H, m), 2.80 (2 H, d, J = 10.6 Hz) , 3.09 (2H, d, J = 7.3 Hz), 3.24 (4H, s), 3.49 (2H, s), 3.71-3.87 (1H, m), 5.29 (1H, d, J = 8.3 Hz), 7.43-7.23 (5H, m).

LC / MS [Condition 1]: Retention time 0.69 minutes; m / z 578.0 [M + H] ⁺ (ESI positive ion mode), m / z 622.1 [M + HCOO] ⁻ (ESI negative ion mode)

実施例１０２
（１ｒ，４ｒ）−Ｎ−（１−ベンジルピペリジン−４−イル）−４−｛［８−（３−メトキシベンジル）−２−オキソ−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル］メチル｝シクロヘキサンカルボキサミド（化合物番号１０２）の製造
ベンジルブロミドの代わりに３−メトキシベンジルブロミドを用いること以外は実質的に実施例９８と同様に反応を行って、表題化合物（１３ｍｇ、収率６１％）を白色固体として得た。

^１Ｈ−ＮＭＲ（３００ＭＨｚ，ＣＤＣｌ_３）δ：１．０１（２Ｈ，ｄｑ，Ｊ＝３．０，１１．９Ｈｚ），２．０３−１．３３（１６Ｈ，ｍ），２．１１（２Ｈ，ｔ，Ｊ＝１０．９Ｈｚ），２．４７−２．６３（４Ｈ，ｍ），２．８０（２Ｈ，ｄ，Ｊ＝１０．９Ｈｚ），３．０９（２Ｈ，ｄ，Ｊ＝７．３Ｈｚ），３．２４（２Ｈ，ｓ），３．４９（２Ｈ，ｓ），３．５０（２Ｈ，ｓ），３．７１−３．８５（１Ｈ，ｍ），３．８１（３Ｈ，ｓ），５．２８（１Ｈ，ｄ，Ｊ＝７．３Ｈｚ），６．８０（１Ｈ，ｄｄ，Ｊ＝７．６，３．０Ｈｚ），６．８５−６．９４（２Ｈ，ｍ），７．１９−７．３７（６Ｈ，ｍ）．

ＬＣ／ＭＳ［条件１］：保持時間１．２５分；ｍ／ｚ５８９．０［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ６３３．０［Ｍ＋ＨＣＯＯ］^―（ＥＳＩ負イオンモード）

Example 102
(1r, 4r) -N- (1-Benzylpiperidin-4-yl) -4-{[8- (3-methoxybenzyl) -2-oxo-1-oxa-3,8-diazaspiro [4.5] Decan-3-yl] methyl} cyclohexanecarboxamide (Compound No. 102) The reaction was conducted in substantially the same manner as in Example 98 except that 3-methoxybenzyl bromide was used instead of benzyl bromide to give the title compound (13 mg Yield 61%) as a white solid.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.01 (2H, dq, J = 3.0, 11.9 Hz), 2.03-1.33 (16H, m), 2.11 (2H, t, J = 10.9 Hz), 2.47-2.63 (4H, m), 2.80 (2H, d, J = 10.9 Hz), 3.09 (2H, d, J = 7.3 Hz) ), 3.24 (2H, s), 3.49 (2H, s), 3.50 (2H, s), 3.71-3.85 (1H, m), 3.81 (3H, s) 5.28 (1H, d, J = 7.3 Hz), 6.80 (1H, dd, J = 7.6, 3.0 Hz), 6.85-6.94 (2H, m), 7. 19-7.37 (6H, m).

LC / MS [Condition 1]: Retention time 1.25 minutes; m / z 589.0 [M + H] ⁺ (ESI positive ion mode), m / z 633.0 [M + HCOO] ⁻ (ESI negative ion mode)

実施例１０３
４−［（３−｛［（１ｒ，４ｒ）−４−（１−ベンジルピペリジン−４−イルカルバモイル）シクロヘキシル］メチル｝−２−オキソ−１−オキサ−３，８−ジアザスピロ［４．５］デカン−８−イル）メチル］安息香酸メチル（化合物番号１０３）の製造
ベンジルブロミドの代わりに４−（ブロモメチル）安息香酸メチルを用いること以外は実質的に実施例９８と同様に反応を行って、表題化合物（３０ｍｇ、収率６５％）を白色固体として得た。

^１Ｈ−ＮＭＲ（３００ＭＨｚ，ＣＤＣｌ_３）δ：１．０１（２Ｈ，ｑ，Ｊ＝１２．２Ｈｚ），１．３３−２．０３（１６Ｈ，ｍ），２．１１（２Ｈ，ｔ，Ｊ＝１１．１Ｈｚ），２．４８−２．６２（４Ｈ，ｍ），２．８０（２Ｈ，ｄ，Ｊ＝１１．６Ｈｚ），３．０９（２Ｈ，ｄ，Ｊ＝７．３Ｈｚ），３．２５（２Ｈ，ｓ），３．４９（２Ｈ，ｓ），３．５７（２Ｈ，ｓ），３．７０−３．８５（１Ｈ，ｍ），３．９１（３Ｈ，ｓ），５．２９（１Ｈ，ｄ，Ｊ＝７．６Ｈｚ），７．３５−７．２２（５Ｈ，ｍ），７．３９（２Ｈ，ｄ，Ｊ＝８．３Ｈｚ），７．９９（２Ｈ，ｄ，Ｊ＝８．３Ｈｚ）．

ＬＣ／ＭＳ［条件１］：保持時間１．０９分；ｍ／ｚ６１７．０［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ６６１．０［Ｍ＋ＨＣＯＯ］^―（ＥＳＩ負イオンモード）

Example 103
4-[(3-{[(1r, 4r) -4- (1-benzylpiperidin-4-ylcarbamoyl) cyclohexyl] methyl} -2-oxo-1-oxa-3,8-diazaspiro [4.5] Decan-8-yl) methyl] Preparation of methyl benzoate (Compound No. 103) The reaction was carried out in substantially the same manner as in Example 98 except that methyl 4- (bromomethyl) benzoate was used instead of benzyl bromide. The title compound (30 mg, 65% yield) was obtained as a white solid.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.01 (2H, q, J = 12.2 Hz), 1.33-2.03 (16H, m), 2.11 (2H, t, J = 11.1 Hz), 2.48-2.62 (4 H, m), 2.80 (2 H, d, J = 11.6 Hz), 3.09 (2 H, d, J = 7.3 Hz), 3. 25 (2H, s), 3.49 (2H, s), 3.57 (2H, s), 3.70-3.85 (1H, m), 3.91 (3H, s), 5.29 (1H, d, J = 7.6 Hz), 7.35-7.22 (5H, m), 7.39 (2H, d, J = 8.3 Hz), 7.99 (2H, d, J = 8.3 Hz).

LC / MS [Condition 1]: Retention time 1.09 minutes; m / z 617.0 [M + H] ⁺ (ESI positive ion mode), m / z 661.0 [M + HCOO] ⁻ (ESI negative ion mode)

実施例１０４
４−［（３−｛［（１ｒ，４ｒ）−４−（１−ベンジルピペリジン−４−イルカルバモイル）シクロヘキシル］メチル｝−２−オキソ−１−オキサ−３，８−ジアザスピロ［４．５］デカン−８−イル）メチル］安息香酸（化合物番号１０４）の製造
２−（テトラヒドロフラン−２−イル）酢酸エチルの代わりに実施例１０３で得た４−［（３−｛［（１ｒ，４ｒ）−４−（１−ベンジルピペリジン−４−イルカルバモイル）シクロヘキシル］メチル｝−２−オキソ−１−オキサ−３，８−ジアザスピロ［４．５］デカン−８−イル）メチル］安息香酸メチルを用いること以外は、実質的に参考例１４と同様に反応を行って、表題化合物（１．２ｍｇ、収率５％）を白色固体として得た。

^１Ｈ−ＮＭＲ（３００ＭＨｚ，ＣＤＣｌ_３）δ：０．９８（２Ｈ，ｑ，Ｊ＝１３．１Ｈｚ），１．４３（２Ｈ，ｑ，Ｊ＝１３．５Ｈｚ），１．４６−１．６５（１Ｈ，ｍ），１．７７−１．９３（１３Ｈ，ｍ），２．３３（２Ｈ，ｔ，Ｊ＝１１．１Ｈｚ），２．５５−２．８１（４Ｈ，ｍ），３．０７（２Ｈ，ｄ，Ｊ＝７．０Ｈｚ），３．１３（２Ｈ，ｄ，Ｊ＝１１．５Ｈｚ），３．２５（２Ｈ，ｓ），３．７０（２Ｈ，ｓ），３．７６−３．９３（１Ｈ，ｍ），３．７８（２Ｈ，ｓ），５．７０（１Ｈ，ｄ，Ｊ＝７．８Ｈｚ），７．３０−７．４３（７Ｈ，ｍ），８．０２（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ）．

ＬＣ／ＭＳ［条件１］：保持時間０．９３分；ｍ／ｚ６０２，６［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ６０１．１［Ｍ−Ｈ］^―（ＥＳＩ負イオンモード）

Example 104
4-[(3-{[(1r, 4r) -4- (1-benzylpiperidin-4-ylcarbamoyl) cyclohexyl] methyl} -2-oxo-1-oxa-3,8-diazaspiro [4.5] Decan-8-yl) methyl] benzoic acid (Compound No. 104) Preparation of 4-[(3-{[(1r, 4r)] -4- (1-Benzylpiperidin-4-ylcarbamoyl) cyclohexyl] methyl} -2-oxo-1-oxa-3,8-diazaspiro [4.5] decan-8-yl) methyl] methyl benzoate is used Except for the above, the reaction was carried out in substantially the same manner as in Reference Example 14 to obtain the title compound (1.2 mg, yield 5%) as a white solid.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 0.98 (2H, q, J = 13.1 Hz), 1.43 (2H, q, J = 13.5 Hz), 1.46 to 1.65 ( 1H, m), 1.77-1.93 (13H, m), 2.33 (2H, t, J = 11.1 Hz), 2.55-2.81 (4H, m), 3.07 ( 2H, d, J = 7.0 Hz), 3.13 (2H, d, J = 11.5 Hz), 3.25 (2H, s), 3.70 (2H, s), 3.76-3. 93 (1H, m), 3.78 (2H, s), 5.70 (1H, d, J = 7.8 Hz), 7.30-7.43 (7H, m), 8.02 (2H, d, J = 8.2 Hz).

LC / MS [Condition 1]: Retention time 0.93 min; m / z 602, 6 [M + H] ⁺ (ESI positive ion mode), m / z 601.1 [MH] ⁻ (ESI negative ion mode)

実施例１０５
（１ｒ，４ｒ）−４−（｛２−オキソ−８−［４−（トリフルオロメチル）フェニル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）シクロヘキサンカルボン酸メチル（化合物番号１０５）の製造
参考例６−１で得られた（１ｒ，４ｒ）−４−［（２−オキソ−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル）メチル］シクロヘキサンカルボン酸メチル塩酸塩を脱塩し、（１ｒ，４ｒ）−４−［（２−オキソ−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル）メチル］シクロヘキサンカルボン酸メチルを得た。窒素雰囲気下、得られた（１ｒ，４ｒ）−４−［（２−オキソ−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル）メチル］シクロヘキサンカルボン酸メチル（１００ｍｇ、０．３２ｍｍｏｌ）、酢酸パラジウム（７．２ｍｇ、０．０３２ｍｍｏｌ）、２，２’−ビス（ジフェニルホスフィノ）−１，１’−ビナフタレン（２０ｍｇ、０．０３２ｍｍｏｌ）、炭酸セシウム（２１０ｍｇ、０．６４ｍｍｏｌ）と４−ブロモベンゾトリフルオリド（７２ｍｇ、０．３２ｍｍｏｌ）を１，４−ジオキサン（３．０ｍＬ）に溶解し、窒素雰囲気下、１００℃にて１９時間かき混ぜた。室温まで冷却した後、酢酸エチルと水を加え、２０分間かき混ぜた。不溶物をセライトろ過にて除去し、有機層を飽和食塩水で洗浄した後、無水硫酸ナトリウムで乾燥した。減圧下濃縮乾固した後、得られた残留物をシリカゲルカラムクロマトグラフィー［モリテックス社製プリフパックＮＨ６０μｍ、展開溶媒：ヘキサン／酢酸エチル］にて精製し、表題化合物（１１０ｍｇ、収率７７％）を白色固体として得た。

^１Ｈ−ＮＭＲ（３００ＭＨｚ，ＣＤＣｌ_３）δ：０．９４−１．１３（２Ｈ，ｍ），１．３２−１．５１（２Ｈ，ｍ），１．５２−１．６６（１Ｈ，ｍ），１．７３−１．９１（４Ｈ，ｍ），１．９５−２．１１（４Ｈ，ｍ），２．１８−２．３４（１Ｈ，ｍ），３．１２（２Ｈ，ｄ，Ｊ＝７．４Ｈｚ），３．２９（２Ｈ，ｓ），３．３１−３．４４（２Ｈ，ｍ），３．５２−３．７２（２Ｈ，ｍ），３．６７（３Ｈ，ｓ），６．９４（２Ｈ，ｄ，Ｊ＝８．８Ｈｚ），７．４８（２Ｈ，ｄ，Ｊ＝８．８Ｈｚ）．

ＬＣ／ＭＳ［条件２］：保持時間４．５１分；ｍ／ｚ４５５．０［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）

Example 105
(1r, 4r) -4-({2-oxo-8- [4- (trifluoromethyl) phenyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl) cyclohexane Production of methyl carboxylate (Compound No. 105) (1r, 4r) -4-[(2-oxo-1-oxa-3,8-diazaspiro [4.5] decane-3 obtained in Reference Example 6-1 -Yl) methyl] cyclohexanecarboxylic acid methyl hydrochloride is desalted to give (1r, 4r) -4-[(2-oxo-1-oxa-3,8-diazaspiro [4.5] decan-3-yl) Methyl] methyl cyclohexanecarboxylate was obtained. Under a nitrogen atmosphere, the obtained methyl (1r, 4r) -4-[(2-oxo-1-oxa-3,8-diazaspiro [4.5] decan-3-yl) methyl] cyclohexanecarboxylate (100 mg, 0.32 mmol), palladium acetate (7.2 mg, 0.032 mmol), 2,2′-bis (diphenylphosphino) -1,1′-binaphthalene (20 mg, 0.032 mmol), cesium carbonate (210 mg, 0.32 mmol). 64 mmol) and 4-bromobenzotrifluoride (72 mg, 0.32 mmol) were dissolved in 1,4-dioxane (3.0 mL), and the mixture was stirred at 100 ° C. for 19 hours under a nitrogen atmosphere. After cooling to room temperature, ethyl acetate and water were added and stirred for 20 minutes. Insolubles were removed by Celite filtration, and the organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After concentrating to dryness under reduced pressure, the resulting residue was purified by silica gel column chromatography [Polipack NH 60 μm, developed by Moritex, developing solvent: hexane / ethyl acetate], and the title compound (110 mg, 77% yield) was white. Obtained as a solid.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 0.94-1.13 (2H, m), 1.32-1.51 (2H, m), 1.52-1.66 (1H, m) , 1.73-1.91 (4H, m), 1.95-2.11 (4H, m), 2.18-2.34 (1H, m), 3.12 (2H, d, J = 7.4 Hz), 3.29 (2H, s), 3.31-3.44 (2H, m), 3.52-3.72 (2H, m), 3.67 (3H, s), 6 .94 (2H, d, J = 8.8 Hz), 7.48 (2H, d, J = 8.8 Hz).

LC / MS [Condition 2]: Retention time 4.51 minutes; m / z 455.0 [M + H] ⁺ (ESI positive ion mode)

参考例１０６
（１ｒ，４ｒ）−４−（｛２−オキソ−８−［４−（トリフルオロメチル）フェニル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）シクロヘキサンカルボン酸の製造
実施例１０５で得られた（１ｒ，４ｒ）−４−（｛２−オキソ−８−［４−（トリフルオロメチル）フェニル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）シクロヘキサンカルボン酸メチル（１１０ｍｇ、０．２５ｍｍｏｌ）をメタノール（１．５ｍＬ）とテトラヒドロフラン（１．５ｍＬ）の混合溶媒に溶解し、５Ｍ水酸化ナトリウム水溶液（０．６０ｍＬ）を加えて、室温にて９時間かき混ぜた。０℃に冷却した後、５Ｍ塩酸を加えてｐＨを４に調整した。析出した白色固体をろ取し、５０℃で１時間減圧乾燥して表題化合物のテトラヒドロフラン−メタノール和物（１１０ｍｇ）を得た。

Reference Example 106
(1r, 4r) -4-({2-oxo-8- [4- (trifluoromethyl) phenyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl) cyclohexane Preparation of carboxylic acid (1r, 4r) -4-({2-oxo-8- [4- (trifluoromethyl) phenyl] -1-oxa-3,8-diazaspiro [4. 5] Decan-3-yl} methyl) methyl cyclohexanecarboxylate (110 mg, 0.25 mmol) was dissolved in a mixed solvent of methanol (1.5 mL) and tetrahydrofuran (1.5 mL), and 5 M aqueous sodium hydroxide solution (0. 60 mL) was added and stirred at room temperature for 9 hours. After cooling to 0 ° C., the pH was adjusted to 4 by adding 5M hydrochloric acid. The precipitated white solid was collected by filtration and dried under reduced pressure at 50 ° C. for 1 hour to obtain the tetrahydrofuran-methanol hydrate (110 mg) of the title compound.

実施例１０６
（１ｒ，４ｒ）−４−（｛２−オキソ−８−［４−（トリフルオロメチル）フェニル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）−Ｎ−［（テトラヒドロフラン−２−イル）メチル］シクロヘキサンカルボキサミド（化合物番号１０６）の製造
参考例１０６で得られた（１ｒ，４ｒ）−４−（｛２−オキソ−８−［４−（トリフルオロメチル）フェニル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）シクロヘキサンカルボン酸（５０ｍｇ、０．１１ｍｍｏｌ）、テトラヒドロフルフリルアミン（２３ｍｇ、０．２３ｍｍｏｌ）、１−ヒドロキシベンゾトリアゾール（２３ｍｇ、０．１７ｍｍｏｌ）をクロロホルムに溶解した後、トリエチルアミン（１２ｍｇ、０．１１ｍｍｏｌ）と１−エチル−３−（３−ジメチルアミノプロピル）カルボジイミド塩酸塩（３３ｍｇ、０．１７ｍｍｏｌ）を加えて、室温で１１時間かき混ぜた。水を加えて有機層を分離し、これを飽和炭酸水素ナトリウム溶液と飽和食塩水で洗浄した。有機層を無水硫酸ナトリウムで乾燥した後、減圧下濃縮乾固した。得られた残留物をシリカゲルカラムクロマトグラフィー［モリテックス社製プリフパックＮＨ６０μｍ、展開溶媒：クロロホルム／酢酸エチル＝３／１〜クロロホルム／メタノール＝１０／１］にて精製し、表題化合物（３９ｍｇ、収率６５％）を白色固体として得た。

^１Ｈ−ＮＭＲ（３００ＭＨｚ，ＣＤＣｌ_３）δ：１．０４（２Ｈ，ｑ，Ｊ＝１１．７Ｈｚ），１．４０−１．６７（３Ｈ，ｍ），１．７２−２．１２（１３Ｈ，ｍ），３．０３−３．１８（１Ｈ，ｍ），３．１２（２Ｈ，ｄ，Ｊ＝７．４Ｈｚ），３．２９（２Ｈ，ｓ），３．３２−３．４４（２Ｈ，ｍ），３．５３−３．６５（３Ｈ，ｍ），３．７０−４．０１（３Ｈ，ｍ），５．７５−５．８９（１Ｈ，ｂｒｍ），６．９４（２Ｈ，ｄ，Ｊ＝８．８Ｈｚ），７．４８（２Ｈ，ｄ，Ｊ＝８．８Ｈｚ）．

Example 106
(1r, 4r) -4-({2-oxo-8- [4- (trifluoromethyl) phenyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl)- Production of N-[(tetrahydrofuran-2-yl) methyl] cyclohexanecarboxamide (Compound No. 106) (1r, 4r) -4-({2-oxo-8- [4- (trifluoro) obtained in Reference Example 106 Methyl) phenyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl) cyclohexanecarboxylic acid (50 mg, 0.11 mmol), tetrahydrofurfurylamine (23 mg, 0.23 mmol), 1 -Hydroxybenzotriazole (23 mg, 0.17 mmol) was dissolved in chloroform and then triethylamine (12 mg, 0.11 mm). l) and 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (33 mg, 0.17 mmol) was added and stirred at room temperature for 11 hours. Water was added to separate the organic layer, which was washed with saturated sodium bicarbonate solution and saturated brine. The organic layer was dried over anhydrous sodium sulfate and then concentrated to dryness under reduced pressure. The obtained residue was purified by silica gel column chromatography [Polipack NH 60 μm, manufactured by Moritex Corp., developing solvent: chloroform / ethyl acetate = 3/1 to chloroform / methanol = 10/1] to give the title compound (39 mg, yield 65 %) As a white solid.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.04 (2H, q, J = 11.7 Hz), 1.40-1.67 (3H, m), 1.7-2.12 (13H, m), 3.03-3.18 (1H, m), 3.12 (2H, d, J = 7.4 Hz), 3.29 (2H, s), 3.32-3.44 (2H, m), 3.53-3.65 (3H, m), 3.70-4.01 (3H, m), 5.75-5.89 (1H, brm), 6.94 (2H, d, J = 8.8 Hz), 7.48 (2H, d, J = 8.8 Hz).

実施例１０７
（１ｒ，４ｒ）−Ｎ−シクロヘキシル−４−（｛２−オキソ−８−［４−（トリフルオロメチル）フェニル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）シクロヘキサンカルボキサミド（化合物番号１０７）の製造
参考例１０６で得られた（１ｒ，４ｒ）−４−（｛２−オキソ−８−［４−（トリフルオロメチル）フェニル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）シクロヘキサンカルボン酸（１０ｍｇ、０．０２３ｍｍｏｌ）、シクロヘキシルアミン（２．３ｍｇ、０．０２３ｍｍｏｌ）、１−ヒドロキシベンゾトリアゾール（５．７ｍｇ、０．０３０ｍｍｏｌ）をクロロホルムに溶解した後、１−エチル−３−（３−ジメチルアミノプロピル）カルボジイミド塩酸塩（５．７ｍｇ、０．０３０ｍｍｏｌ）を加えて、室温で３日間かき混ぜた。水を加えて有機層を分離し、これを飽和炭酸水素ナトリウム溶液と飽和食塩水で洗浄した。有機層を無水硫酸ナトリウムで乾燥した後、減圧下濃縮乾固した。得られた残留物を分取用薄層クロマトグラフィー［メルク社製ＰＬＣガラスプレート シリカゲル６０Ｆ_２５４、展開溶媒：酢酸エチル１００％］にて精製し、表題化合物（７．６ｍｇ、収率６３％）を白色固体として得た。

^１Ｈ−ＮＭＲ（３００ＭＨｚ，ＣＤＣｌ_３）δ：０．９１−２．１１（２４Ｈ，ｍ），３．１２（２Ｈ，ｄ，Ｊ＝７．２Ｈｚ），３．２９（２Ｈ，ｓ），３．３８（２Ｈ，ｔ，Ｊ＝１１．６Ｈｚ），３．５９（２Ｈ，ｄ，Ｊ＝１３．５Ｈｚ），３．６８−３．８３（１Ｈ，ｍ），５．２８（１Ｈ，ｄ，Ｊ＝７．４Ｈｚ），６．９４（２Ｈ，ｄ，Ｊ＝８．８Ｈｚ），７．４８（２Ｈ，ｄ，Ｊ＝８．８Ｈｚ）．

Example 107
(1r, 4r) -N-cyclohexyl-4-({2-oxo-8- [4- (trifluoromethyl) phenyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl } Methyl) cyclohexanecarboxamide (Compound No. 107) (1r, 4r) -4-({2-oxo-8- [4- (trifluoromethyl) phenyl] -1-oxa-) obtained in Reference Example 106 3,8-diazaspiro [4.5] decan-3-yl} methyl) cyclohexanecarboxylic acid (10 mg, 0.023 mmol), cyclohexylamine (2.3 mg, 0.023 mmol), 1-hydroxybenzotriazole (5.7 mg) , 0.030 mmol) in chloroform, 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride 5.7 mg, 0.030 mmol) was added and stirred at room temperature for 3 days. Water was added to separate the organic layer, which was washed with saturated sodium bicarbonate solution and saturated brine. The organic layer was dried over anhydrous sodium sulfate and then concentrated to dryness under reduced pressure. The resulting residue was purified by preparative thin layer chromatography [Merck PLC glass plate silica gel _{60F 254,} developing solvent: ethyl acetate 100%] to give the title compound (7.6 mg, 63% yield) Obtained as a white solid.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 0.91-2.11 (24H, m), 3.12 (2H, d, J = 7.2 Hz), 3.29 (2H, s), 3 .38 (2H, t, J = 11.6 Hz), 3.59 (2H, d, J = 13.5 Hz), 3.68-3.83 (1H, m), 5.28 (1H, d, J = 7.4 Hz), 6.94 (2H, d, J = 8.8 Hz), 7.48 (2H, d, J = 8.8 Hz).

参考例１０８−１
３−［３−（メトキシカルボニル）ベンジル］−２−オキソ−１−オキサ−３，８−ジアザスピロ［４．５］デカン−８−カルボン酸ｔ−ブチルの製造
３−（アミノメチル）安息香酸メチル塩酸塩（９５０ｍｇ、０．４７ｍｍｏｌ）を水（１．０ｍＬ）に溶解した後、５Ｍ水酸化ナトリウム水溶液（０．０９４ｍＬ、０．４７ｍｍｏｌ）と参考例１−１で得られた１−オキサ−６−アザスピロ［２．５］オクタン−６−カルボン酸ｔ−ブチル（１００ｍｇ、０．４７ｍｍｏｌ）のメタノール（１．０ｍＬ）溶液を加え、室温で１０日間かき混ぜた。減圧下濃縮して、メタノールを留去した。残留反応混合物にクロロホルムを加えて有機層を分離し、これを飽和食塩水で洗浄した。有機層を無水硫酸ナトリウムで乾燥した後、減圧下濃縮乾固した。得られた残留物をシリカゲルカラムクロマトグラフィー［モリテックス社製プリフパックＳＩ６０μｍ、展開溶媒：ヘキサン／酢酸エチル］にて精製し、３−｛［（４−ヒドロキシピペリジン−４−イル）メチルアミノ］メチル｝安息香酸メチル（９６ｍｇ、収率５４％）を無色油状物として得た。これをクロロホルム（２．０ｍＬ）に溶解し、１，１’−カルボニルジイミダゾール（８２ｍｇ、０．５１ｍｍｏｌ）を加えた後、５０℃で３時間かき混ぜた。さらに１，１’−カルボニルジイミダゾール（８２ｍｇ、０．５１ｍｍｏｌ）を加えた後、５０℃で３時間かき混ぜた。水を加えて室温で１０分間かき混ぜ、発泡が収まった後、有機層を分離し、これを飽和食塩水で洗浄した。有機層を無水硫酸ナトリウムで乾燥した後、減圧下濃縮乾固した。得られた残留物をシリカゲルカラムクロマトグラフィー［モリテックス社製プリフパックＳＩ６０μｍ、展開溶媒：ヘキサン／酢酸エチル］にて精製し、表題化合物（５５ｍｇ、収率２９％）を得た。

Reference Example 108-1
Preparation of t-butyl 3- [3- (methoxycarbonyl) benzyl] -2-oxo-1-oxa-3,8-diazaspiro [4.5] decane-8-carboxylate methyl 3- (aminomethyl) benzoate Hydrochloric acid salt (950 mg, 0.47 mmol) was dissolved in water (1.0 mL), and then 5M aqueous sodium hydroxide solution (0.094 mL, 0.47 mmol) and 1-oxa-6 obtained in Reference Example 1-1 were used. -Azaspiro [2.5] octane-6-carboxylate t-butyl (100 mg, 0.47 mmol) in methanol (1.0 mL) was added and stirred at room temperature for 10 days. The mixture was concentrated under reduced pressure to distill off methanol. Chloroform was added to the residual reaction mixture to separate the organic layer, which was washed with saturated brine. The organic layer was dried over anhydrous sodium sulfate and then concentrated to dryness under reduced pressure. The obtained residue was purified by silica gel column chromatography [Polipack SI 60 μm manufactured by Moritex, developing solvent: hexane / ethyl acetate], and 3-{[(4-hydroxypiperidin-4-yl) methylamino] methyl} benzoic acid Methyl acid (96 mg, 54% yield) was obtained as a colorless oil. This was dissolved in chloroform (2.0 mL), 1,1′-carbonyldiimidazole (82 mg, 0.51 mmol) was added, and the mixture was stirred at 50 ° C. for 3 hr. Further, 1,1′-carbonyldiimidazole (82 mg, 0.51 mmol) was added, followed by stirring at 50 ° C. for 3 hours. Water was added and the mixture was stirred at room temperature for 10 minutes. After the foaming had subsided, the organic layer was separated and washed with saturated brine. The organic layer was dried over anhydrous sodium sulfate and then concentrated to dryness under reduced pressure. The obtained residue was purified by silica gel column chromatography [Polipack SI 60 μm, developed by Mortex, developing solvent: hexane / ethyl acetate] to obtain the title compound (55 mg, yield 29%).

参考例１０８−２
３−（｛２−オキソ−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）安息香酸メチルの製造
参考例１０８−１で得られた３−［３−（メトキシカルボニル）ベンジル］−２−オキソ−１−オキサ−３，８−ジアザスピロ［４．５］デカン−８−カルボン酸ｔ−ブチル（５０ｍｇ、０．１２ｍｍｏｌ）をメタノール（０．１０ｍＬ）に溶解した後、４Ｍ塩化水素−ジオキサン溶液（１．５ｍＬ）を加えて室温で４０分間かき混ぜた。反応混合物を減圧下濃縮乾固し、さらにメタノールで３回共沸し、３−［（２−オキソ−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル）メチル］安息香酸メチルの塩酸塩を白色固体として得た。この塩酸塩をＮ，Ｎ−ジメチルホルムアミド（１．０ｍＬ）に懸濁し、１−（ブロモメチル）−４−（トリフルオロメチル）ベンゼン（３６ｍｇ、０．１５ｍｍｏｌ）とトリエチルアミン（３０ｍｇ、０．３０ｍｍｏｌ）を加えた後、室温で４日間かき混ぜた。水と酢酸エチルを加えて有機層を分離し、これを水と飽和食塩水で洗浄した。有機層を無水硫酸ナトリウムで乾燥した後、減圧下濃縮乾固した。得られた残留物をシリカゲルカラムクロマトグラフィー［モリテックス社製プリフパックＮＨ６０μｍ、展開溶媒：ヘキサン／酢酸エチル］にて精製し、表題化合物（３４ｍｇ、収率５０％）を無色油状物として得た。

Reference Example 108-2
Reference example for production of methyl 3-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl) benzoate 3- [3- (methoxycarbonyl) benzyl] -2-oxo-1-oxa-3,8-diazaspiro [4.5] decane-8-carboxylate t-butyl (50 mg, 0 .12 mmol) was dissolved in methanol (0.10 mL), 4M hydrogen chloride-dioxane solution (1.5 mL) was added, and the mixture was stirred at room temperature for 40 min. The reaction mixture was concentrated to dryness under reduced pressure and further azeotroped with methanol three times to give 3-[(2-oxo-1-oxa-3,8-diazaspiro [4.5] decan-3-yl) methyl] benzoic acid. Methyl acid hydrochloride was obtained as a white solid. This hydrochloride was suspended in N, N-dimethylformamide (1.0 mL), and 1- (bromomethyl) -4- (trifluoromethyl) benzene (36 mg, 0.15 mmol) and triethylamine (30 mg, 0.30 mmol) were added. After the addition, the mixture was stirred at room temperature for 4 days. Water and ethyl acetate were added to separate the organic layer, which was washed with water and saturated brine. The organic layer was dried over anhydrous sodium sulfate and then concentrated to dryness under reduced pressure. The obtained residue was purified by silica gel column chromatography [Polipack NH 60 μm, developed by Moritex, developing solvent: hexane / ethyl acetate] to obtain the title compound (34 mg, yield 50%) as a colorless oil.

参考例１０８−３
３−（｛２−オキソ−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）安息香酸の製造
参考例１０８−２で得られた３−（｛２−オキソ−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）安息香酸メチル（３４ｍｇ、０．０７８ｍｍｏｌ）をメタノール（１．０ｍＬ）に溶解した後、５Ｍ水酸化ナトリウム水溶液（０．２５ｍＬ）を加えて、室温にて１５時間かき混ぜた。０℃に冷却した後、５Ｍ塩酸を加えてｐＨを４に調整した。クロロホルムと２−プロパノールの混合溶媒（１０：１）を加えて有機層を分離し、水層に再度クロロホルムと２−プロパノールの混合溶媒（１０：１）を加えて有機層を分離した。得られた有機層を合わせて、無水硫酸ナトリウムで乾燥した後、減圧下濃縮乾固し、表題化合物の２−プロパノール和物（４４ｍｇ）を得た。

Reference Example 108-3
Reference Example 108 for Production of 3-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl) benzoic acid 3-({2-Oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl) benzoic acid obtained in step-2 Methyl acid (34 mg, 0.078 mmol) was dissolved in methanol (1.0 mL), 5M aqueous sodium hydroxide solution (0.25 mL) was added, and the mixture was stirred at room temperature for 15 hr. After cooling to 0 ° C., the pH was adjusted to 4 by adding 5M hydrochloric acid. A mixed solvent of chloroform and 2-propanol (10: 1) was added to separate the organic layer, and a mixed solvent of chloroform and 2-propanol (10: 1) was again added to the aqueous layer to separate the organic layer. The obtained organic layers were combined, dried over anhydrous sodium sulfate, and then concentrated to dryness under reduced pressure to give the title compound 2-propanol hydrate (44 mg).

実施例１０８
ｔ−ブチル ３−［３−（｛２−オキソ−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）ベンズアミド］プロピルカルバメート（化合物番号１０８）の製造
参考例１０８−３で得られた３−（｛２−オキソ−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）安息香酸（１０ｍｇ、０．０２２ｍｍｏｌ）、Ｎ−（ｔ−ブトキシカルボニル）−１，３−ジアミノプロパン（４．７ｍｇ、０．０２７ｍｍｏｌ）、１−ヒドロキシベンゾトリアゾール（３．６ｍｇ、０．０２７ｍｍｏｌ）をクロロホルム（１．０ｍＬ）に溶解した後、１−エチル−３−（３−ジメチルアミノプロピル）カルボジイミド塩酸塩（５．１ｍｇ、０．０２７ｍｍｏｌ）を加えて、室温で３日間かき混ぜた。反応混合物にトリエチルアミン（２．７ｍｇ、０．０２７ｍｍｏｌ）を加えた後、さらに室温で２日間かき混ぜた。水を加えて有機層を分離し、無水硫酸ナトリウムで乾燥した後、減圧下濃縮乾固した。得られた残留物を分取用薄層クロマトグラフィー［富士シリシア社製クロマトレックスＮＨ−ＰＬＣ０５プレート、展開溶媒：酢酸エチル１００％］にて精製し、表題化合物（８．４ｍｇ、収率６３％）を無色油状物として得た。

^１Ｈ−ＮＭＲ（３００ＭＨｚ，ＣＤＣｌ_３）δ：１．４５（９Ｈ，ｓ），１．６６−１．７８（４Ｈ，ｍ），１．８６−１．９６（２Ｈ，ｍ），２．４５−２．５９（４Ｈ，ｍ），３．１４（２Ｈ，Ｓ），３．２５（２Ｈ，ｑ，Ｊ＝６．４Ｈｚ），３．５１（２Ｈ，ｑ，Ｊ＝６．４Ｈｚ），３．５５（２Ｈ，ｓ），４．４７（２Ｈ，ｓ），４．８５−４．８９（１Ｈ，ｂｒｍ），７．３３（１Ｈ，ｂｒｓ），７．３８−７．４９（４Ｈ，ｍ），７．５６（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ），７．７７（２Ｈ，ｓ）．

ＬＣ／ＭＳ［条件２］：保持時間３．３０分；ｍ／ｚ６０４．８［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）

Example 108
t-butyl 3- [3-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl) benzamide Preparation of propyl carbamate (Compound No. 108) 3-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [ 4.5] decan-3-yl} methyl) benzoic acid (10 mg, 0.022 mmol), N- (t-butoxycarbonyl) -1,3-diaminopropane (4.7 mg, 0.027 mmol), 1-hydroxy After benzotriazole (3.6 mg, 0.027 mmol) was dissolved in chloroform (1.0 mL), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimi Hydrochloride (5.1 mg, 0.027 mmol) was added and stirred at room temperature for 3 days. Triethylamine (2.7 mg, 0.027 mmol) was added to the reaction mixture, and the mixture was further stirred at room temperature for 2 days. Water was added to separate the organic layer, dried over anhydrous sodium sulfate, and concentrated to dryness under reduced pressure. The obtained residue was purified by preparative thin layer chromatography [Chromatolex NH-PLC05 plate, developed by Fuji Silysia, developing solvent: ethyl acetate 100%] to give the title compound (8.4 mg, yield 63%). Was obtained as a colorless oil.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.45 (9H, s), 1.66-1.78 (4H, m), 1.86-1.96 (2H, m), 2.45 -2.59 (4H, m), 3.14 (2H, S), 3.25 (2H, q, J = 6.4 Hz), 3.51 (2H, q, J = 6.4 Hz), 3 .55 (2H, s), 4.47 (2H, s), 4.85-4.89 (1H, brm), 7.33 (1H, brs), 7.38-7.49 (4H, m ), 7.56 (2H, d, J = 8.2 Hz), 7.77 (2H, s).

LC / MS [Condition 2]: Retention time 3.30 minutes; m / z 604.8 [M + H] ⁺ (ESI positive ion mode)

実施例１０９
Ｎ−（１−ベンジルピペリジン−４−イル）−３−（｛２−オキソ−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）ベンズアミド（化合物番号１０９）の製造
参考例１０８−３で得られた３−（｛２−オキソ−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）安息香酸（１０ｍｇ、０．０２２ｍｍｏｌ）、４−アミノ−１−ベンジルピペリジン（４．７ｍｇ、０．０２５ｍｍｏｌ）、１−ヒドロキシベンゾトリアゾール（３．６ｍｇ、０．０２７ｍｍｏｌ）をクロロホルム（１．０ｍＬ）に溶解した後、１−エチル−３−（３−ジメチルアミノプロピル）カルボジイミド塩酸塩（５．１ｍｇ、０．０２７ｍｍｏｌ）を加えて、室温で３日間かき混ぜた。反応混合物にトリエチルアミン（２．７ｍｇ、０．０２７ｍｍｏｌ）を加えた後、さらに室温で２日間かき混ぜた。水を加えて有機層を分離し、無水硫酸ナトリウムで乾燥した後、減圧下濃縮乾固した。得られた残留物を分取用薄層クロマトグラフィー［富士シリシア社製クロマトレックスＮＨ−ＰＬＣ０５プレート、展開溶媒：酢酸エチル１００％］にて精製し、表題化合物（１４ｍｇ、収率８２％）を無色油状物として得た。

^１Ｈ−ＮＭＲ（３００ＭＨｚ，ＣＤＣｌ_３）δ：１．４９−１．７９（４Ｈ，ｍ），１．８５−１．９７（２Ｈ，ｍ），１．９７−２．０７（２Ｈ，ｍ），２．１２−２．２６（２Ｈ，ｍ），２．４４−２．５９（４Ｈ，ｍ），２．８２−２．９０（２Ｈ，ｍ），３．１４（２Ｈ，ｓ），３．５２（２Ｈ，ｓ），３．５５（２Ｈ，ｓ），３．９１−４．０８（１Ｈ，ｍ），４．４７（２Ｈ，ｓ），５．９７（１Ｈ，ｄ，Ｊ＝７．５Ｈｚ），７．２３−７．３７（５Ｈ，ｍ），７．３８−７．４７（４Ｈ，ｍ），７．５３−７．５９（２Ｈ，ｍ），７．６２−７．６９（２Ｈ，ｍ）．

ＬＣ／ＭＳ［条件２］：保持時間２．８４分；ｍ／ｚ６２０．９［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）

Example 109
N- (1-benzylpiperidin-4-yl) -3-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decane- Preparation of 3-yl} methyl) benzamide (Compound No. 109) 3-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3, obtained in Reference Example 108-3 8-diazaspiro [4.5] decan-3-yl} methyl) benzoic acid (10 mg, 0.022 mmol), 4-amino-1-benzylpiperidine (4.7 mg, 0.025 mmol), 1-hydroxybenzotriazole ( After dissolving 3.6 mg, 0.027 mmol) in chloroform (1.0 mL), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (5.1 m , Adding 0.027 mmol), it was stirred at room temperature for 3 days. Triethylamine (2.7 mg, 0.027 mmol) was added to the reaction mixture, and the mixture was further stirred at room temperature for 2 days. Water was added to separate the organic layer, dried over anhydrous sodium sulfate, and concentrated to dryness under reduced pressure. The obtained residue was purified by preparative thin-layer chromatography [Chromatolex NH-PLC05 plate, developed by Fuji Silysia, developing solvent: ethyl acetate 100%], and the title compound (14 mg, yield 82%) was colorless. Obtained as an oil.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.49-1.79 (4H, m), 1.85-1.97 (2H, m), 1.97-2.07 (2H, m) 2.12-2.26 (2H, m), 2.44-2.59 (4H, m), 2.82-2.90 (2H, m), 3.14 (2H, s), 3 .52 (2H, s), 3.55 (2H, s), 3.91-4.08 (1H, m), 4.47 (2H, s), 5.97 (1H, d, J = 7) .5 Hz), 7.23-7.37 (5H, m), 7.38-7.47 (4H, m), 7.53-7.59 (2H, m), 7.62-7.69. (2H, m).

LC / MS [Condition 2]: Retention time 2.84 minutes; m / z 620.9 [M + H] ⁺ (ESI positive ion mode)

実施例１１０
３−（｛２−オキソ−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）−Ｎ−［（テトラヒドロフラン−２−イル）メチル］ベンズアミド（化合物番号１１０）の製造
参考例１０８−３で得られた３−（｛２−オキソ−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）安息香酸（１０ｍｇ、０．０２２ｍｍｏｌ）、テトラヒドロフルフリルアミン（２．７ｍｇ、０．０２７ｍｍｏｌ）、１−ヒドロキシベンゾトリアゾール（３．６ｍｇ、０．０２７ｍｍｏｌ）をクロロホルム（１．０ｍＬ）に溶解した後、１−エチル−３−（３−ジメチルアミノプロピル）カルボジイミド塩酸塩（５．１ｍｇ、０．０２７ｍｍｏｌ）を加えて、室温で１２時間かき混ぜた。水を加えて有機層を分離し、無水硫酸ナトリウムで乾燥した後、減圧下濃縮乾固した。得られた残留物を分取用薄層クロマトグラフィー［富士シリシア社製クロマトレックスＮＨ−ＰＬＣ０５プレート、展開溶媒：クロロホルム／メタノール＝１０／１］にて精製し、表題化合物（４．０ｍｇ、収率３４％）を無色油状物として得た。

^１Ｈ−ＮＭＲ（３００ＭＨｚ，ＣＤＣｌ_３）δ：１．５４−１．８０（３Ｈ，ｍ），１．８６−２．１２（５Ｈ，ｍ），２．４４−２．６２（４Ｈ，ｍ），３．１４（２Ｈ，ｓ），３．２６−３．３６（１Ｈ，ｍ），３．５５（２Ｈ，ｓ），３．７１−３．９４（３Ｈ，ｍ），４．０１−４．１３（１Ｈ，ｍ），４．４７（２Ｈ，ｓ），６．４８−６．５８（１Ｈ，ｂｒｍ），７．４１−７．４４（４Ｈ，ｍ），７．５６（２Ｈ，ｄ，Ｊ＝７．８Ｈｚ），７．６７−７．７３（２Ｈ，ｍ）．

ＬＣ／ＭＳ［条件２］：保持時間５．４２分；ｍ／ｚ５３２．２［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）

Example 110
3-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl) -N-[(tetrahydrofuran- Preparation of 2-yl) methyl] benzamide (Compound No. 110) 3-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3, obtained in Reference Example 108-3 8-diazaspiro [4.5] decan-3-yl} methyl) benzoic acid (10 mg, 0.022 mmol), tetrahydrofurfurylamine (2.7 mg, 0.027 mmol), 1-hydroxybenzotriazole (3.6 mg, 0 0.027 mmol) in chloroform (1.0 mL), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (5.1 m , Adding 0.027 mmol), it was stirred at room temperature for 12 hours. Water was added to separate the organic layer, dried over anhydrous sodium sulfate, and concentrated to dryness under reduced pressure. The obtained residue was purified by preparative thin layer chromatography [Chromatolex NH-PLC05 plate manufactured by Fuji Silysia, developing solvent: chloroform / methanol = 10/1] to give the title compound (4.0 mg, yield). 34%) as a colorless oil.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.54-1.80 (3H, m), 1.86-2.12 (5H, m), 2.44-2.62 (4H, m) 3.14 (2H, s), 3.26-3.36 (1H, m), 3.55 (2H, s), 3.71-3.94 (3H, m), 4.01-4 .13 (1H, m), 4.47 (2H, s), 6.48-6.58 (1H, brm), 7.41-7.44 (4H, m), 7.56 (2H, d) , J = 7.8 Hz), 7.67-7.73 (2H, m).

LC / MS [condition 2]: retention time of 5.42 minutes; m / z 532.2 [M + H] ⁺ (ESI positive ion mode)

参考例１１１−１
２−オキソ−１−オキサ−３，８−ジアザスピロ［４．５］デカン−８−カルボン酸ｔ−ブチルの製造
ＪＰ２００８−５４６８２０記載の方法を用いて合成した。

Reference Example 111-1
Preparation of t-butyl 2-oxo-1-oxa-3,8-diazaspiro [4.5] decane-8-carboxylate Synthesized using the method described in JP2008-546820.

参考例１１１−２
６−（ヒドロキシメチル）ニコチン酸エチルの製造
ピリジン−２，５−ジカルボン酸ジエチル（東京化成工業（株）より購入）（３５０ｍｇ、１．６ｍｍｏｌ）をテトラヒドロフラン（３．３ｍＬ）とエタノール（６．７ｍＬ）に溶解した後、０℃に冷却した。塩化カルシウム（６９０ｍｇ、６．２５ｍｍｏｌ）を加えた後、水素化ホウ素ナトリウム（１５０ｍｇ、４．０ｍｍｏｌ）を徐々に加え、同じ温度で１時間かき混ぜた。飽和塩化アンモニウム水溶液を加えた後、０℃で４０分間かき混ぜた。クロロホルムと水を加えた後、有機層を分離し、飽和食塩水で洗浄した。有機層を無水硫酸ナトリウムで乾燥した後、減圧下濃縮乾固して表題化合物（２３０ｍｇ、収率８１％）を白色固体として得た。

Reference Example 111-2
Preparation of ethyl 6- (hydroxymethyl) nicotinate Diethyl pyridine-2,5-dicarboxylate (purchased from Tokyo Chemical Industry Co., Ltd.) (350 mg, 1.6 mmol) in tetrahydrofuran (3.3 mL) and ethanol (6.7 mL) ) And then cooled to 0 ° C. After adding calcium chloride (690 mg, 6.25 mmol), sodium borohydride (150 mg, 4.0 mmol) was gradually added and stirred at the same temperature for 1 hour. A saturated aqueous ammonium chloride solution was added, and the mixture was stirred at 0 ° C. for 40 min. After adding chloroform and water, the organic layer was separated and washed with saturated brine. The organic layer was dried over anhydrous sodium sulfate and then concentrated to dryness under reduced pressure to obtain the title compound (230 mg, yield 81%) as a white solid.

参考例１１１−３
３−｛［５−（エトキシカルボニル）ピリジン−２−イル］メチル｝−２−オキソ−１−オキサ−３，８−ジアザスピロ［４．５］デカン−８−カルボン酸ｔ−ブチルの製造
参考例１１１−２で得られた６−（ヒドロキシメチル）ニコチン酸エチル（１００ｍｇ、０．５５ｍｍｏｌ）をテトラヒドロフラン（４．０ｍＬ）に溶解して０℃に冷却した後、塩化メタンスルホニル（７５ｍｇ、０．６６ｍｍｏｌ）とトリエチルアミン（７３ｍｇ、０．７２ｍｍｏｌ）を加え、３０分間かき混ぜた。さらに、塩化メタンスルホニル（３８ｍｇ、０．３３ｍｍｏｌ）とトリエチルアミン（３７ｍｇ、０．３６ｍｍｏｌ）を加え、３０分間かき混ぜた。酢酸エチルと水を加えた後、有機層を分離し、飽和食塩水で洗浄した。有機層を無水硫酸ナトリウムで乾燥した後、減圧下濃縮乾固して６−（（メチルスルホニルオキシ）メチル）ニコチン酸エチル（１８０ｍｇ）を得た。参考例１１１−１で得られた２−オキソ−１−オキサ−３，８−ジアザスピロ［４．５］デカン−８−カルボン酸ｔ−ブチル（１００ｍｇ、０．３９ｍｍｏｌ）をＮ，Ｎ−ジメチルホルムアミド（１．０ｍＬ）に溶解し、０℃で水素化ナトリウム（＞５５％、流動パラフィン分散、関東化学（株）より購入）（１９ｍｇ、０．４３ｍｍｏｌ）を加えた後、同じ温度で２０分間かき混ぜた。得られた反応混合物に６−［（メチルスルホニルオキシ）メチル］ニコチン酸エチル（１１０ｍｇ）のＮ，Ｎ−ジメチルホルムアミド（１．０ｍＬ）溶液を加えた後、室温で終夜かき混ぜた。さらに、水素化ナトリウム（＞５５％、流動パラフィン分散、関東化学（株）より購入）（９ｍｇ、０．２２ｍｍｏｌ）を加えた後、室温で１時間かき混ぜた。水と酢酸エチルを加えた後、有機層を分離し、水と飽和食塩水で洗浄した。有機層を無水硫酸ナトリウムで乾燥した後、減圧下濃縮乾固した。得られた残留物を酢酸エチル／ヘキサンにて再結晶し、表題化合物（８６ｍｇ）を２−オキソ−１−オキサ−３，８−ジアザスピロ［４．５］デカン−８−カルボン酸ｔ−ブチルとの混合物として得た。

Reference Example 111-3
Reference example for production of t-butyl 3-{[5- (ethoxycarbonyl) pyridin-2-yl] methyl} -2-oxo-1-oxa-3,8-diazaspiro [4.5] decane-8-carboxylate The ethyl 6- (hydroxymethyl) nicotinate (100 mg, 0.55 mmol) obtained in 111-2 was dissolved in tetrahydrofuran (4.0 mL), cooled to 0 ° C., and then methanesulfonyl chloride (75 mg, 0.66 mmol). ) And triethylamine (73 mg, 0.72 mmol) were added and stirred for 30 minutes. Further, methanesulfonyl chloride (38 mg, 0.33 mmol) and triethylamine (37 mg, 0.36 mmol) were added and stirred for 30 minutes. After adding ethyl acetate and water, the organic layer was separated and washed with saturated brine. The organic layer was dried over anhydrous sodium sulfate and then concentrated to dryness under reduced pressure to obtain ethyl 6-((methylsulfonyloxy) methyl) nicotinate (180 mg). 2-Oxo-1-oxa-3,8-diazaspiro [4.5] decane-8-carboxylate t-butyl (100 mg, 0.39 mmol) obtained in Reference Example 111-1 was replaced with N, N-dimethylformamide. (1.0 mL) dissolved in sodium hydride (> 55%, liquid paraffin dispersion, purchased from Kanto Chemical Co., Inc.) (19 mg, 0.43 mmol) at 0 ° C., and stirred at the same temperature for 20 minutes It was. A solution of ethyl 6-[(methylsulfonyloxy) methyl] nicotinate (110 mg) in N, N-dimethylformamide (1.0 mL) was added to the resulting reaction mixture, and the mixture was stirred overnight at room temperature. Further, sodium hydride (> 55%, liquid paraffin dispersion, purchased from Kanto Chemical Co., Inc.) (9 mg, 0.22 mmol) was added, followed by stirring at room temperature for 1 hour. After adding water and ethyl acetate, the organic layer was separated and washed with water and saturated brine. The organic layer was dried over anhydrous sodium sulfate and then concentrated to dryness under reduced pressure. The obtained residue was recrystallized from ethyl acetate / hexane, and the title compound (86 mg) was combined with t-butyl 2-oxo-1-oxa-3,8-diazaspiro [4.5] decane-8-carboxylate. As a mixture of

参考例１１１−４
６−（｛２−オキソ−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）ニコチン酸エチルの製造
参考例１１１−３で得られた３−｛［５−（エトキシカルボニル）ピリジン−２−イル］メチル｝−２−オキソ−１−オキサ−３，８−ジアザスピロ［４．５］デカン−８−カルボン酸ｔ−ブチル（８６ｍｇ）を１，４−ジオキサン（０．５０ｍＬ）に溶解した後、４Ｍ塩化水素−ジオキサン溶液（２．０ｍＬ）を加え、室温で１時間かき混ぜた。反応懸濁液にエタノール（０．２０ｍＬ）を加えた後、室温で終夜かき混ぜた。反応混合物を減圧下濃縮乾固し、さらにメタノールで３回共沸し、６−［（２−オキソ−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル）メチル］ニコチン酸エチル塩酸塩を白色固体として得た。この塩酸塩をＮ，Ｎ−ジメチルホルムアミド（１．０ｍＬ）に懸濁し、４−（トリフルオロメチル）ベンジルブロミド（６２ｍｇ、０．２６ｍｍｏｌ）とトリエチルアミン（５２ｍｇ、０．５２ｍｍｏｌ）を加えた後、室温で２４時間かき混ぜた。水と酢酸エチルを加えて有機層を分離し、これを水と飽和食塩水で洗浄した。有機層を無水硫酸ナトリウムで乾燥した後、減圧下濃縮乾固した。得られた残留物をシリカゲルカラムクロマトグラフィー［モリテックス社製プリフパックＳＩ６０μｍ、展開溶媒：クロロホルム／メタノール］にて精製し、表題化合物（４９ｍｇ、収率２６％）を得た。

Reference Example 111-4
Reference Example for Preparation of Ethyl 6-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl) nicotinate 3-{[5- (Ethoxycarbonyl) pyridin-2-yl] methyl} -2-oxo-1-oxa-3,8-diazaspiro [4.5] decane-8-carboxylic acid obtained from 111-3 After dissolving t-butyl (86 mg) in 1,4-dioxane (0.50 mL), 4M hydrogen chloride-dioxane solution (2.0 mL) was added, and the mixture was stirred at room temperature for 1 hr. Ethanol (0.20 mL) was added to the reaction suspension, and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated to dryness under reduced pressure and further azeotroped with methanol three times to give 6-[(2-oxo-1-oxa-3,8-diazaspiro [4.5] decan-3-yl) methyl] nicotine. Ethyl acid hydrochloride was obtained as a white solid. This hydrochloride was suspended in N, N-dimethylformamide (1.0 mL), 4- (trifluoromethyl) benzyl bromide (62 mg, 0.26 mmol) and triethylamine (52 mg, 0.52 mmol) were added, and room temperature was then added. Stir for 24 hours. Water and ethyl acetate were added to separate the organic layer, which was washed with water and saturated brine. The organic layer was dried over anhydrous sodium sulfate and then concentrated to dryness under reduced pressure. The obtained residue was purified by silica gel column chromatography [Molytex Prefpack SI 60 μm, developing solvent: chloroform / methanol] to obtain the title compound (49 mg, yield 26%).

参考例１１１−５
６−（｛２−オキソ−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）ニコチン酸の製造
参考例１１１−４で得られた６−（｛２−オキソ−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）ニコチン酸エチル（４９ｍｇ、０．１０ｍｍｏｌ）をメタノール（１．０ｍＬ）に溶解した後、５Ｍ水酸化ナトリウム溶液（０．１０ｍＬ、０．５１ｍｍｏｌ）を加えて、室温で終夜かき混ぜた。反応混合物を０℃に冷却した後、５Ｍ塩酸を加えてｐＨを５に調整した。水を加えた後、白色固体をろ取し、５０℃で１時間減圧下乾燥することで、表題化合物（１２ｍｇ、２７％）を得た。濾液にクロロホルム／イソプロピルアルコール（５／１）の混合溶媒を加えた後、有機層を分離し、水層をクロロホルム／イソプロピルアルコール（５／１）の混合溶媒で抽出した。水層に食塩を加えた後、さらにクロロホルム／イソプロピルアルコール（５／１）の混合溶媒で１回抽出した。合わせた有機層を無水硫酸ナトリウムで乾燥した後、減圧下濃縮乾固し、表題化合物（２４ｍｇ、５２％）を得た。

Reference Example 111-5
Preparation of 6-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl) nicotinic acid Reference Example 111 6-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl) nicotine obtained in -4 Ethyl acid (49 mg, 0.10 mmol) was dissolved in methanol (1.0 mL), 5M sodium hydroxide solution (0.10 mL, 0.51 mmol) was added, and the mixture was stirred at room temperature overnight. The reaction mixture was cooled to 0 ° C., and 5 M hydrochloric acid was added to adjust the pH to 5. After adding water, the white solid was collected by filtration and dried under reduced pressure at 50 ° C. for 1 hour to obtain the title compound (12 mg, 27%). After adding a mixed solvent of chloroform / isopropyl alcohol (5/1) to the filtrate, the organic layer was separated, and the aqueous layer was extracted with a mixed solvent of chloroform / isopropyl alcohol (5/1). After adding sodium chloride to the aqueous layer, the mixture was further extracted once with a mixed solvent of chloroform / isopropyl alcohol (5/1). The combined organic layers were dried over anhydrous sodium sulfate and then concentrated to dryness under reduced pressure to obtain the title compound (24 mg, 52%).

実施例１１１
６−（｛２−オキソ−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）−Ｎ−［（テトラヒドロフラン−２−イル）メチル］ニコチンアミド（化合物番号１１１）の製造
参考例１１１−５で得られた６−（｛２−オキソ−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）ニコチン酸（１０ｍｇ、０．０２２ｍｍｏｌ）、テトラヒドロフルフリルアミン（２．７ｍｇ、０．０２７ｍｍｏｌ）と１−ヒドロキシベンゾトリアゾール（３．６ｍｇ、０．０２７ｍｍｏｌ）をクロロホルム（１．０ｍＬ）に溶解した後、１−エチル−３−（３−ジメチルアミノプロピル）カルボジイミド塩酸塩（５．１ｍｇ、０．０２７ｍｍｏｌ）を加えて、室温で１５時間かき混ぜた。水を加えて有機層を分離し、水層をクロロホルムで抽出した。合わせた有機層を飽和炭酸水素ナトリウム水溶液と飽和食塩水で洗浄した。有機層を無水硫酸ナトリウムで乾燥した後、減圧下濃縮乾固した。得られた残留物を分取用薄層クロマトグラフィー［メルク社製ＰＬＣガラスプレート シリカゲル６０Ｆ_２５４、展開溶媒：クロロホルム／メタノール＝１０／１］にて精製し、表題化合物（８．４ｍｇ、収率７２％）を淡黄色油状物として得た。

^１Ｈ−ＮＭＲ（３００ＭＨｚ，ＣＤＣｌ_３）δ：１．５４−１．６７（２Ｈ，ｍ），１．７０−１．８６（２Ｈ，ｍ），１．８８−２．１２（４Ｈ，ｍ），２．４８−２．６１（４Ｈ，ｍ），３．２７−３．３７（１Ｈ，ｍ），３．３３（２Ｈ，ｓ），３．５６（２Ｈ，ｓ），３．７３−３．９５（３Ｈ，ｍ），４．０２−４．１４（１Ｈ，ｍ），４．５９（２Ｈ，ｓ），６．４７−６．５４（１Ｈ，ｂｒｍ），７．３８（１Ｈ，ｄ，Ｊ＝７．８Ｈｚ），７．４３（２Ｈ，ｄ，Ｊ＝７．８Ｈｚ），７．５７（２Ｈ，ｄ，Ｊ＝７．８Ｈｚ），８．０８（１Ｈ，ｄｄ，Ｊ＝７．８，２．４Ｈｚ），８．９３（１Ｈ，ｄ，Ｊ＝２．４Ｈｚ）．

ＬＣ／ＭＳ［条件２］：保持時間５．１９分；ｍ／ｚ５３３．３［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）

Example 111
6-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl) -N-[(tetrahydrofuran- 2- (yl) methyl] nicotinamide (Compound No. 111) 6-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3 obtained in Reference Example 111-5 , 8-diazaspiro [4.5] decan-3-yl} methyl) nicotinic acid (10 mg, 0.022 mmol), tetrahydrofurfurylamine (2.7 mg, 0.027 mmol) and 1-hydroxybenzotriazole (3.6 mg, 0.027 mmol) was dissolved in chloroform (1.0 mL), and then 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (5. mg, 0.027 mmol) was added and stirred at room temperature for 15 hr. Water was added to separate the organic layer, and the aqueous layer was extracted with chloroform. The combined organic layers were washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine. The organic layer was dried over anhydrous sodium sulfate and then concentrated to dryness under reduced pressure. The resulting residue was purified by preparative thin layer chromatography [Merck PLC glass plate silica gel _{60F 254,} developing solvent: chloroform / methanol = 10/1] to give the title compound (8.4 mg, yield 72 %) As a pale yellow oil.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.54-1.67 (2H, m), 1.70-1.86 (2H, m), 1.88-2.12 (4H, m) 2.48-2.61 (4H, m), 3.27-3.37 (1H, m), 3.33 (2H, s), 3.56 (2H, s), 3.73-3 .95 (3H, m), 4.02-4.14 (1H, m), 4.59 (2H, s), 6.47-6.54 (1H, brm), 7.38 (1H, d , J = 7.8 Hz), 7.43 (2H, d, J = 7.8 Hz), 7.57 (2H, d, J = 7.8 Hz), 8.08 (1H, dd, J = 7. 8, 2.4 Hz), 8.93 (1H, d, J = 2.4 Hz).

LC / MS [Condition 2]: Retention time 5.19 minutes; m / z 533.3 [M + H] ⁺ (ESI positive ion mode)

参考例１１２−１
６−（ヒドロキシメチル）ピコリン酸メチルの製造
ピリジン−２，６−ジカルボン酸ジエチル（東京化成工業（株）より購入）（１．０ｇ、５．１ｍｍｏｌ）をジクロロメタン（３５ｍＬ）とメタノール（１５ｍＬ）に溶解した後、０℃に冷却した。水素化ホウ素ナトリウム（１９５ｍｇ、５．２ｍｍｏｌ）を徐々に加え、室温で３時間かき混ぜた。飽和塩化アンモニウム水溶液を加えた後、０℃で４０分間かき混ぜた。クロロホルムと水を加えた後、有機層を分離し、飽和食塩水で洗浄した。有機層を無水硫酸ナトリウムで乾燥した後、減圧下濃縮乾固した。得られた残留物をシリカゲルカラムクロマトグラフィー［モリテックス社製プリフパックＳＩ６０μｍ、展開溶媒：ヘキサン／酢酸エチル］にて精製し、表題化合物（３００ｍｇ、収率３６％）を得た。

Reference Example 112-1
Preparation of methyl 6- (hydroxymethyl) picolinate Diethyl pyridine-2,6-dicarboxylate (purchased from Tokyo Chemical Industry Co., Ltd.) (1.0 g, 5.1 mmol) in dichloromethane (35 mL) and methanol (15 mL) After dissolution, it was cooled to 0 ° C. Sodium borohydride (195 mg, 5.2 mmol) was gradually added and stirred at room temperature for 3 hours. A saturated aqueous ammonium chloride solution was added, and the mixture was stirred at 0 ° C. for 40 min. After adding chloroform and water, the organic layer was separated and washed with saturated brine. The organic layer was dried over anhydrous sodium sulfate and then concentrated to dryness under reduced pressure. The obtained residue was purified by silica gel column chromatography [Polipack SI 60 μm, developed by Mortex, developing solvent: hexane / ethyl acetate] to obtain the title compound (300 mg, yield 36%).

参考例１１２−２
３−｛［６−（メトキシカルボニル）ピリジン−２−イル］メチル｝−２−オキソ−１−オキサ−３，８−ジアザスピロ［４．５］デカン−８−カルボン酸ｔ−ブチルの製造
参考例１１２−１で得られた６−（ヒドロキシメチル）ピコリン酸メチル（１００ｍｇ、０．６０ｍｍｏｌ）をテトラヒドロフラン（４．０ｍＬ）に溶解して０℃に冷却した後、塩化メタンスルホニル（７５ｍｇ、０．６６ｍｍｏｌ）とトリエチルアミン（７３ｍｇ、０．７２ｍｍｏｌ）を加え、３０分間かき混ぜた。さらに、塩化メタンスルホニル（３８ｍｇ、０．３３ｍｍｏｌ）とトリエチルアミン（３７ｍｇ、０．３６ｍｍｏｌ）を加え、３０分間かき混ぜた。酢酸エチルと水を加えた後、有機層を分離し、飽和食塩水で洗浄した。有機層を無水硫酸ナトリウムで乾燥した後、減圧下濃縮乾固して６−（（メチルスルホニルオキシ）メチル）ピコリン酸メチル（１９０ｍｇ）を得た。参考例１１１−１で得られた２−オキソ−１−オキサ−３，８−ジアザスピロ［４．５］デカン−８−カルボン酸ｔ−ブチル（１００ｍｇ、０．３９ｍｍｏｌ）をＮ，Ｎ−ジメチルホルムアミド（１．０ｍＬ）に溶解し、０℃で水素化ナトリウム（＞５５％、流動パラフィン分散、関東化学（株）より購入）（１９ｍｇ、０．４３ｍｍｏｌ）を加えた後、同じ温度で２０分間かき混ぜた。得られた反応混合物に６−［（メチルスルホニルオキシ）メチル］ピコリン酸メチル（１１０ｍｇ）のＮ，Ｎ−ジメチルホルムアミド（１．０ｍＬ）溶液を加えた後、室温で終夜かき混ぜた。水と酢酸エチルを加えた後、有機層を分離し、水と飽和食塩水で洗浄した。有機層を無水硫酸ナトリウムで乾燥した後、減圧下濃縮乾固した。得られた残留物をシリカゲルカラムクロマトグラフィー［モリテックス社製プリフパックＮＨ６０μｍ、展開溶媒：ヘキサン／酢酸エチル］にて精製し、表題化合物（９３ｍｇ、収率６０％）を得た。

Reference Example 112-2
Reference example for production of t-butyl 3-{[6- (methoxycarbonyl) pyridin-2-yl] methyl} -2-oxo-1-oxa-3,8-diazaspiro [4.5] decane-8-carboxylate Methyl 6- (hydroxymethyl) picolinate (100 mg, 0.60 mmol) obtained in 112-1 was dissolved in tetrahydrofuran (4.0 mL) and cooled to 0 ° C., and then methanesulfonyl chloride (75 mg, 0.66 mmol). ) And triethylamine (73 mg, 0.72 mmol) were added and stirred for 30 minutes. Further, methanesulfonyl chloride (38 mg, 0.33 mmol) and triethylamine (37 mg, 0.36 mmol) were added and stirred for 30 minutes. After adding ethyl acetate and water, the organic layer was separated and washed with saturated brine. The organic layer was dried over anhydrous sodium sulfate and then concentrated to dryness under reduced pressure to obtain methyl 6-((methylsulfonyloxy) methyl) picolinate (190 mg). 2-Oxo-1-oxa-3,8-diazaspiro [4.5] decane-8-carboxylate t-butyl (100 mg, 0.39 mmol) obtained in Reference Example 111-1 was replaced with N, N-dimethylformamide. (1.0 mL) dissolved in sodium hydride (> 55%, liquid paraffin dispersion, purchased from Kanto Chemical Co., Inc.) (19 mg, 0.43 mmol) at 0 ° C., and stirred at the same temperature for 20 minutes It was. A solution of methyl 6-[(methylsulfonyloxy) methyl] picolinate (110 mg) in N, N-dimethylformamide (1.0 mL) was added to the resulting reaction mixture, and the mixture was stirred overnight at room temperature. After adding water and ethyl acetate, the organic layer was separated and washed with water and saturated brine. The organic layer was dried over anhydrous sodium sulfate and then concentrated to dryness under reduced pressure. The obtained residue was purified by silica gel column chromatography [Polipack NH 60 μm, developed by Mortex, developing solvent: hexane / ethyl acetate] to obtain the title compound (93 mg, yield 60%).

参考例１１２−３
６−（｛２−オキソ−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）ピコリン酸メチルの製造
参考例１１２−２で得られた３−｛［６−（メトキシカルボニル）ピリジン−２−イル］メチル｝−２−オキソ−１−オキサ−３，８−ジアザスピロ［４．５］デカン−８−カルボン酸ｔ−ブチル（９３ｍｇ）をメタノール（０．２０ｍＬ）に溶解した後、４Ｍ塩化水素−ジオキサン溶液（２．０ｍＬ）を加え、室温で１時間かき混ぜた。反応混合物を減圧下濃縮乾固し、さらにメタノールで３回共沸し、６−［（２−オキソ−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル）メチル］ピコリン酸メチルの塩酸塩を白色固体として得た。この塩酸塩をＮ，Ｎ−ジメチルホルムアミド（２．０ｍＬ）に懸濁し、４−（トリフルオロメチル）ベンジルブロミド（６０ｍｇ、０．２５ｍｍｏｌ）とトリエチルアミン（５１ｍｇ、０．５１ｍｍｏｌ）を加えた後、室温で２４時間かき混ぜた。水と酢酸エチルを加えて有機層を分離し、これを水と飽和食塩水で洗浄した。有機層を無水硫酸ナトリウムで乾燥した後、減圧下濃縮乾固した。得られた残留物をシリカゲルカラムクロマトグラフィー［モリテックス社製プリフパックＳＩ６０μｍ、展開溶媒：クロロホルム／メタノール］にて精製し、表題化合物（４８ｍｇ、収率４５％）を得た。

Reference Example 112-3
Reference Example for Production of Methyl 6-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl) picolinate 3-{[6- (Methoxycarbonyl) pyridin-2-yl] methyl} -2-oxo-1-oxa-3,8-diazaspiro [4.5] decane-8-carboxylic acid obtained in 112-2 After dissolving t-butyl (93 mg) in methanol (0.20 mL), 4M hydrogen chloride-dioxane solution (2.0 mL) was added, and the mixture was stirred at room temperature for 1 hr. The reaction mixture was concentrated to dryness under reduced pressure, further azeotroped with methanol three times, and 6-[(2-oxo-1-oxa-3,8-diazaspiro [4.5] decan-3-yl) methyl] picoline. Methyl acid hydrochloride was obtained as a white solid. This hydrochloride was suspended in N, N-dimethylformamide (2.0 mL), 4- (trifluoromethyl) benzyl bromide (60 mg, 0.25 mmol) and triethylamine (51 mg, 0.51 mmol) were added, and room temperature was then added. Stir for 24 hours. Water and ethyl acetate were added to separate the organic layer, which was washed with water and saturated brine. The organic layer was dried over anhydrous sodium sulfate and then concentrated to dryness under reduced pressure. The obtained residue was purified by silica gel column chromatography [Polipack SI 60 μm, developed by Morexex, developing solvent: chloroform / methanol] to obtain the title compound (48 mg, yield 45%).

参考例１１２−４
６−（｛２−オキソ−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）ピコリン酸の製造
参考例１１２−３で得られた６−（｛２−オキソ−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）ピコリン酸メチル（４８ｍｇ、０．１０ｍｍｏｌ）をメタノール（１．０ｍＬ）に溶解した後、５Ｍ水酸化ナトリウム溶液（０．１０ｍＬ、０．５１ｍｍｏｌ）を加えて、室温で終夜かき混ぜた。反応混合物を０℃に冷却した後、５Ｍ塩酸を加えてｐＨを５に調整した。水とクロロホルム／２−プロパノール（５／１）の混合溶媒を加えた後、有機層を分離し、水層をクロロホルム／２−プロパノール（５／１）の混合溶媒で抽出した。水層に食塩を加えた後、さらにクロロホルム／２−プロパノール（５／１）の混合溶媒で１回抽出した。合わせた有機層を無水硫酸ナトリウムで乾燥した後、減圧下濃縮乾固し、表題化合物（４２ｍｇ、９１％）を得た。

Reference Example 112-4
Preparation of 6-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl) picolinic acid Reference Example 112 6-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl) picoline obtained in -3 Methyl acid (48 mg, 0.10 mmol) was dissolved in methanol (1.0 mL), 5M sodium hydroxide solution (0.10 mL, 0.51 mmol) was added, and the mixture was stirred at room temperature overnight. The reaction mixture was cooled to 0 ° C., and 5 M hydrochloric acid was added to adjust the pH to 5. After adding a mixed solvent of water and chloroform / 2-propanol (5/1), the organic layer was separated, and the aqueous layer was extracted with a mixed solvent of chloroform / 2-propanol (5/1). After adding salt to the aqueous layer, the mixture was further extracted once with a mixed solvent of chloroform / 2-propanol (5/1). The combined organic layers were dried over anhydrous sodium sulfate and then concentrated to dryness under reduced pressure to obtain the title compound (42 mg, 91%).

実施例１１２
６−（｛２−オキソ−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）−Ｎ−［（テトラヒドロフラン−２−イル）メチル］ピコリンアミド（化合物番号１１２）の製造
参考例１１２−４で得られた６−（｛２−オキソ−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）ピコリン酸（１０ｍｇ、０．０２２ｍｍｏｌ）、テトラヒドロフルフリルアミン（２．７ｍｇ、０．０２７ｍｍｏｌ）と１−ヒドロキシベンゾトリアゾール（３．６ｍｇ、０．０２７ｍｍｏｌ）をクロロホルム（１．０ｍＬ）に溶解した後、１−エチル−３−（３−ジメチルアミノプロピル）カルボジイミド塩酸塩（５．１ｍｇ、０．０２７ｍｍｏｌ）を加えて、室温で１５時間かき混ぜた。水を加えて有機層を分離し、水層をクロロホルムで抽出した。合わせた有機層を飽和炭酸水素ナトリウム水溶液と飽和食塩水で洗浄した。有機層を無水硫酸ナトリウムで乾燥した後、減圧下濃縮乾固した。得られた残留物を分取用薄層クロマトグラフィー［メルク社製ＰＬＣガラスプレート シリカゲル６０Ｆ_２５４、展開溶媒：クロロホルム／メタノール＝１０／１］にて精製し、表題化合物（５．９ｍｇ、収率５０％）を無色油状物として得た。

^１Ｈ−ＮＭＲ（３００ＭＨｚ，ＣＤＣｌ_３）δ：１．５３−１．６８（２Ｈ，ｍ），１．７１−２．０９（６Ｈ，ｍ），２．４８−２．６３（４Ｈ，ｍ），３．３１（２Ｈ，ｓ），３．３３−３．４６（１Ｈ，ｍ），３．５７（２Ｈ，ｓ），３．６９−３．８０（２Ｈ，ｍ），３．８５−３．９４（１Ｈ，ｍ），４．０２−４．１３（１Ｈ，ｍ），４．６０（２Ｈ，ｓ），７．４２（３Ｈ，ｔ，Ｊ＝７．０Ｈｚ），７．５７（２Ｈ，ｄ，Ｊ＝７．８Ｈｚ），７．８５（１Ｈ，ｔ，Ｊ＝７．７Ｈｚ），８．１３（１Ｈ，ｄ，Ｊ＝７．２Ｈｚ），８．１７−８．２５（１Ｈ，ｍ）．

ＬＣ／ＭＳ［条件２］：保持時間５．３５分；ｍ／ｚ５３３．２［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）

Example 112
6-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl) -N-[(tetrahydrofuran- 2- (yl) methyl] picolinamide (Compound No. 112) 6-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3 obtained in Reference Example 112-4 , 8-diazaspiro [4.5] decan-3-yl} methyl) picolinic acid (10 mg, 0.022 mmol), tetrahydrofurfurylamine (2.7 mg, 0.027 mmol) and 1-hydroxybenzotriazole (3.6 mg, 0.027 mmol) was dissolved in chloroform (1.0 mL), and then 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (5. mg, 0.027 mmol) was added and stirred at room temperature for 15 hr. Water was added to separate the organic layer, and the aqueous layer was extracted with chloroform. The combined organic layers were washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine. The organic layer was dried over anhydrous sodium sulfate and then concentrated to dryness under reduced pressure. The resulting residue was purified by preparative thin layer chromatography [Merck PLC glass plate silica gel _{60F 254,} developing solvent: chloroform / methanol = 10/1] to give the title compound (5.9 mg, yield 50 %) As a colorless oil.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.53-1.68 (2H, m), 1.71-2.09 (6H, m), 2.48-2.63 (4H, m) 3.31 (2H, s), 3.33-3.46 (1H, m), 3.57 (2H, s), 3.69-3.80 (2H, m), 3.85-3 .94 (1H, m), 4.02-4.13 (1H, m), 4.60 (2H, s), 7.42 (3H, t, J = 7.0 Hz), 7.57 (2H) , D, J = 7.8 Hz), 7.85 (1H, t, J = 7.7 Hz), 8.13 (1H, d, J = 7.2 Hz), 8.17-8.25 (1H, m).

LC / MS [Condition 2]: Retention time 5.35 minutes; m / z 533.2 [M + H] ⁺ (ESI positive ion mode)

実施例１１３
ｔ−ブチル ３−［４−（｛２−オキソ−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）ベンズアミド］プロピルカルバメート（化合物番号１１３）の製造
参考例２１で得られた４−（｛２−オキソ−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）安息香酸（１０ｍｇ、０．０２２ｍｍｏｌ）、Ｎ−（ｔ−ブトキシカルボニル）−１，３−ジアミノプロパン（４．７ｍｇ、０．０２７ｍｍｏｌ）、１−ヒドロキシベンゾトリアゾール（３．６ｍｇ、０．０２７ｍｍｏｌ）をクロロホルム（１．０ｍＬ）に溶解した後、１−エチル−３−（３−ジメチルアミノプロピル）カルボジイミド塩酸塩（５．１ｍｇ、０．０２７ｍｍｏｌ）を加えて、室温で３日間かき混ぜた。水を加えて有機層を分離し、無水硫酸ナトリウムで乾燥した後、減圧下濃縮乾固した。得られた残留物を分取用薄層クロマトグラフィー［富士シリシア社製クロマトレックスＮＨ−ＰＬＣ０５プレート］にて精製し、表題化合物（１２ｍｇ、収率９０％）を白色固体として得た。

^１Ｈ−ＮＭＲ（３００ＭＨｚ，ＣＤＣｌ_３）δ：１．４５（９Ｈ，ｓ），１．６５−１．８０（４Ｈ，ｍ），１．８５−１．９６（２Ｈ，ｍ），２．４４−２．６１（４Ｈ，ｍ），３．１２（２Ｈ，ｓ），３．２５（２Ｈ，ｑ，Ｊ＝６．０Ｈｚ），３．５１（２Ｈ，ｑ，Ｊ＝６．０Ｈｚ），３．５５（２Ｈ，ｓ），４．４７（２Ｈ，ｓ），４．８０−４．９２（１Ｈ，ｍ），７．３０（１Ｈ，ｂｒｓ），７．３４（２Ｈ，ｄ，Ｊ＝８．３Ｈｚ），７．４２（２Ｈ，ｄ，Ｊ＝８．３Ｈｚ），７．５６（２Ｈ，ｄ，Ｊ＝８．０Ｈｚ），７．８５（２Ｈ，ｄ，Ｊ＝８．０Ｈｚ）．

Example 113
t-butyl 3- [4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl) benzamide Preparation of propyl carbamate (Compound No. 113) 4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4. 5] Decan-3-yl} methyl) benzoic acid (10 mg, 0.022 mmol), N- (t-butoxycarbonyl) -1,3-diaminopropane (4.7 mg, 0.027 mmol), 1-hydroxybenzotriazole (3.6 mg, 0.027 mmol) was dissolved in chloroform (1.0 mL), and then 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride Salt (5.1 mg, 0.027 mmol) was added and stirred at room temperature for 3 days. Water was added to separate the organic layer, dried over anhydrous sodium sulfate, and concentrated to dryness under reduced pressure. The obtained residue was purified by preparative thin layer chromatography [Chromatolex NH-PLC05 plate manufactured by Fuji Silysia Co., Ltd.] to obtain the title compound (12 mg, yield 90%) as a white solid.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.45 (9H, s), 1.65-1.80 (4H, m), 1.85-1.96 (2H, m), 2.44 -2.61 (4H, m), 3.12 (2H, s), 3.25 (2H, q, J = 6.0 Hz), 3.51 (2H, q, J = 6.0 Hz), 3 .55 (2H, s), 4.47 (2H, s), 4.80-4.92 (1H, m), 7.30 (1H, brs), 7.34 (2H, d, J = 8) .3 Hz), 7.42 (2H, d, J = 8.3 Hz), 7.56 (2H, d, J = 8.0 Hz), 7.85 (2H, d, J = 8.0 Hz).

実施例１１４
Ｎ−（１−ベンジルピペリジン−４−イル）−４−（｛２−オキソ−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）ベンズアミド（化合物番号１１４）の製造
参考例２１で得られた４−（｛２−オキソ−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）安息香酸（１０ｍｇ、０．０２２ｍｍｏｌ）、４−アミノ−１−ベンジルピペリジン（５．１ｍｇ、０．０２７ｍｍｏｌ）、１−ヒドロキシベンゾトリアゾール（３．６ｍｇ、０．０２７ｍｍｏｌ）をクロロホルム（１．０ｍＬ）に溶解した後、１−エチル−３−（３−ジメチルアミノプロピル）カルボジイミド塩酸塩（５．１ｍｇ、０．０２７ｍｍｏｌ）を加えて、室温で１５時間かき混ぜた。水を加えて有機層を分離し、無水硫酸ナトリウムで乾燥した後、減圧下濃縮乾固した。得られた残留物を分取用薄層クロマトグラフィー［富士シリシア社製クロマトレックスＮＨ−ＰＬＣ０５プレート、展開溶媒：酢酸エチル１００％］にて精製し、表題化合物（９．９ｍｇ、収率７３％）を白色固体として得た。

^１Ｈ−ＮＭＲ（３００ＭＨｚ，ＣＤＣｌ_３）δ：１．４８−１．７８（４Ｈ，ｍ），１．８６−１．９５（２Ｈ，ｍ），１．９８−２．０７（２Ｈ，ｍ），２．１２−２．２１（２Ｈ，ｍ），２．４５−２．５９（４Ｈ，ｍ），２．８０−２．９１（２Ｈ，ｍ），３．１１（２Ｈ，ｓ），３．５２（２Ｈ，ｓ），３．５５（２Ｈ，ｓ），３．９３−４．０９（１Ｈ，ｍ），４．４６（２Ｈ，ｓ），５．９３−６．０１（１Ｈ，ｍ），７．２３−７．３４（５Ｈ，ｍ），７．３２（２Ｈ，ｄ，Ｊ＝８．３Ｈｚ），７．４２（２Ｈ，ｄ，Ｊ＝８．０Ｈｚ），７．５６（２Ｈ，ｄ，Ｊ＝８．０Ｈｚ），７．７３（２Ｈ，ｄ，Ｊ＝８．３Ｈｚ）．

ＬＣ／ＭＳ［条件２］：保持時間４．９３分；ｍ／ｚ６２１．３［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）

Example 114
N- (1-benzylpiperidin-4-yl) -4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decane- Preparation of 3-yl} methyl) benzamide (Compound No. 114) 4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8- Diazaspiro [4.5] decan-3-yl} methyl) benzoic acid (10 mg, 0.022 mmol), 4-amino-1-benzylpiperidine (5.1 mg, 0.027 mmol), 1-hydroxybenzotriazole (3. 6 mg, 0.027 mmol) was dissolved in chloroform (1.0 mL) and then 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (5.1 mg, 0 027Mmol) was added and stirred at room temperature for 15 hr. Water was added to separate the organic layer, dried over anhydrous sodium sulfate, and concentrated to dryness under reduced pressure. The obtained residue was purified by preparative thin-layer chromatography [Chromatolex NH-PLC05 plate manufactured by Fuji Silysia Ltd., developing solvent: 100% ethyl acetate] to give the title compound (9.9 mg, yield 73%). Was obtained as a white solid.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.48-1.78 (4H, m), 1.86-1.95 (2H, m), 1.98-2.07 (2H, m) 2.12-2.21 (2H, m), 2.45-2.59 (4H, m), 2.80-2.91 (2H, m), 3.11 (2H, s), 3 .52 (2H, s), 3.55 (2H, s), 3.93-4.09 (1H, m), 4.46 (2H, s), 5.93-6.01 (1H, m ), 7.23-7.34 (5H, m), 7.32 (2H, d, J = 8.3 Hz), 7.42 (2H, d, J = 8.0 Hz), 7.56 (2H) , D, J = 8.0 Hz), 7.73 (2H, d, J = 8.3 Hz).

LC / MS [Condition 2]: Retention time 4.93 minutes; m / z 621.3 [M + H] ⁺ (ESI positive ion mode)

参考例１１５−１
３−［２−メトキシ−４−（メトキシカルボニル）ベンジル］−２−オキソ−１−オキサ−３，８−ジアザスピロ［４．５］デカン−８−カルボン酸ｔ−ブチルの製造
参考例１１１−１で得られた２−オキソ−１−オキサ−３，８−ジアザスピロ［４．５］デカン−８−カルボン酸ｔ−ブチル（２００ｍｇ、０．７８ｍｍｏｌ）をＮ，Ｎ−ジメチルホルムアミド（１．５ｍＬ）に溶かし、水素化ナトリウム（＞５５％、流動パラフィン分散、関東化学（株）より購入）（４１ｍｇ、０．７８ｍｍｏｌ）を加えて３０分撹拌後、４−（ブロモメチル）−３−メトキシ安息香酸メチル（トランスワールドケミカルズインコーポレイティッド、ｔｒａｎｓ ｗｏｒｌｄ ｃｈｅｍｉｃａｌｓ ｉｎｃ．より購入）（２００ｍｇ、０．７８ｍｍｏｌ）を加え、室温で１７時間撹拌した。反応停止後、反応混合物に飽和塩化アンモニウム水溶液（２．０ｍＬ）と酢酸エチル（２．０ｍＬ）を加えた。酢酸エチル（１０ｍＬ）で２回抽出し、有機層を合わせたものに飽和食塩水（１０ｍＬ）を加えて分液操作を行った。有機層を分離し、無水硫酸マグネシウムで乾燥後、減圧下濃縮乾固した。得られた残留物をシリカゲルカラムクロマトグラフィー［充填剤：富士シリシア製ＦＬ１００Ｄ、展開溶媒：ｎ−ヘキサン／酢酸エチル＝１／１］にて精製し、３−［２−メトキシ−４−（メトキシカルボニル）ベンジル］−２−オキソ−１−オキサ−３，８−ジアザスピロ［４．５］デカン−８−カルボン酸ｔ−ブチル（２４０ｍｇ、収率７１％）を白色固体として得た。

^１Ｈ−ＮＭＲ（３００ＭＨｚ，ＣＤＣｌ_３）δ：１．４５（９Ｈ，ｓ），１．６０（２Ｈ，ｄｔ，Ｊ＝５．１，１３．０Ｈｚ），１．８５（２Ｈ，ｄ，Ｊ＝１３．６Ｈｚ），３．１６（２Ｈ，ｓ），３．２７（２Ｈ，ｄｔ，Ｊ＝２．４，１２．３Ｈｚ），３．８１（２Ｈ，ｄ，Ｊ＝１１．６Ｈｚ），３．９０（３Ｈ，ｓ），３．９３（３Ｈ，ｓ），４．５０（２Ｈ，ｓ），７．３１（１Ｈ，ｄ，Ｊ＝７．８Ｈｚ），７．５５（１Ｈ，ｄ，Ｊ＝１．４Ｈｚ），７．６４（１Ｈ，ｄｄ，Ｊ＝１．４，７．８Ｈｚ）．

ＬＣ／ＭＳ［条件１］：保持時間４．２３分；ｍ／ｚ４３４．８［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ４７９．０［Ｍ＋ＨＣＯＯ］^―（ＥＳＩ負イオンモード）

Reference Example 115-1
Production of t-butyl 3- [2-methoxy-4- (methoxycarbonyl) benzyl] -2-oxo-1-oxa-3,8-diazaspiro [4.5] decane-8-carboxylate Reference Example 111-1 2-oxo-1-oxa-3,8-diazaspiro [4.5] decane-8-carboxylate t-butyl (200 mg, 0.78 mmol) obtained in 1 above was added to N, N-dimethylformamide (1.5 mL). Dissolved in 1, sodium hydride (> 55%, liquid paraffin dispersion, purchased from Kanto Chemical Co., Inc.) (41 mg, 0.78 mmol) and stirred for 30 minutes, methyl 4- (bromomethyl) -3-methoxybenzoate (Purchased from Transworld Chemicals Inc., trans world chemicals Inc.) (200 mg, 0.78 mmol) It was stirred at room temperature for 17 hours. After stopping the reaction, saturated aqueous ammonium chloride solution (2.0 mL) and ethyl acetate (2.0 mL) were added to the reaction mixture. Extraction was performed twice with ethyl acetate (10 mL), and a saturated saline solution (10 mL) was added to the combined organic layer for liquid separation operation. The organic layer was separated, dried over anhydrous magnesium sulfate, and concentrated to dryness under reduced pressure. The obtained residue was purified by silica gel column chromatography [filler: FL100D manufactured by Fuji Silysia, developing solvent: n-hexane / ethyl acetate = 1/1] to give 3- [2-methoxy-4- (methoxycarbonyl). )] Benzyl] -2-oxo-1-oxa-3,8-diazaspiro [4.5] decane-8-carboxylate t-butyl (240 mg, 71% yield) was obtained as a white solid.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.45 (9H, s), 1.60 (2H, dt, J = 5.1, 13.0 Hz), 1.85 (2H, d, J = 13.6 Hz), 3.16 (2H, s), 3.27 (2H, dt, J = 2.4, 12.3 Hz), 3.81 (2H, d, J = 11.6 Hz), 3. 90 (3H, s), 3.93 (3H, s), 4.50 (2H, s), 7.31 (1H, d, J = 7.8 Hz), 7.55 (1H, d, J = 1.4 Hz), 7.64 (1H, dd, J = 1.4, 7.8 Hz).

LC / MS [Condition 1]: Retention time 4.23 minutes; m / z 434.8 [M + H] ⁺ (ESI positive ion mode), m / z 479.0 [M + HCOO] ⁻ (ESI negative ion mode)

参考例１１５−２
３−メトキシ−４−［（２−オキソ−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル）メチル］安息香酸メチル塩酸塩の製造
参考例１１５−１で得られた３−［２−メトキシ−４−（メトキシカルボニル）ベンジル］−２−オキソ−１−オキサ−３，８−ジアザスピロ［４．５］デカン−８−カルボン酸ｔ−ブチル（２２０ｍｇ、０．５０ｍｍｏｌ）をクロロホルム（１．０ｍＬ）に溶かし、４Ｍ塩化水素−ジオキサン溶液（３ｍＬ）を加え、室温で１時間撹拌した。反応停止後、反応混合物を減圧下濃縮乾固し、３−メトキシ−４−［（２−オキソ−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル）メチル］安息香酸メチル塩酸塩（１８０ｍｇ、収率９７％）を白色固体として得た。

^１Ｈ−ＮＭＲ（３００ＭＨｚ，ＣＤＣｌ_３）δ：１．９３−２．３２（４Ｈ，ｍ），３．１４−３．５２（６Ｈ，ｍ），３．９０（３Ｈ，ｓ），３．９３（３Ｈ，ｓ），４．４９（２Ｈ，ｓ），７．３１（１Ｈ，ｄ，Ｊ＝７．８Ｈｚ），７．５６（１Ｈ，ｄ，Ｊ＝１．４Ｈｚ），７．６３（１Ｈ，ｄｄ，Ｊ＝１．４，７．８Ｈｚ）．

Reference Example 115-2
Preparation of 3-methoxy-4-[(2-oxo-1-oxa-3,8-diazaspiro [4.5] decan-3-yl) methyl] benzoic acid methyl hydrochloride Obtained in Reference Example 115-1. 3- [2-Methoxy-4- (methoxycarbonyl) benzyl] -2-oxo-1-oxa-3,8-diazaspiro [4.5] decane-8-carboxylate t-butyl (220 mg, 0.50 mmol) Was dissolved in chloroform (1.0 mL), 4M hydrogen chloride-dioxane solution (3 mL) was added, and the mixture was stirred at room temperature for 1 hr. After the reaction was stopped, the reaction mixture was concentrated to dryness under reduced pressure, and 3-methoxy-4-[(2-oxo-1-oxa-3,8-diazaspiro [4.5] decan-3-yl) methyl] benzoic acid. Methyl hydrochloride (180 mg, 97% yield) was obtained as a white solid.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.93-2.32 (4H, m), 3.14-3.52 (6H, m), 3.90 (3H, s), 3.93 (3H, s), 4.49 (2H, s), 7.31 (1H, d, J = 7.8 Hz), 7.56 (1H, d, J = 1.4 Hz), 7.63 (1H , Dd, J = 1.4, 7.8 Hz).

参考例１１５−３
３−メトキシ−４−（｛２−オキソ−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）安息香酸メチルの製造
参考例１１５−２で得られた３−メトキシ−４−［（２−オキソ−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル）メチル］安息香酸メチル塩酸塩（１８０ｍｇ、０．４８ｍｍｏｌ）をクロロホルム（１．０ｍＬ）に溶かした後、Ｎ，Ｎ−ジメチルホルムアミド（１．０ｍＬ）を加えた。４−（トリフルオロメチル）ベンジルブロミド（１３０ｍｇ、０．５２ｍｍｏｌ）、トリエチルアミン（０．２０ｍＬ、１．４ｍｍｏｌ）を順次加えて室温で１６時間撹拌した。反応停止後、反応混合物を減圧下濃縮してクロロホルムを除いた後、水（２．０ｍＬ）を加えた。析出した固体をろ取した後、減圧下５０℃で乾燥させ、３−メトキシ−４−（｛２−オキソ−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）安息香酸メチル（１９０ｍｇ、収率８０％）を白色固体として得た。

^１Ｈ−ＮＭＲ（３００ＭＨｚ，ＣＤＣｌ_３）δ：１．７９−１．６６（２Ｈ，ｍ），１．８５−１．９６（２Ｈ，ｍ），２．５９−２．４８（４Ｈ，ｂｒｍ），３．１６（２Ｈ，ｓ），３．５５（２Ｈ，ｂｒｓ），３．８９（３Ｈ，ｓ），３．９２（３Ｈ，ｓ），４．５０（２Ｈ，ｓ），７．３０（１Ｈ，ｄ，Ｊ＝７．５Ｈｚ），７．４２（２Ｈ，ｄ，Ｊ＝７．８Ｈｚ），７．５１−７．６０（３Ｈ，ｍ），７．６３（１Ｈ，ｄｄ，Ｊ＝７．８，１．４Ｈｚ）．

ＬＣ／ＭＳ［条件１］：保持時間３．２８分；ｍ／ｚ４９２．８［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ５３６．９［Ｍ＋ＨＣＯＯ］^―（ＥＳＩ負イオンモード）

Reference Example 115-3
3-methoxy-4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl) methyl benzoate of reference example 115-2 in the obtained 3-methoxy-4 - [(2-oxo-1-oxa-3,8-diazaspiro [4.5] decan-3-yl) methyl] benzoate hydrochloride (180 mg, 0.48 mmol) was dissolved in chloroform (1.0 mL), and N, N-dimethylformamide (1.0 mL) was added. 4- (Trifluoromethyl) benzyl bromide (130 mg, 0.52 mmol) and triethylamine (0.20 mL, 1.4 mmol) were sequentially added, and the mixture was stirred at room temperature for 16 hours. After stopping the reaction, the reaction mixture was concentrated under reduced pressure to remove chloroform, and then water (2.0 mL) was added. The precipitated solid was collected by filtration and dried at 50 ° C. under reduced pressure to give 3-methoxy-4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8- Diazaspiro [4.5] decan-3-yl} methyl) methyl benzoate (190 mg, 80% yield) was obtained as a white solid.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.79-1.66 (2H, m), 1.85-1.96 (2H, m), 2.59-2.48 (4H, brm) 3.16 (2H, s), 3.55 (2H, brs), 3.89 (3H, s), 3.92 (3H, s), 4.50 (2H, s), 7.30 ( 1H, d, J = 7.5 Hz), 7.42 (2H, d, J = 7.8 Hz), 7.51-7.60 (3H, m), 7.63 (1H, dd, J = 7) .8, 1.4 Hz).

LC / MS [Condition 1]: Retention time 3.28 minutes; m / z 492.8 [M + H] ⁺ (ESI positive ion mode), m / z 536.9 [M + HCOO] ⁻ (ESI negative ion mode)

参考例１１５−４
３−メトキシ−４−（｛２−オキソ−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）安息香酸の製造
参考例１１５−３で得られた３−メトキシ−４−（｛２−オキソ−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）安息香酸メチル（１７０ｍｇ、０．３５ｍｍｏｌ）を１，４−ジオキサン（１．５ｍＬ）に溶かした後、１Ｍ水酸化ナトリウム水溶液（１．４ｍＬ）を加えて室温で撹拌した。２１時間後、１Ｍ塩酸（１．３ｍＬ）を加えて反応を停止した。反応混合物を酢酸エチル（１０ｍＬ）で２回抽出し、合わせた有機層を飽和食塩水（１０ｍＬ）で洗浄した。有機層を分離し、無水硫酸マグネシウムで乾燥した後、減圧下濃縮乾固した。析出した固体をジイソプロピルエーテルで洗浄し、３−メトキシ−４−（｛２−オキソ−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）安息香酸（１４０．０ｍｇ、収率８４％）を白色固体として得た。

^１Ｈ−ＮＭＲ（３００ＭＨｚ，ＣＤＣｌ_３）δ：１．９４（４Ｈ，ｍ），２．７７（２Ｈ，ｔ，Ｊ＝１０．２Ｈｚ），２．９８−３．１５（４Ｈ，ｍ），３．８８（３Ｈ，ｓ），３．９０（２Ｈ，ｓ），４．４９（２Ｈ，ｓ），７．２７（１Ｈ，ｄ，Ｊ＝７．８Ｈｚ），７．５０−７．６５（６Ｈ，ｍ）．

ＬＣ／ＭＳ［条件１］：保持時間３．０４分；ｍ／ｚ４７８．８［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ４７６．９［Ｍ−Ｈ］^―（ＥＳＩ負イオンモード）

Reference Example 115-4
Of 3-methoxy-4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl) benzoic acid 3-methoxy-4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decane obtained in Preparation Reference Example 115-3 -3-yl} methyl) methyl benzoate (170 mg, 0.35 mmol) was dissolved in 1,4-dioxane (1.5 mL), 1M aqueous sodium hydroxide solution (1.4 mL) was added, and the mixture was stirred at room temperature. . After 21 hours, 1M hydrochloric acid (1.3 mL) was added to stop the reaction. The reaction mixture was extracted twice with ethyl acetate (10 mL), and the combined organic layers were washed with saturated brine (10 mL). The organic layer was separated, dried over anhydrous magnesium sulfate, and concentrated to dryness under reduced pressure. The precipitated solid was washed with diisopropyl ether, and 3-methoxy-4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decane. -3-yl} methyl) benzoic acid (140.0 mg, 84% yield) was obtained as a white solid.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.94 (4H, m), 2.77 (2H, t, J = 10.2 Hz), 2.98-3.15 (4H, m), 3 .88 (3H, s), 3.90 (2H, s), 4.49 (2H, s), 7.27 (1H, d, J = 7.8 Hz), 7.50-7.65 (6H) , M).

LC / MS [Condition 1]: Retention time 3.04 minutes; m / z 478.8 [M + H] ⁺ (ESI positive ion mode), m / z 476.9 [M−H] ⁻ (ESI negative ion mode)

実施例１１５
３−メトキシ−４−（｛２−オキソ−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）−Ｎ−［（テトラヒドロフラン−２−イル）メチル］ベンズアミド（化合物番号１１５）の製造
参考例１１５−４で得られた３−メトキシ−４−（｛２−オキソ−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）安息香酸（３０ｍｇ、０．０６３ｍｍｏｌ）、１−エチル−３−（３−ジメチルアミノプロピル）カルボジイミド塩酸塩（２４ｍｇ、０．１３ｍｍｏｌ）および１−ヒドロキシベンゾトリアゾール（１７ｍｇ、０．１３ｍｍｏｌ）をクロロホルム（１．０ｍＬ）に溶かした後、テトラヒドロフルフリルアミン（東京化成工業（株）より購入）（０．０１３ｍＬ、０．１３ｍｍｏｌ）とトリエチルアミン（０．０１８ｍＬ、０．１３ｍｍｏｌ）を室温にて加え、２０時間撹拌した。反応停止後、反応混合物に水（２．０ｍＬ）と酢酸エチル（２．０ｍＬ）を加えたのち、酢酸エチル（１０ｍＬ）で２回抽出し、合わせた有機層を飽和食塩水（１０ｍＬ）で洗浄した。有機層を分離し、無水硫酸マグネシウムで乾燥した後、減圧下濃縮乾固した。得られた固体をヘキサンで洗浄し、減圧下５０℃で乾燥させ、３−メトキシ−４−（｛２−オキソ−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）−Ｎ−［（テトラヒドロフラン−２−イル）メチル］ベンズアミド（２３ｍｇ、収率６６％）を白色固体として得た。

^１Ｈ−ＮＭＲ（３００ＭＨｚ，ＣＤＣｌ_３）δ：１．５４−１．７９（３Ｈ，ｍ），１．８４−１．９８（４Ｈ，ｍ），１．９８−２．１１（１Ｈ，ｍ），２．５３（４Ｈ，ｂｒｓ），３．１５（２Ｈ，ｓ），３．３４（１Ｈ，ｄｄｄ，Ｊ＝１４．０，７．２，５．１Ｈｚ），３．５６（２Ｈ，ｂｒｓ），３．７３−３．８５（２Ｈ，ｍ），３．８５−３．９４（４Ｈ，ｍ），４．０７（１Ｈ，ｄｑ，Ｊ＝３．４，７．２Ｈｚ），４．４８（２Ｈ，ｓ），６．５１（１Ｈ，ｔ，Ｊ＝５．５Ｈｚ），７．２２（１Ｈ，ｄｄ，Ｊ＝７．８，１．７Ｈｚ），７．２８（１Ｈ，ｄ，Ｊ＝７．８Ｈｚ），７．３９−７．４８（３Ｈ，ｍ），７．５７（２Ｈ，ｄ，Ｊ＝７．８Ｈｚ）．

ＬＣ／ＭＳ［条件１］：保持時間３．１８分；ｍ／ｚ５６１．８［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ６０６．０［Ｍ＋ＨＣＯＯ］^―（ＥＳＩ負イオンモード）

Example 115
3-Methoxy-4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl) -N- Production of [(tetrahydrofuran-2-yl) methyl] benzamide (Compound No. 115) 3-methoxy-4-({2-oxo-8- [4- (trifluoromethyl) benzyl ] obtained in Reference Example 115-4 ] 1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl) benzoic acid (30 mg, 0.063 mmol), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (24 mg, 0.13 mmol) and 1-hydroxybenzotriazole (17 mg, 0.13 mmol) were dissolved in chloroform (1.0 mL). Furyl amine (purchased from Tokyo Chemical Industry (Ltd.)) (0.013 mL, 0.13 mmol) and added triethylamine (0.018 mL, 0.13 mmol) and was stirred at room temperature for 20 hours. After stopping the reaction, water (2.0 mL) and ethyl acetate (2.0 mL) were added to the reaction mixture, followed by extraction twice with ethyl acetate (10 mL), and the combined organic layer was washed with saturated brine (10 mL). did. The organic layer was separated, dried over anhydrous magnesium sulfate, and concentrated to dryness under reduced pressure. The obtained solid was washed with hexane, dried at 50 ° C. under reduced pressure, and 3-methoxy-4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8 -Diazaspiro [4.5] decan-3-yl} methyl) -N-[(tetrahydrofuran-2-yl) methyl] benzamide (23 mg, 66% yield) was obtained as a white solid.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.54-1.79 (3H, m), 1.84-1.98 (4H, m), 1.98-2.11 (1H, m) , 2.53 (4H, brs), 3.15 (2H, s), 3.34 (1H, ddd, J = 14.0, 7.2, 5.1 Hz), 3.56 (2H, brs) , 3.73-3.85 (2H, m), 3.85-3.94 (4H, m), 4.07 (1H, dq, J = 3.4, 7.2 Hz), 4.48 ( 2H, s), 6.51 (1H, t, J = 5.5 Hz), 7.22 (1H, dd, J = 7.8, 1.7 Hz), 7.28 (1H, d, J = 7) .8 Hz), 7.39-7.48 (3H, m), 7.57 (2H, d, J = 7.8 Hz).

LC / MS [Condition 1]: Retention time 3.18 minutes; m / z 561.8 [M + H] ⁺ (ESI positive ion mode), m / z 606.0 [M + HCOO] ⁻ (ESI negative ion mode)

実施例１１６
４−［３−メトキシ−４−（｛２−オキソ−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）ベンズアミド］ピペリジン−１−カルボン酸ｔ−ブチル（化合物番号１１６）の製造
テトラヒドロフルフリルアミンの代わりに、４−アミノピペリジン−１−カルボン酸ｔ−ブチル（アルドリッチ（株）より購入）を用いること以外は実質的に実施例１１５と同様に反応を行なって、表題化合物を白色固体（１００ｍｇ、収率８４％）として得た。

^１Ｈ−ＮＭＲ（３００ＭＨｚ，ＣＤＣｌ_３）δ：１．４０（２Ｈ，ｔｄ，Ｊ＝１２．３，３．７Ｈｚ），１．４７（９Ｈ，ｓ），１．６４−１．７９（２Ｈ，ｂｒｍ），１．８９（２Ｈ，ｄ，Ｊ＝１３．０Ｈｚ），２．０２（２Ｈ，ｄｄ，Ｊ＝１２．６，２．７Ｈｚ），２．４１−２．６３（４Ｈ，ｂｒｍ），２．９１（２Ｈ，ｔ，Ｊ＝１３．０Ｈｚ），３．１５（２Ｈ，ｓ），３．５５（２Ｈ，ｂｒｓ），３．９０（３Ｈ，ｓ），４．０１−４．２１（３Ｈ，ｍ），４．４８（２Ｈ，ｓ），６．００（１Ｈ，ｄ，Ｊ＝８．２Ｈｚ），７．１７（１Ｈ，ｄｄ，Ｊ＝７．８，１．７Ｈｚ），７．２９（１Ｈ，ｄ，Ｊ＝７．８Ｈｚ），７．３８−７．４７（３Ｈ，ｍ），７．５６（２Ｈ，ｄ，Ｊ＝７．８Ｈｚ）．

ＬＣ／ＭＳ［条件１］：保持時間３．５８分；ｍ／ｚ６６０．９［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ７０５．０［Ｍ＋ＨＣＯＯ］^―（ＥＳＩ負イオンモード）

Example 116
4- [3-methoxy-4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl) Benzamide] Production of t-butyl piperidine-1-carboxylate (Compound No. 116) Instead of using tetrahydrofurfurylamine, t-butyl 4-aminopiperidine-1-carboxylate (purchased from Aldrich) was used. The reaction was carried out substantially as in Example 115 to give the title compound as a white solid (100 mg, 84% yield).

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.40 (2H, td, J = 12.3, 3.7 Hz), 1.47 (9H, s), 1.64-1.79 (2H, brm), 1.89 (2H, d, J = 13.0 Hz), 2.02 (2H, dd, J = 12.6, 2.7 Hz), 2.41-2.63 (4H, brm), 2.91 (2H, t, J = 13.0 Hz), 3.15 (2H, s), 3.55 (2H, brs), 3.90 (3H, s), 4.01-4.21 ( 3H, m), 4.48 (2H, s), 6.00 (1H, d, J = 8.2 Hz), 7.17 (1H, dd, J = 7.8, 1.7 Hz), 7. 29 (1H, d, J = 7.8 Hz), 7.38-7.47 (3H, m), 7.56 (2H, d, J = 7.8 Hz).

LC / MS [Condition 1]: Retention time 3.58 minutes; m / z 660.9 [M + H] ⁺ (ESI positive ion mode), m / z 705.0 [M + HCOO] ⁻ (ESI negative ion mode)

参考例１１７
３−メトキシ−４−（｛２−オキソ−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）−Ｎ−（ピペリジン−４−イル）ベンズアミド２塩酸塩の製造
実施例１１６で得られた４−［３−メトキシ−４−（｛２−オキソ−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）ベンズアミド］ピペリジン−１−カルボン酸ｔ−ブチル（６０ｍｇ、０．０９０ｍｍｏｌ）を４Ｍ塩化水素−ジオキサン溶液（１．０ｍＬ）に溶かし、室温で１時間撹拌した。反応停止後、反応混合物を減圧下濃縮乾固し、３−メトキシ−４−（｛２−オキソ−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）−Ｎ−（ピペリジン−４−イル）ベンズアミド２塩酸塩（６３ｍｇ、収率１００％）を白色固体として得た。

ＬＣ／ＭＳ［条件１］：保持時間１．４０分；ｍ／ｚ５６０．８［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）

Reference Example 117
3-Methoxy-4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl) -N- Preparation of (piperidin-4-yl) benzamide dihydrochloride 4- [3-methoxy-4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-] obtained in Example 116 Oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl) benzamide] piperidine-1-carboxylate t-butyl (60 mg, 0.090 mmol) in 4M hydrogen chloride-dioxane solution (1.0 mL). And stirred at room temperature for 1 hour. After the reaction was terminated, the reaction mixture was concentrated to dryness under reduced pressure, and 3-methoxy-4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4 .5] decan-3-yl} methyl) -N- (piperidin-4-yl) benzamide dihydrochloride (63 mg, 100% yield) was obtained as a white solid.

LC / MS [Condition 1]: Retention time 1.40 minutes; m / z 560.8 [M + H] ⁺ (ESI positive ion mode)

実施例１１７
Ｎ−［１−（シアノメチル）ピペリジン−４−イル］−３−メトキシ−４−（｛２−オキソ−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）ベンズアミド（化合物番号１１７）の製造
参考例１１７で得られた３−メトキシ−４−（｛２−オキソ−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）−Ｎ−（ピペリジン−４−イル）ベンズアミド２塩酸塩（３２ｍｇ、０．０５０ｍｍｏｌ）をＮ，Ｎ−ジメチルホルムアミド（１．０ｍＬ）に溶かし、ブロモアセトニトリル（東京化成工業（株）より購入）（０．００６７ｍＬ、０．１０ｍｍｏｌ）およびトリエチルアミン（０．０２１ｍＬ、０．１５ｍｍｏｌ）を順次加えて室温で１日間撹拌した。反応混合物に飽和塩化アンモニウム水溶液（２．０ｍＬ）と酢酸エチル（２．０ｍＬ）を加えたのち、酢酸エチル（１０ｍＬ）で２回抽出し、合わせた有機層を飽和食塩水（１０ｍＬ）で洗浄した。有機層を分離し、無水硫酸マグネシウムで乾燥した後、減圧下濃縮乾固した。得られた残留物を分取用薄層クロマトグラフィー［富士シリシア社製クロマトレックスＮＨ−ＰＬＣ０５プレート、展開溶媒：酢酸エチル］にて精製し、Ｎ−［１−（シアノメチル）ピペリジン−４−イル］−３−メトキシ−４−（｛２−オキソ−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）ベンズアミド（１８ｍｇ、収率６０％）を白色固体として得た。

^１Ｈ−ＮＭＲ（３００ＭＨｚ，ＣＤＣｌ_３）δ：１．５５−１．７９（４Ｈ，ｍ），１．８９（２Ｈ，ｄ，Ｊ＝１３．３Ｈｚ），２．１０（２Ｈ，ｄｄ，Ｊ＝１３．０，３．１Ｈｚ），２．４５−２．６１（６Ｈ，ｍ），２．８４（２Ｈ，ｄｔ，Ｊ＝１１．６，３．４Ｈｚ），３．１６（２Ｈ，ｓ），３．５４（２Ｈ，ｓ），３．５５（２Ｈ，ｂｒｓ），３．８９（３Ｈ，ｓ），３．９４−４．１１（１Ｈ，ｍ），４．４８（２Ｈ，ｓ），６．０８（１Ｈ，ｄ，Ｊ＝７．８Ｈｚ），７．１９（１Ｈ，ｄｄ，Ｊ＝７．８，１．４Ｈｚ），７．２８（１Ｈ，ｄ，Ｊ＝７．８Ｈｚ），７．３９−７．４６（３Ｈ，ｍ），７．５６（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ）．

ＬＣ／ＭＳ［条件１］：保持時間３．０２分；ｍ／ｚ５９９．９［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ６４４．１［Ｍ＋ＨＣＯＯ］^―（ＥＳＩ負イオンモード）

Example 117
N- [1- (cyanomethyl) piperidin-4-yl] -3-methoxy-4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [ 4.5] Preparation of decan-3-yl} methyl) benzamide (Compound No. 117) 3-methoxy-4-({2-oxo-8- [4- (trifluoromethyl) benzyl] obtained in Reference Example 117 ] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl) -N- (piperidin-4-yl) benzamide dihydrochloride (32 mg, 0.050 mmol) was added to N, N- Dissolved in dimethylformamide (1.0 mL), bromoacetonitrile (purchased from Tokyo Chemical Industry Co., Ltd.) (0.0067 mL, 0.10 mmol) and triethylamine (0.021 mL, .15Mmol) added sequentially and stirred at room temperature for 1 day. A saturated aqueous ammonium chloride solution (2.0 mL) and ethyl acetate (2.0 mL) were added to the reaction mixture, followed by extraction twice with ethyl acetate (10 mL), and the combined organic layer was washed with saturated brine (10 mL). . The organic layer was separated, dried over anhydrous magnesium sulfate, and concentrated to dryness under reduced pressure. The obtained residue was purified by preparative thin-layer chromatography [Chromatolex NH-PLC05 plate manufactured by Fuji Silysia, developing solvent: ethyl acetate], and N- [1- (cyanomethyl) piperidin-4-yl] -3-methoxy-4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl) benzamide ( 18 mg, 60% yield) was obtained as a white solid.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.55-1.79 (4H, m), 1.89 (2H, d, J = 13.3 Hz), 2.10 (2H, dd, J = 13.0, 3.1 Hz), 2.45-2.61 (6H, m), 2.84 (2H, dt, J = 11.6, 3.4 Hz), 3.16 (2H, s), 3.54 (2H, s), 3.55 (2H, brs), 3.89 (3H, s), 3.94-4.11 (1H, m), 4.48 (2H, s), 6 .08 (1H, d, J = 7.8 Hz), 7.19 (1H, dd, J = 7.8, 1.4 Hz), 7.28 (1H, d, J = 7.8 Hz), 7. 39-7.46 (3H, m), 7.56 (2H, d, J = 8.2 Hz).

LC / MS [Condition 1]: Retention time 3.02 minutes; m / z 599.9 [M + H] ⁺ (ESI positive ion mode), m / z 644.1 [M + HCOO] ⁻ (ESI negative ion mode)

実施例１１８
４−［３−メトキシ−４−（｛２−オキソ−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）ベンズアミド］ピペリジン−１−カルボン酸メチル（化合物番号１１８）の製造
ブロモアセトニトリルの代わりに、クロロギ酸メチル（東京化成工業（株）より購入）を用いること以外は実質的に実施例１１７と同様に反応を行なって、表題化合物を白色固体（２０ｍｇ、収率６４％）として得た。

^１Ｈ−ＮＭＲ（３００ＭＨｚ，ＣＤＣｌ_３）δ：１．４４（２Ｈ，ｄｑ，Ｊ＝３．４，１１．９Ｈｚ），１．６５−１．７８（２Ｈ，ｍ），１．８８（２Ｈ，ｄ，Ｊ＝１３．６Ｈｚ），２．０４（２Ｈ，ｄｄ，Ｊ＝１２．６，２．７Ｈｚ），２．４３−２．６２（４Ｈ，ｂｒｍ），２．９７（２Ｈ，ｔ，Ｊ＝１２．３Ｈｚ），３．１６（２Ｈ，ｓ），３．５５（２Ｈ，ｂｒｓ），３．７０（３Ｈ，ｓ），３．８９（３Ｈ，ｓ），４．０４−４．２６（３Ｈ，ｍ），４．４７（２Ｈ，ｓ），６．１３（１Ｈ，ｄ，Ｊ＝７．８Ｈｚ），７．１９（１Ｈ，ｄｄ，Ｊ＝７．８，１．４Ｈｚ），７．２８（１Ｈ，ｄ，Ｊ＝７．８Ｈｚ），７．４１（１Ｈ，ｄ，Ｊ＝１．４Ｈｚ），７．４２（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ），７．５６（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ）．

ＬＣ／ＭＳ［条件１］：保持時間３．２２分；ｍ／ｚ６１８．９［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ６６３．１［Ｍ＋ＨＣＯＯ］^―（ＥＳＩ負イオンモード）

Example 118
4- [3-methoxy-4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl) Benzamide] Preparation of methyl piperidine-1-carboxylate (Compound No. 118) The reaction was carried out in substantially the same manner as in Example 117, except that methyl chloroformate (purchased from Tokyo Chemical Industry Co., Ltd.) was used instead of bromoacetonitrile. To give the title compound as a white solid (20 mg, 64% yield).

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.44 (2H, dq, J = 3.4, 11.9 Hz), 1.65-1.78 (2H, m), 1.88 (2H, d, J = 13.6 Hz), 2.04 (2H, dd, J = 12.6, 2.7 Hz), 2.43-2.62 (4H, brm), 2.97 (2H, t, J = 12.3 Hz), 3.16 (2H, s), 3.55 (2H, brs), 3.70 (3H, s), 3.89 (3H, s), 4.04-4.26 ( 3H, m), 4.47 (2H, s), 6.13 (1H, d, J = 7.8 Hz), 7.19 (1H, dd, J = 7.8, 1.4 Hz), 7. 28 (1H, d, J = 7.8 Hz), 7.41 (1 H, d, J = 1.4 Hz), 7.42 (2H, d, J = 8.2 Hz), 7.56 (2H, d , J = 8 2Hz).

LC / MS [Condition 1]: Retention time 3.22 min; m / z 618.9 [M + H] ⁺ (ESI positive ion mode), m / z 663.1 [M + HCOO] ⁻ (ESI negative ion mode)

参考例１１９−１
４−（１−エトキシ−１−オキソプロパン−２−イル）−４−ヒドロキシピペリジン−１−カルボン酸ｔ−ブチルの製造
１Ｍリチウムヘキサメチルジシラジド テトラヒドロフラン溶液（アルドリッチ（株）より購入）（９．９ｍＬ、９．９ｍｍｏｌ）のテトラヒドロフラン溶液（２５ｍＬ）にアルゴン雰囲気下、−７８℃においてプロピオン酸エチル（東京化成工業（株）より購入）（１．１ｍＬ、９．９ｍｍｏｌ）をゆっくり滴下した。同じ温度で１０分間撹拌した後、１−ｔ−ブトキシカルボニル−４−ピペリジン（和光純薬工業（株）より購入）（１．８ｇ、９．０ｍｍｏｌ）のテトラヒドロフラン溶液（５．０ｍＬ）をゆっくり加えた。徐々に室温まで昇温しながら１日間撹拌した後、飽和塩化アンモニウム水溶液（１０ｍＬ）と酢酸エチル（１０ｍＬ）を加えた。反応物を酢酸エチル（１０ｍＬ）で２回抽出し、合わせた有機層を飽和食塩水（２０ｍＬ）で洗浄した。有機層を分離し、無水硫酸マグネシウムで乾燥した後、減圧下濃縮乾固し、４−（１−エトキシ−１−オキソプロパン−２−イル）−４−ヒドロキシピペリジン−１−カルボン酸ｔ−ブチルを黄色油状物（２．５ｇ）として得た。未精製のまま次の反応に使用した。

Reference Example 119-1
Preparation of t-butyl 4- (1-ethoxy-1-oxopropan-2-yl) -4-hydroxypiperidine-1-carboxylate 1M lithium hexamethyldisilazide tetrahydrofuran solution (purchased from Aldrich) (9 (9 mL, 9.9 mmol) in tetrahydrofuran (25 mL) was slowly added dropwise with ethyl propionate (purchased from Tokyo Chemical Industry Co., Ltd.) (1.1 mL, 9.9 mmol) at −78 ° C. in an argon atmosphere. After stirring for 10 minutes at the same temperature, a tetrahydrofuran solution (5.0 mL) of 1-t-butoxycarbonyl-4-piperidine (purchased from Wako Pure Chemical Industries, Ltd.) (1.8 g, 9.0 mmol) was slowly added. It was. After stirring for one day while gradually warming to room temperature, saturated aqueous ammonium chloride solution (10 mL) and ethyl acetate (10 mL) were added. The reaction was extracted twice with ethyl acetate (10 mL), and the combined organic layers were washed with saturated brine (20 mL). The organic layer was separated, dried over anhydrous magnesium sulfate, concentrated to dryness under reduced pressure, and t-butyl 4- (1-ethoxy-1-oxopropan-2-yl) -4-hydroxypiperidine-1-carboxylate. As a yellow oil (2.5 g). The crude product was used in the next reaction without purification.

参考例１１９−２
２−［１−（ｔ−ブトキシカルボニル）−４−ヒドロキシピペリジン−４−イル］プロピオン酸の製造
参考例１１９−１で得られた４−（１−エトキシ−１−オキソプロパン−２−イル）−４−ヒドロキシピペリジン−１−カルボン酸ｔ−ブチルのメタノール溶液（３６ｍＬ）に１Ｍ水酸化ナトリウム水溶液（３６ｍＬ）を加えて室温で３日間撹拌した。反応温度を０℃にした後、１Ｍ塩酸（３０ｍＬ）を加え、ｐＨ８程度に調整した後、酢酸エチル（２０ｍＬ）を加えて水層を２回洗浄した。得られた水層に１Ｍ塩酸を加えてｐＨ４に調整した後、酢酸エチル（２０ｍＬ）で３回抽出し、合わせた有機層を飽和食塩水（４０ｍＬ）で洗浄した。有機層を分離し、無水硫酸マグネシウムで乾燥した後、減圧下濃縮乾固して２−［１−（ｔ−ブトキシカルボニル）−４−ヒドロキシピペリジン−４−イル］プロピオン酸を黄色油状物（７９０ｍｇ）として得た。未精製のまま次の反応に使用した。

Reference Example 119-2
Production of 2- [1- (t-butoxycarbonyl) -4-hydroxypiperidin-4-yl] propionic acid 4- (1-ethoxy-1-oxopropan-2-yl) obtained in Reference Example 119-1 To a methanol solution (36 mL) of t-butyl-4-hydroxypiperidine-1-carboxylate was added 1M aqueous sodium hydroxide solution (36 mL), and the mixture was stirred at room temperature for 3 days. After the reaction temperature was adjusted to 0 ° C., 1M hydrochloric acid (30 mL) was added to adjust the pH to about 8, and then ethyl acetate (20 mL) was added to wash the aqueous layer twice. The resulting aqueous layer was adjusted to pH 4 by adding 1 M hydrochloric acid, extracted three times with ethyl acetate (20 mL), and the combined organic layer was washed with saturated brine (40 mL). The organic layer was separated, dried over anhydrous magnesium sulfate, and concentrated to dryness under reduced pressure to give 2- [1- (t-butoxycarbonyl) -4-hydroxypiperidin-4-yl] propionic acid as a yellow oil (790 mg). ). The crude product was used in the next reaction without purification.

参考例１１９−３
４−メチル−２−オキソ−１−オキサ−３，８−ジアザスピロ［４．５］デカン−８−カルボン酸ｔ−ブチルの製造
参考例１１９−２で得られた２−［１−（ｔ−ブトキシカルボニル）−４−ヒドロキシピペリジン−４−イル］プロピオン酸のトルエン溶液（１５ｍＬ）にトリエチルアミン（０．４５ｍＬ、３．２ｍｍｏｌ）およびジフェニルホスホリルアジド（０．８１ｍＬ、３．８ｍｍｏｌ）を加えて７０℃で３０分間撹拌した後、反応溶液を加熱還流した。６時間後、飽和炭酸水素ナトリウム水溶液（１０ｍＬ）を加え、ｐＨ８程度に調整した後、酢酸エチル（２０ｍＬ）を加えて５回抽出し、合わせた有機層を飽和食塩水（５０ｍＬ）で洗浄した。有機層を分離し、無水硫酸マグネシウムで乾燥した後、減圧下濃縮乾固した。得られた残留物をシリカゲルカラムクロマトグラフィー［充填剤：山善Ｈｉ−ＦＬＡＳＨカラムｓｉｚｅＬ（４０μｍ、３０ｇ）、展開溶媒：ヘキサン／酢酸エチル＝１／１ ４００ｍＬ、その後酢酸エチル３００ｍＬ］にて精製し、４−メチル−２−オキソ−１−オキサ−３，８−ジアザスピロ［４．５］デカン−８−カルボン酸ｔ−ブチル（３１０ｍｇ、３段階での収率１３％）を淡黄色固体として得た。

^１Ｈ−ＮＭＲ（３００ＭＨｚ，ＣＤＣｌ_３）δ：１．１９（３Ｈ，ｄ，Ｊ＝６．５Ｈｚ），１．４６（９Ｈ，ｓ），１．６１（２Ｈ，ｄｄｄ，Ｊ＝３１．０，１３．２，４．４Ｈｚ），１．８７（２Ｈ，ｔｄ，Ｊ＝１３．２，２．７Ｈｚ），３．１４（２Ｈ，ｑ，Ｊ＝１３．２Ｈｚ），３．５９（１Ｈ，ｑ，Ｊ＝６．５Ｈｚ），４．０２（２Ｈ，ｂｒｓ），５．０４（１Ｈ，ｂｒｓ）．

Reference Example 119-3
Preparation of t-butyl 4-methyl-2-oxo-1-oxa-3,8-diazaspiro [4.5] decane-8-carboxylate 2- [1- (t- Triethylamine (0.45 mL, 3.2 mmol) and diphenylphosphoryl azide (0.81 mL, 3.8 mmol) were added to a toluene solution (15 mL) of butoxycarbonyl) -4-hydroxypiperidin-4-yl] propionic acid at 70 ° C. After stirring for 30 minutes, the reaction solution was heated to reflux. Six hours later, a saturated aqueous sodium hydrogen carbonate solution (10 mL) was added to adjust the pH to about 8, and then ethyl acetate (20 mL) was added and extracted five times. The combined organic layers were washed with saturated brine (50 mL). The organic layer was separated, dried over anhydrous magnesium sulfate, and concentrated to dryness under reduced pressure. The obtained residue was purified by silica gel column chromatography [filler: Yamazen Hi-FLASH column size L (40 μm, 30 g), developing solvent: hexane / ethyl acetate = 1/1 400 mL, and then ethyl acetate 300 mL]. -Methyl-2-oxo-1-oxa-3,8-diazaspiro [4.5] decane-8-carboxylate t-butyl (310 mg, 13% yield over 3 steps) was obtained as a pale yellow solid.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.19 (3H, d, J = 6.5 Hz), 1.46 (9H, s), 1.61 (2H, ddd, J = 31.0, 13.2, 4.4 Hz), 1.87 (2H, td, J = 13.2, 2.7 Hz), 3.14 (2H, q, J = 13.2 Hz), 3.59 (1H, q , J = 6.5 Hz), 4.02 (2H, brs), 5.04 (1H, brs).

参考例１１９−４
４−（ブロモメチル）安息香酸メチルの製造
４−（ブロモメチル）安息香酸（東京化成工業（株）より購入）（５００ｍｇ、２．３ｍｍｏｌ）に１０％塩化水素−メタノール溶液（１０ｍＬ）を加えて６０℃で撹拌した。２時間後、反応を停止し、室温で飽和炭酸水素ナトリウム水溶液（２０ｍＬ）を加えた。酢酸エチル（２０ｍＬ）を加えて２回抽出し、合わせた有機層を飽和食塩水（４０ｍＬ）で洗浄した。有機層を分離して無水硫酸マグネシウムで乾燥した後、減圧下濃縮乾固し、４−（ブロモメチル）安息香酸メチルと４−（クロロメチル）安息香酸メチルの２：３混合物を淡黄色固体（３９０ｍｇ）として得た。未精製のまま次の反応に使用した。

４−（ブロモメチル）安息香酸メチル
^１Ｈ−ＮＭＲ（３００ＭＨｚ，ＣＤＣｌ_３）δ：３．９２（３Ｈ，ｓ），４．５０（２Ｈ，ｓ），７．４６（２Ｈ，ｄ，Ｊ＝８．０Ｈｚ），８．０１（２Ｈ，ｄ，Ｊ＝８．０Ｈｚ）．

４−（クロロメチル）安息香酸メチル
^１Ｈ−ＮＭＲ（３００ＭＨｚ，ＣＤＣｌ_３）δ：３．９２（３Ｈ，ｓ），４．６２（２Ｈ，ｓ），７．４６（２Ｈ，ｄ，Ｊ＝８．０Ｈｚ），８．０４（２Ｈ，ｄ，Ｊ＝８．０Ｈｚ）．

Reference Example 119-4
Preparation of methyl 4- (bromomethyl) benzoate 4- (Bromomethyl) benzoic acid (purchased from Tokyo Chemical Industry Co., Ltd.) (500 mg, 2.3 mmol) was added with a 10% hydrogen chloride-methanol solution (10 mL) at 60 ° C. Stir with. After 2 hours, the reaction was stopped, and saturated aqueous sodium hydrogen carbonate solution (20 mL) was added at room temperature. Ethyl acetate (20 mL) was added and extracted twice, and the combined organic layer was washed with saturated brine (40 mL). The organic layer was separated, dried over anhydrous magnesium sulfate, concentrated to dryness under reduced pressure, and a 2: 3 mixture of methyl 4- (bromomethyl) benzoate and methyl 4- (chloromethyl) benzoate was prepared as a pale yellow solid (390 mg). ). The crude product was used in the next reaction without purification.

4- (Bromomethyl) methyl benzoate
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 3.92 (3H, s), 4.50 (2H, s), 7.46 (2H, d, J = 8.0 Hz), 8.01 (2H , D, J = 8.0 Hz).

4- (Chloromethyl) benzoic acid methyl ester
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 3.92 (3H, s), 4.62 (2H, s), 7.46 (2H, d, J = 8.0 Hz), 8.04 (2H , D, J = 8.0 Hz).

参考例１１９−５
３−［４−（メトキシカルボニル）ベンジル］−４−メチル−２−オキソ−１−オキサ−３，８−ジアザスピロ［４．５］デカン−８−カルボン酸ｔ−ブチルの製造
参考例１１９−３で得られた４−メチル−２−オキソ−１−オキサ−３，８−ジアザスピロ［４．５］デカン−８−カルボン酸ｔ−ブチル（２００ｍｇ、０．７４ｍｍｏｌ）をＮ，Ｎ−ジメチルホルムアミド（４．０ｍＬ）に溶かし、水素化ナトリウム（＞５５％、流動パラフィン分散、関東化学（株）より購入）（３９ｍｇ、０．８９ｍｍｏｌ）を加えて３０分撹拌した後、参考例１１９−４で得られた４−（ブロモメチル）安息香酸メチルと４−（クロロメチル）安息香酸メチルの２：３混合物（１８０ｍｇ、０．８９ｍｍｏｌ）を加え、室温で撹拌した。２８時間後、飽和塩化アンモニウム水溶液（５．０ｍＬ）と酢酸エチル（５．０ｍＬ）を加えた。酢酸エチル（１０ｍＬ）で２回抽出し、合わせた有機層を飽和食塩水（１０ｍＬ）で洗浄した。有機層を分離し、無水硫酸マグネシウムで乾燥した後、減圧下濃縮乾固した。得られた残留物をシリカゲルカラムクロマトグラフィー［充填剤：山善Ｈｉ−ＦＬＡＳＨカラムｓｉｚｅＬ（４０μｍ、３０ｇ）、展開溶媒：ヘキサン／酢酸エチル＝１／１］にて精製し、３−［４−（メトキシカルボニル）ベンジル］−４−メチル−２−オキソ−１−オキサ−３，８−ジアザスピロ［４．５］デカン−８−カルボン酸ｔ−ブチル（２９０．０ｍｇ、収率９５％）を無色油状物として得た。

^１Ｈ−ＮＭＲ（３００ＭＨｚ，ＣＤＣｌ_３）δ：１．０９（３Ｈ，ｄ，Ｊ＝６．５Ｈｚ），１．４５（９Ｈ，ｓ），１．４７−１．６２（２Ｈ，ｍ），１．６６−１．８４（２Ｈ，ｍ），３．１４（２Ｈ，ｄｄ，Ｊ＝２２．８，１０．９Ｈｚ），３．２６（１Ｈ，ｑ，Ｊ＝６．５Ｈｚ），３．９２（３Ｈ，ｓ），３．９４−４．１１（２Ｈ，ｍ），４．１６（１Ｈ，ｄ，Ｊ＝１５．７Ｈｚ），４．８０（１Ｈ，ｄ，Ｊ＝１５．７Ｈｚ），７．３６（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ），８．０３（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ）．

Reference Example 119-5
Preparation of t-butyl 3- [4- (methoxycarbonyl) benzyl] -4-methyl-2-oxo-1-oxa-3,8-diazaspiro [4.5] decane-8-carboxylate Reference Example 119-3 4-methyl-2-oxo-1-oxa-3,8-diazaspiro [4.5] decane-8-carboxylate t-butyl (200 mg, 0.74 mmol) obtained in the above step was added to N, N-dimethylformamide ( 4.0 mL), sodium hydride (> 55%, liquid paraffin dispersion, purchased from Kanto Chemical Co., Inc.) (39 mg, 0.89 mmol) was added and stirred for 30 minutes, and then obtained in Reference Example 119-4. The resulting 2: 3 mixture (180 mg, 0.89 mmol) of methyl 4- (bromomethyl) benzoate and methyl 4- (chloromethyl) benzoate was added and stirred at room temperature. After 28 hours, a saturated aqueous ammonium chloride solution (5.0 mL) and ethyl acetate (5.0 mL) were added. The mixture was extracted twice with ethyl acetate (10 mL), and the combined organic layer was washed with saturated brine (10 mL). The organic layer was separated, dried over anhydrous magnesium sulfate, and concentrated to dryness under reduced pressure. The obtained residue was purified by silica gel column chromatography [filler: Yamazen Hi-FLASH column size L (40 μm, 30 g), developing solvent: hexane / ethyl acetate = 1/1], and 3- [4- (methoxy Carbonyl) benzyl] -4-methyl-2-oxo-1-oxa-3,8-diazaspiro [4.5] decane-8-carboxylate t-butyl (290.0 mg, yield 95%) as a colorless oil Got as.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.09 (3H, d, J = 6.5 Hz), 1.45 (9H, s), 1.47-1.62 (2H, m), 1 .66-1.84 (2H, m), 3.14 (2H, dd, J = 22.8, 10.9 Hz), 3.26 (1H, q, J = 6.5 Hz), 3.92 ( 3H, s), 3.94-4.11 (2H, m), 4.16 (1H, d, J = 15.7 Hz), 4.80 (1H, d, J = 15.7 Hz), 7. 36 (2H, d, J = 8.2 Hz), 8.03 (2H, d, J = 8.2 Hz).

参考例１１９−６
４−［（４−メチル−２−オキソ−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル）メチル］安息香酸メチル塩酸塩の製造
参考例１１９−５で得られた３−［４−（メトキシカルボニル）ベンジル］−４−メチル−２−オキソ−１−オキサ−３，８−ジアザスピロ［４．５］デカン−８−カルボン酸ｔ−ブチル（２８０ｍｇ、０．６７ｍｍｏｌ）に４Ｍ塩化水素−ジオキサン溶液（３ｍＬ）を加え、室温で３時間撹拌した。反応停止後、反応混合物を減圧下濃縮乾固し、４−［（４−メチル−２−オキソ−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル）メチル］安息香酸メチル塩酸塩（２６０ｍｇ、収率１００％）を白色固体として得た。

^１Ｈ−ＮＭＲ（３００ＭＨｚ，ＣＤＣｌ_３）δ：１．１５（３Ｈ，ｄ，Ｊ＝６．５Ｈｚ），１．９４（２Ｈ，ｄｄ，Ｊ＝３５．６，１４．３Ｈｚ），２．０９−２．３１（２Ｈ，ｍ），３．１７−３．３８（３Ｈ，ｍ），３．３８−３．５５（２Ｈ，ｍ），３．９３（３Ｈ，ｓ），４．１４（１Ｈ，ｄ，Ｊ＝１５．６Ｈｚ），４．７９（１Ｈ，ｄ，Ｊ＝１５．６Ｈｚ），７．３４（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ），８．０３（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ），９．７０（２Ｈ，ｂｒｓ）．

Reference Example 119-6
Preparation of 4-[(4-methyl-2-oxo-1-oxa-3,8-diazaspiro [4.5] decan-3-yl) methyl] benzoic acid methyl hydrochloride Obtained in Reference Example 119-5 3- [4- (methoxycarbonyl) benzyl] -4-methyl-2-oxo-1-oxa-3,8-diazaspiro [4.5] decane-8-carboxylate t-butyl (280 mg, 0.67 mmol) To the mixture was added 4M hydrogen chloride-dioxane solution (3 mL), and the mixture was stirred at room temperature for 3 hours. After the reaction was stopped, the reaction mixture was concentrated to dryness under reduced pressure to give 4-[(4-methyl-2-oxo-1-oxa-3,8-diazaspiro [4.5] decan-3-yl) methyl] benzoic acid. Methyl hydrochloride (260 mg, 100% yield) was obtained as a white solid.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.15 (3H, d, J = 6.5 Hz), 1.94 (2H, dd, J = 35.6, 14.3 Hz), 2.09− 2.31 (2H, m), 3.17-3.38 (3H, m), 3.38-3.55 (2H, m), 3.93 (3H, s), 4.14 (1H, d, J = 15.6 Hz), 4.79 (1H, d, J = 15.6 Hz), 7.34 (2H, d, J = 8.2 Hz), 8.03 (2H, d, J = 8) .2 Hz), 9.70 (2H, brs).

参考例１１９−７
４−（｛４−メチル−２−オキソ−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）安息香酸メチルの製造
参考例１１９−６で得られた４−［（４−メチル−２−オキソ−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル）メチル］安息香酸メチル塩酸塩（２００ｍｇ、０．５６ｍｍｏｌ）にＮ，Ｎ−ジメチルホルムアミド（２．０ｍＬ）を加えた。４−（トリフルオロメチル）ベンジルブロミド（１５０ｍｇ、０．６１ｍｍｏｌ）、トリエチルアミン（０．２３ｍＬ、１．７ｍｍｏｌ）を順次加えて室温で撹拌した。２１時間後、反応を停止し、水（３．０ｍＬ）を加えた。析出した固体をろ取した後、減圧下５０℃で乾燥させ、４−（｛４−メチル−２−オキソ−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）安息香酸メチル（２４０ｍｇ、収率８８％）を白色固体として得た。

^１Ｈ−ＮＭＲ（３００ＭＨｚ，ＣＤＣｌ_３）δ：１．１０（３Ｈ，ｄ，Ｊ＝６．５Ｈｚ），１．５３−１．８７（４Ｈ，ｍ），２．３８−２．５５（２Ｈ，ｍ），２．７０（２Ｈ，ｔ，Ｊ＝１１．５Ｈｚ），３．２７（１Ｈ，ｑ，Ｊ＝６．５Ｈｚ），３．５７（２Ｈ，ｓ），３．９２（３Ｈ，ｓ），４．１５（１Ｈ，ｄ，Ｊ＝１５．６Ｈｚ），４．７９（１Ｈ，ｄ，Ｊ＝１５．６Ｈｚ），７．３５（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ），７．４３（２Ｈ，ｄ，Ｊ＝７．８Ｈｚ），７．５６（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ），８．０２（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ）．

Reference Example 119-7
4-({4-Methyl-2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl) methyl benzoate 4 obtained in reference example 119-6 of - [(4-methyl-2-oxo-1-oxa-3,8-diazaspiro [4.5] decan-3-yl) methyl] benzoate hydrochloride N, N-dimethylformamide (2.0 mL) was added to (200 mg, 0.56 mmol). 4- (Trifluoromethyl) benzyl bromide (150 mg, 0.61 mmol) and triethylamine (0.23 mL, 1.7 mmol) were sequentially added and stirred at room temperature. After 21 hours, the reaction was stopped and water (3.0 mL) was added. The precipitated solid was collected by filtration and dried at 50 ° C. under reduced pressure to give 4-({4-methyl-2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8- Diazaspiro [4.5] decan-3-yl} methyl) methyl benzoate (240 mg, 88% yield) was obtained as a white solid.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.10 (3H, d, J = 6.5 Hz), 1.53-1.87 (4H, m), 2.38-2.55 (2H, m), 2.70 (2H, t, J = 11.5 Hz), 3.27 (1H, q, J = 6.5 Hz), 3.57 (2H, s), 3.92 (3H, s) 4.15 (1H, d, J = 15.6 Hz), 4.79 (1 H, d, J = 15.6 Hz), 7.35 (2H, d, J = 8.2 Hz), 7.43 ( 2H, d, J = 7.8 Hz), 7.56 (2H, d, J = 8.2 Hz), 8.02 (2H, d, J = 8.2 Hz).

参考例１１９−８
４−（｛４−メチル−２−オキソ−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）安息香酸の製造
参考例１１９−７で得られた４−（｛４−メチル−２−オキソ−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）安息香酸メチル（２４０ｍｇ、０．４９ｍｍｏｌ）を１，４−ジオキサン（３．０ｍＬ）とメタノール（２．０ｍＬ）の混合溶媒に溶かした後、１Ｍ水酸化ナトリウム水溶液（３．０ｍＬ）を加えて室温で撹拌した。２時間後、１Ｍ塩酸（３．０ｍＬ）を加えて反応を停止した。反応物を酢酸エチル（１０ｍＬ）で２回抽出し、合わせた有機層を飽和食塩水（１０ｍＬ）で洗浄した。有機層を分離し、無水硫酸マグネシウムで乾燥した後、減圧下濃縮乾固した。４−（｛４−メチル−２−オキソ−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）安息香酸（１７０ｍｇ、収率７７％）を白色固体として得た。

ＬＣ／ＭＳ［条件１］：保持時間３．１０分；ｍ／ｚ４６２．７［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ４６０．９［Ｍ−Ｈ］^―（ＥＳＩ負イオンモード）

Reference Example 119-8
Of 4-({4-methyl-2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl) benzoic acid 4-({4-Methyl-2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decane obtained in Preparation Reference Example 119-7 -3-yl} methyl) methyl benzoate (240 mg, 0.49 mmol) was dissolved in a mixed solvent of 1,4-dioxane (3.0 mL) and methanol (2.0 mL), and then 1M aqueous sodium hydroxide solution (3 0.0 mL) was added and stirred at room temperature. After 2 hours, 1M hydrochloric acid (3.0 mL) was added to stop the reaction. The reaction was extracted twice with ethyl acetate (10 mL), and the combined organic layers were washed with saturated brine (10 mL). The organic layer was separated, dried over anhydrous magnesium sulfate, and concentrated to dryness under reduced pressure. 4-({4-Methyl-2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl) benzoic acid ( 170 mg, 77% yield) was obtained as a white solid.

LC / MS [Condition 1]: Retention time 3.10 minutes; m / z 462.7 [M + H] ⁺ (ESI positive ion mode), m / z 460.9 [M−H] ⁻ (ESI negative ion mode)

実施例１１９
４−（｛４−メチル−２−オキソ−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）−Ｎ−［（テトラヒドロフラン−２−イル）メチル］ベンズアミド（化合物番号１１９）の製造
参考例１１９−８で得られた４−（｛４−メチル−２−オキソ−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）安息香酸（４０ｍｇ、０．０８６ｍｍｏｌ）、１−エチル−３−（３−ジメチルアミノプロピル）カルボジイミド塩酸塩（３３ｍｇ、０．１７ｍｍｏｌ）および１−ヒドロキシベンゾトリアゾール（２３ｍｇ、０．１７ｍｍｏｌ）をクロロホルム（１．０ｍＬ）に溶かした後、テトラヒドロフルフリルアミン（東京化成工業（株）より購入）（０．０１８ｍＬ、０．１７ｍｍｏｌ）とトリエチルアミン（０．０２４ｍＬ、０．１７ｍｍｏｌ）を室温にて加え、３日間撹拌した。反応混合物に水（２．０ｍＬ）と酢酸エチル（２．０ｍＬ）を加えたのち、酢酸エチル（１０ｍＬ）で２回抽出し、合わせた有機層を飽和食塩水（１０ｍＬ）で洗浄した。有機層を分離し、無水硫酸マグネシウムで乾燥した後、減圧下濃縮乾固した。残留物をシリカゲルカラムクロマトグラフィー［充填剤：富士シリシア製ＦＬ１００Ｄ、展開溶媒：酢酸エチル／メタノール＝１０／１］にて精製し、４−（｛４−メチル−２−オキソ−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）−Ｎ−［（テトラヒドロフラン−２−イル）メチル］ベンズアミド（４３ｍｇ、収率９１％）を白色粉末として得た。

^１Ｈ−ＮＭＲ（３００ＭＨｚ，ＣＤＣｌ_３）δ：１．０９（３Ｈ，ｄ，Ｊ＝６．５Ｈｚ），１．５９−１．８５（５Ｈ，ｍ），１．８７−１．９８（２Ｈ，ｍ），１．９８−２．１０（１Ｈ，ｍ），２．３８−２．５４（２Ｈ，ｍ），２．６９（２Ｈ，ｔ，Ｊ＝１１．９Ｈｚ），３．２４（１Ｈ，ｑ，Ｊ＝６．５Ｈｚ），３．２７−３．３８（１Ｈ，ｍ），３．５６（２Ｈ，ｂｒｓ），３．７２−３．９４（３Ｈ，ｍ），４．０７（１Ｈ，ｄｑ，Ｊ＝２．９，７．４Ｈｚ），４．１２（１Ｈ，ｄ，Ｊ＝１５．６Ｈｚ），４．７９（１Ｈ，ｄ，Ｊ＝１５．６Ｈｚ），６．４８（１Ｈ，ｔ，Ｊ＝４．９Ｈｚ），７．３４（２Ｈ，ｄ，Ｊ＝７．８Ｈｚ），７．４３（２Ｈ，ｄ，Ｊ＝８．０Ｈｚ），７．５６（２Ｈ，ｄ，Ｊ＝８．０Ｈｚ），７．７６（２Ｈ，ｄ，Ｊ＝７．８Ｈｚ）．

ＬＣ／ＭＳ［条件１］：保持時間３．１８分；ｍ／ｚ５４５．９［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ５９０．１［Ｍ＋ＨＣＯＯ］^―（ＥＳＩ負イオンモード）

Example 119
4-({4-Methyl-2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl) -N- Preparation of [(tetrahydrofuran-2-yl) methyl] benzamide (Compound No. 119) 4-({4-Methyl-2-oxo-8- [4- (trifluoromethyl) benzyl ] obtained in Reference Example 119-8 ] -1-Oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl) benzoic acid (40 mg, 0.086 mmol), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (33 mg, 0.17 mmol) and 1-hydroxybenzotriazole (23 mg, 0.17 mmol) were dissolved in chloroform (1.0 mL). Triethanolamine (Tokyo Chemical Industry Co., Ltd. purchased from) (0.018mL, 0.17mmol) and added triethylamine (0.024mL, 0.17mmol) and at room temperature, the mixture was stirred for 3 days. Water (2.0 mL) and ethyl acetate (2.0 mL) were added to the reaction mixture, followed by extraction twice with ethyl acetate (10 mL), and the combined organic layer was washed with saturated brine (10 mL). The organic layer was separated, dried over anhydrous magnesium sulfate, and concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography [filler: FL100D manufactured by Fuji Silysia, developing solvent: ethyl acetate / methanol = 10/1], and 4-({4-methyl-2-oxo-8- [4- (Trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl) -N-[(tetrahydrofuran-2-yl) methyl] benzamide (43 mg, yield 91 %) As a white powder.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.09 (3H, d, J = 6.5 Hz), 1.59-1.85 (5H, m), 1.87-1.98 (2H, m), 1.98-2.10 (1H, m), 2.38-2.54 (2H, m), 2.69 (2H, t, J = 11.9 Hz), 3.24 (1H, q, J = 6.5 Hz), 3.27-3.38 (1H, m), 3.56 (2H, brs), 3.72-3.94 (3H, m), 4.07 (1H, dq, J = 2.9, 7.4 Hz), 4.12 (1H, d, J = 15.6 Hz), 4.79 (1H, d, J = 15.6 Hz), 6.48 (1H, t , J = 4.9 Hz), 7.34 (2H, d, J = 7.8 Hz), 7.43 (2H, d, J = 8.0 Hz), 7.56 (2H, d, J = 8. 0 Hz), 7.7 (2H, d, J = 7.8Hz).

LC / MS [Condition 1]: Retention time 3.18 minutes; m / z 545.9 [M + H] ⁺ (ESI positive ion mode), m / z 590.1 [M + HCOO] ⁻ (ESI negative ion mode)

実施例１２０
４−［４−（｛４−メチル−２−オキソ−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）ベンズアミド］ピペリジン−１−カルボン酸ｔ−ブチル（化合物番号１２０）の製造
テトラヒドロフルフリルアミンの代わりに、４−アミノピペリジン−１−カルボン酸ｔ−ブチル（アルドリッチ（株）より購入）を用いること以外は実質的に実施例１１９と同様に反応を行なって、表題化合物を白色固体（１５０ｍｇ、収率８９％）として得た。

^１Ｈ−ＮＭＲ（３００ＭＨｚ，ＣＤＣｌ_３）δ：１．０９（３Ｈ，ｄ，Ｊ＝６．５Ｈｚ），１．３２−１．４９（２Ｈ，ｍ），１．４７（９Ｈ，ｓ），１．６０−１．８５（４Ｈ，ｍ），１．９６−２．０７（２Ｈ，ｍ），２．３８−２．５４（２Ｈ，ｍ），２．６９（２Ｈ，ｔ，Ｊ＝１２．７Ｈｚ），２．９１（２Ｈ，ｔ，Ｊ＝１２．７Ｈｚ），３．２４（１Ｈ，ｑ，Ｊ＝６．５Ｈｚ），３．５６（２Ｈ，ｓ），４．０２−４．２１（３Ｈ，ｂｒｍ），４．１３（１Ｈ，ｄ，Ｊ＝１５．６Ｈｚ），４．７９（１Ｈ，ｄ，Ｊ＝１５．６Ｈｚ），５．９３（１Ｈ，ｄ，Ｊ＝８．２Ｈｚ），７．３５（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ），７．４２（２Ｈ，ｄ，Ｊ＝７．８Ｈｚ），７．５６（２Ｈ，ｄ，Ｊ＝７．８Ｈｚ），７．７２（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ）．

ＬＣ／ＭＳ［条件１］：保持時間３．６２分；ｍ／ｚ６４５．０［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ６４３．１［Ｍ−Ｈ］^―（ＥＳＩ負イオンモード）

Example 120
4- [4-({4-Methyl-2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl) Benzamide] Preparation of t-butyl piperidine-1-carboxylate (Compound No. 120) Instead of using tetrahydrofurfurylamine, t-butyl 4-aminopiperidine-1-carboxylate (purchased from Aldrich Co.) was used. The reaction was carried out substantially as in Example 119 to give the title compound as a white solid (150 mg, 89% yield).

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.09 (3H, d, J = 6.5 Hz), 1.32-1.49 (2H, m), 1.47 (9H, s), 1 60-1.85 (4H, m), 1.96-2.07 (2H, m), 2.38-2.54 (2H, m), 2.69 (2H, t, J = 12. 7 Hz), 2.91 (2H, t, J = 12.7 Hz), 3.24 (1 H, q, J = 6.5 Hz), 3.56 (2H, s), 4.02-4.21 ( 3H, brm), 4.13 (1H, d, J = 15.6 Hz), 4.79 (1H, d, J = 15.6 Hz), 5.93 (1H, d, J = 8.2 Hz), 7.35 (2H, d, J = 8.2 Hz), 7.42 (2H, d, J = 7.8 Hz), 7.56 (2H, d, J = 7.8 Hz), 7.72 (2H , D, J = .2Hz).

LC / MS [Condition 1]: Retention time 3.62 minutes; m / z 645.0 [M + H] ⁺ (ESI positive ion mode), m / z 643.1 [M−H] ⁻ (ESI negative ion mode)

参考例１２１
４−（｛４−メチル−２−オキソ−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）−Ｎ−（ピペリジン−４−イル）ベンズアミド２塩酸塩の製造
実施例１２０で得られた４−［４−（｛４−メチル−２−オキソ−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）ベンズアミド］ピペリジン−１−カルボン酸ｔ−ブチル（１１０ｍｇ、０．１８ｍｍｏｌ）を４Ｍ塩化水素−ジオキサン溶液（２．０ｍＬ）に溶かし、室温で１時間撹拌した。反応停止後、反応混合物を減圧下濃縮乾固し、４−（｛４−メチル−２−オキソ−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）−Ｎ−（ピペリジン−４−イル）ベンズアミド２塩酸塩（１３０ｍｇ）を白色固体として得た。未精製のまま次の反応に使用した。

Reference Example 121
4-({4-Methyl-2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl) -N- Preparation of (piperidin-4-yl) benzamide dihydrochloride 4- [4-({4-methyl-2-oxo-8- [4- (trifluoromethyl) benzyl] -1-] obtained in Example 120 Oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl) benzamide] piperidine-1-carboxylate (110 mg, 0.18 mmol) in 4M hydrogen chloride-dioxane solution (2.0 mL) And stirred at room temperature for 1 hour. After stopping the reaction, the reaction mixture was concentrated to dryness under reduced pressure, and 4-({4-methyl-2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4 .5] Decan-3-yl} methyl) -N- (piperidin-4-yl) benzamide dihydrochloride (130 mg) was obtained as a white solid. The crude product was used in the next reaction without purification.

実施例１２１
Ｎ−［１−（シアノメチル）ピペリジン−４−イル］−４−（｛４−メチル−２−オキソ−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）ベンズアミド（化合物番号１２１）の製造
参考例１２１で得られた４−（｛４−メチル−２−オキソ−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）−Ｎ−（ピペリジン−４−イル）ベンズアミド２塩酸塩（５４ｍｇ、０．０８８ｍｍｏｌ）をＮ，Ｎ−ジメチルホルムアミド（１．０ｍＬ）に溶かし、ブロモアセトニトリル（東京化成工業（株）より購入）（０．０１２ｍＬ、０．１８ｍｍｏｌ）およびトリエチルアミン（０．０３７ｍＬ、０．２６ｍｍｏｌ）を順次加えて室温で２日間撹拌した。反応混合物に水（２．０ｍＬ）と酢酸エチル（２．０ｍＬ）を加えたのち、酢酸エチル（１０ｍＬ）で２回抽出し、合わせた有機層を飽和炭酸水素ナトリウム水溶液（１０ｍＬ）、飽和食塩水（１０ｍＬ）で順次洗浄した。有機層を分離し、無水硫酸マグネシウムで乾燥した後、減圧下濃縮乾固した。出てきた固体にヘキサン／酢酸エチル（４／１、５．０ｍＬ）を加え振とうした後、固体をろ取し、減圧下５０℃で乾燥させ、Ｎ−［１−（シアノメチル）ピペリジン−４−イル］−４−（｛４−メチル−２−オキソ−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）ベンズアミド（３５ｍｇ、収率６８％）を白色粉末として得た。

^１Ｈ−ＮＭＲ（３００ＭＨｚ，ＣＤＣｌ_３）δ：１．１０（３Ｈ，ｄ，Ｊ＝６．５Ｈｚ），１．５６−１．８６（６Ｈ，ｍ），２．０６−２．１６（２Ｈ，ｍ），２．３９−２．５８（２Ｈ，ｂｒｍ），２．５３（２Ｈ，ｔｄ，Ｊ＝１１．０，２．５Ｈｚ），２．６２−２．７８（２Ｈ，ｂｒｍ），２．８３（２Ｈ，ｄｔ，Ｊ＝１２．３，３．３Ｈｚ），３．２６（１Ｈ，ｑ，Ｊ＝６．５Ｈｚ），３．５４（２Ｈ，ｓ），３．５８（２Ｈ，ｂｒｓ），３．９６−４．１０（１Ｈ，ｍ），４．１３（１Ｈ，ｄ，Ｊ＝１５．６Ｈｚ），４．７９（１Ｈ，ｄ，Ｊ＝１５．６Ｈｚ），５．９６（１Ｈ，ｄ，Ｊ＝８．２Ｈｚ），７．３５（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ），７．４０−７．５１（２Ｈ，ｂｒｍ），７．５３−７．６３（２Ｈ，ｂｒｍ），７．７３（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ）．

ＬＣ／ＭＳ［条件１］：保持時間３．００分；ｍ／ｚ５８３．８［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ５８２．１［Ｍ−Ｈ］^―（ＥＳＩ負イオンモード）

Example 121
N- [1- (cyanomethyl) piperidin-4-yl] -4-({4-methyl-2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [ 4.5] Preparation of decan-3-yl} methyl) benzamide (Compound No. 121) 4-({4-Methyl-2-oxo-8- [4- (trifluoromethyl) benzyl] obtained in Reference Example 121 ] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl) -N- (piperidin-4-yl) benzamide dihydrochloride (54 mg, 0.088 mmol) was added to N, N- Dissolved in dimethylformamide (1.0 mL), bromoacetonitrile (purchased from Tokyo Chemical Industry Co., Ltd.) (0.012 mL, 0.18 mmol) and triethylamine (0.037 mL, 0.2 mmol) was sequentially added and stirred at room temperature for 2 days. Water (2.0 mL) and ethyl acetate (2.0 mL) were added to the reaction mixture, and the mixture was extracted twice with ethyl acetate (10 mL). The combined organic layers were saturated aqueous sodium hydrogen carbonate solution (10 mL) and saturated brine. Washed sequentially with (10 mL). The organic layer was separated, dried over anhydrous magnesium sulfate, and concentrated to dryness under reduced pressure. Hexane / ethyl acetate (4/1, 5.0 mL) was added to the solid that appeared and shaken, and then the solid was collected by filtration, dried at 50 ° C. under reduced pressure, and N- [1- (cyanomethyl) piperidine-4. -Yl] -4-({4-methyl-2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl ) Benzamide (35 mg, 68% yield) was obtained as a white powder.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.10 (3H, d, J = 6.5 Hz), 1.56-1.86 (6H, m), 2.06-2.16 (2H, m), 2.39-2.58 (2H, brm), 2.53 (2H, td, J = 11.0, 2.5 Hz), 2.62-2.78 (2H, brm), 2. 83 (2H, dt, J = 12.3, 3.3 Hz), 3.26 (1H, q, J = 6.5 Hz), 3.54 (2H, s), 3.58 (2H, brs), 3.96-4.10 (1H, m), 4.13 (1H, d, J = 15.6 Hz), 4.79 (1H, d, J = 15.6 Hz), 5.96 (1H, d , J = 8.2 Hz), 7.35 (2H, d, J = 8.2 Hz), 7.40-7.51 (2H, brm), 7.53-7.63 (2H, brm), .73 (2H, d, J = 8.2Hz).

LC / MS [Condition 1]: Retention time 3.00 minutes; m / z 583.8 [M + H] ⁺ (ESI positive ion mode), m / z 582.1 [M−H] ⁻ (ESI negative ion mode)

実施例１２２
４−［４−（｛４−メチル−２−オキソ−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）ベンズアミド］ピペリジン−１−カルボン酸メチル（化合物番号１２２）の製造
ブロモアセトニトリルの代わりに、クロロギ酸メチル（東京化成工業（株）より購入）を用いること以外は実質的に実施例１２１と同様に反応を行なって、表題化合物を白色粉末（４６ｍｇ、収率８７％）として得た。

^１Ｈ−ＮＭＲ（３００ＭＨｚ，ＣＤＣｌ_３）δ：１．１０（３Ｈ，ｄ，Ｊ＝６．５Ｈｚ），１．３４−１．５０（２Ｈ，ｍ），１．６３−１．８５（４Ｈ，ｍ），２．０５（２Ｈ，ｄｄ，Ｊ＝１２．７，３．３Ｈｚ），２．３８−２．５５（２Ｈ，ｂｒｍ），２．６０−２．７８（２Ｈ，ｂｒｍ），２．９７（２Ｈ，ｔ，Ｊ＝１２．３Ｈｚ），３．２５（１Ｈ，ｑ，Ｊ＝６．５Ｈｚ），３．５７（２Ｈ，ｂｒｓ），３．７０（３Ｈ，ｓ），４．０５−４．２６（３Ｈ，ｍ），４．１３（１Ｈ，ｄ，Ｊ＝１５．３Ｈｚ），４．７８（１Ｈ，ｄ，Ｊ＝１５．３Ｈｚ），５．９６（１Ｈ，ｄ，Ｊ＝７．８Ｈｚ），７．３５（２Ｈ，ｄ，Ｊ＝８．６Ｈｚ），７．３９−７．４９（２Ｈ，ｂｒｍ），７．５２−７．６２（２Ｈ，ｂｒｍ），７．７３（２Ｈ，ｄ，Ｊ＝７．８Ｈｚ）．

ＬＣ／ＭＳ［条件１］：保持時間３．２２分；ｍ／ｚ６０２．９［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ６０１．０［Ｍ−Ｈ］^―（ＥＳＩ負イオンモード）

Example 122
4- [4-({4-Methyl-2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl) Benzamide] Production of methyl piperidine-1-carboxylate (Compound No. 122) The reaction was carried out in substantially the same manner as in Example 121 except that methyl chloroformate (purchased from Tokyo Chemical Industry Co., Ltd.) was used instead of bromoacetonitrile. To give the title compound as a white powder (46 mg, 87% yield).

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.10 (3H, d, J = 6.5 Hz), 1.34-1.50 (2H, m), 1.63-1.85 (4H, m), 2.05 (2H, dd, J = 12.7, 3.3 Hz), 2.38-2.55 (2H, brm), 2.60-2.78 (2H, brm), 2. 97 (2H, t, J = 12.3 Hz), 3.25 (1H, q, J = 6.5 Hz), 3.57 (2H, brs), 3.70 (3H, s), 4.05- 4.26 (3H, m), 4.13 (1H, d, J = 15.3 Hz), 4.78 (1H, d, J = 15.3 Hz), 5.96 (1H, d, J = 7) .8 Hz), 7.35 (2H, d, J = 8.6 Hz), 7.39-7.49 (2H, brm), 7.52-7.62 (2H, brm), 7.73 ( H, d, J = 7.8Hz).

LC / MS [Condition 1]: Retention time 3.22 minutes; m / z 602.9 [M + H] ⁺ (ESI positive ion mode), m / z 601.0 [M−H] ⁻ (ESI negative ion mode)

実施例１２３
３−｛［（１ｒ，４ｒ）−４−（１−ベンジルピペリジン−４−イルカルバモイル）シクロヘキシル］メチル｝−２−オキソ−１−オキサ−３，８−ジアザスピロ［４．５］デカン−８−カルボン酸ｔ−ブチル（化合物番号１２３）の製造
参考例２−３で得られた、（１ｒ，４ｒ）−４−｛［８−（ｔ−ブトキシカルボニル）−２−オキソ−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル］メチル｝シクロヘキサンカルボン酸（０．２９ｇ、０．７３ｍｍｏｌ）をクロロホルム（３．０ｍＬ）に溶解し、４−アミノ−１−ベンジルピペリジン（０．２１ｇ、１．１ｍｍｏｌ）、１−ヒドロキシベンゾトリアゾール（３０ｍｇ、０．２２ｍｍｏｌ）及び１−エチル−３−（３−ジメチルアミノプロピル）カルボジイミド塩酸塩（０．２１ｇ、１．１ｍｍｏｌ）を加え、室温にて４日間かき混ぜた。反応終了後、反応混合物に水（５．０ｍＬ）を加えて有機層を分離し、さらにその有機層を水（１０ｍＬ）で洗浄したのち、減圧下濃縮乾固した。残留物に酢酸エチル（３．０ｍＬ）を加えて、よく振とうしたのち不溶物をろ取して、３−｛［（１ｒ，４ｒ）−４−（１−ベンジルピペリジン−４−イルカルバモイル）シクロヘキシル］メチル｝−２−オキソ−１−オキサ−３，８−ジアザスピロ［４．５］デカン−８−カルボン酸ｔ−ブチル（０．３５ｇ、収率８３％）を白色固体として得た。

^１Ｈ−ＮＭＲ（３００ＭＨｚ，ＣＤＣｌ_３）δ：１．０２（２Ｈ，ｄｑ，Ｊ＝２．９，１２．７Ｈｚ），１．３３−１．７２（２Ｈ，ｍ），１．４６（９Ｈ，ｓ），１．７６（２Ｈ，ｄ，Ｊ＝１３．１Ｈｚ），１．８２−１．９５（６Ｈ，ｍ），１．９７（１Ｈ，ｔｔ，Ｊ＝１２．３，３．７Ｈｚ），２．１１（２Ｈ，ｔ，Ｊ＝１２．３Ｈｚ），２．７２−２．８７（２Ｈ，ｍ），３．１０（２Ｈ，ｄ，Ｊ＝７．４Ｈｚ），３．２０−３．３５（２Ｈ，ｍ），３．２５（２Ｈ，ｓ），３．４９（２Ｈ，ｓ），３．６５−３．９７（３Ｈ，ｍ），５．２８（１Ｈ，ｄ，Ｊ＝８．２Ｈｚ），７．２１−７．３６（５Ｈ，ｍ）．

Example 123
3-{[(1r, 4r) -4- (1-Benzylpiperidin-4-ylcarbamoyl) cyclohexyl] methyl} -2-oxo-1-oxa-3,8-diazaspiro [4.5] decane-8- Production of t-butyl carboxylate (Compound No. 123) (1r, 4r) -4-{[8- (t-butoxycarbonyl) -2-oxo-1-oxa-3 obtained in Reference Example 2-3 , 8-diazaspiro [4.5] decan-3-yl] methyl} cyclohexanecarboxylic acid (0.29 g, 0.73 mmol) was dissolved in chloroform (3.0 mL) and 4-amino-1-benzylpiperidine (0 .21 g, 1.1 mmol), 1-hydroxybenzotriazole (30 mg, 0.22 mmol) and 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride 0.21 g, 1.1 mmol) and the mixture was stirred at room temperature for 4 days. After completion of the reaction, water (5.0 mL) was added to the reaction mixture to separate the organic layer. The organic layer was further washed with water (10 mL) and then concentrated to dryness under reduced pressure. Ethyl acetate (3.0 mL) was added to the residue, and after shaking well, the insoluble material was collected by filtration to give 3-{[(1r, 4r) -4- (1-benzylpiperidin-4-ylcarbamoyl) Cyclohexyl] methyl} -2-oxo-1-oxa-3,8-diazaspiro [4.5] decane-8-carboxylate t-butyl (0.35 g, 83% yield) was obtained as a white solid.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.02 (2H, dq, J = 2.9, 12.7 Hz), 1.33-1.72 (2H, m), 1.46 (9H, s), 1.76 (2H, d, J = 13.1 Hz), 1.82-1.95 (6H, m), 1.97 (1H, tt, J = 12.3, 3.7 Hz), 2.11 (2H, t, J = 12.3 Hz), 2.72-2.87 (2H, m), 3.10 (2H, d, J = 7.4 Hz), 3.20-3.35 (2H, m), 3.25 (2H, s), 3.49 (2H, s), 3.65-3.97 (3H, m), 5.28 (1H, d, J = 8.2 Hz) ), 7.21-7.36 (5H, m).

実施例１２４
（１ｒ，４ｒ）−Ｎ−（１−ベンジルピペリジン−４−イル）−４−（｛２−オキソ−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）シクロヘキサンカルボキサミド（化合物番号１２４）の製造
参考例６−３で得られた、（１ｒ，４ｒ）−４−（｛２−オキソ−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）シクロヘキサンカルボン酸（９１ｍｇ、０．２０ｍｍｏｌ）、４−アミノ−１−ベンジルピペリジン（５７ｍｇ、０．３０ｍｍｏｌ）及び１−ヒドロキシベンゾトリアゾール（８ｍｇ、０．０６０ｍｏｌ）をクロロホルム（２．０ｍＬ）に溶解した後、室温にて、１−エチル−３−（３−ジメチルアミノプロピル）カルボジイミド塩酸塩（５８ｍｇ、０．３０ｍｍｏｌ）を加え、室温で３日間かき混ぜた。その後、水（２．０ｍＬ）を加えて、有機層を分離したのち減圧下濃縮した。残留物に酢酸エチル（３．０ｍＬ）を加えて、よく振とうしたのち、不溶物をろ取した。これをシリカゲルカラムクロマトグラフィー［充填剤：富士シリシア製ＮＨ−ＤＭ１０２０、展開溶媒：クロロホルム／酢酸エチル＝１０／１］にて精製し、（１ｒ，４ｒ）−Ｎ−（１−ベンジルピペリジン−４−イル）−４−（｛２−オキソ−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）シクロヘキサンカルボキサミド（１０９ｍｇ、収率８７％）を白色固体として得た。

^１Ｈ−ＮＭＲ（３００ＭＨｚ，ＣＤＣｌ_３）δ：１．０１（２Ｈ，ｄｑ，Ｊ＝３．７，１２．３Ｈｚ），１．３３−１．６４（５Ｈ，ｍ），１．６９−１．８３（４Ｈ，ｍ），１．８３−２．０３（７Ｈ，ｍ），２．１１（２Ｈ，ｔ，Ｊ＝１１．５Ｈｚ），２．４５−２．６４（４Ｈ，ｍ），２．７９（２Ｈ，ｄ，Ｊ＝１１．９Ｈｚ），３．０９（２Ｈ，ｄ，Ｊ＝７．０Ｈｚ），３．２５（２Ｈ，ｓ），３．４８（２Ｈ，ｓ），３．５７（２Ｈ，ｂｒ ｓ），３．６９−３．８７（１Ｈ，ｍ），５．２７（１Ｈ，ｂｒｄ，Ｊ＝７．８Ｈｚ），７．２１−７．３３（５Ｈ，ｍ），７．４４（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ），７．５７（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ）．

ＬＣ／ＭＳ［条件２］：保持時間３．１６分；ｍ／ｚ３１４．２［Ｍ＋２Ｈ］^２＋、６２７．４［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）

Example 124
(1r, 4r) -N- (1-Benzylpiperidin-4-yl) -4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [ 4.5] Decan-3-yl} methyl) cyclohexanecarboxamide (Compound No. 124) obtained in Reference Example 6-3, (1r, 4r) -4-({2-oxo-8- [4- (Trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl) cyclohexanecarboxylic acid (91 mg, 0.20 mmol), 4-amino-1-benzylpiperidine ( 57 mg, 0.30 mmol) and 1-hydroxybenzotriazole (8 mg, 0.060 mol) were dissolved in chloroform (2.0 mL), and then at room temperature, 1-ethyl-3 (3-dimethylaminopropyl) carbodiimide hydrochloride (58 mg, 0.30 mmol) and the mixture was stirred at room temperature for 3 days. Thereafter, water (2.0 mL) was added, and the organic layer was separated and concentrated under reduced pressure. Ethyl acetate (3.0 mL) was added to the residue and shaken well, and then the insoluble material was collected by filtration. This was purified by silica gel column chromatography [filler: NH-DM1020 manufactured by Fuji Silysia, developing solvent: chloroform / ethyl acetate = 10/1], and (1r, 4r) -N- (1-benzylpiperidine-4- Yl) -4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl) cyclohexanecarboxamide (109 mg Yield 87%) as a white solid.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.01 (2H, dq, J = 3.7, 12.3 Hz), 1.33-1.64 (5H, m), 1.69-1. 83 (4H, m), 1.83 to 2.03 (7H, m), 2.11 (2H, t, J = 11.5 Hz), 2.45-2.64 (4H, m), 2. 79 (2H, d, J = 11.9 Hz), 3.09 (2H, d, J = 7.0 Hz), 3.25 (2H, s), 3.48 (2H, s), 3.57 ( 2H, br s), 3.69-3.87 (1H, m), 5.27 (1H, brd, J = 7.8 Hz), 7.21-7.33 (5H, m), 7.44. (2H, d, J = 8.2 Hz), 7.57 (2H, d, J = 8.2 Hz).

LC / MS [Condition 2]: Retention time 3.16 minutes; m / z 314.2 [M + 2H] ²⁺ , 627.4 [M + H] ⁺ (ESI positive ion mode)

実施例１２５
ｔ−ブチル ３−［（１ｒ，４ｒ）−４−（｛２−オキソ−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）シクロヘキサンカルボキサミド］プロピルカルバメート（化合物番号１２５）の製造
４−アミノ−１−ベンジルピペリジンの代わりにＮ−（ｔ−ブトキシカルボニル）−１，３−ジアミノプロパンを用いること以外は実質的に実施例１２４と同様に反応を行って、表題化合物（０．２３ｇ、収率８４％）を白色固体として得た。

^１Ｈ−ＮＭＲ（３００ＭＨｚ，ＣＤＣｌ_３）δ：１．０３（２Ｈ，ｄｑ，Ｊ＝２．９，１２．７Ｈｚ），１．３４−１．５３（７Ｈ，ｍ），１．５３−１．６８（３Ｈ，ｍ），１．６９−１．８５（４Ｈ，ｍ），１．８５−１．９８（４Ｈ，ｍ），２．０５（１Ｈ，ｔｔ，Ｊ＝１２．７，３．３Ｈｚ），２．４３−２．７１（４Ｈ，ｍ），３．０９（２Ｈ，ｄ，Ｊ＝７．４Ｈｚ），３．１５（２Ｈ，ｄｔ，Ｊ＝６．５，６．１Ｈｚ），３．２５（２Ｈ，ｓ），３．２８（２Ｈ，ｄｔ，Ｊ＝６．１，６．１Ｈｚ），３．５７（２Ｈ，ｓ），４．８８（１Ｈ，ｂｒ ｓ），６．１９（１Ｈ，ｂｒ ｓ），７．４４（２Ｈ，ｄ，Ｊ＝８．６Ｈｚ），７．５７（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ）．

ＬＣ／ＭＳ［条件２］：保持時間３．６４分；ｍ／ｚ６１１．４［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ６５５．８［Ｍ＋ＨＣＯＯ］^―（ＥＳＩ負イオンモード）

Example 125
t-butyl 3-[(1r, 4r) -4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decane-3 Preparation of -yl} methyl) cyclohexanecarboxamido] propyl carbamate (Compound No. 125) Substantially except that N- (t-butoxycarbonyl) -1,3-diaminopropane is used instead of 4-amino-1-benzylpiperidine Was reacted in the same manner as in Example 124 to obtain the title compound (0.23 g, yield 84%) as a white solid.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.03 (2H, dq, J = 2.9, 12.7 Hz), 1.34 to 1.53 (7H, m), 1.53-1. 68 (3H, m), 1.69-1.85 (4H, m), 1.85-1.98 (4H, m), 2.05 (1H, tt, J = 12.7, 3.3 Hz) ), 2.43-2.71 (4H, m), 3.09 (2H, d, J = 7.4 Hz), 3.15 (2H, dt, J = 6.5, 6.1 Hz), 3 .25 (2H, s), 3.28 (2H, dt, J = 6.1, 6.1 Hz), 3.57 (2H, s), 4.88 (1H, br s), 6.19 ( 1H, br s), 7.44 (2H, d, J = 8.6 Hz), 7.57 (2H, d, J = 8.2 Hz).

LC / MS [Condition 2]: Retention time 3.64 min; m / z 611.4 [M + H] ⁺ (ESI positive ion mode), m / z 655.8 [M + HCOO] ⁻ (ESI negative ion mode)

実施例１２６
（１ｒ，４ｒ）−Ｎ−シクロヘキシル−４−（｛２−オキソ−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）シクロヘキサンカルボキサミド（化合物番号１２６）の製造
参考例６−３で得られた、（１ｒ，４ｒ）−４−（｛２−オキソ−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）シクロヘキサンカルボン酸（０．４２ｇ、０．９３ｍｍｏｌ）、シクロヘキシルアミン（０．１６ｍＬ、１．４ｍｍｏｌ）、および１−ヒドロキシベンゾトリアゾール（３８ｍｇ、０．２８ｍｏｌ）をクロロホルム（８．０ｍＬ）に溶解した後、室温にて、１−エチル−３−（３−ジメチルアミノプロピル）カルボジイミド塩酸塩（０．２７ｇ、１．４ｍｍｏｌ）を加え、室温で１日間かき混ぜた。水（８．０ｍＬ）を加えてよく振とうした後に、有機層を分離して減圧下濃縮乾固した。残留物に水（２０ｍＬ）を加えてよく振とうした後に、不溶物をろ取して、（１ｒ，４ｒ）−Ｎ−シクロヘキシル−４−（｛２−オキソ−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）シクロヘキサンカルボキサミド（０．４５ｇ、収率８９％）を白色固体として得た。

^１Ｈ−ＮＭＲ（３００ＭＨｚ，ＣＤＣｌ_３）δ：０．８９−１．２４（５Ｈ，ｍ），１．２６−１．５２（４Ｈ，ｍ），１．５２−１．８３（８Ｈ，ｍ），１．８４−２．０３（７Ｈ，ｍ），２．４３−２．６６（４Ｈ，ｍ），３．０９（２Ｈ，ｄ，Ｊ＝７．４Ｈｚ），３．２５（２Ｈ，ｂｒ ｓ），３．５７（２Ｈ，ｂｒ ｓ），３．６５−３．８３（１Ｈ，ｍ），５．２６（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ），７．４４（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ），７．５７（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ）．

ＬＣ／ＭＳ［条件２］：保持時間３．６２分；ｍ／ｚ５３６．２［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）

Example 126
(1r, 4r) -N-cyclohexyl-4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl } Methyl) Cyclohexanecarboxamide (Compound No. 126) (1r, 4r) -4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1 obtained in Reference Example 6-3 -Oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl) cyclohexanecarboxylic acid (0.42 g, 0.93 mmol), cyclohexylamine (0.16 mL, 1.4 mmol), and 1-hydroxy After benzotriazole (38 mg, 0.28 mol) was dissolved in chloroform (8.0 mL), 1-ethyl-3- (3-dimethylaminopropiol was obtained at room temperature. ) Carbodiimide hydrochloride (0.27 g, 1.4 mmol) and the mixture was stirred at room temperature for 1 day. After adding water (8.0 mL) and shaking well, the organic layer was separated and concentrated to dryness under reduced pressure. After adding water (20 mL) to the residue and shaking well, the insoluble material was collected by filtration to give (1r, 4r) -N-cyclohexyl-4-({2-oxo-8- [4- (trifluoro). Methyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl) cyclohexanecarboxamide (0.45 g, 89% yield) was obtained as a white solid.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 0.89-1.24 (5H, m), 1.26-1.52 (4H, m), 1.52-1.83 (8H, m) 1.84.03 (7H, m), 2.43-2.66 (4H, m), 3.09 (2H, d, J = 7.4 Hz), 3.25 (2H, br s) ), 3.57 (2H, br s), 3.65-3.83 (1H, m), 5.26 (2H, d, J = 8.2 Hz), 7.44 (2H, d, J = 8.2 Hz), 7.57 (2H, d, J = 8.2 Hz).

LC / MS [Condition 2]: retention time 3.62 minutes; m / z 536.2 [M + H] ⁺ (ESI positive ion mode)

実施例１２７
（１ｒ，４ｒ）−４−（｛２−オキソ−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）−Ｎ−［１−（ピリジン−３−イルメチル）ピペリジン−４−イル］シクロヘキサンカルボキサミド（化合物番号１２７）の製造
参考例６−３で得られた、（１ｒ，４ｒ）−４−（｛２−オキソ−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）シクロヘキサンカルボン酸（０．３６ｇ、０．７９ｍｍｏｌ）、参考例６４で得られた、４−アミノ−１−（ピリジン−３−イルメチル）ピペリジン三塩酸塩、トリエチルアミン（０．６６ｍＬ、４．８ｍｍｏｌ）および１−ヒドロキシベンゾトリアゾール（３２ｍｇ、０．２４ｍｏｌ）をクロロホルム（２０ｍＬ）に溶解した後、室温にて、１−エチル−３−（３−ジメチルアミノプロピル）カルボジイミド塩酸塩（０．２３ｇ、１．２ｍｍｏｌ）を加え、室温で１日間かき混ぜた。水（８．０ｍＬ）を加えてよく振とうした後に、有機層を分離して減圧下濃縮乾固した。残留物に酢酸エチル（２０ｍＬ）を加えてよく振とうした後、不溶物をろ取して、（１ｒ，４ｒ）−４−（｛２−オキソ−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）−Ｎ−［１−（ピリジン−３−イルメチル）ピペリジン−４−イル］シクロヘキサンカルボキサミド（０．４４ｇ、収率８９％）を白色固体として得た。

^１Ｈ−ＮＭＲ（３００ＭＨｚ，ＣＤＣｌ_３）δ：１．０１（２Ｈ，ｄｑ，Ｊ＝３．３，１２．７Ｈｚ），１．３１−１．６４（５Ｈ，ｍ），１．６８−１．８４（４Ｈ，ｍ），１．８４−２．０４（７Ｈ，ｍ），２．１３（２Ｈ，ｄｔ，Ｊ＝１．６，１１．９Ｈｚ），２．４０−２．６７（４Ｈ，ｍ），２．７８（２Ｈ，ｄ，Ｊ＝１１．９Ｈｚ），３．０９（２Ｈ，ｄ，Ｊ＝７．４Ｈｚ），３．２５（２Ｈ，ｓ），３．４９（２Ｈ，ｓ），３．５７（２Ｈ，ｓ），３．６９−３．８８（１Ｈ，ｍ），５．３１（１Ｈ，ｄ，Ｊ＝８．６Ｈｚ），７．２５（１Ｈ，ｄｄ，Ｊ＝４．９，７．８Ｈｚ），７．４４（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ），７．５７（２Ｈ，ｄ，Ｊ＝７．８Ｈｚ），７．６３（１Ｈ，ｄｔ，Ｊ＝７．８，２．０Ｈｚ），８．５０（１Ｈ，ｄｄ，Ｊ＝４．９，１．６Ｈｚ），８．５４（１Ｈ，ｄ，Ｊ＝２．５Ｈｚ）．

ＬＣ／ＭＳ［条件１］：保持時間１．２２分；ｍ／ｚ６２８．０［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ６７２．１［Ｍ＋ＨＣＯＯ］^―（ＥＳＩ負イオンモード）

Example 127
(1r, 4r) -4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl)- Production of N- [1- (pyridin-3-ylmethyl) piperidin-4-yl] cyclohexanecarboxamide (Compound No. 127) (1r, 4r) -4-({2-oxo -8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl) cyclohexanecarboxylic acid (0.36 g, 0.79 mmol), reference 4-amino-1- (pyridin-3-ylmethyl) piperidine trihydrochloride, triethylamine (0.66 mL, 4.8 mmol) and 1-hydroxybenzotriazole obtained in Example 64 32 mg, 0.24 mol) was dissolved in chloroform (20 mL), and 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (0.23 g, 1.2 mmol) was added at room temperature. Stir for 1 day. After adding water (8.0 mL) and shaking well, the organic layer was separated and concentrated to dryness under reduced pressure. After adding ethyl acetate (20 mL) to the residue and shaking well, the insoluble material was collected by filtration to give (1r, 4r) -4-({2-oxo-8- [4- (trifluoromethyl) benzyl. ] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl) -N- [1- (pyridin-3-ylmethyl) piperidin-4-yl] cyclohexanecarboxamide (0.44 g, Yield 89%) was obtained as a white solid.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.01 (2H, dq, J = 3.3, 12.7 Hz), 1.31-1.64 (5H, m), 1.68-1. 84 (4H, m), 1.84-2.04 (7H, m), 2.13 (2H, dt, J = 1.6, 11.9 Hz), 2.40-2.67 (4H, m ), 2.78 (2H, d, J = 11.9 Hz), 3.09 (2H, d, J = 7.4 Hz), 3.25 (2H, s), 3.49 (2H, s), 3.57 (2H, s), 3.69-3.88 (1H, m), 5.31 (1H, d, J = 8.6 Hz), 7.25 (1H, dd, J = 4.9) , 7.8 Hz), 7.44 (2H, d, J = 8.2 Hz), 7.57 (2H, d, J = 7.8 Hz), 7.63 (1H, dt, J = 7.8, 2.0Hz), 8.5 (1H, dd, J = 4.9,1.6Hz), 8.54 (1H, d, J = 2.5Hz).

LC / MS [Condition 1]: Retention time 1.22 minutes; m / z 628.0 [M + H] ⁺ (ESI positive ion mode), m / z 672.1 [M + HCOO] ⁻ (ESI negative ion mode)

実施例１２８
（１ｒ，４ｒ）−Ｎ−（３−アミノプロピル）−４−（｛２−オキソ−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）シクロヘキサンカルボキサミド塩酸塩（化合物番号１２８）の製造
実施例１２５で得られた、ｔ−ブチル ３−［（１ｒ，４ｒ）−４−（｛２−オキソ−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）シクロヘキサンカルボキサミド］プロピルカルバメート（２７ｍｇ、０．０４４ｍｍｏｌ）をメタノール（１．０ｍＬ）に溶解し、室温にて２Ｍ塩化水素−メタノール溶液（０．２０ｍＬ、０．４０ｍｍｏｌ）を加えて、室温にて５時間、４０℃にて２時間静置したのち、減圧下濃縮乾固した。残留物に酢酸エチル（２．０ｍＬ）を加えた後に減圧下濃縮乾固して、（１ｒ，４ｒ）−Ｎ−（３−アミノプロピル）−４−（｛２−オキソ−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）シクロヘキサンカルボキサミド塩酸塩（２７ｍｇ、収率定量的）を白色固体として得た。

^１Ｈ−ＮＭＲ（３００ＭＨｚ，ＤＭＳＯ−ｄ_６）δ：０．８９（２Ｈ，ｑ，Ｊ＝１１．９Ｈｚ），１．３３（２Ｈ，ｑ，Ｊ＝１２．７Ｈｚ），１．４４−１．６１（１Ｈ，ｍ），１．５９−１．７９（６Ｈ，ｍ），１．９６−２．２９（５Ｈ，ｍ），２．６３−２．８２（２Ｈ，ｍ），２．８９−３．０３（２Ｈ，ｍ），３．０３−３．２２（４Ｈ，ｍ），３．２２−３．４６（４Ｈ，ｍ），４．４５（２Ｈ，ｄ，Ｊ＝３．７Ｈｚ），７．５９−８．０９（８Ｈ，ｍ），１１．０３−１１．４７（１Ｈ，ｍ）．

ＬＣ／ＭＳ［条件２］：保持時間０．９８分；ｍ／ｚ５１１．３［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）

Example 128
(1r, 4r) -N- (3-aminopropyl) -4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] Decan-3-yl} methyl) cyclohexanecarboxamide hydrochloride (Compound No. 128) t-butyl 3-[(1r, 4r) -4-({2-oxo-8- [ 4- (Trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl) cyclohexanecarboxamido] propylcarbamate (27 mg, 0.044 mmol) in methanol (1.0 mL) 2M hydrogen chloride-methanol solution (0.20 mL, 0.40 mmol) was added at room temperature, and the mixture was allowed to stand at room temperature for 5 hours and at 40 ° C. for 2 hours. The solution was concentrated to dryness under reduced pressure. Ethyl acetate (2.0 mL) was added to the residue and then concentrated to dryness under reduced pressure to give (1r, 4r) -N- (3-aminopropyl) -4-({2-oxo-8- [4- (Trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl) cyclohexanecarboxamide hydrochloride (27 mg, quantitative yield) was obtained as a white solid.

¹ H-NMR (300 MHz, DMSO-d ₆ ) δ: 0.89 (2H, q, J = 11.9 Hz), 1.33 (2H, q, J = 12.7 Hz), 1.44-1. 61 (1H, m), 1.59-1.79 (6H, m), 1.96-2.29 (5H, m), 2.62-2.82 (2H, m), 2.89- 3.03 (2H, m), 3.03-3.22 (4H, m), 3.22-3.46 (4H, m), 4.45 (2H, d, J = 3.7 Hz), 7.59-8.09 (8H, m), 11.3-11-147 (1H, m).

LC / MS [Condition 2]: Retention time 0.98 min; m / z 511.3 [M + H] ⁺ (ESI positive ion mode)

実施例１２９
メチル ３−［（１ｒ，４ｒ）−４−（｛２−オキソ−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）シクロヘキサンカルボキサミド］プロピルカルバメート（化合物番号１２９）の製造
実施例１２８で得られた、（１ｒ，４ｒ）−Ｎ−（３−アミノプロピル）−４−（｛２−オキソ−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）シクロヘキサンカルボキサミド塩酸塩（１０ｍｇ、０．０１７ｍｍｏｌ）を酢酸エチル（１．０ｍＬ）に懸濁し、トリエチルアミン（０．０１２ｍＬ、０．０８６ｍｍｏｌ）を加えたのち、室温にて、クロロギ酸メチル（０．００１６ｍＬ、０．０２１ｍｍｏｌ）の酢酸エチル（０．１０ｍＬ）溶液を加えた。室温にて４０分間かきまぜたのち水（１．０ｍＬ）を加えて有機層を分離し、減圧下濃縮乾固して、メチル ３−［（１ｒ，４ｒ）−４−（｛２−オキソ−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）シクロヘキサンカルボキサミド］プロピルカルバメート（９．０ｍｇ、収率９３％）を白色固体として得た。

^１Ｈ−ＮＭＲ（３００ＭＨｚ，ＣＤＣｌ_３）δ：１．０２（２Ｈ，ｄｑ，Ｊ＝２．９，１２．３Ｈｚ），１．４８（２Ｈ，ｄｑ，Ｊ＝２．９，１２．３Ｈｚ），１．５４−１．６９（３Ｈ，ｍ），１．６９−１．８５（４Ｈ，ｍ），１．８５−１．９８（４Ｈ，ｍ），２．０４（１Ｈ，ｔｔ，Ｊ＝１１．５，３．３Ｈｚ），２．４５−２．６５（４Ｈ，ｍ），３．０９（２Ｈ，ｄ，Ｊ＝７．４Ｈｚ），３．２０（２Ｈ，ｄｔ，Ｊ＝６．１，５．７Ｈｚ），３．２５（２Ｈ，ｓ），３．３０（２Ｈ，ｄｔ，Ｊ＝５．７，６．１Ｈｚ），３．５７（２Ｈ，ｓ），３．６７（３Ｈ，ｓ），５．１８（１Ｈ，ｂｒ ｓ），６．０７（１Ｈ，ｂｒ ｓ），７．４４（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ），７．５７（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ）．

ＬＣ／ＭＳ［条件２］：保持時間３．２６分；ｍ／ｚ５６９．３［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ６１３．６［Ｍ＋ＨＣＯＯ］^―（ＥＳＩ負イオンモード）

Example 129
Methyl 3-[(1r, 4r) -4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl } Methyl) cyclohexanecarboxamido] propyl carbamate (Compound No. 129) (1r, 4r) -N- (3-aminopropyl) -4-({2-oxo-8- [4 ] obtained in Example 128 -(Trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl) cyclohexanecarboxamide hydrochloride (10 mg, 0.017 mmol) in ethyl acetate (1.0 mL) And triethylamine (0.012 mL, 0.086 mmol) was added, followed by methyl chloroformate (0.0016 mL, 0.021 mm) at room temperature. ol) in ethyl acetate (0.10 mL) was added. After stirring at room temperature for 40 minutes, water (1.0 mL) was added, the organic layer was separated, concentrated to dryness under reduced pressure, and methyl 3-[(1r, 4r) -4-({2-oxo-8 -[4- (Trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl) cyclohexanecarboxamido] propyl carbamate (9.0 mg, 93% yield). Obtained as a white solid.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.02 (2H, dq, J = 2.9, 12.3 Hz), 1.48 (2H, dq, J = 2.9, 12.3 Hz), 1.54-1.69 (3H, m), 1.69-1.85 (4H, m), 1.85-1.98 (4H, m), 2.04 (1H, tt, J = 11) .5, 3.3 Hz), 2.45-2.65 (4H, m), 3.09 (2H, d, J = 7.4 Hz), 3.20 (2H, dt, J = 6.1) 5.7 Hz), 3.25 (2H, s), 3.30 (2H, dt, J = 5.7, 6.1 Hz), 3.57 (2H, s), 3.67 (3H, s) 5.18 (1H, br s), 6.07 (1 H, br s), 7.44 (2H, d, J = 8.2 Hz), 7.57 (2H, d, J = 8.2 Hz) .

LC / MS [Condition 2]: retention time 3.26 min; m / z 569.3 [M + H] ⁺ (ESI positive ion mode), m / z 613.6 [M + HCOO] ⁻ (ESI negative ion mode)

実施例１３０
（１ｒ，４ｒ）−Ｎ−メチル−４−（｛２−オキソ−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）シクロヘキサンカルボキサミド（化合物番号１３０）の製造
参考例６−３で得られた、（１ｒ，４ｒ）−４−（｛２−オキソ−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）シクロヘキサンカルボン酸（２０ｍｇ、０．０４４ｍｍｏｌ）、メチルアミン塩酸塩（５ｍｇ、０．０６６ｍｍｏｌ）、トリエチルアミン（０．０３６ｍＬ、０．２６ｍｍｏｌ）および１−ヒドロキシベンゾトリアゾール（２ｍｇ、０．０１３ｍｍｏｌ）をクロロホルム（０．４０ｍＬ）とＮ，Ｎ−ジメチルホルムアミド（０．４０ｍＬ）の混合溶媒に懸濁した後、室温にて、１−エチル−３−（３−ジメチルアミノプロピル）カルボジイミド塩酸塩（１５ｍｇ、０．０７８ｍｍｏｌ）を加えた。室温で１日間かき混ぜたのち、減圧下濃縮乾固して、得られた残留物に水（１．０ｍＬ）と酢酸エチル（２．０ｍＬ）を加えて有機層を分離した。これを減圧下濃縮乾固して、（１ｒ，４ｒ）−Ｎ−メチル−４−（｛２−オキソ−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）シクロヘキサンカルボキサミド（２１ｍｇ、収率定量的）を白色固体として得た。

^１Ｈ−ＮＭＲ（３００ＭＨｚ，ＣＤＣｌ_３）δ：１．０２（２Ｈ，ｄｑ，Ｊ＝３．３，１２．３Ｈｚ），１．４８（２Ｈ，ｄｑ，Ｊ＝２．９，１２．７Ｈｚ），１．５２−１．６８（１Ｈ，ｍ），１．６９−１．８５（４Ｈ，ｍ），１．８５−１．９８（４Ｈ，ｍ），２．０１（１Ｈ，ｔｔ，Ｊ＝１１．５，３．７Ｈｚ），２．４４−２．７２（４Ｈ，ｍ），２．８０（３Ｈ，ｄ，Ｊ＝４．９Ｈｚ），３．０９（２Ｈ，ｄ，Ｊ＝７．０Ｈｚ），３．２５（２Ｈ，ｓ），３．５７（２Ｈ，ｓ），５．４３（１Ｈ，ｂｒ ｓ），７．４４（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ），７．５７（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ）．

ＬＣ／ＭＳ［条件２］：保持時間３．０８分；ｍ／ｚ４６８．２［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）

Example 130
(1r, 4r) -N-methyl-4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl } Methyl) Cyclohexanecarboxamide (Compound No. 130) (1r, 4r) -4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1 obtained in Reference Example 6-3 -Oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl) cyclohexanecarboxylic acid (20 mg, 0.044 mmol), methylamine hydrochloride (5 mg, 0.066 mmol), triethylamine (0.036 mL, 0.26 mmol) and 1-hydroxybenzotriazole (2 mg, 0.013 mmol) with chloroform (0.40 mL) and N, N-dimethylformaldehyde. Was suspended in a mixed solvent of an amide (0.40 mL), was added at room temperature, 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (15 mg, 0.078 mmol). After stirring at room temperature for 1 day, the mixture was concentrated to dryness under reduced pressure, and water (1.0 mL) and ethyl acetate (2.0 mL) were added to the resulting residue to separate the organic layer. This was concentrated to dryness under reduced pressure to give (1r, 4r) -N-methyl-4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro. [4.5] Decan-3-yl} methyl) cyclohexanecarboxamide (21 mg, quantitative yield) was obtained as a white solid.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.02 (2H, dq, J = 3.3, 12.3 Hz), 1.48 (2H, dq, J = 2.9, 12.7 Hz), 1.52-1.68 (1H, m), 1.69-1.85 (4H, m), 1.85-1.98 (4H, m), 2.01 (1H, tt, J = 11) .5, 3.7 Hz), 2.44-2.72 (4 H, m), 2.80 (3 H, d, J = 4.9 Hz), 3.09 (2 H, d, J = 7.0 Hz) , 3.25 (2H, s), 3.57 (2H, s), 5.43 (1H, br s), 7.44 (2H, d, J = 8.2 Hz), 7.57 (2H, d, J = 8.2 Hz).

LC / MS [Condition 2]: Retention time 3.08 minutes; m / z 468.2 [M + H] ⁺ (ESI positive ion mode)

参考例１３１
１−ベンジル−Ｎ−メチルピペリジン−４−アミン２塩酸塩の製造
１）４−アミノ−１−ベンジルピペリジン（東京化成工業（株）より購入）（１．０ｇ、５．３ｍｍｏｌ）をクロロホルム（５．０ｍＬ）に溶解し、０℃にて二炭酸ｔ−ブチル（１．３ｇ、５．８ｍｍｏｌ）のクロロホルム（５ｍＬ）溶液を加えた。室温にて５分静置した後、減圧下濃縮乾固濃縮乾固して、ｔ−ブチル １−ベンジルピペリジン−４−イルカルバメート（１．５ｇ、収率定量的）を白色個体として得た。

^１Ｈ−ＮＭＲ（３００ＭＨｚ，ＣＤＣｌ_３）δ：１．３５−１．５０（１Ｈ，ｍ），１．４４（９Ｈ，ｓ），１．９０（２Ｈ，ｄ，Ｊ＝１１．２Ｈｚ），２．０８（２Ｈ，ｄｔ，Ｊ＝２．３，１１．２Ｈｚ），２．７０−２．８９（２Ｈ，ｍ），３．４８（２Ｈ，ｓ），４．４１（１Ｈ，ｂｒ ｓ），７．１８−７．３７（５Ｈ，ｍ）．

２）得られた、ｔ−ブチル １−ベンジルピペリジン−４−イルカルバメート（０．１０ｇ、０．３４ｍｍｏｌ）をＮ，Ｎ−ジメチルホルムアミド（１．０ｍＬ）に溶解し、カリウムｔ−ブトキシド（４３ｍｇ、０．３８ｍｍｏｌ）を加えて、室温にて１０分間かきまぜたのちにヨウ化メチル（０．０２４ｍＬ、０．３８ｍｍｏｌ）を加えて１日間室温にて１日間かきまぜた。水（２．０ｍＬ）、ｎ−ヘキサン（２．０ｍＬ）、酢酸エチル（２．０ｍＬ）を加えて有機層を分離し、これを水（２．０ｍＬ×１）で洗浄したのちに減圧下濃縮乾固した。残留物をシリカゲルカラムクロマトグラフィー［充填剤：富士シリシア製ＮＨ−ＤＭ１０２０、展開溶媒：ｎ−ヘキサン／酢酸エチル＝１０／１］にて精製し、ｔ−ブチル １−ベンジルピペリジン−４−イル（メチル）カルバメート（６４ｍｇ、収率６１％）を無色油状物として得た。

^１Ｈ−ＮＭＲ（３００ＭＨｚ，ＣＤＣｌ_３）δ：１．４５（９Ｈ，ｓ），１．５３−１．６４（２Ｈ，ｍ），１．７２（２Ｈ，ｄｑ，Ｊ＝３．７，１２．７Ｈｚ），２．０３（２Ｈ，ｔ，Ｊ＝１１．１Ｈｚ），２．７３（３Ｈ，ｓ），２．８７−２．９８（２Ｈ，ｍ），３．４９（３Ｈ，ｓ），３．５５−４．２１（１Ｈ，ｂｒ ｍ），７．３７−７．１８（５Ｈ，ｍ）．

３）得られた、ｔ−ブチル １−ベンジルピペリジン−４−イル（メチル）カルバメート（５６ｍｇ、０．１９ｍｍｏｌ）をメタノール（２.５ｍＬ）に溶解し、２Ｍ塩化水素−メタノール溶液（０．５０ｍＬ、１．０ｍｍｏｌ）を加えて、５０℃にて３時間静置したのち、減圧下濃縮乾固して、１−ベンジル−Ｎ−メチルピペリジン−４−アミン２塩酸塩（５０ｍｇ、収率定量的）を白色固体として得た。

Reference Example 131
Preparation of 1-benzyl-N-methylpiperidin-4-amine dihydrochloride 1) 4-amino-1-benzylpiperidine (purchased from Tokyo Chemical Industry Co., Ltd.) (1.0 g, 5.3 mmol) in chloroform (5 In 0 mL) and a solution of t-butyl dicarbonate (1.3 g, 5.8 mmol) in chloroform (5 mL) was added at 0 ° C. The mixture was allowed to stand at room temperature for 5 minutes, and then concentrated under reduced pressure to dryness and concentrated to dryness to obtain t-butyl 1-benzylpiperidin-4-ylcarbamate (1.5 g, quantitative yield) as a white solid.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.35 to 1.50 (1H, m), 1.44 (9H, s), 1.90 (2H, d, J = 11.2 Hz), 2 .08 (2H, dt, J = 2.3, 11.2 Hz), 2.70-2.89 (2H, m), 3.48 (2H, s), 4.41 (1H, br s), 7.18-7.37 (5H, m).

2) The obtained t-butyl 1-benzylpiperidin-4-ylcarbamate (0.10 g, 0.34 mmol) was dissolved in N, N-dimethylformamide (1.0 mL), and potassium t-butoxide (43 mg, 0.38 mmol) was added and stirred for 10 minutes at room temperature, methyl iodide (0.024 mL, 0.38 mmol) was added and stirred for 1 day at room temperature for 1 day. Water (2.0 mL), n-hexane (2.0 mL) and ethyl acetate (2.0 mL) were added to separate the organic layer, which was washed with water (2.0 mL × 1) and then concentrated under reduced pressure. Dried to dryness. The residue was purified by silica gel column chromatography [filler: NH-DM1020 manufactured by Fuji Silysia, developing solvent: n-hexane / ethyl acetate = 10/1], and tert-butyl 1-benzylpiperidin-4-yl (methyl ) Carbamate (64 mg, 61% yield) was obtained as a colorless oil.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.45 (9H, s), 1.53-1.64 (2H, m), 1.72 (2H, dq, J = 3.7, 12. 7 Hz), 2.03 (2H, t, J = 11.1 Hz), 2.73 (3H, s), 2.87-2.98 (2H, m), 3.49 (3H, s), 3 .55-4.21 (1H, br m), 7.37-7.18 (5H, m).

3) The obtained t-butyl 1-benzylpiperidin-4-yl (methyl) carbamate (56 mg, 0.19 mmol) was dissolved in methanol (2.5 mL), and a 2M hydrogen chloride-methanol solution (0.50 mL, 1.0 mmol) and left to stand at 50 ° C. for 3 hours, and then concentrated to dryness under reduced pressure to give 1-benzyl-N-methylpiperidin-4-amine dihydrochloride (50 mg, quantitative yield). Was obtained as a white solid.

実施例１３１
（１ｒ，４ｒ）−Ｎ−（１−ベンジルピペリジン−４−イル）−Ｎ−メチル−４−（｛２−オキソ−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）シクロヘキサンカルボキサミド（化合物番号１３１）の製造
参考例６−３で得られた、（１ｒ，４ｒ）−４−（｛２−オキソ−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）シクロヘキサンカルボン酸（２０ｍｇ、０．０４４ｍｍｏｌ）、参考例１３１で得られた、１−ベンジル−Ｎ−メチルピペリジン−４−アミン二塩酸塩（１５ｍｇ、０．０５３ｍｍｏｌ）、トリエチルアミン（０．０１８ｍＬ、０．１３ｍｍｏｌ）および１−ヒドロキシベンゾトリアゾール（２ｍｇ、０．０１３ｍｏｌ）をクロロホルム（０．４０ｍＬ）に溶解した後、室温にて、１−エチル−３−（３−ジメチルアミノプロピル）カルボジイミド塩酸塩（１３ｍｇ、０．０６６ｍｍｏｌ）を加え、室温にて１０日間かき混ぜた。水（１．０ｍＬ）を加えてよく振とうした後に、酢酸エチル（２．０ｍＬ）を加えて有機層を分離し、減圧下濃縮乾固した。残留物をシリカゲルカラムクロマトグラフィー［充填剤：富士シリシア製ＮＨ−ＤＭ１０２０、展開溶媒：クロロホルム／酢酸エチル＝１０／１］にて精製し、（１ｒ，４ｒ）−Ｎ−（１−ベンジルピペリジン−４−イル）−Ｎ−メチル−４−（｛２−オキソ−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）シクロヘキサンカルボキサミド（２４ｍｇ、収率８６％）を無色油状物として得た。

^１Ｈ−ＮＭＲ（３００ＭＨｚ，ＣＤＣｌ_３）δ：０．９３−１．１７（２Ｈ，ｍ），１．４２−２．１５（１５Ｈ，ｍ），２．４２（１Ｈ，ｔｔ，Ｊ＝１１．９，２．９Ｈｚ），２．４８−２．６５（４Ｈ，ｍ），２．８１＆２．８７（合計３Ｈ，それぞれ ｓ），２．８７−３．０３（２Ｈ，ｍ），３．１０＆３．１１（合計２Ｈ，それぞれ ｄ，それぞれＪ＝７．４Ｈｚ、Ｊ＝７．０Ｈｚ），３．２５（２Ｈ，ｓ），３．４９（１．２Ｈ，ｓ），３．５３（０．８Ｈ，ｓ），３．５７（２Ｈ，ｂｒｓ），４．４０−４．５６（０．６Ｈ，ｍ），７．２２−７．３７（５Ｈ，ｍ），７．４４（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ），７．５７（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ）．（アミド回転異性体の３：２混合物）

ＬＣ／ＭＳ［条件２］：保持時間３．３０分；ｍ／ｚ３２１．２［Ｍ＋２Ｈ］^２＋、６４１．４［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）

Example 131
(1r, 4r) -N- (1-benzylpiperidin-4-yl) -N-methyl-4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3, Preparation of 8-diazaspiro [4.5] decan-3-yl} methyl) cyclohexanecarboxamide (Compound No. 131) (1r, 4r) -4-({2-oxo-8) obtained in Reference Example 6-3 -[4- (Trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl) cyclohexanecarboxylic acid (20 mg, 0.044 mmol), obtained in Reference Example 131 1-benzyl-N-methylpiperidin-4-amine dihydrochloride (15 mg, 0.053 mmol), triethylamine (0.018 mL, 0.13 mmol) and 1-hydro Cibenzotriazole (2 mg, 0.013 mol) was dissolved in chloroform (0.40 mL), and 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (13 mg, 0.066 mmol) was then added at room temperature. In addition, the mixture was stirred at room temperature for 10 days. After adding water (1.0 mL) and shaking well, ethyl acetate (2.0 mL) was added to separate the organic layer, which was concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography [filler: NH-DM1020 manufactured by Fuji Silysia, developing solvent: chloroform / ethyl acetate = 10/1], and (1r, 4r) -N- (1-benzylpiperidine-4 -Yl) -N-methyl-4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl ) Cyclohexanecarboxamide (24 mg, 86% yield) was obtained as a colorless oil.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 0.93-1.17 (2H, m), 1.42-2.15 (15H, m), 2.42 (1H, tt, J = 11.1. 9, 2.9 Hz), 2.48-2.65 (4 H, m), 2.81 & 2.87 (total 3 H, s respectively), 2.87-3.03 (2 H, m), 3.10 & 3. 11 (total 2H, d respectively, J = 7.4 Hz, J = 7.0 Hz), 3.25 (2H, s), 3.49 (1.2 H, s), 3.53 (0.8 H, s), 3.57 (2H, brs), 4.40-4.56 (0.6H, m), 7.22-7.37 (5H, m), 7.44 (2H, d, J = 8.2 Hz), 7.57 (2H, d, J = 8.2 Hz). (3: 2 mixture of amide rotamers)

LC / MS [condition 2]: retention time 3.30 minutes; m / z 321.2 [M + 2H] ²⁺ , 641.4 [M + H] ⁺ (ESI positive ion mode)

参考例１３２−１
（１ｒ，４ｒ）−４−（｛２−オキソ−８−［４−（トリフルオロメチル）ベンゾイル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）シクロヘキサンカルボン酸メチルの製造
参考例６−１で得られた、（１ｒ，４ｒ）−４−［（２−オキソ−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル）メチル］シクロヘキサンカルボン酸メチル塩酸塩（５０ｍｇ、０．１４ｍｍｏｌ）を酢酸エチル（２．５ｍＬ）に懸濁し、トリエチルアミン（０．０８０ｍＬ、０．５８ｍｍｏｌ）を加えて、室温にて塩化４−（トリフルオロメチル）ベンゾイル（０．０２４ｍＬ、０．１６ｍｍｏｌ）を加えて、室温にて２０分間かきまぜた。水（１ｍＬ）を加えてよく振とうした後、有機層を分離し、減圧下濃縮乾固して、（１ｒ，４ｒ）−４−（｛２−オキソ−８−［４−（トリフルオロメチル）ベンゾイル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）シクロヘキサンカルボン酸メチル（７１ｍｇ、収率定量的）を白色固体として得た。

^１Ｈ−ＮＭＲ（３００ＭＨｚ，ＣＤＣｌ_３）δ：１．０３（２Ｈ，ｄｑ，Ｊ＝３．３，１２．７Ｈｚ），１．４１（２Ｈ，ｄｑ，Ｊ＝３．７，１３．５Ｈｚ），１．５０−２．１６（９Ｈ，ｍ），２．２６（１Ｈ，ｔｔ，Ｊ＝１２．３，３．７Ｈｚ），３．１１（２Ｈ，ｄ，Ｊ＝７．４Ｈｚ），３．１８−３．６３（５Ｈ，ｍ），３．６６（３Ｈ，ｓ），４．４１−４．６７（１Ｈ，ｂｒ ｍ），７．５２（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ），７．６９（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ）．

ＬＣ／ＭＳ［条件２］：保持時間４．３９分；ｍ／ｚ４８３．２［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ５２７．６［Ｍ＋ＨＣＯＯ］^―（ＥＳＩ負イオンモード）

Reference Example 132-1
(1r, 4r) -4-({2-oxo-8- [4- (trifluoromethyl) benzoyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl) cyclohexane Production of methyl carboxylate (1r, 4r) -4-[(2-oxo-1-oxa-3,8-diazaspiro [4.5] decan-3-yl) methyl obtained in Reference Example 6-1 Cyclohexanecarboxylic acid methyl hydrochloride (50 mg, 0.14 mmol) was suspended in ethyl acetate (2.5 mL), triethylamine (0.080 mL, 0.58 mmol) was added, and 4- (trifluoromethyl chloride) was added at room temperature. ) Benzoyl (0.024 mL, 0.16 mmol) was added and stirred at room temperature for 20 minutes. After adding water (1 mL) and shaking well, the organic layer was separated and concentrated to dryness under reduced pressure to give (1r, 4r) -4-({2-oxo-8- [4- (trifluoromethyl). ) Benzoyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl) methyl cyclohexanecarboxylate (71 mg, quantitative yield) was obtained as a white solid.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.03 (2H, dq, J = 3.3, 12.7 Hz), 1.41 (2H, dq, J = 3.7, 13.5 Hz), 1.50-2.16 (9H, m), 2.26 (1H, tt, J = 12.3, 3.7 Hz), 3.11 (2H, d, J = 7.4 Hz), 3.18 −3.63 (5H, m), 3.66 (3H, s), 4.41−4.67 (1H, br m), 7.52 (2H, d, J = 8.2 Hz), 7. 69 (2H, d, J = 8.2 Hz).

LC / MS [Condition 2]: Retention time 4.39 minutes; m / z 483.2 [M + H] ⁺ (ESI positive ion mode), m / z 527.6 [M + HCOO] ⁻ (ESI negative ion mode)

参考例１３２−２
（１ｒ，４ｒ）−４−（｛２−オキソ−８−［４−（トリフルオロメチル）ベンゾイル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）シクロヘキサンカルボン酸の製造
参考例１３２−１で得られた、（１ｒ，４ｒ）−４−（｛２−オキソ−８−［４−（トリフルオロメチル）ベンゾイル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）シクロヘキサンカルボン酸メチル（６２ｍｇ、０．１３ｍｍｏｌ）を１，４−ジオキサン（３．０ｍＬ）に溶解し、水（０．６０ｍＬ）と１Ｍ水酸化ナトリウム水溶液（０．１９ｍＬ）とを加えて、室温にて４時間かきまぜたのち、水（１ｍＬ）を加え、減圧下濃縮して、ジオキサンを留去した。残留物に水（１．０ｍＬ）と１Ｍ塩酸（０．３０ｍＬ）とを加えてｐＨ２に調整し、酢酸エチル（４．０ｍＬ）で抽出したのち、減圧下濃縮乾固して、（１ｒ，４ｒ）−４−（｛２−オキソ−８−［４−（トリフルオロメチル）ベンゾイル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）シクロヘキサンカルボン酸（５８ｍｇ、収率９６％）を白色固体として得た。

Reference Example 132-2
(1r, 4r) -4-({2-oxo-8- [4- (trifluoromethyl) benzoyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl) cyclohexane Production of Carboxylic Acid (1r, 4r) -4-({2-oxo-8- [4- (trifluoromethyl) benzoyl] -1-oxa-3,8-diazaspiro obtained in Reference Example 132-1 [4.5] Decan-3-yl} methyl) methyl cyclohexanecarboxylate (62 mg, 0.13 mmol) was dissolved in 1,4-dioxane (3.0 mL), water (0.60 mL) and 1M sodium hydroxide Aqueous solution (0.19 mL) was added, and the mixture was stirred at room temperature for 4 hr. Water (1 mL) was added, and the mixture was concentrated under reduced pressure to distill off dioxane. Water (1.0 mL) and 1M hydrochloric acid (0.30 mL) were added to the residue to adjust the pH to 2, followed by extraction with ethyl acetate (4.0 mL), and then concentrated to dryness under reduced pressure to give (1r, 4r ) -4-({2-Oxo-8- [4- (trifluoromethyl) benzoyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl) cyclohexanecarboxylic acid (58 mg) Yield 96%) as a white solid.

実施例１３２
（１ｒ，４ｒ）−Ｎ−（１−ベンジルピペリジン−４−イル）−４−（｛２−オキソ−８−［４−（トリフルオロメチル）ベンゾイル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）シクロヘキサンカルボキサミド（化合物番号１３２）の製造
参考例１３２−２で得られた、（１ｒ，４ｒ）−４−（｛２−オキソ−８−［４−（トリフルオロメチル）ベンゾイル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）シクロヘキサンカルボン酸（２８ｍｇ、０．０６０ｍｍｏｌ）と４−アミノ−１−ベンジルピペリジン（１６ｍｇ、０．０９０ｍｍｏｌ）をＮ，Ｎ−ジメチルホルムアミド（０．３０ｍＬ）に溶解し、１−ヒドロキシベンゾトリアゾール（３ｍｇ、０．０１８ｍｍｏｌ）、１−エチル−３−（３−ジメチルアミノプロピル）カルボジイミド塩酸塩（１７ｍｇ、０．０９０ｍｍｏｌ）を加えて、室温で１１日間かき混ぜた。水（１．０ｍＬ）と酢酸エチル（２．０ｍＬ）を加えて良く振とうしたのち、有機層を分離し、減圧下濃縮乾固した。残留物に酢酸エチル（１．０ｍＬ）を加えて、良く振とうしたのち、不溶物をろ取して、（１ｒ，４ｒ）−Ｎ−（１−ベンジルピペリジン−４−イル）−４−（｛２−オキソ−８−［４−（トリフルオロメチル）ベンゾイル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）シクロヘキサンカルボキサミド（１２ｍｇ、収率３２％）を微黄固体として得た。

^１Ｈ−ＮＭＲ（３００ＭＨｚ，ＣＤＣｌ_３）δ：１．０２（２Ｈ，ｄｑ，Ｊ＝２．５，１２．３Ｈｚ），１．３３−２．０５（３Ｈ，ｍ），１．９７（１Ｈ，ｔｔ，Ｊ＝１１．９，３．３Ｈｚ），２．１１（２Ｈ，ｄｔ，Ｊ＝２．０，１１．５Ｈｚ），２．８０（２Ｈ，ｄ，Ｊ＝１１．９Ｈｚ），３．１１（２Ｈ，ｄ，Ｊ＝７．４Ｈｚ），３．１８−３．６７（５Ｈ，ｍ），３．４９（２Ｈ，ｓ），３．６９−３．８８（１Ｈ，ｍ），４．４２−４．６８（１Ｈ，ｂｒ ｍ），５．２７（１Ｈ，ｄ，Ｊ＝７．８Ｈｚ），７．１９−７．３７（５Ｈ，ｍ），７．５２（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ），７．６９（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ）．

ＬＣ／ＭＳ［条件２］：保持時間３．４８分；ｍ／ｚ６４１．４［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ６８５．６［Ｍ＋ＨＣＯＯ］^―（ＥＳＩ負イオンモード）

Example 132
(1r, 4r) -N- (1-Benzylpiperidin-4-yl) -4-({2-oxo-8- [4- (trifluoromethyl) benzoyl] -1-oxa-3,8-diazaspiro [ 4.5] Decan-3-yl} methyl) cyclohexanecarboxamide (Compound No. 132) (1r, 4r) -4-({2-oxo-8- [4-) obtained in Reference Example 132-2 (Trifluoromethyl) benzoyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl) cyclohexanecarboxylic acid (28 mg, 0.060 mmol) and 4-amino-1-benzylpiperidine ( 16 mg, 0.090 mmol) dissolved in N, N-dimethylformamide (0.30 mL) and 1-hydroxybenzotriazole (3 mg, 0.018 mmol) 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (17 mg, 0.090 mmol) was added and stirred 11 days at room temperature. After adding water (1.0 mL) and ethyl acetate (2.0 mL) and shaking well, the organic layer was separated and concentrated to dryness under reduced pressure. After adding ethyl acetate (1.0 mL) to the residue and shaking well, the insoluble material was collected by filtration to give (1r, 4r) -N- (1-benzylpiperidin-4-yl) -4- ( {2-Oxo-8- [4- (trifluoromethyl) benzoyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl) cyclohexanecarboxamide (12 mg, 32% yield) Was obtained as a slightly yellow solid.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.02 (2H, dq, J = 2.5, 12.3 Hz), 1.33-2.05 (3H, m), 1.97 (1H, tt, J = 11.9, 3.3 Hz), 2.11 (2H, dt, J = 2.0, 11.5 Hz), 2.80 (2H, d, J = 11.9 Hz), 3.11 (2H, d, J = 7.4 Hz), 3.18-3.67 (5H, m), 3.49 (2H, s), 3.69-3.88 (1H, m), 4.42 -4.68 (1H, br m), 5.27 (1H, d, J = 7.8 Hz), 7.19-7.37 (5H, m), 7.52 (2H, d, J = 8) .2 Hz), 7.69 (2H, d, J = 8.2 Hz).

LC / MS [Condition 2]: Retention time 3.48 min; m / z 641.4 [M + H] ⁺ (ESI positive ion mode), m / z 685.6 [M + HCOO] ⁻ (ESI negative ion mode)

参考例１３３−１
４−アミノシクロヘキサンカルボン酸メチル塩酸塩の製造
４−アミノシクロヘキサンカルボン酸（東京化成工業（株）より購入）（２．０ｇ、１４ｍｍｏｌ）を２Ｍ塩化水素−メタノール溶液（５０ｍＬ）に溶解し、室温にて１日間静置したのち、減圧下濃縮乾固濃縮乾固して、４−アミノシクロヘキサンカルボン酸メチル塩酸塩（２．６ｇ、収率９６％）を白色固体として得た。

^１Ｈ−ＮＭＲ（ＣＤＣｌ_３）δ：１．３８−２．３０（８Ｈ，ｍ），２．３３（０．２５Ｈ，ｔ，Ｊ＝１１．５Ｈｚ），２．４９−２．６３（０．７５Ｈ，ｍ），３．０３−３．２１（０．２５Ｈ，ｂｒ ｍ），３．２１−３．４１（０．７５Ｈ，ｂｒ ｍ），３．６７（０．７５Ｈ，ｓ），３．７１（２．２５Ｈ，ｓ），７．８７−８．６８（３Ｈ，ｂｒ ｓ）．（シス体−トランス体の約３：１混合物）

Reference Example 133-1
Preparation of 4-aminocyclohexanecarboxylic acid methyl hydrochloride 4-Aminocyclohexanecarboxylic acid (purchased from Tokyo Chemical Industry Co., Ltd.) (2.0 g, 14 mmol) was dissolved in a 2M hydrogen chloride-methanol solution (50 mL) at room temperature. The mixture was allowed to stand for 1 day and then concentrated to dryness under reduced pressure to give dry 4-methylcyclohexanecarboxylic acid methyl hydrochloride (2.6 g, yield 96%) as a white solid.

¹ H-NMR (CDCl ₃ ) δ: 1.38-2.30 (8H, m), 2.33 (0.25H, t, J = 11.5 Hz), 2.49-2.63 (0. 75H, m), 3.03-3.21 (0.25H, br m), 3.21-3.41 (0.75H, br m), 3.67 (0.75H, s), 3. 71 (2.25H, s), 7.87-8.68 (3H, br s). (About 3: 1 mixture of cis-trans form)

参考例１３３−２
３−［４−（メトキシカルボニル）シクロヘキシル］−２−オキソ−１−オキサ−３，８−ジアザスピロ［４．５］デカン−８−カルボン酸ｔ−ブチルの製造
１）参考例１３３−１で得られた、４−アミノシクロヘキサンカルボン酸メチル塩酸塩（０．２５ｇ、１．３ｍｍｏｌ）、参考例１−１で得られた１−オキサ−６−アザスピロ［２．５］オクタン−６−カルボン酸ｔ−ブチル（０．２５ｇ、１．２ｍｍｏｌ）を水（２．５ｍＬ）に懸濁し、メタノール（４.０ｍＬ）と１Ｍ水酸化ナトリウム水溶液（１．２ｍＬ、１．２ｍｍｏｌ）を加え、室温で３日間かき混ぜた後、減圧下メタノールを留去した。残留物に水（１．０ｍＬ）とクロロホルム（５．０ｍＬ）を加えて有機層を分離し、減圧下濃縮乾固して、４−ヒドロキシ−４−｛［４−（メトキシカルボニル）シクロヘキシルアミノ］メチル｝ピペリジン−１−カルボン酸ｔ−ブチルの粗物（０．４３ｇ）を無色油状物として得た。

２）４−ヒドロキシ−４−｛［４−（メトキシカルボニル）シクロヘキシルアミノ］メチル｝ピペリジン−１−カルボン酸ｔ−ブチルの粗物（０．４３ｇ）を１，４−ジオキサン（７．０ｍＬ）に溶解し、１，１’−カルボニルジイミダゾール（０．５７ｇ、３．６ｍｍｏｌ）を加え、９０℃で２日間かき混ぜたのち、室温まで冷却し、減圧下濃縮乾固した。水（５．０ｍＬ）、１Ｍ塩酸（６．０ｍＬ）、酢酸エチル（５．０ｍＬ）、ｎ−ヘキサン（２．０ｍＬ）を加えて有機層を分離し、減圧下濃縮乾固濃縮乾固した。残留物をシリカゲルカラムクロマトグラフィー［充填剤：富士シリシア製ＦＬ１００Ｄ、展開溶媒：ｎ−ヘキサン／酢酸エチル＝１／１］にて精製し、３−［４−（メトキシカルボニル）シクロヘキシル］−２−オキソ−１−オキサ−３，８−ジアザスピロ［４．５］デカン−８−カルボン酸ｔ−ブチル（６８ｍｇ、収率１４％、シス体−トランス体の約１：１混合物）を無色油状物として得た。

^１Ｈ−ＮＭＲ（ＣＤＣｌ_３）δ：１．３０−１．７５（８Ｈ，ｍ），１．４６（９Ｈ，ｓ），１．７８−１．９７（３Ｈ，ｍ），２．０３−２．１４（１Ｈ，ｍ），２．１４−２．３０（１．５Ｈ，ｍ），２．６６（０．５Ｈ，ｂｒ ｓ），３．２０（１Ｈ，ｓ），３．２１（１Ｈ，ｓ），３．２７（２Ｈ，ｔ，Ｊ＝１１．５Ｈｚ），３．６３−３．９４（３Ｈ，ｍ），３．６８（１．５Ｈ，ｓ），３．７０（１．５Ｈ，ｓ）．（シス体−トランス体の約１：１混合物）

Reference Example 133-2
Preparation of t-butyl 3- [4- (methoxycarbonyl) cyclohexyl] -2-oxo-1-oxa-3,8-diazaspiro [4.5] decane-8-carboxylate 1) Obtained in Reference Example 133-1 4-aminocyclohexanecarboxylic acid methyl hydrochloride (0.25 g, 1.3 mmol), 1-oxa-6-azaspiro [2.5] octane-6-carboxylic acid t obtained in Reference Example 1-1 -Butyl (0.25 g, 1.2 mmol) was suspended in water (2.5 mL), methanol (4.0 mL) and 1 M aqueous sodium hydroxide solution (1.2 mL, 1.2 mmol) were added, and the mixture was stirred at room temperature for 3 days. After stirring, methanol was distilled off under reduced pressure. Water (1.0 mL) and chloroform (5.0 mL) were added to the residue, the organic layer was separated, concentrated to dryness under reduced pressure, and 4-hydroxy-4-{[4- (methoxycarbonyl) cyclohexylamino]. A crude product (0.43 g) of methyl} piperidine-1-carboxylate was obtained as a colorless oil.

2) 4-hydroxy-4-{[4- (methoxycarbonyl) cyclohexylamino] methyl} piperidine-1-carboxylate crude (0.43 g) in 1,4-dioxane (7.0 mL) After dissolution, 1,1′-carbonyldiimidazole (0.57 g, 3.6 mmol) was added, and the mixture was stirred at 90 ° C. for 2 days, cooled to room temperature, and concentrated to dryness under reduced pressure. Water (5.0 mL), 1M hydrochloric acid (6.0 mL), ethyl acetate (5.0 mL) and n-hexane (2.0 mL) were added to separate the organic layer, which was concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography [filler: FL100D manufactured by Fuji Silysia, developing solvent: n-hexane / ethyl acetate = 1/1] to give 3- [4- (methoxycarbonyl) cyclohexyl] -2-oxo. -1-Oxa-3,8-diazaspiro [4.5] decane-8-carboxylate t-butyl (68 mg, yield 14%, approximately 1: 1 mixture of cis-trans) was obtained as a colorless oil. It was.

¹ H-NMR (CDCl ₃ ) δ: 1.30-1.75 (8H, m), 1.46 (9H, s), 1.78-1.97 (3H, m), 2.03-2 .14 (1H, m), 2.14-2.30 (1.5H, m), 2.66 (0.5H, br s), 3.20 (1H, s), 3.21 (1H, s), 3.27 (2H, t, J = 11.5 Hz), 3.63-3.94 (3H, m), 3.68 (1.5H, s), 3.70 (1.5H, s). (About 1: 1 mixture of cis-trans form)

参考例１３３−３
４−｛２−オキソ−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝シクロヘキサンカルボン酸メチルの製造
１）参考例１３３−２で得られた、３−［４−（メトキシカルボニル）シクロヘキシル］−２−オキソ−１−オキサ−３，８−ジアザスピロ［４．５］デカン−８−カルボン酸ｔ−ブチル（６８ｍｇ、０．１７ｍｍｏｌ、シス体−トランス体の約１：１混合物）をメタノール（１．０ｍＬ）に溶解し、２Ｍ塩化水素−メタノール溶液（０．３０ｍＬ、０．６０ｍｍｏｌ）を加えて、室温にて３日間静置したのち、減圧下濃縮乾固して、４−（２−オキソ−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル）シクロヘキサンカルボン酸メチル（５７ｍｇ、収率定量的）を得た。

２）得られた、４−（２−オキソ−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル）シクロヘキサンカルボン酸メチル（５７ｍｇ、０．１７ｍｍｏｌ）をＮ，Ｎ−ジメチルホルムアミド（１．０ｍＬ）に溶解し、トリエチルアミン（０．０７２ｍＬ、０．５１ｍｍｏｌ）と４−（トリフルオロメチル）ベンジルブロミド（４５ｍｇ、０．１９ｍｍｏｌ、東京化成工業（株）より購入）の酢酸エチル（０．２０ｍＬ）溶液を室温にて加えたのち、室温にて１日間かき混ぜた。反応混合物に水（２ｍＬ）を加えたのち、不溶物をろ取して、４−｛２−オキソ−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝シクロヘキサンカルボン酸メチル（６５ｍｇ、２工程収率８３％）を白色固体として得た。

^１Ｈ−ＮＭＲ（ＣＤＣｌ_３）δ：１．３２−２．００（１０Ｈ，ｍ），２．０１−２．１４（０．８Ｈ，ｍ），２．１４−２．３３（１．６Ｈ，ｍ），２．４３−２．６２（４Ｈ，ｍ），２．６２−２．７０（０．６Ｈ，ｍ），３．１９＆３．２１（合計２Ｈ，それぞれ ｓ），３．５６（２Ｈ，ｂｒ ｓ），３．６５−３．８０（１Ｈ，ｍ），３．６７＆３．７１（合計３Ｈ，それぞれ ｓ），７．４４（２Ｈ，ｄ，Ｊ＝７．９Ｈｚ），７．５７（２Ｈ，ｄ，Ｊ＝７．９Ｈｚ）．（シス体−トランス体の約３：２混合物）

ＬＣ／ＭＳ［条件２］：保持時間３．４０分；ｍ／ｚ４５５．２［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）

Reference Example 133-3
Preparation of methyl 4- {2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} cyclohexanecarboxylate 1) Reference example T-butyl 3- [4- (methoxycarbonyl) cyclohexyl] -2-oxo-1-oxa-3,8-diazaspiro [4.5] decane-8-carboxylate obtained in 133-2 (68 mg, 0.17 mmol, about 1: 1 mixture of cis isomer-trans isomer) was dissolved in methanol (1.0 mL), and 2M hydrogen chloride-methanol solution (0.30 mL, 0.60 mmol) was added. The mixture was allowed to stand for days and then concentrated to dryness under reduced pressure to give methyl 4- (2-oxo-1-oxa-3,8-diazaspiro [4.5] decan-3-yl) cyclohexanecarboxylate (57 mg). To obtain a quantitative yield).

2) The methyl 4- (2-oxo-1-oxa-3,8-diazaspiro [4.5] decan-3-yl) cyclohexanecarboxylate (57 mg, 0.17 mmol) obtained was converted to N, N-dimethyl. Dissolved in formamide (1.0 mL), ethyl acetate of triethylamine (0.072 mL, 0.51 mmol) and 4- (trifluoromethyl) benzyl bromide (45 mg, 0.19 mmol, purchased from Tokyo Chemical Industry Co., Ltd.) 0.20 mL) solution was added at room temperature and then stirred at room temperature for 1 day. After adding water (2 mL) to the reaction mixture, the insoluble material was collected by filtration, and 4- {2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [ 4.5] Methyl decan-3-yl} cyclohexanecarboxylate (65 mg, 83% yield over 2 steps) was obtained as a white solid.

¹ H-NMR (CDCl ₃ ) δ: 1.32-2.00 (10H, m), 2.01-2.14 (0.8H, m), 2.14-2.33 (1.6H, m), 2.43-2.62 (4H, m), 2.62-2.70 (0.6H, m), 3.19 & 3.21 (total 2H, s respectively), 3.56 (2H, br s), 3.65-3.80 (1H, m), 3.67 & 3.71 (total 3H, s), 7.44 (2H, d, J = 7.9 Hz), 7.57 (2H) , D, J = 7.9 Hz). (About 3: 2 mixture of cis-trans form)

LC / MS [Condition 2]: Retention time 3.40 minutes; m / z 455.2 [M + H] ⁺ (ESI positive ion mode)

参考例１３３−４
４−｛２−オキソ−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝シクロヘキサンカルボン酸の製造
参考例１３３−３で得られた、４−｛２−オキソ−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝シクロヘキサンカルボン酸メチル（６０ｍｇ、０．１３ｍｍｏｌ）を１，４−ジオキサン（３．０ｍＬ）に溶解し、水（０．５０ｍＬ）と１Ｍ水酸化ナトリウム水溶液（０．２０ｍＬ、０．２０ｍｍｏｌ）を加えて、室温にて１０日間かきまぜたのち、減圧下濃縮して１，４−ジオキサンを留去した。残留物に１Ｍ塩酸（０．２５ｍＬ、０．２５ｍｍｏｌ）を加えてｐＨ６に調整し、析出した固体をろ取して、４−｛２−オキソ−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝シクロヘキサンカルボン酸（３７ｍｇ、収率６５％）を白色固体として得た。

Reference Example 133-4
Preparation of 4- {2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} cyclohexanecarboxylic acid Reference Example 133-3 4- {2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} cyclohexanecarboxylate ( 60 mg, 0.13 mmol) was dissolved in 1,4-dioxane (3.0 mL), water (0.50 mL) and 1M aqueous sodium hydroxide solution (0.20 mL, 0.20 mmol) were added, and the mixture was stirred at room temperature for 10 minutes. After stirring for one day, 1,4-dioxane was distilled off by concentration under reduced pressure. To the residue was added 1M hydrochloric acid (0.25 mL, 0.25 mmol) to adjust to pH 6, and the precipitated solid was collected by filtration to give 4- {2-oxo-8- [4- (trifluoromethyl) benzyl]. -1-Oxa-3,8-diazaspiro [4.5] decan-3-yl} cyclohexanecarboxylic acid (37 mg, yield 65%) was obtained as a white solid.

実施例１３３
Ｎ−（１−ベンジルピペリジン−４−イル）−４−｛２−オキソ−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝シクロヘキサンカルボキサミド（化合物番号１３３）の製造
参考例１３３−４で得られた、４−｛２−オキソ−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝シクロヘキサンカルボン酸（１９ｍｇ、０．０４３ｍｍｏｌ）をＮ，Ｎ−ジメチルホルムアミド（０．４０ｍＬ）に懸濁し、４−アミノ−１−ベンジルピペリジン（１２ｍｇ、０．０６５ｍｍｏｌ）のクロロホルム（０．３０ｍＬ）溶液と１−ヒドロキシベンゾトリアゾール（３ｍｇ、０．０２２ｍｍｏｌ）を加えた後、室温にて、１−エチル−３−（３−ジメチルアミノプロピル）カルボジイミド塩酸塩（１２ｍｇ、０．０６５ｍｍｏｌ）を加え、室温で８日間かき混ぜた。その後、水（２．０ｍＬ）と酢酸エチル（４．０ｍＬ）を加えて、有機層を分離し、減圧下濃縮乾固した。残留物をシリカゲルカラムクロマトグラフィー［充填剤：富士シリシア製ＮＨ−ＤＭ１０２０、展開溶媒：クロロホルム／酢酸エチル＝２／１］にて精製し、Ｎ−（１−ベンジルピペリジン−４−イル）−４−｛２−オキソ−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝シクロヘキサンカルボキサミド（１４ｍｇ、収率５４％）を白色固体として得た。

^１Ｈ−ＮＭＲ（ＣＤＣｌ_３）δ：１．３３−２．０６（１６．２Ｈ，ｍ），２．１１（２H，ｔ，Ｊ＝１１．９Ｈｚ）２．３６（０．８Ｈ，ｂｒｓ），２．４３−２．６６（４Ｈ，ｍ），２．８２（２Ｈ，ｂｒ ｄ，Ｊ＝１１．９Ｈｚ），３．２０（０．４Ｈ，ｓ），３．２３（１．６Ｈ，ｓ），３．４９（２Ｈ，ｓ），３．５５（２Ｈ，ｂｒｓ），３．６２−３．８９（２Ｈ，ｍ），５．２５（０．２Ｈ，ｄ，Ｊ＝８．２Ｈｚ），５．３３（０．８Ｈ，ｄ，Ｊ＝７．８Ｈｚ），７．１９−７．３６（５Ｈ，ｍ），７．４３（２Ｈ，ｄ，Ｊ＝８．０Ｈｚ），７．５７（２Ｈ，ｄ，Ｊ＝８．０Ｈｚ）．（シス体−トランス体の約４：１混合物）

ＬＣ／ＭＳ［条件１］：保持時間３．００分；ｍ／ｚ３０７．１［Ｍ＋２Ｈ］^２＋、６１３．０［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）

Example 133
N- (1-benzylpiperidin-4-yl) -4- {2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decane-3 Preparation of 4- yl} cyclohexanecarboxamide (Compound No. 133) 4- {2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8- obtained in Reference Example 133-4 Diazaspiro [4.5] decan-3-yl} cyclohexanecarboxylic acid (19 mg, 0.043 mmol) was suspended in N, N-dimethylformamide (0.40 mL) and 4-amino-1-benzylpiperidine (12 mg, 0 0.065 mmol) in chloroform (0.30 mL) and 1-hydroxybenzotriazole (3 mg, 0.022 mmol) were added at room temperature, - ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (12 mg, 0.065 mmol) and the mixture was stirred at room temperature for 8 days. Then, water (2.0 mL) and ethyl acetate (4.0 mL) were added, the organic layer was separated, and concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography [filler: NH-DM1020 manufactured by Fuji Silysia, developing solvent: chloroform / ethyl acetate = 2/1], and N- (1-benzylpiperidin-4-yl) -4- {2-Oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} cyclohexanecarboxamide (14 mg, 54% yield) on white Obtained as a solid.

¹ H-NMR (CDCl ₃ ) δ: 1.33-2.06 (16.2 H, m), 2.11 (2 H, t, J = 11.9 Hz) 2.36 (0.8 H, brs), 2.4-3.66 (4H, m), 2.82 (2H, br d, J = 11.9 Hz), 3.20 (0.4 H, s), 3.23 (1.6 H, s) 3.49 (2H, s), 3.55 (2H, brs), 3.62-3.89 (2H, m), 5.25 (0.2H, d, J = 8.2 Hz), 5 .33 (0.8H, d, J = 7.8 Hz), 7.19-7.36 (5H, m), 7.43 (2H, d, J = 8.0 Hz), 7.57 (2H, d, J = 8.0 Hz). (About 4: 1 mixture of cis-trans form)

LC / MS [Condition 1]: Retention time 3.00 min; m / z 307.1 [M + 2H] ²⁺ , 613.0 [M + H] ⁺ (ESI positive ion mode)

実施例１３４
ｔ−ブチル ３−（４−｛２−オキソ−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝シクロヘキサンカルボキサミド）プロピルカルバメート（化合物番号１３４）の製造
４−アミノ−１−ベンジルピペリジンの代わりにＮ−（ｔ−ブトキシカルボニル）−１，３−ジアミノプロパンを用いること以外は実質的に実施例１３３と同様に反応を行って、表題化合物（２２ｍｇ、収率９２％）を白色固体として得た。

^１Ｈ−ＮＭＲ（ＣＤＣｌ_３）δ：１．４４（９Ｈ，ｂｒ ｓ），１．４９−２．２０（１４．２Ｈ，ｍ），２．４０−２．４９（０．８Ｈ，ｂｒ ｓ），２．４６−２．６３（４Ｈ，ｍ），３．１８（２Ｈ，ｄｔ，Ｊ＝６．１，６．１Ｈｚ），３．２１＆３．２５（合わせて２Ｈ，それぞれ ｓ），３．３０（２Ｈ，ｄｔ，Ｊ＝６．５，５．７Ｈｚ），３．５６（２Ｈ，ｂｒ ｓ），３．６５−３．８３（１Ｈ，ｍ），４．７２−４．９３（１Ｈ，ｍ），６．３１−６．５７（１Ｈ，ｍ），７．４４（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ），７．５７（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ）．（シス体−トランス体の約４：１混合物）

ＬＣ／ＭＳ［条件１］：保持時間３．５２分；ｍ／ｚ５９６．９［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ６４１．２［Ｍ＋ＨＣＯＯ］^―（ＥＳＩ負イオンモード）

Example 134
t-butyl 3- (4- {2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} cyclohexanecarboxamido) propyl Preparation of carbamate (Compound No. 134) The reaction was carried out in substantially the same manner as in Example 133, except that N- (t-butoxycarbonyl) -1,3-diaminopropane was used instead of 4-amino-1-benzylpiperidine. Performed to give the title compound (22 mg, 92% yield) as a white solid.

¹ H-NMR (CDCl ₃ ) δ: 1.44 (9H, br s), 1.49-2.20 (14.2 H, m), 2.40-2.49 (0.8 H, br s) , 2.46-2.63 (4H, m), 3.18 (2H, dt, J = 6.1, 6.1 Hz), 3.21 & 3.25 (total 2H, s respectively), 3.30 (2H, dt, J = 6.5, 5.7 Hz), 3.56 (2H, brs), 3.65-3.83 (1H, m), 4.72-4.93 (1H, m ), 6.31-6.57 (1H, m), 7.44 (2H, d, J = 8.2 Hz), 7.57 (2H, d, J = 8.2 Hz). (About 4: 1 mixture of cis-trans form)

LC / MS [Condition 1]: retention time 3.52 minutes; m / z 596.9 [M + H] ⁺ (ESI positive ion mode), m / z 641.2 [M + HCOO] ⁻ (ESI negative ion mode)

参考例１３５
４−アミノピペリジン−１−カルボン酸メチル塩酸塩の製造
ピペリジン−４−イルカルバミン酸ｔ−ブチル（７９０ｍｇ、３．９ｍｍｏｌ）をクロロホルム（１０ｍＬ）に溶解し、氷冷下、クロロギ酸メチル（０．３１ｍＬ、３．９ｍｍｏｌ）とトリエチルアミン（０．５５ｍＬ、３．９ｍｍｏｌ）を加えた後、室温にて１日間かき混ぜた。反応終了後、反応混合物をクロロホルムで希釈し、水を加えた後、有機層を分離した。有機層を水と飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥した後、減圧留去して、４−（ｔ−ブトキシカルボニルアミノ）ピペリジン−１−カルボン酸メチル（８８０ｍｇ）を得た。４−（ｔ−ブトキシカルボニルアミノ）ピペリジン−１−カルボン酸メチル（８８０ｍｇ）をメタノール（２．０ｍＬ）と４Ｍ塩化水素−ジオキサン溶液（８．０ｍＬ）に溶解し、室温にて３時間かき混ぜた。減圧下、反応混合物を濃縮乾固した後、得られた固体をジエチルエーテルで洗浄し、室温で減圧乾燥することで、表題化合物（６００ｍｇ、収率９６％）を白色固体として得た。

４−（ｔ−ブトキシカルボニルアミノ）ピペリジン−１−カルボン酸メチル
^１Ｈ−ＮＭＲ（ＣＤＣｌ_３）δ：１．１９−１．３７（２Ｈ，ｍ），１．４４（９Ｈ，ｓ），１．８７−２．０１（２Ｈ，ｍ），２．８２−２．９９（２Ｈ，ｍ），３．４９−３．７２（１Ｈ，ｍ），３．６９（３Ｈ，ｓ），３．９１−４．１９（２Ｈ，ｍ），４．３４−４．５２（１Ｈ，ｂｒｍ）．

４−アミノピペリジン−１−カルボン酸メチル塩酸塩
^１Ｈ−ＮＭＲ（ＣＤＣｌ_３）δ：１．６０−１．９１（２Ｈ，ｍ），１．８３（２Ｈ，ｓ），２．０４−２．２５（２Ｈ，ｍ），２．７３−３．０３（２Ｈ，ｍ），３．２４−３．４７（１Ｈ，ｍ），３．７０（３Ｈ，ｓ），４．０３−４．３９（２Ｈ，ｍ），８．４９（３Ｈ，ｂｒｓ）．

Reference Example 135
Preparation of methyl 4-aminopiperidine-1-carboxylate Hydrochloride t-butyl piperidin-4-ylcarbamate (790 mg, 3.9 mmol) was dissolved in chloroform (10 mL), and methyl chloroformate (0. 31 mL, 3.9 mmol) and triethylamine (0.55 mL, 3.9 mmol) were added, and the mixture was stirred at room temperature for 1 day. After completion of the reaction, the reaction mixture was diluted with chloroform, water was added, and the organic layer was separated. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and evaporated under reduced pressure to give methyl 4- (t-butoxycarbonylamino) piperidine-1-carboxylate (880 mg). Methyl 4- (t-butoxycarbonylamino) piperidine-1-carboxylate (880 mg) was dissolved in methanol (2.0 mL) and 4M hydrogen chloride-dioxane solution (8.0 mL), and the mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated to dryness under reduced pressure, and the obtained solid was washed with diethyl ether and dried under reduced pressure at room temperature to give the title compound (600 mg, yield 96%) as a white solid.

4- (t-Butoxycarbonylamino) piperidine-1-carboxylate methyl
¹ H-NMR (CDCl ₃ ) δ: 1.19-1.37 (2H, m), 1.44 (9H, s), 1.87-2.01 (2H, m), 2.82-2 .99 (2H, m), 3.49-3.72 (1H, m), 3.69 (3H, s), 3.91-4.19 (2H, m), 4.34-4.52 (1H, brm).

4-Aminopiperidine-1-carboxylic acid methyl hydrochloride
¹ H-NMR (CDCl ₃ ) δ: 1.60-1.91 (2H, m), 1.83 (2H, s), 2.04-2.25 (2H, m), 2.73-3 .03 (2H, m), 3.24-3.47 (1H, m), 3.70 (3H, s), 4.03-4.39 (2H, m), 8.49 (3H, brs) ).

実施例１３５
４−［６−（｛２−オキソ−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）ニコチンアミド］ピペリジン−１−カルボン酸メチル（化合物番号１３５）の製造
テトラヒドロフルフリルアミンの代わりに参考例１３５で得られた４−アミノピペリジン−１−カルボン酸メチル塩酸塩とトリエチルアミンを用いること以外は実質的に実施例１１１と同様に反応を行って、表題化合物（１４ｍｇ、定量的）を無定形固体として得た。

^１Ｈ−ＮＭＲ（ＣＤＣｌ_３）δ：１．３７−１．５４（２Ｈ，ｍ），１．６９−１．８４（２Ｈ，ｍ），１．８９−２．１１（４Ｈ，ｍ），２．４２−２．６４（４Ｈ，ｍ），２．９６（２Ｈ，ｔ，Ｊ＝１２．５Ｈｚ），３．３３（２Ｈ，ｓ），３．５６（２Ｈ，ｓ），３．６９（３Ｈ，ｓ），４．０４−４．２７（３Ｈ，ｍ），４．５７（２Ｈ，ｓ），６．４８（１Ｈ，ｂｒ ｍ），７．３５（１Ｈ，ｄ，Ｊ＝８．０Ｈｚ），７．４３（２Ｈ，ｄ，Ｊ＝８．０Ｈｚ），７．５７（２Ｈ，ｄ，Ｊ＝８．０Ｈｚ），８．１０（１Ｈ，ｄｄ，Ｊ＝８．０，２．２Ｈｚ），８．９３（１Ｈ，ｄ，Ｊ＝２．２Ｈｚ）．
ＬＣ／ＭＳ［条件１］：保持時間４．６８分；ｍ／ｚ５９０．３［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）

Example 135
4- [6-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl) nicotinamide] piperidine Preparation of Methyl-1-Carboxylate (Compound No. 135) Substantially Examples except that 4-aminopiperidine-1-carboxylic acid methyl hydrochloride obtained in Reference Example 135 and triethylamine were used instead of tetrahydrofurfurylamine The reaction was carried out in the same manner as 111 to give the title compound (14 mg, quantitative) as an amorphous solid.

¹ H-NMR (CDCl ₃ ) δ: 1.37-1.54 (2H, m), 1.69-1.84 (2H, m), 1.89-2.11 (4H, m), 2 .42-2.64 (4H, m), 2.96 (2H, t, J = 12.5 Hz), 3.33 (2H, s), 3.56 (2H, s), 3.69 (3H , S), 4.04-4.27 (3H, m), 4.57 (2H, s), 6.48 (1H, br m), 7.35 (1H, d, J = 8.0 Hz) , 7.43 (2H, d, J = 8.0 Hz), 7.57 (2H, d, J = 8.0 Hz), 8.10 (1H, dd, J = 8.0, 2.2 Hz), 8.93 (1H, d, J = 2.2 Hz).
LC / MS [Condition 1]: Retention time 4.68 minutes; m / z 590.3 [M + H] ⁺ (ESI positive ion mode)

実施例１３６
４−［（１ｒ，４ｒ）−４−（｛２−オキソ−８−［４−（トリフルオロメチル）フェニル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）シクロヘキサンカルボキサミド］ピペリジン−１−カルボン酸メチル（化合物番号１３６）の製造
シクロヘキシルアミンの代わりに参考例１３５で得られた４−アミノピペリジン−１−カルボン酸メチル塩酸塩とトリエチルアミンを用いること以外は実質的に実施例１０７と同様に反応を行って、表題化合物（１１ｍｇ、収率８３％）を無色固体として得た。

^１Ｈ−ＮＭＲ（ＣＤＣｌ_３）δ：０．９５−１．１２（２Ｈ，ｍ），１．２２−１．３７（２Ｈ，ｍ），１．４１−１．６７（３Ｈ，ｍ），１．７３−２．０８（１１Ｈ，ｍ），２．９０（２Ｈ，ｔ，Ｊ＝１２．１Ｈｚ），３．１２（２Ｈ，ｄ，Ｊ＝７．４Ｈｚ），３．２９（２Ｈ，ｓ），３．３１−３．４３（２Ｈ，ｍ），３．５３−３．６４（２Ｈ，ｍ），３．６９（３Ｈ，ｓ），３．８５−４．００（１Ｈ，ｍ），４．００−４．２３（２Ｈ，ｍ），５．３５−５．４８（１Ｈ，ｂｒ ｍ），６．９４（２Ｈ，ｄ，Ｊ＝８．８Ｈｚ），７．４８（２Ｈ，ｄ，Ｊ＝８．８Ｈｚ）．

ＬＣ／ＭＳ［条件１］：保持時間５．８分；ｍ／ｚ５８２．４［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ６２５．６［Ｍ＋ＨＣＯＯ］^―（ＥＳＩ負イオンモード）

Example 136
4-[(1r, 4r) -4-({2-oxo-8- [4- (trifluoromethyl) phenyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} Methyl) cyclohexanecarboxamide] Preparation of methyl piperidine-1-carboxylate (Compound No. 136) Except for using 4-aminopiperidine-1-carboxylic acid methyl hydrochloride and triethylamine obtained in Reference Example 135 instead of cyclohexylamine The reaction was carried out substantially in the same manner as in Example 107 to obtain the title compound (11 mg, yield 83%) as a colorless solid.

¹ H-NMR (CDCl ₃ ) δ: 0.95-1.12 (2H, m), 1.22-1.37 (2H, m), 1.41-1.67 (3H, m), 1 .73-2.08 (11H, m), 2.90 (2H, t, J = 12.1 Hz), 3.12 (2H, d, J = 7.4 Hz), 3.29 (2H, s) 3.31-3.43 (2H, m), 3.53-3.64 (2H, m), 3.69 (3H, s), 3.85-4.00 (1H, m), 4 .00-4.23 (2H, m), 5.35-5.48 (1H, br m), 6.94 (2H, d, J = 8.8 Hz), 7.48 (2H, d, J = 8.8 Hz).

LC / MS [Condition 1]: Retention time 5.8 minutes; m / z 582.4 [M + H] ⁺ (ESI positive ion mode), m / z 625.6 [M + HCOO] ⁻ (ESI negative ion mode)

実施例１３７
３−｛［５−（４−ベンゾイルピペリジン−１−カルボニル）ピリジン−２−イル］メチル｝−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−２−オン（化合物番号１３７）の製造
テトラヒドロフルフリルアミンの代わりに４−ベンゾイルピペリジン塩酸塩とトリエチルアミンを用いること以外は実質的に実施例１１１と同様に反応を行って、表題化合物（１４ｍｇ、収率８０％）を白色固体として得た。

^１Ｈ−ＮＭＲ（ＣＤＣｌ_３）δ：１．７１−２．１０（８Ｈ，ｍ），２．４９−２．６２（４Ｈ，ｍ），３．０２−３．３２（２Ｈ，ｍ），３．３５（２Ｈ，ｓ），３．５２−３．６５（１Ｈ，ｍ），３．５６（２Ｈ，ｓ），３．７３−３．９５（１Ｈ，ｍ），４．５３−４．７３（１Ｈ，ｍ），４．５８（２Ｈ，ｓ），７．３４−７．６４（８Ｈ，ｍ），７．７６（１Ｈ，ｄｄ，Ｊ＝７．８，２．０Ｈｚ），７．９５（２Ｈ，ｄｄ，Ｊ＝８．４，１．２Ｈｚ），８．６２（１Ｈ，ｄ，Ｊ＝２．０Ｈｚ）．

ＬＣ／ＭＳ［条件１］：保持時間３．３５分；ｍ／ｚ６２１．０［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ６５５．２［Ｍ＋Ｃｌ］^―（ＥＳＩ負イオンモード）

Example 137
3-{[5- (4-Benzoylpiperidin-1-carbonyl) pyridin-2-yl] methyl} -8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4. 5] Production of decan-2-one (Compound No. 137) The reaction was conducted in substantially the same manner as in Example 111 except that 4-benzoylpiperidine hydrochloride and triethylamine were used instead of tetrahydrofurfurylamine to give the title compound ( 14 mg, 80% yield) was obtained as a white solid.

¹ H-NMR (CDCl ₃ ) δ: 1.71-2.10 (8H, m), 2.49-2.62 (4H, m), 3.02-3.32 (2H, m), 3 .35 (2H, s), 3.52-3.65 (1H, m), 3.56 (2H, s), 3.73-3.95 (1H, m), 4.53-4.73 (1H, m), 4.58 (2H, s), 7.34-7.64 (8H, m), 7.76 (1H, dd, J = 7.8, 2.0 Hz), 7.95. (2H, dd, J = 8.4, 1.2 Hz), 8.62 (1H, d, J = 2.0 Hz).

LC / MS [Condition 1]: Retention time 3.35 minutes; m / z 621.0 [M + H] ⁺ (ESI positive ion mode), m / z 655.2 [M + Cl] ⁻ (ESI negative ion mode)

実施例１３８
１−［６−（｛２−オキソ−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）ピリジン−３−イル］−３−［（テトラヒドロフラン−２−イル）メチル］ウレア（化合物番号１３８）の製造
４−（｛２−オキソ−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）安息香酸の代わりに参考例１１１−５で得られた６−（｛２−オキソ−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）ニコチン酸を、Ｎ−（ｔ−ブトキシカルボニル）−１，３−ジアミノプロパンの代わりにテトラヒドロフルフリルアミンを用いること以外は実質的に実施例８３と同様に反応を行って、表題化合物（１．９ｍｇ、収率５％）を無色油状物として得た。

^１Ｈ−ＮＭＲ（ＣＤＣｌ_３）δ：１．６９−１．８１（２Ｈ，ｍ），１．８４−２．０６（６Ｈ，ｍ），２．４５−２．６１（４Ｈ，ｍ），２．６６−２．８５（１Ｈ，ｍ），３．１２−３．２３（１Ｈ，ｍ），３．２８（２Ｈ，ｓ），３．５１−３．６２（１Ｈ，ｍ），３．５５（２Ｈ，ｓ），３．７３−３．９５（２Ｈ，ｍ），３．９９−４．０９（１Ｈ，ｍ），４．４７（２Ｈ，ｓ），５．２４−５．３７（１Ｈ，ｂｒｍ），７．１９（１Ｈ，ｄ，Ｊ＝８．４Ｈｚ），７．４３（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ），７．５６（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ），７．９２（１Ｈ，ｄｄ，Ｊ＝８．４，２．６Ｈｚ），８．３９（１Ｈ，ｄ，Ｊ＝２．６Ｈｚ）．

ＬＣ／ＭＳ［条件１］：保持時間２．７９分；ｍ／ｚ５４７．６［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ５４６．１［Ｍ−Ｈ］^―（ＥＳＩ負イオンモード）

Example 138
1- [6-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl) pyridine-3- Preparation of yl] -3-[(tetrahydrofuran-2-yl) methyl] urea (Compound No. 138) 4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3, 6-({2-oxo-8- [4- (trifluoromethyl) benzyl]] obtained in Reference Example 111-5 instead of 8-diazaspiro [4.5] decan-3-yl} methyl) benzoic acid -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl) nicotinic acid and tetrahydrofurfurylamine in place of N- (t-butoxycarbonyl) -1,3-diaminopropane about Outside by carrying out the reaction using substantially similar to Example 83 to give the title compound (1.9 mg, 5% yield) as a colorless oil.

¹ H-NMR (CDCl ₃ ) δ: 1.69-1.81 (2H, m), 1.84-2.06 (6H, m), 2.45-2.61 (4H, m), 2 .66-2.85 (1H, m), 3.12-3.23 (1H, m), 3.28 (2H, s), 3.51-3.62 (1H, m), 3.55 (2H, s), 3.73-3.95 (2H, m), 3.99-4.09 (1H, m), 4.47 (2H, s), 5.24-5.37 (1H , Brm), 7.19 (1H, d, J = 8.4 Hz), 7.43 (2H, d, J = 8.2 Hz), 7.56 (2H, d, J = 8.2 Hz), 7 .92 (1H, dd, J = 8.4, 2.6 Hz), 8.39 (1H, d, J = 2.6 Hz).

LC / MS [Condition 1]: Retention time 2.79 minutes; m / z 547.6 [M + H] ⁺ (ESI positive ion mode), m / z 546.1 [MH] ⁻ (ESI negative ion mode)

参考例１３９−１
３−｛１−［４−（メトキシカルボニル）フェニル］エチル｝−２−オキソ−１−オキサ−３，８−ジアザスピロ［４．５］デカン−８−カルボン酸ｔ−ブチルの製造
６−（ヒドロキシメチル）ニコチン酸エチルの代わりに４−（１−ヒドロキシエチル）安息香酸メチルを用いること以外は実質的に参考例１１１−３と同様に反応を行って、表題化合物（２２ｍｇ、収率２７％）を無色油状物として得た。

^１Ｈ−ＮＭＲ（ＣＤＣｌ_３）δ：１．４４（９Ｈ，ｓ），１．６０（３Ｈ，ｄ，Ｊ＝７．２Ｈｚ），１．６４−１．７８（２Ｈ，ｍ），１．８２−１．９４（２Ｈ，ｍ），２．８３（１Ｈ，ｄ，Ｊ＝８．５Ｈｚ），３．１９（１Ｈ，ｄ，Ｊ＝８．５Ｈｚ），３．１９−３．３６（２Ｈ，ｍ），３．６５−３．９１（２Ｈ，ｍ），３．９２（３Ｈ，ｓ），５．２８（１Ｈ，ｑ，Ｊ＝７．２Ｈｚ），７．３９（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ），８．０４（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ）．

ＬＣ／ＭＳ［条件１］：保持時間４．４２分；ｍ／ｚ４４１．０［Ｍ＋Ｎａ］^＋（ＥＳＩ正イオンモード）

Reference Example 139-1
Preparation of t-butyl 3- {1- [4- (methoxycarbonyl) phenyl] ethyl} -2-oxo-1-oxa-3,8-diazaspiro [4.5] decane-8-carboxylate 6- (hydroxy The reaction was conducted in substantially the same manner as in Reference Example 111-3 except that methyl 4- (1-hydroxyethyl) benzoate was used instead of methyl) ethyl nicotinate to give the title compound (22 mg, 27% yield). Was obtained as a colorless oil.

¹ H-NMR (CDCl ₃ ) δ: 1.44 (9H, s), 1.60 (3H, d, J = 7.2 Hz), 1.64-1.78 (2H, m), 1.82 -1.94 (2H, m), 2.83 (1H, d, J = 8.5 Hz), 3.19 (1H, d, J = 8.5 Hz), 3.19-3.36 (2H, m), 3.65-3.91 (2H, m), 3.92 (3H, s), 5.28 (1H, q, J = 7.2 Hz), 7.39 (2H, d, J = 8.2 Hz), 8.04 (2H, d, J = 8.2 Hz).

LC / MS [Condition 1]: retention time 4.42 minutes; m / z 441.0 [M + Na] ⁺ (ESI positive ion mode)

参考例１３９−２
４−（１−｛２−オキソ−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝エチル）安息香酸メチルの製造
３−｛［５−（エトキシカルボニル）ピリジン−２−イル］メチル｝−２−オキソ−１−オキサ−３，８−ジアザスピロ［４．５］デカン−８−カルボン酸ｔ−ブチルの代わりに参考例１３９−１で得られた３−｛１−［４−（メトキシカルボニル）フェニル］エチル｝−２−オキソ−１−オキサ−３，８−ジアザスピロ［４．５］デカン−８−カルボン酸ｔ−ブチルを用いること以外は実質的に参考例１１１−４と同様に反応を行って、表題化合物（２６ｍｇ、収率５６％）を無色油状物として得た。

^１Ｈ−ＮＭＲ（ＣＤＣｌ_３）δ：１．５９（３Ｈ，ｄ，Ｊ＝７．２Ｈｚ），１．６１−１．８４（２Ｈ，ｍ），１．８８−１．９８（１Ｈ，ｍ），２．４３−２．６０（４Ｈ，ｍ），２．８３（１Ｈ，ｄ，Ｊ＝８．５Ｈｚ），３．１９（１Ｈ，ｄ，Ｊ＝８．５Ｈｚ），３．５４（２Ｈ，ｓ），３．９２（３Ｈ，ｓ），５．２７（１Ｈ，ｑ，Ｊ＝７．２Ｈｚ），７．３９（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ），７．４１（２Ｈ，ｄ，Ｊ＝８．５Ｈｚ），７．５６（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ），８．０３（２Ｈ，ｄ，Ｊ＝８．５Ｈｚ）．

ＬＣ／ＭＳ［条件１］：保持時間３．１４分；ｍ／ｚ４７７．０［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）

Reference Example 139-2
Preparation of methyl 4- (1- {2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} ethyl) benzoate Reference instead of t-butyl 3-{[5- (ethoxycarbonyl) pyridin-2-yl] methyl} -2-oxo-1-oxa-3,8-diazaspiro [4.5] decane-8-carboxylate 3- {1- [4- (methoxycarbonyl) phenyl] ethyl} -2-oxo-1-oxa-3,8-diazaspiro [4.5] decane-8-carboxylic acid t obtained in Example 139-1 The reaction was carried out substantially in the same manner as in Reference Example 111-4 except that -butyl was used to give the title compound (26 mg, yield 56%) as a colorless oil.

¹ H-NMR (CDCl ₃ ) δ: 1.59 (3H, d, J = 7.2 Hz), 1.61-1.84 (2H, m), 1.88-1.98 (1H, m) , 2.4-2.60 (4H, m), 2.83 (1H, d, J = 8.5 Hz), 3.19 (1H, d, J = 8.5 Hz), 3.54 (2H, s), 3.92 (3H, s), 5.27 (1H, q, J = 7.2 Hz), 7.39 (2H, d, J = 8.2 Hz), 7.41 (2H, d, J = 8.5 Hz), 7.56 (2H, d, J = 8.2 Hz), 8.03 (2H, d, J = 8.5 Hz).

LC / MS [Condition 1]: Retention time 3.14 minutes; m / z 477.0 [M + H] ⁺ (ESI positive ion mode)

参考例１３９−３
４−（１−｛２−オキソ−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝エチル）安息香酸の製造
６−（｛２−オキソ−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）ニコチン酸エチルの代わりに参考例１３９−２で得られた４−（１−｛２−オキソ−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝エチル）安息香酸メチルを用いること以外は実質的に参考例１１１−５と同様に反応を行って、表題化合物（２４ｍｇ、定量的）を無色油状物として得た。

Reference Example 139-3
Preparation of 4- (1- {2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} ethyl) benzoic acid 6 -({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl) reference example instead of ethyl nicotinate 4- (1- {2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} obtained in 139-2 Ethyl) The reaction was carried out in substantially the same manner as in Reference Example 111-5 except that methyl benzoate was used to give the title compound (24 mg, quantitative) as a colorless oil.

実施例１３９
３−｛１−［４−（４−ベンゾイルピペリジン−１−カルボニル）フェニル］エチル｝−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−２−オン（化合物番号１３９）の製造
６−（｛２−オキソ−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）ニコチン酸の代わりに参考例１３９−３で得られた４−（１−｛２−オキソ−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝エチル）安息香酸を、テトラヒドロフルフリルアミンの代わりに４−ベンゾイルピペリジン塩酸塩とトリエチルアミンを用いること以外は実質的に実施例１１１と同様に反応を行って、表題化合物（９．３ｍｇ、収率８５％）を無色油状物として得た。

^１Ｈ−ＮＭＲ（ＣＤＣｌ_３）δ：１．４７−１．７１（５Ｈ，ｍ），１．７０−２．０９（６Ｈ，ｍ），２．３９−２．６３（４Ｈ，ｍ），２．８７（１Ｈ，ｄ，Ｊ＝８．５Ｈｚ），３．００−３．２４（２Ｈ，ｍ），３．１８（１Ｈ，ｄ，Ｊ＝８．５Ｈｚ），３．４６−３．６３（１Ｈ，ｍ），３．５５（２Ｈ，ｓ），３．７０−３．９７（１Ｈ，ｍ），４．５４−４．８２（１Ｈ，ｍ），５．２４（１Ｈ，ｑ，Ｊ＝７．２Ｈｚ），７．３３−７．６３（１１Ｈ，ｍ），７．９１−７．９８（２Ｈ，ｍ）．

ＬＣ／ＭＳ［条件１］：保持時間３．５４分；ｍ／ｚ６３４．０［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ６７８．３［Ｍ＋ＨＣＯＯ］^―（ＥＳＩ負イオンモード）

Example 139
3- {1- [4- (4-Benzoylpiperidine-1-carbonyl) phenyl] ethyl} -8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] Preparation of decan-2-one (Compound No. 139) 6-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decane-3 4- (1- {2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-] obtained in Reference Example 139-3 instead of -yl} methyl) nicotinic acid Diazaspiro [4.5] decan-3-yl} ethyl) benzoic acid is substantially the same as Example 111 except that 4-benzoylpiperidine hydrochloride and triethylamine are used in place of tetrahydrofurfurylamine. Performing response, to give the title compound (9.3 mg, 85% yield) as a colorless oil.

¹ H-NMR (CDCl ₃ ) δ: 1.47-1.71 (5H, m), 1.70-2.09 (6H, m), 2.39-2.63 (4H, m), 2 .87 (1H, d, J = 8.5 Hz), 3.00-3.24 (2H, m), 3.18 (1H, d, J = 8.5 Hz), 3.46-3.63 ( 1H, m), 3.55 (2H, s), 3.70-3.97 (1H, m), 4.54-4.82 (1H, m), 5.24 (1H, q, J = 7.2 Hz), 7.33-7.63 (11H, m), 7.91-7.98 (2H, m).

LC / MS [Condition 1]: retention time 3.54 minutes; m / z 634.0 [M + H] ⁺ (ESI positive ion mode), m / z 678.3 [M + HCOO] ⁻ (ESI negative ion mode)

実施例１４０
４−（１−｛２−オキソ−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝エチル）−Ｎ−［（テトラヒドロフラン−２−イル）メチル］ベンズアミド（化合物番号１４０）の製造
４−ベンゾイルピペリジン塩酸塩とトリエチルアミンの代わりにテトラヒドロフルフリルアミンを用いること以外は実質的に実施例１３９と同様に反応を行って、表題化合物（６．８ｍｇ、収率７３％）を無色油状物として得た。

^１Ｈ−ＮＭＲ（ＣＤＣｌ_３）δ：１．５３−１．６５（５Ｈ，ｍ），１．７２−１．８４（２Ｈ，ｍ），１．８８−２．１１（４Ｈ，ｍ），２．４１−２．６１（４Ｈ，ｍ），２．８２（１Ｈ，ｄ，Ｊ＝８．５Ｈｚ），３．１８（１Ｈ，ｄ，Ｊ＝８．５Ｈｚ），３．２７−３．３９（１Ｈ，ｍ），３．５５（２Ｈ，ｓ），３．７２−３．９５（３Ｈ，ｍ），４．０１−４．１３（１Ｈ，ｍ），５．２６（１Ｈ，ｑ，Ｊ＝７．２Ｈｚ），６．４３−６．５４（１Ｈ，ｂｒｍ），７．３８（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ），７．４２（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ），７．５６（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ），７．７７（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ）．

ＬＣ／ＭＳ［条件１］：保持時間３．１２分；ｍ／ｚ５４６．０［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ５８０．２［Ｍ＋Ｃｌ］^―（ＥＳＩ負イオンモード）

Example 140
4- (1- {2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} ethyl) -N-[( Preparation of tetrahydrofuran-2-yl) methyl] benzamide (Compound No. 140) The reaction was carried out in substantially the same manner as in Example 139 except that tetrahydrofurfurylamine was used in place of 4-benzoylpiperidine hydrochloride and triethylamine. The compound (6.8 mg, 73% yield) was obtained as a colorless oil.

¹ H-NMR (CDCl ₃ ) δ: 1.53-1.65 (5H, m), 1.72-1.84 (2H, m), 1.88-2.11 (4H, m), 2 .41-2.61 (4H, m), 2.82 (1H, d, J = 8.5 Hz), 3.18 (1H, d, J = 8.5 Hz), 3.27-3.39 ( 1H, m), 3.55 (2H, s), 3.72-3.95 (3H, m), 4.01-4.13 (1H, m), 5.26 (1H, q, J = 7.2 Hz), 6.43-6.54 (1 H, brm), 7.38 (2 H, d, J = 8.2 Hz), 7.42 (2 H, d, J = 8.2 Hz), 7. 56 (2H, d, J = 8.2 Hz), 7.77 (2H, d, J = 8.2 Hz).

LC / MS [Condition 1]: Retention time 3.12 minutes; m / z 546.0 [M + H] ⁺ (ESI positive ion mode), m / z 580.2 [M + Cl] ⁻ (ESI negative ion mode)

実施例１４１
４−［４−（１−｛２−オキソ−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝エチル）ベンズアミド］ピペリジン−１−カルボン酸メチル（化合物番号１４１）の製造
４−ベンゾイルピペリジン塩酸塩の代わりに参考例１３５で得られた４−アミノピペリジン−１−カルボン酸メチル塩酸塩を用いること以外は実質的に実施例１３９と同様に反応を行って、表題化合物（８．６ｍｇ、収率８２％）を無色固体として得た。

^１Ｈ−ＮＭＲ（ＣＤＣｌ_３）δ：１．３３−１．６５（６Ｈ，ｍ），１．７１−１．８２（２Ｈ，ｍ），１．８８−１．９７（１Ｈ，ｍ），２．００−２．０９（２Ｈ，ｍ），２．３９−２．６０（４Ｈ，ｍ），２．８２（１Ｈ，ｄ，Ｊ＝８．５Ｈｚ），２．９７（２Ｈ，ｔ，Ｊ＝１２．３Ｈｚ），３．１９（１Ｈ，ｄ，Ｊ＝８．５Ｈｚ），３．５４（２Ｈ，ｓ），３．７０（３Ｈ，ｓ），４．０４−４．２６（３Ｈ，ｍ），５．２５（１Ｈ，ｑ，Ｊ＝７．２Ｈｚ），５．９３−６．０３（１Ｈ，ｂｒｍ），７．３９（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ），７．４１（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ），７．５６（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ），７．７４（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ）．

ＬＣ／ＭＳ［条件１］：保持時間３．２分；ｍ／ｚ６０３．０［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ６３７．２［Ｍ＋Ｃｌ］^―（ＥＳＩ負イオンモード）

Example 141
4- [4- (1- {2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} ethyl) benzamide] Preparation of methyl piperidine-1-carboxylate (Compound No. 141) Substantially except that 4-aminopiperidine-1-carboxylate methyl hydrochloride obtained in Reference Example 135 was used instead of 4-benzoylpiperidine hydrochloride The reaction was carried out in the same manner as in Example 139 to obtain the title compound (8.6 mg, yield 82%) as a colorless solid.

¹ H-NMR (CDCl ₃ ) δ: 1.33-1.65 (6H, m), 1.71-1.82 (2H, m), 1.88-1.97 (1H, m), 2 .00-2.09 (2H, m), 2.39-2.60 (4H, m), 2.82 (1H, d, J = 8.5 Hz), 2.97 (2H, t, J = 12.3 Hz), 3.19 (1 H, d, J = 8.5 Hz), 3.54 (2 H, s), 3.70 (3 H, s), 4.04-4.26 (3 H, m) , 5.25 (1H, q, J = 7.2 Hz), 5.93-6.03 (1H, brm), 7.39 (2H, d, J = 8.2 Hz), 7.41 (2H, d, J = 8.2 Hz), 7.56 (2H, d, J = 8.2 Hz), 7.74 (2H, d, J = 8.2 Hz).

LC / MS [Condition 1]: Retention time 3.2 minutes; m / z 603.0 [M + H] ⁺ (ESI positive ion mode), m / z 637.2 [M + Cl] ⁻ (ESI negative ion mode)

参考例１４２−１
５−（クロロメチル）チアゾール−２−カルボン酸エチルの製造
２−アミノ−２−チオキソ酢酸エチル（１．０ｇ、７．５ｍｍｏｌ）と１，３−ジクロロプロパン−２−オン（１．１ｇ、８．５ｍｍｏｌ）をトルエン（１５ｍＬ）に溶解し、１１０℃にて５時間半かき混ぜた。反応混合物を室温まで冷却した後、酢酸エチルで希釈し、飽和炭酸水素ナトリウム水溶液を加えた。有機層を分離し、水と飽和食塩水で洗浄した後、無水硫酸ナトリウムで乾燥した。有機層を減圧下濃縮した後、得られた残留物をシリカゲルカラムクロマトグラフィー［モリテックス社製プリフパック２Ｌ４０μｍ、展開溶媒：ヘキサン／酢酸エチル＝６／１］にて精製し、表題化合物（１．３ｇ、収率８２％）を黄色油状物として得た。

^１Ｈ−ＮＭＲ（ＣＤＣｌ_３）δ：１．４５（３Ｈ，ｔ，Ｊ＝７．０Ｈｚ），４．５０（２Ｈ，ｑ，Ｊ＝７．０Ｈｚ），４．７８（２Ｈ，ｓ），７．６３（１Ｈ，ｓ）．

ＬＣ／ＭＳ［条件１］：保持時間３．６２分；ｍ／ｚ２０６．０［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）

Reference Example 142-1
Preparation of ethyl 5- (chloromethyl) thiazole-2-carboxylate ethyl 2-amino-2-thioxoacetate (1.0 g, 7.5 mmol) and 1,3-dichloropropan-2-one (1.1 g, 8 0.5 mmol) was dissolved in toluene (15 mL) and stirred at 110 ° C. for 5 and a half hours. The reaction mixture was cooled to room temperature, diluted with ethyl acetate, and saturated aqueous sodium hydrogen carbonate solution was added. The organic layer was separated, washed with water and saturated brine, and dried over anhydrous sodium sulfate. After the organic layer was concentrated under reduced pressure, the obtained residue was purified by silica gel column chromatography [Polipack 2L 40 μm, developed by Morexex, developing solvent: hexane / ethyl acetate = 6/1], and the title compound (1.3 g, Yield 82%) was obtained as a yellow oil.

¹ H-NMR (CDCl ₃ ) δ: 1.45 (3H, t, J = 7.0 Hz), 4.50 (2H, q, J = 7.0 Hz), 4.78 (2H, s), 7 .63 (1H, s).

LC / MS [Condition 1]: Retention time 3.62 minutes; m / z 206.0 [M + H] ⁺ (ESI positive ion mode)

参考例１４２−２
５−（アジドメチル）チアゾール−２−カルボン酸エチルの製造
参考例１４２−１で得られた５−（クロロメチル）チアゾール−２−カルボン酸エチル（１．３ｇ、６．１ｍｍｏｌ）をＮ，Ｎ−ジメチルホルムアミド（２０ｍＬ）に溶解した後、アジ化ナトリウム（４４０ｍｇ、６．７ｍｍｏｌ）を加え、室温で３日間かき混ぜた。反応混合物を酢酸エチルで希釈した後、水を加えた。有機層を分離し、水と飽和食塩水で洗浄した後、無水硫酸ナトリウムで乾燥した。減圧下、有機層の溶液が約１０ｍＬになるまで濃縮した後、０．０２０ｍＬを採取して減圧濃縮し、表題化合物を得た。残りの溶液は、そのまま次の反応に使用した。

^１Ｈ−ＮＭＲ（ＣＤＣｌ_３）δ：１．４５（３Ｈ，ｔ，Ｊ＝７．２Ｈｚ），４．５０（２Ｈ，ｑ，Ｊ＝７．２Ｈｚ），４．６３（２Ｈ，ｓ），７．５５（１Ｈ，ｓ）．

Reference Example 142-2
Preparation of ethyl 5- (azidomethyl) thiazole-2-carboxylate Ethyl 5- (chloromethyl) thiazole-2-carboxylate (1.3 g, 6.1 mmol) obtained in Reference Example 142-1 was converted to N, N- After dissolving in dimethylformamide (20 mL), sodium azide (440 mg, 6.7 mmol) was added, and the mixture was stirred at room temperature for 3 days. The reaction mixture was diluted with ethyl acetate and water was added. The organic layer was separated, washed with water and saturated brine, and dried over anhydrous sodium sulfate. After concentration under reduced pressure until the organic layer solution was about 10 mL, 0.020 mL was collected and concentrated under reduced pressure to obtain the title compound. The remaining solution was used for the next reaction as it was.

¹ H-NMR (CDCl ₃ ) δ: 1.45 (3H, t, J = 7.2 Hz), 4.50 (2H, q, J = 7.2 Hz), 4.63 (2H, s), 7 .55 (1H, s).

参考例１４２−３
５−（アミノメチル）チアゾール−２−カルボン酸エチルの製造
参考例１４２−２で得られた５−（アジドメチル）チアゾール−２−カルボン酸エチルの酢酸エチル溶液（約１０ｍＬ）にエタノール（１０ｍＬ）を加えた後、アルゴン雰囲気下、１０重量％パラジウム−炭素（３００ｍｇ）を加えた。反応系内を再びアルゴンで満たした後、水素に置換し、室温で１日間かき混ぜた。反応系内をアルゴンに置換した後、反応混合物をセライトでろ過し、不溶物を除去した。ろ液を減圧濃縮した後、アルゴン雰囲気下、１０重量％パラジウム−炭素（６００ｍｇ）を加えた。反応系内を再びアルゴンで満たした後、水素に置換し、室温で５時間かき混ぜた。反応系内をアルゴンに置換した後、反応混合物をセライトでろ過し、不溶物を除去した。溶液が約１５ｍＬになるまで溶媒を留去した後、０．０６ｍＬを採取して減圧濃縮し、表題化合物を得た。残りの溶液は、そのまま次の反応に用いられた。

^１Ｈ−ＮＭＲ（ＣＤＣｌ_３）δ：１．４４（３Ｈ，ｔ，Ｊ＝７．２Ｈｚ），４．０８（２Ｈ，ｓ），４．４９（２Ｈ，ｑ，Ｊ＝７．２Ｈｚ），７．４２（１Ｈ，ｓ）．

Reference Example 142-3
Preparation of ethyl 5- (aminomethyl) thiazole-2-carboxylate Ethanol (10 mL) was added to an ethyl acetate solution (about 10 mL) of ethyl 5- (azidomethyl) thiazole-2-carboxylate obtained in Reference Example 142-2. After the addition, 10 wt% palladium-carbon (300 mg) was added under an argon atmosphere. The reaction system was again filled with argon, replaced with hydrogen, and stirred at room temperature for 1 day. After replacing the inside of the reaction system with argon, the reaction mixture was filtered through celite to remove insoluble matters. The filtrate was concentrated under reduced pressure, and 10 wt% palladium-carbon (600 mg) was added under an argon atmosphere. After the reaction system was again filled with argon, it was replaced with hydrogen and stirred at room temperature for 5 hours. After replacing the inside of the reaction system with argon, the reaction mixture was filtered through celite to remove insoluble matters. After the solvent was distilled off until the solution reached about 15 mL, 0.06 mL was collected and concentrated under reduced pressure to obtain the title compound. The remaining solution was directly used for the next reaction.

¹ H-NMR (CDCl ₃ ) δ: 1.44 (3H, t, J = 7.2 Hz), 4.08 (2H, s), 4.49 (2H, q, J = 7.2 Hz), 7 .42 (1H, s).

参考例１４２−４
５−（｛［１−（ｔ−ブトキシカルボニル）−４−ヒドロキシピペリジン−４−イル］メチルアミノ｝メチル）チアゾール−２−カルボン酸エチルの製造
参考例１４２−３で得られた５−（アミノメチル）チアゾール−２−カルボン酸エチルのエタノール溶液（約１５ｍＬ）に水（１０ｍＬ）と参考例１−１で得られた１−オキサ−６−アザスピロ［２．５］オクタン−６−カルボン酸ｔ−ブチル（１．２ｇ、５．４ｍｍｏｌ）を加えた後、室温で３日間かき混ぜた。反応混合物を減圧濃縮し、クロロホルムと水で希釈した後、有機層を分離し、水層をクロロホルムで抽出した。合わせた有機層を水と飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥した後、減圧濃縮し、主として表題化合物を含む混合物（２．５ｇ）を黄色油状物として得た。

Reference Example 142-4
Preparation of ethyl 5-({[1- (t-butoxycarbonyl) -4-hydroxypiperidin-4-yl] methylamino} methyl) thiazole-2-carboxylate 5- (amino obtained in Reference Example 142-3 1-oxa-6-azaspiro [2.5] octane-6-carboxylic acid t obtained in Reference Example 1-1 with water (10 mL) in an ethanol solution (about 15 mL) of ethyl methyl) thiazole-2-carboxylate After adding -butyl (1.2 g, 5.4 mmol), the mixture was stirred at room temperature for 3 days. The reaction mixture was concentrated under reduced pressure, diluted with chloroform and water, the organic layer was separated, and the aqueous layer was extracted with chloroform. The combined organic layers were washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a mixture (2.5 g) containing mainly the title compound as a yellow oil.

参考例１４２−５
３−｛［２−（エトキシカルボニル）チアゾール−５−イル］メチル｝−２−オキソ−１−オキサ−３，８−ジアザスピロ［４．５］デカン−８−カルボン酸ｔ−ブチルの製造
参考例１４２−４で得られた５−（｛［１−（ｔ−ブトキシカルボニル）−４−ヒドロキシピペリジン−４−イル］メチルアミノ｝メチル）チアゾール−２−カルボン酸エチルを含む混合物（２．５ｇ）をテトラヒドロフラン（３０ｍＬ）に溶解し、１，１’−カルボニルジイミダゾール（１．５ｇ、９．３ｍｍｏｌ）を加え、７０℃にて２時間かき混ぜた。室温で１日間かき混ぜた後、反応混合物に１，１’−カルボニルジイミダゾール（１．５ｇ、９．３ｍｍｏｌ）を加え、再び７０℃で３時間かき混ぜた。反応混合物を冷却した後、水を加え、発泡が収まるまでかき混ぜた。反応混合物を酢酸エチルで希釈した後、飽和炭酸水素ナトリウム水溶液を加えた。有機層を分離し、水と飽和食塩水で洗浄した後、無水硫酸ナトリウムで乾燥した。有機層を減圧下濃縮した後、得られた残留物をシリカゲルカラムクロマトグラフィー［モリテックス社製プリフパック２Ｌ４０μｍ、展開溶媒：ヘキサン／酢酸エチル］にて精製し、表題化合物（８５０ｇ、収率３０％）を黄色油状物として得た。

^１Ｈ−ＮＭＲ（ＣＤＣｌ_３）δ：１．４４（３Ｈ，ｔ，Ｊ＝７．２Ｈｚ），１．４５（９Ｈ，ｓ），１．５５−１．７３（２Ｈ，ｍ），１．８０−１．９５（２Ｈ，ｍ），３．２９（２Ｈ，ｔ，Ｊ＝１１．１Ｈｚ），３．３９（２Ｈ，ｓ），３．７２−３．８９（２Ｈ，ｍ），４．４９（２Ｈ，ｑ，Ｊ＝７．２Ｈｚ），４．６４（２Ｈ，ｓ），７．５５（１Ｈ，ｓ）．

ＬＣ／ＭＳ［条件１］：保持時間４．０２分；ｍ／ｚ４４８．０［Ｍ＋Ｎａ］^＋（ＥＳＩ正イオンモード）

Reference Example 142-5
3 - {[2- (ethoxycarbonyl) thiazol-5-yl] methyl} -2-oxo-1-oxa-3,8-diazaspiro [4.5] manufacturing reference decane-8-carboxylic acid t- butyl Mixture (2.5 g) containing ethyl 5-({[1- (t-butoxycarbonyl) -4-hydroxypiperidin-4-yl] methylamino} methyl) thiazole-2-carboxylate obtained in Example 142-4 ) Was dissolved in tetrahydrofuran (30 mL), 1,1′-carbonyldiimidazole (1.5 g, 9.3 mmol) was added, and the mixture was stirred at 70 ° C. for 2 hours. After stirring at room temperature for 1 day, 1,1′-carbonyldiimidazole (1.5 g, 9.3 mmol) was added to the reaction mixture, and the mixture was stirred again at 70 ° C. for 3 hours. After cooling the reaction mixture, water was added and stirred until foaming subsided. The reaction mixture was diluted with ethyl acetate, and saturated aqueous sodium hydrogen carbonate solution was added. The organic layer was separated, washed with water and saturated brine, and dried over anhydrous sodium sulfate. After the organic layer was concentrated under reduced pressure, the obtained residue was purified by silica gel column chromatography [Polipack 2L 40 μm, developed by Moritex, developing solvent: hexane / ethyl acetate] to give the title compound (850 g, yield 30%). Obtained as a yellow oil.

¹ H-NMR (CDCl ₃ ) δ: 1.44 (3H, t, J = 7.2 Hz), 1.45 (9H, s), 1.55-1.73 (2H, m), 1.80 -1.95 (2H, m), 3.29 (2H, t, J = 11.1 Hz), 3.39 (2H, s), 3.72-3.89 (2H, m), 4.49 (2H, q, J = 7.2 Hz), 4.64 (2H, s), 7.55 (1H, s).

LC / MS [Condition 1]: Retention time 4.02 minutes; m / z 448.0 [M + Na] ⁺ (ESI positive ion mode)

参考例１４２−６
５−（｛２−オキソ−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）チアゾール−２−カルボン酸エチルの製造
３−｛［５−（エトキシカルボニル）ピリジン−２−イル］メチル｝−２−オキソ−１−オキサ−３，８−ジアザスピロ［４．５］デカン−８−カルボン酸ｔ−ブチルの代わりに参考例１４２−５で得られた３−｛［２−（エトキシカルボニル）チアゾール−５−イル］メチル｝−２−オキソ−１−オキサ−３，８−ジアザスピロ［４．５］デカン−８−カルボン酸ｔ−ブチルを用いること以外は実質的に参考例１１１−４と同様に反応を行って、表題化合物（１４０ｍｇ、収率６３％）を得た。

^１Ｈ−ＮＭＲ（ＣＤＣｌ_３）δ：１．４４（３Ｈ，ｔ，Ｊ＝７．２Ｈｚ），１．６７−１．８６（２Ｈ，ｍ），１．８６−２．００（２Ｈ，ｍ），２．４１−２．６３（４Ｈ，ｍ），３．３８（２Ｈ，ｓ），３．５６（２Ｈ，ｓ），４．４８（２Ｈ，ｑ，Ｊ＝７．１Ｈｚ），４．６３（２Ｈ，ｓ），７．４３（２Ｈ，ｄ，Ｊ＝８．３Ｈｚ），７．５４（１Ｈ，ｓ），７．５７（２Ｈ，ｄ，Ｊ＝８．３Ｈｚ）．

ＬＣ／ＭＳ［条件１］：保持時間２．３６分；ｍ／ｚ４８３．８［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）

Reference Example 142-6
5-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl) thiazole-2-carboxylate Preparation of 3-{[5- (ethoxycarbonyl) pyridin-2-yl] methyl} -2-oxo-1-oxa-3,8-diazaspiro [4.5] decane-8-carboxylate instead of t-butyl 3-{[2- (ethoxycarbonyl) thiazol-5-yl] methyl} -2-oxo-1-oxa-3,8-diazaspiro [4.5] decane-8 obtained in Reference Example 142-5 -The reaction was carried out in substantially the same manner as in Reference Example 111-4 except that t-butyl carboxylate was used to obtain the title compound (140 mg, yield 63%).

¹ H-NMR (CDCl ₃ ) δ: 1.44 (3H, t, J = 7.2 Hz), 1.67-1.86 (2H, m), 1.86-2.00 (2H, m) , 2.41-2.63 (4H, m), 3.38 (2H, s), 3.56 (2H, s), 4.48 (2H, q, J = 7.1 Hz), 4.63 (2H, s), 7.43 (2H, d, J = 8.3 Hz), 7.54 (1H, s), 7.57 (2H, d, J = 8.3 Hz).

LC / MS [Condition 1]: Retention time 2.36 minutes; m / z 483.8 [M + H] ⁺ (ESI positive ion mode)

参考例１４２−７
５−（｛２−オキソ−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）チアゾール−２−カルボン酸の製造
６−（｛２−オキソ−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）ニコチン酸エチルの代わりに参考例１４２−６で得られた５−（｛２−オキソ−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）チアゾール−２−カルボン酸エチルを用いること以外は実質的に参考例１１１−５と同様に反応を行って、表題化合物（１１０ｍｇ、収率８１％）を得た。

^１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ_６）δ：１．７１−１．８９（４Ｈ，ｍ），３．３３（２Ｈ，ｓ），３．６９（２Ｈ，ｓ），４．５０（２Ｈ，ｓ），７．５６（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ），７．７０（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ），７．８４（１Ｈ，ｓ），ｐｉｐｅｒｉｄｉｎｅ ２Ｈはピークが重なって見えない．

ＬＣ／ＭＳ［条件１］：保持時間２．３６分；ｍ／ｚ４５５．９［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ４５３．０［Ｍ−Ｈ］^―（ＥＳＩ負イオンモード）

Reference Example 142-7
Of 5-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl) thiazole-2-carboxylic acid Preparation 6-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl) instead of ethyl nicotinate 5-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} obtained in Reference Example 142-6 The reaction was carried out in substantially the same manner as in Reference Example 111-5, except that ethyl methyl) thiazole-2-carboxylate was used, to give the title compound (110 mg, yield 81%).

¹ H-NMR (DMSO-d ₆ ) δ: 1.71-1.89 (4H, m), 3.33 (2H, s), 3.69 (2H, s), 4.50 (2H, s) ), 7.56 (2H, d, J = 8.2 Hz), 7.70 (2H, d, J = 8.2 Hz), 7.84 (1H, s), piperidine 2H cannot be seen due to overlapping peaks .

LC / MS [Condition 1]: Retention time 2.36 minutes; m / z 455.9 [M + H] ⁺ (ESI positive ion mode), m / z 453.0 [M−H] ⁻ (ESI negative ion mode)

実施例１４２
３−｛［２−（４−ベンゾイルピペリジン−１−カルボニル）チアゾール−５−イル］メチル｝−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−２−オン（化合物番号１４２）の製造
６−（｛２−オキソ−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）ニコチン酸の代わりに参考例１４２−７で得られた５−（｛２−オキソ−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）チアゾール−２−カルボン酸を、テトラヒドロフルフリルアミンの代わりに４−ベンゾイルピペリジン塩酸塩とトリエチルアミンを用いること以外は実質的に実施例１１１と同様に反応を行って、表題化合物（１４ｍｇ、収率７３％）を得た。

^１Ｈ−ＮＭＲ（ＣＤＣｌ_３）δ：１．６８−２．１０（８Ｈ，ｍ），２．４６−２．６０（４Ｈ，ｍ），３．０３−３．２８（１Ｈ，ｍ），３．３１（２Ｈ，ｓ），３．４０−３．６８（２Ｈ，ｍ），３．５５（２Ｈ，ｓ），４．５１−４．７３（１Ｈ，ｍ），４．５６（２Ｈ，ｄ，Ｊ＝２．７Ｈｚ），５．２０−５．４３（１Ｈ，ｍ），７．３６−７．６７（８Ｈ，ｍ），７．９５（２Ｈ，ｄ，Ｊ＝７．２Ｈｚ）．

ＬＣ／ＭＳ［条件１］：保持時間３．４５分；ｍ／ｚ６２７．１［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ６６１．３［Ｍ＋Ｃｌ］^―（ＥＳＩ負イオンモード）

Example 142
3-{[2- (4-Benzoylpiperidin-1-carbonyl) thiazol-5-yl] methyl} -8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4. 5] Preparation of decan-2-one (Compound No. 142) 6-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decane 5-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-] obtained in Reference Example 142-7 instead of -3-yl} methyl) nicotinic acid Diazaspiro [4.5] decan-3-yl} methyl) thiazole-2-carboxylic acid is substantially the same except that 4-benzoylpiperidine hydrochloride and triethylamine are used instead of tetrahydrofurfurylamine. The reaction was carried out in the same manner as in Example 111 to give the title compound (14 mg, 73% yield).

¹ H-NMR (CDCl ₃ ) δ: 1.68-2.10 (8H, m), 2.46-2.60 (4H, m), 3.03-3.28 (1H, m), 3 .31 (2H, s), 3.40-3.68 (2H, m), 3.55 (2H, s), 4.51-4.73 (1H, m), 4.56 (2H, d) , J = 2.7 Hz), 5.20-5.43 (1H, m), 7.36-7.67 (8H, m), 7.95 (2H, d, J = 7.2 Hz).

LC / MS [Condition 1]: Retention time 3.45 minutes; m / z 627.1 [M + H] ⁺ (ESI positive ion mode), m / z 661.3 [M + Cl] ⁻ (ESI negative ion mode)

実施例１４３
Ｎ−（ベンゾ［ｄ］［１，３］ジオキソール−５−イルメチル）−６−（｛２−オキソ−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）ニコチンアミド（化合物番号１４３）の製造
テトラヒドロフルフリルアミンの代わりにピペロニルアミンを用いること以外は実質的に実施例１１１と同様に反応を行って、表題化合物（７．１ｍｇ、収率６８％）を無色油状物として得た。

^１Ｈ−ＮＭＲ（ＣＤＣｌ_３）δ：１．７０−１．８２（２Ｈ，ｍ），１．９０−２．０１（２Ｈ，ｍ），２．４６−２．６０（４Ｈ，ｍ），３．３２（２Ｈ，ｓ），３．５６（２Ｈ，ｓ），４．５５（２Ｈ，ｄ，Ｊ＝５．８Ｈｚ），４．５７（２Ｈ，ｓ），５．９６（２Ｈ，ｓ），６．３７（１Ｈ，ｂｒｓ），６．７５−６．８６（３Ｈ，ｍ），７．３７（１Ｈ，ｄ，Ｊ＝８．２Ｈｚ），７．４３（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ），７．５６（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ），８．０９（１Ｈ，ｄｄ，Ｊ＝８．２，２．０Ｈｚ），８．９２（１Ｈ，ｄ，Ｊ＝２．０Ｈｚ）．

ＬＣ／ＭＳ［条件１］：保持時間３．２分；ｍ／ｚ５８２．９［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ６１７．１［Ｍ＋Ｃｌ］^―（ＥＳＩ負イオンモード）

Example 143
N- (benzo [d] [1,3] dioxol-5-ylmethyl) -6-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [ 4.5] Preparation of decan-3-yl} methyl) nicotinamide (Compound No. 143) The reaction was conducted in substantially the same manner as in Example 111 except that piperonylamine was used instead of tetrahydrofurfurylamine. 7.1 mg, 68% yield) was obtained as a colorless oil.

¹ H-NMR (CDCl ₃ ) δ: 1.70-1.82 (2H, m), 1.90-2.01 (2H, m), 2.46-2.60 (4H, m), 3 .32 (2H, s), 3.56 (2H, s), 4.55 (2H, d, J = 5.8 Hz), 4.57 (2H, s), 5.96 (2H, s), 6.37 (1H, brs), 6.75-6.86 (3H, m), 7.37 (1H, d, J = 8.2 Hz), 7.43 (2H, d, J = 8.2 Hz) ), 7.56 (2H, d, J = 8.2 Hz), 8.09 (1H, dd, J = 8.2, 2.0 Hz), 8.92 (1H, d, J = 2.0 Hz) .

LC / MS [Condition 1]: Retention time 3.2 minutes; m / z 582.9 [M + H] ⁺ (ESI positive ion mode), m / z 617.1 [M + Cl] ⁻ (ESI negative ion mode)

実施例１４４
３−（｛５−［４−（４−フルオロベンゾイル）ピペリジン−１−カルボニル］ピリジン−２−イル｝メチル）−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−２−オン（化合物番号１４４）の製造
テトラヒドロフルフリルアミンの代わりに４−（４−フルオロベンゾイル）ピペリジン塩酸塩とトリエチルアミンを用いること以外は実質的に実施例１１１と同様に反応を行って、表題化合物（４．９ｍｇ、収率４３％）を無色油状物として得た。

^１Ｈ−ＮＭＲ（ＣＤＣｌ_３）δ：１．６９−２．０８（８Ｈ，ｍ），２．４５−２．６５（４Ｈ，ｍ），３．０１−３．２７（２Ｈ，ｍ），３．３５（２Ｈ，ｓ），３．４１−３．６５（１Ｈ，ｍ），３．５７（２Ｈ，ｓ），４．４７−４．７６（１Ｈ，ｍ），４．５７（２Ｈ，ｓ），７．１７（２Ｈ，ｔ，Ｊ＝８．５Ｈｚ），７．３６（１Ｈ，ｄ，Ｊ＝７．８Ｈｚ），７．４３（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ），７．５７（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ），７．７６（１Ｈ，ｄｄ，Ｊ＝７．８，２．０Ｈｚ），７．９４−８．０２（２Ｈ，ｍ），８．６１（１Ｈ，ｄ，Ｊ＝２．０Ｈｚ）．１Ｈｉｎｖｉｓｉｂｌｅ（ｂｒｏａｄ）

ＬＣ／ＭＳ［条件１］：保持時間３．４分；ｍ／ｚ６３９．１［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ６７３．３［Ｍ＋Ｃｌ］^―（ＥＳＩ負イオンモード）

Example 144
3-({5- [4- (4-Fluorobenzoyl) piperidin-1-carbonyl] pyridin-2-yl} methyl) -8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8 -Preparation of diazaspiro [4.5] decan-2-one (Compound No. 144) Substantially as Example 111 except that 4- (4-fluorobenzoyl) piperidine hydrochloride and triethylamine were used instead of tetrahydrofurfurylamine. The reaction was performed in the same manner to obtain the title compound (4.9 mg, yield 43%) as a colorless oil.

¹ H-NMR (CDCl ₃ ) δ: 1.69-2.08 (8H, m), 2.45-2.65 (4H, m), 3.01-3.27 (2H, m), 3 .35 (2H, s), 3.41-3.65 (1H, m), 3.57 (2H, s), 4.47-4.76 (1H, m), 4.57 (2H, s) ), 7.17 (2H, t, J = 8.5 Hz), 7.36 (1H, d, J = 7.8 Hz), 7.43 (2H, d, J = 8.2 Hz), 7.57 (2H, d, J = 8.2 Hz), 7.76 (1H, dd, J = 7.8, 2.0 Hz), 7.94-8.02 (2H, m), 8.61 (1H, d, J = 2.0 Hz). 1Hinvisible (broad)

LC / MS [Condition 1]: Retention time 3.4 minutes; m / z 639.1 [M + H] ⁺ (ESI positive ion mode), m / z 673.3 [M + Cl] ⁻ (ESI negative ion mode)

実施例１４５
３−（｛５−［４−（６−フルオロベンゾ［ｄ］イソオキサゾール−３−イル）ピペリジン−１−カルボニル］ピリジン−２−イル｝メチル）−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−２−オン（化合物番号１４５）の製造
テトラヒドロフルフリルアミンの代わりに６−フルオロ−３−（ピペリジン−４−イル）ベンゾ［ｄ］イソオキサゾールを用いること以外は実質的に実施例１１１と同様に反応を行って、表題化合物（７．６ｍｇ、収率６６％）を無色油状物として得た。

^１Ｈ−ＮＭＲ（ＣＤＣｌ_３）δ：１．４０−１．６０（１Ｈ，ｍ），１．７２−１．８７（２Ｈ，ｍ），１．９１−２．３１（６Ｈ，ｍ），２．４６−２．６５（４Ｈ，ｍ），３．０９−３．４７（４Ｈ，ｍ），３．３５（２Ｈ，ｓ），３．５７（２Ｈ，ｓ），４．５８（２Ｈ，ｓ），７．０９（１Ｈ，ｔｄ，Ｊ＝８．９，２．０Ｈｚ），７．３８（２Ｈ，ｄ，Ｊ＝７．８Ｈｚ），７．４４（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ），７．５７（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ），７．６３（１Ｈ，ｄｄ，Ｊ＝８．７，４．９Ｈｚ），７．７８（１Ｈ，ｄｄ，Ｊ＝８．２，２．０Ｈｚ），８．６５（１Ｈ，ｄ，Ｊ＝１．４Ｈｚ）．

ＬＣ／ＭＳ［条件１］：保持時間３．４７分；ｍ／ｚ６５２．１［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ６８６．３［Ｍ＋Ｃｌ］^―（ＥＳＩ負イオンモード）

Example 145
3-({5- [4- (6-Fluorobenzo [d] isoxazol-3-yl) piperidin-1-carbonyl] pyridin-2-yl} methyl) -8- [4- (trifluoromethyl) benzyl Preparation of 1-oxa-3,8-diazaspiro [4.5] decan-2-one (Compound No. 145) 6-Fluoro-3- (piperidin-4-yl) benzo [d] instead of tetrahydrofurfurylamine The reaction was carried out in substantially the same manner as in Example 111 except that isoxazole was used to give the title compound (7.6 mg, yield 66%) as a colorless oil.

¹ H-NMR (CDCl ₃ ) δ: 1.40-1.60 (1H, m), 1.72-1.87 (2H, m), 1.91-2.31 (6H, m), 2 .46-2.65 (4H, m), 3.09-3.47 (4H, m), 3.35 (2H, s), 3.57 (2H, s), 4.58 (2H, s) ), 7.09 (1H, td, J = 8.9, 2.0 Hz), 7.38 (2H, d, J = 7.8 Hz), 7.44 (2H, d, J = 8.2 Hz) 7.57 (2H, d, J = 8.2 Hz), 7.63 (1H, dd, J = 8.7, 4.9 Hz), 7.78 (1H, dd, J = 8.2, 2) .0Hz), 8.65 (1H, d, J = 1.4 Hz).

LC / MS [Condition 1]: Retention time 3.47 minutes; m / z 652.1 [M + H] ⁺ (ESI positive ion mode), m / z 686.3 [M + Cl] ⁻ (ESI negative ion mode)

参考例１４６
３−｛［（１ｒ，４ｒ）−４−（４−ベンゾイルピペリジン−１−カルボニル）シクロヘキシル］メチル｝−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−２−オンの製造
ピペリジンの代わりに、フェニル（ピペリジン−４−イル）メタノン塩酸塩（市販）とトリエチルアミンを用いること以外は実質的に実施例１６と同様に反応を行なって、表題化合物（３７ｍｇ、収率５９％）を白色粉末として得た。

^１Ｈ−ＮＭＲ（３００ＭＨｚ、ＣＤＣｌ_３）δ：１．０５（２Ｈ，ｑ，Ｊ＝１１．９Ｈｚ），１．４６−１．７１（４Ｈ，ｍ），１．７１−１．８７（７Ｈ，ｍ），１．８７−２．００（４Ｈ，ｍ），２．４６（１Ｈ，ｔｔ，Ｊ＝１１．９，３．３Ｈｚ），２．５６（４Ｈ，ｂｒ ｓ），２．８１（１Ｈ，ｔ，Ｊ＝１１．４Ｈｚ），３．１１（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ），３．１３−３．２９（３Ｈ，ｍ），３．５１（１Ｈ，ｔｔ，Ｊ＝１１．０，４．５Ｈｚ），３．５７（２Ｈ，ｓ），３．９８（１Ｈ，ｄ，Ｊ＝１３．５Ｈｚ），４．６０（１Ｈ，ｄ，Ｊ＝１３．１Ｈｚ），７．３９−７．６２（７Ｈ，ｍ），７．９３（２Ｈ，ｄ，Ｊ＝６．５Ｈｚ）．

ＬＣ／ＭＳ［条件１］：保持時間３．５６分；ｍ／ｚ６２６．０［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ６７０．２［Ｍ＋ＨＣＯＯ］^―（ＥＳＩ負イオンモード）

Reference Example 146
3-{[(1r, 4r) -4- (4-Benzoylpiperidine-1-carbonyl) cyclohexyl] methyl} -8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [ 4.5] Production of decan-2-one The reaction was carried out in substantially the same manner as in Example 16 except that phenyl (piperidin-4-yl) methanone hydrochloride (commercially available) and triethylamine were used instead of piperidine. The title compound (37 mg, 59% yield) was obtained as a white powder.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.05 (2H, q, J = 11.9 Hz), 1.46-1.71 (4H, m), 1.71-1.87 (7H, m), 1.87-2.00 (4H, m), 2.46 (1H, tt, J = 11.9, 3.3 Hz), 2.56 (4H, br s), 2.81 (1H) , T, J = 11.4 Hz), 3.11 (2H, d, J = 8.2 Hz), 3.13-3.29 (3H, m), 3.51 (1H, tt, J = 11.1). 0, 4.5 Hz), 3.57 (2H, s), 3.98 (1 H, d, J = 13.5 Hz), 4.60 (1 H, d, J = 13.1 Hz), 7.39- 7.62 (7H, m), 7.93 (2H, d, J = 6.5 Hz).

LC / MS [Condition 1]: retention time 3.56 minutes; m / z 626.0 [M + H] ⁺ (ESI positive ion mode), m / z 670.2 [M + HCOO] ⁻ (ESI negative ion mode)

実施例１４６
３−｛［（１ｒ，４ｒ）−４−（４−ベンゾイルピペリジン−１−カルボニル）シクロヘキシル］メチル｝−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−２−オン塩酸塩（化合物番号１４６）の製造
参考例１４６で得られた３−｛［（１ｒ，４ｒ）−４−（４−ベンゾイルピペリジン−１−カルボニル）シクロヘキシル］メチル｝−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−２−オン（１７ｍｇ、０．０２８ｍｍｏｌ）をメタノール（１．０ｍＬ）に溶解した後、室温にて４Ｍ塩化水素−ジオキサン溶液（市販）（０．０２１ｍＬ、０．０８３ｍｍｏｌ）を加えて、６０℃で５時間かき混ぜた。その後、減圧下濃縮乾固して３−｛［（１ｒ，４ｒ）−４−（４−ベンゾイルピペリジン−１−カルボニル）シクロヘキシル］メチル｝−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−２−オン塩酸塩（１９ｍｇ、定量的）を白色粉末として得た。

^１Ｈ−ＮＭＲ（３００ＭＨｚ、ＣＤＣｌ_３）δ：１．０４（２Ｈ，ｑ，Ｊ＝１１．４Ｈｚ），１．４６−１．９９（１１Ｈ，ｍ），２．０５（２Ｈ，ｄ，Ｊ＝１３．９Ｈｚ），２．４６（１Ｈ，ｔｔ，Ｊ＝１１．４，２．９Ｈｚ），２．６４−２．９３（３Ｈ，ｍ），３．０２−３．２８（５Ｈ，ｍ），３．３０−３．４３（２Ｈ，ｂｒ ｍ），３．３８（２Ｈ，ｓ），３．５２（１Ｈ，ｔｔ，Ｊ＝１１．０，３．７Ｈｚ），３．９７（１Ｈ，ｂｒ ｓ），４．１７（２Ｈ，ｄ，Ｊ＝５．３Ｈｚ），４．５７（１Ｈ，ｂｒ ｓ），７．４２−７．５２（２Ｈ，ｍ），７．５３−７．６３（１Ｈ，ｍ），７．７３（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ），７．８５（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ），７．８９−７．９７（２Ｈ，ｍ），１３．２６（１Ｈ，ｓ）．

Example 146
3-{[(1r, 4r) -4- (4-Benzoylpiperidine-1-carbonyl) cyclohexyl] methyl} -8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [ 4.5] Preparation of decan-2-one hydrochloride (Compound No. 146) 3-{[(1r, 4r) -4- (4-benzoylpiperidine-1-carbonyl) cyclohexyl] methyl obtained in Reference Example 146 } -8- [4- (Trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-2-one (17 mg, 0.028 mmol) dissolved in methanol (1.0 mL) Then, 4M hydrogen chloride-dioxane solution (commercially available) (0.021 mL, 0.083 mmol) was added at room temperature, and the mixture was stirred at 60 ° C. for 5 hours. Then, it was concentrated to dryness under reduced pressure, and 3-{[(1r, 4r) -4- (4-benzoylpiperidine-1-carbonyl) cyclohexyl] methyl} -8- [4- (trifluoromethyl) benzyl] -1 -Oxa-3,8-diazaspiro [4.5] decan-2-one hydrochloride (19 mg, quantitative) was obtained as a white powder.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.04 (2H, q, J = 11.4 Hz), 1.46-1.99 (11H, m), 2.05 (2H, d, J = 13.9 Hz), 2.46 (1H, tt, J = 11.4, 2.9 Hz), 2.64-2.93 (3H, m), 3.02-3.28 (5H, m), 3.30-3.43 (2H, br m), 3.38 (2H, s), 3.52 (1 H, tt, J = 11.0, 3.7 Hz), 3.97 (1 H, br s) ), 4.17 (2H, d, J = 5.3 Hz), 4.57 (1H, brs), 7.42-7.52 (2H, m), 7.53-7.63 (1H, m), 7.73 (2H, d, J = 8.2 Hz), 7.85 (2H, d, J = 8.2 Hz), 7.89-7.97 (2H, m), 13.26 ( 1H, s .

実施例１４７
３−（｛（１ｒ，４ｒ）−４−［４−（テトラヒドロフラン−２−カルボニル）ピペラジン−１−カルボニル］シクロヘキシル｝メチル）−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−２−オン（化合物番号１４７）の製造
ピペリジンの代わりに、ピペラジン−１−イル（テトラヒドロフラン−２−イル）メタノン（市販）を用いること以外は実質的に実施例１６と同様に反応を行なって、表題化合物（４８ｍｇ、収率７２％）を白色粉末として得た。

^１Ｈ−ＮＭＲ（３００ＭＨｚ、ＣＤＣｌ_３）δ：１．０５（２Ｈ，ｑ，Ｊ＝１１．９Ｈｚ），１．４５−１．７０（３Ｈ，ｍ），１．７０−１．８６（６Ｈ，ｍ），１．８７−２．１１（５Ｈ，ｍ），２．２４−２．５１（２Ｈ，ｍ），２．５６（４Ｈ，ｂｒ ｓ），３．１１（２Ｈ，ｄ，Ｊ＝７．４Ｈｚ），３．２６（２Ｈ，ｓ），３．３３−３．６３（７Ｈ，ｍ），３．６４−３．９８（５Ｈ，ｍ），４．５９（１Ｈ，ｔ，Ｊ＝６．１Ｈｚ），７．４３（２Ｈ，ｄ，Ｊ＝７．８Ｈｚ），７．５７（２Ｈ，ｄ，Ｊ＝７．８Ｈｚ）．

ＬＣ／ＭＳ［条件１］：保持時間３．１０分；ｍ／ｚ６２０．９［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ６６５．２［Ｍ＋ＨＣＯＯ］^―（ＥＳＩ負イオンモード）

Example 147
3-({(1r, 4r) -4- [4- (tetrahydrofuran-2-carbonyl) piperazine-1-carbonyl] cyclohexyl} methyl) -8- [4- (trifluoromethyl) benzyl] -1-oxa- Preparation of 3,8-diazaspiro [4.5] decan-2-one (Compound No. 147) Substantially except that piperazin-1-yl (tetrahydrofuran-2-yl) methanone (commercially available) is used instead of piperidine The reaction was carried out in the same manner as in Example 16 to obtain the title compound (48 mg, yield 72%) as a white powder.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.05 (2H, q, J = 11.9 Hz), 1.45-1.70 (3H, m), 1.70-1.86 (6H, m), 1.87-2.11 (5H, m), 2.24-2.51 (2H, m), 2.56 (4H, brs), 3.11 (2H, d, J = 7) .4 Hz), 3.26 (2H, s), 3.33-3.63 (7H, m), 3.64-3.98 (5H, m), 4.59 (1H, t, J = 6) .1 Hz), 7.43 (2H, d, J = 7.8 Hz), 7.57 (2H, d, J = 7.8 Hz).

LC / MS [Condition 1]: Retention time 3.10 minutes; m / z 620.9 [M + H] ⁺ (ESI positive ion mode), m / z 665.2 [M + HCOO] ⁻ (ESI negative ion mode)

実施例１４８
４−［（１ｒ，４ｒ）−４−（｛２−オキソ−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イルメチル）｝シクロヘキサンカルボニル］ピペラジン−１−カルボン酸ｔ−ブチル（化合物番号１４８）の製造
ピペリジンの代わりに、ピペラジン−１−カルボン酸ｔ−ブチル（市販）を用いること以外は実質的に実施例１６と同様に反応を行なって、表題化合物（１３７ｍｇ、収率９２％）を白色粉末として得た。

^１Ｈ−ＮＭＲ（３００ＭＨｚ、ＣＤＣｌ_３）δ：１．０４（２Ｈ，ｑ，Ｊ＝１１．９Ｈｚ），１．４７（９Ｈ，ｓ），１．５１−１．６９（３Ｈ，ｍ），１．７０−１．８６（６Ｈ，ｍ），１．８７−２．０２（２Ｈ，ｍ），２．４２（１Ｈ，ｔ，Ｊ＝１１．４Ｈｚ），２．５６（４Ｈ，ｂｒ ｓ），３．１０（２Ｈ，ｄ，Ｊ＝６．１Ｈｚ），３．２６（２Ｈ，ｓ），３．３４−３．４６（４Ｈ，ｍ），３．４４（２Ｈ，ｓ），３．５７（４Ｈ，ｓ），７．４３（２Ｈ，ｄ，Ｊ＝７．８Ｈｚ），７．５７（２Ｈ，ｄ，Ｊ＝７．８Ｈｚ）．

ＬＣ／ＭＳ［条件１］：保持時間３．４２分；ｍ／ｚ６２２．９［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ６６７．１［Ｍ＋ＨＣＯＯ］^―（ＥＳＩ負イオンモード）

Example 148
4-[(1r, 4r) -4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-ylmethyl) } Cyclohexanecarbonyl] Production of t-butyl piperazine-1-carboxylate (Compound No. 148) Substantially the same as Example 16 except that t-butyl piperazine-1-carboxylate (commercially available) was used instead of piperidine. The title compound (137 mg, 92% yield) was obtained as a white powder.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.04 (2H, q, J = 11.9 Hz), 1.47 (9H, s), 1.51-1.69 (3H, m), 1 .70-1.86 (6H, m), 1.87-2.02 (2H, m), 2.42 (1H, t, J = 11.4 Hz), 2.56 (4H, br s), 3.10 (2H, d, J = 6.1 Hz), 3.26 (2H, s), 3.34-3.46 (4H, m), 3.44 (2H, s), 3.57 ( 4H, s), 7.43 (2H, d, J = 7.8 Hz), 7.57 (2H, d, J = 7.8 Hz).

LC / MS [Condition 1]: Retention time 3.42 minutes; m / z 622.9 [M + H] ⁺ (ESI positive ion mode), m / z 667.1 [M + HCOO] ⁻ (ESI negative ion mode)

参考例１４９
３−｛［（１ｒ，４ｒ）−４−（ピペラジン−１−カルボニル）シクロヘキシル］メチル｝−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−２−オン二塩酸塩の製造
実施例１４８で得られた４−［（１ｒ，４ｒ）−４−（｛２−オキソ−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イルメチル）｝シクロヘキサンカルボニル］ピペラジン−１−カルボン酸ｔ−ブチル（８９ｍｇ、０．１４ｍｍｏｌ）をメタノール（１．０ｍＬ）に溶解し、室温にて４Ｍ塩化水素−ジオキサン溶液（市販）（０．３６ｍＬ、１．４ｍｍｏｌ）を加えて、６０℃で４時間かき混ぜた。その後、減圧下濃縮乾固して３−｛［（１ｒ，４ｒ）−４−（ピペラジン−１−カルボニル）シクロヘキシル］メチル｝−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−２−オン二塩酸塩（８３ｍｇ、定量的）を白色粉末で得た。

ＬＣ／ＭＳ［条件１］：保持時間０．９６分；ｍ／ｚ５２３．０［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード

Reference Example 149
3-{[(1r, 4r) -4- (piperazine-1-carbonyl) cyclohexyl] methyl} -8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5 ] Preparation of decan-2-one dihydrochloride 4-[(1r, 4r) -4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-] obtained in Example 148 Oxa-3,8-diazaspiro [4.5] decan-3-ylmethyl)} cyclohexanecarbonyl] piperazine-1-carboxylate (89 mg, 0.14 mmol) was dissolved in methanol (1.0 mL) at room temperature. 4M hydrogen chloride-dioxane solution (commercially available) (0.36 mL, 1.4 mmol) was added and stirred at 60 ° C. for 4 hours. Then, it was concentrated to dryness under reduced pressure, and 3-{[(1r, 4r) -4- (piperazine-1-carbonyl) cyclohexyl] methyl} -8- [4- (trifluoromethyl) benzyl] -1-oxa- 3,8-Diazaspiro [4.5] decan-2-one dihydrochloride (83 mg, quantitative) was obtained as a white powder.

LC / MS [Condition 1]: Retention time 0.96 minutes; m / z 523.0 [M + H] ⁺ (ESI positive ion mode

実施例１４９
４−［（１ｒ，４ｒ）−４−（｛２−オキソ−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）シクロヘキサンカルボニル］ピペラジン−１−カルボン酸メチル（化合物番号１４９）の製造
参考例１４９で得られた３−｛［（１ｒ，４ｒ）−４−（ピペラジン−１−カルボニル）シクロヘキシル］メチル｝−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−２−オン二塩酸塩（２６ｍｇ、０．０４４ｍｍｏｌ）をジメチルホルムアミド（０．５ｍＬ）に溶解し、室温にてトリエチルアミン（０．０３１ｍＬ、０．２２ｍｍｏｌ）とクロロギ酸メチル（０．００７ｍＬ、０．０８８ｍｍｏｌ）を加えて、室温にて３日間かき混ぜた。その後、反応混合物にクロロホルム（３．０ｍＬ）と飽和炭酸水素ナトリウム水溶液（３．０ｍＬ）を加えて、有機層を分離した。有機層を無水硫酸ナトリウムで乾燥した後、減圧下濃縮した。得られた残留物をシリカゲルクロマトグラフィー［充填剤：富士シリシア社社製ＦＬ１００Ｄ、展開溶媒：クロロホルム／メタノール＝２０／１］にて精製し、４−［（１ｒ，４ｒ）−４−（｛２−オキソ−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）シクロヘキサンカルボニル］ピペラジン−１−カルボン酸メチル（１６ｍｇ、収率６３％）を白色粉末として得た。

^１Ｈ−ＮＭＲ（３００ＭＨｚ、ＣＤＣｌ_３）δ：１．０５（２Ｈ，ｑ，Ｊ＝１１．６Ｈｚ），１．４５−１．６９（３Ｈ，ｍ），１．７８（６Ｈ，ｄ，Ｊ＝１１．４Ｈｚ），１．９４（２Ｈ，ｄ，Ｊ＝１３．１Ｈｚ），２．４２（１Ｈ，ｔｔ，Ｊ＝１１．９，２．９Ｈｚ），２．５５（４Ｈ，ｂｒ ｓ），３．１０（２Ｈ，ｄ，Ｊ＝７．４Ｈｚ），３．２６（２Ｈ，ｓ），３．４７（６Ｈ，ｂｒ ｓ），３．５３−３．６４（４Ｈ，ｍ），３．７２（３Ｈ，ｓ），７．４３（２Ｈ，ｄ，Ｊ＝７．８Ｈｚ），７．５６（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ）．
ＬＣ／ＭＳ［条件１］：保持時間３．２２分；ｍ／ｚ５８０．９［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ６２５．１［Ｍ＋ＨＣＯＯ］^―（ＥＳＩ負イオンモード）

Example 149
4-[(1r, 4r) -4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} Preparation of methyl) cyclohexanecarbonyl] piperazine-1-carboxylate (Compound No. 149) 3-{[(1r, 4r) -4- (piperazine-1-carbonyl) cyclohexyl] methyl}-obtained in Reference Example 149 8- [4- (Trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-2-one dihydrochloride (26 mg, 0.044 mmol) was added to dimethylformamide (0.5 mL). And triethylamine (0.031 mL, 0.22 mmol) and methyl chloroformate (0.007 mL, 0.088 mmol) were added at room temperature. And the mixture was stirred for days. Thereafter, chloroform (3.0 mL) and saturated aqueous sodium hydrogen carbonate solution (3.0 mL) were added to the reaction mixture, and the organic layer was separated. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography [filler: FL100D manufactured by Fuji Silysia Ltd., developing solvent: chloroform / methanol = 20/1], and 4-[(1r, 4r) -4-({2 -Oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl) cyclohexanecarbonyl] piperazine-1-carboxylate (16 mg Yield 63%) as a white powder.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.05 (2H, q, J = 11.6 Hz), 1.45-1.69 (3H, m), 1.78 (6H, d, J = 11.4 Hz), 1.94 (2 H, d, J = 13.1 Hz), 2.42 (1 H, tt, J = 11.9, 2.9 Hz), 2.55 (4 H, br s), 3 .10 (2H, d, J = 7.4 Hz), 3.26 (2H, s), 3.47 (6H, brs), 3.53-3.64 (4H, m), 3.72 ( 3H, s), 7.43 (2H, d, J = 7.8 Hz), 7.56 (2H, d, J = 8.2 Hz).
LC / MS [Condition 1]: retention time 3.22 minutes; m / z 580.9 [M + H] ⁺ (ESI positive ion mode), m / z 625.1 [M + HCOO] ⁻ (ESI negative ion mode)

実施例１５０
２−｛４−［（１ｒ，４ｒ）−４−（｛２−オキソ−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）シクロヘキサンカルボニル］ピペラジン−１−イル｝アセトニトリル（化合物番号１５０）の製造
クロロギ酸メチルの代わりに、２−ブロモアセトニトリル（市販）を用いること以外は実質的に実施例１４９と同様に反応を行なって、表題化合物（７．０ｍｇ、収率３３％）を無色油状物として得た。

^１Ｈ−ＮＭＲ（３００ＭＨｚ、ＣＤＣｌ_３）δ：１．０４（２Ｈ，ｄｑ，Ｊ＝３．７，１２．３Ｈｚ），１．４６−１．６９（３Ｈ，ｍ），１．７９（６Ｈ，ｄ，Ｊ＝１１．４Ｈｚ），１．８８−２．０１（２Ｈ，ｍ），２．４２（１Ｈ，ｔｔ，Ｊ＝１０．６，２．５Ｈｚ），２．５７（８Ｈ，ｂｒ ｓ），３．１０（２Ｈ，ｄ，Ｊ＝７．４Ｈｚ），３．２６（２Ｈ，ｓ），３．４６−３．７２（８Ｈ，ｍ），７．４３（２Ｈ，ｄ，Ｊ＝７．８Ｈｚ），７．５７（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ）．
ＬＣ／ＭＳ［条件１］：保持時間３．１２分；ｍ／ｚ５６２．３［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ６０６．１［Ｍ＋ＨＣＯＯ］^―（ＥＳＩ負イオンモード）

Example 150
2- {4-[(1r, 4r) -4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decane-3 Preparation of -Il } methyl) cyclohexanecarbonyl] piperazin-1-yl} acetonitrile (Compound No. 150) Substantially the same as Example 149, except that 2-bromoacetonitrile (commercially available) was used instead of methyl chloroformate. The reaction was performed to give the title compound (7.0 mg, yield 33%) as a colorless oil.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.04 (2H, dq, J = 3.7, 12.3 Hz), 1.46 to 1.69 (3H, m), 1.79 (6H, d, J = 11.4 Hz), 1.88-2.01 (2H, m), 2.42 (1H, tt, J = 10.6, 2.5 Hz), 2.57 (8H, br s) 3.10 (2H, d, J = 7.4 Hz), 3.26 (2H, s), 3.46-3.72 (8H, m), 7.43 (2H, d, J = 7. 8 Hz), 7.57 (2H, d, J = 8.2 Hz).
LC / MS [Condition 1]: Retention time 3.12 minutes; m / z 562.3 [M + H] ⁺ (ESI positive ion mode), m / z 606.1 [M + HCOO] ⁻ (ESI negative ion mode)

実施例１５１
３−｛［（１ｒ，４ｒ）−４−（４−アセチルピペラジン−１−カルボニル）シクロヘキシル］メチル｝−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−２−オン（化合物番号１５１）の製造
クロロギ酸メチルの代わりに、アセチルクロリドを用いること以外は実質的に実施例１４９と同様に反応を行なって、表題化合物（９．０ｍｇ、収率３６％）を白色粉末として得た。

^１Ｈ−ＮＭＲ（３００ＭＨｚ、ＣＤＣｌ_３）δ：１．０５（２Ｈ，ｑ，Ｊ＝１２．０Ｈｚ），１．４７−１．７０（３Ｈ，ｍ），１．７９（６Ｈ，ｄ，Ｊ＝１１．０Ｈｚ），１．９４（２Ｈ，ｄ，Ｊ＝１３．１Ｈｚ），２．１２（３Ｈ，ｓ），２．３６−２．５１（１Ｈ，ｍ），２．５６（４Ｈ，ｂｒ ｓ），３．１１（２Ｈ，ｄ，Ｊ＝７．４Ｈｚ），３．２６（２Ｈ，ｓ），３．３８−３．５３（４Ｈ，ｂｒ ｍ），３．５７（２Ｈ，ｓ），３．５５−３．６９（４Ｈ，ｂｒ ｍ），７．４３（２Ｈ，ｄ，Ｊ＝７．８Ｈｚ），７．５６（２Ｈ，ｄ，Ｊ＝７．８Ｈｚ）．

ＬＣ／ＭＳ［条件１］：保持時間２．９８分；ｍ／ｚ５６４．９［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ６０９．２［Ｍ＋ＨＣＯＯ］^―（ＥＳＩ負イオンモード）

Example 151
3-{[(1r, 4r) -4- (4-acetylpiperazine-1-carbonyl) cyclohexyl] methyl} -8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [ 4.5] Production of decan-2-one (Compound No. 151) The reaction was conducted in substantially the same manner as in Example 149 except that acetyl chloride was used instead of methyl chloroformate to give the title compound (9.0 mg Yield 36%) as a white powder.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.05 (2H, q, J = 12.0 Hz), 1.47-1.70 (3H, m), 1.79 (6H, d, J = 11.0 Hz), 1.94 (2H, d, J = 13.1 Hz), 2.12 (3H, s), 2.36-2.51 (1 H, m), 2.56 (4H, br s) ), 3.11 (2H, d, J = 7.4 Hz), 3.26 (2H, s), 3.38-3.53 (4H, br m), 3.57 (2H, s), 3 .55-3.69 (4H, br m), 7.43 (2H, d, J = 7.8 Hz), 7.56 (2H, d, J = 7.8 Hz).

LC / MS [Condition 1]: Retention time 2.98 minutes; m / z 564.9 [M + H] ⁺ (ESI positive ion mode), m / z 609.2 [M + HCOO] ⁻ (ESI negative ion mode)

実施例１５２
４−［（１ｒ，４ｒ）−４−（｛２−オキソ−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）シクロヘキサンカルボキサミド］ピペリジン−１−カルボン酸エチル（化合物番号１５２）の製造
ピペリジンの代わりに、４−アミノピペリジン−１−カルボン酸エチル（市販）を用いること以外は実質的に実施例１６と同様に反応を行なって、表題化合物（５８ｍｇ、収率９２％）を白色粉末として得た。

^１Ｈ−ＮＭＲ（３００ＭＨｚ、ＣＤＣｌ_３）δ：１．０１（２Ｈ，ｄｑ，Ｊ＝２．９，１２．３Ｈｚ），１．１８−１．３６（５Ｈ，ｍ），１．３８−１．６６（３Ｈ，ｍ），１．６７−２．０６（１１Ｈ，ｍ），２．５５（４Ｈ，ｂｒ ｓ），２．８９（２Ｈ，ｔ，Ｊ＝１１．９Ｈｚ），３．０９（２Ｈ，ｄ，Ｊ＝７．４Ｈｚ），３．２５（２Ｈ，ｓ），３．５７（２Ｈ，ｓ），３．８２−４．００（１Ｈ，ｍ），４．０１−４．１９（４Ｈ，ｍ），５．２９（１Ｈ，ｄ，Ｊ＝７．８Ｈｚ），７．４３（２Ｈ，ｄ，Ｊ＝７．４Ｈｚ），７．５７（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ）．

ＬＣ／ＭＳ［条件１］：保持時間３．３６分；ｍ／ｚ６０８．９［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ６５３．２［Ｍ＋ＨＣＯＯ］^―（ＥＳＩ負イオンモード）

Example 152
4-[(1r, 4r) -4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} Methyl) cyclohexanecarboxamide] Preparation of ethyl piperidine-1-carboxylate (Compound No. 152) Substantially the same as Example 16 except that ethyl 4-aminopiperidine-1-carboxylate (commercially available) was used instead of piperidine. The title compound (58 mg, 92% yield) was obtained as a white powder.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.01 (2H, dq, J = 2.9, 12.3 Hz), 1.18-1.36 (5H, m), 1.38-1. 66 (3H, m), 1.67-2.06 (11H, m), 2.55 (4H, brs), 2.89 (2H, t, J = 11.9 Hz), 3.09 (2H , D, J = 7.4 Hz), 3.25 (2H, s), 3.57 (2H, s), 3.82-4.00 (1H, m), 4.01-4.19 (4H M), 5.29 (1H, d, J = 7.8 Hz), 7.43 (2H, d, J = 7.4 Hz), 7.57 (2H, d, J = 8.2 Hz).

LC / MS [Condition 1]: Retention time 3.36 minutes; m / z 608.9 [M + H] ⁺ (ESI positive ion mode), m / z 653.2 [M + HCOO] ⁻ (ESI negative ion mode)

実施例１５３
（１ｒ，４ｒ）−Ｎ−ブチル−４−｛［８−（４−シアノベンジル）−２−オキソ−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル］メチル｝シクロヘキサンカルボキサミド（化合物番号１５３）の製造
（１ｒ，４ｒ）−４−（｛２−オキソ−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）シクロヘキサンカルボン酸の代わりに参考例１７−２で得られた（１ｒ，４ｒ）−４−｛［８−（４−シアノベンジル）−２−オキソ−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル］メチル｝シクロヘキサンカルボン酸を、ピペリジンの代わりにｎ−ブチルアミン（市販）を、クロロホルムの代わりにジメチルホルムアミドを用いること以外は実質的に実施例１６と同様に反応を行なって、表題化合物（２３ｍｇ、収率３７％）を白色粉末として得た。

^１Ｈ−ＮＭＲ（３００ＭＨｚ、ＣＤＣｌ_３）δ：０．９２（３Ｈ，ｔ，Ｊ＝７．０Ｈｚ），１．０１（２Ｈ，ｄｑ，Ｊ＝４．１，１２．７Ｈｚ），１．２３−１．６６（７Ｈ，ｍ），１．６８−２．０６（９Ｈ，ｍ），２．５８（４Ｈ，ｂｒ ｓ），３．０９（２Ｈ，ｄ，Ｊ＝７．４Ｈｚ），３．１６−３．３０（４Ｈ，ｍ），３．５９（２Ｈ，ｓ），５．３９（１Ｈ，ｔ，Ｊ＝６．１Ｈｚ），７．４５（２Ｈ，ｄ，Ｊ＝７．８Ｈｚ），７．６１（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ）．

ＬＣ／ＭＳ［条件１］：保持時間２．９６分；ｍ／ｚ４６６．９［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ５１１．１［Ｍ＋ＨＣＯＯ］^―（ＥＳＩ負イオンモード）

Example 153
(1r, 4r) -N-butyl-4-{[8- (4-cyanobenzyl) -2-oxo-1-oxa-3,8-diazaspiro [4.5] decan-3-yl] methyl} cyclohexane Preparation of carboxamide (Compound No. 153) (1r, 4r) -4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decane (1r, 4r) -4-{[8- (4-cyanobenzyl) -2-oxo-1-oxa-3] obtained in Reference Example 17-2 instead of -3-yl} methyl) cyclohexanecarboxylic acid , 8-diazaspiro [4.5] decan-3-yl] methyl} cyclohexanecarboxylic acid, n-butylamine (commercially available) instead of piperidine, and dimethylformamide instead of chloroform Outside by performing the same reaction as substantially Example 16 to give the title compound (23 mg, 37% yield) as a white powder.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 0.92 (3H, t, J = 7.0 Hz), 1.01 (2H, dq, J = 4.1, 12.7 Hz), 1.23- 1.66 (7H, m), 1.68-2.06 (9H, m), 2.58 (4H, brs), 3.09 (2H, d, J = 7.4 Hz), 3.16 -3.30 (4H, m), 3.59 (2H, s), 5.39 (1H, t, J = 6.1 Hz), 7.45 (2H, d, J = 7.8 Hz), 7 .61 (2H, d, J = 8.2 Hz).

LC / MS [Condition 1]: Retention time 2.96 minutes; m / z 466.9 [M + H] ⁺ (ESI positive ion mode), m / z 511.1 [M + HCOO] ⁻ (ESI negative ion mode)

実施例１５４
４−［（３−｛［（１ｒ，４ｒ）−４−（４−ベンゾイルピペリジン−１−カルボニル）シクロヘキシル］メチル｝−２−オキソ−１−オキサ−３，８−ジアザスピロ［４．５］デカン−８−イル）メチル］ベンゾニトリル（化合物番号１５４）の製造
ｎ−ブチルアミンの代わりに、フェニル（ピペリジン−４−イル）メタノン塩酸塩（市販）とトリエチルアミンを用いること以外は実質的に実施例１５３と同様に反応を行なって、表題化合物（３７ｍｇ、収率５６％）を白色粉末として得た。

^１Ｈ−ＮＭＲ（３００ＭＨｚ、ＣＤＣｌ_３）δ：１．０５（２Ｈ，ｄｑ，Ｊ＝２．９，１１．９Ｈｚ），１．４３−２．０６（１５Ｈ，ｍ），２．４７（１Ｈ，ｔｔ，Ｊ＝１１．４，２．９Ｈｚ），２．５５（４Ｈ，ｂｒ ｓ），２．８１（１Ｈ，ｔ，Ｊ＝１１．９Ｈｚ），３．１１（２Ｈ，ｄ，Ｊ＝５．７Ｈｚ），３．２０（１Ｈ，ｔ，Ｊ＝１２．７Ｈｚ），３．２６（２Ｈ，ｓ），３．４４−３．５６（１Ｈ，ｍ），３．５７（２Ｈ，ｓ），３．９８（１Ｈ，ｄ，Ｊ＝１２．７Ｈｚ），４．５９（１Ｈ，ｄ，Ｊ＝１２．７Ｈｚ），７．３９−７．５３（４Ｈ，ｍ），７．５４−７．６５（３Ｈ，ｍ），７．９３（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ）．

ＬＣ／ＭＳ［条件１］：保持時間３．２８分；ｍ／ｚ５８２．９［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ６２７．２［Ｍ＋ＨＣＯＯ］^―（ＥＳＩ負イオンモード）

Example 154
4-[(3-{[(1r, 4r) -4- (4-Benzoylpiperidine-1-carbonyl) cyclohexyl] methyl} -2-oxo-1-oxa-3,8-diazaspiro [4.5] decane Preparation of -8-yl) methyl] benzonitrile (Compound No. 154) Substantially Example 153 except that phenyl (piperidin-4-yl) methanone hydrochloride (commercially available) and triethylamine were used instead of n-butylamine. The title compound (37 mg, yield 56%) was obtained as a white powder.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.05 (2H, dq, J = 2.9, 11.9 Hz), 1.43-2.06 (15H, m), 2.47 (1H, tt, J = 11.4, 2.9 Hz), 2.55 (4H, br s), 2.81 (1H, t, J = 11.9 Hz), 3.11 (2H, d, J = 5. 7 Hz), 3.20 (1 H, t, J = 12.7 Hz), 3.26 (2 H, s), 3.44-3.56 (1 H, m), 3.57 (2 H, s), 3 .98 (1H, d, J = 12.7 Hz), 4.59 (1 H, d, J = 12.7 Hz), 7.39-7.53 (4H, m), 7.54-7.65 ( 3H, m), 7.93 (2H, d, J = 8.2 Hz).

LC / MS [condition 1]: retention time 3.28 minutes; m / z 582.9 [M + H] ⁺ (ESI positive ion mode), m / z 627.2 [M + HCOO] ⁻ (ESI negative ion mode)

実施例１５５
（１ｒ，４ｒ）−Ｎ−（ベンゾ［ｄ］［１，３］ジオキソール−５−イルメチル）−４−｛［８−（４−シアノベンジル）−２−オキソ−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル］メチル｝シクロヘキサンカルボキサミド（化合物番号１５５）の製造
ｎ−ブチルアミンの代わりに、ベンゾ［ｄ］［１，３］ジオキソール−５−イルメタンアミン（市販）を用いること以外は実質的に実施例１５３と同様に反応を行なって、表題化合物（２１ｍｇ、収率３０％）を無色油状物として得た。

^１Ｈ−ＮＭＲ（３００ＭＨｚ、ＣＤＣｌ_３）δ：１．０１（２Ｈ，ｄｑ，Ｊ＝３．７，１２．７Ｈｚ），１．４０−１．６８（３Ｈ，ｍ），１．７０−１．８６（４Ｈ，ｍ），１．８７−１．９９（４Ｈ，ｍ），２．０４（１Ｈ，ｔｔ，Ｊ＝１１．０，２．９Ｈｚ），２．５５（４Ｈ，ｂｒ ｓ），３．０９（２Ｈ，ｄ，Ｊ＝７．４Ｈｚ），３．２５（２Ｈ，ｓ），３．５６（２Ｈ，ｓ），４．３２（２Ｈ，ｄ，Ｊ＝５．７Ｈｚ），５．６８（１Ｈ，ｔ，Ｊ＝５．５Ｈｚ），５．９３（２Ｈ，ｓ），６．６６−６．７８（３Ｈ，ｍ），７．４４（２Ｈ，ｄ，Ｊ＝７．８Ｈｚ），７．６０（２Ｈ，ｄ，Ｊ＝７．８Ｈｚ）．

ＬＣ／ＭＳ［条件１］：保持時間３．０６分；ｍ／ｚ５４４．９［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ５８９．２［Ｍ＋ＨＣＯＯ］^―（ＥＳＩ負イオンモード）

Example 155
(1r, 4r) -N- (Benzo [d] [1,3] dioxol-5-ylmethyl) -4-{[8- (4-cyanobenzyl) -2-oxo-1-oxa-3,8- Preparation of diazaspiro [4.5] decan-3-yl] methyl} cyclohexanecarboxamide (Compound No. 155) Instead of n-butylamine, benzo [d] [1,3] dioxol-5-ylmethanamine (commercially available) The reaction was carried out substantially in the same manner as in Example 153, except that the title compound (21 mg, yield 30%) was obtained as a colorless oil.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.01 (2H, dq, J = 3.7, 12.7 Hz), 1.40-1.68 (3H, m), 1.70-1. 86 (4H, m), 1.87-1.99 (4H, m), 2.04 (1H, tt, J = 11.0, 2.9 Hz), 2.55 (4H, brs), 3 .09 (2H, d, J = 7.4 Hz), 3.25 (2H, s), 3.56 (2H, s), 4.32 (2H, d, J = 5.7 Hz), 5.68 (1H, t, J = 5.5 Hz), 5.93 (2H, s), 6.66-6.78 (3H, m), 7.44 (2H, d, J = 7.8 Hz), 7 .60 (2H, d, J = 7.8 Hz).

LC / MS [Condition 1]: Retention time 3.06 minutes; m / z 544.9 [M + H] ⁺ (ESI positive ion mode), m / z 589.2 [M + HCOO] ⁻ (ESI negative ion mode)

実施例１５６
（１ｒ，４ｒ）−４−｛［８−（４−シアノベンジル）−２−オキソ−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル］メチル｝−Ｎ−（２，３−ジヒドロ−１Ｈ−インデン−２−イル）シクロヘキサンカルボキサミド（化合物番号１５６）の製造
ｎ−ブチルアミンの代わりに、２，３−ジヒドロ−１Ｈ−インデン−２−アミン（市販）を用いること以外は実質的に実施例１５３と同様に反応を行なって、表題化合物（２６ｍｇ、収率４８％）を黄色粉末として得た。

^１Ｈ−ＮＭＲ（３００ＭＨｚ、ＣＤＣｌ_３）δ：０．９８（２Ｈ，ｄｑ，Ｊ＝３．７，１３．１Ｈｚ），１．３６−１．６５（３Ｈ，ｍ），１．６６−２．０１（９Ｈ，ｍ），２．５５（４Ｈ，ｂｒ ｓ），２．７６（２Ｈ，ｄｄ，Ｊ＝１６．８，４．５Ｈｚ），３．０７（２Ｈ，ｄ，Ｊ＝７．４Ｈｚ），３．２４（２Ｈ，ｓ），３．３１（２Ｈ，ｄｄ，Ｊ＝１５．９，７．８Ｈｚ），３．５６（２Ｈ，ｓ），４．７３（１Ｈ，ｄｔｔ，Ｊ＝７．８，７．０，４．１Ｈｚ），５．６４（１Ｈ，ｄ，Ｊ＝７．８Ｈｚ），７．１０−７．２９（４Ｈ，ｍ），７．４３（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ），７．６０（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ）．

ＬＣ／ＭＳ［条件１］：保持時間３．２２分；ｍ／ｚ５２６．９［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ５７１．１［Ｍ＋ＨＣＯＯ］^―（ＥＳＩ負イオンモード）

Example 156
(1r, 4r) -4-{[8- (4-Cyanobenzyl) -2-oxo-1-oxa-3,8-diazaspiro [4.5] decan-3-yl] methyl} -N- (2 , 3-Dihydro-1H-inden-2-yl) cyclohexanecarboxamide (Compound No. 156) In place of n-butylamine, except that 2,3-dihydro-1H-inden-2-amine (commercially available) is used. The reaction was carried out substantially in the same manner as in Example 153 to obtain the title compound (26 mg, yield 48%) as a yellow powder.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 0.98 (2H, dq, J = 3.7, 13.1 Hz), 1.36 to 1.65 (3H, m), 1.66-2. 01 (9 H, m), 2.55 (4 H, br s), 2.76 (2 H, dd, J = 16.8, 4.5 Hz), 3.07 (2 H, d, J = 7.4 Hz) , 3.24 (2H, s), 3.31 (2H, dd, J = 15.9, 7.8 Hz), 3.56 (2H, s), 4.73 (1H, dtt, J = 7. 8, 7.0, 4.1 Hz), 5.64 (1H, d, J = 7.8 Hz), 7.10-7.29 (4H, m), 7.43 (2H, d, J = 8) .2 Hz), 7.60 (2H, d, J = 8.2 Hz).

LC / MS [Condition 1]: Retention time 3.22 minutes; m / z 526.9 [M + H] ⁺ (ESI positive ion mode), m / z 571.1 [M + HCOO] ⁻ (ESI negative ion mode)

実施例１５７
（１ｒ，４ｒ）−Ｎ−メトキシ−Ｎ−メチル−４−（｛２−オキソ−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）シクロヘキサンカルボキサミド（化合物番号１５７）の製造
ピペリジンの代わりに、Ｎ，Ｏ−ジメチルヒドロキシルアミン塩酸塩（市販）とトリエチルアミンを用いること以外は実質的に実施例１６と同様に反応を行なって、表題化合物（１４０ｍｇ、収率７７％）を白色粉末として得た。

^１Ｈ−ＮＭＲ（３００ＭＨｚ、ＣＤＣｌ_３）δ：１．０７（２Ｈ，ｄｑ，Ｊ＝２．６，１２．６Ｈｚ），１．４１−１．６８（３Ｈ，ｍ），１．６９−２．００（８Ｈ，ｍ），２．５７（４Ｈ，ｂｒ ｓ），２．６５（１Ｈ，ｔ，Ｊ＝１０．６Ｈｚ），３．１１（２Ｈ，ｄ，Ｊ＝７．３Ｈｚ），３．１７（３Ｈ，ｓ），３．２６（２Ｈ，ｓ），３．５７（２Ｈ，ｓ），３．６９（３Ｈ，ｓ），７．４４（２Ｈ，ｄ，Ｊ＝７．９Ｈｚ），７．５７（２Ｈ，ｄ，Ｊ＝７．９Ｈｚ）．

ＬＣ／ＭＳ［条件１］：保持時間３．１８分；ｍ／ｚ４９８．４［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）

Example 157
(1r, 4r) -N-methoxy-N-methyl-4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decane Preparation of -3-yl} methyl) cyclohexanecarboxamide (Compound No. 157) In substantially the same manner as in Example 16 except that N, O-dimethylhydroxylamine hydrochloride (commercially available) and triethylamine were used instead of piperidine. To give the title compound (140 mg, 77% yield) as a white powder.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.07 (2H, dq, J = 2.6, 12.6 Hz), 1.41-1.68 (3H, m), 1.69-2. 00 (8H, m), 2.57 (4H, br s), 2.65 (1 H, t, J = 10.6 Hz), 3.11 (2H, d, J = 7.3 Hz), 3.17 (3H, s), 3.26 (2H, s), 3.57 (2H, s), 3.69 (3H, s), 7.44 (2H, d, J = 7.9 Hz), 7. 57 (2H, d, J = 7.9 Hz).

LC / MS [Condition 1]: Retention time 3.18 minutes; m / z 498.4 [M + H] ⁺ (ESI positive ion mode)

参考例１５８
４−｛［８−（ｔ−ブトキシカルボニル）−２−オキソ−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル］メチル｝安息香酸の製造
３−｛［（１ｒ，４ｒ）−４−（メトキシカルボニル）シクロヘキシル］メチル｝−２−オキソ−１−オキサ−３，８−ジアザスピロ［４．５］デカン−８−カルボン酸ｔ−ブチルの代わりに実施例１で得られた、４−（｛２−オキソ−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）安息香酸メチルを用いること以外は実質的に参考例２−３と同様に反応を行なって、表題化合物（９００ｍｇ、収率９３％）を白色粉末として得た。

^１Ｈ−ＮＭＲ（３００ＭＨｚ、ＣＤＣｌ_３）δ：１．４５（９Ｈ，ｓ），１．５５−１．６８（２Ｈ，ｍ），１．８７（２Ｈ，ｄ，Ｊ＝１３．１Ｈｚ），３．１５（２Ｈ，ｓ），３．２８（２Ｈ，ｔｄ，Ｊ＝１２．３，２．９Ｈｚ），３．８２（２Ｈ，ｄｔ，Ｊ＝１３．５，４．１Ｈｚ），４．５１（２Ｈ，ｓ），７．３７（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ），８．０９（２Ｈ，ｄ，Ｊ＝８．６Ｈｚ）．

ＬＣ／ＭＳ［条件１］：保持時間３．８８分；、ｍ／ｚ３８９．０［Ｍ−Ｈ］^―（ＥＳＩ負イオンモード）

Reference Example 158
Preparation of 4-{[8- (t-butoxycarbonyl) -2-oxo-1-oxa-3,8-diazaspiro [4.5] decan-3-yl] methyl} benzoic acid 3-{[(1r, 4r) -4- (methoxycarbonyl) cyclohexyl] methyl} -2-oxo-1-oxa-3,8-diazaspiro [4.5] decane-8-obtained in Example 1 instead of t-butyl carboxylate Furthermore, methyl 4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl) benzoate is used. Except for the above, the reaction was carried out in substantially the same manner as in Reference Example 2-3 to give the title compound (900 mg, yield 93%) as a white powder.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.45 (9H, s), 1.55-1.68 (2H, m), 1.87 (2H, d, J = 13.1 Hz), 3 .15 (2H, s), 3.28 (2H, td, J = 12.3, 2.9 Hz), 3.82 (2H, dt, J = 13.5, 4.1 Hz), 4.51 ( 2H, s), 7.37 (2H, d, J = 8.2 Hz), 8.09 (2H, d, J = 8.6 Hz).

LC / MS [Condition 1]: retention time 3.88 min ;, m / z 389.0 [M−H] ⁻ (ESI negative ion mode)

実施例１５８
３−［４−（４−ベンゾイルピペリジン−１−カルボニル）ベンジル］−２−オキソ−１−オキサ−３，８−ジアザスピロ［４．５］デカン−８−カルボン酸ｔ−ブチル（化合物番号１５８）の製造
（１ｒ，４ｒ）−４−｛［８−（ｔ−ブトキシカルボニル）−２−オキソ−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル］メチル｝シクロヘキサンカルボン酸の代わりに参考例１５８で得られた４−｛［８−（ｔ−ブトキシカルボニル）−２−オキソ−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル］メチル｝安息香酸を、テトラヒドロフルフリルアミンの代わりにフェニル（ピペリジン−４−イル）メタノン塩酸塩（市販）とトリエチルアミンを用いること以外は実質的に実施例２と同様に反応を行って表題化合物（１．１ｇ、収率８８％）を白色粉末で得た。

^１Ｈ−ＮＭＲ（３００ＭＨｚ、ＣＤＣｌ_３）δ：１．４５（９Ｈ，ｓ），１．５２−１．６９（２Ｈ，ｍ），１．７１−２．１５（６Ｈ，ｍ），２．９６−３．２２（２Ｈ，ｍ），３．１３（２Ｈ，ｓ），３．２９（２Ｈ，ｔ，Ｊ＝１２．７Ｈｚ），３．４７−３．６４（１Ｈ，ｍ），３．６６−４．００（３Ｈ，ｍ），４．４５（２Ｈ，ｓ），４．６８（１Ｈ，ｂｒ ｓ），７．３０（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ），７．３６−７．５３（４Ｈ，ｍ），７．５４−７．６３（１Ｈ，ｍ），７．９４（２Ｈ，ｄ，Ｊ＝７．８Ｈｚ）．

ＬＣ／ＭＳ［条件１］：保持時間４．３９分；ｍ／ｚ６０６．２［Ｍ＋ＨＣＯＯ］^―（ＥＳＩ負イオンモード）

Example 158
3- [4- (4-Benzoylpiperidine-1-carbonyl) benzyl] -2-oxo-1-oxa-3,8-diazaspiro [4.5] decane-8-carboxylate t-butyl (Compound No. 158) manufacturing (1r, 4r) -4 - { [8- (t- butoxycarbonyl) -2-oxo-1-oxa-3,8-diazaspiro [4.5] decan-3-yl] methyl} cyclohexanecarboxylic acid 4-{[8- (t-butoxycarbonyl) -2-oxo-1-oxa-3,8-diazaspiro [4.5] decan-3-yl] methyl} benzoic acid obtained in Reference Example 158 instead of The acid was reacted in substantially the same manner as in Example 2 except that phenyl (piperidin-4-yl) methanone hydrochloride (commercially available) and triethylamine were used instead of tetrahydrofurfurylamine. Title compound (1.1 g, 88% yield) as a white powder.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.45 (9H, s), 1.52-1.69 (2H, m), 1.71-2.15 (6H, m), 2.96 -3.22 (2H, m), 3.13 (2H, s), 3.29 (2H, t, J = 12.7 Hz), 3.47-3.64 (1H, m), 3.66 -4.00 (3H, m), 4.45 (2H, s), 4.68 (1H, br s), 7.30 (2H, d, J = 8.2 Hz), 7.36-7. 53 (4H, m), 7.54-7.63 (1H, m), 7.94 (2H, d, J = 7.8 Hz).

LC / MS [Condition 1]: Retention time 4.39 minutes; m / z 606.2 [M + HCOO] ⁻ (ESI negative ion mode)

実施例１５９
３−［４−（４−オキソピペリジン−１−カルボニル）ベンジル］−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−２−オン（化合物番号１５９）の製造
（１ｒ，４ｒ）−４−（｛２−オキソ−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）シクロヘキサンカルボン酸の代わりに参考例２１で得られた４−（｛２−オキソ−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）安息香酸を、４−アミノピペリジン−１−カルボン酸ｔ−ブチルの代わりにピペリジン−４−オン−水和物−塩酸塩（市販）とトリエチルアミンを用いること以外は実質的に実施例６と同様に反応を行って表題化合物（２４０ｍｇ、収率９９％）を黄色粉末として得た。

^１Ｈ−ＮＭＲ（３００ＭＨｚ、ＣＤＣｌ_３）δ：１．７４（２Ｈ，ｄｔ，Ｊ＝１３．５，７．０Ｈｚ），１．９２（２Ｈ，ｄ，Ｊ＝１３．１Ｈｚ），２．３４−２．６８（８Ｈ，ｂｒ ｍ），３．１５（２Ｈ，ｓ），３．５６（２Ｈ，ｓ），３．８８（４Ｈ，ｂｒ ｓ），４．４６（２Ｈ，ｓ），７．３４（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ），７．４２（２Ｈ，ｄ，Ｊ＝７．８Ｈｚ），７．４６（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ），７．５６（２Ｈ，ｄ，Ｊ＝７．８Ｈｚ）．

ＬＣ／ＭＳ［条件１］：保持時間３．１６分；ｍ／ｚ５２９．９［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ５７４．２［Ｍ＋ＨＣＯＯ］^―（ＥＳＩ負イオンモード）

Example 159
3- [4- (4-Oxopiperidin-1-carbonyl) benzyl] -8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-2-one Preparation of (Compound No. 159) (1r, 4r) -4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decane- 4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro] obtained in Reference Example 21 instead of 3-yl} methyl) cyclohexanecarboxylic acid [ 4.5] decan-3-yl} methyl) benzoic acid using piperidin-4-one-hydrate-hydrochloride (commercially available) and triethylamine instead of t-butyl 4-aminopiperidine-1-carboxylate about Outside the title compound by performing the reaction as a substantially Example 6 (240 mg, 99% yield) as a yellow powder.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.74 (2H, dt, J = 13.5, 7.0 Hz), 1.92 (2H, d, J = 13.1 Hz), 2.34- 2.68 (8H, br m), 3.15 (2H, s), 3.56 (2H, s), 3.88 (4H, br s), 4.46 (2H, s), 7.34 (2H, d, J = 8.2 Hz), 7.42 (2H, d, J = 7.8 Hz), 7.46 (2H, d, J = 8.2 Hz), 7.56 (2H, d, J = 7.8 Hz).

LC / MS [Condition 1]: Retention time 3.16 minutes; m / z 529.9 [M + H] ⁺ (ESI positive ion mode), m / z 574.2 [M + HCOO] ⁻ (ESI negative ion mode)

実施例１６０
１−（ベンゾ［ｄ］［１，３］ジオキソール−５−イルメチル）−３−［４−（｛２−オキソ−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）フェニル］尿素（化合物番号１６０）の製造
Ｎ−（ｔ−ブトキシカルボニル）−１，３−ジアミノプロパンの代わりにベンゾ［ｄ］［１，３］ジオキソール−５−イルメタンアミン（市販）を用いること以外は実質的に実施例８３と同様に反応を行って、表題化合物（２４ｍｇ、収率２０％）を黄色無定形物として得た。

^１Ｈ−ＮＭＲ（３００ＭＨｚ、ＣＤＣｌ_３）δ：１．４９−１．７９（２Ｈ，ｍ），１．７８−１．９３（２Ｈ，ｍ），２．５０（４Ｈ，ｂｒ ｓ），３．１１（２Ｈ，ｓ），３．５４（２Ｈ，ｓ），４．２６−４．３８（４Ｈ，ｍ），５．２３（１Ｈ，ｔ，Ｊ＝５．７Ｈｚ），５．９１（２Ｈ，ｓ），６．６６−６．８３（４Ｈ，ｍ），７．１３（２Ｈ，ｄ，Ｊ＝８．６Ｈｚ），７．２７（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ），７．４２（２Ｈ，ｄ，Ｊ＝７．８Ｈｚ），７．５６（２Ｈ，ｄ，Ｊ＝７．８Ｈｚ）．

ＬＣ／ＭＳ［条件１］：保持時間３．６４分；ｍ／ｚ５９６．９［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ６４１．１［Ｍ＋ＨＣＯＯ］^―（ＥＳＩ負イオンモード）

Example 160
1- (Benzo [d] [1,3] dioxol-5-ylmethyl) -3- [4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8 -Preparation of diazaspiro [4.5] decan-3-yl} methyl) phenyl] urea (Compound No. 160) Benzo [d] [1, instead of N- (t-butoxycarbonyl) -1,3-diaminopropane 3] The reaction was carried out in substantially the same manner as in Example 83 except that dioxol-5-ylmethanamine (commercially available) was used to give the title compound (24 mg, yield 20%) as a yellow amorphous product.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.49-1.79 (2H, m), 1.78-1.93 (2H, m), 2.50 (4H, brs), 3. 11 (2H, s), 3.54 (2H, s), 4.26-4.38 (4H, m), 5.23 (1H, t, J = 5.7 Hz), 5.91 (2H, s), 6.66-6.83 (4H, m), 7.13 (2H, d, J = 8.6 Hz), 7.27 (2H, d, J = 8.2 Hz), 7.42 ( 2H, d, J = 7.8 Hz), 7.56 (2H, d, J = 7.8 Hz).

LC / MS [Condition 1]: Retention time 3.64 minutes; m / z 596.9 [M + H] ⁺ (ESI positive ion mode), m / z 641.1 [M + HCOO] ⁻ (ESI negative ion mode)

実施例１６１
４−ベンゾイル−Ｎ−［４−（｛２−オキソ−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）フェニル］ピペリジン−１−カルボキサミド（化合物番号１６１）の製造
参考例９３で得られた３−（４−アミノベンジル）−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−２−オン二塩酸塩（７７ｍｇ、０．１６ｍｍｏｌ）をクロロホルム（１．０ｍＬ）に溶解し、０℃でピリジン（０．０９０ｍＬ、１．１ｍｍｏｌ）とクロロギ酸４−ニトロフェニル（３８ｍｇ、０．１９ｍｍｏｌ）を加えて、室温で１日間かき混ぜた。その後、トリエチルアミン（０．０５６ｍＬ、０．４０ｍｍｏｌ）とフェニル（ピペリジン−４−イル）メタノン塩酸塩（市販）（４３ｍｇ、０．１９ｍｍｏｌ）を加えて、室温で１日間かき混ぜた。反応混合物にクロロホルム（３．０ｍＬ）と飽和炭酸水素ナトリウム水溶液（３．０ｍＬ）を加え、有機層を分離した後、無水硫酸ナトリウムで乾燥し、減圧下濃縮した。得られた残留物をシリカゲルクロマトグラフィー［充填剤：富士シリシア社社製アミンシリカＮＨ−ＤＭ１０２０、展開溶媒：酢酸エチル］にて精製し、４−ベンゾイル−Ｎ−［４−（｛２−オキソ−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）フェニル］ピペリジン−１−カルボキサミド（２３ｍｇ、収率２３％）を白色粉末として得た。

^１Ｈ−ＮＭＲ（３００ＭＨｚ、ＣＤＣｌ_３）δ：１．６２−１．７７（２Ｈ，ｍ），１．７６−２．０３（６Ｈ，ｍ），２．５０（４Ｈ，ｂｒ ｓ），３．１０（２Ｈ，ｓ），３．１３（４Ｈ，ｄｔ，Ｊ＝２．９，１２．７Ｈｚ），３．５１（１Ｈ，ｔｔ，Ｊ＝１１．０，４．１Ｈｚ），３．５４（２Ｈ，ｂｒ ｓ），４．１１（２Ｈ，ｄｔ，Ｊ＝１３．２，３．５Ｈｚ），４．３６（２Ｈ，ｓ），６．４４（１Ｈ，ｓ），７．１８（２Ｈ，ｄ，Ｊ＝９．０Ｈｚ），７．３４（２Ｈ，ｄ，Ｊ＝８．６Ｈｚ），７．３７−７．６３（７Ｈ，ｍ），７．９５（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ）．

ＬＣ／ＭＳ［条件１］：保持時間３．８２分；ｍ／ｚ６３５．０［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ６３３．２［Ｍ−Ｈ］^―（ＥＳＩ負イオンモード）

Example 161
4-benzoyl-N- [4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl) Preparation of phenyl] piperidine-1-carboxamide (Compound No. 161) 3- (4-aminobenzyl) -8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8 obtained in Reference Example 93 -Diazaspiro [4.5] decan-2-one dihydrochloride (77 mg, 0.16 mmol) was dissolved in chloroform (1.0 mL) and pyridine (0.090 mL, 1.1 mmol) and chloroformate 4 at 0 ° C. -Nitrophenyl (38 mg, 0.19 mmol) was added and stirred at room temperature for 1 day. Then, triethylamine (0.056 mL, 0.40 mmol) and phenyl (piperidin-4-yl) methanone hydrochloride (commercially available) (43 mg, 0.19 mmol) were added, and the mixture was stirred at room temperature for 1 day. Chloroform (3.0 mL) and saturated aqueous sodium hydrogen carbonate solution (3.0 mL) were added to the reaction mixture, and the organic layer was separated, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography [filler: amine silica NH-DM1020 manufactured by Fuji Silysia Ltd., developing solvent: ethyl acetate], and 4-benzoyl-N- [4-({2-oxo-8 -[4- (Trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl) phenyl] piperidine-1-carboxamide (23 mg, 23% yield). Obtained as a white powder.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.62-1.77 (2H, m), 1.76-2.03 (6H, m), 2.50 (4H, brs), 3. 10 (2H, s), 3.13 (4H, dt, J = 2.9, 12.7 Hz), 3.51 (1H, tt, J = 11.0, 4.1 Hz), 3.54 (2H , Br s), 4.11 (2H, dt, J = 13.2, 3.5 Hz), 4.36 (2H, s), 6.44 (1H, s), 7.18 (2H, d, J = 9.0 Hz), 7.34 (2H, d, J = 8.6 Hz), 7.37-7.63 (7H, m), 7.95 (2H, d, J = 8.2 Hz).

LC / MS [Condition 1]: retention time 3.82 minutes; m / z 635.0 [M + H] ⁺ (ESI positive ion mode), m / z 633.2 [M−H] ⁻ (ESI negative ion mode)

実施例１６２
３−｛４−［４−（４−フルオロベンゾイル）ピペリジン−１−カルボニル］ベンジル｝−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−２−オン（化合物番号１６２）の製造
４−（２−アミノエチル）モルホリンの代わりに（４−フルオロフェニル）（ピペリジン−４−イル）メタノン塩酸塩（市販）を用いる以外は実質的に実施例４４と同様に反応を行って、表題化合物（４１ｍｇ、収率７２％）を黄色無定形物として得た。

^１Ｈ−ＮＭＲ（３００ＭＨｚ、ＣＤＣｌ_３）δ：１．６３−２．１１（８Ｈ，ｍ），２．５４（４Ｈ，ｂｒ ｓ），２．９８−３．２６（２Ｈ，ｂｒ ｍ），３．１４（２Ｈ，ｓ），３．３９−３．６８（３Ｈ，ｂｒ ｍ），３．８４（１Ｈ，ｂｒ ｓ），４．４４（２Ｈ，ｓ），４．６７（１Ｈ，ｂｒ ｓ），７．１５（２Ｈ，ｔ，Ｊ＝８．２Ｈｚ），７．３０（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ），７．３５−７．５０（４Ｈ，ｍ），７．５０−７．６２（２Ｈ，ｍ），７．９７（２Ｈ，ｄｄ，Ｊ＝９．０，５．７Ｈｚ）．

ＬＣ／ＭＳ［条件１］：保持時間３．５４分；ｍ／ｚ６３８．１［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ６８２．３［Ｍ＋ＨＣＯＯ］^―（ＥＳＩ負イオンモード）

Example 162
3- {4- [4- (4-Fluorobenzoyl) piperidine-1-carbonyl] benzyl} -8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] Preparation of decan-2-one (Compound No. 162) Substantially except that (4-fluorophenyl) (piperidin-4-yl) methanone hydrochloride (commercially available) is used instead of 4- (2-aminoethyl) morpholine. The reaction was carried out in the same manner as in Example 44 to obtain the title compound (41 mg, yield 72%) as a yellow amorphous product.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.63-2.11 (8H, m), 2.54 (4H, br s), 2.98-3.26 (2H, br m), 3 .14 (2H, s), 3.39-3.68 (3H, br m), 3.84 (1H, br s), 4.44 (2H, s), 4.67 (1H, br s) 7.15 (2H, t, J = 8.2 Hz), 7.30 (2H, d, J = 8.2 Hz), 7.35-7.50 (4H, m), 7.50-7. 62 (2H, m), 7.97 (2H, dd, J = 9.0, 5.7 Hz).

LC / MS [Condition 1]: Retention time 3.54 minutes; m / z 638.1 [M + H] ⁺ (ESI positive ion mode), m / z 682.3 [M + HCOO] ⁻ (ESI negative ion mode)

実施例１６３
３−［４−（４−ヒドロキシ−４−フェニルピペリジン−１−カルボニル）ベンジル］−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−２−オン（化合物番号１６３）の製造
４−（２−アミノエチル）モルホリンの代わりに４−フェニルピペリジン−４−オール（市販）を用いる以外は実質的に実施例４４と同様に反応を行って、表題化合物（４１ｍｇ、収率７６％）を黄色無定形物として得た。

^１Ｈ−ＮＭＲ（３００ＭＨｚ、ＣＤＣｌ_３）δ：１．４８−２．０２（８Ｈ，ｍ），２．１５（１Ｈ，ｂｒ ｓ），２．５７（４Ｈ，ｂｒ ｓ），３．１４（２Ｈ，ｓ），３．３５（１Ｈ，ｂｒ ｓ），３．４７−３．７３（４Ｈ，ｂｒ ｍ），４．４４（２Ｈ，ｓ），４．６７（１Ｈ，ｂｒ ｓ），７．２６−７．３３（３Ｈ，ｍ），７．３３−７．５１（８Ｈ，ｍ），７．５７（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ）．

ＬＣ／ＭＳ［条件１］：保持時間３．３６分；ｍ／ｚ６０８．１［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ６５２．３［Ｍ＋ＨＣＯＯ］^―（ＥＳＩ負イオンモード）

Example 163
3- [4- (4-Hydroxy-4-phenylpiperidine-1-carbonyl) benzyl] -8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decane Preparation of 2-one (Compound No. 163) The reaction was carried out in substantially the same manner as in Example 44 except that 4-phenylpiperidin-4-ol (commercially available) was used instead of 4- (2-aminoethyl) morpholine. The title compound (41 mg, 76% yield) was obtained as a yellow amorphous product.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.48-2.02 (8H, m), 2.15 (1H, br s), 2.57 (4H, br s), 3.14 (2H , S), 3.35 (1H, br s), 3.47-3.73 (4H, br m), 4.44 (2H, s), 4.67 (1H, br s), 7.26. -7.33 (3H, m), 7.33-7.51 (8H, m), 7.57 (2H, d, J = 8.2 Hz).

LC / MS [Condition 1]: Retention time 3.36 minutes; m / z 608.1 [M + H] ⁺ (ESI positive ion mode), m / z 652.3 [M + HCOO] ⁻ (ESI negative ion mode)

実施例１６４
１−［４−（｛２−オキソ−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）ベンゾイル］ピペリジン−４−カルボニトリル（化合物番号１６４）の製造
４−（２−アミノエチル）モルホリンの代わりにピペリジン−４−カルボニトリル（市販）を用いる以外は実質的に実施例４４と同様に反応を行って、表題化合物（３８ｍｇ、収率７９％）を黄色無定形物として得た。

^１Ｈ−ＮＭＲ（３００ＭＨｚ、ＣＤＣｌ_３）δ：１．５３−２．０７（８Ｈ，ｍ），２．５９（４Ｈ，ｂｒ ｓ），２．９４（１Ｈ，ｔｔ，Ｊ＝７．０，４．５Ｈｚ），３．１５（２Ｈ，ｓ），３．２８−４．０１（６Ｈ，ｂｒ ｍ），４．４４（２Ｈ，ｓ），７．３１（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ），７．３８（２Ｈ，ｄ，Ｊ＝８．６Ｈｚ），７．４１−７．５１（２Ｈ，ｍ），７．５８（２Ｈ，ｄ，Ｊ＝７．８Ｈｚ）．

ＬＣ／ＭＳ［条件１］：保持時間３．１０分；ｍ／ｚ５４１．０［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ５８５．３［Ｍ＋ＨＣＯＯ］^―（ＥＳＩ負イオンモード）

Example 164
1- [4-({2-Oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl) benzoyl] piperidine- Preparation of 4-carbonitrile (Compound No. 164) The reaction was carried out in substantially the same manner as in Example 44 except that piperidine-4-carbonitrile (commercially available) was used instead of 4- (2-aminoethyl) morpholine. The title compound (38 mg, yield 79%) was obtained as a yellow amorphous product.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.53 to 2.07 (8H, m), 2.59 (4H, brs), 2.94 (1H, tt, J = 7.0, 4 .5Hz), 3.15 (2H, s), 3.28-4.01 (6H, br m), 4.44 (2H, s), 7.31 (2H, d, J = 8.2 Hz) 7.38 (2H, d, J = 8.6 Hz), 7.41-7.51 (2H, m), 7.58 (2H, d, J = 7.8 Hz).

LC / MS [Condition 1]: Retention time 3.10 minutes; m / z 541.0 [M + H] ⁺ (ESI positive ion mode), m / z 585.3 [M + HCOO] ⁻ (ESI negative ion mode)

実施例１６５
４−［４−（｛２−オキソ−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）ベンゾイル］ピペラジン−１−カルボン酸ｔ−ブチル（化合物番号１６５）の製造
４−（２−アミノエチル）モルホリンの代わりにピペラジン−１−カルボン酸ｔ−ブチル（市販）を用いる以外は実質的に実施例４４と同様に反応を行って、表題化合物（３７ｍｇ、収率６６％）を黄色無定形物として得た。

^１Ｈ−ＮＭＲ（３００ＭＨｚ、ＣＤＣｌ_３）δ：１．４６（９Ｈ，ｓ），１．６４−１．８４（２Ｈ，ｍ），１．９２（２Ｈ，ｄ，Ｊ＝１２．７Ｈｚ），２．５４（４Ｈ，ｂｒ ｓ），３．１４（２Ｈ，ｓ），３．２２−３．８４（１０Ｈ，ｂｒ ｍ），４．４４（２Ｈ，ｓ），７．３１（２Ｈ，ｄ，Ｊ＝７．８Ｈｚ），７．３５−７．４９（４Ｈ，ｍ），７．５７（２Ｈ，ｄ，Ｊ＝７．４Ｈｚ）．

ＬＣ／ＭＳ［条件１］：保持時間３．４６分；ｍ／ｚ６１７．１［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ６６１．３［Ｍ＋ＨＣＯＯ］^―（ＥＳＩ負イオンモード）

Example 165
4- [4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl) benzoyl] piperazine- Production of t-butyl 1-carboxylate (Compound No. 165) Substantially the same as Example 44, except that t-butyl piperazine-1-carboxylate (commercially available) was used instead of 4- (2-aminoethyl) morpholine. The title compound (37 mg, 66% yield) was obtained as a yellow amorphous product.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.46 (9H, s), 1.64-1.84 (2H, m), 1.92 (2H, d, J = 12.7 Hz), 2 .54 (4H, br s), 3.14 (2H, s), 3.22-3.84 (10H, br m), 4.44 (2H, s), 7.31 (2H, d, J = 7.8 Hz), 7.35-7.49 (4 H, m), 7.57 (2 H, d, J = 7.4 Hz).

LC / MS [Condition 1]: Retention time 3.46 minutes; m / z 617.1 [M + H] ⁺ (ESI positive ion mode), m / z 661.3 [M + HCOO] ⁻ (ESI negative ion mode)

実施例１６６
３−［４−（４−メトキシピペリジン−１−カルボニル）ベンジル］−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−２−オン（化合物番号１６６）の製造
４−（２−アミノエチル）モルホリンの代わりに４−メトキシピペリジン（市販）を用いる以外は実質的に実施例４４と同様に反応を行って、表題化合物（３３ｍｇ、収率６８％）を黄色無定形物として得た。

^１Ｈ−ＮＭＲ（３００ＭＨｚ、ＣＤＣｌ_３）δ：１．４１−２．０７（８Ｈ，ｍ），２．５５（４Ｈ，ｂｒ ｓ），３．１３（２Ｈ，ｓ），３．２１（１Ｈ，ｂｒ ｓ），３．３６（３Ｈ，ｓ），３．４０−３．７４（５Ｈ，ｍ），３．４７（１Ｈ，ｔｔ，Ｊ＝７．４，３．７Ｈｚ），３．９９（１Ｈ，ｂｒ ｓ），４．４４（２Ｈ，ｓ），７．２９（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ），７．３３−７．４９（４Ｈ，ｍ），７．５７（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ）．

ＬＣ／ＭＳ［条件１］：保持時間３．１４分；ｍ／ｚ５４６．１［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ５９０．３［Ｍ＋ＨＣＯＯ］^―（ＥＳＩ負イオンモード）

Example 166
3- [4- (4-Methoxypiperidin-1-carbonyl) benzyl] -8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-2-one Preparation of (Compound No. 166) The reaction was conducted in substantially the same manner as in Example 44 except that 4-methoxypiperidine (commercially available) was used instead of 4- (2-aminoethyl) morpholine to give the title compound (33 mg, yield). 68%) was obtained as a yellow amorphous product.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.41-2.07 (8H, m), 2.55 (4H, brs), 3.13 (2H, s), 3.21 (1H, br s), 3.36 (3H, s), 3.40-3.74 (5H, m), 3.47 (1H, tt, J = 7.4, 3.7 Hz), 3.99 (1H) , Br s), 4.44 (2H, s), 7.29 (2H, d, J = 8.2 Hz), 7.33-7.49 (4H, m), 7.57 (2H, d, J = 8.2 Hz).

LC / MS [Condition 1]: Retention time 3.14 minutes; m / z 546.1 [M + H] ⁺ (ESI positive ion mode), m / z 590.3 [M + HCOO] ⁻ (ESI negative ion mode)

実施例１６７
Ｎ−［（６−クロロピリジン−３−イル）メチル］−４−（｛２−オキソ−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）ベンズアミド（化合物番号１６７）の製造
４−（２−アミノエチル）モルホリンの代わりに（６−クロロピリジン−３−イル）メタンアミン（市販）を用いる以外は実質的に実施例４４と同様に反応を行って、表題化合物（３４ｍｇ、収率６７％）を黄色無定形物として得た。

^１Ｈ−ＮＭＲ（３００ＭＨｚ、ＣＤＣｌ_３）δ：１．６１−１．９６（４Ｈ，ｍ），２．５４（４Ｈ，ｂｒ ｓ），３．１２（２Ｈ，ｓ），３．５７（２Ｈ，ｂｒ ｓ），４．４５（２Ｈ，ｓ），４．６３（２Ｈ，ｄ，Ｊ＝６．１Ｈｚ），６．６３（１Ｈ，ｔ，Ｊ＝５．７Ｈｚ），７．３０（１Ｈ，ｄ，Ｊ＝８．６Ｈｚ），７．３３（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ），７．３７−７．４９（２Ｈ，ｂｒ ｍ），７．５６（２Ｈ，ｄ，Ｊ＝７．８Ｈｚ），７．７０（１Ｈ，ｄｄ，Ｊ＝８．２，２．５Ｈｚ），７．７７（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ），８．３７（１Ｈ，ｄ，Ｊ＝２．５Ｈｚ）．

ＬＣ／ＭＳ［条件１］：保持時間３．２６分；ｍ／ｚ５７３．０［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ５７１．２［Ｍ−Ｈ］^―（ＥＳＩ負イオンモード）

Example 167
N-[(6-chloropyridin-3-yl) methyl] -4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5 Preparation of decan-3-yl} methyl) benzamide (Compound No. 167) Substantially except that (6-chloropyridin-3-yl) methanamine (commercially available) is used instead of 4- (2-aminoethyl) morpholine. The reaction was carried out in the same manner as in Example 44 to obtain the title compound (34 mg, yield 67%) as a yellow amorphous product.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.61-1.96 (4H, m), 2.54 (4H, br s), 3.12 (2H, s), 3.57 (2H, br s), 4.45 (2H, s), 4.63 (2H, d, J = 6.1 Hz), 6.63 (1H, t, J = 5.7 Hz), 7.30 (1H, d) , J = 8.6 Hz), 7.33 (2H, d, J = 8.2 Hz), 7.37-7.49 (2H, br m), 7.56 (2H, d, J = 7.8 Hz). ), 7.70 (1H, dd, J = 8.2, 2.5 Hz), 7.77 (2H, d, J = 8.2 Hz), 8.37 (1H, d, J = 2.5 Hz) .

LC / MS [Condition 1]: retention time 3.26 minutes; m / z 573.0 [M + H] ⁺ (ESI positive ion mode), m / z 571.2 [M−H] ⁻ (ESI negative ion mode)

参考例１６８−１
４−［メトキシ（メチル）カルバモイル］ピペリジン−１−カルボン酸ｔ−ブチルの製造
１−（ｔ−ブトキシカルボニル）ピペリジン−４−カルボン酸（市販）（１．０ｇ、４．４ｍｍｏｌ）とＮ，Ｏ−ジメチルヒドロキシルアミン塩酸塩（市販）（４７０ｍｇ、４．８ｍｍｏｌ）、１−ヒドロキシベンゾトリアゾール（６００ｍｇ、４．４ｍｏｌ）、そしてトリエチルアミン（１．８ｍＬ、１３ｍｍｏｌ）をクロロホルム（１０ｍｌ）に溶解した後、室温にて１−エチル−３−（３−ジメチルアミノプロピル）カルボジイミド塩酸塩（４６ｍｇ、０．２２ｍｍｏｌ）を加え、室温で３日間かき混ぜた。その後、反応混合物にクロロホルム（１０ｍＬ）と飽和炭酸水素ナトリウム水溶液（５．０ｍＬ）を加え、有機層を分離した。有機層を無水硫酸ナトリウムで乾燥した後、減圧下濃縮乾固して４−［メトキシ（メチル）カルバモイル］ピペリジン−１−カルボン酸ｔ−ブチル（１．２ｇ、定量的）を無色油状物として得た。

^１Ｈ−ＮＭＲ（３００ＭＨｚ、ＣＤＣｌ_３）δ：１．４６（９Ｈ，ｓ），１．６１−１．７７（４Ｈ，ｍ），２．６６−２．８９（３Ｈ，ｂｒ ｍ），３．１８（３Ｈ，ｓ），３．７１（３Ｈ，ｓ），４．０３−４．２４（２Ｈ，ｂｒ ｍ）．

Reference Example 168-1
Preparation of t-butyl 4- [methoxy (methyl) carbamoyl] piperidine-1-carboxylate 1- (t-butoxycarbonyl) piperidine-4-carboxylic acid (commercially available) (1.0 g, 4.4 mmol) and N, O -Dimethylhydroxylamine hydrochloride (commercially available) (470 mg, 4.8 mmol), 1-hydroxybenzotriazole (600 mg, 4.4 mol), and triethylamine (1.8 mL, 13 mmol) were dissolved in chloroform (10 ml), then at room temperature. 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (46 mg, 0.22 mmol) was added and stirred at room temperature for 3 days. Thereafter, chloroform (10 mL) and saturated aqueous sodium hydrogen carbonate solution (5.0 mL) were added to the reaction mixture, and the organic layer was separated. The organic layer was dried over anhydrous sodium sulfate and then concentrated to dryness under reduced pressure to give t-butyl 4- [methoxy (methyl) carbamoyl] piperidine-1-carboxylate (1.2 g, quantitative) as a colorless oil. It was.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.46 (9H, s), 1.61-1.77 (4H, m), 2.66-2.89 (3H, br m), 3. 18 (3H, s), 3.71 (3H, s), 4.03-4.24 (2H, br m).

参考例１６８−２
４−アセチルピペリジン−１−カルボン酸ｔ−ブチルの製造
窒素雰囲気下、１．１Ｍ臭化メチルマグネシウム−テトラヒドロフラン溶液（市販）（０．６８ｍＬ、０．６８ｍｍｏｌ）をテトラヒドロフランに溶解し、０℃にて参考例１６８−１で得られた４−［メトキシ（メチル）カルバモイル］ピペリジン−１−カルボン酸ｔ−ブチル（９３ｍｇ、０．３４ｍｍｏｌ）を加えて、室温で１日間かき混ぜた。その後、反応混合物に酢酸エチル（２．０ｍＬ）と飽和塩化アンモニウム水溶液（２．０ｍＬ）を加え、有機層を分離した。得られた有機層を無水硫酸ナトリウムで乾燥し、減圧下濃縮した。得られた残留物をシリカゲルクロマトグラフィー［充填剤：富士シリシア社製ＦＬ１００Ｄ、展開溶媒：ヘキサン／酢酸エチル＝２／１］にて精製し、４−アセチルピペリジン−１−カルボン酸ｔ−ブチル（４５ｍｇ、収率５９％）を無色油状物として得た。

^１Ｈ−ＮＭＲ（３００ＭＨｚ、ＣＤＣｌ_３）δ：１．４５（９Ｈ，ｓ），１．４２−１．６３（２Ｈ，ｍ），１．８３（２Ｈ，ｄｄ，Ｊ＝１３．１，２．５Ｈｚ），２．１６（３Ｈ，ｓ），２．４５（１Ｈ，ｔｔ，Ｊ＝１１．４，３．７Ｈｚ），２．７８（２Ｈ，ｔｄ，Ｊ＝１３．１，２．９Ｈｚ），４．１０（２Ｈ，ｄｔ，Ｊ＝１３．１，３．３Ｈｚ）．

Reference Example 168-2
Preparation of t-butyl 4-acetylpiperidine-1-carboxylate Under a nitrogen atmosphere, 1.1 M methylmagnesium bromide-tetrahydrofuran solution (commercially available) (0.68 mL, 0.68 mmol) was dissolved in tetrahydrofuran at 0 ° C. 4- [Methoxy (methyl) carbamoyl] piperidine-1-carboxylate t-butyl (93 mg, 0.34 mmol) obtained in Reference Example 168-1 was added, and the mixture was stirred at room temperature for 1 day. Thereafter, ethyl acetate (2.0 mL) and saturated aqueous ammonium chloride solution (2.0 mL) were added to the reaction mixture, and the organic layer was separated. The obtained organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography [filler: FL100D manufactured by Fuji Silysia Ltd., developing solvent: hexane / ethyl acetate = 2/1], and t-butyl 4-acetylpiperidine-1-carboxylate (45 mg). Yield 59%) as a colorless oil.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.45 (9H, s), 1.42-1.63 (2H, m), 1.83 (2H, dd, J = 13.1, 2. 5 Hz), 2.16 (3 H, s), 2.45 (1 H, tt, J = 11.4, 3.7 Hz), 2.78 (2 H, td, J = 13.1, 2.9 Hz), 4.10 (2H, dt, J = 13.1, 3.3 Hz).

参考例１６８−３
１−（ピペリジン−４−イル）エタノン塩酸塩の製造
参考例１６８−２で得られた４−アセチルピペリジン−１−カルボン酸ｔ−ブチル（４５ｍｇ、０．２０ｍｍｏｌ）をメタノール（０．５０ｍＬ）に溶解し、室温にて１０％塩化水素−メタノール溶液（市販）（０．３０ｍＬ、０．７０ｍｍｏｌ）を加えて、５０℃で３時間かき混ぜた。その後、減圧下濃縮乾固して、１−（ピペリジン−４−イル）エタノン塩酸塩（３３ｍｇ、定量的）を黄色粉末として得た。

ＬＣ／ＭＳ［条件１］：保持時間０．６１分；ｍ／ｚ１２８．０［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）

Reference Example 168-3
Preparation of 1- (piperidin-4-yl) ethanone hydrochloride 4-acetylpiperidine-1-carboxylate t-butyl (45 mg, 0.20 mmol) obtained in Reference Example 168-2 was added to methanol (0.50 mL). After dissolution, a 10% hydrogen chloride-methanol solution (commercially available) (0.30 mL, 0.70 mmol) was added at room temperature, and the mixture was stirred at 50 ° C. for 3 hr. Thereafter, the mixture was concentrated to dryness under reduced pressure to obtain 1- (piperidin-4-yl) ethanone hydrochloride (33 mg, quantitative) as a yellow powder.

LC / MS [Condition 1]: Retention time 0.61 min; m / z 128.0 [M + H] ⁺ (ESI positive ion mode)

実施例１６８
３−［４−（４−アセチルピペリジン−１−カルボニル）ベンジル］−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−２−オン（化合物番号１６８）の製造
４−（２−アミノエチル）モルホリンの代わりに参考例１６８−３で得られた１−（ピペリジン−４−イル）エタノン塩酸塩を用いる以外は実質的に実施例４４と同様に反応を行って、表題化合物（３６ｍｇ、収率７３％）を黄色無定形物として得た。

^１Ｈ−ＮＭＲ（３００ＭＨｚ、ＣＤＣｌ_３）δ：１．６２−２．０９（８Ｈ，ｍ），２．１９（３Ｈ，ｓ），２．３９−２．７２（５Ｈ，ｍ），３．００（２Ｈ，ｂｒ ｓ），３．１４（２Ｈ，ｓ），３．５８（２Ｈ，ｂｒ ｓ），３．７８（１Ｈ，ｂｒ ｓ），４．４４（２Ｈ，ｓ），４．６２（１Ｈ，ｂｒ ｓ），７．２９（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ），７．３８（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ），７．４０−７．５０（２Ｈ，ｂｒ ｍ），７．５７（２Ｈ，ｄ，Ｊ＝７．８Ｈｚ）．

ＬＣ／ＭＳ［条件１］：保持時間３．１２分；ｍ／ｚ５５８．０［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ６０２．３［Ｍ＋ＨＣＯＯ］^―（ＥＳＩ負イオンモード）

Example 168
3- [4- (4-Acetylpiperidin-1-carbonyl) benzyl] -8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-2-one Preparation of (Compound No. 168) Substantially Example 44 except that 1- (piperidin-4-yl) ethanone hydrochloride obtained in Reference Example 168-3 was used instead of 4- (2-aminoethyl) morpholine. The title compound (36 mg, yield 73%) was obtained as a yellow amorphous product.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.62-2.09 (8H, m), 2.19 (3H, s), 2.39-2.72 (5H, m), 3.00 (2H, br s), 3.14 (2H, s), 3.58 (2H, br s), 3.78 (1H, br s), 4.44 (2H, s), 4.62 (1H , Br s), 7.29 (2H, d, J = 8.2 Hz), 7.38 (2H, d, J = 8.2 Hz), 7.40-7.50 (2H, br m), 7 .57 (2H, d, J = 7.8 Hz).

LC / MS [Condition 1]: Retention time 3.12 minutes; m / z 558.0 [M + H] ⁺ (ESI positive ion mode), m / z 602.3 [M + HCOO] ⁻ (ESI negative ion mode)

参考例１６９−１
４−（チオフェン−２−カルボニル）ピペリジン−１−カルボン酸ｔ−ブチルの製造
１．１Ｍ臭化メチルマグネシウム−テトラヒドロフラン溶液の代わりに１．０Ｍ２−チエニルリチウム−テトラヒドロフラン溶液（市販）を用いること以外は実質的に参考例１６８−２と同様に反応を行って、表題化合物（９２ｍｇ、収率８０％）を褐色油状物として得た。

^１Ｈ−ＮＭＲ（３００ＭＨｚ、ＣＤＣｌ_３）δ：１．４７（９Ｈ，ｓ），１．６６−１．９２（４Ｈ，ｍ），２．８７（２Ｈ，ｔｄ，Ｊ＝１１．９，３．７Ｈｚ），３．２４（１Ｈ，ｔｔ，Ｊ＝１０．８，４．０Ｈｚ），４．１７（２Ｈ，ｄｔ，Ｊ＝１３．１，２．９Ｈｚ），７．１４（１Ｈ，ｔ，Ｊ＝４．５Ｈｚ），７．６５（１Ｈ，ｄ，Ｊ＝４．９Ｈｚ），７．７３（１Ｈ，ｄ，Ｊ＝３．９Ｈｚ）．

Reference Example 169-1
Preparation of t-butyl 4- (thiophene-2-carbonyl) piperidine-1-carboxylate A 1.0 M2-thienyllithium-tetrahydrofuran solution (commercially available) was used in place of the 1.1 M methylmagnesium bromide-tetrahydrofuran solution. The reaction was carried out substantially in the same manner as in Reference Example 168-2 to give the title compound (92 mg, yield 80%) as a brown oil.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.47 (9H, s), 1.66-1.92 (4H, m), 2.87 (2H, td, J = 11.9, 3. 7 Hz), 3.24 (1 H, tt, J = 10.8, 4.0 Hz), 4.17 (2 H, dt, J = 13.1, 2.9 Hz), 7.14 (1 H, t, J = 4.5 Hz), 7.65 (1H, d, J = 4.9 Hz), 7.73 (1H, d, J = 3.9 Hz).

参考例１６９−２
ピペリジン−４−イル（チオフェン−２−イル）メタノン塩酸塩の製造
４−アセチルピペリジン−１−カルボン酸ｔ−ブチルの代わりに４−（チオフェン−２−カルボニル）ピペリジン−１−カルボン酸ｔ−ブチルを用いること以外は実質的に参考例１６８−３と同様に反応を行って、表題化合物（７２ｍｇ、定量的）を茶色粉末として得た。

ＬＣ／ＭＳ［条件１］：保持時間０．６５分；ｍ／ｚ１９６．０［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）

Reference Example 169-2
Preparation of piperidin-4 -yl (thiophen-2-yl) methanone hydrochloride 4- (thiophen-2-carbonyl) piperidine-1-carboxylate t-butyl instead of 4-acetylpiperidine-1-carboxylate The title compound (72 mg, quantitative) was obtained as a brown powder in substantially the same manner as in Reference Example 168-3 except that was used.

LC / MS [Condition 1]: Retention time 0.65 min; m / z 196.0 [M + H] ⁺ (ESI positive ion mode)

実施例１６９
３−｛４−［４−（チオフェン−２−カルボニル）ピペリジン−１−カルボニル］ベンジル｝−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−２−オン（化合物番号１６９）の製造
４−（２−アミノエチル）モルホリンの代わりに参考例１６９−２で得られたピペリジン−４−イル（チオフェン−２−イル）メタノン塩酸塩を用いる以外は実質的に実施例４４と同様に反応を行って、表題化合物（４３ｍｇ、収率７６％）を黄色無定形物として得た。

^１Ｈ−ＮＭＲ（３００ＭＨｚ、ＣＤＣｌ_３）δ：１．６２−２．１９（８Ｈ，ｍ），２．５３（４Ｈ，ｂｒ ｓ），２．９２−３．２３（２Ｈ，ｍ），３．１３（２Ｈ，ｓ），３．３０−３．４７（１Ｈ，ｍ），３．５６（２Ｈ，ｂｒ ｓ），３．８５（１Ｈ，ｂｒ ｓ），４．４４（２Ｈ，ｓ），４．６８（１Ｈ，ｂｒ ｓ），７．１５（１Ｈ，ｄｄ，Ｊ＝４．９，３．７Ｈｚ），７．３０（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ），７．３５−７．４８（４Ｈ，ｍ），７．５６（２Ｈ，ｄ，Ｊ＝７．８Ｈｚ），７．６７（１Ｈ，ｄｄ，Ｊ＝４．９，１．２Ｈｚ），７．７５（１Ｈ，ｄｄ，Ｊ＝３．７，１．２Ｈｚ）．

ＬＣ／ＭＳ［条件１］：保持時間３．４４分；ｍ／ｚ６２６．１［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ６７０．３［Ｍ＋ＨＣＯＯ］^―（ＥＳＩ負イオンモード）

Example 169
3- {4- [4- (Thiophen-2-carbonyl) piperidine-1-carbonyl] benzyl} -8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5 Preparation of decan-2-one (Compound No. 169) Piperidin-4-yl (thiophen-2-yl) methanone hydrochloride obtained in Reference Example 169-2 was used instead of 4- (2-aminoethyl) morpholine. The reaction was carried out in substantially the same manner as in Example 44 except for using the title compound (43 mg, yield 76%) as a yellow amorphous product.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.62-2.19 (8H, m), 2.53 (4H, brs), 2.92-3.23 (2H, m), 3. 13 (2H, s), 3.30-3.47 (1H, m), 3.56 (2H, br s), 3.85 (1H, br s), 4.44 (2H, s), 4 .68 (1H, brs), 7.15 (1H, dd, J = 4.9, 3.7 Hz), 7.30 (2H, d, J = 8.2 Hz), 7.35-7.48 (4H, m), 7.56 (2H, d, J = 7.8 Hz), 7.67 (1H, dd, J = 4.9, 1.2 Hz), 7.75 (1H, dd, J = 3.7, 1.2 Hz).

LC / MS [Condition 1]: retention time 3.44 minutes; m / z 626.1 [M + H] ⁺ (ESI positive ion mode), m / z 670.3 [M + HCOO] ⁻ (ESI negative ion mode)

参考例１７０−１
４−（ジメチルカルバモイル）ピペリジン−１−カルボン酸ｔ−ブチルの製造
Ｎ，Ｏ−ジメチルヒドロキシルアミン塩酸塩の代わりに、ジメチルアミン塩酸塩を用いること以外は実質的に参考例１６８−１と同様に反応を行って、表題化合物（２４０ｍｇ、定量的）を黄色油状物として得た。

^１Ｈ−ＮＭＲ（３００ＭＨｚ、ＣＤＣｌ_３）δ：１．４６（９Ｈ，ｓ），１．６０−１．８０（４Ｈ，ｍ），２．５３−２．８４（３Ｈ，ｍ），２．９５（３Ｈ，ｓ），３．０６（３Ｈ，ｓ），４．１５（２Ｈ，ｄ，Ｊ＝１０．６Ｈｚ）．
ＬＣ／ＭＳ［条件１］：保持時間３．６４分；ｍ／ｚ２５７．１［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）

Reference Example 170-1
Preparation of 4- (dimethylcarbamoyl) piperidine-1-carboxylate t-butyl Substantially the same as Reference Example 168-1 except that dimethylamine hydrochloride was used instead of N, O-dimethylhydroxylamine hydrochloride The reaction was performed to give the title compound (240 mg, quantitative) as a yellow oil.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.46 (9H, s), 1.60-1.80 (4H, m), 2.53-2.84 (3H, m), 2.95 (3H, s), 3.06 (3H, s), 4.15 (2H, d, J = 10.6 Hz).
LC / MS [Condition 1]: retention time 3.64 minutes; m / z 257.1 [M + H] ⁺ (ESI positive ion mode)

参考例１７０−２
Ｎ，Ｎ−ジメチルピペリジン−４−カルボキサミド塩酸塩の製造
４−アセチルピペリジン−１−カルボン酸ｔ−ブチルの代わりに参考例１７０−１で得られた４−（ジメチルカルバモイル）ピペリジン−１−カルボン酸ｔ−ブチルを用いること以外は実質的に参考例１６８−３と同様に反応を行って、表題化合物（１８１ｍｇ、定量的）を無色粉末として得た。

ＬＣ／ＭＳ［条件１］：保持時間０．５９分；ｍ／ｚ１５７．０［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）

Reference Example 170-2
Preparation of N, N-dimethylpiperidine-4-carboxamide hydrochloride 4- (dimethylcarbamoyl) piperidine-1-carboxylic acid obtained in Reference Example 170-1 instead of t-butyl 4-acetylpiperidine-1-carboxylate The reaction was carried out substantially in the same manner as in Reference Example 168-3 except that t-butyl was used to give the title compound (181 mg, quantitative) as a colorless powder.

LC / MS [Condition 1]: Retention time 0.59 minutes; m / z 157.0 [M + H] ⁺ (ESI positive ion mode)

実施例１７０
Ｎ，Ｎ−ジメチル−１−［４−（｛２−オキソ−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）ベンゾイル］ピペリジン−４−カルボキサミド（化合物番号１７０）の製造
４−（２−アミノエチル）モルホリンの代わりに参考例１７０−２で得られたＮ，Ｎ−ジメチルピペリジン−４−カルボキサミド塩酸塩を用いること以外は実質的に実施例４４と同様に反応を行って、表題化合物（３５ｍｇ、収率６８％）を黄色無定形物として得た。

^１Ｈ−ＮＭＲ（３００ＭＨｚ、ＣＤＣｌ_３）δ：１．６２−２．００（８Ｈ，ｍ），２．５３（４Ｈ，ｂｒ ｓ），２．７２−２．８５（１Ｈ，ｍ），２．８７−３．０３（２Ｈ，ｂｒ ｍ），２．９６（３Ｈ，ｓ），３．０８（３Ｈ，ｓ），３．１３（２Ｈ，ｓ），３．５６（２Ｈ，ｂｒ ｓ），３．８０（１Ｈ，ｂｒ ｓ），４．４４（２Ｈ，ｓ），４．６８（１Ｈ，ｂｒ ｓ），７．２８（２Ｈ，ｄ，Ｊ＝７．８Ｈｚ），７．３４−７．５０（２Ｈ，ｂｒ ｍ），７．３９（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ），７．５７（２Ｈ，ｂｒ ｄ，Ｊ＝７．４Ｈｚ）．

ＬＣ／ＭＳ［条件１］：保持時間３．０４分；ｍ／ｚ５８７．１［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ６３１．４［Ｍ＋ＨＣＯＯ］^―（ＥＳＩ負イオンモード）

Example 170
N, N-dimethyl-1- [4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} Preparation of methyl) benzoyl] piperidine-4-carboxamide (Compound No. 170) N, N-dimethylpiperidine-4-carboxamide hydrochloride obtained in Reference Example 170-2 was used instead of 4- (2-aminoethyl) morpholine. The reaction was carried out substantially in the same manner as in Example 44 except for using, to give the title compound (35 mg, yield 68%) as a yellow amorphous product.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.62-2.00 (8H, m), 2.53 (4H, brs), 2.72-2.85 (1H, m), 2. 87-3.03 (2H, br m), 2.96 (3H, s), 3.08 (3H, s), 3.13 (2H, s), 3.56 (2H, br s), 3 .80 (1H, br s), 4.44 (2H, s), 4.68 (1H, br s), 7.28 (2H, d, J = 7.8 Hz), 7.34-7.50 (2H, br m), 7.39 (2H, d, J = 8.2 Hz), 7.57 (2H, br d, J = 7.4 Hz).

LC / MS [Condition 1]: Retention time 3.04 minutes; m / z 587.1 [M + H] ⁺ (ESI positive ion mode), m / z 631.4 [M + HCOO] ⁻ (ESI negative ion mode)

参考例１７１−１
４−｛［８−（４−シアノベンジル）−２−オキソ−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル］メチル｝安息香酸メチルの製造
４−（トリフルオロメチル）ベンジルブロミドの代わりに、４−シアノベンジルブロミド（市販）を用いること以外は実質的に実施例１と同様に反応を行って、表題化合物（８２０ｍｇ、収率９５％）を得た。

ＬＣ／ＭＳ［条件１］：保持時間１．３６分；ｍ／ｚ４２０．０［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード

Reference Example 171-1
Preparation of methyl 4-{[8- (4-cyanobenzyl) -2-oxo-1-oxa-3,8-diazaspiro [4.5] decan-3-yl] methyl} benzoate 4- (trifluoromethyl ) The reaction was conducted in substantially the same manner as in Example 1 except that 4-cyanobenzyl bromide (commercially available) was used instead of benzyl bromide to obtain the title compound (820 mg, yield 95%).

LC / MS [Condition 1]: Retention time 1.36 minutes; m / z 420.0 [M + H] ⁺ (ESI positive ion mode

参考例１７１−２
４−｛［８−（４−シアノベンジル）−２−オキソ−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル］メチル｝安息香酸の製造
４−（｛２−オキソ−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）安息香酸メチルの代わりに参考例１７１−１で得られた４−｛［８−（４−シアノベンジル）−２−オキソ−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル］メチル｝安息香酸メチルを用いること以外は実質的に参考例２１と同様に反応を行って、表題化合物（７３０ｍｇ、収率９２％）を無色無定形物として得た。

^１Ｈ−ＮＭＲ（３００ＭＨｚ、ＣＤＣｌ_３）δ：１．７４−１．９８（４Ｈ，ｂｒ ｍ），２．５４−２．７９（４Ｈ，ｂｒ ｍ），３．１１（２Ｈ，ｓ），３．６８（２Ｈ，ｓ），４．４８（２Ｈ，ｓ），７．３４（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ），７．４６（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ），７．６１（２Ｈ，ｄ，Ｊ＝８．６Ｈｚ），８．０５（２Ｈ，ｄ，Ｊ＝８．６Ｈｚ）．

ＬＣ／ＭＳ［条件１］：保持時間１．１４分；ｍ／ｚ４０５．９［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ４０４．１［Ｍ−Ｈ］^―（ＥＳＩ負イオンモード）

Reference Example 171-2
Preparation of 4-{[8- (4-Cyanobenzyl) -2-oxo-1-oxa-3,8-diazaspiro [4.5] decan-3-yl] methyl} benzoic acid 4-({2-oxo -8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl) obtained in Reference Example 171-1 instead of methyl benzoate 4-{[8- (4-cyanobenzyl) -2-oxo-1-oxa-3,8-diazaspiro [4.5] decan-3-yl] methyl} substantially except that methyl benzoate is used. The reaction was carried out in the same manner as in Reference Example 21 to give the title compound (730 mg, yield 92%) as a colorless amorphous product.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.74-1.98 (4H, br m), 2.54-2.79 (4H, br m), 3.11 (2H, s), 3 .68 (2H, s), 4.48 (2H, s), 7.34 (2H, d, J = 8.2 Hz), 7.46 (2H, d, J = 8.2 Hz), 7.61 (2H, d, J = 8.6 Hz), 8.05 (2H, d, J = 8.6 Hz).

LC / MS [Condition 1]: Retention time 1.14 minutes; m / z 405.9 [M + H] ⁺ (ESI positive ion mode), m / z 404.1 [M−H] ⁻ (ESI negative ion mode)

実施例１７１
４−［（３−｛４−［４−（６−フルオロベンゾ［ｄ］イソキサゾール−３−イル）ピペリジン−１−カルボニル］ベンジル｝−２−オキソ−１−オキサ−３，８−ジアザスピロ［４．５］デカン−８−イル）メチル］ベンゾニトリル（化合物番号１７１）の製造
４−（｛２−オキソ−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）安息香酸の代わりに参考例１７１−２で得られた４−｛［８−（４−シアノベンジル）−２−オキソ−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル］メチル｝安息香酸を、４−（２−アミノエチル）モルホリンの代わりに６−フルオロ−３−（ピペリジン−４−イル）ベンゾ［ｄ］イソキサゾール（市販）とトリエチルアミンを用いること以外は実質的に実施例４４と同様に反応を行って、表題化合物（３６ｍｇ、収率６０％）を無色無定形物として得た。

^１Ｈ−ＮＭＲ（３００ＭＨｚ、ＣＤＣｌ_３）δ：１．６２−１．８２（２Ｈ，ｍ），１．８３−２．３６（６Ｈ，ｍ），２．５２（４Ｈ，ｂｒ ｓ），３．０１−３．３０（２Ｈ，ｂｒ ｍ），３．１４（２Ｈ，ｓ），３．３７（１Ｈ，ｔｔ，Ｊ＝１０．６，４．１Ｈｚ），３．５５（２Ｈ，ｓ），３．９１（１Ｈ，ｂｒ ｓ），４．４５（２Ｈ，ｓ），４．７２（１Ｈ，ｂｒ ｓ），７．０８（１Ｈ，ｔｄ，Ｊ＝８．２，２．５Ｈｚ），７．２６−７．３５（３Ｈ，ｍ），７．３６−７．４８（４Ｈ，ｍ），７．５３−７．６７（３Ｈ，ｍ）．

ＬＣ／ＭＳ［条件１］：保持時間３．３４分；ｍ／ｚ６０８．１［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）

Example 171
4-[(3- {4- [4- (6-Fluorobenzo [d] isoxazol-3-yl) piperidin-1-carbonyl] benzyl} -2-oxo-1-oxa-3,8-diazaspiro [4 .5] Preparation of decan-8-yl) methyl] benzonitrile (Compound No. 171) 4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] Decan-3-yl} methyl) 4-{[8- (4-cyanobenzyl) -2-oxo-1-oxa-3, obtained in Reference Example 171-2 instead of benzoic acid, 8-Diazaspiro [4.5] decan-3-yl] methyl} benzoic acid is replaced with 6-fluoro-3- (piperidin-4-yl) benzo [d] isoxazole instead of 4- (2-aminoethyl) morpholine (Commercially available) and birds Except using ethylamine is carried out the same reaction as substantially Example 44 to give the title compound (36 mg, 60% yield) as a colorless amorphous substance.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.62-1.82 (2H, m), 1.83-2.36 (6H, m), 2.52 (4H, br s), 3. 01-3.30 (2H, br m), 3.14 (2H, s), 3.37 (1H, tt, J = 10.6, 4.1 Hz), 3.55 (2H, s), 3 .91 (1H, br s), 4.45 (2H, s), 4.72 (1H, br s), 7.08 (1 H, td, J = 8.2, 2.5 Hz), 7.26 -7.35 (3H, m), 7.36-7.48 (4H, m), 7.53-7.67 (3H, m).

LC / MS [Condition 1]: Retention time 3.34 minutes; m / z 608.1 [M + H] ⁺ (ESI positive ion mode)

実施例１７２
Ｎ−（ベンゾ［ｄ］［１，３］ジオキソール−５−イルメチル）−４−｛［８−（４−シアノベンジル）−２−オキソ−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル］メチル｝ベンズアミド（化合物番号１７２）の製造
６−フルオロ−３−（ピペリジン−４−イル）ベンゾ［ｄ］イソキサゾールの代わりにベンゾ［ｄ］［１，３］ジオキソール−５−イルメタンアミン（市販）を用いること以外は実質的に実施例１７１と同様に反応を行って、表題化合物（２４ｍｇ、収率４５％）を無色無定形物として得た。

^１Ｈ−ＮＭＲ（３００ＭＨｚ、ＣＤＣｌ_３）δ：１．６３−１．７９（２Ｈ，ｍ），１．８４−１．９７（２Ｈ，ｍ），２．４９−２．５２（４Ｈ，ｂｒ ｍ），３．１１（２Ｈ，ｓ），３．５４（２Ｈ，ｓ），４．４５（２Ｈ，ｓ），４．５４（２Ｈ，ｄ，Ｊ＝５．７Ｈｚ），５．９５（２Ｈ，ｓ），６．３０（１Ｈ，ｔ，Ｊ＝５．１Ｈｚ），６．７７（１Ｈ，ｄ，Ｊ＝７．４Ｈｚ），６．８１（１Ｈ，ｄｄ，Ｊ＝８．０，１．４Ｈｚ），６．８４（１Ｈ，ｄ，Ｊ＝１．６Ｈｚ），７．３２（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ），７．４１（２Ｈ，ｄ，Ｊ＝７．８Ｈｚ），７．５９（２Ｈ，ｄ，Ｊ＝７．４Ｈｚ），７．７６（２Ｈ，ｄ，Ｊ＝７．８Ｈｚ）．

ＬＣ／ＭＳ［条件１］：保持時間３．００分；ｍ／ｚ５３９．０［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）

Example 172
N- (benzo [d] [1,3] dioxol-5-ylmethyl) -4-{[8- (4-cyanobenzyl) -2-oxo-1-oxa-3,8-diazaspiro [4.5] Preparation of decan-3-yl] methyl} benzamide (Compound No. 172) Instead of 6-fluoro-3- (piperidin-4-yl) benzo [d] isoxazole, benzo [d] [1,3] dioxol-5 The reaction was carried out substantially in the same manner as in Example 171 except that ylmethanamine (commercially available) was used to give the title compound (24 mg, yield 45%) as a colorless amorphous product.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.63-1.79 (2H, m), 1.84-1.97 (2H, m), 2.49-2.52 (4H, br m ), 3.11 (2H, s), 3.54 (2H, s), 4.45 (2H, s), 4.54 (2H, d, J = 5.7 Hz), 5.95 (2H, s), 6.30 (1H, t, J = 5.1 Hz), 6.77 (1H, d, J = 7.4 Hz), 6.81 (1H, dd, J = 8.0, 1.4 Hz) ), 6.84 (1H, d, J = 1.6 Hz), 7.32 (2H, d, J = 8.2 Hz), 7.41 (2H, d, J = 7.8 Hz), 7.59 (2H, d, J = 7.4 Hz), 7.76 (2H, d, J = 7.8 Hz).

LC / MS [Condition 1]: Retention time 3.00 minutes; m / z 539.0 [M + H] ⁺ (ESI positive ion mode)

実施例１７３
４−｛［８−（４−シアノベンジル）−２−オキソ−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル］メチル｝−Ｎ−［（テトラヒドロフラン−２−イル）メチル］ベンズアミド（化合物番号１７３）の製造
６−フルオロ−３−（ピペリジン−４−イル）ベンゾ［ｄ］イソキサゾールの代わりに、テトラヒドロフルフリルアミン（市販）を用いること以外は実質的に実施例１７１と同様に反応を行って、表題化合物（２２ｍｇ、収率４６％）を無色無定形物として得た。

^１Ｈ−ＮＭＲ（３００ＭＨｚ、ＣＤＣｌ_３）δ：１．５１−１．８０（３Ｈ，ｍ），１．８２−２．１２（５Ｈ，ｍ），２．３９−２．６６（４Ｈ，ｂｒ ｍ），３．１１（２Ｈ，ｓ），３．３１（１Ｈ，ｄｄｄ，Ｊ＝１３．８，７．７，４．８Ｈｚ），３．５５（２Ｈ，ｂｒ ｓ），３．７２−３．９５（３Ｈ，ｍ），４．０６（１Ｈ，ｄｑ，Ｊ＝３．３，７．４Ｈｚ），４．４６（２Ｈ，ｓ），６．４７（１Ｈ，ｂｒ ｔ，Ｊ＝４．５Ｈｚ），７．３２（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ），７．４２（２Ｈ，ｄ，Ｊ＝７．０Ｈｚ），７．５９（２Ｈ，ｄ，Ｊ＝７．８Ｈｚ），７．７６（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ）．

ＬＣ／ＭＳ［条件１］：保持時間０．６１分；ｍ／ｚ４８９．０［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）

Example 173
4-{[8- (4-Cyanobenzyl) -2-oxo-1-oxa-3,8-diazaspiro [4.5] decan-3-yl] methyl} -N-[(tetrahydrofuran-2-yl) Preparation of methyl] benzamide (Compound No. 173) Substantially Example 171 except that tetrahydrofurfurylamine (commercially available) was used instead of 6-fluoro-3- (piperidin-4-yl) benzo [d] isoxazole. The reaction was performed in the same manner to obtain the title compound (22 mg, yield 46%) as a colorless amorphous product.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.51-1.80 (3H, m), 1.82-2.12 (5H, m), 2.39-2.66 (4H, br m ), 3.11 (2H, s), 3.31 (1H, ddd, J = 13.8, 7.7, 4.8 Hz), 3.55 (2H, br s), 3.72-3. 95 (3H, m), 4.06 (1H, dq, J = 3.3, 7.4 Hz), 4.46 (2H, s), 6.47 (1H, brt, J = 4.5 Hz) , 7.32 (2H, d, J = 8.2 Hz), 7.42 (2H, d, J = 7.0 Hz), 7.59 (2H, d, J = 7.8 Hz), 7.76 ( 2H, d, J = 8.2 Hz).

LC / MS [Condition 1]: Retention time 0.61 min; m / z 489.0 [M + H] ⁺ (ESI positive ion mode)

実施例１７４
４−（４−｛［８−（４−シアノベンジル）−２−オキソ−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル］メチル｝ベンズアミド）ピペリジン−１−カルボン酸メチル（化合物番号１７４）の製造
６−フルオロ−３−（ピペリジン−４−イル）ベンゾ［ｄ］イソキサゾールの代わりに、参考例１３５で得られた４−アミノピペリジン−１−カルボン酸メチル塩酸塩を用いること以外は実質的に実施例１７１と同様に反応を行って、表題化合物（２９ｍｇ、収率５４％）を無色無定形物として得た。

^１Ｈ−ＮＭＲ（３００ＭＨｚ、ＣＤＣｌ_３）δ：１．４２（２Ｈ，ｄｑ，Ｊ＝４．１，１１．９Ｈｚ），１．６３−１．８０（２Ｈ，ｍ），１．９１（２Ｈ，ｂｒ ｄ，Ｊ＝１２．３Ｈｚ），２．０５（２Ｈ，ｂｒ ｄｄ，Ｊ＝２．９，１１．９Ｈｚ），２．５１（４Ｈ，ｂｒ ｓ），２．９７（２Ｈ，ｔ，Ｊ＝１１．４Ｈｚ），３．１２（２Ｈ，ｓ），３．５５（２Ｈ，ｓ），３．７０（３Ｈ，ｓ），４．０４−４．２６（３Ｈ，ｍ），４．４６（２Ｈ，ｓ），５．９５（１Ｈ，ｄ，Ｊ＝７．８Ｈｚ），７．３２（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ），７．４２（２Ｈ，ｄ，Ｊ＝６．５Ｈｚ），７．５９（２Ｈ，ｄ，Ｊ＝７．８Ｈｚ），７．７３（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ）．
ＬＣ／ＭＳ［条件１］：保持時間２．１５分；ｍ／ｚ５４６．１［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）

Example 174
4- (4-{[8- (4-Cyanobenzyl) -2-oxo-1-oxa-3,8-diazaspiro [4.5] decan-3-yl] methyl} benzamido) piperidine-1-carboxylic acid Preparation of methyl (Compound No. 174) Instead of 6-fluoro-3- (piperidin-4-yl) benzo [d] isoxazole, methyl 4-aminopiperidine-1-carboxylate obtained in Reference Example 135 was used. The reaction was carried out in substantially the same manner as in Example 171 except that the title compound (29 mg, yield 54%) was obtained as a colorless amorphous product.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.42 (2H, dq, J = 4.1, 11.9 Hz), 1.63-1.80 (2H, m), 1.91 (2H, br d, J = 12.3 Hz), 2.05 (2H, br dd, J = 2.9, 11.9 Hz), 2.51 (4H, br s), 2.97 (2H, t, J = 11.4 Hz), 3.12 (2H, s), 3.55 (2H, s), 3.70 (3H, s), 4.04-4.26 (3H, m), 4.46 (2H) , S), 5.95 (1H, d, J = 7.8 Hz), 7.32 (2H, d, J = 8.2 Hz), 7.42 (2H, d, J = 6.5 Hz), 7 .59 (2H, d, J = 7.8 Hz), 7.73 (2H, d, J = 8.2 Hz).
LC / MS [Condition 1]: Retention time 2.15 minutes; m / z 546.1 [M + H] ⁺ (ESI positive ion mode)

実施例１７５
４−（｛３−［４−（４−ベンゾイルピペリジン−１−カルボニル）ベンジル］−２−オキソ−１−オキサ−３，８−ジアザスピロ［４．５］デカン−８−イル｝メチル）ベンゾニトリル（化合物番号１７５）の製造
６−フルオロ−３−（ピペリジン−４−イル）ベンゾ［ｄ］イソキサゾールの代わりに、フェニル（ピペリジン−４−イル）メタノン塩酸塩（市販）を用いること以外は実質的に実施例１７１と同様に反応を行って、表題化合物（３４ｍｇ、収率６０％）を無色無定形物として得た。

^１Ｈ−ＮＭＲ（３００ＭＨｚ、ＣＤＣｌ_３）δ：１．６１−２．０９（８Ｈ，ｍ），２．５５（４Ｈ，ｂｒ ｓ），２．９９−３．２６（２Ｈ，ｂｒ ｍ），３．１３（２Ｈ，ｓ），３．４２−３．６８（３Ｈ，ｍ），３．８４（１Ｈ，ｂｒ ｓ），４．４４（２Ｈ，ｓ），４．６７（１Ｈ，ｂｒ ｓ），７．３０（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ），７．３６−７．５２（６Ｈ，ｍ），７．５３−７．６３（３Ｈ，ｍ），７．９４（２Ｈ，ｄ，Ｊ＝７．８Ｈｚ）．

ＬＣ／ＭＳ［条件１］：保持時間３．２４分；ｍ／ｚ５７７．１［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ６１１．３［Ｍ＋Ｃｌ］^―（ＥＳＩ負イオンモード）

Example 175
4-({3- [4- (4-Benzoylpiperidine-1-carbonyl) benzyl] -2-oxo-1-oxa-3,8-diazaspiro [4.5] decan-8-yl} methyl) benzonitrile Preparation of (Compound No. 175) Substantially except that phenyl (piperidin-4-yl) methanone hydrochloride (commercially available) is used instead of 6-fluoro-3- (piperidin-4-yl) benzo [d] isoxazole The product was reacted in the same manner as in Example 171 to give the title compound (34 mg, yield 60%) as a colorless amorphous product.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.61-2.09 (8H, m), 2.55 (4H, br s), 2.99-3.26 (2H, br m), 3 .13 (2H, s), 3.42-3.68 (3H, m), 3.84 (1H, br s), 4.44 (2H, s), 4.67 (1H, br s), 7.30 (2H, d, J = 8.2 Hz), 7.36-7.52 (6H, m), 7.53-7.63 (3H, m), 7.94 (2H, d, J = 7.8 Hz).

LC / MS [Condition 1]: Retention time 3.24 minutes; m / z 577.1 [M + H] ⁺ (ESI positive ion mode), m / z 611.3 [M + Cl] ⁻ (ESI negative ion mode)

実施例１７６
４−（｛２−オキソ−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）−Ｎ−（２，２，３，３，３−ペンタフルオロプロピル）ベンズアミド（化合物番号１７６）の製造
４−（２−アミノエチル）モルホリンの代わりに２，２，３，３，３−ペンタフルオロプロパン−１−アミン（市販）を用いること以外は実質的に実施例４４と同様に反応を行って、表題化合物（１０ｍｇ、収率２０％）を白色粉末として得た。

^１Ｈ−ＮＭＲ（３００ＭＨｚ、ＣＤＣｌ_３）δ：１．６５−１．８２（２Ｈ，ｍ），１．８５−２．０１（２Ｈ，ｍ），２．５３（４Ｈ，ｂｒ ｓ），３．１４（２Ｈ，ｓ），３．５６（２Ｈ，ｂｒ ｓ），４．１９（２Ｈ，ｔｄ，Ｊ＝１４．６，６．４Ｈｚ），４．４７（２Ｈ，ｓ），６．２９（１Ｈ，ｔ，Ｊ＝６．１Ｈｚ），７．３５−７．４７（２Ｈ，ｍ），７．３６（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ），７．５０−７．６２（２Ｈ，ｍ），７．７８（２Ｈ，ｄ，Ｊ＝８．６Ｈｚ）．

ＬＣ／ＭＳ［条件１］：保持時間３．４２分；ｍ／ｚ５８０．０［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ５７８．２［Ｍ−Ｈ］^―（ＥＳＩ負イオンモード）

Example 176
4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl) -N- (2,2 , 3,3,3-Pentafluoropropyl) benzamide (Compound No. 176) 2,2,3,3,3-Pentafluoropropan-1-amine (commercially available instead of 4- (2-aminoethyl) morpholine The title compound (10 mg, yield 20%) was obtained as a white powder in substantially the same manner as in Example 44, except that

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.65 to 1.82 (2H, m), 1.85 to 2.01 (2H, m), 2.53 (4H, br s), 3. 14 (2H, s), 3.56 (2H, br s), 4.19 (2H, td, J = 14.6, 6.4 Hz), 4.47 (2H, s), 6.29 (1H , T, J = 6.1 Hz), 7.35-7.47 (2H, m), 7.36 (2H, d, J = 8.2 Hz), 7.50-7.62 (2H, m) , 7.78 (2H, d, J = 8.6 Hz).

LC / MS [Condition 1]: Retention time 3.42 minutes; m / z 580.0 [M + H] ⁺ (ESI positive ion mode), m / z 578.2 [M−H] ⁻ (ESI negative ion mode)

実施例１７７
Ｎ−メトキシ−Ｎ−メチル−４−（｛２−オキソ−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）ベンズアミド（化合物番号１７７）の製造
（１ｒ，４ｒ）−４−（｛２−オキソ−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）シクロヘキサンカルボン酸の代わりに、参考例２１で得られた４−（｛２−オキソ−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）安息香酸を用いること以外は実質的に実施例１５７と同様に反応を行なって、表題化合物（２４０ｍｇ、収率８５％）を無色無定形物として得た。

^１Ｈ−ＮＭＲ（３００ＭＨｚ、ＣＤＣｌ_３）δ：１．６４−１．８１（２Ｈ，ｍ），１．９２（２Ｈ，ｂｒ ｄ，Ｊ＝１３．５Ｈｚ），２．５３（４Ｈ，ｂｒ ｓ），３．１３（２Ｈ，ｓ），３．３６（３Ｈ，ｓ），３．５４（５Ｈ，ｓ），４．４５（２Ｈ，ｓ），７．２９（２Ｈ，ｄ，Ｊ＝８．６Ｈｚ），７．４２（２Ｈ，ｄ，Ｊ＝７．４Ｈｚ），７．５６（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ），７．６６（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ）．

ＬＣ／ＭＳ［条件１］：保持時間３．０６分；ｍ／ｚ４９２．０［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）

Example 177
N-methoxy-N-methyl-4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl ) Preparation of benzamide (Compound No. 177) (1r, 4r) -4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] 4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8] obtained in Reference Example 21 instead of decan-3-yl} methyl) cyclohexanecarboxylic acid -Diazaspiro [4.5] decan-3-yl} methyl) benzoic acid was used in substantially the same manner as in Example 157 to give the title compound (240 mg, 85% yield) as colorless amorphous. Obtained as a thing.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.64-1.81 (2H, m), 1.92 (2H, br d, J = 13.5 Hz), 2.53 (4H, br s) , 3.13 (2H, s), 3.36 (3H, s), 3.54 (5H, s), 4.45 (2H, s), 7.29 (2H, d, J = 8.6 Hz) ), 7.42 (2H, d, J = 7.4 Hz), 7.56 (2H, d, J = 8.2 Hz), 7.66 (2H, d, J = 8.2 Hz).

LC / MS [Condition 1]: Retention time 3.06 minutes; m / z 492.0 [M + H] ⁺ (ESI positive ion mode)

実施例１７８
１−（２−クロロエチル）−３−［４−（｛２−オキソ−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）フェニル］尿素塩酸塩（化合物番号１７８）の製造
参考例９３で得られた３−（４−アミノベンジル）−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−２−オン二塩酸塩（４４ｍｇ、０．０９０ｍｍｏｌ）をトルエン（１．０ｍＬ）に溶解し、室温にて１−クロロ−２−イソシアナートエタン（市販）（０．０２４ｍＬ、０．３０ｍｍｏｌ）を加えて、１００℃で３時間かき混ぜた。反応混合物にヘキサン（１．０ｍＬ）を加え、析出した固体をろ取し、室温にて減圧下乾燥して１−（２−クロロエチル）−３−［４−（｛２−オキソ−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）フェニル］尿素塩酸塩（４８ｍｇ、定量的）を白色粉末として得た。

^１Ｈ−ＮＭＲ（３００ＭＨｚ、ＤＭＳＯ−ｄ_６）δ：２．０４（４Ｈ，ｂｒ ｓ），２．９９−３．３７（６Ｈ，ｍ），３．４０（２Ｈ，ｑ，Ｊ＝６．０Ｈｚ），３．６４（２Ｈ，ｔ，Ｊ＝６．１Ｈｚ），４．２５（２Ｈ，ｓ），４．３３−４．５２（２Ｈ，ｍ），６．４６（１Ｈ，ｔ，Ｊ＝６．１Ｈｚ），７．１２（２Ｈ，ｄ，Ｊ＝８．６Ｈｚ），７．３７（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ），７．７２−７．８９（４Ｈ，ｍ），８．７７（１Ｈ，ｓ），１０．７７（１Ｈ，ｂｒ ｓ）．

ＬＣ／ＭＳ［条件１］：保持時間３．１６分；ｍ／ｚ５２４．９［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ５５９．２［Ｍ＋Ｃｌ］^―（ＥＳＩ負イオンモード）

Example 178
1- (2-Chloroethyl) -3- [4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decane-3- Ill} methyl) phenyl] urea hydrochloride (Compound No. 178) 3- (4-aminobenzyl) -8- [4- (trifluoromethyl) benzyl] -1-oxa-3 obtained in Reference Example 93 , 8-diazaspiro [4.5] decan-2-one dihydrochloride (44 mg, 0.090 mmol) in toluene (1.0 mL) and 1-chloro-2-isocyanatoethane (commercially available) at room temperature. (0.024 mL, 0.30 mmol) was added and stirred at 100 ° C. for 3 hours. Hexane (1.0 mL) was added to the reaction mixture, and the precipitated solid was collected by filtration, dried at room temperature under reduced pressure, and 1- (2-chloroethyl) -3- [4-({2-oxo-8- [ 4- (Trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl) phenyl] urea hydrochloride (48 mg, quantitative) was obtained as a white powder.

¹ H-NMR (300 MHz, DMSO-d ₆ ) δ: 2.04 (4H, br s), 2.99-3.37 (6H, m), 3.40 (2H, q, J = 6.0 Hz) ), 3.64 (2H, t, J = 6.1 Hz), 4.25 (2H, s), 4.33-4.52 (2H, m), 6.46 (1H, t, J = 6) .1 Hz), 7.12 (2H, d, J = 8.6 Hz), 7.37 (2H, d, J = 8.2 Hz), 7.72-7.89 (4H, m), 8.77 (1H, s), 10.77 (1H, br s).

LC / MS [Condition 1]: Retention time 3.16 minutes; m / z 524.9 [M + H] ⁺ (ESI positive ion mode), m / z 559.2 [M + Cl] ⁻ (ESI negative ion mode)

実施例１７９
４−（｛２−オキソ−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）−Ｎ−（２，２，２−トリフルオロエチル）ベンズアミド（化合物番号１７９）の製造
参考例２１で得られた４−（｛２−オキソ−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）安息香酸（５０ｍｇ、０．１１ｍｍｏｌ）をジクロロメタン（１．０ｍＬ）に溶解し、室温にて２，２，２−トリフルオロエタンアミン（市販）（０．０１３ｍＬ、０．１７ｍｍｏｌ）とＯ−（ベンゾトリアゾール−１−イル）−Ｎ，Ｎ，Ｎ’，Ｎ’−テトラメチルウロニウムヘキサフルオロホスファート（６３ｍｇ、０．１７ｍｍｏｌ）、そしてトリエチルアミン（０．０３０ｍＬ、０．２２ｍｍｏｌ）を加えて、室温で１日間かき混ぜた。反応混合物に酢酸エチル（２．０ｍＬ）と飽和炭酸水素ナトリウム水溶液（２．０ｍＬ）を加えて、有機層を分離した。有機層を無水硫酸マグネシウムで乾燥し、減圧下濃縮した。得られた残留物をシリカゲルカラムクロマトグラフィー［充填剤：株式会社山善製ＨＩ−ＦＬＡＳＨ（登録商標）ＣＯＬＵＭＮｓｉｌｉｃａｇｅｌ４０μｍ、展開溶媒：酢酸エチル／メタノール＝１０／１］にて精製し、４−（｛２−オキソ−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）−Ｎ−（２，２，２−トリフルオロエチル）ベンズアミド（４１ｍｇ、収率７０％）を白色粉末として得た。

^１Ｈ−ＮＭＲ（３００ＭＨｚ、ＣＤＣｌ_３）δ：１．６７−１．８５（２Ｈ，ｍ），１．８６−１．９７（２Ｈ，ｍ），２．５５（４Ｈ，ｂｒ ｓ），３．１３（２Ｈ，ｓ），３．５７（２Ｈ，ｂｒ ｓ），４．１３（２Ｈ，ｄｑ，Ｊ＝６．５，８．６Ｈｚ），４．４７（２Ｈ，ｓ），６．３５（１Ｈ，ｔ，Ｊ＝６．１Ｈｚ），７．３６（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ），７．４３（２Ｈ，ｄ，Ｊ＝７．８Ｈｚ），７．５６（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ），７．７９（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ）．

ＬＣ／ＭＳ［条件１］：保持時間３．０２分；ｍ／ｚ５３０．０［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ５２８．１［Ｍ−Ｈ］^―（ＥＳＩ負イオンモード）

Example 179
4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl) -N- (2,2 , 2-Trifluoroethyl) benzamide (Compound No. 179) 4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8 obtained in Reference Example 21 -Diazaspiro [4.5] decan-3-yl} methyl) benzoic acid (50 mg, 0.11 mmol) dissolved in dichloromethane (1.0 mL) and 2,2,2-trifluoroethanamine (commercially available) at room temperature ) (0.013 mL, 0.17 mmol) and O- (benzotriazol-1-yl) -N, N, N ′, N′-tetramethyluronium hexafluorophosphate (63 mg, 0.17 mmol), Added triethylamine (0.030 mL, 0.22 mmol) and was stirred at room temperature for 1 day. Ethyl acetate (2.0 mL) and saturated aqueous sodium hydrogen carbonate solution (2.0 mL) were added to the reaction mixture, and the organic layer was separated. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography [filler: HI-FLASH (registered trademark) COLUMNsilica gel 40 μm, manufactured by Yamazen Co., Ltd., developing solvent: ethyl acetate / methanol = 10/1], and 4-({2- Oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl) -N- (2,2,2-trifluoroethyl ) Benzamide (41 mg, 70% yield) was obtained as a white powder.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.67-1.85 (2H, m), 1.86-1.97 (2H, m), 2.55 (4H, br s), 3. 13 (2H, s), 3.57 (2H, br s), 4.13 (2H, dq, J = 6.5, 8.6 Hz), 4.47 (2H, s), 6.35 (1H) , T, J = 6.1 Hz), 7.36 (2H, d, J = 8.2 Hz), 7.43 (2H, d, J = 7.8 Hz), 7.56 (2H, d, J = 8.2 Hz), 7.79 (2H, d, J = 8.2 Hz).

LC / MS [Condition 1]: Retention time 3.02 minutes; m / z 530.0 [M + H] ⁺ (ESI positive ion mode), m / z 528.1 [M−H] ⁻ (ESI negative ion mode)

実施例１８０
Ｎ−（４−シアノベンジル）−４−（｛２−オキソ−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）ベンズアミド（化合物番号１８０）の製造
参考例２１で得られた、４−（｛２−オキソ−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）安息香酸（４７ｍｇ、０．１０ｍｍｏｌ）と、４−（アミノメチル）ベンゾニトリル塩酸塩（市販）（１９ｍｇ、０．１１ｍｍｏｌ）、１−ヒドロキシベンゾトリアゾール（７．０ｍｇ、０．０５０ｍｏｌ）、そしてトリエチルアミン（０．０４２ｍＬ、０．３０ｍｍｏｌ）をクロロホルム（１．０ｍＬ）に溶解し、室温にて１−エチル−３−（３−ジメチルアミノプロピル）カルボジイミド塩酸塩（２１ｍｇ、０．１１ｍｍｏｌ）を加え、室温で１日間かき混ぜた。その後、反応混合物に酢酸エチル（２．０ｍＬ）と水（２．０ｍＬ）を加えて有機層を分離した。有機層を無水硫酸マグネシウムで乾燥した後、減圧下濃縮した。得られた残留物をシリカゲルカラムクロマトグラフィー［充填剤：株式会社山善製ＨＩ−ＦＬＡＳＨ（登録商標）ＣＯＬＵＭＮｓｉｌｉｃａｇｅｌ４０μｍ、展開溶媒：酢酸エチル／メタノール＝１０／１］にて精製し、Ｎ−（４−シアノベンジル）−４−（｛２−オキソ−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）ベンズアミド（４１ｍｇ、収率７３％）を無色無定形物として得た。

^１Ｈ−ＮＭＲ（３００ＭＨｚ、ＣＤＣｌ_３）δ：１．６４−１．８２（２Ｈ，ｍ），１．８５−１．９８（２Ｈ，ｍ），２．５２（４Ｈ，ｂｒ ｓ），３．１３（２Ｈ，ｓ），３．５６（２Ｈ，ｂｒ ｓ），４．４６（２Ｈ，ｓ），４．７１（２Ｈ，ｄ，Ｊ＝６．１Ｈｚ），６．５４（１Ｈ，ｔ，Ｊ＝５．７Ｈｚ），７．３４（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ），７．３７−７．４９（２Ｈ，ｍ），７．４５（２Ｈ，ｄ，Ｊ＝８．６Ｈｚ），７．５２−７．６３（２Ｈ，ｍ），７．６３（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ），７．７９（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ）．

ＬＣ／ＭＳ［条件２］：保持時間３．４１分；ｍ／ｚ５６２．８［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）

Example 180
N- (4-cyanobenzyl) -4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} Production of methyl) benzamide (Compound No. 180) 4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4] obtained in Reference Example 21 .5] decan-3-yl} methyl) benzoic acid (47 mg, 0.10 mmol) and 4- (aminomethyl) benzonitrile hydrochloride (commercially available) (19 mg, 0.11 mmol), 1-hydroxybenzotriazole (7 0.0 mg, 0.050 mol) and triethylamine (0.042 mL, 0.30 mmol) were dissolved in chloroform (1.0 mL) and 1-ethyl-3- (3- Methyl aminopropyl) carbodiimide hydrochloride (21 mg, 0.11 mmol) and the mixture was stirred at room temperature for 1 day. Thereafter, ethyl acetate (2.0 mL) and water (2.0 mL) were added to the reaction mixture to separate the organic layer. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography [filler: HI-FLASH (registered trademark) COLUMNsilica gel 40 μm, manufactured by Yamazen Co., Ltd., developing solvent: ethyl acetate / methanol = 10/1], and N- (4-cyano (Benzyl) -4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl) benzamide (41 mg, Yield 73%) was obtained as a colorless amorphous product.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.64-1.82 (2H, m), 1.85-1.98 (2H, m), 2.52 (4H, br s), 3. 13 (2H, s), 3.56 (2H, br s), 4.46 (2H, s), 4.71 (2H, d, J = 6.1 Hz), 6.54 (1H, t, J = 5.7 Hz), 7.34 (2H, d, J = 8.2 Hz), 7.37-7.49 (2H, m), 7.45 (2H, d, J = 8.6 Hz), 7 .52-7.63 (2H, m), 7.63 (2H, d, J = 8.2 Hz), 7.79 (2H, d, J = 8.2 Hz).

LC / MS [Condition 2]: retention time 3.41 min; m / z 562.8 [M + H] ⁺ (ESI positive ion mode)

実施例１８１
４−（｛２−オキソ−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）−Ｎ−［４−（トリフルオロメチル）ベンジル］ベンズアミド（化合物番号１８１）の製造
４−（アミノメチル）ベンゾニトリル塩酸塩の代わりに［４−（トリフルオロメチル）フェニル］メタンアミン（市販）を用いること以外は実質的に実施例１８０と同様に反応を行って、表題化合物（４７ｍｇ、収率７６％）を無色無定形物として得た。

^１Ｈ−ＮＭＲ（３００ＭＨｚ、ＣＤＣｌ_３）δ：１．６２−１．８０（２Ｈ，ｍ），１．８４−１．９６（２Ｈ，ｍ），２．５１（４Ｈ，ｂｒ ｓ），３．１２（２Ｈ，ｓ），３．５５（２Ｈ，ｂｒ ｓ），４．４６（２Ｈ，ｓ），４．７０（２Ｈ，ｄ，Ｊ＝５．７Ｈｚ），６．５０（１Ｈ，ｔ，Ｊ＝５．３Ｈｚ），７．３４（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ），７．４３（２Ｈ，ｄ，Ｊ＝１５．１Ｈｚ），７．４５（２Ｈ，ｄ，Ｊ＝１５．５Ｈｚ），７．５６（２Ｈ，ｄ，Ｊ＝１３．５Ｈｚ），７．５９（２Ｈ，ｄ，Ｊ＝１３．５Ｈｚ），７．７８（２Ｈ，ｄ，Ｊ＝７．８Ｈｚ）．

ＬＣ／ＭＳ［条件２］：保持時間３．９６分；ｍ／ｚ６０５．９［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）

Example 181
4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl) -N- [4- ( Preparation of ( trifluoromethyl) benzyl] benzamide (Compound No. 181) Substantially carried out except that [4- (trifluoromethyl) phenyl] methanamine (commercially available) is used instead of 4- (aminomethyl) benzonitrile hydrochloride. The reaction was carried out in the same manner as in Example 180 to obtain the title compound (47 mg, yield 76%) as a colorless amorphous product.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.62-1.80 (2H, m), 1.84-1.96 (2H, m), 2.51 (4H, br s), 3. 12 (2H, s), 3.55 (2H, br s), 4.46 (2H, s), 4.70 (2H, d, J = 5.7 Hz), 6.50 (1H, t, J = 5.3 Hz), 7.34 (2H, d, J = 8.2 Hz), 7.43 (2H, d, J = 15.1 Hz), 7.45 (2H, d, J = 15.5 Hz) 7.56 (2H, d, J = 13.5 Hz), 7.59 (2H, d, J = 13.5 Hz), 7.78 (2H, d, J = 7.8 Hz).

LC / MS [Condition 2]: Retention time 3.96 minutes; m / z 605.9 [M + H] ⁺ (ESI positive ion mode)

参考例１８２−１
（テトラヒドロフラン−２−イル）メチルカルバミン酸ｔ−ブチルの製造
テトラヒドロフルフリルアミン（０．８６ｇ、８．５ｍｍｏｌ）をクロロホルム（９ｍＬ）に溶解し、ジ炭酸ジｔ−ブチル（２．０４ｇ、９．３ｍｍｏｌ）を加え、室温で１時間かき混ぜた。その後、反応混合物を減圧下濃縮して、表題化合物（１．９ｇ、収率定量的）を淡黄色油状物として得た。

^１Ｈ−ＮＭＲ（３００ＭＨｚ，ＣＤＣｌ_３）δ：１．４４（９Ｈ，ｓ），１．５１−１．６７（１Ｈ，ｍ），１．８３−２．０２（３Ｈ，ｍ），３．０６（１Ｈ，ｄｄｄ，Ｊ＝１３．５，５．７，５．７Ｈｚ），３．３８（１Ｈ，ｄｄｄ，Ｊ＝１３．５，６．１，３．７Ｈｚ），３．７４（１Ｈ，ｄｔ，Ｊ＝８．２，６．５Ｈｚ），３．８５（１Ｈ，ｄｔ，Ｊ＝８．２，６．５Ｈｚ），３．９０−４．００（１Ｈ，ｍ），４．８８（１Ｈ，ｂｒ ｓ）．

ＬＣ／ＭＳ［条件１］：保持時間３．３８分；ｍ／ｚ１０１．７８［Ｍ−Ｂｏｃ］^＋（ＥＳＩ正イオンモード）

Reference Example 182-1
Preparation of t-butyl (tetrahydrofuran-2-yl) methylcarbamate Tetrahydrofurfurylamine (0.86 g, 8.5 mmol) was dissolved in chloroform (9 mL) and di-t-butyl dicarbonate (2.04 g, 9.3 mmol). And stirred at room temperature for 1 hour. The reaction mixture was then concentrated under reduced pressure to give the title compound (1.9 g, quantitative yield) as a pale yellow oil.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.44 (9H, s), 1.51-1.67 (1H, m), 1.83 to 2.02 (3H, m), 3.06 (1H, ddd, J = 13.5, 5.7, 5.7 Hz), 3.38 (1H, ddd, J = 13.5, 6.1, 3.7 Hz), 3.74 (1H, dt , J = 8.2, 6.5 Hz), 3.85 (1H, dt, J = 8.2, 6.5 Hz), 3.90-4.00 (1H, m), 4.88 (1H, br s).

LC / MS [Condition 1]: Retention time 3.38 minutes; m / z 101.78 [M-Boc] ⁺ (ESI positive ion mode)

参考例１８２−２
メチル［（テトラヒドロフラン−２−イル）メチル］カルバミン酸ｔ−ブチルの製造
参考例１８２−１で得られた（テトラヒドロフラン−２−イル）メチルカルバミン酸ｔ−ブチル（１３２ｍｇ、０．６６ｍｍｏｌ）をＮ，Ｎ−ジメチルホルムアミド（２ｍＬ）に溶解し、カリウムｔ−ブトキシド（８１ｍｇ、０．７２ｍｍｏｌ）、ヨウ化メチル（０．０４５ｍＬ、０．７２ｍｍｏｌ）を加えて室温で３時間かき混ぜた。その後、カリウムｔ−ブトキシド（８１ｍｇ、０．７２ｍｍｏｌ）、ヨウ化メチル（０．０４５ｍＬ、０．７２ｍｍｏｌ）を追加し、室温で２時間かき混ぜた。その後、反応混合物に水（５．０ｍＬ）と酢酸エチル（５．０ｍＬ）を加えて分液した後、有機層を水で洗浄した。有機層を無水硫酸マグネシウムで乾燥し、減圧下濃縮した後、シリカゲルカラムクロマトグラフィー［充填剤：富士シリシア社製ＮＨ−ＤＭ１０２０、展開溶媒：ヘキサン／酢酸エチル＝１０／１］にて精製し、表題化合物（９０ｍｇ、収率６４％）を淡黄色油状物として得た。

^１Ｈ−ＮＭＲ（３００ＭＨｚ，ＣＤＣｌ_３）δ：１．４５（９Ｈ，ｓ），１．４８−１．７０（１Ｈ，ｍ），１．７８−２．０１（３Ｈ，ｍ），２．９３（３Ｈ，ｓ），３．０１−３．６０（２Ｈ，ｍ），３．７４（１Ｈ，ｑ，Ｊ＝７．４Ｈｚ），３．８５（１Ｈ，ｑ，Ｊ＝７．２Ｈｚ），３．９６−４．１１（１Ｈ，ｍ）．

ＬＣ／ＭＳ［条件１］：保持時間３．７８分；ｍ／ｚ１１５．９１［Ｍ−Ｂｏｃ］^＋（ＥＳＩ正イオンモード）

Reference Example 182-2
Production of t-butyl methyl [(tetrahydrofuran-2-yl) methyl] carbamate t-butyl (tetrahydrofuran-2-yl) methylcarbamate (132 mg, 0.66 mmol) obtained in Reference Example 182-1 was replaced with N, N. -Dissolved in dimethylformamide (2 mL), potassium t-butoxide (81 mg, 0.72 mmol) and methyl iodide (0.045 mL, 0.72 mmol) were added, and the mixture was stirred at room temperature for 3 hours. Thereafter, potassium t-butoxide (81 mg, 0.72 mmol) and methyl iodide (0.045 mL, 0.72 mmol) were added, and the mixture was stirred at room temperature for 2 hours. Thereafter, water (5.0 mL) and ethyl acetate (5.0 mL) were added to the reaction mixture for liquid separation, and the organic layer was washed with water. The organic layer was dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography [filler: NH-DM1020 manufactured by Fuji Silysia Ltd., developing solvent: hexane / ethyl acetate = 10/1]. The compound (90 mg, yield 64%) was obtained as a pale yellow oil.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.45 (9H, s), 1.48-1.70 (1H, m), 1.78-2.01 (3H, m), 2.93 (3H, s), 3.01-3.60 (2H, m), 3.74 (1H, q, J = 7.4 Hz), 3.85 (1H, q, J = 7.2 Hz), 3 .96-4.11 (1H, m).

LC / MS [Condition 1]: Retention time 3.78 minutes; m / z 115.91 [M-Boc] ⁺ (ESI positive ion mode)

参考例１８２−３
Ｎ−メチル−１−（テトラヒドロフラン−２−イル）メタンアミン塩酸塩の製造
参考例１８２−２で得られたメチル［（テトラヒドロフラン−２−イル）メチル］カルバミン酸ｔ−ブチル（９０ｍｇ、０．６６ｍｍｏｌ）をメタノール（１．０ｍＬ）に溶解し、４Ｍ塩化水素−ジオキサン溶液（２．０ｍＬ）を加えて室温で１２時間かき混ぜた。その後、反応混合物を濃縮して、表題化合物（６３ｍｇ、収率定量的）を淡黄色油状物として得た。

^１Ｈ−ＮＭＲ（３００ＭＨｚ，ＣＤＣｌ_３）δ：１．５５−１．６９（１Ｈ，ｍ），２．２１−１．８１（３Ｈ，ｍ），２．８０（３Ｈ，ｔ，Ｊ＝５．３Ｈｚ），２．８４−２．９８（１Ｈ，ｍ），３．０７−３．２０（１Ｈ，ｍ），３．８０（１Ｈ，ｄｔ，Ｊ＝７．８，７．０Ｈｚ），３．９６（１Ｈ，ｄｔ，Ｊ＝８．２，７．０Ｈｚ），４．３６−４．４７（１Ｈ，ｍ），９．２９（１Ｈ，ｂｒｓ），９．５３（１Ｈ，ｂｒｓ）．

Reference Example 182-2
Production of N-methyl-1- (tetrahydrofuran-2-yl) methanamine hydrochloride t-butyl methyl [(tetrahydrofuran-2-yl) methyl] carbamate obtained in Reference Example 182-2 (90 mg, 0.66 mmol) Was dissolved in methanol (1.0 mL), 4M hydrogen chloride-dioxane solution (2.0 mL) was added, and the mixture was stirred at room temperature for 12 hr. The reaction mixture was then concentrated to give the title compound (63 mg, quantitative yield) as a pale yellow oil.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.55-1.69 (1H, m), 2.21-1.81 (3H, m), 2.80 (3H, t, J = 5. 3 Hz), 2.84-2.98 (1 H, m), 3.07-3.20 (1 H, m), 3.80 (1 H, dt, J = 7.8, 7.0 Hz), 3. 96 (1H, dt, J = 8.2, 7.0 Hz), 4.36-4.47 (1H, m), 9.29 (1H, brs), 9.53 (1H, brs).

実施例１８２
（１ｒ，４ｒ）−Ｎ−メチル−４−（｛２−オキソ−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）−Ｎ−［（テトラヒドロフラン−２−イル）メチル］シクロヘキサンカルボキサミド（化合物番号１８２）の製造
テトラヒドロフルフリルアミンの代わりに、参考例１８２−３で得られたＮ−メチル−１−（テトラヒドロフラン−２−イル）メタンアミン塩酸塩を用いること以外は実質的に実施例１０と同様に反応を行なって、表題化合物（６８ｍｇ、収率８５％）を無色油状物として得た。

^１Ｈ−ＮＭＲ（３００ＭＨｚ，ＣＤＣｌ_３）δ：０．９５−１．１４（２Ｈ，ｍ），１．４２−２．０３（１５Ｈ，ｍ），２．４７（１Ｈ，ｔｔ，Ｊ＝１１．９，３．１Ｈｚ），２．４９−２．６５（４Ｈ，ｍ），２．９７（１．０５Ｈ，ｓ），３．０５−３．１７（４．６Ｈ，ｍ），３．２５（２Ｈ，ｓ），３．２９（０．３５Ｈ，ｄｄ，Ｊ＝１４．６，３．７Ｈｚ），３．４３（０．３５Ｈ，ｄｄ，Ｊ＝１５．０，７．５Ｈｚ），３．５７（２Ｈ，ｓ），３．８９−３．６８（２．６５Ｈ，ｍ），４．０９−３．９５（１Ｈ，ｍ），７．４３（２Ｈ，ｄ，Ｊ＝７．８Ｈｚ），７．５６（２Ｈ，ｄ，Ｊ＝７．８Ｈｚ）．

ＬＣ／ＭＳ［条件１］：保持時間３．０６分；ｍ／ｚ５５１．９［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ５９６．０［Ｍ＋ＨＣＯＯ］^―（ＥＳＩ負イオンモード）

Example 182
(1r, 4r) -N-methyl-4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl } Methyl) -N-[(tetrahydrofuran-2-yl) methyl] cyclohexanecarboxamide (Compound No. 182) Instead of tetrahydrofurfurylamine, N-methyl-1- (tetrahydrofuran-) obtained in Reference Example 182-2 The reaction was carried out in substantially the same manner as in Example 10 except that 2-yl) methanamine hydrochloride was used to give the title compound (68 mg, yield 85%) as a colorless oil.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 0.95-1.14 (2H, m), 1.42-2.03 (15H, m), 2.47 (1H, tt, J = 11.1. 9, 3.1 Hz), 2.49-2.65 (4 H, m), 2.97 (1.05 H, s), 3.05-3.17 (4.6 H, m), 3.25 ( 2H, s), 3.29 (0.35H, dd, J = 14.6, 3.7 Hz), 3.43 (0.35H, dd, J = 15.0, 7.5 Hz), 3.57 (2H, s), 3.89-3.68 (2.65H, m), 4.09-3.95 (1H, m), 7.43 (2H, d, J = 7.8 Hz), 7 .56 (2H, d, J = 7.8 Hz).

LC / MS [Condition 1]: Retention time 3.06 minutes; m / z 551.9 [M + H] ⁺ (ESI positive ion mode), m / z 596.0 [M + HCOO] ⁻ (ESI negative ion mode)

実施例１８３
１−メチル−３−［４−（｛２−オキソ−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）フェニル］−１−［（テトラヒドロフラン−２−イル）メチル］尿素（化合物番号１８３）の製造
Ｎ−（ｔ−ブトキシカルボニル）−１，３−ジアミノプロパンの代わりに、参考例１８２−３で得られたＮ−メチル−１−（テトラヒドロフラン−２−イル）メタンアミン塩酸塩を用いること以外は実質的に実施例８３と同様に反応を行って、表題化合物（２４ｍｇ、収率３９％）を白色固体として得た。

^１Ｈ−ＮＭＲ（３００ＭＨｚ，ＣＤＣｌ_３）δ：１．６２−１．７６（３Ｈ，ｍ），１．８９（２Ｈ，ｂｒ ｄ，Ｊ＝１３．１），１．９４−２．０９（３Ｈ，ｍ），２．４２−２．５９（４Ｈ，ｍ），３．０２（３Ｈ，ｓ），３．０９（２Ｈ，ｓ），３．３４（１Ｈ，ｄｄ，Ｊ＝１６．０，６．５Ｈｚ），３．５５（２Ｈ，ｓ），３．５８（１Ｈ，ｄｄ，Ｊ＝１６．０，１．６Ｈｚ），３．９０（１Ｈ，ｄｔ，Ｊ＝８．２，６．１Ｈｚ），３．９８（１Ｈ，ｄｔ，Ｊ＝８．２，７．０Ｈｚ），４．０８−４．１８（１Ｈ，ｍ），４．３５（２Ｈ，ｓ），７．１５（２Ｈ，ｄ，Ｊ＝８．６Ｈｚ），７．３１（２Ｈ，ｄ，Ｊ＝８．６Ｈｚ），７．４２（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ），７．５６（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ），８．５４（１Ｈ，ｂｒ ｓ）．

ＬＣ／ＭＳ［条件１］：保持時間３．３５分；ｍ／ｚ５６０．９［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ５５９．１［Ｍ−Ｈ］^―（ＥＳＩ負イオンモード）

Example 183
1-methyl-3- [4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl) Preparation of phenyl] -1-[(tetrahydrofuran-2-yl) methyl] urea (Compound No. 183) Obtained in Reference Example 182-2 instead of N- (t-butoxycarbonyl) -1,3-diaminopropane The reaction was conducted in substantially the same manner as in Example 83 except that N-methyl-1- (tetrahydrofuran-2-yl) methanamine hydrochloride was used to give the title compound (24 mg, yield 39%) as a white solid. Obtained.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.62-1.76 (3H, m), 1.89 (2H, br d, J = 13.1), 1.94-2.09 (3H , M), 2.42-2.59 (4H, m), 3.02 (3H, s), 3.09 (2H, s), 3.34 (1H, dd, J = 16.0, 6 .5 Hz), 3.55 (2 H, s), 3.58 (1 H, dd, J = 16.0, 1.6 Hz), 3.90 (1 H, dt, J = 8.2, 6.1 Hz) , 3.98 (1H, dt, J = 8.2, 7.0 Hz), 4.08-4.18 (1H, m), 4.35 (2H, s), 7.15 (2H, d, J = 8.6 Hz), 7.31 (2H, d, J = 8.6 Hz), 7.42 (2H, d, J = 8.2 Hz), 7.56 (2H, d, J = 8.2 Hz) ), 8.54 (1H, r s).

LC / MS [Condition 1]: Retention time 3.35 minutes; m / z 560.9 [M + H] ⁺ (ESI positive ion mode), m / z 559.1 [M−H] ⁻ (ESI negative ion mode)

実施例１８４
３−｛［（１ｒ，４ｒ）−４−（４−モルホリノピペリジン−１−カルボニル）シクロヘキシル］メチル｝−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−２−オン（化合物番号１８４）の製造
テトラヒドロフルフリルアミンの代わりに、４−モルホリノピペリジンを用いること以外は実質的に実施例１０と同様に反応を行なって、表題化合物（２３ｍｇ、収率５３％）を白色固体として得た。

^１Ｈ−ＮＭＲ（３００ＭＨｚ，ＣＤＣｌ_３）δ：１．０４（２Ｈ，ｑ，Ｊ＝１２．３Ｈｚ），１．３１−１．６８（５Ｈ，ｍ），１．７１−２．００（１０Ｈ，ｍ），２．３０−２．６５（１１Ｈ，ｍ），３．０２（１Ｈ，ｔ，Ｊ＝１２．３Ｈｚ），３．１０（２Ｈ，ｄ，Ｊ＝７．４Ｈｚ），３．２５（２Ｈ，ｓ），３．５７（２Ｈ，ｓ），３．６８−３．７５（４Ｈ，ｍ），３．９３（１Ｈ，ｄ，Ｊ＝１３．５Ｈｚ），４．６３（１Ｈ，ｄ，Ｊ＝１３．９Ｈｚ），７．４４（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ），７．５７（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ）．

ＬＣ／ＭＳ［条件１］：保持時間１．３４分；ｍ／ｚ６０６．７［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ６５１．２［Ｍ＋ＨＣＯＯ］^―（ＥＳＩ負イオンモード）

Example 184
3-{[(1r, 4r) -4- (4-morpholinopiperidine-1-carbonyl) cyclohexyl] methyl} -8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [ 4.5] Preparation of decan-2-one (Compound No. 184) The reaction was conducted in substantially the same manner as in Example 10 except that 4-morpholinopiperidine was used instead of tetrahydrofurfurylamine to give the title compound (23 mg Yield 53%) as a white solid.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.04 (2H, q, J = 12.3 Hz), 1.31-1.68 (5H, m), 1.71-2.00 (10H, m), 2.30-2.65 (11H, m), 3.02 (1H, t, J = 12.3 Hz), 3.10 (2H, d, J = 7.4 Hz), 3.25 ( 2H, s), 3.57 (2H, s), 3.68-3.75 (4H, m), 3.93 (1H, d, J = 13.5 Hz), 4.63 (1H, d, J = 13.9 Hz), 7.44 (2H, d, J = 8.2 Hz), 7.57 (2H, d, J = 8.2 Hz).

LC / MS [Condition 1]: Retention time 1.34 minutes; m / z 606.7 [M + H] ⁺ (ESI positive ion mode), m / z 651.2 [M + HCOO] ⁻ (ESI negative ion mode)

実施例１８５
３−（｛（１ｒ，４ｒ）−４−［（１，１−ジオキソ−チオモルホリン−４−イル）カルボニル］シクロヘキシル｝メチル）−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−２−オン（化合物番号１８５）の製造
テトラヒドロフルフリルアミンの代わりに、チオモルホリン １、１−ジオキシドを用いること以外は実質的に実施例１０と同様に反応を行なって、表題化合物（２３ｍｇ、収率４８％）を白色固体として得た。

^１Ｈ−ＮＭＲ（３００ＭＨｚ，ＣＤＣｌ_３）δ：１．０６（２Ｈ，ｑｄ，Ｊ＝１２．７，２．５Ｈｚ），１．４８−１．７１（３Ｈ，ｍ），１．７２−１．８７（６Ｈ，ｍ），１．９４（２Ｈ，ｄ，Ｊ＝１２．７Ｈｚ），２．４６（１Ｈ，ｔｔ，Ｊ＝１１．９，３．３Ｈｚ），２．４９−２．６６（４Ｈ，ｍ），２．９９−３．０７（４Ｈ，ｍ），３．１１（２Ｈ，ｄ，Ｊ＝７．４Ｈｚ），３．２６（２Ｈ，ｓ），３．５７（２Ｈ，ｓ），３．９１−４．１８（４Ｈ，ｂｒ ｍ），７．４４（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ），７．５７（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ）．

ＬＣ／ＭＳ［条件１］：保持時間３．０３分；ｍ／ｚ５７１．８［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ６１６．１［Ｍ＋ＨＣＯＯ］^―（ＥＳＩ負イオンモード）

Example 185
3-({(1r, 4r) -4-[(1 , 1-dioxo-thiomorpholin-4-yl) carbonyl] cyclohexyl} methyl) -8- [4- (trifluoromethyl) benzyl] -1-oxa Preparation of -3,8-diazaspiro [4.5] decan-2-one (Compound No. 185) Substantially the same as Example 10 except that thiomorpholine 1,1-dioxide was used instead of tetrahydrofurfurylamine. The title compound (23 mg, 48% yield) was obtained as a white solid.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.06 (2H, qd, J = 12.7, 2.5 Hz), 1.48-1.71 (3H, m), 1.72-1. 87 (6H, m), 1.94 (2H, d, J = 12.7 Hz), 2.46 (1H, tt, J = 11.9, 3.3 Hz), 2.49-2.66 (4H , M), 2.99-3.07 (4H, m), 3.11 (2H, d, J = 7.4 Hz), 3.26 (2H, s), 3.57 (2H, s), 3.91-4.18 (4H, br m), 7.44 (2H, d, J = 8.2 Hz), 7.57 (2H, d, J = 8.2 Hz).

LC / MS [Condition 1]: Retention time 3.03 minutes; m / z 571.8 [M + H] ⁺ (ESI positive ion mode), m / z 616.1 [M + HCOO] ⁻ (ESI negative ion mode)

参考例１８６−１
２−［（テトラヒドロフラン−３−イル）メチル］イソインドリン−１，３−ジオンの製造
（テトラヒドロフラン−３−イル）メタノール（９５０ｍｇ、９．３ｍｍｏｌ）、フタルイミド（１．３７ｇ、９．３ｍｍｏｌ）とトリフェニルホスフィン（２．７ｇ、１０ｍｍｏｌ）をテトラヒドロフラン（９．０ｍＬ）に溶解し、氷冷下、アゾジカルボン酸ジイソプロピル（２．０ｍＬ、１０ｍｍｏｌ）を滴下した。反応混合物を室温で３時間かき混ぜた後、減圧下濃縮した。得られた残留物に２−プロパノール（２４ｍＬ）を加え、固体をろ取した。得られた固体にさらに２−プロパノール（１０ｍＬ）を加えて洗浄し、固体をろ取した。得られた固体を減圧下乾燥し、表題化合物（１．３ｇ、収率６２％）を白色固体として得た。

^１Ｈ−ＮＭＲ（３００ＭＨｚ，ＣＤＣｌ_３）δ：１．７２（１Ｈ，ｄｄｔ，Ｊ＝１３．９，６．５，６．５Ｈｚ），２．０１（１Ｈ，ｄｔｄ，Ｊ＝１２．７，７．８，５．３Ｈｚ），２．７３（１Ｈ，ｔｔ，Ｊ＝７．４，７．４Ｈｚ），３．６１（１Ｈ，ｄｄ，Ｊ＝９．０，５．７Ｈｚ），３．６９（１Ｈ，ｄｄ，Ｊ＝１３．５，７．０Ｈｚ），３．８０−３．７２（２Ｈ，ｍ），３．８３（１Ｈ，ｄｄ，Ｊ＝９．０，７．２Ｈｚ），３．９４（１Ｈ，ｄｄｄ，Ｊ＝８．２，８．２，５．７Ｈｚ），７．７０−７．７７（２Ｈ，ｍ），７．８３−７．９０（２Ｈ，ｍ）．

Reference Example 186-1
Preparation of 2-[(tetrahydrofuran-3-yl) methyl] isoindoline-1,3-dione (tetrahydrofuran-3-yl) methanol (950 mg, 9.3 mmol), phthalimido (1.37 g, 9.3 mmol) and tri Phenylphosphine (2.7 g, 10 mmol) was dissolved in tetrahydrofuran (9.0 mL), and diisopropyl azodicarboxylate (2.0 mL, 10 mmol) was added dropwise under ice cooling. The reaction mixture was stirred at room temperature for 3 hours and then concentrated under reduced pressure. To the obtained residue, 2-propanol (24 mL) was added, and the solid was collected by filtration. To the obtained solid, 2-propanol (10 mL) was further added for washing, and the solid was collected by filtration. The obtained solid was dried under reduced pressure to obtain the title compound (1.3 g, yield 62%) as a white solid.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.72 (1H, ddt, J = 13.9, 6.5, 6.5 Hz), 2.01 (1H, dtd, J = 12.7, 7 .8, 5.3 Hz), 2.73 (1H, tt, J = 7.4, 7.4 Hz), 3.61 (1H, dd, J = 9.0, 5.7 Hz), 3.69 ( 1H, dd, J = 13.5, 7.0 Hz), 3.80-3.72 (2H, m), 3.83 (1H, dd, J = 9.0, 7.2 Hz), 3.94 (1H, ddd, J = 8.2, 8.2, 5.7 Hz), 7.70-7.77 (2H, m), 7.83-7.90 (2H, m).

参考例１８６−２
（テトラヒドロフラン−３−イル）メタンアミンの製造
参考例１８６−１で得られた２−［（テトラヒドロフラン−３−イル）メチル］イソインドリン−１，３−ジオン（１．３ｇ、５．８ｍｍｏｌ）をエタノール（１３ｍＬ）に溶解し、ヒドラジン一水和物（０．４ｍＬ）を加え８５℃で２時間かき混ぜた。その後、反応混合物を濃縮して、表題化合物（６３ｍｇ、収率定量的）を淡黄色油状物として得た。

^１Ｈ−ＮＭＲ（３００ＭＨｚ，ＣＤＣｌ_３）δ：１．５８（１Ｈ，ｄｄｔ，Ｊ＝１１．９，７．３，７．３Ｈｚ），２．０４（１Ｈ，ｄｔｄ，Ｊ＝１２．９，７．９，５．３Ｈｚ），２．２９（１Ｈ，ｔｔｔ，Ｊ＝７．３，７．３，７．３Ｈｚ），２．７２（２Ｈ，ｄ，Ｊ＝６．９Ｈｚ），３．５１（１Ｈ，ｄｄ，Ｊ＝８．６，５．９Ｈｚ），３．７４（１Ｈ，ｄｔ，Ｊ＝８．３，７．６Ｈｚ），３．８４（１Ｈ，ｄｄ，Ｊ＝８．３，５．３Ｈｚ），３．８７（１Ｈ，ｄｔ，Ｊ＝８．６，７．３Ｈｚ）．

Reference Example 186-2
Production of (tetrahydrofuran-3-yl) methanamine 2-[(tetrahydrofuran-3-yl) methyl] isoindoline-1,3-dione (1.3 g, 5.8 mmol) obtained in Reference Example 186-1 was added to ethanol. (13 mL), hydrazine monohydrate (0.4 mL) was added, and the mixture was stirred at 85 ° C. for 2 hr. The reaction mixture was then concentrated to give the title compound (63 mg, quantitative yield) as a pale yellow oil.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.58 (1H, ddt, J = 11.9, 7.3, 7.3 Hz), 2.04 (1H, dtd, J = 12.9, 7 .9, 5.3 Hz), 2.29 (1H, ttt, J = 7.3, 7.3, 7.3 Hz), 2.72 (2H, d, J = 6.9 Hz), 3.51 ( 1H, dd, J = 8.6, 5.9 Hz), 3.74 (1H, dt, J = 8.3, 7.6 Hz), 3.84 (1H, dd, J = 8.3, 5. 3 Hz), 3.87 (1H, dt, J = 8.6, 7.3 Hz).

実施例１８６
（１ｒ，４ｒ）−４−（｛２−オキソ−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）−Ｎ−［（テトラヒドロフラン−３−イル）メチル］シクロヘキサンカルボキサミド（化合物番号１８６）の製造
テトラヒドロフルフリルアミンの代わりに、参考例１８６−２で得られた（テトラヒドロフラン−３−イル）メタンアミンを用いること以外は実質的に実施例１０と同様に反応を行なって、表題化合物（４４ｍｇ、収率７５％）を白色固体として得た。

^１Ｈ−ＮＭＲ（３００ＭＨｚ，ＣＤＣｌ_３）δ：１．０２（２Ｈ，ｑｄ，Ｊ＝１２．９，３．０Ｈｚ），１．３９−１．６８（４Ｈ，ｍ），１．７１−１．８５（４Ｈ，ｍ），１．８５−２．０９（６Ｈ，ｍ），２．３９−２．６１（５Ｈ，ｍ），３．０９（２Ｈ，ｄ，Ｊ＝７．３Ｈｚ），３．２０−３．３４（４Ｈ，ｍ），３．５２（１Ｈ，ｄｄ，Ｊ＝８．９，５．３ｚ），３．５７（２Ｈ，ｓ），３．７３（１Ｈ，ｄｄ，Ｊ＝１５．９，８．３Ｈｚ），３．８０（１Ｈ，ｄｄ，Ｊ＝８．９，７．３Ｈｚ），３．８８（１Ｈ，ｄｄｄ，Ｊ＝８．３，８．３，５．３Ｈｚ），５．６９（１Ｈ，ｔ，Ｊ＝５．６Ｈｚ），７．４４（２Ｈ，ｄ，Ｊ＝８．３Ｈｚ），７．５７（２Ｈ，ｄ，Ｊ＝８．３Ｈｚ）．

ＬＣ／ＭＳ［条件１］：保持時間２．９９分；ｍ／ｚ５３７．９［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ５８２．１［Ｍ＋ＨＣＯＯ］^―（ＥＳＩ負イオンモード）

Example 186
(1r, 4r) -4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl)- Production of N-[(tetrahydrofuran-3-yl) methyl] cyclohexanecarboxamide (Compound No. 186) Instead of using tetrahydrofurfurylamine, (tetrahydrofuran-3-yl) methanamine obtained in Reference Example 186-2 was used. The reaction was carried out substantially in the same manner as in Example 10 to obtain the title compound (44 mg, yield 75%) as a white solid.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.02 (2H, qd, J = 12.9, 3.0 Hz), 1.39-1.68 (4H, m), 1.71-1. 85 (4H, m), 1.85 to 2.09 (6H, m), 2.39-2.61 (5H, m), 3.09 (2H, d, J = 7.3 Hz), 3. 20-3.34 (4H, m), 3.52 (1H, dd, J = 8.9, 5.3z), 3.57 (2H, s), 3.73 (1H, dd, J = 15) .9, 8.3 Hz), 3.80 (1H, dd, J = 8.9, 7.3 Hz), 3.88 (1H, ddd, J = 8.3, 8.3, 5.3 Hz), 5.69 (1H, t, J = 5.6 Hz), 7.44 (2H, d, J = 8.3 Hz), 7.57 (2H, d, J = 8.3 Hz).

LC / MS [Condition 1]: Retention time 2.99 minutes; m / z 537.9 [M + H] ⁺ (ESI positive ion mode), m / z 582.1 [M + HCOO] ⁻ (ESI negative ion mode)

実施例１８７
（１ｒ，４ｒ）−Ｎ−［（２，２−ジメチル−１，３−ジオキソラン−４−イル）メチル］−４−（｛２−オキソ−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）シクロヘキサンカルボキサミド（化合物番号１８７）の製造
テトラヒドロフルフリルアミンの代わりに、２、２−ジメチル−１、３−ジオキソラン−４−メタンアミンを用いること以外は実質的に実施例１０と同様に反応を行なって、表題化合物（２８ｍｇ、収率６９％）を白色固体として得た。

^１Ｈ−ＮＭＲ（３００ＭＨｚ，ＣＤＣｌ_３）δ：１．０３（２Ｈ，ｑ，Ｊ＝１２．９Ｈｚ），１．３５（３Ｈ，ｓ），１．４３（３Ｈ，ｓ），１．４５−１．６４（３Ｈ，ｍ），１．７２−１．８５（４Ｈ，ｍ），１．８８−１．９９（４Ｈ，ｍ），２．０６（１Ｈ，ｔｔ，Ｊ＝１２．２，３．３Ｈｚ），２．４９−２．６１（４Ｈ，ｍ），３．１０（２Ｈ，ｄ，Ｊ＝７．３Ｈｚ），３．２６（２Ｈ，ｓ），３．３２（１Ｈ，ｄｄｄ，Ｊ＝１３．９，５．９，５．９Ｈｚ），３．５３（１Ｈ，ｄｄｄ，Ｊ＝１４．２，５．９，３．６Ｈｚ），３．５７（２Ｈ，ｓ），３．６１（１Ｈ，ｄｄ，Ｊ＝８．３，６．３Ｈｚ），４．０３（１Ｈ，ｄｄ，Ｊ＝８．４，６．４Ｈｚ），４．２６−４．１８（１Ｈ，ｑｄ，Ｊ＝６．３，３．３Ｈｚ），５．７９（１Ｈ，ｔ，Ｊ＝５．８Ｈｚ），７．４４（２Ｈ，ｄ，Ｊ＝７．９Ｈｚ），７．５７（２Ｈ，ｄ，Ｊ＝７．９Ｈｚ）．

ＬＣ／ＭＳ［条件１］：保持時間３．１９分；ｍ／ｚ５６７．８［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ６１２．１［Ｍ＋ＨＣＯＯ］^―（ＥＳＩ負イオンモード）

Example 187
(1r, 4r) -N-[(2,2-Dimethyl-1,3-dioxolan-4-yl) methyl] -4-({2-oxo-8- [4- (trifluoromethyl) benzyl]- Preparation of 1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl) cyclohexanecarboxamide (Compound No. 187) 2,2-dimethyl-1,3-dioxolane- in place of tetrahydrofurfurylamine The reaction was carried out in substantially the same manner as in Example 10 except that 4-methanamine was used to obtain the title compound (28 mg, yield 69%) as a white solid.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.03 (2H, q, J = 12.9 Hz), 1.35 (3H, s), 1.43 (3H, s), 1.45-1 .64 (3H, m), 1.72-1.85 (4H, m), 1.88-1.99 (4H, m), 2.06 (1H, tt, J = 12.2, 3.. 3 Hz), 2.49-2.61 (4 H, m), 3.10 (2 H, d, J = 7.3 Hz), 3.26 (2 H, s), 3.32 (1 H, ddd, J = 13.9, 5.9, 5.9 Hz), 3.53 (1H, ddd, J = 14.2, 5.9, 3.6 Hz), 3.57 (2H, s), 3.61 (1H , Dd, J = 8.3, 6.3 Hz), 4.03 (1H, dd, J = 8.4, 6.4 Hz), 4.26-4.18 (1H, qd, J = 6.3) , 3.3 Hz), 5 79 (1H, t, J = 5.8Hz), 7.44 (2H, d, J = 7.9Hz), 7.57 (2H, d, J = 7.9Hz).

LC / MS [Condition 1]: Retention time 3.19 minutes; m / z 567.8 [M + H] ⁺ (ESI positive ion mode), m / z 612.1 [M + HCOO] ⁻ (ESI negative ion mode)

実施例１８８
Ｎ−メチル−１−［（１ｒ，４ｒ）−４−（｛２−オキソ−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）シクロヘキサンカルボニル］ピペリジン−４−カルボキサミド（化合物番号１８８）の製造
テトラヒドロフルフリルアミンの代わりに、ピペリジン−４−カルボン酸メチルアミドを用いること以外は実質的に実施例１０と同様に反応を行なって、表題化合物（２２ｍｇ、収率５７％）を白色固体として得た。

^１Ｈ−ＮＭＲ（３００ＭＨｚ，ＣＤＣｌ_３）δ：１．０４（２Ｈ，ｑ，Ｊ＝１２．６Ｈｚ），１．４６−１．７１（５Ｈ，ｍ），１．７２−１．９９（１０Ｈ，ｍ），２．３１（１Ｈ，ｔｔ，Ｊ＝１１．２，３．６Ｈｚ），２．３８−２．６７（６Ｈ，ｍ），２．８２（３Ｈ，ｄ，Ｊ＝５．０Ｈｚ），３．０４（１Ｈ，ｔ，Ｊ＝１１．９Ｈｚ），３．１０（２Ｈ，ｄ，Ｊ＝６．９Ｈｚ），３．２６（２Ｈ，ｓ），３．５７（２Ｈ，ｓ），３．９４（１Ｈ，ｄ，Ｊ＝１２．９Ｈｚ），４．６２（１Ｈ，ｄ，Ｊ＝１２．２Ｈｚ），５．４３−５．５２（１Ｈ，ｍ），７．４４（２Ｈ，ｄ，Ｊ＝８．３Ｈｚ），７．５７（２Ｈ，ｄ，Ｊ＝７．９Ｈｚ）．

ＬＣ／ＭＳ［条件１］：保持時間３．０２分；ｍ／ｚ５７８．９［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ６２３．１［Ｍ＋ＨＣＯＯ］^―（ＥＳＩ負イオンモード）

Example 188
N-methyl-1-[(1r, 4r) -4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decane- Preparation of 3-yl} methyl) cyclohexanecarbonyl] piperidine-4-carboxamide (Compound No. 188) Substantially the same reaction as in Example 10 except that piperidine-4-carboxylic acid methylamide was used instead of tetrahydrofurfurylamine. To give the title compound (22 mg, 57% yield) as a white solid.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.04 (2H, q, J = 12.6 Hz), 1.46-1.71 (5H, m), 1.72-1.99 (10H, m), 2.31 (1H, tt, J = 11.2, 3.6 Hz), 2.38-2.67 (6H, m), 2.82 (3H, d, J = 5.0 Hz), 3.04 (1H, t, J = 11.9 Hz), 3.10 (2H, d, J = 6.9 Hz), 3.26 (2H, s), 3.57 (2H, s), 3. 94 (1H, d, J = 12.9 Hz), 4.62 (1 H, d, J = 12.2 Hz), 5.43-5.52 (1 H, m), 7.44 (2H, d, J = 8.3 Hz), 7.57 (2H, d, J = 7.9 Hz).

LC / MS [Condition 1]: Retention time 3.02 minutes; m / z 578.9 [M + H] ⁺ (ESI positive ion mode), m / z 623.1 [M + HCOO] ⁻ (ESI negative ion mode)

実施例１８９
１−［（１ｒ，４ｒ）−４−（｛２−オキソ−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）シクロヘキサンカルボニル］ピペリジン−４−カルボニトリル（化合物番号１８９）の製造
テトラヒドロフルフリルアミンの代わりに、４−シアノピペリジンを用いること以外は実質的に実施例１０と同様に反応を行なって、表題化合物（２７ｍｇ、収率７１％）を白色固体として得た。

^１Ｈ−ＮＭＲ（３００ＭＨｚ，ＣＤＣｌ_３）δ：１．０４（２Ｈ，ｑ，Ｊ＝１２．９Ｈｚ），１．４５−１．６８（３Ｈ，ｍ），１．７１−２．００（１２Ｈ，ｍ），２．４２（１Ｈ，ｔｔ，Ｊ＝１１．７，３．０Ｈｚ），２．４８−２．６５（４Ｈ，ｍ），２．８９（１Ｈ，ｔｔ，Ｊ＝７．３，４．６Ｈｚ），３．１１（２Ｈ，ｄ，Ｊ＝７．３Ｈｚ），３．２６（２Ｈ，ｓ），３．３８−３．８７（４Ｈ，ｍ），３．５７（２Ｈ，ｓ），７．４４（２Ｈ，ｄ，Ｊ＝８．３Ｈｚ），７．５７（２Ｈ，ｄ，Ｊ＝７．９Ｈｚ）．

ＬＣ／ＭＳ［条件１］：保持時間３．１９分；ｍ／ｚ５４６．８［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ５９１．１［Ｍ＋ＨＣＯＯ］^―（ＥＳＩ負イオンモード）

Example 189
1-[(1r, 4r) -4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} Methyl) cyclohexanecarbonyl] piperidine-4-carbonitrile (Compound No. 189) The title compound was reacted in substantially the same manner as in Example 10 except that 4-cyanopiperidine was used instead of tetrahydrofurfurylamine. (27 mg, 71% yield) was obtained as a white solid.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.04 (2H, q, J = 12.9 Hz), 1.45 to 1.68 (3H, m), 1.71-2.00 (12H, m), 2.42 (1H, tt, J = 11.7, 3.0 Hz), 2.48-2.65 (4H, m), 2.89 (1H, tt, J = 7.3, 4) .6 Hz), 3.11 (2H, d, J = 7.3 Hz), 3.26 (2H, s), 3.38-3.87 (4H, m), 3.57 (2H, s), 7.44 (2H, d, J = 8.3 Hz), 7.57 (2H, d, J = 7.9 Hz).

LC / MS [condition 1]: retention time 3.19 minutes; m / z 546.8 [M + H] ⁺ (ESI positive ion mode), m / z 591.1 [M + HCOO] ⁻ (ESI negative ion mode)

実施例１９０
３−｛［（１ｒ，４ｒ）−４−（４−オキソピペリジン−１−カルボニル）シクロヘキシル］メチル｝−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−２−オン（化合物番号１９０）の製造
テトラヒドロフルフリルアミンの代わりに、ピペリジン−４−オン一水和物一塩酸塩を用いること以外は実質的に実施例１０と同様に反応を行なって、表題化合物（３９ｍｇ、収率９９％）を白色固体として得た。

^１Ｈ−ＮＭＲ（３００ＭＨｚ，ＣＤＣｌ_３）δ：１．０７（２Ｈ，ｑｄ，Ｊ＝１２．６，５．３Ｈｚ），１．５０−１．７０（３Ｈ，ｍ），１．７２−１．８８（６Ｈ，ｍ），１．９５（２Ｈ，ｄ，Ｊ＝１３．２Ｈｚ），２．４１−２．６６（９Ｈ，ｍ），３．１２（２Ｈ，ｄ，Ｊ＝７．３Ｈｚ），３．２７（２Ｈ，ｓ），３．５８（２Ｈ，ｓ），３．９５−３．７２（４Ｈ，ｍ），７．４４（２Ｈ，ｄ，Ｊ＝７．９Ｈｚ），７．５７（２Ｈ，ｄ，Ｊ＝７．９Ｈｚ）．

ＬＣ／ＭＳ［条件１］：保持時間３．０５分；ｍ／ｚ５３５．８７［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ５８０．１［Ｍ＋ＨＣＯＯ］^―（ＥＳＩ負イオンモード）

Example 190
3-{[(1r, 4r) -4- (4-oxopiperidine-1-carbonyl) cyclohexyl] methyl} -8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [ 4.5] Preparation of decan-2-one (Compound No. 190) The reaction was substantially the same as Example 10 except that piperidin-4-one monohydrate monohydrochloride was used instead of tetrahydrofurfurylamine. To give the title compound (39 mg, 99% yield) as a white solid.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.07 (2H, qd, J = 12.6, 5.3 Hz), 1.50-1.70 (3H, m), 1.72-1. 88 (6H, m), 1.95 (2H, d, J = 13.2 Hz), 2.41-2.66 (9H, m), 3.12 (2H, d, J = 7.3 Hz), 3.27 (2H, s), 3.58 (2H, s), 3.95-3.72 (4H, m), 7.44 (2H, d, J = 7.9 Hz), 7.57 ( 2H, d, J = 7.9 Hz).

LC / MS [Condition 1]: Retention time 3.05 minutes; m / z 535.87 [M + H] ⁺ (ESI positive ion mode), m / z 580.1 [M + HCOO] ⁻ (ESI negative ion mode)

実施例１９１
３−｛［（１ｒ，４ｒ）−４−（４−ベンジルピペリジン−１−カルボニル）シクロヘキシル］メチル｝−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−２−オン（化合物番号１９１）の製造
テトラヒドロフルフリルアミンの代わりに、４−ベンジルピペリジンを用いること以外は実質的に実施例１０と同様に反応を行なって、表題化合物（３５ｍｇ、収率７８％）を白色固体として得た。

^１Ｈ−ＮＭＲ（３００ＭＨｚ，ＣＤＣｌ_３）δ：０．９２−１．２３（４Ｈ，ｍ），１．４３−１．８６（１２Ｈ，ｍ），１．９４（２Ｈ，ｄ，Ｊ＝１３．１Ｈｚ），２．３７−２．６５（８Ｈ，ｍ），２．９３（１Ｈ，ｔ，Ｊ＝１２．３Ｈｚ），３．１０（２Ｈ，ｄ，Ｊ＝７．４Ｈｚ），３．２５（２Ｈ，ｓ），３．５７（２Ｈ，ｓ），３．８５（１Ｈ，ｄ，Ｊ＝１２．３Ｈｚ），４．６０（１Ｈ，ｄ，Ｊ＝１３．１Ｈｚ），７．０９−７．３３（５Ｈ，ｍ），７．４４（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ），７．５７（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ）．

ＬＣ／ＭＳ［条件１］：保持時間３．８３分；ｍ／ｚ６１２．０［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ６５６．２［Ｍ＋ＨＣＯＯ］^―（ＥＳＩ負イオンモード）

Example 191
3-{[(1r, 4r) -4- (4-benzylpiperidine-1-carbonyl) cyclohexyl] methyl} -8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [ 4.5] Preparation of decan-2-one (Compound No. 191) The reaction was conducted in substantially the same manner as in Example 10 except that 4-benzylpiperidine was used instead of tetrahydrofurfurylamine to give the title compound (35 mg Yield 78%) as a white solid.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 0.92-1.23 (4H, m), 1.43-1.86 (12H, m), 1.94 (2H, d, J = 13. 1 Hz), 2.37-2.65 (8 H, m), 2.93 (1 H, t, J = 12.3 Hz), 3.10 (2 H, d, J = 7.4 Hz), 3.25 ( 2H, s), 3.57 (2H, s), 3.85 (1H, d, J = 12.3 Hz), 4.60 (1H, d, J = 13.1 Hz), 7.09-7. 33 (5H, m), 7.44 (2H, d, J = 8.2 Hz), 7.57 (2H, d, J = 8.2 Hz).

LC / MS [Condition 1]: Retention time 3.83 minutes; m / z 612.0 [M + H] ⁺ (ESI positive ion mode), m / z 656.2 [M + HCOO] ⁻ (ESI negative ion mode)

実施例１９２
（１ｒ，４ｒ）−４−（｛２−オキソ−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）−Ｎ−（テトラヒドロ−２Ｈ−ピラン−４−イル）シクロヘキサンカルボチオアミド（化合物番号１９２）の製造
実施例８０で得られた、（１ｒ，４ｒ）−４−（｛２−オキソ−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）−Ｎ−（テトラヒドロ−２Ｈ−ピラン−４−イル）シクロヘキサンカルボキサミド（１６ｍｇ、０．０３０ｍｍｏｌ）をトルエン（２．０ｍＬ）に溶解し、ローソン試薬（２５ｍｇ、０．０６１ｍｍｏｌ）を加えて８０℃で３時間かき混ぜた。冷却後、反応混合物に酢酸エチル（５．０ｍＬ）と飽和炭酸水素ナトリウム水溶液（３．０ｍＬ）を加え、有機層を分離した。水層を酢酸エチル（５．０ｍＬ）で抽出した後、合わせた有機層を無水硫酸マグネシウムで乾燥し、減圧下濃縮した。得られた残留物をシリカゲルカラムクロマトグラフィー［充填剤：富士シリシア社製アミンシリカＮＨ−ＤＭ１０２０、展開溶媒：ヘキサン／酢酸エチル＝１／１］にて精製し、表題化合物（９．３ｍｇ、収率５５％）を白色固体として得た。

^１Ｈ−ＮＭＲ（３００ＭＨｚ，ＣＤＣｌ_３）δ：１．０６（２Ｈ，ｑ，Ｊ＝１１．９Ｈｚ），１．５４（２Ｈ，ｑｄ，Ｊ＝１２．３，４．５Ｈｚ），１．６２−２．００（１１Ｈ，ｍ），２．０８（２Ｈ，ｄ，Ｊ＝１０．６Ｈｚ），２．３６（１Ｈ，ｔｔ，Ｊ＝１１．９，４．１Ｈｚ），２．４５−２．６６（４Ｈ，ｍ），３．１０（２Ｈ，ｄ，Ｊ＝７．４Ｈｚ），３．２５（２Ｈ，ｓ），３．５１（２Ｈ，ｄｄｄ，Ｊ＝１１．５，１１．５，２．０Ｈｚ），３．５７（２Ｈ，ｓ），３．９２−４．０４（２Ｈ，ｍ），４．６５（１Ｈ，ｄｔｔ，Ｊ＝１５．１，７．４，４．１Ｈｚ），７．２１−７．２８（１Ｈ，ｍ），７．４４（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ），７．５７（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ）．

ＬＣ／ＭＳ［条件１］：保持時間３．３９分；ｍ／ｚ５５３．８［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ５８８．１［Ｍ＋ＨＣＯＯ］^―（ＥＳＩ負イオンモード）

Example 192
(1r, 4r) -4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl)- Preparation of N- (tetrahydro-2H-pyran-4-yl) cyclohexanecarbothioamide (Compound No. 192) (1r, 4r) -4-({2-oxo-8- [4- (Trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl) -N- (tetrahydro-2H-pyran-4-yl) cyclohexanecarboxamide (16 mg, 0 0.030 mmol) was dissolved in toluene (2.0 mL), Lawesson's reagent (25 mg, 0.061 mmol) was added, and the mixture was stirred at 80 ° C. for 3 hours. After cooling, ethyl acetate (5.0 mL) and saturated aqueous sodium hydrogen carbonate solution (3.0 mL) were added to the reaction mixture, and the organic layer was separated. The aqueous layer was extracted with ethyl acetate (5.0 mL), and the combined organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography [filler: amine silica NH-DM1020 manufactured by Fuji Silysia Co., developing solvent: hexane / ethyl acetate = 1/1] to give the title compound (9.3 mg, yield 55). %) As a white solid.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.06 (2H, q, J = 11.9 Hz), 1.54 (2H, qd, J = 12.3, 4.5 Hz), 1.62- 2.00 (11H, m), 2.08 (2H, d, J = 10.6 Hz), 2.36 (1H, tt, J = 11.9, 4.1 Hz), 2.45-2.66 (4H, m), 3.10 (2H, d, J = 7.4 Hz), 3.25 (2H, s), 3.51 (2H, ddd, J = 11.5, 11.5, 2.. 0 Hz), 3.57 (2H, s), 3.92-4.04 (2H, m), 4.65 (1H, dtt, J = 15.1, 7.4, 4.1 Hz), 7. 21-7.28 (1H, m), 7.44 (2H, d, J = 8.2 Hz), 7.57 (2H, d, J = 8.2 Hz).

LC / MS [Condition 1]: Retention time 3.39 minutes; m / z 553.8 [M + H] ⁺ (ESI positive ion mode), m / z 588.1 [M + HCOO] ⁻ (ESI negative ion mode)

実施例１９３
３−（｛（１ｒ，４ｒ）−４−［４−（６−フルオロベンゾ［ｄ］イソオキサゾール−３−イル）ピペリジン−１−カルボニル］シクロヘキシル｝メチル）−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−２−オン（化合物番号１９３）の製造
テトラヒドロフルフリルアミンの代わりに、６−フルオロ−３−（４−ピペリジニル）−１，２−ベンズイソキサゾール（和光純薬社より購入）を用いること以外は実質的に実施例１０と同様に反応を行なって、表題化合物（２６ｍｇ、収率７０％）を白色固体として得た。

^１Ｈ−ＮＭＲ（３００ＭＨｚ，ＣＤＣｌ_３）δ：１．０７（２Ｈ，ｑ，Ｊ＝１２．３Ｈｚ），１．４９−１．７１（３Ｈ，ｍ），１．７２−２．０３（１０Ｈ，ｍ），２．０７−２．２５（２Ｈ，ｍ），２．５０（１Ｈ，ｔｔ，Ｊ＝１１．９，３．３Ｈｚ），２．５０−２．６４（４Ｈ，ｍ），２．８８（１Ｈ，ｔ，Ｊ＝１２．７Ｈｚ），３．１１（２Ｈ，ｄ，Ｊ＝７．４Ｈｚ），３．２０−３．４１（１Ｈ，ｍ），３．２７（２Ｈ，ｓ），３．３３（１Ｈ，ｔｔ，Ｊ＝１１．１，３．７Ｈｚ），３．５８（２Ｈ，ｓ），４．０５（１Ｈ，ｄ，Ｊ＝１３．５Ｈｚ），４．６７（１Ｈ，ｄ，Ｊ＝１３．１Ｈｚ），７．０８（１Ｈ，ｔｄ，Ｊ＝８．８，２．０Ｈｚ），７．２６（１Ｈ，ｄｄ，Ｊ＝８．２，２．０Ｈｚ），７．４４（２Ｈ，ｄ，Ｊ＝７．８Ｈｚ），７．５７（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ），７．６２（１Ｈ，ｄｄ，Ｊ＝８．６，４．９Ｈｚ）．

ＬＣ／ＭＳ［条件１］：保持時間３．８１分；ｍ／ｚ６５７．０［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ７０１．２［Ｍ＋ＨＣＯＯ］^―（ＥＳＩ負イオンモード）

Example 193
3-({(1r, 4r) -4- [4- (6-Fluorobenzo [d] isoxazol-3-yl) piperidin-1-carbonyl] cyclohexyl} methyl) -8- [4- (trifluoromethyl ) Preparation of benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-2-one (Compound No. 193) Instead of tetrahydrofurfurylamine, 6-fluoro-3- (4-piperidinyl) -1 , 2-Benzisoxazole (purchased from Wako Pure Chemical Industries, Ltd.) was used, and the reaction was carried out in substantially the same manner as in Example 10 to obtain the title compound (26 mg, yield 70%) as a white solid. .

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.07 (2H, q, J = 12.3 Hz), 1.49-1.71 (3H, m), 1.72 to 2.03 (10H, m), 2.07-2.25 (2H, m), 2.50 (1H, tt, J = 11.9, 3.3 Hz), 2.50-2.64 (4H, m), 2. 88 (1H, t, J = 12.7 Hz), 3.11 (2H, d, J = 7.4 Hz), 3.20-3.41 (1H, m), 3.27 (2H, s), 3.33 (1H, tt, J = 11.1, 3.7 Hz), 3.58 (2H, s), 4.05 (1H, d, J = 13.5 Hz), 4.67 (1H, d , J = 13.1 Hz), 7.08 (1H, td, J = 8.8, 2.0 Hz), 7.26 (1H, dd, J = 8.2, 2.0 Hz), 7.44 ( 2H, d, = 7.8Hz), 7.57 (2H, d, J = 8.2Hz), 7.62 (1H, dd, J = 8.6,4.9Hz).

LC / MS [condition 1]: retention time 3.81 minutes; m / z 657.0 [M + H] ⁺ (ESI positive ion mode), m / z 701.2 [M + HCOO] ⁻ (ESI negative ion mode)

実施例１９４
（１ｒ，４ｒ）−Ｎ−［１−（イソキサゾール−５−イル）エチル］−４−（｛２−オキソ−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）シクロヘキサンカルボキサミド（化合物番号１９４）の製造
テトラヒドロフルフリルアミンの代わりに、１−（イソオキサゾール−５−イル）エチルアミン（ＰＣＴ／ＪＰ２００８／０７０６２１記載の方法を用いて合成）を用いること以外は実質的に実施例１０と同様に反応を行なって、表題化合物（７．１ｍｇ、収率３４％）を淡黄色油状物として得た。

^１Ｈ−ＮＭＲ（３００ＭＨｚ，ＣＤＣｌ_３）δ：１．０２（２Ｈ，ｑ，Ｊ＝１２．３Ｈｚ），１．４０−１．６４（３Ｈ，ｍ），１．５４（３Ｈ，ｄ，Ｊ＝７．０Ｈｚ），１．７１−１．９９（８Ｈ，ｍ），２．０５（１Ｈ，ｔｔ，Ｊ＝１２．３，３．３Ｈｚ），２．５０−２．６３（４Ｈ，ｍ），３．０９（２Ｈ，ｄ，Ｊ＝７．４Ｈｚ），３．２５（２Ｈ，ｓ），３．５８（２Ｈ，ｓ），５．３６（１Ｈ，ｑｄ，Ｊ＝７．４，７．４Ｈｚ），５．８４（１Ｈ，ｄ，Ｊ＝８．２Ｈｚ），６．１１（１Ｈ，ｄ，Ｊ＝１．６Ｈｚ），７．４４（２Ｈ，ｄ，Ｊ＝７．８Ｈｚ），７．５７（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ），８．１７（１Ｈ，ｄ，Ｊ＝１．６Ｈｚ）．

ＬＣ／ＭＳ［条件１］：保持時間３．３３分；ｍ／ｚ５４８．８［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ５９３．１［Ｍ＋ＨＣＯＯ］^―（ＥＳＩ負イオンモード）

Example 194
(1r, 4r) -N- [1- (isoxazol-5-yl) ethyl] -4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8- Preparation of diazaspiro [4.5] decan-3-yl} methyl) cyclohexanecarboxamide (Compound No. 194) Instead of tetrahydrofurfurylamine, 1- (isoxazol-5-yl) ethylamine (PCT / JP2008 / 070621) The title compound (7.1 mg, 34% yield) was obtained as a pale yellow oil in substantially the same manner as in Example 10 except that was used.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.02 (2H, q, J = 12.3 Hz), 1.40-1.64 (3H, m), 1.54 (3H, d, J = 7.0 Hz), 1.71-1.99 (8H, m), 2.05 (1H, tt, J = 12.3, 3.3 Hz), 2.50-2.63 (4H, m), 3.09 (2H, d, J = 7.4 Hz), 3.25 (2H, s), 3.58 (2H, s), 5.36 (1H, qd, J = 7.4, 7.4 Hz) ), 5.84 (1H, d, J = 8.2 Hz), 6.11 (1H, d, J = 1.6 Hz), 7.44 (2H, d, J = 7.8 Hz), 7.57 (2H, d, J = 8.2 Hz), 8.17 (1H, d, J = 1.6 Hz).

LC / MS [Condition 1]: Retention time 3.33 minutes; m / z 548.8 [M + H] ⁺ (ESI positive ion mode), m / z 593.1 [M + HCOO] ⁻ (ESI negative ion mode)

参考例１９５
３−イソプロピル−５−（ピペリジン−４−イル）−１，２，４−オキサジアゾール塩酸塩の製造
Ｊｏｕｒｎａｌ ｏｆ Ｍｅｄｉｃｉｎａｌ Ｃｈｅｍｉｓｔｒｙ （２００８， ５１， ５１７２−５１７５） 記載の方法を用いて合成した。

Reference Example 195
Preparation of 3-isopropyl-5- (piperidin-4-yl) -1,2,4-oxadiazole hydrochloride The compound was synthesized using the method described in Journal of Medicinal Chemistry (2008, 51, 5172-5175).

実施例１９５
３−（｛（１ｒ，４ｒ）−４−［４−（３−イソプロピル−１，２，４−オキサジアゾール−５−イル）ピペリジン−１−カルボニル］シクロヘキシル｝メチル）−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−２−オン（化合物番号１９５）の製造
テトラヒドロフルフリルアミンの代わりに、参考例１９５で得られた３−イソプロピル−５−（ピペリジン−４−イル）−１，２，４−オキサジアゾール塩酸塩を用いること以外は実質的に実施例１０と同様に反応を行なって、表題化合物（３９ｍｇ、収率７３％）を白色固体として得た。

^１Ｈ−ＮＭＲ（３００ＭＨｚ，ＣＤＣｌ_３）δ：１．０５（２Ｈ，ｑ，Ｊ＝１１．９Ｈｚ），１．３３（６Ｈ，ｄ，Ｊ＝６．９Ｈｚ），１．４６−１．７０（３Ｈ，ｍ），１．７１−２．００（１０Ｈ，ｍ），２．０３−２．２１（２Ｈ，ｍ），２．４６（１Ｈ，ｔｔ，Ｊ＝１１．９，３．０Ｈｚ），２．４９−２．６２（４Ｈ，ｍ），２．８８（１Ｈ，ｔ，Ｊ＝１１．９Ｈｚ），３．０１−３．２８（５Ｈ，ｍ），３．２６（２Ｈ，ｓ），３．５７（２Ｈ，ｓ），３．９４（１Ｈ，ｄ，Ｊ＝１３．２Ｈｚ），４．５２（１Ｈ，ｄ，Ｊ＝１２．９Ｈｚ），７．４４（２Ｈ，ｄ，Ｊ＝８．３Ｈｚ），７．５８（２Ｈ，ｄ，Ｊ＝７．９Ｈｚ）．

ＬＣ／ＭＳ［条件１］：保持時間３．６４分；ｍ／ｚ６３１．９［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ６７６．２［Ｍ＋ＨＣＯＯ］^―（ＥＳＩ負イオンモード）

Example 195
3-({(1r, 4r) -4- [4- (3-isopropyl-1,2,4-oxadiazol-5-yl) piperidin-1-carbonyl] cyclohexyl} methyl) -8- [4- Preparation of (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-2-one (Compound No. 195) Instead of tetrahydrofurfurylamine, obtained in Reference Example 195 The reaction was carried out in substantially the same manner as in Example 10 except that isopropyl-5- (piperidin-4-yl) -1,2,4-oxadiazole hydrochloride was used, and the title compound (39 mg, yield 73) was obtained. %) As a white solid.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.05 (2H, q, J = 11.9 Hz), 1.33 (6H, d, J = 6.9 Hz), 1.46-1.70 ( 3H, m), 1.71-2.00 (10H, m), 2.03-2.21 (2H, m), 2.46 (1H, tt, J = 11.9, 3.0 Hz), 2.49-2.62 (4H, m), 2.88 (1H, t, J = 11.9 Hz), 3.01-3.28 (5H, m), 3.26 (2H, s), 3.57 (2H, s), 3.94 (1H, d, J = 13.2 Hz), 4.52 (1H, d, J = 12.9 Hz), 7.44 (2H, d, J = 8) .3 Hz), 7.58 (2H, d, J = 7.9 Hz).

LC / MS [Condition 1]: retention time 3.64 minutes; m / z 631.9 [M + H] ⁺ (ESI positive ion mode), m / z 676.2 [M + HCOO] ⁻ (ESI negative ion mode)

実施例１９６
３−｛［（１ｒ，４ｒ）−４−（４−メトキシピペリジン−１−カルボニル）シクロヘキシル］メチル｝−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−２−オン（化合物番号１９６）の製造
テトラヒドロフルフリルアミンの代わりに、４−メトキシピペリジンを用いること以外は実質的に実施例１０と同様に反応を行なって、表題化合物（３４ｍｇ、収率８７％）を白色固体として得た。

^１Ｈ−ＮＭＲ（３００ＭＨｚ，ＣＤＣｌ_３）δ：１．０４（２Ｈ，ｑ，Ｊ＝１２．３Ｈｚ），１．４３−２．００（１５Ｈ，ｍ），２．４５（１Ｈ，ｔｔ，Ｊ＝１１．５，２．９Ｈｚ），２．５１−２．６３（４Ｈ，ｍ），３．１０（２Ｈ，ｄ，Ｊ＝７．４Ｈｚ），３．１８−３．３３（４Ｈ，ｍ），３．３６（３Ｈ，ｓ），３．４３（１Ｈ，ｔｔ，Ｊ＝７．４，３．７Ｈｚ），３．５７（２Ｈ，ｓ），３．６２−３．７４（１Ｈ，ｍ），３．８４−３．９９（１Ｈ，ｍ），７．４４（２Ｈ，ｄ，Ｊ＝７．８Ｈｚ），７．５７（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ）．

ＬＣ／ＭＳ［条件１］：保持時間３．２３分；ｍ／ｚ５５１．８［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ５９６．０［Ｍ＋ＨＣＯＯ］^―（ＥＳＩ負イオンモード）

Example 196
3-{[(1r, 4r) -4- (4-methoxypiperidine-1-carbonyl) cyclohexyl] methyl} -8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [ 4.5] Preparation of decan-2-one (Compound No. 196) The reaction was conducted in substantially the same manner as in Example 10 except that 4-methoxypiperidine was used instead of tetrahydrofurfurylamine to give the title compound (34 mg Yield 87%) as a white solid.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.04 (2H, q, J = 12.3 Hz), 1.43-2.00 (15H, m), 2.45 (1H, tt, J = 11.5, 2.9 Hz), 2.51-2.63 (4H, m), 3.10 (2H, d, J = 7.4 Hz), 3.18-3.33 (4H, m), 3.36 (3H, s), 3.43 (1H, tt, J = 7.4, 3.7 Hz), 3.57 (2H, s), 3.62-3.74 (1H, m), 3.84-3.99 (1H, m), 7.44 (2H, d, J = 7.8 Hz), 7.57 (2H, d, J = 8.2 Hz).

LC / MS [Condition 1]: Retention time 3.23 minutes; m / z 551.8 [M + H] ⁺ (ESI positive ion mode), m / z 596.0 [M + HCOO] ⁻ (ESI negative ion mode)

実施例１９７
３−｛［（１ｒ，４ｒ）−４−（４−メトキシピペリジン−１−カルボニル）シクロヘキシル］メチル｝−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−２−オン塩酸塩（化合物番号１９７）の製造
実施例１９６で得られた、３−｛［（１ｒ，４ｒ）−４−（４−メトキシピペリジン−１−カルボニル）シクロヘキシル］メチル｝−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−２−オン（２．３ｍｇ、０．００４２ｍｍｏｌ）をメタノール（１．０ｍＬ）に溶解し、１０重量％塩化水素−メタノール溶液を加え、室温で１時間かき混ぜた。その後、反応混合物を減圧下濃縮し、表題化合物（２．３ｍｇ、９２％）を白色固体として得た。

^１Ｈ−ＮＭＲ（３００ＭＨｚ，ＣＤＣｌ_３）δ：１．０３（２Ｈ，ｑ，Ｊ＝１１．５Ｈｚ），１．４３−１．９２（１１Ｈ，ｍ），２．０５（２Ｈ，ｄ，Ｊ＝１３．５Ｈｚ），２．４４（１Ｈ，ｔ，Ｊ＝１１．９Ｈｚ），２．７５（２Ｈ，ｔ，Ｊ＝１２．７Ｈｚ），３．０１−３．５０（１４Ｈ，ｍ），３．５５−３．９７（２Ｈ，ｍ），４．１８（２Ｈ，ｓ），７．７３（２Ｈ，ｄ，Ｊ＝７．８Ｈｚ），７．８５（２Ｈ，ｄ，Ｊ＝７．８Ｈｚ），１３．１８（１Ｈ，ｂｒ ｓ）．

ＬＣ／ＭＳ［条件１］：保持時間３．３６分；ｍ／ｚ５５１．９［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ５８６．２［Ｍ＋Ｃｌ］^―（ＥＳＩ負イオンモード）

Example 197
3-{[(1r, 4r) -4- (4-methoxypiperidine-1-carbonyl) cyclohexyl] methyl} -8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [ 4.5] Preparation of decan-2-one hydrochloride (Compound No. 197) 3-{[(1r, 4r) -4- (4-methoxypiperidine-1-carbonyl) cyclohexyl] obtained in Example 196 Methyl} -8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-2-one (2.3 mg, 0.0042 mmol) in methanol (1.0 mL) 10 wt% hydrogen chloride-methanol solution was added and stirred at room temperature for 1 hour. The reaction mixture was then concentrated under reduced pressure to give the title compound (2.3 mg, 92%) as a white solid.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.03 (2H, q, J = 11.5 Hz), 1.43-1.92 (11H, m), 2.05 (2H, d, J = 13.5 Hz), 2.44 (1 H, t, J = 11.9 Hz), 2.75 (2 H, t, J = 12.7 Hz), 3.01-3.50 (14 H, m), 3. 55-3.97 (2H, m), 4.18 (2H, s), 7.73 (2H, d, J = 7.8 Hz), 7.85 (2H, d, J = 7.8 Hz), 13.18 (1H, br s).

LC / MS [Condition 1]: Retention time 3.36 minutes; m / z 551.9 [M + H] ⁺ (ESI positive ion mode), m / z 586.2 [M + Cl] ⁻ (ESI negative ion mode)

参考例１９８−１
４−メチル−３−（トリフルオロメチル）安息香酸メチルの製造
４−メチル−３−（トリフルオロメチル）安息香酸（市販）（１．３ｇ、６．２ｍｍｏｌ）をメタノール（６．０ｍＬ）に溶解し、濃硫酸（０．５ｍＬ）を加え、６０℃で１０時間かき混ぜた。反応混合物を室温まで冷却した後、水（１５ｍＬ）と酢酸エチル（１５ｍＬ）を加え、有機層を分離した。得られた有機層を飽和炭酸水素ナトリウム水溶液、飽和食塩水と水で１回ずつ洗浄した。得られた有機層を硫酸マグネシウムで乾燥した後、減圧下濃縮し、表題化合物（１．４ｇ、収率定量的）を無色液体として得た。

^１Ｈ−ＮＭＲ（３００ＭＨｚ，ＣＤＣｌ_３）δ：２．５６−２．５３（３Ｈ，ｍ），３．９４（３Ｈ，ｓ），７．３７（１Ｈ，ｄ，Ｊ＝７．８Ｈｚ），８．０９（１Ｈ，ｄ，Ｊ＝７．８Ｈｚ），８．２８（１Ｈ，ｓ）．

Reference Example 198-1
Preparation of methyl 4-methyl-3- (trifluoromethyl) benzoate 4-methyl-3- (trifluoromethyl) benzoic acid (commercially available) (1.3 g, 6.2 mmol) dissolved in methanol (6.0 mL) Concentrated sulfuric acid (0.5 mL) was added and stirred at 60 ° C. for 10 hours. After the reaction mixture was cooled to room temperature, water (15 mL) and ethyl acetate (15 mL) were added, and the organic layer was separated. The obtained organic layer was washed once with a saturated aqueous sodium hydrogen carbonate solution, saturated brine and water. The obtained organic layer was dried over magnesium sulfate and concentrated under reduced pressure to give the title compound (1.4 g, quantitative yield) as a colorless liquid.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 2.56-2.53 (3H, m), 3.94 (3H, s), 7.37 (1H, d, J = 7.8 Hz), 8 .09 (1H, d, J = 7.8 Hz), 8.28 (1H, s).

参考例１９８−２
３−［４−（メトキシカルボニル）−２−（トリフルオロメチル）ベンジル］−２−オキソ−１−オキサ−３，８−ジアザスピロ［４．５］デカン−８−カルボン酸ｔ−ブチルの製造
参考例１９８−１で得られた４−メチル−３−（トリフルオロメチル）安息香酸メチル（１１０ｍｇ、０．５０ｍｍｏｌ）をクロロホルム（２．０ｍＬ）に溶解し、８０℃まで加熱した後、Ｎ−ブロモスクシンイミド（１７９ｍｇ、１．０ｍｍｏｌ）とアゾビスイソブチロニトリル（１７ｍｇ、０．１０ｍｍｏｌ）を加え、８０℃で３時間かき混ぜた。反応混合物を室温まで冷却した後、水（５．０ｍＬ）とクロロホルム（５．０ｍＬ）を加え、有機層を分離した。有機層を無水硫酸マグネシウムで乾燥した後、減圧下濃縮した。得られた残留物をシリカゲルカラムクロマトグラフィー［充填剤：Ｍｅｒｃｋ ＧＭＢＨ製シリカゲル６０（０．０４０−０．０６３ｍｍ）、展開溶媒：ヘキサン／酢酸エチル＝１０／１］にて精製し、淡黄色油状物（１５６ｍｇ）を得た。
参考例１１１−１で得られた２−オキソ−１−オキサ−３，８−ジアザスピロ［４．５］デカン−８−カルボン酸ｔ−ブチル（１３０ｍｇ、０．５０ｍｍｏｌ）をＮ，Ｎ−ジメチルホルムアミド（２．０ｍＬ）に溶かし、ナトリウムｔ−ブトキシド（５３ｍｇ、０．５５ｍｍｏｌ）を加えて３０分撹拌した後、先に得られた淡黄色油状物（１５６ｍｇ）のＮ，Ｎ−ジメチルホルムアミド（２．０ｍＬ）溶液を加え、３時間かき混ぜた。その後、水（１０ｍＬ）と酢酸エチル（１０ｍＬ）を加えた後、有機層を分離した。得られた有機層を飽和食塩水で２回洗浄し、無水硫酸マグネシウムで乾燥した後、減圧下濃縮した。得られた残留物をシリカゲルカラムクロマトグラフィー［充填剤：Ｍｅｒｃｋ ＧＭＢＨ製シリカゲル６０（０．０４０−０．０６３ｍｍ）、展開溶媒：ヘキサン／酢酸エチル＝３／１］にて精製することにより、表題化合物（１２０ｍｇ、収率４９％）を無色油状物として得た。

^１Ｈ−ＮＭＲ（３００ＭＨｚ，ＣＤＣｌ_３）δ：１．４５（９Ｈ，ｓ），１．５２−１．７０（２Ｈ，ｍ），１．８１−１．９３（２Ｈ，ｍ），３．１６（２Ｈ，ｓ），３．２２−３．３５（２Ｈ，ｍ），３．７５−３．８９（２Ｈ，ｍ），３．９６（３Ｈ，ｓ），４．６９（２Ｈ，ｓ），７．６１（１Ｈ，ｄ，Ｊ＝８．２Ｈｚ），８．２３（１Ｈ，ｄ，Ｊ＝８．２Ｈｚ），８．３５（１Ｈ，ｓ）．

ＬＣ／ＭＳ［条件１］：保持時間３．３６分；ｍ／ｚ４９４．８［Ｍ＋Ｎａ］^＋（ＥＳＩ正イオンモード）

Reference Example 198-2
Reference for production of t-butyl 3- [4- (methoxycarbonyl) -2- (trifluoromethyl) benzyl] -2-oxo-1-oxa-3,8-diazaspiro [4.5] decane-8-carboxylate Methyl 4-methyl-3- (trifluoromethyl) benzoate (110 mg, 0.50 mmol) obtained in Example 198-1 was dissolved in chloroform (2.0 mL), heated to 80 ° C., and then N-bromo. Succinimide (179 mg, 1.0 mmol) and azobisisobutyronitrile (17 mg, 0.10 mmol) were added, and the mixture was stirred at 80 ° C. for 3 hours. After the reaction mixture was cooled to room temperature, water (5.0 mL) and chloroform (5.0 mL) were added, and the organic layer was separated. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography [filler: silica gel 60 (0.040-0.063 mm) manufactured by Merck GMBH, developing solvent: hexane / ethyl acetate = 10/1], and pale yellow oily substance (156 mg) was obtained.
2-Oxo-1-oxa-3,8-diazaspiro [4.5] decane-8-carboxylate t-butyl (130 mg, 0.50 mmol) obtained in Reference Example 111-1 was replaced with N, N-dimethylformamide. (2.0 mL), sodium t-butoxide (53 mg, 0.55 mmol) was added, and the mixture was stirred for 30 minutes, and then the pale yellow oil (156 mg) obtained above, N, N-dimethylformamide (2. 0 mL) solution was added and stirred for 3 hours. Then, water (10 mL) and ethyl acetate (10 mL) were added, and then the organic layer was separated. The obtained organic layer was washed twice with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue is purified by silica gel column chromatography [filler: silica gel 60 (0.040-0.063 mm) manufactured by Merck GMBH, developing solvent: hexane / ethyl acetate = 3/1] to give the title compound. (120 mg, 49% yield) was obtained as a colorless oil.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.45 (9H, s), 1.52-1.70 (2H, m), 1.81-1.93 (2H, m), 3.16 (2H, s), 3.22-3.35 (2H, m), 3.75-3.89 (2H, m), 3.96 (3H, s), 4.69 (2H, s), 7.61 (1H, d, J = 8.2 Hz), 8.23 (1H, d, J = 8.2 Hz), 8.35 (1H, s).

LC / MS [Condition 1]: Retention time 3.36 minutes; m / z 494.8 [M + Na] ⁺ (ESI positive ion mode)

参考例１９８−３
４−［（２−オキソ−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル）メチル］−３−（トリフルオロメチル）安息香酸メチル塩酸塩の製造
参考例１９８−２で得られた３−［４−（メトキシカルボニル）−２−（トリフルオロメチル）ベンジル］−２−オキソ−１−オキサ−３，８−ジアザスピロ［４．５］デカン−８−カルボン酸ｔ−ブチル（１２０ｍｇ、０．０２５ｍｍｏｌ）を１，４−ジオキサン（２．０ｍＬ）、メタノール（０．５０ｍＬ）に溶解し、４Ｍ塩化水素−ジオキサン溶液（１．０ｍＬ）を加えて室温で１２時間撹拌した。反応混合物を減圧下濃縮した後、残留物に酢酸エチルを加えて再度減圧下濃縮乾固し、表題化合物（１００ｍｇ、収率９９％）を白色固体として得た。

ＬＣ／ＭＳ［条件１］：保持時間２．３３分；ｍ／ｚ３７３．０［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）

Reference Example 198-3
4-[(2-oxo-1-oxa-3,8-diazaspiro [4.5] decan-3-yl) methyl] -3- (trifluoromethyl) benzoic acid methyl hydrochloride Reference Example 198-2 3- [4- (methoxycarbonyl) -2- (trifluoromethyl) benzyl] -2-oxo-1-oxa-3,8-diazaspiro [4.5] decane-8-carboxylic acid t- Butyl (120 mg, 0.025 mmol) was dissolved in 1,4-dioxane (2.0 mL) and methanol (0.50 mL), 4M hydrogen chloride-dioxane solution (1.0 mL) was added, and the mixture was stirred at room temperature for 12 hr. . The reaction mixture was concentrated under reduced pressure, ethyl acetate was added to the residue, and the mixture was concentrated again to dryness under reduced pressure to give the title compound (100 mg, yield 99%) as a white solid.

LC / MS [Condition 1]: Retention time 2.33 minutes; m / z 373.0 [M + H] ⁺ (ESI positive ion mode)

参考例１９８−４
４−（｛２−オキソ−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）−３−（トリフルオロメチル）安息香酸メチルの製造
参考例１９８−３で得られた４−［（２−オキソ−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル）メチル］−３−（トリフルオロメチル）安息香酸メチル塩酸塩（１００ｍｇ、０．２４ｍｍｏｌ）をＮ，Ｎ−ジメチルホルムアミド（２．０ｍＬ）に懸濁し、トリエチルアミン（０．１０ｍＬ、０．７３ｍｍｏｌ）と４−（トリフルオロメチル）ベンジルブロミド（６４ｍｇ、０．２７ｍｍｏｌ）を加え、室温で７時間かき混ぜた。その後、反応混合物に水（１０ｍＬ）と酢酸エチル（１０ｍＬ）を加えた後、有機層を分離し、飽和食塩水で洗浄した。有機層を無水硫酸ナトリウムで乾燥した後、減圧下濃縮した。得られた残留物をシリカゲルカラムクロマトグラフィー［充填剤：富士シリシア社製アミンシリカＮＨ−ＤＭ１０２０、展開溶媒：ヘキサン／酢酸エチル＝３／１］にて精製し、表題化合物（１００ｍｇ、収率８５％）を無色油状物として得た。

^１Ｈ−ＮＭＲ（３００ＭＨｚ，ＣＤＣｌ_３）δ：１．６７−１．８５（２Ｈ，ｍ），１．８９−２．００（２Ｈ，ｍ），２．４７−２．６６（４Ｈ，ｍ），３．１７（２Ｈ，ｓ），３．５８（２Ｈ，ｓ），３．９６（３Ｈ，ｓ），４．６８（２Ｈ，ｓ），７．６９−７．３９（５Ｈ，ｍ），８．２１（１Ｈ，ｄ，Ｊ＝７．８Ｈｚ），８．３５（１Ｈ，ｓ）．

ＬＣ／ＭＳ［条件１］：保持時間３．５６分；ｍ／ｚ５３０．９［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）

Reference Example 198-4
4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl) -3- (trifluoromethyl ) Preparation of methyl benzoate 4-[(2-oxo-1-oxa-3,8-diazaspiro [4.5] decan-3-yl) methyl] -3- (tri Fluoromethyl) benzoic acid methyl hydrochloride (100 mg, 0.24 mmol) was suspended in N, N-dimethylformamide (2.0 mL), triethylamine (0.10 mL, 0.73 mmol) and 4- (trifluoromethyl) benzyl. Bromide (64 mg, 0.27 mmol) was added and stirred at room temperature for 7 hours. Thereafter, water (10 mL) and ethyl acetate (10 mL) were added to the reaction mixture, and then the organic layer was separated and washed with saturated brine. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography [filler: amine silica NH-DM1020 manufactured by Fuji Silysia Ltd., developing solvent: hexane / ethyl acetate = 3/1] to give the title compound (100 mg, yield 85%). Was obtained as a colorless oil.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.67-1.85 (2H, m), 1.89-2.00 (2H, m), 2.47-2.66 (4H, m) 3.17 (2H, s), 3.58 (2H, s), 3.96 (3H, s), 4.68 (2H, s), 7.69-7.39 (5H, m), 8.21 (1H, d, J = 7.8 Hz), 8.35 (1H, s).

LC / MS [Condition 1]: Retention time 3.56 minutes; m / z 530.9 [M + H] ⁺ (ESI positive ion mode)

参考例１９８−５
４−（｛２−オキソ−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）−３−（トリフルオロメチル）安息香酸の製造
参考例１９８−４で得られた４−（｛２−オキソ−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）−３−（トリフルオロメチル）安息香酸メチル（７１ｍｇ、０．１３ｍｍｏｌ）をメタノール（２．０ｍＬ）に懸濁し、５０℃に加熱して溶かした後、１Ｍ水酸化ナトリウム水溶液（０．６８ｍＬ、０．６８ｍｍｏｌ）を加え、５０℃で１時間かき混ぜた。反応終了後、反応混合物を室温まで冷却した後、減圧下メタノールを留去した。得られた残留物に水を加え、１Ｍ塩酸（０．６８ｍＬ、０．６８ｍｍｏｌ）を滴下した。析出した白色固体をろ過後、減圧下乾固し、表題化合物（６０ｍｇ、収率８６％）を白色固体として得た。

^１Ｈ−ＮＭＲ（３００ＭＨｚ，ＣＤＣｌ_３）δ：１．６０−２．０８（４Ｈ，ｍ），２．６７−２．８１（２Ｈ，ｍ），２．９４−３．０７（４Ｈ，ｍ），３．８８（２Ｈ，ｓ），４．６７（２Ｈ，ｓ），７．４８−７．５５（３Ｈ，ｍ），７．６２（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ），８．２１（１Ｈ，ｄ，Ｊ＝８．２Ｈｚ），８．３７（１Ｈ，ｓ）．

ＬＣ／ＭＳ［条件１］：保持時間３．３６分；ｍ／ｚ５１６．９［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ５１５．１［Ｍ−Ｈ］^―（ＥＳＩ負イオンモード）

Reference Example 198-5
4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl) -3- (trifluoromethyl ) Preparation of benzoic acid 4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decane obtained in Reference Example 198-4 After suspending methyl-3-yl} methyl) -3- (trifluoromethyl) benzoate (71 mg, 0.13 mmol) in methanol (2.0 mL) and heating to 50 ° C., 1M sodium hydroxide was dissolved. Aqueous solution (0.68 mL, 0.68 mmol) was added and stirred at 50 ° C. for 1 hour. After completion of the reaction, the reaction mixture was cooled to room temperature, and methanol was distilled off under reduced pressure. Water was added to the obtained residue, and 1M hydrochloric acid (0.68 mL, 0.68 mmol) was added dropwise. The precipitated white solid was filtered and then dried under reduced pressure to obtain the title compound (60 mg, yield 86%) as a white solid.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.60-2.08 (4H, m), 2.67-2.81 (2H, m), 2.94-3.07 (4H, m) 3.88 (2H, s), 4.67 (2H, s), 7.48-7.55 (3H, m), 7.62 (2H, d, J = 8.2 Hz), 8.21. (1H, d, J = 8.2 Hz), 8.37 (1H, s).

LC / MS [Condition 1]: Retention time 3.36 minutes; m / z 516.9 [M + H] ⁺ (ESI positive ion mode), m / z 515.1 [M−H] ⁻ (ESI negative ion mode)

実施例１９８
４−［４−（｛２−オキソ−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）−３−（トリフルオロメチル）ベンズアミド］ピペリジン−１−カルボン酸メチル（化合物番号１９８）の製造
参考例１９８−５で得られた４−（｛２−オキソ−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）−３−（トリフルオロメチル）安息香酸（２５ｍｇ、０．０４８ｍｍｏｌ）、参考例１３５で得られた４−アミノピペリジン−１−カルボン酸メチル塩酸塩（１１ｍｇ、０．０７３ｍｍｏｌ）、トリエチルアミン（９．９μＬ、０．０７３ｍｍｏｌ）と１−ヒドロキシベンゾトリアゾール（６．４ｍｇ、０．０４８ｍｍｏｌ）をクロロホルム（１．０ｍＬ）に溶解した後、１−エチル−３−（３−ジメチルアミノプロピル）カルボジイミド塩酸塩（１４ｍｇ、０．０７３ｍｍｏｌ）を加えて、室温で６０時間かき混ぜた。その後、反応混合物に水（２．０ｍＬ）を加えて有機層を分離し、無水硫酸ナトリウムで乾燥した後、減圧下濃縮乾固した。得られた残留物をシリカゲルカラムクロマトグラフィー［充填剤：富士シリシア社製ＮＨ−ＤＭ１０２０、展開溶媒：ヘキサン／酢酸エチル＝１／１］にて精製し、表題化合物（２５ｍｇ、収率８０％）を淡黄色固体として得た。

^１Ｈ−ＮＭＲ（３００ＭＨｚ，ＣＤＣｌ_３）δ：１．３７−１．５２（２Ｈ，ｍ），１．６８−１．８１（２Ｈ，ｍ），１．８７−１．９８（２Ｈ，ｍ），２．００−２．１１（２Ｈ，ｍ），２．４８−２．５９（４Ｈ，ｍ），２．９７（２Ｈ，ｔ，Ｊ＝１２．６Ｈｚ），３．１５（２Ｈ，ｓ），３．５６（２Ｈ，ｓ），３．７１（３Ｈ，ｓ），４．０７−４．２５（３Ｈ，ｍ），４．６７（２Ｈ，ｓ），６．０９（１Ｈ，ｄ，Ｊ＝７．６Ｈｚ），７．４３（２Ｈ，ｄ，Ｊ＝７．９Ｈｚ），７．５４−７．６２（３Ｈ，ｍ），７．９１（１Ｈ，ｄ，Ｊ＝８．３Ｈｚ），８．０８（１Ｈ，ｓ）．

ＬＣ／ＭＳ［条件１］：保持時間３．４１分；ｍ／ｚ６５７．１［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ６５５．３［Ｍ−Ｈ］^―（ＥＳＩ負イオンモード）

Example 198
4- [4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl) -3- ( 4-({2-oxo-8- [4- (trifluoromethyl) benzyl]-] obtained in Reference Example 198-5 of Preparation of Methyl (trifluoromethyl) benzamide] piperidine-1-carboxylate (Compound No. 198) 1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl) -3- (trifluoromethyl) benzoic acid (25 mg, 0.048 mmol), 4-amino obtained in Reference Example 135 Piperidine-1-carboxylic acid methyl hydrochloride (11 mg, 0.073 mmol), triethylamine (9.9 μL, 0.073 mmol) and 1-hydroxybenzotriazole (6.4 mg) Was dissolved 0.048 mmol) in chloroform (1.0 mL), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (14 mg, 0.073 mmol) was added and stirred at room temperature for 60 hours. Thereafter, water (2.0 mL) was added to the reaction mixture, the organic layer was separated, dried over anhydrous sodium sulfate, and then concentrated to dryness under reduced pressure. The obtained residue was purified by silica gel column chromatography [filler: NH-DM1020 manufactured by Fuji Silysia Ltd., developing solvent: hexane / ethyl acetate = 1/1] to give the title compound (25 mg, yield 80%). Obtained as a pale yellow solid.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.37-1.52 (2H, m), 1.68-1.81 (2H, m), 1.87-1.98 (2H, m) , 2.00-2.11 (2H, m), 2.48-2.59 (4H, m), 2.97 (2H, t, J = 12.6 Hz), 3.15 (2H, s) , 3.56 (2H, s), 3.71 (3H, s), 4.07-4.25 (3H, m), 4.67 (2H, s), 6.09 (1H, d, J = 7.6 Hz), 7.43 (2H, d, J = 7.9 Hz), 7.54-7.62 (3H, m), 7.91 (1H, d, J = 8.3 Hz), 8 .08 (1H, s).

LC / MS [Condition 1]: Retention time 3.41 min; m / z 657.1 [M + H] ⁺ (ESI positive ion mode), m / z 655.3 [M−H] ⁻ (ESI negative ion mode)

実施例１９９
３−［４−（４−ベンゾイルピペリジン−１−カルボニル）−２−（トリフルオロメチル）ベンジル］−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−２−オン（化合物番号１９９）の製造
４−アミノピペリジン−１−カルボン酸メチル塩酸塩の代わりに、４−ベンゾイルピペリジン塩酸塩を用いること以外は実質的に実施例１９８と同様に反応を行なって、表題化合物（９．０ｍｇ、収率８４％）を無色油状物として得た。

^１Ｈ−ＮＭＲ（３００ＭＨｚ，ＣＤＣｌ_３）δ：１．６３−２．１３（８Ｈ，ｍ），２．４２−２．６４（４Ｈ，ｍ），３．０３−３．２６（２Ｈ，ｍ），３．１７（２Ｈ，ｓ），３．４３−３．８８（４Ｈ，ｍ），４．５２−４．７２（１Ｈ，ｍ），４．６５（２Ｈ，ｓ），７．３８−７．５３（４Ｈ，ｍ），７．５３−７．６４（５Ｈ，ｍ），７．７４（１Ｈ，ｓ），７．９８−７．９１（２Ｈ，ｍ）．

ＬＣ／ＭＳ［条件１］：保持時間３．７１分；ｍ／ｚ６８８．０［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ７３２．３［Ｍ＋ＨＣＯＯ］^―（ＥＳＩ負イオンモード）

Example 199
3- [4- (4-Benzoylpiperidine-1-carbonyl) -2- (trifluoromethyl) benzyl] -8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4 .5] Production of decan-2-one (Compound No. 199) Substantially the same as Example 198, except that 4-benzoylpiperidine hydrochloride was used in place of methyl 4-aminopiperidine-1-carboxylate. The title compound (9.0 mg, 84% yield) was obtained as a colorless oil.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.63 to 2.13 (8H, m), 2.42-2.64 (4H, m), 3.03-3.26 (2H, m) 3.17 (2H, s), 3.43-3.88 (4H, m), 4.52-4.72 (1H, m), 4.65 (2H, s), 7.38-7. .53 (4H, m), 7.53-7.64 (5H, m), 7.74 (1H, s), 7.98-7.91 (2H, m).

LC / MS [Condition 1]: Retention time 3.71 min; m / z 688.0 [M + H] ⁺ (ESI positive ion mode), m / z 732.3 [M + HCOO] ⁻ (ESI negative ion mode)

実施例２００
Ｎ−（ベンゾ［ｄ］［１，３］ジオキソール−５−イルメチル）−４−（｛２−オキソ−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）−３−（トリフルオロメチル）ベンズアミド（化合物番号２００）の製造
４−アミノピペリジン−１−カルボン酸メチル塩酸塩とトリエチルアミンの代わりに、ピペロニルアミンを用いること以外は実質的に実施例１９８と同様に反応を行なって、表題化合物（９．５ｍｇ、収率９３％）を無色油状物として得た。

^１Ｈ−ＮＭＲ（３００ＭＨｚ，ＣＤＣｌ_３）δ：１．６８−１．８０（２Ｈ，ｍ），１．８７−１．９８（２Ｈ，ｍ），２．４８−２．６５（４Ｈ，ｍ），３．１４（２Ｈ，ｓ），３．５６（２Ｈ，ｓ），４．５６（２Ｈ，ｄ，Ｊ＝５．３Ｈｚ），４．６６（２Ｈ，ｓ），５．９６（２Ｈ，ｓ），６．３８（１Ｈ，ｔ，Ｊ＝５．３Ｈｚ），６．７２−６．９７（３Ｈ，ｍ），７．４２（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ），７．５４−７．６５（３Ｈ，ｍ），７．９３（１Ｈ，ｄ，Ｊ＝８．２Ｈｚ），８．１１（１Ｈ，ｓ）．

ＬＣ／ＭＳ［条件１］：保持時間３．６１分；ｍ／ｚ６５０．０［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ６４８．２［Ｍ−Ｈ］^―（ＥＳＩ負イオンモード）

Example 200
N- (benzo [d] [1,3] dioxol-5-ylmethyl) -4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [ 4.5] Preparation of decan-3-yl} methyl) -3- (trifluoromethyl) benzamide (Compound No. 200) Use piperonylamine instead of methyl 4-aminopiperidine-1-carboxylate and triethylamine Except for the above, the reaction was carried out in substantially the same manner as in Example 198 to give the title compound (9.5 mg, yield 93%) as a colorless oil.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.68-1.80 (2H, m), 1.87-1.98 (2H, m), 2.48-2.65 (4H, m) 3.14 (2H, s), 3.56 (2H, s), 4.56 (2H, d, J = 5.3 Hz), 4.66 (2H, s), 5.96 (2H, s) ), 6.38 (1H, t, J = 5.3 Hz), 6.72-6.97 (3H, m), 7.42 (2H, d, J = 8.2 Hz), 7.54-7 .65 (3H, m), 7.93 (1H, d, J = 8.2 Hz), 8.11 (1H, s).

LC / MS [Condition 1]: Retention time 3.61 min; m / z 650.0 [M + H] ⁺ (ESI positive ion mode), m / z 648.2 [M−H] ⁻ (ESI negative ion mode)

実施例２０１
４−（｛２−オキソ−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）−Ｎ−［（テトラヒドロフラン−２−イル）メチル］−３−（トリフルオロメチル）ベンズアミド（化合物番号２０１）の製造
４−アミノピペリジン−１−カルボン酸メチル塩酸塩とトリエチルアミンの代わりに、テトラヒドロフルフリルアミンを用いること以外は実質的に実施例１９８と同様に反応を行なって、表題化合物（２．６ｍｇ、収率２８％）を無色油状物として得た。

^１Ｈ−ＮＭＲ（３００ＭＨｚ，ＣＤＣｌ_３）δ：１．５１−１．８１（３Ｈ，ｍ），１．８７−２．１３（５Ｈ，ｍ），２．４６−２．６４（４Ｈ，ｍ），３．１４（２Ｈ，ｓ），３．３１（１Ｈ，ｄｄｄ，Ｊ＝１３．９，７．９，４．６Ｈｚ），３．５６（２Ｈ，ｓ），３．７４−３．９７（３Ｈ，ｍ），４．０７（１Ｈ，ｑｄ，Ｊ＝７．３，３．０Ｈｚ），４．６７（２Ｈ，ｓ），６．５５（１Ｈ，ｔ，Ｊ＝５．３Ｈｚ），７．４３（２Ｈ，ｄ，Ｊ＝７．９Ｈｚ），７．５４−７．６２（３Ｈ，ｍ），７．９３（１Ｈ，ｄｄ，Ｊ＝７．９，２．０Ｈｚ），８．１１（１Ｈ，ｄ，Ｊ＝２．０Ｈｚ）．

ＬＣ／ＭＳ［条件１］：保持時間３．３７分；ｍ／ｚ６００．０［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ５９８．２［Ｍ−Ｈ］^―（ＥＳＩ負イオンモード）

Example 201
4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl) -N-[(tetrahydrofuran- Preparation of 2-yl) methyl] -3- (trifluoromethyl) benzamide (Compound No. 201) Substantially except that 4-aminopiperidine-1-carboxylic acid methyl hydrochloride and triethylamine are used instead of tetrahydrofurfurylamine Was reacted in the same manner as in Example 198 to give the title compound (2.6 mg, yield 28%) as a colorless oil.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.51-1.81 (3H, m), 1.87-2.13 (5H, m), 2.46-2.64 (4H, m) , 3.14 (2H, s), 3.31 (1H, ddd, J = 13.9, 7.9, 4.6 Hz), 3.56 (2H, s), 3.74-3.97 ( 3H, m), 4.07 (1H, qd, J = 7.3, 3.0 Hz), 4.67 (2H, s), 6.55 (1H, t, J = 5.3 Hz), 7. 43 (2H, d, J = 7.9 Hz), 7.54-7.62 (3H, m), 7.93 (1H, dd, J = 7.9, 2.0 Hz), 8.11 (1H , D, J = 2.0 Hz).

LC / MS [Condition 1]: Retention time 3.37 minutes; m / z 600.0 [M + H] ⁺ (ESI positive ion mode), m / z 598.2 [M−H] ⁻ (ESI negative ion mode)

実施例２０２
４−［３−（｛２−オキソ−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）ベンズアミド）ピペリジン−１−カルボン酸メチル（化合物番号２０２）の製造
参考例１０８−３で得られた３−（｛２−オキソ−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）安息香酸（２８ｍｇ、０．０６２ｍｍｏｌ）、参考例１３５で得られた４−アミノピペリジン−１−カルボン酸メチル塩酸塩（１５ｍｇ、０．０７５ｍｍｏｌ）、トリエチルアミン（１３μＬ、０．０９４ｍｍｏｌ）と１−ヒドロキシベンゾトリアゾール（８．４ｍｇ、０．０６２ｍｍｏｌ）をクロロホルム（１．０ｍＬ）に溶解した後、１−エチル−３−（３−ジメチルアミノプロピル）カルボジイミド塩酸塩（１８ｍｇ、０．０９４ｍｍｏｌ）を加えて、室温で３６時間かき混ぜた。反応終了後、水（３．０ｍＬ）を加えて有機層を分離し、無水硫酸ナトリウムで乾燥した後、減圧下濃縮乾固した。得られた残留物をシリカゲルカラムクロマトグラフィー［充填剤：富士シリシア社製ＮＨ−ＤＭ１０２０、展開溶媒：ヘキサン／酢酸エチル＝１／１］にて精製し、表題化合物（３１ｍｇ、収率８３％）を白色固体として得た。

^１Ｈ−ＮＭＲ（３００ＭＨｚ，ＣＤＣｌ_３）δ：１．３６−１．５３（２Ｈ，ｍ），１．６７−１．８１（２Ｈ，ｍ），１．８６−１．９９（２Ｈ，ｍ），１．９９−２．１２（２Ｈ，ｍ），２．４７−２．６１（４Ｈ，ｍ），２．９７（２Ｈ，ｔ，Ｊ＝１１．９Ｈｚ），３．１４（２Ｈ，ｓ），３．５５（２Ｈ，ｓ），３．７１（３Ｈ，ｓ），４．０８−４．２４（３Ｈ，ｍ），４．４６（２Ｈ，ｓ），６．０３（１Ｈ，ｄ，Ｊ＝７．０Ｈｚ），７．３９−７．４８（４Ｈ，ｍ），７．５６（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ），７．７２−７．６４（２Ｈ，ｍ）．

ＬＣ／ＭＳ［条件１］：保持時間３．０１分；ｍ／ｚ５８９．１［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ６２３．２［Ｍ＋Ｃｌ］^―（ＥＳＩ負イオンモード）

Example 202
4- [3-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl) benzamide) piperidine- Production of methyl 1-carboxylate (Compound No. 202) 3-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8- Diazaspiro [4.5] decan-3-yl} methyl) benzoic acid (28 mg, 0.062 mmol), 4-aminopiperidine-1-carboxylic acid methyl hydrochloride obtained in Reference Example 135 (15 mg, 0.075 mmol) , Triethylamine (13 μL, 0.094 mmol) and 1-hydroxybenzotriazole (8.4 mg, 0.062 mmol) were dissolved in chloroform (1.0 mL). After 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (18 mg, 0.094 mmol) was added and stirred at room temperature for 36 hours. After completion of the reaction, water (3.0 mL) was added to separate the organic layer, dried over anhydrous sodium sulfate, and concentrated to dryness under reduced pressure. The obtained residue was purified by silica gel column chromatography [filler: NH-DM1020 manufactured by Fuji Silysia Ltd., developing solvent: hexane / ethyl acetate = 1/1] to give the title compound (31 mg, yield 83%). Obtained as a white solid.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.36-1.53 (2H, m), 1.67-1.81 (2H, m), 1.86-1.99 (2H, m) 1.99-2.12 (2H, m), 2.47-2.61 (4H, m), 2.97 (2H, t, J = 11.9 Hz), 3.14 (2H, s) , 3.55 (2H, s), 3.71 (3H, s), 4.08-4.24 (3H, m), 4.46 (2H, s), 6.03 (1H, d, J = 7.0 Hz), 7.39-7.48 (4H, m), 7.56 (2H, d, J = 8.2 Hz), 7.72-7.64 (2H, m).

LC / MS [Condition 1]: Retention time 3.01 minutes; m / z 589.1 [M + H] ⁺ (ESI positive ion mode), m / z 623.2 [M + Cl] ⁻ (ESI negative ion mode)

実施例２０３
３−［３−（４−ベンゾイルピペリジン−１−カルボニル）ベンジル］−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−２−オン（化合物番号２０３）の製造
４−アミノピペリジン−１−カルボン酸メチル塩酸塩の代わりに、４−ベンゾイルピペリジン塩酸塩を用いること以外は実質的に実施例２０２と同様に反応を行なって、表題化合物（４．８ｍｇ、収率１７％）を無色油状物として得た。

^１Ｈ−ＮＭＲ（３００ＭＨｚ，ＣＤＣｌ_３）δ：１．６７−２．０５（８Ｈ，ｍ），２．４２−２．６５（４Ｈ，ｍ），３．００−３．２９（４Ｈ，ｍ），３．４９−３．６２（３Ｈ，ｍ），３．７５−４．０１（１Ｈ，ｂｒ ｍ），４．４４（２Ｈ，ｓ），４．５８−４．７７（１Ｈ，ｂｒ ｍ），７．２８−７．６３（１１Ｈ，ｍ），７．８８−８．０１（２Ｈ，ｍ）．

ＬＣ／ＭＳ［条件１］：保持時間３．５１分；ｍ／ｚ６２０．２［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ６５４．４［Ｍ＋Ｃｌ］^―（ＥＳＩ負イオンモード）

Example 203
3- [3- (4-Benzoylpiperidin-1-carbonyl) benzyl] -8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-2-one Preparation of (Compound No. 203) The title compound was reacted in the same manner as in Example 202 except that 4-benzoylpiperidine hydrochloride was used instead of 4-aminopiperidine-1-carboxylic acid methyl hydrochloride. (4.8 mg, 17% yield) was obtained as a colorless oil.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.67-2.05 (8H, m), 2.42-2.65 (4H, m), 3.00-3.29 (4H, m) , 3.49-3.62 (3H, m), 3.75-4.01 (1H, br m), 4.44 (2H, s), 4.58-4.77 (1H, br m). , 7.28-7.63 (11H, m), 7.88-8.01 (2H, m).

LC / MS [condition 1]: retention time 3.51 minutes; m / z 620.2 [M + H] ⁺ (ESI positive ion mode), m / z 654.4 [M + Cl] ⁻ (ESI negative ion mode)

実施例２０４
Ｎ−（ベンゾ［ｄ］［１，３］ジオキソール−５−イルメチル）−３−（｛２−オキソ−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）ベンズアミド（化合物番号２０４）の製造
４−アミノピペリジン−１−カルボン酸メチル塩酸塩とトリエチルアミンの代わりに、ピペロニルアミンを用いること以外は実質的に実施例２０２と同様に反応を行なって、表題化合物（１７ｍｇ、収率６５％）を白色固体として得た。

^１Ｈ−ＮＭＲ（３００ＭＨｚ，ＣＤＣｌ_３）δ：１．６６−１．７８（２Ｈ，ｍ），１．８５−１．９５（２Ｈ，ｍ），２．４５−２．５８（４Ｈ，ｍ），３．１４（２Ｈ，ｓ），３．５５（２Ｈ，ｓ），４．４６（２Ｈ，ｓ），４．５４（２Ｈ，ｄ，Ｊ＝５．７Ｈｚ），５．９４（２Ｈ，ｓ），６．４０（１Ｈ，ｔ，Ｊ＝５．７Ｈｚ），６．７３−６．８７（３Ｈ，ｍ），７．３８−７．４６（４Ｈ，ｍ），７．５６（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ），７．７３−７．６５（２Ｈ，ｍ）．

ＬＣ／ＭＳ［条件１］：保持時間３．３７分；ｍ／ｚ５８２．０［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ６１６．３［Ｍ＋Ｃｌ］^―（ＥＳＩ負イオンモード）

Example 204
N- (benzo [d] [1,3] dioxol-5-ylmethyl) -3-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [ 4.5] Preparation of decan-3-yl} methyl) benzamide (Compound No. 204) Substantially Example 202 except that 4-aminopiperidine-1-carboxylic acid methyl hydrochloride and triethylamine were used instead of piperonylamine. The title compound (17 mg, yield 65%) was obtained as a white solid.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.66-1.78 (2H, m), 1.85-1.95 (2H, m), 2.45-2.58 (4H, m) 3.14 (2H, s), 3.55 (2H, s), 4.46 (2H, s), 4.54 (2H, d, J = 5.7 Hz), 5.94 (2H, s) ), 6.40 (1H, t, J = 5.7 Hz), 6.73-6.87 (3H, m), 7.38-7.46 (4H, m), 7.56 (2H, d) , J = 8.2 Hz), 7.73-7.65 (2H, m).

LC / MS [Condition 1]: Retention time 3.37 minutes; m / z 582.0 [M + H] ⁺ (ESI positive ion mode), m / z 616.3 [M + Cl] ⁻ (ESI negative ion mode)

参考例２０５−１
３−［３−メトキシ−４−（メトキシカルボニル）ベンジル］−２−オキソ−１−オキサ−３，８−ジアザスピロ［４．５］デカン−８−カルボン酸ｔ−ブチルの製造
２−メトキシ−４−メチル安息香酸メチル（市販）（１２０ｍｇ、０．６４ｍｍｏｌ）をクロロホルム（２．０ｍＬ）に溶解し、８０℃まで加熱した後、Ｎ−ブロモスクシンイミド（１７２ｍｇ、０．９６ｍｍｏｌ）とアゾビスイソブチロニトリル（２１ｍｇ、０．１３ｍｍｏｌ）を加え、８０℃で１．５時間かき混ぜた。反応混合物を室温まで冷却した後、飽和炭酸水素ナトリウム水溶液（５．０ｍＬ）とクロロホルム（５．０ｍＬ）を加え、有機層を分離した。得られた有機層を無水硫酸マグネシウムで乾燥した後、減圧下濃縮した。得られた残留物をシリカゲルカラムクロマトグラフィー［充填剤：Ｍｅｒｃｋ ＧＭＢＨ製シリカゲル６０（０．０４０−０．０６３ｍｍ）、展開溶媒：ヘキサン／酢酸エチル＝４／１］にて精製し、無色油状物（１９９ｍｇ）を得た。
参考例１１１−１で得られた２−オキソ−１−オキサ−３，８−ジアザスピロ［４．５］デカン−８−カルボン酸ｔ−ブチル（１６４ｍｇ、０．６４ｍｍｏｌ）をＮ，Ｎ−ジメチルホルムアミド（２．０ｍＬ）に溶かし、ナトリウムｔ−ブトキシド（６８ｍｇ、０．７０ｍｍｏｌ）を加えて３０分撹拌した後、先に得られた淡黄色油状物（１９９ｍｇ）のＮ，Ｎ−ジメチルホルムアミド（２．０ｍＬ）溶液を加え、２時間かき混ぜた。その後、水と酢酸エチルを加えて有機層を分離し、有機層を飽和食塩水で２回洗浄した。有機層を無水硫酸マグネシウムで乾燥した後、減圧下濃縮し、得られた残留物をシリカゲルカラムクロマトグラフィー［充填剤：Ｍｅｒｃｋ ＧＭＢＨ製シリカゲル６０（０．０４０−０．０６３ｍｍ）、展開溶媒：ヘキサン／酢酸エチル＝１／１］にて精製することにより、表題化合物（１２０ｍｇ、４５％）を淡黄色油状物として得た。

^１Ｈ−ＮＭＲ（３００ＭＨｚ，ＣＤＣｌ_３）δ：１．４５（９Ｈ，ｓ），１．５４−１．６８（２Ｈ，ｍ），１．７９−１．９０（２Ｈ，ｍ），３．１３（２Ｈ，ｓ），３．２２−３．３６（２Ｈ，ｍ），３．７０−３．８６（２Ｈ，ｍ），３．８９（３Ｈ，ｓ），３．９０（３Ｈ，ｓ），４．４４（２Ｈ，ｓ），６．８１−６．９２（２Ｈ，ｍ），７．７７（１Ｈ，ｄ，Ｊ＝７．８Ｈｚ）．

ＬＣ／ＭＳ［条件１］：保持時間４．０３分；ｍ／ｚ４５７．０［Ｍ＋Ｎａ］^＋（ＥＳＩ正イオンモード）

Reference Example 205-1
Preparation of t-butyl 3- [3-methoxy-4- (methoxycarbonyl) benzyl] -2-oxo-1-oxa-3,8-diazaspiro [4.5] decane-8-carboxylate 2-methoxy-4 -Methyl methyl benzoate (commercially available) (120 mg, 0.64 mmol) was dissolved in chloroform (2.0 mL), heated to 80 ° C., then N-bromosuccinimide (172 mg, 0.96 mmol) and azobisisobutyro Nitrile (21 mg, 0.13 mmol) was added and stirred at 80 ° C. for 1.5 hours. The reaction mixture was cooled to room temperature, saturated aqueous sodium hydrogen carbonate solution (5.0 mL) and chloroform (5.0 mL) were added, and the organic layer was separated. The obtained organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography [filler: silica gel 60 (0.040-0.063 mm) manufactured by Merck GMBH, developing solvent: hexane / ethyl acetate = 4/1], and colorless oil ( 199 mg) was obtained.
2-Oxo-1-oxa-3,8-diazaspiro [4.5] decane-8-carboxylate t-butyl (164 mg, 0.64 mmol) obtained in Reference Example 111-1 was replaced with N, N-dimethylformamide. (2.0 mL), sodium t-butoxide (68 mg, 0.70 mmol) was added, and the mixture was stirred for 30 minutes, and then the pale yellow oil (199 mg) obtained above, N, N-dimethylformamide (2. 0 mL) solution was added and stirred for 2 hours. Thereafter, water and ethyl acetate were added to separate the organic layer, and the organic layer was washed twice with saturated brine. The organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography [filler: silica gel 60 (0.040-0.063 mm) manufactured by Merck GMBH, developing solvent: hexane / Purification by ethyl acetate = 1/1] gave the title compound (120 mg, 45%) as a pale yellow oil.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.45 (9H, s), 1.54-1.68 (2H, m), 1.79-1.90 (2H, m), 3.13 (2H, s), 3.22-3.36 (2H, m), 3.70-3.86 (2H, m), 3.89 (3H, s), 3.90 (3H, s), 4.44 (2H, s), 6.81-6.92 (2H, m), 7.77 (1H, d, J = 7.8 Hz).

LC / MS [Condition 1]: Retention time 4.03 min; m / z 457.0 [M + Na] ⁺ (ESI positive ion mode)

参考例２０５−２
２−メトキシ−４−［（２−オキソ−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル）メチル］安息香酸メチル塩酸塩の製造
参考例２０５−１で得られた３−［３−メトキシ−４−（メトキシカルボニル）ベンジル］−２−オキソ−１−オキサ−３，８−ジアザスピロ［４．５］デカン−８−カルボン酸ｔ−ブチル（１２０ｍｇ、０．０２９ｍｍｏｌ）をメタノール（１．０ｍＬ）に溶解し、４Ｍ塩化水素−ジオキサン溶液（２．０ｍＬ）を加えて室温で１時間撹拌した。その後、減圧下濃縮乾固し、表題化合物（１１０ｍｇ、収率定量的）を淡黄色油状物として得た。

^１Ｈ−ＮＭＲ（３００ＭＨｚ，ＣＤ_３ＯＤ）δ：２．２０−１．９４（４Ｈ，ｍ），３．３９−３．２３（４Ｈ，ｍ），３．３８（２Ｈ，ｓ），３．８５（３Ｈ，ｓ），３．８８（３Ｈ，ｓ），４．４８（２Ｈ，ｓ），６．９５（１Ｈ，ｄｄ，Ｊ＝８．２，１．４Ｈｚ），７．０４−７．０６（１Ｈ，ｍ），７．７２−７．７８（１Ｈ，ｍ）．

ＬＣ／ＭＳ［条件１］：保持時間０．５８分；ｍ／ｚ３３５．１［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）

Reference Example 205-2
Preparation of 2-methoxy-4-[(2-oxo-1-oxa-3,8-diazaspiro [4.5] decan-3-yl) methyl] benzoic acid methyl hydrochloride Obtained in Reference Example 205-1 3- [3-Methoxy-4- (methoxycarbonyl) benzyl] -2-oxo-1-oxa-3,8-diazaspiro [4.5] decane-8-carboxylate t-butyl (120 mg, 0.029 mmol) Was dissolved in methanol (1.0 mL), 4M hydrogen chloride-dioxane solution (2.0 mL) was added, and the mixture was stirred at room temperature for 1 hr. Thereafter, the mixture was concentrated to dryness under reduced pressure to give the title compound (110 mg, quantitative yield) as a pale yellow oil.

¹ H-NMR (300 MHz, CD ₃ OD) δ: 2.20-1.94 (4H, m), 3.39-3.23 (4H, m), 3.38 (2H, s), 3. 85 (3H, s), 3.88 (3H, s), 4.48 (2H, s), 6.95 (1H, dd, J = 8.2, 1.4 Hz), 7.04-7. 06 (1H, m), 7.72-7.78 (1H, m).

LC / MS [Condition 1]: Retention time 0.58 minutes; m / z 335.1 [M + H] ⁺ (ESI positive ion mode)

参考例２０５−３
２−メトキシ−４−（｛２−オキソ−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）安息香酸メチルの製造
参考例２０５−２で得られた２−メトキシ−４−［（２−オキソ−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル）メチル］安息香酸メチル塩酸塩（１１０ｍｇ、０．２９ｍｍｏｌ）をＮ，Ｎ−ジメチルホルムアミド（２．０ｍＬ）に懸濁し、トリエチルアミン（０．１２ｍＬ、０．８５ｍｍｏｌ）と４−（トリフルオロメチル）ベンジルブロミド（８２ｍｇ、０．３４ｍｍｏｌ）を加え、室温で１．５時間かき混ぜた。水と酢酸エチルを加えて有機層を分離し、飽和食塩水で洗浄した。得られた有機層を無水硫酸ナトリウムで乾燥した後、減圧下濃縮した。得られた残留物をシリカゲルカラムクロマトグラフィー［充填剤：富士シリシア社製アミンシリカＮＨ−ＤＭ１０２０、展開溶媒：ヘキサン／酢酸エチル＝１／１］にて精製し、表題化合物（８８ｍｇ、収率６３％）を無色油状物として得た。

^１Ｈ−ＮＭＲ（３００ＭＨｚ，ＣＤＣｌ_３）δ：１．６５−１．７９（２Ｈ，ｍ），１．８５−１．９６（２Ｈ，ｍ），２．４６−２．６０（４Ｈ，ｍ），３．１３（２Ｈ，ｓ），３．５５（２Ｈ，ｓ），３．８９（６Ｈ，ｓ），４．４３（２Ｈ，ｓ），６．８２−６．９０（２Ｈ，ｍ），７．４２（２Ｈ，ｄ，Ｊ＝７．９Ｈｚ），７．５６（２Ｈ，ｄ，Ｊ＝８．３Ｈｚ），７．７７（１Ｈ，ｄ，Ｊ＝７．６Ｈｚ）．

ＬＣ／ＭＳ［条件１］：保持時間３．０２分；ｍ／ｚ４９２．９［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）

Reference Example 205-3
2-methoxy-4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl) methyl benzoate of reference example 205-2 obtained in 2-methoxy-4 - [(2-oxo-1-oxa-3,8-diazaspiro [4.5] decan-3-yl) methyl] benzoate hydrochloride (110 mg, 0.29 mmol) was suspended in N, N-dimethylformamide (2.0 mL) and triethylamine (0.12 mL, 0.85 mmol) and 4- (trifluoromethyl) benzyl bromide (82 mg, 0.34 mmol). And stirred at room temperature for 1.5 hours. Water and ethyl acetate were added, the organic layer was separated, and washed with saturated brine. The obtained organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography [filler: amine silica NH-DM1020 manufactured by Fuji Silysia Ltd., developing solvent: hexane / ethyl acetate = 1/1], and the title compound (88 mg, yield 63%). Was obtained as a colorless oil.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.65-1.79 (2H, m), 1.85-1.96 (2H, m), 2.46-2.60 (4H, m) 3.13 (2H, s), 3.55 (2H, s), 3.89 (6H, s), 4.43 (2H, s), 6.82-6.90 (2H, m), 7.42 (2H, d, J = 7.9 Hz), 7.56 (2H, d, J = 8.3 Hz), 7.77 (1H, d, J = 7.6 Hz).

LC / MS [Condition 1]: Retention time 3.02 minutes; m / z 492.9 [M + H] ⁺ (ESI positive ion mode)

参考例２０５−４
２−メトキシ−４−（｛２−オキソ−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）安息香酸の製造
参考例２０５−３）で得られた２−メトキシ−４−（｛２−オキソ−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）安息香酸メチル（８８ｍｇ、０．１８ｍｍｏｌ）をメタノール（２．０ｍＬ）に懸濁し、５０℃まで加熱して溶かした後、１Ｍ水酸化ナトリウム水溶液（０．３６ｍＬ、０．３６ｍｍｏｌ）を加え、５０℃で２時間かき混ぜた。その後、反応混合物を室温まで冷却し、１Ｍ塩酸（０．３６ｍＬ、０．３６ｍｍｏｌ）を滴下した。酢酸エチル（５．０ｍＬ）と水（５．０ｍＬ）を加えた後、有機層を分離し、減圧下濃縮して表題化合物（７８ｍｇ、収率９１％）を白色固体として得た。

^１Ｈ−ＮＭＲ（３００ＭＨｚ，ＣＤＣｌ_３）δ：１．６８−１．８２（２Ｈ，ｍ），１．８５−１．９８（２Ｈ，ｍ），２．４６−２．６４（４Ｈ，ｍ），３．１７（２Ｈ，ｓ），３．５７（２Ｈ，ｓ），４．０３（３Ｈ，ｓ），４．４５（２Ｈ，ｓ），６．９３−７．０２（２Ｈ，ｍ），７．４２（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ），７．５６（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ），８．１２（１Ｈ，ｄ，Ｊ＝７．８Ｈｚ）．

ＬＣ／ＭＳ［条件１］：保持時間２．４２分；ｍ／ｚ４７９．１［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ４７７．１［Ｍ−Ｈ］^―（ＥＳＩ負イオンモード）

Reference Example 205-4
Of 2-methoxy-4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl) benzoic acid 2-methoxy-4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] obtained in Production Reference Example 205-3) Decan-3-yl} methyl) methyl benzoate (88 mg, 0.18 mmol) was suspended in methanol (2.0 mL), dissolved by heating to 50 ° C., and then 1M aqueous sodium hydroxide solution (0.36 mL, 0 .36 mmol) was added and stirred at 50 ° C. for 2 hours. The reaction mixture was then cooled to room temperature and 1M hydrochloric acid (0.36 mL, 0.36 mmol) was added dropwise. After adding ethyl acetate (5.0 mL) and water (5.0 mL), the organic layer was separated and concentrated under reduced pressure to give the title compound (78 mg, 91% yield) as a white solid.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.68-1.82 (2H, m), 1.85-1.98 (2H, m), 2.46-2.64 (4H, m) 3.17 (2H, s), 3.57 (2H, s), 4.03 (3H, s), 4.45 (2H, s), 6.93-7.02 (2H, m), 7.42 (2H, d, J = 8.2 Hz), 7.56 (2H, d, J = 8.2 Hz), 8.12 (1H, d, J = 7.8 Hz).

LC / MS [Condition 1]: Retention time 2.42 minutes; m / z 479.1 [M + H] ⁺ (ESI positive ion mode), m / z 477.1 [MH] ⁻ (ESI negative ion mode)

実施例２０５
３−［４−［４−ベンゾイルピペリジン−１−カルボニル）−３−メトキシベンジル］−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−２−オン（化合物番号２０５）の製造
参考例２０５−４で得られた２−メトキシ−４−（｛２−オキソ−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）安息香酸（８．３ｍｇ、０．０１７ｍｍｏｌ）、４−ベンゾイルピペリジン塩酸塩（４．７ｍｇ、０．０２１ｍｍｏｌ）、トリエチルアミン（３．６μＬ、０．０２６ｍｍｏｌ）と１−ヒドロキシベンゾトリアゾール（２．３ｍｇ、０．０２７ｍｍｏｌ）をクロロホルム（１．０ｍＬ）に溶解した後、１−エチル−３−（３−ジメチルアミノプロピル）カルボジイミド塩酸塩（５．１ｍｇ、０．０１７ｍｍｏｌ）を加えて、室温で３日間かき混ぜた。その後、反応混合物に水（２．０ｍＬ）を加えて有機層を分離し、無水硫酸ナトリウムで乾燥した後、減圧下濃縮した。得られた残留物を分取用薄層クロマトグラフィー［富士シリシア社製クロマトレックスＮＨ−ＰＬＣ０５プレート、展開溶媒：酢酸エチル１００％］にて精製し、表題化合物（８．４ｍｇ、収率７５％）を淡黄色固体として得た。

^１Ｈ−ＮＭＲ（３００ＭＨｚ，ＣＤＣｌ_３）δ：１．６９−２．０８（８Ｈ，ｍ），２．４７−２．６２（４Ｈ，ｍ），２．９９−３．２５（４Ｈ，ｍ），３．４５−３．６５（４Ｈ，ｍ），３．８１−３．８７（３Ｈ，ｍ），４．２８−４．５６（２Ｈ，ｍ），４．７０−４．８０（１Ｈ，ｍ），６．７９−６．９１（２Ｈ，ｍ），７．１９−７．２６（１Ｈ，ｍ），７．４３（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ），７．５０（２Ｈ，ｄ，Ｊ＝７．８Ｈｚ），７．４０−７．６３（３Ｈ，ｍ），７．９５（２Ｈ，ｄ，Ｊ＝７．４Ｈｚ）．

ＬＣ／ＭＳ［条件１］：保持時間３．３１分；ｍ／ｚ６５０．２［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ６８４．３［Ｍ＋Ｃｌ］^―（ＥＳＩ負イオンモード）

Example 205
3- [4- [4-Benzoylpiperidine-1-carbonyl) -3-methoxybenzyl] -8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decane 2 -Methoxy-4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3 obtained in Production Reference Example 205-4 of 2-one (Compound No. 205) , 8-diazaspiro [4.5] decan-3-yl} methyl) benzoic acid (8.3 mg, 0.017 mmol), 4-benzoylpiperidine hydrochloride (4.7 mg, 0.021 mmol), triethylamine (3.6 μL) , 0.026 mmol) and 1-hydroxybenzotriazole (2.3 mg, 0.027 mmol) were dissolved in chloroform (1.0 mL), and then 1-ethyl-3- 3-dimethylaminopropyl) carbodiimide hydrochloride (5.1 mg, 0.017 mmol) was added and stirred at room temperature for 3 days. Then, water (2.0 mL) was added to the reaction mixture, the organic layer was separated, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by preparative thin-layer chromatography [Chromatolex NH-PLC05 plate manufactured by Fuji Silysia, developing solvent: ethyl acetate 100%] to give the title compound (8.4 mg, yield 75%). Was obtained as a pale yellow solid.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.69-2.08 (8H, m), 2.47-2.62 (4H, m), 2.99-3.25 (4H, m) 3.45-3.65 (4H, m), 3.81-3.87 (3H, m), 4.28-4.56 (2H, m), 4.70-4.80 (1H, m), 6.79-6.91 (2H, m), 7.19-7.26 (1H, m), 7.43 (2H, d, J = 8.2 Hz), 7.50 (2H, d, J = 7.8 Hz), 7.40-7.63 (3H, m), 7.95 (2H, d, J = 7.4 Hz).

LC / MS [Condition 1]: Retention time 3.31 min; m / z 650.2 [M + H] ⁺ (ESI positive ion mode), m / z 684.3 [M + Cl] ⁻ (ESI negative ion mode)

実施例２０６
４−［２−メトキシ−４−（｛２−オキソ−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）ベンズアミド］ピペリジン−１−カルボン酸メチル（化合物番号２０６）の製造
４−ベンゾイルピペリジン塩酸塩の代わりに、参考例１３５で得られた４−アミノピペリジン−１−カルボン酸メチル塩酸塩を用いること以外は実質的に実施例２０５と同様に反応を行なって、表題化合物（８．７ｍｇ、収率８１％）を淡黄色油状物として得た。

^１Ｈ−ＮＭＲ（３００ＭＨｚ，ＣＤＣｌ_３）δ：１．３７−１．６１（２Ｈ，ｍ），１．６３−１．７９（２Ｈ，ｍ），１．８２−１．９６（２Ｈ，ｍ），１．９６−２．０８（２Ｈ，ｍ），２．４３−２．６０（４Ｈ，ｍ），２．９７−３．１３（２Ｈ，ｍ），３．１４（２Ｈ，ｓ），３．５５（２Ｈ，ｓ），３．７１（３Ｈ，ｓ），３．９４（３Ｈ，ｓ），３．９６−４．２５（３Ｈ，ｍ），４．４３（２Ｈ，ｓ），６．９０（１Ｈ，ｓ），６．９５（１Ｈ，ｄ，Ｊ＝７．８Ｈｚ），７．４２（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ），７．５６（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ），７．７５（１Ｈ，ｄ，Ｊ＝７．８Ｈｚ），８．１７（１Ｈ，ｄ，Ｊ＝７．８Ｈｚ）．

ＬＣ／ＭＳ［条件１］：保持時間３．０７分；ｍ／ｚ６１９．２［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ６５３．４［Ｍ＋Ｃｌ］^―（ＥＳＩ負イオンモード）

Example 206
4- [2-methoxy-4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl) Benzamide] Preparation of methyl piperidine-1-carboxylate (Compound No. 206) Instead of using 4-benzoylpiperidine hydrochloride, 4-aminopiperidine-1-carboxylate methyl hydrochloride obtained in Reference Example 135 was used. The reaction was carried out substantially in the same manner as in Example 205 to give the title compound (8.7 mg, yield 81%) as a pale yellow oil.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.37-1.61 (2H, m), 1.63-1.79 (2H, m), 1.82-1.96 (2H, m) 1.96-2.08 (2H, m), 2.43-2.60 (4H, m), 2.97-3.13 (2H, m), 3.14 (2H, s), 3 .55 (2H, s), 3.71 (3H, s), 3.94 (3H, s), 3.96-4.25 (3H, m), 4.43 (2H, s), 6. 90 (1H, s), 6.95 (1H, d, J = 7.8 Hz), 7.42 (2H, d, J = 8.2 Hz), 7.56 (2H, d, J = 8.2 Hz) ), 7.75 (1H, d, J = 7.8 Hz), 8.17 (1H, d, J = 7.8 Hz).

LC / MS [Condition 1]: Retention time 3.07 minutes; m / z 619.2 [M + H] ⁺ (ESI positive ion mode), m / z 653.4 [M + Cl] ⁻ (ESI negative ion mode)

実施例２０７
２−メトキシ−４−（｛−オキソ−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）−Ｎ−［（テトラヒドロフラン−２−イル）メチル］ベンズアミド（化合物番号２０７）の製造
４−ベンゾイルピペリジン塩酸塩とトリエチルアミンの代わりに、テトラヒドロフルフリルアミンを用いること以外は実質的に実施例２０５と同様に反応を行なって、表題化合物（６．５ｍｇ、収率６７％）を淡黄色油状物として得た。

^１Ｈ−ＮＭＲ（３００ＭＨｚ，ＣＤＣｌ_３）δ：１．８０−１．６０（３Ｈ，ｍ），２．０８−１．８５（５Ｈ，ｍ），２．４５−２．６６（４Ｈ，ｍ），３．１３（２Ｈ，ｓ），３．４５（１Ｈ，ｄｄｄ，Ｊ＝１３．９，６．８，５．５Ｈｚ），３．５５（２Ｈ，ｓ），３．７４（１Ｈ，ｄｄｄ，Ｊ＝１３．５，５．７，３．３Ｈｚ），３．７９（１Ｈ，ｄｔ，Ｊ＝８．２，６．５Ｈｚ），３．９０（１Ｈ，ｄｔ，Ｊ＝８．２，６．５Ｈｚ），３．９５（３Ｈ，ｓ），４．０８（１Ｈ，ｑｄ，Ｊ＝７．０，３．７Ｈｚ），４．４３（２Ｈ，ｓ），６．８７−６．９８（２Ｈ，ｍ），７．４２（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ），７．５６（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ），８．０９（１Ｈ，ｔ，Ｊ＝５．７Ｈｚ），８．１７（１Ｈ，ｄ，Ｊ＝８．２Ｈｚ）．

ＬＣ／ＭＳ［条件１］：保持時間２．９９分；ｍ／ｚ５６２．０［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ５９６．１［Ｍ＋Ｃｌ］^―（ＥＳＩ負イオンモード）

Example 207
2-Methoxy-4-({-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl) -N- [ Preparation of (tetrahydrofuran-2-yl) methyl] benzamide (Compound No. 207) The reaction was carried out in substantially the same manner as in Example 205 except that tetrahydrofurfurylamine was used instead of 4-benzoylpiperidine hydrochloride and triethylamine. The title compound (6.5 mg, 67% yield) was obtained as a pale yellow oil.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.80-1.60 (3H, m), 2.08-1.85 (5H, m), 2.45-2.66 (4H, m) , 3.13 (2H, s), 3.45 (1H, ddd, J = 13.9, 6.8, 5.5 Hz), 3.55 (2H, s), 3.74 (1H, ddd, J = 13.5, 5.7, 3.3 Hz), 3.79 (1H, dt, J = 8.2, 6.5 Hz), 3.90 (1H, dt, J = 8.2, 6. 5Hz), 3.95 (3H, s), 4.08 (1H, qd, J = 7.0, 3.7 Hz), 4.43 (2H, s), 6.87-6.98 (2H, m), 7.42 (2H, d, J = 8.2 Hz), 7.56 (2H, d, J = 8.2 Hz), 8.09 (1H, t, J = 5.7 Hz), 8. 17 (1H, d, J = 8 2Hz).

LC / MS [Condition 1]: Retention time 2.99 minutes; m / z 562.0 [M + H] ⁺ (ESI positive ion mode), m / z 596.1 [M + Cl] ⁻ (ESI negative ion mode)

実施例２０８
Ｎ−（ベンゾ［ｄ］［１，３］ジオキソール−５−イルメチル）−２−メトキシ−４−（｛２−オキソ−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）ベンズアミド（化合物番号２０８）の製造
４−ベンゾイルピペリジン塩酸塩とトリエチルアミンの代わりに、ピペロニルアミンを用いること以外は実質的に実施例２０５と同様に反応を行なって、表題化合物（９．１ｍｇ、収率８６％）を淡黄色油状物として得た。

^１Ｈ−ＮＭＲ（３００ＭＨｚ，ＣＤＣｌ_３）δ：１．６６−１．８０（２Ｈ，ｍ），１．８５−１．９８（２Ｈ，ｍ），２．４４−２．６１（４Ｈ，ｍ），３．１４（２Ｈ，ｓ），３．５５（２Ｈ，ｓ），３．９１（３Ｈ，ｓ），４．４３（２Ｈ，ｓ），４．５７（２Ｈ，ｄ，Ｊ＝５．７Ｈｚ），５．９４（２Ｈ，ｓ），６．７１−７．０１（５Ｈ，ｍ），７．４２（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ），７．５６（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ），８．０５（１Ｈ，ｔ，Ｊ＝６．１Ｈｚ），８．２１（１Ｈ，ｄ，Ｊ＝７．８Ｈｚ）．

ＬＣ／ＭＳ［条件１］：保持時間３．２３分；ｍ／ｚ６１２．０［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ６４６．２［Ｍ＋Ｃｌ］^―（ＥＳＩ負イオンモード）

Example 208
N- (benzo [d] [1,3] dioxol-5-ylmethyl) -2-methoxy-4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3, Preparation of 8-diazaspiro [4.5] decan-3-yl} methyl) benzamide (Compound No. 208) Substantially the same as Example 205, except that piperonylamine is used instead of 4-benzoylpiperidine hydrochloride and triethylamine. The title compound (9.1 mg, yield 86%) was obtained as a pale yellow oil.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.66-1.80 (2H, m), 1.85-1.98 (2H, m), 2.44-2.61 (4H, m) 3.14 (2H, s), 3.55 (2H, s), 3.91 (3H, s), 4.43 (2H, s), 4.57 (2H, d, J = 5.7 Hz) ), 5.94 (2H, s), 6.71-7.01 (5H, m), 7.42 (2H, d, J = 8.2 Hz), 7.56 (2H, d, J = 8) 0.2 Hz), 8.05 (1H, t, J = 6.1 Hz), 8.21 (1H, d, J = 7.8 Hz).

LC / MS [Condition 1]: Retention time 3.23 min; m / z 612.0 [M + H] ⁺ (ESI positive ion mode), m / z 646.2 [M + Cl] ⁻ (ESI negative ion mode)

実施例２０９
４−（４−フルオロベンゾイル）−Ｎ−［３−（｛２−オキソ−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）フェニル］ピペリジン−１−カルボキサミド（化合物番号２０９）の製造
参考例１０８−３で得られた３−（｛２−オキソ−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）安息香酸（５０ｍｇ、０．１１ｍｍｏｌ）をトルエン（１．０ｍＬ）に懸濁し、トリエチルアミン（０．０２３ｍＬ、０．２２ｍｍｏｌ）およびジフェニルホスホリルアジド（０．０１４ｍＬ、０．１３ｍｍｏｌ）を加え、室温で４日間かき混ぜた。反応混合物に水（３．０）ｍＬを加えた後、有機層を分離した。得られた有機層を無水硫酸マグネシウムで乾燥した後、減圧下濃縮し、淡黄色油状物（７４ｍｇ）を得た。この油状物（３７ｍｇ）をトルエン（３．０ｍＬ）に溶解し、１１０℃で２時間かき混ぜた。その後、反応混合物に４−（４−フルオロベンゾイル）ピペリジン塩酸塩（２７ｍｇ、０．１１ｍｍｏｌ）およびトリエチルアミン（０．０１５ｍＬ、０．１１ｍｍｏｌ）のトルエン（１．０ｍＬ）溶液を加え、５時間かき混ぜた。反応混合物を室温まで冷却し、酢酸エチル（３．０ｍＬ）と水（３．０ｍＬ）を加えて有機層を分離した後、水層を酢酸エチル（３ｍＬ）で抽出した。合わせた有機層を無水硫酸マグネシウムで乾燥し、減圧下濃縮した。得られた残留物をシリカゲルカラムクロマトグラフィー［充填剤：富士シリシア社製アミンシリカＮＨ−ＤＭ１０２０、展開溶媒：酢酸エチル］にて精製し、表題化合物（２．３ｍｇ、収率７％）を無色油状物として得た。

^１Ｈ−ＮＭＲ（３００ＭＨｚ，ＣＤＣｌ_３）δ：１．６６−２．００（８Ｈ，ｍ），２．４７−２．６０（４Ｈ，ｍ），３．１２（２Ｈ，ｄｄｄ，Ｊ＝１３．５，１１．５，２．９Ｈｚ），３．１６（２Ｈ，ｓ），３．４７（１Ｈ，ｔｔ，Ｊ＝１１．１，４．１Ｈｚ），３．５５（２Ｈ，ｓ），４．０７−４．１６（２Ｈ，ｍ），４．３８（２Ｈ，ｓ），６．４４（１Ｈ，ｓ），６．９１−６．９６（１Ｈ，ｍ），７．１７（２Ｈ，ｔ，Ｊ＝８．６Ｈｚ），７．２２−７．３７（３Ｈ，ｍ），７．４３（２Ｈ，ｄ，Ｊ＝７．８Ｈｚ），７．５６（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ），７．９５−８．０３（２Ｈ，ｄｄ，Ｊ＝９．０，５．３Ｈｚ）．

ＬＣ／ＭＳ［条件１］：保持時間３．４３分；ｍ／ｚ６５３．１［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ６５１．１［Ｍ−Ｈ］^―（ＥＳＩ負イオンモード）

Example 209
4- (4-Fluorobenzoyl) -N- [3-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decane-3 -Il} methyl) phenyl] piperidine-1-carboxamide (Compound No. 209) 3-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1 obtained in Reference Example 108-3 -Oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl) benzoic acid (50 mg, 0.11 mmol) was suspended in toluene (1.0 mL) and triethylamine (0.023 mL, 0.22 mmol). ) And diphenylphosphoryl azide (0.014 mL, 0.13 mmol) were added and stirred at room temperature for 4 days. After adding water (3.0) mL to the reaction mixture, the organic layer was separated. The obtained organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure to obtain a pale yellow oil (74 mg). This oil (37 mg) was dissolved in toluene (3.0 mL) and stirred at 110 ° C. for 2 hours. Thereafter, a toluene (1.0 mL) solution of 4- (4-fluorobenzoyl) piperidine hydrochloride (27 mg, 0.11 mmol) and triethylamine (0.015 mL, 0.11 mmol) was added to the reaction mixture, and the mixture was stirred for 5 hours. The reaction mixture was cooled to room temperature, ethyl acetate (3.0 mL) and water (3.0 mL) were added to separate the organic layer, and the aqueous layer was extracted with ethyl acetate (3 mL). The combined organic layers were dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography [filler: amine silica NH-DM1020 manufactured by Fuji Silysia Ltd., developing solvent: ethyl acetate] to give the title compound (2.3 mg, yield 7%) as a colorless oil. Got as.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.66-2.00 (8H, m), 2.47-2.60 (4H, m), 3.12 (2H, ddd, J = 13. 5, 11.5, 2.9 Hz), 3.16 (2 H, s), 3.47 (1 H, tt, J = 11.1, 4.1 Hz), 3.55 (2 H, s), 4. 07-4.16 (2H, m), 4.38 (2H, s), 6.44 (1H, s), 6.91-6.96 (1H, m), 7.17 (2H, t, J = 8.6 Hz), 7.22-7.37 (3H, m), 7.43 (2H, d, J = 7.8 Hz), 7.56 (2H, d, J = 8.2 Hz), 7.95-8.03 (2H, dd, J = 9.0, 5.3 Hz).

LC / MS [Condition 1]: retention time 3.43 minutes; m / z 653.1 [M + H] ⁺ (ESI positive ion mode), m / z 651.1 [M−H] ⁻ (ESI negative ion mode)

実施例２１０
１−［３−（｛２−オキソ−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）フェニル］−３−［（テトラヒドロフラン−２−イル）メチル］尿素（化合物番号２１０）の製造
参考例１０８−３で得られた３−（｛２−オキソ−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）安息香酸（５０ｍｇ、０．１１ｍｍｏｌ）をトルエン（１．０ｍＬ）に懸濁し、トリエチルアミン（０．０２３ｍＬ、０．２２ｍｍｏｌ）およびジフェニルホスホリルアジド（０．０１４ｍＬ、０．１３ｍｍｏｌ）を加え室温で４日間かき混ぜた。水（３．０ｍＬ）を加えて有機層を分離した後、有機層を無水硫酸マグネシウムで乾燥し、減圧下濃縮して淡黄色油状物（７４ｍｇ）を得た。この油状物（３７ｍｇ）をトルエン（３．０ｍＬ）に溶解し、１１０℃で２時間かき混ぜた。その後、反応溶液にテトラヒドロフルフリルアミン（０．０１２ｍＬ、０．１１ｍｍｏｌ）を加え、５時間かき混ぜた。反応混合物を室温まで冷却し、酢酸エチル（３．０ｍＬ）と水（３．０ｍＬ）を加えて有機層を分離した後、水層を酢酸エチル（３．０ｍＬ）で抽出した。合わせた有機層を無水硫酸マグネシウムで乾燥し、減圧下濃縮した。得られた残留物をシリカゲルカラムクロマトグラフィー［充填剤：富士シリシア社製アミンシリカＮＨ−ＤＭ１０２０、展開溶媒：酢酸エチル］にて精製後、さらに分取用薄層クロマトグラフィー［富士シリシア社製クロマトレックスＮＨ−ＰＬＣ０５プレート、展開溶媒：酢酸エチル１００％］にて精製し、表題化合物（１１ｍｇ、収率３５％）を無色油状物として得た。

^１Ｈ−ＮＭＲ（３００ＭＨｚ，ＣＤＣｌ_３）δ：１．６４−１．７９（３Ｈ，ｍ），１．８５−２．０５（５Ｈ，ｍ），２．４５−２．６２（４Ｈ，ｍ），３．１５（２Ｈ，ｓ），３．１５（１Ｈ，ｄｄｄ，Ｊ＝１４．３，６．５，５．３Ｈｚ），３．５５（２Ｈ，ｓ），３．５７（１Ｈ，ｄｄｄ，Ｊ＝１４．３，６．５，２．９Ｈｚ），３．７８（１Ｈ，ｄｔ，Ｊ＝８．２，７．０Ｈｚ），３．８８（１Ｈ，ｄｔ，Ｊ＝８．２，６．５Ｈｚ），４．０２（１Ｈ，ｑｄ，Ｊ＝７．０，３．３Ｈｚ），４．３８（２Ｈ，ｓ），５．０７（１Ｈ，ｔ，Ｊ＝５．７Ｈｚ），６．９０−６．９６（１Ｈ，ｍ），７．２７−７．３１（４Ｈ，ｍ），７．４２（２Ｈ，ｄ，Ｊ＝７．８Ｈｚ），７．５６（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ）．

ＬＣ／ＭＳ［条件１］：保持時間２．９９分；ｍ／ｚ５４７．０［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ５４５．１［Ｍ−Ｈ］^―（ＥＳＩ負イオンモード）

Example 210
1- [3-({2-Oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl) phenyl] -3 Production of-[(tetrahydrofuran-2-yl) methyl] urea (Compound No. 210) 3-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1 obtained in Reference Example 108-3 -Oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl) benzoic acid (50 mg, 0.11 mmol) was suspended in toluene (1.0 mL) and triethylamine (0.023 mL, 0.22 mmol). ) And diphenylphosphoryl azide (0.014 mL, 0.13 mmol) were added and stirred at room temperature for 4 days. Water (3.0 mL) was added to separate the organic layer, and the organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain a pale yellow oil (74 mg). This oil (37 mg) was dissolved in toluene (3.0 mL) and stirred at 110 ° C. for 2 hours. Thereafter, tetrahydrofurfurylamine (0.012 mL, 0.11 mmol) was added to the reaction solution, and the mixture was stirred for 5 hours. The reaction mixture was cooled to room temperature, ethyl acetate (3.0 mL) and water (3.0 mL) were added to separate the organic layer, and then the aqueous layer was extracted with ethyl acetate (3.0 mL). The combined organic layers were dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography [filler: amine silica NH-DM1020 manufactured by Fuji Silysia Ltd., developing solvent: ethyl acetate], and further subjected to preparative thin layer chromatography [chromatolex NH manufactured by Fuji Silysia Ltd. -PLC05 plate, developing solvent: ethyl acetate 100%] to give the title compound (11 mg, yield 35%) as a colorless oil.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.64-1.79 (3H, m), 1.85-2.05 (5 H, m), 2.45-2.62 (4H, m) , 3.15 (2H, s), 3.15 (1H, ddd, J = 14.3, 6.5, 5.3 Hz), 3.55 (2H, s), 3.57 (1H, ddd, J = 14.3, 6.5, 2.9 Hz), 3.78 (1H, dt, J = 8.2, 7.0 Hz), 3.88 (1H, dt, J = 8.2, 6. 5 Hz), 4.02 (1H, qd, J = 7.0, 3.3 Hz), 4.38 (2H, s), 5.07 (1H, t, J = 5.7 Hz), 6.90− 6.96 (1H, m), 7.27-7.31 (4H, m), 7.42 (2H, d, J = 7.8 Hz), 7.56 (2H, d, J = 8.2 Hz) ).

LC / MS [Condition 1]: Retention time 2.99 minutes; m / z 547.0 [M + H] ⁺ (ESI positive ion mode), m / z 545.1 [MH] ⁻ (ESI negative ion mode)

参考例２１１−１
（１ｓ,４ｓ）−４−（ヒドロキシメチル）シクロヘキサンカルボン酸メチルの製造
ｃｉｓ−４−（ヒドロキシメチル）シクロヘキサンカルボン酸（東京化成工業社より購入）（５００ｍｇ、３．２ｍｍｏｌ）をメタノール（１０ｍＬ）に溶かし、次いで濃硫酸（１７μＬ）を加えた後、８０℃で２時間加熱撹拌した。反応混合物に飽和炭酸水素ナトリウム水溶液（５．０ｍＬ）と酢酸エチル（５．０ｍＬ）を加えて振とうした後、有機層を分離した。次いで水層を酢酸エチル（１０ｍＬ）で２回抽出した後、合わせた有機層を飽和塩化ナトリウム水溶液（１０ｍＬ）にて洗浄した。有機層を分離し、無水硫酸マグネシウムで乾燥した後、減圧下濃縮乾固し、（１ｓ,４ｓ）−４−（ヒドロキシメチル）シクロヘキサンカルボン酸メチル（５２２ｍｇ、収率９６％）を無色油状物として得た。得られた油状物は、未精製のまま次の反応に用いた。

^１Ｈ−ＮＭＲ（３００ＭＨｚ，ＣＤＣｌ_３）δ：１．１９−１．７３（１Ｈ，ｂｒ ｓ），１．２２−１．３８（２Ｈ，ｍ），１．５０−１．７０（５Ｈ，ｍ），１．９４−２．０９（２Ｈ，ｍ），２．５８（１Ｈ，ｔｔ，Ｊ＝４．９，４．１Ｈｚ），３．５０（２Ｈ，ｄ，Ｊ＝５．９Ｈｚ），３．６９（３Ｈ，ｓ）．

Reference Example 211-1
Production of methyl (1s, 4s) -4- (hydroxymethyl) cyclohexanecarboxylate cis-4- (hydroxymethyl) cyclohexanecarboxylic acid (purchased from Tokyo Chemical Industry Co., Ltd.) (500 mg, 3.2 mmol) in methanol (10 mL) After dissolving, concentrated sulfuric acid (17 μL) was added, and the mixture was stirred with heating at 80 ° C. for 2 hr. A saturated aqueous sodium hydrogen carbonate solution (5.0 mL) and ethyl acetate (5.0 mL) were added to the reaction mixture and shaken, and then the organic layer was separated. The aqueous layer was then extracted twice with ethyl acetate (10 mL), and the combined organic layers were washed with a saturated aqueous sodium chloride solution (10 mL). The organic layer was separated, dried over anhydrous magnesium sulfate, and concentrated to dryness under reduced pressure to give methyl (1s, 4s) -4- (hydroxymethyl) cyclohexanecarboxylate (522 mg, yield 96%) as a colorless oil. Obtained. The obtained oil was used for the next reaction without purification.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.19-1.73 (1H, brs), 1.22-1.38 (2H, m), 1.50-1.70 (5H, m ), 1.94-2.09 (2H, m), 2.58 (1H, tt, J = 4.9, 4.1 Hz), 3.50 (2H, d, J = 5.9 Hz), 3 .69 (3H, s).

参考例２１１−２
（１ｓ,４ｓ）−４−[(トリフルオロメチルスルホニルオキシ)メチル]シクロヘキサンカルボン酸メチルの製造
参考例２１１−１で得られた（１ｓ,４ｓ）−４−（ヒドロキシメチル）シクロヘキサンカルボン酸メチル（２００ｍｇ、１．１６ｍｍｏｌ）とピリジン（１８７μＬ、２．３２ｍｍｏｌ）をジクロロメタン（１０ｍＬ）に溶かした後、反応溶液を−７８℃に冷却し、次いで、トリフルオロメタンスルホン酸無水物（東京化成工業（株）より購入）（３４３μＬ、２．１ｍｍｏｌ）をゆっくり加えた。一時間半同温で撹拌した後、反応混合物に水（５ｍＬ）と酢酸エチル（５ｍＬ）を加えて有機層を分離した。水層を酢酸エチル（１０ｍＬ）で２回抽出し、合わせた有機層を飽和炭酸水素ナトリウム水溶液（１０ｍＬ）と飽和塩化ナトリウム水溶液（１０ｍＬ）で洗浄したのち、無水硫酸マグネシウムで乾燥し、減圧下濃縮乾固して、（１ｓ,４ｓ）−４−[(トリフルオロメチルスルホニルオキシ)メチル]シクロヘキサンカルボン酸メチル（２６６ｍｇ、収率７５％）を無色油状物として得た。得られた生成物は、これ以上精製せずに次の反応に用いた。

^１Ｈ−ＮＭＲ（３００ＭＨｚ，ＣＤＣｌ_３）δ：１．２２−１．４２（２Ｈ，ｍ），１．５１−１．７５（４Ｈ，ｍ），１．８４−２．１４（３Ｈ，ｍ），２．６４（１Ｈ，ｔｔ，Ｊ＝４．５，４．５Ｈｚ），３．７０（３Ｈ，ｓ），４．３５（２Ｈ，ｄ，Ｊ＝７．４Ｈｚ）．

Reference Example 211-2
Production of methyl (1s, 4s) -4-[(trifluoromethylsulfonyloxy) methyl] cyclohexanecarboxylate Methyl (1s, 4s) -4- (hydroxymethyl) cyclohexanecarboxylate obtained in Reference Example 211-1 ( 200 mg, 1.16 mmol) and pyridine (187 μL, 2.32 mmol) were dissolved in dichloromethane (10 mL), the reaction solution was cooled to −78 ° C., and then trifluoromethanesulfonic anhydride (Tokyo Chemical Industry Co., Ltd.). Purchased more) (343 μL, 2.1 mmol) was added slowly. After stirring at the same temperature for 1.5 hours, water (5 mL) and ethyl acetate (5 mL) were added to the reaction mixture, and the organic layer was separated. The aqueous layer was extracted twice with ethyl acetate (10 mL), and the combined organic layer was washed with saturated aqueous sodium hydrogen carbonate solution (10 mL) and saturated aqueous sodium chloride solution (10 mL), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. Drying afforded methyl (1s, 4s) -4-[(trifluoromethylsulfonyloxy) methyl] cyclohexanecarboxylate (266 mg, 75% yield) as a colorless oil. The obtained product was used in the next reaction without further purification.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.22-1.42 (2H, m), 1.51-1.75 (4H, m), 1.84-2.14 (3H, m) , 2.64 (1H, tt, J = 4.5, 4.5 Hz), 3.70 (3H, s), 4.35 (2H, d, J = 7.4 Hz).

参考例２１１−３
３−{[(１ｓ,４ｓ)−４−(メトキシカルボニル)シクロヘキシル]メチル}−２−オキソ−１−オキサ−３，８−ジアザスピロ[４.５]デカン−８−カルボン酸ｔ−ブチルの製造
参考例１１１−１で得られた２−オキソ−１−オキサ−３，８−ジアザスピロ[４.５]デカン−８−カルボン酸ｔ−ブチル（０．１１ｇ、０．４３ｍｍｏｌ）をテトラヒドロフラン（１．０ｍＬ）に溶かした後、水素化ナトリウム（＞５５重量％、流動パラフィン分散、関東化学（株）より購入）（２３ｍｇ、０．５２ｍｍｏｌ）を加えて室温で一時間撹拌した。次いで、反応混合物に参考例２１１−２で得られた（１ｓ,４ｓ）−４−[（トリフルオロメチルスルホニルオキシ）メチル]シクロヘキサンカルボン酸メチル（０．２８ｇ、０．８５ｍｍｏｌ）のテトラヒドロフラン溶液（１．０ｍＬ）とヨウ化ナトリウム（関東化学（株）より購入）（６．５ｍｇ、０．０４ｍｍｏｌ）を加えた後、８０℃で一時間撹拌した。その後、反応混合物に水（２．０ｍＬ）と酢酸エチル（２．０ｍＬ）を加えて振とうし、有機層を分離した後、水層を酢酸エチル（１０ｍＬ）で２回抽出した。合わせた有機層を飽和塩化ナトリウム水溶液（１０ｍＬ）で洗浄した後、無水硫酸マグネシウムで乾燥し、減圧下濃縮乾固した。得られた無色油状物をシリカゲルカラムクロマトグラフィー［充填剤：富士シリシア社製ＦＬ１００Ｄ、展開溶媒：ヘキサン／酢酸エチル＝２／１］にて精製し、３−{[(１ｓ,４ｓ)−４−(メトキシカルボニル)シクロヘキシル]メチル}−２−オキソ−１−オキサ−３，８−ジアザスピロ[４.５]デカン−８−カルボン酸ｔ−ブチル（０．１０ｇ、収率５７％）を白色固体として得た。

^１Ｈ−ＮＭＲ（３００ＭＨｚ，ＣＤＣｌ_３）δ：１．２０−１．３５（２Ｈ，ｍ），１．４６（９Ｈ，ｓ），１．４９−１．７３（７Ｈ，ｍ），１．８８（２Ｈ，ｄ，Ｊ＝１２．９Ｈｚ），１．９８−２．１１（２Ｈ，ｍ），２．５２−２．６１（１Ｈ，ｍ），３．１３（２Ｈ，ｄ，Ｊ＝７．６Ｈｚ），３．２０−３．３４（４Ｈ，ｍ），３．６８（３Ｈ，ｓ），３．７７−３．９２（２Ｈ，ｂｒ ｍ）．

Reference Example 211-3
Preparation of 3-{[(1s, 4s) -4- (methoxycarbonyl) cyclohexyl] methyl} -2-oxo-1-oxa-3,8-diazaspiro [4.5] decane-8-carboxylate t-butyl 2-Oxo-1-oxa-3,8-diazaspiro [4.5] decane-8-carboxylate t-butyl (0.11 g, 0.43 mmol) obtained in Reference Example 111-1 was added to tetrahydrofuran (1. (0 mL), sodium hydride (> 55 wt%, liquid paraffin dispersion, purchased from Kanto Chemical Co., Inc.) (23 mg, 0.52 mmol) was added, and the mixture was stirred at room temperature for 1 hour. Next, a tetrahydrofuran solution (1) of methyl (1s, 4s) -4-[(trifluoromethylsulfonyloxy) methyl] cyclohexanecarboxylate (0.28 g, 0.85 mmol) obtained in Reference Example 211-2 was added to the reaction mixture. 0.0 mL) and sodium iodide (purchased from Kanto Chemical Co., Inc.) (6.5 mg, 0.04 mmol) were added, followed by stirring at 80 ° C. for 1 hour. Thereafter, water (2.0 mL) and ethyl acetate (2.0 mL) were added to the reaction mixture and shaken to separate the organic layer, and then the aqueous layer was extracted twice with ethyl acetate (10 mL). The combined organic layers were washed with a saturated aqueous sodium chloride solution (10 mL), dried over anhydrous magnesium sulfate, and concentrated to dryness under reduced pressure. The resulting colorless oil was purified by silica gel column chromatography [filler: FL100D manufactured by Fuji Silysia Ltd., developing solvent: hexane / ethyl acetate = 2/1] to give 3-{[(1s, 4s) -4- (Methoxycarbonyl) cyclohexyl] methyl} -2-oxo-1-oxa-3,8-diazaspiro [4.5] decane-8-carboxylate t-butyl (0.10 g, 57% yield) as a white solid Obtained.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.20-1.35 (2H, m), 1.46 (9H, s), 1.49-1.73 (7H, m), 1.88 (2H, d, J = 12.9 Hz), 1.98-2.11 (2H, m), 2.52-2.61 (1H, m), 3.13 (2H, d, J = 7. 6 Hz), 3.20-3.34 (4H, m), 3.68 (3H, s), 3.77-3.92 (2H, br m).

参考例２１１−４
（１ｓ,４ｓ）−４−（{２−オキソ−８−[４−（トリフルオロメチル）ベンジル]−１−オキサ−３，８−ジアザスピロ[４.５]デカン−３−イル}メチル）シクロヘキサンカルボン酸メチルの製造
３−｛［５−（エトキシカルボニル）ピリジン−２−イル］メチル｝−２−オキソ−１−オキサ−３，８−ジアザスピロ［４．５］デカン−８−カルボン酸ｔ−ブチルの代わりに参考例２１１−３で得られた３−{[(１ｓ,４ｓ)−４−(メトキシカルボニル)シクロヘキシル]メチル}−２−オキソ−１−オキサ−３，８−ジアザスピロ[４.５]デカン−８−カルボン酸ｔ−ブチル（１２ｍｇ、０．０３５ｍｍｏｌ）を用いること以外は実質的に参考例１１１−４と同様に反応を行なって、表題化合物を白色固体(１３ｍｇ、収率８１％)として得た。

^１Ｈ−ＮＭＲ（３００ＭＨｚ，ＣＤＣｌ_３）δ：１．１８−１．３４（２Ｈ，ｍ），１．４６−１．６２（４Ｈ，ｍ），１．６７−１．８３（３Ｈ，ｍ），１．９３（２Ｈ，ｄ，Ｊ＝１３．５Ｈｚ），１．９８−２．１０（２Ｈ，ｍ），２．４９−２．６１（５Ｈ，ｍ），３．１２（２Ｈ，ｄ，Ｊ＝７．４Ｈｚ），３．２６（２Ｈ，ｓ），３．５６（２Ｈ，ｂｒ ｓ），３．６７（３Ｈ，ｓ），７．４３（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ），７．５７（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ）．

Reference Example 211-4
(1s, 4s) -4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl) cyclohexane Preparation of methyl carboxylate 3-{[5- (ethoxycarbonyl) pyridin-2-yl] methyl} -2-oxo-1-oxa-3,8-diazaspiro [4.5] decane-8-carboxylic acid t- 3-{[((1s, 4s) -4- (methoxycarbonyl) cyclohexyl] methyl} -2-oxo-1-oxa-3,8-diazaspiro [4. 5] The reaction was performed in substantially the same manner as in Reference Example 111-4 except that t-butyl decane-8-carboxylate (12 mg, 0.035 mmol) was used, and the title compound was converted into a white solid (13 mg, yield 81 %).

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.18-1.34 (2H, m), 1.46-1.62 (4H, m), 1.67-1.83 (3H, m) 1.93 (2H, d, J = 13.5 Hz), 1.98-2.10 (2H, m), 2.49-2.61 (5H, m), 3.12 (2H, d, J = 7.4 Hz), 3.26 (2H, s), 3.56 (2H, br s), 3.67 (3H, s), 7.43 (2H, d, J = 8.2 Hz), 7.57 (2H, d, J = 8.2 Hz).

参考例２１１−５
（１ｓ,４ｓ）−４−（{２−オキソ−８−[４−（トリフルオロメチル）ベンジル]−１−オキサ−３，８−ジアザスピロ[４.５]デカン−３−イル}メチル）シクロヘキサンカルボン酸の製造
（１ｒ，４ｒ）−４−（｛２−オキソ−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）シクロヘキサンカルボン酸メチルの代わりに参考例２１１−４で得られた（１ｓ,４ｓ）−４−（{２−オキソ−８−[４−（トリフルオロメチル）ベンジル]−１−オキサ−３，８−ジアザスピロ[４.５]デカン−３−イル}メチル）シクロヘキサンカルボン酸メチル（１３ｍｇ、０．０２７ｍｍｏｌ）を用いること以外は実質的に参考例６−３と同様に反応を行なって、表題化合物を白色固体(１１ｍｇ、収率９０％)として得た。

ＬＣ／ＭＳ［条件１］：保持時間３．０４分；ｍ／ｚ４５４．８［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ４５３．０［Ｍ−Ｈ］^―（ＥＳＩ負イオンモード）

Reference Example 211-5
(1s, 4s) -4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl) cyclohexane Preparation of carboxylic acid (1r, 4r) -4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl } Methyl) (1s, 4s) -4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-] obtained in Reference Example 211-4 instead of methyl cyclohexanecarboxylate 3,8-diazaspiro [4.5] decan-3-yl} methyl) cyclohexanecarboxylate (13 mg, 0.027 mmol) was used, except that the reaction was carried out in substantially the same manner as in Reference Example 6-3. The title compound is converted to a white solid (1 mg, was obtained as 90% yield).

LC / MS [Condition 1]: Retention time 3.04 minutes; m / z 454.8 [M + H] ⁺ (ESI positive ion mode), m / z 453.0 [M−H] ⁻ (ESI negative ion mode)

実施例２１１
（１ｓ,４ｓ）−４−（{２−オキソ−８−[４−（トリフルオロメチル）ベンジル]−１−オキサ−３，８−ジアザスピロ[４.５]デカン−３−イル}メチル）−Ｎ−[(テトラヒドロフラン−２−イル)メチル]シクロヘキサンカルボキサミド（化合物番号２１１）の製造
（１ｒ，４ｒ）−４−（｛２−オキソ−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）シクロヘキサンカルボン酸の代わりに参考例２１１−５で得られた（１ｓ,４ｓ）−４−（{２−オキソ−８−[４−（トリフルオロメチル）ベンジル]−１−オキサ−３，８−ジアザスピロ[４.５]デカン−３−イル}メチル）シクロヘキサンカルボン酸（１１ｍｇ、０．０２４ｍｍｏｌ）を用いること以外は実質的に実施例１０と同様に反応を行なって、表題化合物を無色油状物（７.３ｍｇ、収率５７％)として得た。

^１Ｈ−ＮＭＲ（３００ＭＨｚ，ＣＤＣｌ_３）δ：１．４０−１．６９（７Ｈ，ｍ），１．７０−２．０４（１０Ｈ，ｍ），２．３０（１Ｈ，ｔｔ，Ｊ＝７．８，３．７Ｈｚ），２．５５（４Ｈ，ｂｒ ｓ），３．１２（１Ｈ，ｄｄｄ，Ｊ＝１３．５，７．４，４．５Ｈｚ），３．２０（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ），３．２７（２Ｈ，ｓ），３．５７（２Ｈ，ｓ），３．５９（１Ｈ，ｄｄｄ，Ｊ＝１３．５，６．５，３．３Ｈｚ），３．７５（１Ｈ，ｄｔ，Ｊ＝８．２，７．０Ｈｚ），３．８５（１Ｈ，ｄｔ，Ｊ＝８．２，７．０Ｈｚ），３．９４（１Ｈ，ｄｑ，Ｊ＝３．３，７．０Ｈｚ），６．００（１Ｈ，ｔ，Ｊ＝４．５Ｈｚ），７．４４（２Ｈ，ｄ，Ｊ＝８．０Ｈｚ），７．５７（２Ｈ，ｄ，Ｊ＝８．０Ｈｚ）．

ＬＣ／ＭＳ［条件１］：保持時間３．１５分；ｍ／ｚ５３７．９［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ５８２．１［Ｍ＋ＨＣＯＯ］^―（ＥＳＩ負イオンモード）

Example 211
(1s, 4s) -4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl)- Preparation of N-[(tetrahydrofuran-2-yl) methyl] cyclohexanecarboxamide (Compound No. 211) (1r, 4r) -4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1- (1s, 4s) -4-({2-oxo-8) obtained in Reference Example 211-5 instead of oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl) cyclohexanecarboxylic acid -[4- (Trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl) cyclohexanecarboxylic acid (11 mg, 0.024 mmol) is substantially used except that Conducted 10 by performing the same reaction as the title compound was obtained as a colorless oil (7.3 mg, 57% yield).

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.40-1.69 (7H, m), 1.70-2.04 (10H, m), 2.30 (1H, tt, J = 7. 8, 3.7 Hz), 2.55 (4 H, br s), 3.12 (1 H, ddd, J = 13.5, 7.4, 4.5 Hz), 3.20 (2 H, d, J = 8.2 Hz), 3.27 (2H, s), 3.57 (2H, s), 3.59 (1H, ddd, J = 13.5, 6.5, 3.3 Hz), 3.75 ( 1H, dt, J = 8.2, 7.0 Hz), 3.85 (1H, dt, J = 8.2, 7.0 Hz), 3.94 (1H, dq, J = 3.3, 7.). 0 Hz), 6.00 (1H, t, J = 4.5 Hz), 7.44 (2H, d, J = 8.0 Hz), 7.57 (2H, d, J = 8.0 Hz).

LC / MS [Condition 1]: Retention time 3.15 minutes; m / z 537.9 [M + H] ⁺ (ESI positive ion mode), m / z 582.1 [M + HCOO] ⁻ (ESI negative ion mode)

実施例２１２
４−［（１ｓ,４ｓ）−４−（｛２−オキソ−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）シクロヘキサンカルボキサミド］ピペリジン−１−カルボン酸ｔ−ブチル（化合物番号２１２）の製造
テトラヒドロフルフリルアミンの代わりに、４−アミノ−１−ｔ−ブトキシカルボニルピペリジン（アルドリッチ社より購入）を用いること以外は実質的に実施例２１１と同様に反応を行なって、表題化合物を白色固体(４８ｍｇ、収率６９％)として得た。

^１Ｈ−ＮＭＲ（ＣＤＣｌ_３）δ：１．２７（２Ｈ，ｄｑ，Ｊ＝４．１，１１．５Ｈｚ），１．４１−１．６９（６Ｈ，ｍ），１．４６（９Ｈ，ｓ），１．７１−１．９９（９Ｈ，ｍ），２．２５（１Ｈ，ｔｔ，Ｊ＝７．４，４．１Ｈｚ），２．４７−２．６４（４Ｈ，ｂｒ ｍ），２．８４（２Ｈ，ｔ，Ｊ＝１２．７Ｈｚ），３．１９（２Ｈ，ｄ，Ｊ＝７．８Ｈｚ），３．２７（２Ｈ，ｓ），３．５７（２Ｈ，ｓ），３．９１（１Ｈ，ｄｔｔ，Ｊ＝７．４，１１．５，３．７Ｈｚ），３．９３−４．１５（２Ｈ，ｍ），５．３９（１Ｈ，ｄ，Ｊ＝７．８Ｈｚ），７．４４（２Ｈ，ｄ，Ｊ＝８．４Ｈｚ），７．５７（２Ｈ，ｄ，Ｊ＝８．４Ｈｚ）．

ＬＣ／ＭＳ［条件１］：保持時間３．６２分；ｍ／ｚ６３６．９［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ６８１．１［Ｍ＋ＨＣＯＯ］^―（ＥＳＩ負イオンモード）

Example 212
4-[(1s, 4s) -4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} Methyl) cyclohexanecarboxamide] Preparation of t-butyl piperidine-1-carboxylate (Compound No. 212) Instead of using tetrahydrofurfurylamine, 4-amino-1-t-butoxycarbonylpiperidine (purchased from Aldrich) was used. The reaction was carried out substantially as in Example 211 to obtain the title compound as a white solid (48 mg, yield 69%).

¹ H-NMR (CDCl ₃ ) δ: 1.27 (2H, dq, J = 4.1, 11.5 Hz), 1.41-1.69 (6H, m), 1.46 (9H, s) , 1.71-1.99 (9H, m), 2.25 (1H, tt, J = 7.4, 4.1 Hz), 2.47-2.64 (4H, br m), 2.84. (2H, t, J = 12.7 Hz), 3.19 (2H, d, J = 7.8 Hz), 3.27 (2H, s), 3.57 (2H, s), 3.91 (1H , Dtt, J = 7.4, 11.5, 3.7 Hz), 3.93-4.15 (2H, m), 5.39 (1H, d, J = 7.8 Hz), 7.44 ( 2H, d, J = 8.4 Hz), 7.57 (2H, d, J = 8.4 Hz).

LC / MS [Condition 1]: Retention time 3.62 minutes; m / z 636.9 [M + H] ⁺ (ESI positive ion mode), m / z 681.1 [M + HCOO] ⁻ (ESI negative ion mode)

実施例２１３
（１ｓ,４ｓ）−Ｎ−[１−(シアノメチル)ピペリジン−４−イル]−４−（{２−オキソ−８−[４−（トリフルオロメチル）ベンジル]−１−オキサ−３，８−ジアザスピロ[４.５]デカン−３−イル}メチル）シクロヘキサンカルボキサミド（化合物番号２１３）の製造
実施例２１２で得られた４−［（１ｓ,４ｓ）−４−（｛２−オキソ−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）シクロヘキサンカルボキサミド］ピペリジン−１−カルボン酸ｔ−ブチル（１６ｍｇ、０．０２５ｍｍｏｌ）を４Ｍ塩化水素−ジオキサン溶液（１ｍＬ）に溶かし、室温で１時間撹拌したのち、反応混合物を減圧下濃縮乾固した。得られた残留物をＮ，Ｎ−ジメチルホルムアミド（１．０ｍＬ）に溶かし、ブロモアセトニトリル（東京化成工業社より購入）（６．７μＬ、０．１０ｍｍｏｌ）およびトリエチルアミン（２１μＬ、０．１５ｍｍｏｌ）を順次加えて室温で１日間撹拌した。反応混合物に飽和塩化アンモニウム水溶液（２．０ｍＬ）と酢酸エチル（２．０ｍＬ）を加えて振とうした後、有機層を分離し、水層を酢酸エチル（１０ｍＬ）で２回抽出した。合わせた有機層を飽和塩化ナトリウム水溶液（１０ｍＬ）で洗浄したのち、無水硫酸マグネシウムで乾燥し、減圧下濃縮乾固した。得られた残留物をシリカゲルカラムクロマトグラフィー［充填剤：富士シリシア社製ＦＬ１００Ｄ、展開溶媒：酢酸エチル／メタノール＝５／１］にて精製し、表題化合物を白色固体（６．８ｍｇ、収率４７％）として得た。

^１Ｈ−ＮＭＲ（３００ＭＨｚ，ＣＤＣｌ_３）δ：１．４０−１．７０（８Ｈ，ｍ），１．７０−２．０３（９Ｈ，ｍ），２．２６（１Ｈ，ｔｔ，Ｊ＝７．８，４．１Ｈｚ），２．４６（２Ｈ，ｔｄ，Ｊ＝１１．１，２．５Ｈｚ），２．５０−２．６３（４Ｈ，ｂｒ ｍ），２．７７（２Ｈ，ｄｔ，Ｊ＝１１．９，４．１Ｈｚ），３．１９（２Ｈ，ｄ，Ｊ＝７．４Ｈｚ），３．２７（２Ｈ，ｓ），３．５１（２Ｈ，ｓ），３．５７（２Ｈ，ｂｒ ｓ），３．８２（１Ｈ，ｄｔｔ，Ｊ＝７．８，１０．４，４．０Ｈｚ），５．３７（１Ｈ，ｄ，Ｊ＝７．４Ｈｚ），７．４４（２Ｈ，ｄ，Ｊ＝７．８Ｈｚ），７．５７（２Ｈ，ｄ，Ｊ＝７．８Ｈｚ）．

Example 213
(1s, 4s) -N- [1- (cyanomethyl) piperidin-4-yl] -4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8- Preparation of diazaspiro [4.5] decan-3-yl} methyl) cyclohexanecarboxamide (Compound No. 213) 4-[(1s, 4s) -4-({2-oxo-8- [ 4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl) cyclohexanecarboxamide] piperidine-1-carboxylate (16 mg, 0.025 mmol) ) Was dissolved in 4M hydrogen chloride-dioxane solution (1 mL) and stirred at room temperature for 1 hour, and then the reaction mixture was concentrated to dryness under reduced pressure. The obtained residue was dissolved in N, N-dimethylformamide (1.0 mL), and bromoacetonitrile (purchased from Tokyo Chemical Industry Co., Ltd.) (6.7 μL, 0.10 mmol) and triethylamine (21 μL, 0.15 mmol) were sequentially added. In addition, the mixture was stirred at room temperature for 1 day. A saturated aqueous ammonium chloride solution (2.0 mL) and ethyl acetate (2.0 mL) were added to the reaction mixture, and the mixture was shaken. The organic layer was separated, and the aqueous layer was extracted twice with ethyl acetate (10 mL). The combined organic layers were washed with a saturated aqueous sodium chloride solution (10 mL), dried over anhydrous magnesium sulfate, and concentrated to dryness under reduced pressure. The obtained residue was purified by silica gel column chromatography [filler: FL100D manufactured by Fuji Silysia Ltd., developing solvent: ethyl acetate / methanol = 5/1], and the title compound was purified as a white solid (6.8 mg, yield 47). %).

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.40-1.70 (8H, m), 1.70-2.03 (9H, m), 2.26 (1H, tt, J = 7. 8, 4.1 Hz), 2.46 (2H, td, J = 11.1, 2.5 Hz), 2.50-2.63 (4H, br m), 2.77 (2H, dt, J = 11.9, 4.1 Hz), 3.19 (2H, d, J = 7.4 Hz), 3.27 (2H, s), 3.51 (2H, s), 3.57 (2H, br s) ), 3.82 (1H, dtt, J = 7.8, 10.4, 4.0 Hz), 5.37 (1H, d, J = 7.4 Hz), 7.44 (2H, d, J = 7.8 Hz), 7.57 (2H, d, J = 7.8 Hz).

実施例２１４
４−［（１ｓ,４ｓ）−４−（｛２−オキソ−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）シクロヘキサンカルボキサミド］ピペリジン−１−カルボン酸メチル（化合物番号２１４）の製造
ブロモアセトニトリルの代わりに、クロロギ酸メチル（東京化成工業（株）より購入）を用いること以外は実質的に実施例２１３と同様に反応を行なって、表題化合物を白色固体(１０ｍｇ、収率６８％)として得た。

^１Ｈ−ＮＭＲ（３００ＭＨｚ，ＣＤＣｌ_３）δ：１．２９（２Ｈ，ｄｑ，Ｊ＝４．９，１１．８Ｈｚ），１．４１−１．７２（６Ｈ，ｍ），１．７２−１．９９（９Ｈ，ｍ），２．２５（１Ｈ，ｔｔ，Ｊ＝７．８，３．７Ｈｚ），２．４６−２．６４（４Ｈ，ｂｒ ｍ），２．９０（２Ｈ，ｔ，Ｊ＝１２．７Ｈｚ），３．１９（２Ｈ，ｄ，Ｊ＝７．８Ｈｚ），３．２７（２Ｈ，ｓ），３．５７（２Ｈ，ｂｒ ｓ），３．６９（３Ｈ，ｓ），３．９３（１Ｈ，ｄｔｔ，Ｊ＝７．４，１１．５，３．７Ｈｚ），４．００−４．１３（２Ｈ，ｂｒ ｍ），５．３８（１Ｈ，ｄ，Ｊ＝８．２Ｈｚ），７．４４（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ），７．５７（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ）．

Example 214
4-[(1s, 4s) -4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} Methyl) cyclohexanecarboxamide] Production of methyl piperidine-1-carboxylate (Compound No. 214) Instead of bromoacetonitrile, methyl chloroformate (purchased from Tokyo Chemical Industry Co., Ltd.) was used. The same reaction was performed to obtain the title compound as a white solid (10 mg, yield 68%).

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.29 (2H, dq, J = 4.9, 11.8 Hz), 1.41-1.72 (6H, m), 1.72-1. 99 (9H, m), 2.25 (1 H, tt, J = 7.8, 3.7 Hz), 2.46-2.64 (4H, br m), 2.90 (2H, t, J = 12.7 Hz), 3.19 (2H, d, J = 7.8 Hz), 3.27 (2H, s), 3.57 (2H, br s), 3.69 (3H, s), 3. 93 (1H, dtt, J = 7.4, 11.5, 3.7 Hz), 4.00-4.13 (2H, br m), 5.38 (1H, d, J = 8.2 Hz), 7.44 (2H, d, J = 8.2 Hz), 7.57 (2H, d, J = 8.2 Hz).

実施例２１５
３−（４−{４−[（メトキシイミノ）(フェニル)メチル]ピペリジン−１−カルボニル}ベンジル）−８−[４−(トリフルオロメチル)ベンジル]−１−オキサ−３，８−ジアザスピロ[４.５]デカン−２−オン（化合物番号２１５）の製造
実施例５５で得られた３−[４−(４−ベンゾイルピペリジン−１−カルボニル)ベンジル]−８−[４−(トリフルオロメチル)ベンジル]−１−オキサ−３，８−ジアザスピロ[４.５]デカン−２−オン（３０ｍｇ、０．０４９ｍｍｏｌ）、メトキシアミン塩酸塩（アルドリッチ（株）より購入）（８．２ｍｇ、０．０９８ｍｍｏｌ）と酢酸ナトリウム（純正化学（株）より購入）（８．０ｍｇ、０．０９８ｍｍｏｌ）をエタノール（１．０ｍＬ）に溶かし、１００℃で２８時間撹拌した。その後、反応混合物に水（５．０ｍＬ）と酢酸エチル（５．０ｍＬ）を加えて振とうした後、有機層を分離し、水層を酢酸エチル（１０ｍＬ）で２回抽出した。合わせた有機層を飽和塩化ナトリウム水溶液（１０ｍＬ）で洗浄したのち、無水硫酸マグネシウムで乾燥し、減圧下濃縮乾固した。得られた残留物をシリカゲルカラムクロマトグラフィー［充填剤：富士シリシア社製ＦＬ１００Ｄ、展開溶媒：酢酸エチル／メタノール＝２０／１］にて精製し、３−（４−{４−[（メトキシイミノ）(フェニル)メチル]ピペリジン−１−カルボニル}ベンジル）−８−[４−(トリフルオロメチル)ベンジル]−１−オキサ−３，８−ジアザスピロ[４.５]デカン−２−オン（１４ｍｇ、収率４４％）を無色油状物として得た。

^１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ_６）δ：１．４１（１Ｈ，ｂｒ ｑ，Ｊ＝１１．９Ｈｚ），１．５４−１．８９（７Ｈ，ｂｒ ｍ），２．３４−２．４７（４Ｈ，ｂｒ ｍ），２．７１−２．８９＆３．３４−３．４８（１Ｈ，ｅａｃｈ ｍ），２．７１−３．１５（２Ｈ，ｂｒ ｍ），３．２２（２Ｈ，ｂｒ ｓ），３．５７（２Ｈ，ｓ），３．５８（１Ｈ，ｂｒ ｓ），３．７０＆３．８７（３Ｈ，ｅａｃｈ ｓ），４．３８（２Ｈ，ｓ），４．４８（１Ｈ，ｂｒ ｓ），７．２１−７．４４（９Ｈ，ｍ），７．５３（２Ｈ，ｄ，Ｊ＝８．６Ｈｚ），７．６８（２Ｈ，ｄ，Ｊ＝８．６Ｈｚ）．

ＬＣ／ＭＳ［条件１］：保持時間３．８２分；ｍ／ｚ６４９．０［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ６９３．２［Ｍ＋ＨＣＯＯ］^―（ＥＳＩ負イオンモード）

Example 215
3- (4- {4-[(methoxyimino) (phenyl) methyl] piperidine-1-carbonyl} benzyl) -8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [ 4.5] Preparation of decan-2-one (Compound No. 215) 3- [4- (4-Benzoylpiperidine-1-carbonyl) benzyl] -8- [4- (trifluoromethyl) obtained in Example 55 ) Benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-2-one (30 mg, 0.049 mmol), methoxyamine hydrochloride (purchased from Aldrich Co.) (8.2 mg,. 098 mmol) and sodium acetate (purchased from Junsei Co., Ltd.) (8.0 mg, 0.098 mmol) were dissolved in ethanol (1.0 mL) and stirred at 100 ° C. for 28 hours. Thereafter, water (5.0 mL) and ethyl acetate (5.0 mL) were added to the reaction mixture and shaken, the organic layer was separated, and the aqueous layer was extracted twice with ethyl acetate (10 mL). The combined organic layers were washed with a saturated aqueous sodium chloride solution (10 mL), dried over anhydrous magnesium sulfate, and concentrated to dryness under reduced pressure. The obtained residue was purified by silica gel column chromatography [filler: FL100D manufactured by Fuji Silysia Ltd., developing solvent: ethyl acetate / methanol = 20/1], and 3- (4- {4-[(methoxyimino) (Phenyl) methyl] piperidine-1-carbonyl} benzyl) -8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-2-one (14 mg, yield) 44%) as a colorless oil.

¹ H-NMR (DMSO-d ₆ ) δ: 1.41 (1H, br q, J = 11.9 Hz), 1.54-1.89 (7H, br m), 2.34-2.47 ( 4H, br m), 1.71-2.89 & 3.34-3.48 (1H, each m), 2.71-3.15 (2H, br m), 3.22 (2H, br s), 3.57 (2H, s), 3.58 (1H, br s), 3.70 & 3.87 (3H, each), 4.38 (2H, s), 4.48 (1H, br s) 7.21-7.44 (9H, m), 7.53 (2H, d, J = 8.6 Hz), 7.68 (2H, d, J = 8.6 Hz).

LC / MS [Condition 1]: Retention time 3.82 minutes; m / z 649.0 [M + H] ⁺ (ESI positive ion mode), m / z 693.2 [M + HCOO] ⁻ (ESI negative ion mode)

実施例２１６
３−[４−(４−ベンゾイルピペリジン−１−カルボニル)−２−メトキシベンジル]−８−[４−(トリフルオロメチル)ベンジル]−１−オキサ−３，８−ジアザスピロ[４.５]デカン−２−オン（化合物番号２１６）の製造
テトラヒドロフルフリルアミンの代わりに４−ベンゾイルピペリジン塩酸塩（アクロスより購入）とトリエチルアミンを用いること以外は実質的に実施例１１５と同様に反応を行なって、表題化合物を無色油状物（１６ｍｇ、収率５４％)として得た。

^１Ｈ−ＮＭＲ（３００ＭＨｚ，ＣＤＣｌ_３）δ：１．５８−２．０６（８Ｈ，ｍ），２．４４−２．６３（４Ｈ，ｍ），２．９９−３．２６（２Ｈ，ｍ），３．１６（２Ｈ，ｓ），３．５０−３．６３（１Ｈ，ｍ），３．５６（２Ｈ，ｓ），３．８６（３Ｈ，ｓ），３．８９（１Ｈ，ｂｒ ｓ），４．４７（２Ｈ，ｓ），４．６９（１Ｈ，ｂｒ ｓ），６．９０−７．０３（２Ｈ，ｍ），７．２６（１Ｈ，ｄ，Ｊ＝７．０Ｈｚ），７．３６−７．６５（７Ｈ，ｍ），７．９５（２Ｈ，ｄ，Ｊ＝７．４Ｈｚ）．

ＬＣ／ＭＳ［条件１］：保持時間３．５４分；ｍ／ｚ６５０．２［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ６９４．３［Ｍ＋ＨＣＯＯ］^―（ＥＳＩ負イオンモード）

Example 216
3- [4- (4-Benzoylpiperidine-1-carbonyl) -2-methoxybenzyl] -8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decane Preparation of 2-one (Compound No. 216) The reaction was conducted in substantially the same manner as in Example 115 except that 4-benzoylpiperidine hydrochloride (purchased from Acros) and triethylamine were used instead of tetrahydrofurfurylamine. The compound was obtained as a colorless oil (16 mg, 54% yield).

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.58-2.06 (8H, m), 2.44-2.63 (4H, m), 2.99-3.26 (2H, m) , 3.16 (2H, s), 3.50-3.63 (1H, m), 3.56 (2H, s), 3.86 (3H, s), 3.89 (1H, br s) 4.47 (2H, s), 4.69 (1H, brs), 6.90-7.03 (2H, m), 7.26 (1H, d, J = 7.0 Hz), 7. 36-7.65 (7H, m), 7.95 (2H, d, J = 7.4 Hz).

LC / MS [Condition 1]: Retention time 3.54 minutes; m / z 650.2 [M + H] ⁺ (ESI positive ion mode), m / z 694.3 [M + HCOO] ⁻ (ESI negative ion mode)

参考例２１７−１
４−（シアノメチル）−４−ヒドロキシピペリジン−１−カルボン酸ｔ−ブチルの製造
アセトニトリル（関東化学株式会社より購入）（１．４ｍＬ、２５ｍｍｏｌ）のテトラヒドロフラン溶液（５０ｍＬ）に、リチウムヘキサメチルジシラジドの１．０Ｍテトラヒドロフラン溶液（アルドリッチ社より購入）（２８ｍＬ，２８ｍｍｏｌ）を−７８℃でゆっくり滴下し、同温にて３０分撹拌した。次いで、Ｎ−（ｔ−ブトキシカルボニル）ピペリジン−４−オン（和光純薬工業株式会社より購入）のテトラヒドロフラン溶液１５ｍＬを加え、徐々に室温まで昇温しながら反応溶液を１２時間撹拌した。その後、反応混合物に水（３０ｍＬ）と酢酸エチル（３０ｍＬ）を加えて振とうし、有機層を分離した後、水層を酢酸エチル（１０ｍＬ）で２回抽出した。合わせた有機層を無水硫酸マグネシウムで乾燥し、減圧下濃縮乾固した後、得られた橙色油状物をシリカゲルカラムクロマトグラフィー［充填剤：富士シリシア社製ＦＬ１００Ｄ、展開溶媒：ヘキサン／酢酸エチル＝１／１］にて精製し、表題化合物を黄色油状物（２．０ｇ、収率３２％)として得た。

^１Ｈ−ＮＭＲ（３００ＭＨｚ，ＣＤＣｌ_３）δ：１．４６（９Ｈ，ｓ），１．５５−１．７９（４Ｈ，ｍ），１．９９（１Ｈ，ｂｒ ｓ），２．５３（２Ｈ，ｓ），３．１５（２Ｈ，ｔ，Ｊ＝１２．３Ｈｚ），３．９０（２Ｈ，ｄ，Ｊ＝１４．３Ｈｚ）．

Reference Example 217-1
Preparation of t-butyl 4- (cyanomethyl) -4-hydroxypiperidine-1-carboxylate To a tetrahydrofuran solution (50 mL) of acetonitrile (purchased from Kanto Chemical Co., Inc.) (1.4 mL, 25 mmol), lithium hexamethyldisilazide 1.0M tetrahydrofuran solution (purchased from Aldrich) (28 mL, 28 mmol) was slowly added dropwise at −78 ° C. and stirred at the same temperature for 30 minutes. Subsequently, 15 mL of tetrahydrofuran solution of N- (t-butoxycarbonyl) piperidin-4-one (purchased from Wako Pure Chemical Industries, Ltd.) was added, and the reaction solution was stirred for 12 hours while gradually warming to room temperature. Thereafter, water (30 mL) and ethyl acetate (30 mL) were added to the reaction mixture and shaken to separate the organic layer, and then the aqueous layer was extracted twice with ethyl acetate (10 mL). The combined organic layers were dried over anhydrous magnesium sulfate and concentrated to dryness under reduced pressure. The obtained orange oil was subjected to silica gel column chromatography [filler: FL100D manufactured by Fuji Silysia Ltd., developing solvent: hexane / ethyl acetate = 1. / 1] to give the title compound as a yellow oil (2.0 g, yield 32%).

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.46 (9H, s), 1.55-1.79 (4H, m), 1.99 (1H, br s), 2.53 (2H, s), 3.15 (2H, t, J = 12.3 Hz), 3.90 (2H, d, J = 14.3 Hz).

参考例２１７−２
２−オキソ−１−オキサ−３，９−ジアザスピロ[５.５]ウンデカン−９−カルボン酸ｔ−ブチルの製造
参考例２１７−１で得られた４−（シアノメチル）−４−ヒドロキシピペリジン−１−カルボン酸ｔ−ブチル（０．５０ｇ、２．１ｍｍｏｌ）と塩化コバルト（II）六水和物（アルドリッチ社より購入）（０．９９ｇ、４．２ｍｍｏｌ）のメタノール溶液（２０ｍｌ）に、０℃にて水素化ホウ素ナトリウム（純正化学（株）より購入）（０．７９ｇ、２１ｍｍｏｌ）を三回に分けて加えた。発泡の消失を確認した後、反応混合物を室温まで昇温し、さらに１２０時間撹拌した。その後、反応混合物を０℃に冷却し、１Ｍ塩酸（１５ｍＬ）を加え、同温にて１０分間撹拌した。次いで、ジエチルエーテル（５０ｍＬ）を加えて振とうし、有機層を分離した。水層に２８重量％アンモニア水（６．０ｍＬ）を加えた後、酢酸エチル(５０ｍＬ)で三回抽出した。合わせた有機層を飽和塩化ナトリウム水溶液（１００ｍＬ）で洗浄し、無水硫酸マグネシウムで乾燥した後、減圧下濃縮乾固した。
得られた残留物を１，４−ジオキサン（１０ｍＬ）に溶かし、カルボニルジイミダゾール（東京化成工業社より購入）（０．３６ｇ、２．２ｍｍｏｌ）を加えた後、室温にて２０時間撹拌した。その後、反応混合物に飽和塩化アンモニウム水溶液（５．０ｍＬ）を加えた後、酢酸エチル（１０ｍＬ）で２回抽出した。合わせた有機層を飽和塩化ナトリウム水溶液（２０ｍＬ）で洗浄した後、無水硫酸マグネシウムで乾燥し、減圧下濃縮乾固した。得られた黄色油状物にジイソプロピルエーテル（１０ｍＬ）を加えて室温で放置した後、沈殿した結晶をろ取し、表題化合物を黄色固体（１２４．４ｍｇ、収率２２％)として得た。

^１Ｈ−ＮＭＲ（３００ＭＨｚ，ＣＤＣｌ_３）δ：１．４６（９Ｈ，ｓ），１．５９（２Ｈ，ｔｄ，Ｊ＝１３．３，４．７Ｈｚ），１．８０−１．９５（４Ｈ，ｍ），３．２９（２Ｈ，ｔ，Ｊ＝１３．１Ｈｚ），３．４１（２Ｈ，ｔｄ，Ｊ＝６．４，２．４Ｈｚ），３．７４−３．９５（２Ｈ，ｍ），５．２７（１Ｈ，ｂｒ ｓ）．

Reference Example 217-2
Preparation of t-butyl 2-oxo-1-oxa-3,9-diazaspiro [5.5] undecane-9-carboxylate 4- (cyanomethyl) -4-hydroxypiperidine-1 obtained in Reference Example 217-1 -To a methanol solution (20 ml) of t-butyl carboxylate (0.50 g, 2.1 mmol) and cobalt (II) chloride hexahydrate (purchased from Aldrich) (0.99 g, 4.2 mmol) at 0 ° C The sodium borohydride (purchased from Pure Chemical Co., Ltd.) (0.79 g, 21 mmol) was added in three portions. After confirming the disappearance of foaming, the reaction mixture was warmed to room temperature and further stirred for 120 hours. Thereafter, the reaction mixture was cooled to 0 ° C., 1M hydrochloric acid (15 mL) was added, and the mixture was stirred at the same temperature for 10 minutes. Next, diethyl ether (50 mL) was added and shaken to separate the organic layer. 28 wt% aqueous ammonia (6.0 mL) was added to the aqueous layer, and the mixture was extracted 3 times with ethyl acetate (50 mL). The combined organic layers were washed with a saturated aqueous sodium chloride solution (100 mL), dried over anhydrous magnesium sulfate, and concentrated to dryness under reduced pressure.
The obtained residue was dissolved in 1,4-dioxane (10 mL), carbonyldiimidazole (purchased from Tokyo Chemical Industry Co., Ltd.) (0.36 g, 2.2 mmol) was added, and the mixture was stirred at room temperature for 20 hours. Thereafter, a saturated aqueous ammonium chloride solution (5.0 mL) was added to the reaction mixture, and the mixture was extracted twice with ethyl acetate (10 mL). The combined organic layers were washed with a saturated aqueous sodium chloride solution (20 mL), dried over anhydrous magnesium sulfate, and concentrated to dryness under reduced pressure. Diisopropyl ether (10 mL) was added to the obtained yellow oil and allowed to stand at room temperature, and the precipitated crystals were collected by filtration to give the title compound as a yellow solid (124.4 mg, yield 22%).

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.46 (9H, s), 1.59 (2H, td, J = 13.3, 4.7 Hz), 1.80-1.95 (4H, m), 3.29 (2H, t, J = 13.1 Hz), 3.41 (2H, td, J = 6.4, 2.4 Hz), 3.74-3.95 (2H, m), 5.27 (1H, br s).

参考例２１７−３
３−[４−(メトキシカルボニル)ベンジル]−２−オキソ−１−オキサ−３，９−ジアザスピロ[５.５]ウンデカン−９−カルボン酸ｔ−ブチルの製造
参考例２１７−２で得られた２−オキソ−１−オキサ−３，９−ジアザスピロ[５．５]ウンデカン−９−カルボン酸ｔ−ブチル（０．１２ｇ、０．４６ｍｍｏｌ）のＮ，Ｎ−ジメチルホルムアミド溶液（１．５ｍＬ）に水素化ナトリウム（５５重量％、流動パラフィンに分散）（関東化学株式会社より購入）（２４ｍｇ、０．５５ｍｍｏｌ）を加え、室温で１時間撹拌した後、４−（ブロモメチル）安息香酸メチル（東京化成工業社より購入）（０．１３ｇ、０．５５ｍｍｏｌ）を加え、室温で４時間撹拌した。反応混合物に水（１．０ｍＬ）を加えて３０分撹拌した後、沈殿した結晶をろ取し、表題化合物を無色固体（０．１４ｇ、収率７１％)として得た。

^１Ｈ−ＮＭＲ（３００ＭＨｚ，ＣＤＣｌ_３）δ：１．４５（９Ｈ，ｓ），１．４９−１．６２（２Ｈ，ｍ），１．７５−１．８８（２Ｈ，ｍ），１．８６（２Ｈ，ｔ，Ｊ＝６．４Ｈｚ），３．２２（２Ｈ，ｔ，Ｊ＝６．４Ｈｚ），３．３２（２Ｈ，ｔ，Ｊ＝１２．３Ｈｚ），３．７６−３．９１（２Ｈ，ｍ），３．９２（３Ｈ，ｓ），４．６２（２Ｈ，ｓ），７．３６（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ），８．０２（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ）．

ＬＣ／ＭＳ［条件１］：保持時間４．２３分；ｍ／ｚ４１８．９［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）

Reference Example 217-3
Preparation of t-butyl 3- [4- (methoxycarbonyl) benzyl] -2-oxo-1-oxa-3,9-diazaspiro [5.5] undecane-9-carboxylate Obtained in Reference Example 217-2 To a solution of t-butyl 2-oxo-1-oxa-3,9-diazaspiro [5.5] undecane-9-carboxylate (0.12 g, 0.46 mmol) in N, N-dimethylformamide (1.5 mL). Sodium hydride (55% by weight, dispersed in liquid paraffin) (purchased from Kanto Chemical Co., Inc.) (24 mg, 0.55 mmol) was added and stirred at room temperature for 1 hour, and then methyl 4- (bromomethyl) benzoate (Tokyo Kasei) (Purchased from Kogyo Co., Ltd.) (0.13 g, 0.55 mmol) was added, and the mixture was stirred at room temperature for 4 hours. Water (1.0 mL) was added to the reaction mixture, and the mixture was stirred for 30 minutes. The precipitated crystals were collected by filtration to give the title compound as a colorless solid (0.14 g, yield 71%).

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.45 (9H, s), 1.49-1.62 (2H, m), 1.75-1.88 (2H, m), 1.86 (2H, t, J = 6.4 Hz), 3.22 (2H, t, J = 6.4 Hz), 3.32 (2H, t, J = 12.3 Hz), 3.76-3.91 ( 2H, m), 3.92 (3H, s), 4.62 (2H, s), 7.36 (2H, d, J = 8.2 Hz), 8.02 (2H, d, J = 8. 2 Hz).

LC / MS [Condition 1]: Retention time 4.23 minutes; m / z 418.9 [M + H] ⁺ (ESI positive ion mode)

参考例２１７−４
４−({２−オキソ−９−[４−（トリフルオロメチル）ベンジル]−１−オキサ−３，９−ジアザスピロ[５.５]ウンデカン−３−イル}メチル)安息香酸メチルの製造
４−メチル−２−オキソ−１−オキサ−３，８−ジアザスピロ［４．５］デカン−８−カルボン酸ｔ−ブチルの代わりに参考例２１７−３で得られた３−[４−(メトキシカルボニル)ベンジル]−２−オキソ−１−オキサ−３，９−ジアザスピロ[５.５]ウンデカン−９−カルボン酸ｔ−ブチル（４４ｍｇ、０．１１ｍｍｏｌ）を用いること以外は実質的に参考例１１９−５と同様に反応を行なって、表題化合物を黄色油状物（４８ｍｇ、収率９５％)として得た。

^１Ｈ−ＮＭＲ（３００ＭＨｚ，ＣＤＣｌ_３）δ：１．６０−１．９１（６Ｈ，ｍ），２．４９−２．７０（４Ｈ，ｂｒ ｍ），３．１３−３．２４（２Ｈ，ｍ），３．６０（２Ｈ，ｓ），３．９１（３Ｈ，ｓ），４．６１（２Ｈ，ｓ），７．３５（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ），７．４５（２Ｈ，ｄ，Ｊ＝７．８Ｈｚ），７．５６（２Ｈ，ｄ，Ｊ＝７．８Ｈｚ），７．９９（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ）．

ＬＣ／ＭＳ［条件１］：保持時間３．５０分；ｍ／ｚ４７６．９［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）

Reference Example 217-4
Preparation of methyl 4-({2-oxo-9- [4- (trifluoromethyl) benzyl] -1-oxa-3,9-diazaspiro [5.5] undecan-3-yl} methyl) benzoate 4- 3- [4- (methoxycarbonyl) -methyl-3-oxo-1-oxa-3,8-diazaspiro [4.5] decane-8-carboxylate 3- [4- (methoxycarbonyl) obtained in Reference Example 217-3 Benzyl] -2-oxo-1-oxa-3,9-diazaspiro [5.5] undecane-9-carboxylate t-butyl (44 mg, 0.11 mmol) substantially except Reference Example 119-5 The title compound was obtained as a yellow oil (48 mg, yield 95%).

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.60-1.91 (6H, m), 2.49-2.70 (4H, br m), 3.13-3.24 (2H, m ), 3.60 (2H, s), 3.91 (3H, s), 4.61 (2H, s), 7.35 (2H, d, J = 8.2 Hz), 7.45 (2H, d, J = 7.8 Hz), 7.56 (2H, d, J = 7.8 Hz), 7.99 (2H, d, J = 8.2 Hz).

LC / MS [Condition 1]: Retention time 3.50 minutes; m / z 476.9 [M + H] ⁺ (ESI positive ion mode)

参考例２１７−５
４−({２−オキソ−９−[４−（トリフルオロメチル）ベンジル]−１−オキサ−３，９−ジアザスピロ[５.５]ウンデカン−３−イル}メチル)安息香酸の製造
４−（｛２−オキソ−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）安息香酸メチルの代わりに参考例２１７−４で得られた４−({２−オキソ−９−[４−（トリフルオロメチル）ベンジル]−１−オキサ−３，９−ジアザスピロ[５.５]ウンデカン−３−イル}メチル)安息香酸メチル（４７ｍｇ、０．１０ｍｍｏｌ）を用いること以外は実質的に参考例２１と同様に反応を行なって、表題化合物を無色固体（３２ｍｇ、収率６９％)として得た。

ＬＣ／ＭＳ［条件１］：保持時間３．１８分；ｍ／ｚ４６２．９［Ｍ＋Ｈ］＋（ＥＳＩ正イオンモード）、ｍ／ｚ４６１．１［Ｍ−Ｈ］-（ＥＳＩ負イオンモード）

Reference Example 217-5
Preparation of 4-({2-Oxo-9- [4- (trifluoromethyl) benzyl] -1-oxa-3,9-diazaspiro [5.5] undecan-3-yl} methyl) benzoic acid 4- ( {2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl) Reference Example 217- in place of methyl benzoate 4-({2-oxo-9- [4- (trifluoromethyl) benzyl] -1-oxa-3,9-diazaspiro [5.5] undecan-3-yl} methyl) benzoic acid obtained in 4 The reaction was performed in substantially the same manner as in Reference Example 21 except that methyl (47 mg, 0.10 mmol) was used to give the title compound as a colorless solid (32 mg, yield 69%).

LC / MS [Condition 1]: Retention time 3.18 minutes; m / z 462.9 [M + H] + (ESI positive ion mode), m / z 461.1 [M−H] − (ESI negative ion mode)

実施例２１７
３−[４−(４−ベンゾイルピペリジン−１−カルボニル)ベンジル]−９−[４−(トリフルオロメチル)ベンジル]−１−オキサ−３，９−ジアザスピロ[５.５]ウンデカン−２−オン（化合物番号２１７）の製造
４−（｛２−オキソ−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）安息香酸の代わりに参考例２１７−５で得られた４−({２−オキソ−９−[４−（トリフルオロメチル）ベンジル]−１−オキサ−３，９−ジアザスピロ[５.５]ウンデカン−３−イル}メチル)安息香酸（５．４ｍｇ、０．０１２ｍｍｏｌ）を用いること以外は実質的に実施例５５と同様に反応を行なって、表題化合物を無色油状物（２．７ｍｇ、収率３６％)として得た。

^１Ｈ−ＮＭＲ（３００ＭＨｚ，ＣＤＣｌ_３）δ：１．６３−１．９５（１０Ｈ，ｍ），２．４９−２．６９（４Ｈ，ｂｒ ｍ），３．００−３．２５（２Ｈ，ｍ），３．２０（２Ｈ，ｔ，Ｊ＝６．４Ｈｚ），３．４８−３．６２（１Ｈ，ｂｒ ｍ），３．５９（２Ｈ，ｓ），３．８５（１Ｈ，ｂｒ ｓ），４．５９（２Ｈ，ｓ），４．６２（１Ｈ，ｂｒ ｓ），７．３２（２Ｈ，ｄ，Ｊ＝８．４Ｈｚ），７．３６−７．６３（９Ｈ，ｍ），７．９５（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ）．

ＬＣ／ＭＳ［条件１］：保持時間３．７８分；ｍ／ｚ６３４．０［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ６７８．２［Ｍ＋ＨＣＯＯ］^―（ＥＳＩ負イオンモード）

Example 217
3- [4- (4-Benzoylpiperidine-1-carbonyl) benzyl] -9- [4- (trifluoromethyl) benzyl] -1-oxa-3,9-diazaspiro [5.5] undecan-2-one Preparation of (Compound No. 217) 4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl) 4-({2-oxo-9- [4- (trifluoromethyl) benzyl] -1-oxa-3,9-diazaspiro [5.5] undecane obtained in Reference Example 217-5 instead of benzoic acid The reaction was carried out in substantially the same manner as in Example 55 except that -3-yl} methyl) benzoic acid (5.4 mg, 0.012 mmol) was used to give the title compound as a colorless oil (2.7 mg, yield). 36%).

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.63-1.95 (10H, m), 2.49-2.69 (4H, br m), 3.00-3.25 (2H, m ), 3.20 (2H, t, J = 6.4 Hz), 3.48-3.62 (1H, br m), 3.59 (2H, s), 3.85 (1H, br s), 4.59 (2H, s), 4.62 (1H, br s), 7.32 (2H, d, J = 8.4 Hz), 7.36-7.63 (9H, m), 7.95 (2H, d, J = 8.2 Hz).

LC / MS [Condition 1]: Retention time 3.78 minutes; m / z 634.0 [M + H] ⁺ (ESI positive ion mode), m / z 678.2 [M + HCOO] ⁻ (ESI negative ion mode)

実施例２１８
４−（{２−オキソ−９−[４−（トリフルオロメチル）ベンジル]−１−オキサ−３，９−ジアザスピロ[５.５]ウンデカン−３−イル}メチル）−Ｎ−[(テトラヒドロフラン−２−イル)メチル]ベンズアミド（化合物番号２１８）の製造
４−ベンゾイルピペリジン塩酸塩の代わりに、テトラヒドロフルフリルアミン（東京化成工業社より購入）を用いること以外は実質的に実施例２１７と同様に反応を行なって、表題化合物を黄色固体(１１ｍｇ、収率７５％)として得た。

^１Ｈ−ＮＭＲ（３００ＭＨｚ，ＣＤＣｌ_３）δ：１．５８−１．７５（３Ｈ，ｍ），１．７６−２．０８（７Ｈ，ｍ），２．４９−２．６６（４Ｈ，ｂｒ ｍ），３．１８（２Ｈ，ｔ，Ｊ＝６．１Ｈｚ），３．３２（１Ｈ，ｄｄｄ，Ｊ＝１３．９，７．８，４．９Ｈｚ），３．５８（２Ｈ，ｓ），３．７２−３．９６（３Ｈ，ｍ），４．０２−４．１３（１Ｈ，ｍ），４．６０（２Ｈ，ｓ），６．４４−６．４８（１Ｈ，ｂｒ ｍ），７．３５（２Ｈ，ｄ，Ｊ＝７．８Ｈｚ），７．４４（２Ｈ，ｄ，Ｊ＝７．８Ｈｚ），７．５６（２Ｈ，ｄ，Ｊ＝７．８Ｈｚ），７．７５（２Ｈ，ｄ，Ｊ＝７．８Ｈｚ）．

ＬＣ／ＭＳ［条件１］：保持時間３．４２分；ｍ／ｚ５４５．９［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）

Example 218
4-({2-oxo-9- [4- (trifluoromethyl) benzyl] -1-oxa-3,9-diazaspiro [5.5] undecan-3-yl} methyl) -N-[(tetrahydrofuran- Preparation of 2-yl) methyl] benzamide (Compound No. 218) In substantially the same manner as in Example 217, except that tetrahydrofurfurylamine (purchased from Tokyo Chemical Industry Co., Ltd.) was used instead of 4-benzoylpiperidine hydrochloride. To give the title compound as a yellow solid (11 mg, 75% yield).

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.58-1.75 (3H, m), 1.76-2.08 (7H, m), 2.49-2.66 (4H, br m ), 3.18 (2H, t, J = 6.1 Hz), 3.32 (1H, ddd, J = 13.9, 7.8, 4.9 Hz), 3.58 (2H, s), 3 .72-3.96 (3H, m), 4.02-4.13 (1H, m), 4.60 (2H, s), 6.44-6.48 (1H, br m), 7. 35 (2H, d, J = 7.8 Hz), 7.44 (2H, d, J = 7.8 Hz), 7.56 (2H, d, J = 7.8 Hz), 7.75 (2H, d , J = 7.8 Hz).

LC / MS [Condition 1]: retention time 3.42 minutes; m / z 545.9 [M + H] ⁺ (ESI positive ion mode)

実施例２１９
Ｎ−（ベンゾ[ｄ][１，３]ジオキソール−５−イルメチル）−４−({２−オキソ−９−[４−（トリフルオロメチル）ベンジル]−１−オキサ−３，９−ジアザスピロ[５.５]ウンデカン−３−イル}メチル）ベンズアミド（化合物番号２１９）の製造
４−ベンゾイルピペリジン塩酸塩の代わりに、ピペロニルアミン（東京化成工業社より購入）を用いること以外は実質的に実施例２１７と同様に反応を行なって、表題化合物を無色固体(５．３ｍｇ、収率３３％)として得た。

^１Ｈ−ＮＭＲ（３００ＭＨｚ，ＣＤＣｌ_３）δ：１．５８−１．７３（２Ｈ，ｍ），１．７８−１．９１（４Ｈ，ｍ），２．５２−２．６４（４Ｈ，ｂｒ ｍ），３．１８（２Ｈ，ｔ，Ｊ＝７．０Ｈｚ），３．５８（２Ｈ，ｓ），４．５４（２Ｈ，ｄ，Ｊ＝５．３Ｈｚ），４．６０（２Ｈ，ｓ），５．９５（２Ｈ，ｓ），６．３１（１Ｈ，ｔ，Ｊ＝４．９Ｈｚ），６．７７（１Ｈ，ｄ，Ｊ＝８．０Ｈｚ），６．８１（１Ｈ，ｄｄ，Ｊ＝８．０，１．２Ｈｚ），６．８５（１Ｈ，ｄ，Ｊ＝１．２Ｈｚ），７．３５（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ），７．４３（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ），７．５６（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ），７．７４（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ）．

ＬＣ／ＭＳ［条件１］：保持時間３．６８分；ｍ／ｚ５９６．０［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ５９４．２［Ｍ−Ｈ］^―（ＥＳＩ負イオンモード）

Example 219
N- (benzo [d] [1,3] dioxol-5-ylmethyl) -4-({2-oxo-9- [4- (trifluoromethyl) benzyl] -1-oxa-3,9-diazaspiro [ 5.5] Preparation of undecan -3-yl} methyl) benzamide (Compound No. 219) Example 217 was substantially used except that piperonylamine (purchased from Tokyo Chemical Industry Co., Ltd.) was used instead of 4-benzoylpiperidine hydrochloride. The title compound was obtained as a colorless solid (5.3 mg, yield 33%).

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.58-1.73 (2H, m), 1.78-1.91 (4H, m), 2.52-2.64 (4H, br m ), 3.18 (2H, t, J = 7.0 Hz), 3.58 (2H, s), 4.54 (2H, d, J = 5.3 Hz), 4.60 (2H, s), 5.95 (2H, s), 6.31 (1H, t, J = 4.9 Hz), 6.77 (1H, d, J = 8.0 Hz), 6.81 (1H, dd, J = 8) 0.0, 1.2 Hz), 6.85 (1H, d, J = 1.2 Hz), 7.35 (2H, d, J = 8.2 Hz), 7.43 (2H, d, J = 8. 2 Hz), 7.56 (2H, d, J = 8.2 Hz), 7.74 (2H, d, J = 8.2 Hz).

LC / MS [Condition 1]: Retention time 3.68 minutes; m / z 596.0 [M + H] ⁺ (ESI positive ion mode), m / z 594.2 [MH] ⁻ (ESI negative ion mode)

実施例２２０
４−[４−({２−オキソ−９−[４−(トリフルオロメチル)ベンジル]−１−オキサ−３，９−ジアザスピロ[５.５]ウンデカン−３−イル}メチル)ベンズアミド]ピペリジン−１−カルボン酸メチル（化合物番号２２０）の製造
４−ベンゾイルピペリジン塩酸塩の代わりに、参考例１３５で合成した４−アミノピペリジン−１−カルボン酸メチル塩酸塩を用いること以外は実質的に実施例２１７と同様に反応を行なって、表題化合物を黄色油状物(９．４ｍｇ、収率６１％)として得た。

^１Ｈ−ＮＭＲ（３００ＭＨｚ，ＣＤＣｌ_３）δ：１．３４−１．５２（２Ｈ，ｍ），１．５７−１．７５（２Ｈ，ｍ），１．７７−１．８９（４Ｈ，ｍ），１．９８−２．１０（２Ｈ，ｍ），２．４９−２．６４（４Ｈ，ｂｒ ｍ），２．９７（２Ｈ，ｔ，Ｊ＝１２．３Ｈｚ），３．１８（２Ｈ，ｔ，Ｊ＝５．７Ｈｚ），３．５９（２Ｈ，ｓ），３．７０（３Ｈ，ｓ），４．００−４．３１（３Ｈ，ｂｒ ｍ），４．６０（２Ｈ，ｓ），６．１２（１Ｈ，ｄ，Ｊ＝８．２Ｈｚ），７．３５（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ），７．４４（２Ｈ，ｄ，Ｊ＝７．８Ｈｚ），７．５７（２Ｈ，ｄ，Ｊ＝７．８Ｈｚ），７．７３（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ）．

ＬＣ／ＭＳ［条件１］：保持時間３．１４分；ｍ／ｚ６０３．０［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ６０１．２［Ｍ−Ｈ］^―（ＥＳＩ負イオンモード）

Example 220
4- [4-({2-oxo-9- [4- (trifluoromethyl) benzyl] -1-oxa-3,9-diazaspiro [5.5] undecan-3-yl} methyl) benzamido] piperidine- Preparation of methyl 1-carboxylate (Compound No. 220) Substantially Examples except that 4-aminopiperidine-1-carboxylic acid methyl hydrochloride synthesized in Reference Example 135 was used instead of 4-benzoylpiperidine hydrochloride The reaction was carried out in the same manner as 217 to give the title compound as a yellow oil (9.4 mg, 61% yield).

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.34 to 1.52 (2H, m), 1.57-1.75 (2H, m), 1.77 to 1.89 (4H, m) 1.98-2.10 (2H, m), 2.49-2.64 (4H, br m), 2.97 (2H, t, J = 12.3 Hz), 3.18 (2H, t , J = 5.7 Hz), 3.59 (2H, s), 3.70 (3H, s), 4.00-4.31 (3H, br m), 4.60 (2H, s), 6 .12 (1H, d, J = 8.2 Hz), 7.35 (2H, d, J = 8.2 Hz), 7.44 (2H, d, J = 7.8 Hz), 7.57 (2H, d, J = 7.8 Hz), 7.73 (2H, d, J = 8.2 Hz).

LC / MS [Condition 1]: Retention time 3.14 minutes; m / z 603.0 [M + H] ⁺ (ESI positive ion mode), m / z 601.2 [M−H] ⁻ (ESI negative ion mode)

実施例２２１
３−{４−[４−(３−イソプロピル−１，２，４−オキサジアゾール−５−イル)ピペリジン−１−カルボニル]ベンジル}−９−[４−(トリフルオロメチル)ベンジル]−１−オキサ−３，９−ジアザスピロ[５.５]ウンデカン−２−オン（化合物番号２２１）の製造
４−ベンゾイルピペリジン塩酸塩の代わりに、３−イソプロピル−５−（ピペリジン−４−イル）−１，２，４−オキサジアゾール塩酸塩を用いること以外は実質的に実施例２１７と同様に反応を行なって、表題化合物を無色油状物(１９ｍｇ、収率４２％)として得た。

^１Ｈ−ＮＭＲ（３００ＭＨｚ，ＣＤＣｌ_３）δ：１．３４（６Ｈ，ｄ，Ｊ＝６．８Ｈｚ），１．６１−１．７７（２Ｈ，ｍ），１．７７−１．９９（６Ｈ，ｍ），２．０１−２．２８（２Ｈ，ｂｒ ｍ），２．４９−２．６９（４Ｈ，ｂｒ ｍ），３．０８（１Ｈ，ｓｅｐ，Ｊ＝６．８Ｈｚ），３．１０−３．２６（５Ｈ，ｍ），３．５９（２Ｈ，ｓ），３．８５（１Ｈ，ｂｒ ｓ），４．５９（１Ｈ，ｂｒ ｓ），４．６０（２Ｈ，ｓ），７．３３（２Ｈ，ｄ，Ｊ＝７．８Ｈｚ），７．３８（２Ｈ，ｄ，Ｊ＝７．８Ｈｚ），７．４４（２Ｈ，ｄ，Ｊ＝７．８Ｈｚ），７．５７（２Ｈ，ｄ，Ｊ＝７．８Ｈｚ）．

ＬＣ／ＭＳ［条件１］：保持時間３．２２分；ｍ／ｚ６４０．１［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ６８４．２［Ｍ＋ＨＣＯＯ］^―（ＥＳＩ負イオンモード）

Example 221
3- {4- [4- (3-Isopropyl-1,2,4-oxadiazol-5-yl) piperidin-1-carbonyl] benzyl} -9- [4- (trifluoromethyl) benzyl] -1 Preparation of Oxa-3,9-diazaspiro [5.5] undecan-2-one (Compound No. 221) Instead of 4-benzoylpiperidine hydrochloride, 3-isopropyl-5- (piperidin-4-yl) -1 The reaction was carried out in substantially the same manner as in Example 217 except that 2,4-oxadiazole hydrochloride was used to give the title compound as a colorless oil (19 mg, yield 42%).

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.34 (6H, d, J = 6.8 Hz), 1.61-1.77 (2H, m), 1.77-1.99 (6H, m), 2.01-2.28 (2H, br m), 2.49-2.69 (4H, br m), 3.08 (1H, sep, J = 6.8 Hz), 3.10- 3.26 (5H, m), 3.59 (2H, s), 3.85 (1H, br s), 4.59 (1H, br s), 4.60 (2H, s), 7.33 (2H, d, J = 7.8 Hz), 7.38 (2H, d, J = 7.8 Hz), 7.44 (2H, d, J = 7.8 Hz), 7.57 (2H, d, J = 7.8 Hz).

LC / MS [Condition 1]: retention time 3.22 minutes; m / z 640.1 [M + H] ⁺ (ESI positive ion mode), m / z 684.2 [M + HCOO] ⁻ (ESI negative ion mode)

参考例２２２−１
３−{[５−(エトキシカルボニル)ピリジン−２−イル]メチル}−２−オキソ−１−オキサ−３，９−ジアザスピロ[５.５]ウンデカン−９−カルボン酸ｔ−ブチルの製造
２−オキソ−１−オキサ−３，８−ジアザスピロ［４．５］デカン−８−カルボン酸ｔ−ブチルの代わりに参考例２１７−２で得られた２−オキソ−１−オキサ−３，９−ジアザスピロ[５.５]ウンデカン−９−カルボン酸ｔ−ブチル（０．２１ｇ、０．７８ｍｍｏｌ）を用いること以外は実質的に参考例１１１−３と同様に反応を行なって、表題化合物を黄色油状物（８０ｍｇ、収率２４％)として得た。

^１Ｈ−ＮＭＲ（３００ＭＨｚ，ＣＤＣｌ_３）δ：１．４１（３Ｈ，ｔ，Ｊ＝７．４Ｈｚ），１．４６（９Ｈ，ｓ），１．５２−１．６７（２Ｈ，ｍ），１．８４−１．９９（４Ｈ，ｍ），３．３１（２Ｈ，ｔ，Ｊ＝１２．７Ｈｚ），３．４７（２Ｈ，ｔ，Ｊ＝６．１Ｈｚ），３．７４−３．９８（２Ｈ，ｍ），４．４１（２Ｈ，ｑ，Ｊ＝７．４Ｈｚ），４．７１（２Ｈ，ｓ），７．４２（１Ｈ，ｄ，Ｊ＝７．８Ｈｚ），８．２７（１Ｈ，ｄｄ，Ｊ＝８．２，１．６Ｈｚ），９．１３（１Ｈ，ｓ）．

Reference Example 222-1
Preparation of t-butyl 3-{[5- (ethoxycarbonyl) pyridin-2-yl] methyl} -2-oxo-1-oxa-3,9-diazaspiro [5.5] undecane-9-carboxylate 2-Oxo-1-oxa-3,9-diazaspiro obtained in Reference Example 217-2 in place of t-butyl oxo-1-oxa-3,8-diazaspiro [4.5] decane-8-carboxylate [5.5] The reaction was carried out in substantially the same manner as in Reference Example 111-3 except that t-butyl undecane-9-carboxylate (0.21 g, 0.78 mmol) was used. (80 mg, 24% yield).

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.41 (3H, t, J = 7.4 Hz), 1.46 (9H, s), 1.52-1.67 (2H, m), 1 .84-1.99 (4H, m), 3.31 (2H, t, J = 12.7 Hz), 3.47 (2H, t, J = 6.1 Hz), 3.74-3.98 ( 2H, m), 4.41 (2H, q, J = 7.4 Hz), 4.71 (2H, s), 7.42 (1H, d, J = 7.8 Hz), 8.27 (1H, dd, J = 8.2, 1.6 Hz), 9.13 (1H, s).

参考例２２２−２
６−（{２−オキソ−９−[４−（トリフルオロメチル）ベンジル]−１−オキサ−３，９−ジアザスピロ[５.５]ウンデカン−３−イル}メチル）ニコチン酸エチルの製造
３−｛［５−（エトキシカルボニル）ピリジン−２−イル］メチル｝−２−オキソ−１−オキサ−３，８−ジアザスピロ［４．５］デカン−８−カルボン酸ｔ−ブチルの代わりに参考例２２２−１で得られた３−{[５−(エトキシカルボニル)ピリジン−２−イル]メチル}−２−オキソ−１−オキサ−３，９−ジアザスピロ[５.５]ウンデカン−９−カルボン酸ｔ−ブチル（７７．０ｍｇ、０．１８ｍｍｏｌ）を用いること以外は実質的に参考例１１１−４と同様に反応を行なって、表題化合物を無色油状物（３６．０ｍｇ、収率４１％)として得た。

^１Ｈ−ＮＭＲ（３００ＭＨｚ，ＣＤＣｌ_３）δ：１．４０（３Ｈ，ｔ，Ｊ＝７．４Ｈｚ），１．６４−１．８０（２Ｈ，ｍ），１．８４−２．００（４Ｈ，ｍ），２．５０−２．６６（４Ｈ，ｍ），３．４３（２Ｈ，ｔ，Ｊ＝６．１Ｈｚ），３．５９（２Ｈ，ｓ），４．４０（２Ｈ，ｑ，Ｊ＝７．０Ｈｚ），４．７１（２Ｈ，ｓ），７．４１（１Ｈ，ｄ，Ｊ＝８．２Ｈｚ），７．４４（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ），７．５７（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ），８．２６（１Ｈ，ｄｄ，Ｊ＝８．２，２．０Ｈｚ），９．１２（１Ｈ，ｄ，Ｊ＝２．０Ｈｚ）．

ＬＣ／ＭＳ［条件１］：保持時間２．９８分；ｍ／ｚ４９１．９［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）

Reference Example 222-2
Preparation of ethyl 6-({2-oxo-9- [4- (trifluoromethyl) benzyl] -1-oxa-3,9-diazaspiro [5.5] undecan-3-yl} methyl) nicotinate 3- {[5- (ethoxycarbonyl) pyridin-2-yl] methyl} -2-oxo-1-oxa-3,8-diazaspiro [4.5] decane-8-carboxylate instead of t-butyl Reference Example 222 3-{[5- (ethoxycarbonyl) pyridin-2-yl] methyl} -2-oxo-1-oxa-3,9-diazaspiro [5.5] undecane-9-carboxylic acid t The reaction was carried out in substantially the same manner as in Reference Example 111-4 except that -butyl (77.0 mg, 0.18 mmol) was used to give the title compound as a colorless oil (36.0 mg, yield 41%). It was.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.40 (3H, t, J = 7.4 Hz), 1.64 to 1.80 (2H, m), 1.84 to 2.00 (4H, m), 2.50-2.66 (4H, m), 3.43 (2H, t, J = 6.1 Hz), 3.59 (2H, s), 4.40 (2H, q, J = 7.0 Hz), 4.71 (2H, s), 7.41 (1H, d, J = 8.2 Hz), 7.44 (2H, d, J = 8.2 Hz), 7.57 (2H, d, J = 8.2 Hz), 8.26 (1H, dd, J = 8.2, 2.0 Hz), 9.12 (1H, d, J = 2.0 Hz).

LC / MS [Condition 1]: Retention time 2.98 min; m / z 491.9 [M + H] ⁺ (ESI positive ion mode)

参考例２２２−３
６−（{２−オキソ−９−[４−（トリフルオロメチル）ベンジル]−１−オキサ−３，９−ジアザスピロ[５.５]ウンデカン−３−イル}メチル）ニコチン酸の製造
６−（｛２−オキソ−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）ニコチン酸エチルの代わりに参考例２２２−２で得られた６−（{２−オキソ−９−[４−（トリフルオロメチル）ベンジル]−１−オキサ−３，９−ジアザスピロ[５.５]ウンデカン−３−イル}メチル）ニコチン酸エチル（３６ｍｇ、０．０７０ｍｍｏｌ）を用いること以外は実質的に参考例１１１−５と同様に反応を行なって、表題化合物を無色固体（３１ｍｇ、収率９１％)として得た。

^１Ｈ−ＮＭＲ（３００ＭＨｚ，ＣＤ_３ＯＤ）δ：１．８０−１．９３（２Ｈ，ｍ），１．９６−２．０８（４Ｈ，ｍ），２．７０（２Ｈ，ｔ，Ｊ＝１１．６Ｈｚ），２．７７−２．９０（２Ｈ，ｍ），３．４５（２Ｈ，ｔ，Ｊ＝６．３Ｈｚ），３．８３（２Ｈ，ｓ），４．６７（２Ｈ，ｓ），７．３６（１Ｈ，ｄ，Ｊ＝７．９Ｈｚ），７．６０（２Ｈ，ｄ，Ｊ＝８．３Ｈｚ），７．６６（２Ｈ，ｄ，Ｊ＝８．３Ｈｚ），８．２７（１Ｈ，ｄｄ，Ｊ＝８．３，２．０Ｈｚ），９．０１（１Ｈ，ｓ）．

ＬＣ／ＭＳ［条件１］：保持時間１．００分；ｍ／ｚ４６３．９［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ４６２．０［Ｍ−Ｈ］^―（ＥＳＩ負イオンモード）

Reference Example 222-3
Preparation of 6-({2-Oxo-9- [4- (trifluoromethyl) benzyl] -1-oxa-3,9-diazaspiro [5.5] undecan-3-yl} methyl) nicotinic acid 6- ( {2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl) Reference Example 222- in place of ethyl nicotinate 6-({2-oxo-9- [4- (trifluoromethyl) benzyl] -1-oxa-3,9-diazaspiro [5.5] undecan-3-yl} methyl) nicotinic acid obtained in The reaction was carried out substantially in the same manner as in Reference Example 111-5 except that ethyl (36 mg, 0.070 mmol) was used to give the title compound as a colorless solid (31 mg, yield 91%).

¹ H-NMR (300 MHz, CD ₃ OD) δ: 1.80-1.93 (2H, m), 1.96-2.08 (4H, m), 2.70 (2H, t, J = 11) .6 Hz), 2.77-2.90 (2H, m), 3.45 (2H, t, J = 6.3 Hz), 3.83 (2H, s), 4.67 (2H, s), 7.36 (1H, d, J = 7.9 Hz), 7.60 (2H, d, J = 8.3 Hz), 7.66 (2H, d, J = 8.3 Hz), 8.27 (1H , Dd, J = 8.3, 2.0 Hz), 9.01 (1H, s).

LC / MS [Condition 1]: Retention time 1.00 min; m / z 463.9 [M + H] ⁺ (ESI positive ion mode), m / z 462.0 [M−H] ⁻ (ESI negative ion mode)

実施例２２２
３−（{５−[４−（４−フルオロベンゾイル）ピペリジン−１−カルボニル]ピリジン−２−イル}メチル）−９−[４−(トリフルオロメチル)ベンジル]−１−オキサ−３，９−ジアザスピロ[５.５]ウンデカン−２−オン（化合物番号２２２）の製造
６−（｛２−オキソ−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）ニコチン酸の代わりに参考例２２２−３で得られた６−（{２−オキソ−９−[４−（トリフルオロメチル）ベンジル]−１−オキサ−３，９−ジアザスピロ[５.５]ウンデカン−３−イル}メチル）ニコチン酸（１４ｍｇ、０．０３０ｍｍｏｌ）、テトラヒドロフルフリルアミンの代わりに４−（４−フルオロベンゾイル）ピペリジン塩酸塩とトリエチルアミンを用いること以外は実質的に実施例１１１と同様に反応を行なって、表題化合物を無色油状物（１３ｍｇ、収率６６％)として得た。

^１Ｈ−ＮＭＲ（３００ＭＨｚ，ＣＤＣｌ_３）δ：１．６０−２．０１（１０Ｈ，ｍ），２．５０−２．６８（４Ｈ，ｍ），２．９８−３．３１（２Ｈ，ｂｒ ｍ），３．４３（２Ｈ，ｔ，Ｊ＝６．１Ｈｚ），３．４７−３．６２（１Ｈ，ｍ），３．５９（２Ｈ，ｓ），３．８４（１Ｈ，ｂｒ ｓ），４．６６（１Ｈ，ｂｒ ｓ），４．６８（２Ｈ，ｓ），７．１７（２Ｈ，ｔ，Ｊ＝８．２Ｈｚ），７．３９（１Ｈ，ｄ，Ｊ＝８．２Ｈｚ），７．４４（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ），７．５７（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ），７．７３（１Ｈ，ｄｄ，Ｊ＝８．２，２．０Ｈｚ），７．９８（２Ｈ，ｄｄ，Ｊ＝８．２，５．３Ｈｚ），８．５９（１Ｈ，ｄ，Ｊ＝２．０Ｈｚ）．

ＬＣ／ＭＳ［条件１］：保持時間３．１８分；ｍ／ｚ６５３．１［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ６９７．２［Ｍ＋ＨＣＯＯ］^―（ＥＳＩ負イオンモード）

Example 222
3-({5- [4- (4-Fluorobenzoyl) piperidin-1-carbonyl] pyridin-2-yl} methyl) -9- [4- (trifluoromethyl) benzyl] -1-oxa-3,9 -Preparation of diazaspiro [5.5] undecan-2-one (Compound No. 222) 6-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [ 4.5] 6-({2-Oxo-9- [4- (trifluoromethyl) benzyl] -1-oxa obtained in Reference Example 222-3 instead of decan-3-yl} methyl) nicotinic acid -3,9-diazaspiro [5.5] undecan-3-yl} methyl) nicotinic acid (14 mg, 0.030 mmol), 4- (4-fluorobenzoyl) piperidine hydrochloride and triethylamine instead of tetrahydrofurfurylamine But using down by performing the same reaction as substantially Example 111, the title compound was obtained as a colorless oil (13 mg, 66% yield).

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.60-2.01 (10H, m), 2.50-2.68 (4H, m), 2.98-3.31 (2H, br m ), 3.43 (2H, t, J = 6.1 Hz), 3.47-3.62 (1H, m), 3.59 (2H, s), 3.84 (1H, br s), 4 .66 (1H, br s), 4.68 (2H, s), 7.17 (2H, t, J = 8.2 Hz), 7.39 (1H, d, J = 8.2 Hz), 7. 44 (2H, d, J = 8.2 Hz), 7.57 (2H, d, J = 8.2 Hz), 7.73 (1H, dd, J = 8.2, 2.0 Hz), 7.98 (2H, dd, J = 8.2, 5.3 Hz), 8.59 (1H, d, J = 2.0 Hz).

LC / MS [Condition 1]: Retention time 3.18 minutes; m / z 653.1 [M + H] ⁺ (ESI positive ion mode), m / z 697.2 [M + HCOO] ⁻ (ESI negative ion mode)

実施例２２３
３−（{５−[４−（３−イソプロピル−１，２，４−オキサジアゾール−５−イル）ピペリジン−１−カルボニル]ピリジン−２−イル}メチル）−９−[４−(トリフルオロメチル)ベンジル]−１−オキサ−３，９−ジアザスピロ[５.５]ウンデカン−２−オン（化合物番号２２３）の製造
４−（４−フルオロベンゾイル）ピペリジン塩酸塩の代わりに、３−イソプロピル−５−（ピペリジン−４−イル）−１，２，４−オキサジアゾール塩酸塩を用いること以外は実質的に実施例２２２と同様に反応を行なって、表題化合物を無色油状物(１４ｍｇ、収率６８％)として得た。

^１Ｈ−ＮＭＲ（３００ＭＨｚ，ＣＤＣｌ_３）δ：１．３４（６Ｈ，ｄ，Ｊ＝７．２Ｈｚ），１．６０−１．８２（２Ｈ，ｍ），１．８２−２．０１（６Ｈ，ｍ），２．０５−２．２９（２Ｈ，ｍ），２．４９−２．６８（４Ｈ，ｍ），３．０８（１Ｈ，ｓｅｐ，Ｊ＝７．２Ｈｚ），３．１４−３．３１（３Ｈ，ｍ），３．４３（２Ｈ，ｔ，Ｊ＝６．５Ｈｚ），３．５９（２Ｈ，ｓ），３．８１（１Ｈ，ｂｒ ｓ），４．５８（１Ｈ，ｂｒ ｓ），４．６８（２Ｈ，ｓ），７．４０（１Ｈ，ｄ，Ｊ＝８．２Ｈｚ），７．４４（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ），７．５７（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ），７．７２（１Ｈ，ｄｄ，Ｊ＝８．２，２．１Ｈｚ），８．５９（１Ｈ，ｄ，Ｊ＝２．０Ｈｚ）．

ＬＣ／ＭＳ［条件１］：保持時間３．１２分；ｍ／ｚ６４１．２［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ６８５．２［Ｍ＋ＨＣＯＯ］^―（ＥＳＩ負イオンモード）

Example 223
3-({5- [4- (3-Isopropyl-1,2,4-oxadiazol-5-yl) piperidin-1-carbonyl] pyridin-2-yl} methyl) -9- [4- (tri Preparation of fluoromethyl) benzyl] -1-oxa-3,9-diazaspiro [5.5] undecan-2-one (Compound No. 223) Instead of 4- (4-fluorobenzoyl) piperidine hydrochloride, 3-isopropyl The reaction was carried out in substantially the same manner as in Example 222 except that -5- (piperidin-4-yl) -1,2,4-oxadiazole hydrochloride was used to give the title compound as a colorless oil (14 mg, Yield 68%).

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.34 (6H, d, J = 7.2 Hz), 1.60-1.82 (2H, m), 1.82-2.01 (6H, m), 2.05-2.29 (2H, m), 2.49-2.68 (4H, m), 3.08 (1H, sep, J = 7.2 Hz), 3.14-3. 31 (3H, m), 3.43 (2H, t, J = 6.5 Hz), 3.59 (2H, s), 3.81 (1H, br s), 4.58 (1H, br s) , 4.68 (2H, s), 7.40 (1H, d, J = 8.2 Hz), 7.44 (2H, d, J = 8.2 Hz), 7.57 (2H, d, J = 8.2 Hz), 7.72 (1H, dd, J = 8.2, 2.1 Hz), 8.59 (1H, d, J = 2.0 Hz).

LC / MS [Condition 1]: Retention time 3.12 minutes; m / z 641.2 [M + H] ⁺ (ESI positive ion mode), m / z 685.2 [M + HCOO] ⁻ (ESI negative ion mode)

実施例２２４
（１ｒ，４ｒ）‐４‐｛［８‐（２‐シアノベンジル）‐２‐オキソ‐１‐オキサ‐３，８‐ジアザスピロ［４．５］デカン‐３‐イル］メチル｝‐Ｎ‐［（テトラヒドロフラン‐２‐イル）メチル］シクロヘキサンカルボキサミド（化合物番号２２４）の製造
３‐（ブロモメチル）ピリジン臭化水素酸塩の代わりに、２‐シアノベンジルブロミド（市販）を用いること以外は実質的に実施例４と同様に反応を行なって、表題化合物（２１．７ｍｇ、収率６３％）を白色粉末として得た。

^１Ｈ‐ＮＭＲ（３００ＭＨｚ，ＣＤＣｌ_３）δ：１．０１（２Ｈ，ｄｑ，Ｊ＝３．７，１３．１Ｈｚ），１．３８−１．６９（４Ｈ，ｍ），１．６９−１．８５（４Ｈ，ｍ），１．８５−２．１３（８Ｈ，ｍ），２．４９−２．７６（４Ｈ，ｂｒ ｍ），３．０９（２Ｈ，ｄ，Ｊ＝７．４Ｈｚ），３．１１（１Ｈ，ｄｄｄ，Ｊ＝１３．９，７．４，４．５Ｈｚ），３．２５（２Ｈ，ｓ），３．５８（１Ｈ，ｄｄｄ，Ｊ＝１３．９，６．５，３．３Ｈｚ），３．７１（２Ｈ，ｓ），３．７４（１Ｈ，ｄｔ，Ｊ＝８．２，６．５Ｈｚ），３．８５（１Ｈ，ｄｔ，Ｊ＝８．２，６．５Ｈｚ），３．９４（１Ｈ，ｄｑ，Ｊ＝３．３，７．１Ｈｚ），５．８０（１Ｈ，ｂｒ ｔ，Ｊ＝５．３Ｈｚ），７．３６（１Ｈ，ｔ，Ｊ＝７．４Ｈｚ），７．４８（１Ｈ，ｄ，Ｊ＝７．４Ｈｚ），７．５５（１Ｈ，ｔ，Ｊ＝７．４Ｈｚ），７．６６（１Ｈ，ｄ，Ｊ＝７．４Ｈｚ）．

ＬＣ／ＭＳ［条件１］：保持時間１．４８分；ｍ／ｚ４９５．０［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ４９３．０［Ｍ−Ｈ］⁻、５２９．１［Ｍ＋Ｃl］⁻、５３９．３［Ｍ＋ＨＣＯＯ］⁻（ＥＳＩ負イオンモード）

Example 224
(1r, 4r) -4-{[8- (2-Cyanobenzyl) -2-oxo-1-oxa-3,8-diazaspiro [4.5] decan-3-yl] methyl} -N-[( Preparation of Tetrahydrofuran-2-yl) methyl] cyclohexanecarboxamide (Compound No. 224) Substantially examples except using 2-cyanobenzyl bromide (commercially available) instead of 3- (bromomethyl) pyridine hydrobromide The reaction was carried out in the same manner as in Example 4 to obtain the title compound (21.7 mg, yield 63%) as a white powder.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.01 (2H, dq, J = 3.7, 13.1 Hz), 1.38-1.69 (4H, m), 1.69-1. 85 (4H, m), 1.85-2.13 (8H, m), 2.49-2.76 (4H, br m), 3.09 (2H, d, J = 7.4 Hz), 3 .11 (1H, ddd, J = 13.9, 7.4, 4.5 Hz), 3.25 (2H, s), 3.58 (1H, ddd, J = 13.9, 6.5, 3 .3 Hz), 3.71 (2H, s), 3.74 (1 H, dt, J = 8.2, 6.5 Hz), 3.85 (1 H, dt, J = 8.2, 6.5 Hz) 3.94 (1H, dq, J = 3.3, 7.1 Hz), 5.80 (1H, br t, J = 5.3 Hz), 7.36 (1H, t, J = 7.4 Hz) , 7.48 (1 H, d, J = 7.4 Hz), 7.55 (1H, t, J = 7.4 Hz), 7.66 (1H, d, J = 7.4 Hz).

LC / MS [Condition 1]: Retention time 1.48 minutes; m / z 495.0 [M + H] ⁺ (ESI positive ion mode), m / z 493.0 [M−H] ⁻ , 529.1 [M + Cl] ⁻ 539.3 [M + HCOO] ⁻ (ESI negative ion mode)

実施例２２５
（１ｒ，４ｒ）‐４‐｛［８‐（３‐シアノベンジル）‐２‐オキソ‐１‐オキサ‐３，８‐ジアザスピロ［４．５］デカン‐３‐イル］メチル｝‐Ｎ‐［（テトラヒドロフラン‐２‐イル）メチル］シクロヘキサンカルボキサミド（化合物番号２２５）の製造
３‐（ブロモメチル）ピリジン臭化水素酸塩の代わりに、３‐シアノベンジルブロミド（市販）を用いること以外は実質的に実施例４と同様に反応を行なって、表題化合物（２３．９ｍｇ、収率６９％）を無色油状物として得た。

^１Ｈ‐ＮＭＲ（３００ＭＨｚ，ＣＤＣｌ_３）δ：１．０２（２Ｈ，ｄｑ，Ｊ＝３．０，１２．７Ｈｚ），１．４０−１．６９（４Ｈ，ｍ），１．７１−１．８４（４Ｈ，ｍ），１．８４−２．１１（８Ｈ，ｍ），２．４２−２．７０（４Ｈ，ｂｒ ｍ），３．０９（２Ｈ，ｄ，Ｊ＝７．４Ｈｚ），３．１１（１Ｈ，ｄｄｄ，Ｊ＝１３．９，７．６，４．５Ｈｚ），３．２６（２Ｈ，ｓ），３．５５（２Ｈ，ｓ），３．５８（１Ｈ，ｄｄｄ，Ｊ＝１３．９，６．５，３．３Ｈｚ），３．７４（１Ｈ，ｄｔ，Ｊ＝８．２，７．０Ｈｚ），３．８５（１Ｈ，ｄｔ，Ｊ＝８．２，６．５Ｈｚ），３．９４（１Ｈ，ｄｑ，Ｊ＝３．３，７．１Ｈｚ），５．８２（１Ｈ，ｂｒ ｔ，Ｊ＝５．３Ｈｚ），７．４２（１Ｈ，ｔ，Ｊ＝７．８Ｈｚ），７．５５（２Ｈ，ｂｒ ｄ，Ｊ＝７．８Ｈｚ），７．６７（１Ｈ，ｓ）．

ＬＣ／ＭＳ［条件１］：保持時間１．６２分；ｍ／ｚ４９４．９［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ４９３．２［Ｍ−Ｈ］⁻、５３９．１［Ｍ＋ＨＣＯＯ］⁻（ＥＳＩ負イオンモード）

Example 225
(1r, 4r) -4-{[8- (3-Cyanobenzyl) -2-oxo-1-oxa-3,8-diazaspiro [4.5] decan-3-yl] methyl} -N-[( Preparation of Tetrahydrofuran-2-yl) methyl] cyclohexanecarboxamide (Compound No. 225) Substantially examples except using 3-cyanobenzyl bromide (commercially available) instead of 3- (bromomethyl) pyridine hydrobromide The reaction was carried out in the same manner as in Example 4 to obtain the title compound (23.9 mg, yield 69%) as a colorless oil.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.02 (2H, dq, J = 3.0, 12.7 Hz), 1.40-1.69 (4H, m), 1.71-1. 84 (4H, m), 1.84-2.11 (8H, m), 2.42-2.70 (4H, br m), 3.09 (2H, d, J = 7.4 Hz), 3 .11 (1H, ddd, J = 13.9, 7.6, 4.5 Hz), 3.26 (2H, s), 3.55 (2H, s), 3.58 (1H, ddd, J = 13.9, 6.5, 3.3 Hz), 3.74 (1H, dt, J = 8.2, 7.0 Hz), 3.85 (1H, dt, J = 8.2, 6.5 Hz) 3.94 (1H, dq, J = 3.3, 7.1 Hz), 5.82 (1H, br t, J = 5.3 Hz), 7.42 (1H, t, J = 7.8 Hz) 7.55 (2 H, br d, J = 7.8 Hz), 7.67 (1H, s).

LC / MS [Condition 1]: Retention time 1.62 minutes; m / z 494.9 [M + H] ⁺ (ESI positive ion mode), m / z 493.2 [M−H] ⁻ , 539.1 [M + HCOO] ⁻ (ESI negative ion mode)

実施例２２６
（１ｒ，４ｒ）‐４‐｛［８‐（シクロヘキシルメチル）‐２‐オキソ‐１‐オキサ‐３，８‐ジアザスピロ［４．５］デカン‐３‐イル］メチル｝‐Ｎ‐［（テトラヒドロフラン‐２‐イル）メチル］シクロヘキサンカルボキサミド（化合物番号２２６）の製造
３‐（ブロモメチル）ピリジン臭化水素酸塩の代わりに、（ブロモメチル）シクロヘキサン（市販）を用いること以外は実質的に実施例４と同様に反応を行なって、表題化合物（３２．７ｍｇ、収率９８％）を白色粉末として得た。

^１Ｈ‐ＮＭＲ（３００ＭＨｚ，ＣＤＣｌ_３）δ：０．８６（２Ｈ，ｂｒ ｑ，Ｊ＝１１．９Ｈｚ），１．０２（２Ｈ，ｄｑ，Ｊ＝３．３，１２．９Ｈｚ），１．１０−１．３５（３Ｈ，ｍ），１．３７−２．１１（２２Ｈ，ｍ），２．０８−２．２４（２Ｈ，ｂｒ ｍ），２．３３−２．６８（４Ｈ，ｂｒ ｍ），３．０９（２Ｈ，ｄ，Ｊ＝７．６Ｈｚ），３．１１（１Ｈ，ｄｄｄ，Ｊ＝１３．９，７．６，４．５Ｈｚ），３．２４（２Ｈ，ｓ），３．５９（１Ｈ，ｄｄｄ，Ｊ＝１３．９，６．５，３．３Ｈｚ），３．７５（１Ｈ，ｄｔ，Ｊ＝８．２，６．９Ｈｚ），３．８６（１Ｈ，ｄｔ，Ｊ＝８．２，６．５Ｈｚ），３．９４（１Ｈ，ｄｑ，Ｊ＝３．３，６．９Ｈｚ），５．８０（１Ｈ，ｂｒ ｔ，Ｊ＝５．３Ｈｚ）．

ＬＣ／ＭＳ［条件１］：保持時間２．７７分；ｍ／ｚ４７６．０［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ４７４．３［Ｍ−Ｈ］⁻、５１０．１［Ｍ＋Ｃｌ］⁻、５２０．２［Ｍ＋ＨＣＯＯ］⁻（ＥＳＩ負イオンモード）

Example 226
(1r, 4r) -4-{[8- (cyclohexylmethyl) -2-oxo-1-oxa-3,8-diazaspiro [4.5] decan-3-yl] methyl} -N-[(tetrahydrofuran- Preparation of 2-yl) methyl] cyclohexanecarboxamide (Compound No. 226) Substantially the same as Example 4 except that (bromomethyl) cyclohexane (commercially available) was used instead of 3- (bromomethyl) pyridine hydrobromide The title compound (32.7 mg, 98% yield) was obtained as a white powder.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 0.86 (2H, br q, J = 11.9 Hz), 1.02 (2H, dq, J = 3.3, 12.9 Hz), 1.10 -1.35 (3H, m), 1.37-2.11 (22H, m), 2.08-2.24 (2H, brm), 2.33-2.68 (4H, brm) 3.09 (2H, d, J = 7.6 Hz), 3.11 (1H, ddd, J = 13.9, 7.6, 4.5 Hz), 3.24 (2H, s), 3. 59 (1H, dddd, J = 13.9, 6.5, 3.3 Hz), 3.75 (1H, dt, J = 8.2, 6.9 Hz), 3.86 (1H, dt, J = 8.2, 6.5 Hz), 3.94 (1H, dq, J = 3.3, 6.9 Hz), 5.80 (1H, br t, J = 5.3 Hz).

LC / MS [Condition 1]: Retention time 2.77 minutes; m / z 476.0 [M + H] ⁺ (ESI positive ion mode), m / z 474.3 [M−H] ⁻ , 510.1 [M + Cl] ⁻ , 520.2 [M + HCOO] ⁻ (ESI negative ion mode)

実施例２２７
（１ｒ，４ｒ）‐４‐｛［８‐（４‐メチルベンジル）‐２‐オキソ‐１‐オキサ‐３，８‐ジアザスピロ［４．５］デカン‐３‐イル］メチル｝‐Ｎ‐［（テトラヒドロフラン‐２‐イル）メチル］シクロヘキサンカルボキサミド（化合物番号２２７）の製造
３‐(ブロモメチル)ピリジン臭化水素酸塩の代わりに、４‐メチルベンジルブロミド（市販）を用いること以外は実質的に実施例４と同様に反応を行なって、表題化合物（１５．８ｍｇ、収率６５％）を無色油状物として得た。

ＬＣ／ＭＳ［条件１］：保持時間２．７８分；ｍ／ｚ４８３．９［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ４８２．０［Ｍ−Ｈ］⁻、５１８．１［Ｍ＋Ｃｌ］⁻、５２８．２［Ｍ＋ＨＣＯＯ］⁻（ＥＳＩ負イオンモード）

Example 227
(1r, 4r) -4-{[8- (4-Methylbenzyl) -2-oxo-1-oxa-3,8-diazaspiro [4.5] decan-3-yl] methyl} -N-[( Preparation of Tetrahydrofuran-2-yl) methyl] cyclohexanecarboxamide (Compound No. 227) Substantially examples except using 4-methylbenzyl bromide (commercially available) instead of 3- (bromomethyl) pyridine hydrobromide The reaction was carried out in the same manner as in 4 to obtain the title compound (15.8 mg, yield 65%) as a colorless oil.

LC / MS [Condition 1]: Retention time 2.78 minutes; m / z 483.9 [M + H] ⁺ (ESI positive ion mode), m / z 482.0 [M−H] ⁻ , 518.1 [M + Cl] ⁻ 528.2 [M + HCOO] ⁻ (ESI negative ion mode)

実施例２２８
（１ｒ，４ｒ）‐４‐［（８‐ベンジル‐２‐オキソ‐１‐オキサ‐３，８‐ジアザスピロ［４．５］デカン‐３‐イル）メチル］‐Ｎ‐［（テトラヒドロフラン‐２‐イル）メチル］シクロヘキサンカルボキサミド（化合物番号２２８）の製造
３‐(ブロモメチル)ピリジン臭化水素酸塩の代わりに、ベンジルブロミド（市販）を用いること以外は実質的に実施例４と同様に反応を行なって、表題化合物（５．６ｍｇ、収率２４％）を無色油状物として得た。

^１Ｈ−ＮＭＲ（３００ＭＨｚ，ＣＤＣｌ_３）δ：１．０１（２Ｈ，ｄｑ，Ｊ＝２．９，１２．７Ｈｚ），１．３８−１．６６（４Ｈ，ｍ），１．６６−２．１２（１２Ｈ，ｍ），２．４４−２．７９（４Ｈ，ｂｒ ｍ），３．０８（２Ｈ，ｄ，Ｊ＝７．４Ｈｚ），３．１１（１Ｈ，ｄｄｄ，Ｊ＝１３．５，７．４，４．９Ｈｚ），３．２５（２Ｈ，ｓ），３．５８（２Ｈ，ｂｒ ｓ），３．５８（１Ｈ，ｄｄｄ，Ｊ＝１３．５，７．０，３．３Ｈｚ），３．７４（１Ｈ，ｄｔ，Ｊ＝８．６，６．５Ｈｚ），３．８５（１Ｈ，ｄｔ，Ｊ＝８．６，６．５Ｈｚ），３．９４（１Ｈ，ｄｑ，Ｊ＝３．３，７．０Ｈｚ），５．７９（１Ｈ，ｂｒ ｔ，Ｊ＝５．３Ｈｚ），７．２５−７．３９（５Ｈ，ｍ）．

Example 228
(1r, 4r) -4-[(8-Benzyl-2-oxo-1-oxa-3,8-diazaspiro [4.5] decan-3-yl) methyl] -N-[(tetrahydrofuran-2-yl ) Preparation of methyl] cyclohexanecarboxamide (Compound No. 228) The reaction was carried out in substantially the same manner as in Example 4 except that benzyl bromide (commercially available) was used instead of 3- (bromomethyl) pyridine hydrobromide. The title compound (5.6 mg, 24% yield) was obtained as a colorless oil.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.01 (2H, dq, J = 2.9, 12.7 Hz), 1.38-1.66 (4H, m), 1.66-2. 12 (12H, m), 2.44-2.79 (4H, br m), 3.08 (2H, d, J = 7.4 Hz), 3.11 (1H, ddd, J = 13.5, 7.4, 4.9 Hz), 3.25 (2 H, s), 3.58 (2 H, br s), 3.58 (1 H, ddd, J = 13.5, 7.0, 3.3 Hz) 3.74 (1H, dt, J = 8.6, 6.5 Hz), 3.85 (1H, dt, J = 8.6, 6.5 Hz), 3.94 (1H, dq, J = 3) .3, 7.0 Hz), 5.79 (1H, br t, J = 5.3 Hz), 7.25-7.39 (5H, m).

実施例２２９
（１ｒ，４ｒ）‐４‐｛［８‐（３‐メトキシベンジル）‐２‐オキソ‐１‐オキサ‐３，８‐ジアザスピロ［４．５］デカン‐３‐イル］メチル｝‐Ｎ‐［（テトラヒドロフラン‐２‐イル）メチル］シクロヘキサンカルボキサミド（化合物番号２２９）の製造
３‐(ブロモメチル)ピリジン臭化水素酸塩の代わりに、３−メトキシベンジルクロライド（市販）を用いること以外は実質的に実施例４と同様に反応を行なって、表題化合物（５．６ｍｇ、収率２２％）を無色油状物として得た。

^１Ｈ−ＮＭＲ（３００ＭＨｚ，ＣＤＣｌ_３）δ：１．０１（２Ｈ，ｄｑ，Ｊ＝３．３，１２．３Ｈｚ），１．３９−１．６７（４Ｈ，ｍ），１．７０−１．８４（４Ｈ，ｍ），１．８４−２．１１（８Ｈ，ｍ），２．４３−２．７１（４Ｈ，ｂｒ ｍ），３．０９（２Ｈ，ｄ，Ｊ＝７．４Ｈｚ），３．１１（１Ｈ，ｄｄｄ，Ｊ＝１３．９，７．４，４．９Ｈｚ），３．２５（２Ｈ，ｓ），３．５２（２Ｈ，ｂｒ ｓ），３．５８（１Ｈ，ｄｄｄ，Ｊ＝１３．９，６．５，３．３Ｈｚ），３．７５（１Ｈ，ｄｔ，Ｊ＝８．２，６．５Ｈｚ），３．８１（３Ｈ，ｓ），３．８５（１Ｈ，ｄｔ，Ｊ＝８．２，６．５Ｈｚ），３．９４（１Ｈ，ｄｑ，Ｊ＝３．３，７．１Ｈｚ），５．８０（１Ｈ，ｂｒ ｔ，Ｊ＝５．７Ｈｚ），６．８１（１Ｈ，ｄｄ，Ｊ＝８．２，２．５Ｈｚ），６．８９（１Ｈ，ｄ，Ｊ＝２．５Ｈｚ），６．８９（１Ｈ，ｄ，Ｊ＝８．２Ｈｚ），７．２３（１Ｈ，ｔ，Ｊ＝８．２Ｈｚ）．

ＬＣ／ＭＳ［条件１］：保持時間２．７５分；ｍ／ｚ４９９．９[Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ４９８．０［Ｍ−Ｈ］⁻、５３４．３［Ｍ＋Ｃｌ］⁻、５４４．３［Ｍ＋ＨＣＯＯ］⁻（ＥＳＩ負イオンモード）

Example 229
(1r, 4r) -4-{[8- (3-Methoxybenzyl) -2-oxo-1-oxa-3,8-diazaspiro [4.5] decan-3-yl] methyl} -N-[( Preparation of Tetrahydrofuran-2-yl) methyl] cyclohexanecarboxamide (Compound No. 229) Substantially examples except using 3-methoxybenzyl chloride (commercially available) instead of 3- (bromomethyl) pyridine hydrobromide The reaction was carried out in the same manner as in 4 to obtain the title compound (5.6 mg, yield 22%) as a colorless oil.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.01 (2H, dq, J = 3.3, 12.3 Hz), 1.39-1.67 (4H, m), 1.70-1. 84 (4H, m), 1.84-2.11 (8H, m), 2.44-2.71 (4H, br m), 3.09 (2H, d, J = 7.4 Hz), 3 .11 (1H, ddd, J = 13.9, 7.4, 4.9 Hz), 3.25 (2H, s), 3.52 (2H, br s), 3.58 (1H, ddd, J = 13.9, 6.5, 3.3 Hz), 3.75 (1H, dt, J = 8.2, 6.5 Hz), 3.81 (3H, s), 3.85 (1H, dt, J = 8.2, 6.5 Hz), 3.94 (1H, dq, J = 3.3, 7.1 Hz), 5.80 (1H, br t, J = 5.7 Hz), 6.81 ( 1H, dd, = 8.2, 2.5 Hz), 6.89 (1H, d, J = 2.5 Hz), 6.89 (1H, d, J = 8.2 Hz), 7.23 (1H, t, J = 8.2 Hz).

LC / MS [Condition 1]: Retention time 2.75 minutes; m / z 499.9 [M + H] ⁺ (ESI positive ion mode), m / z 498.0 [M−H] ⁻ , 534.3 [M + Cl] ⁻ 544.3 [M + HCOO] ⁻ (ESI negative ion mode)

実施例２３０
（１ｒ，４ｒ）‐４‐（｛８‐［３‐フルオロ‐５‐（トリフルオロメチル）ベンジル］‐２‐オキソ‐１‐オキサ‐３，８‐ジアザスピロ［４．５］デカン‐３‐イル｝メチル）‐Ｎ‐［（テトラヒドロフラン‐２‐イル）メチル］シクロヘキサンカルボキサミド（化合物番号２３０）の製造
３‐(ブロモメチル)ピリジン臭化水素酸塩の代わりに、３‐フルオロ‐５‐（トリフルオロメチル）ベンジルブロミド（市販）を用いること以外は実質的に実施例４と同様に反応を行なって、表題化合物（２４．９ｍｇ、収率９０％）を淡黄色油状物として得た。

^１Ｈ−ＮＭＲ（３００ＭＨｚ，ＣＤＣｌ_３）δ：１．０１（２Ｈ，ｄｑ，Ｊ＝２．８，１２．７Ｈｚ），１．３９−１．６８（４Ｈ，ｍ），１．６８−２．１５（１２Ｈ，ｍ），２．４４−２．７６（４Ｈ，ｂｒ ｍ），３．０９（２Ｈ，ｄ，Ｊ＝７．８Ｈｚ），３．１０（１Ｈ，ｄｄｄ，Ｊ＝１３．９，７．６，４．５Ｈｚ），３．２６（２Ｈ，ｓ），３．５８（１Ｈ，ｄｄｄ，Ｊ＝１３．９，６．５，３．３Ｈｚ），３．５８（２Ｈ，ｓ），３．７４（１Ｈ，ｄｔ，Ｊ＝８．２，６．５Ｈｚ），３．８５（１Ｈ，ｄｔ，Ｊ＝８．２，６．５Ｈｚ），３．９３（１Ｈ，ｄｑ，Ｊ＝３．３，７．１Ｈｚ），５．８０（１Ｈ，ｂｒ ｔ，Ｊ＝５．３Ｈｚ），７．２２（１Ｈ，ｄ，Ｊ＝８．６Ｈｚ），７．２９（１Ｈ，ｄ，Ｊ＝８．４Ｈｚ），７．３９（１Ｈ，ｓ）．

ＬＣ／ＭＳ［条件１］：保持時間３．０８分；ｍ／ｚ５５５．８[Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）

Example 230
(1r, 4r) -4-({8- [3-Fluoro-5- (trifluoromethyl) benzyl] -2-oxo-1-oxa-3,8-diazaspiro [4.5] decan-3-yl } Methyl) -N-[(tetrahydrofuran-2-yl) methyl] cyclohexanecarboxamide (Compound No. 230) 3-Fluoro-5- (trifluoromethyl) instead of 3- (bromomethyl) pyridine hydrobromide ) The reaction was carried out in substantially the same manner as in Example 4 except that benzyl bromide (commercially available) was used to obtain the title compound (24.9 mg, yield 90%) as a pale yellow oil.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.01 (2H, dq, J = 2.8, 12.7 Hz), 1.39-1.68 (4H, m), 1.68-2. 15 (12H, m), 2.44-2.76 (4H, br m), 3.09 (2H, d, J = 7.8 Hz), 3.10 (1H, ddd, J = 13.9, 7.6, 4.5 Hz), 3.26 (2H, s), 3.58 (1H, ddd, J = 13.9, 6.5, 3.3 Hz), 3.58 (2H, s), 3.74 (1H, dt, J = 8.2, 6.5 Hz), 3.85 (1H, dt, J = 8.2, 6.5 Hz), 3.93 (1H, dq, J = 3. 3, 7.1 Hz), 5.80 (1 H, br t, J = 5.3 Hz), 7.22 (1 H, d, J = 8.6 Hz), 7.29 (1 H, d, J = 8. 4 Hz), 7. 39 (1H, s).

LC / MS [Condition 1]: Retention time 3.08 minutes; m / z 555.8 [M + H] ⁺ (ESI positive ion mode)

実施例２３１
（１ｒ，４ｒ）‐４‐｛［８‐（４‐t‐ブチルベンジル）‐２‐オキソ‐１‐オキサ‐３，８‐ジアザスピロ［４．５］デカン‐３‐イル］メチル｝‐Ｎ‐［（テトラヒドロフラン‐２‐イル）メチル］シクロヘキサンカルボキサミド（化合物番号２３１）の製造
３‐(ブロモメチル)ピリジン臭化水素酸塩の代わりに、４‐ｔ‐ブチルベンジルブロミド（市販）を用いること以外は実質的に実施例４と同様に反応を行なって、表題化合物（２６．３ｍｇ、収率６１％）を淡黄色粉末として得た。

ＬＣ／ＭＳ［条件１］：保持時間３．３４分；ｍ／ｚ５２５．９[Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ５６０．１［Ｍ＋Ｃｌ］⁻、５７０．２［Ｍ＋ＨＣＯＯ］⁻（ＥＳＩ負イオンモード）

Example 231
(1r, 4r) -4-{[8- (4-tert-butylbenzyl) -2-oxo-1-oxa-3,8-diazaspiro [4.5] decan-3-yl] methyl} -N- Preparation of [(tetrahydrofuran-2-yl) methyl] cyclohexanecarboxamide (Compound No. 231) Substantially except that 4-t-butylbenzyl bromide (commercially available) was used instead of 3- (bromomethyl) pyridine hydrobromide Specifically, the reaction was carried out in the same manner as in Example 4 to obtain the title compound (26.3 mg, yield 61%) as a pale yellow powder.

LC / MS [condition 1]: retention time 3.34 minutes; m / z 525.9 [M + H] ⁺ (ESI positive ion mode), m / z 560.1 [M + Cl] ⁻ , 570.2 [M + HCOO] ⁻ (ESI Negative ion mode)

実施例２３２
（１ｒ，４ｒ）‐４‐｛［８‐（４‐フルオロフェネチル）‐２‐オキソ‐１‐オキサ‐３，８‐ジアザスピロ［４．５］デカン‐３‐イル］メチル｝‐Ｎ‐［（テトラヒドロフラン‐２‐イル）メチル］シクロヘキサンカルボキサミド（化合物番号２３２）の製造
３‐(ブロモメチル)ピリジン臭化水素酸塩の代わりに、４‐フルオロフェネチルブロミド（市販）を用いること以外は実質的に実施例４と同様に反応を行なって、表題化合物（１３．６ｍｇ、収率５４％）を淡黄色油状物として得た。

ＬＣ／ＭＳ［条件１］：保持時間３．１２分；ｍ／ｚ５０２．０[Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ５３６．２［Ｍ＋Ｃｌ］⁻、５４６．２［Ｍ＋ＨＣＯＯ］⁻（ＥＳＩ負イオンモード）

Example 232
(1r, 4r) -4-{[8- (4-Fluorophenethyl) -2-oxo-1-oxa-3,8-diazaspiro [4.5] decan-3-yl] methyl} -N-[( Preparation of Tetrahydrofuran-2-yl) methyl] cyclohexanecarboxamide (Compound No. 232) Substantially examples except using 4-fluorophenethyl bromide (commercially available) instead of 3- (bromomethyl) pyridine hydrobromide The reaction was carried out in the same manner as in 4 to obtain the title compound (13.6 mg, yield 54%) as a pale yellow oil.

LC / MS [Condition 1]: retention time 3.12 minutes; m / z 502.0 [M + H] ⁺ (ESI positive ion mode), m / z 536.2 [M + Cl] ⁻ , 546.2 [M + HCOO] ⁻ (ESI Negative ion mode)

実施例２３３
（１ｒ，４ｒ）‐４‐｛［８‐（４‐フルオロベンジル）‐２‐オキソ‐１‐オキサ‐３，８‐ジアザスピロ［４．５］デカン‐３‐イル］メチル｝‐Ｎ‐［（テトラヒドロフラン‐２‐イル）メチル］シクロヘキサンカルボキサミド（化合物番号２３３）の製造

３‐(ブロモメチル)ピリジン臭化水素酸塩の代わりに、４‐フルオロベンジルブロミド（市販）を用いること以外は実質的に実施例４と同様に反応を行なって、表題化合物（１４．６ｍｇ、収率６０％）を白色粉末として得た。

^１Ｈ−ＮＭＲ（３００ＭＨｚ，ＣＤＣｌ_３）δ：１．０１（２Ｈ，ｄｑ，Ｊ＝３．３，１３．１Ｈｚ），１．３９−１．６７（４Ｈ，ｍ），１．６７−１．８３（４Ｈ，ｍ），１．８３−２．０９（８Ｈ，ｍ），２．４０−２．７０（４Ｈ，ｂｒ ｍ），３．０８（２Ｈ，ｄ，Ｊ＝７．８Ｈｚ），３．１０（１Ｈ，ｄｄｄ，Ｊ＝１３．９，７．６，４．５Ｈｚ），３．２４（２Ｈ，ｓ），３．４９（２Ｈ，ｓ），３．５８（１Ｈ，ｄｄｄ，Ｊ＝１３．９，６．５，３．３Ｈｚ），３．７４（１Ｈ，ｄｔ，Ｊ＝８．２，６．５Ｈｚ），３．８５（１Ｈ，ｄｔ，Ｊ＝８．２，６．５Ｈｚ），３．９３（１Ｈ，ｄｑ，Ｊ＝３．３，７．１Ｈｚ），５．７９（１Ｈ，ｂｒ ｔ，Ｊ＝５．３Ｈｚ），６．９９（２Ｈ，ｔ，Ｊ＝８．６Ｈｚ），７．２７（４Ｈ，ｄｄ，Ｊ＝８．６，４．８Ｈｚ）．

ＬＣ／ＭＳ［条件１］：保持時間１．２６分；ｍ／ｚ４８７．９[Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）

Example 233
(1r, 4r) -4-{[8- (4-Fluorobenzyl) -2-oxo-1-oxa-3,8-diazaspiro [4.5] decan-3-yl] methyl} -N-[( Tetrahydrofuran-2-yl) methyl] cyclohexanecarboxamide (Compound No. 233)

The reaction was conducted in substantially the same manner as in Example 4 except that 4-fluorobenzylbromide (commercially available) was used instead of 3- (bromomethyl) pyridine hydrobromide to give the title compound (14.6 mg, yield). 60%) was obtained as a white powder.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.01 (2H, dq, J = 3.3, 13.1 Hz), 1.39-1.67 (4H, m), 1.67-1. 83 (4H, m), 1.83 to 2.09 (8H, m), 2.40-2.70 (4H, br m), 3.08 (2H, d, J = 7.8 Hz), 3 .10 (1H, ddd, J = 13.9, 7.6, 4.5 Hz), 3.24 (2H, s), 3.49 (2H, s), 3.58 (1H, ddd, J = 13.9, 6.5, 3.3 Hz), 3.74 (1H, dt, J = 8.2, 6.5 Hz), 3.85 (1H, dt, J = 8.2, 6.5 Hz) 3.93 (1H, dq, J = 3.3, 7.1 Hz), 5.79 (1H, br t, J = 5.3 Hz), 6.99 (2H, t, J = 8.6 Hz) , 7.27 (4 H, dd, J = 8.6, 4.8 Hz).

LC / MS [Condition 1]: Retention time 1.26 minutes; m / z 487.9 [M + H] ⁺ (ESI positive ion mode)

実施例２３４
（１ｒ，４ｒ）‐４‐（｛８‐［４‐（メチルチオ）ベンジル］‐２‐オキソ‐１‐オキサ‐３，８‐ジアザスピロ［４．５］デカン‐３‐イル｝メチル）‐Ｎ‐［（テトラヒドロフラン‐２‐イル）メチル］シクロヘキサンカルボキサミド（化合物番号２３４）の製造
３‐(ブロモメチル)ピリジン臭化水素酸塩の代わりに、４‐(メチルチオ)ベンジルブロミド（市販）を用いること以外は実質的に実施例４と同様に反応を行なって、表題化合物（１６．１ｍｇ、収率６２％）を白色粉末として得た。

^１Ｈ−ＮＭＲ（３００ＭＨｚ，ＣＤＣｌ_３）δ：１．０１（２Ｈ，ｂｒ ｑ，Ｊ＝１２．２Ｈｚ），１．３８−２．１１（１６Ｈ，ｍ），２．４３−２．７１（４Ｈ，ｂｒ ｍ），２．４８（３Ｈ，ｓ），３．０８（２Ｈ，ｄ，Ｊ＝６．９Ｈｚ），３．１１（２Ｈ，ｄｄｄ，Ｊ＝１３．５，７．５，４．６Ｈｚ），３．２４（２Ｈ，ｓ），３．４９（２Ｈ，ｓ），３．５８（１Ｈ，ｄｄｄ，Ｊ＝１３．５，６．８，３．３Ｈｚ），３．７４（１Ｈ，ｄｔ，Ｊ＝８．３，６．６Ｈｚ），３．８５（１Ｈ，ｄｔ，Ｊ＝８．３，６．６Ｈｚ），３．９４（１Ｈ，ｄｑ，Ｊ＝３．３，６．９Ｈｚ），５．８１（１Ｈ，ｂｒ ｔ，Ｊ＝４．６Ｈｚ），７．２２（４Ｈ，ｓ）．

ＬＣ／ＭＳ［条件１］：保持時間２．９６分；ｍ／ｚ５１６．０[Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ５１４．１［Ｍ−Ｈ］⁻（ＥＳＩ負イオンモード）５５０．３［Ｍ＋Ｃｌ］⁻（ＥＳＩ負イオンモード）

Example 234
(1r, 4r) -4-({8- [4- (methylthio) benzyl] -2-oxo-1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl) -N- Preparation of [(Tetrahydrofuran-2-yl) methyl] cyclohexanecarboxamide (Compound No. 234) Substantially except that 4- (methylthio) benzyl bromide (commercially available) was used instead of 3- (bromomethyl) pyridine hydrobromide Specifically, the reaction was carried out in the same manner as in Example 4 to obtain the title compound (16.1 mg, yield 62%) as a white powder.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.01 (2H, br q, J = 12.2 Hz), 1.38-2.11 (16H, m), 2.43-2.71 (4H , Br m), 2.48 (3H, s), 3.08 (2H, d, J = 6.9 Hz), 3.11 (2H, ddd, J = 13.5, 7.5, 4.6 Hz) ), 3.24 (2H, s), 3.49 (2H, s), 3.58 (1H, ddd, J = 13.5, 6.8, 3.3 Hz), 3.74 (1H, dt) , J = 8.3, 6.6 Hz), 3.85 (1H, dt, J = 8.3, 6.6 Hz), 3.94 (1H, dq, J = 3.3, 6.9 Hz), 5.81 (1H, br t, J = 4.6 Hz), 7.22 (4H, s).

LC / MS [Condition 1]: Retention time 2.96 minutes; m / z 516.0 [M + H] ⁺ (ESI positive ion mode), m / z 514.1 [MH] ⁻ (ESI negative ion mode) 550. 3 [M + Cl] ⁻ (ESI negative ion mode)

実施例２３５
（１ｒ，４ｒ）‐４‐（｛８‐［３，５‐ビス（トリフルオロメチル）ベンジル］‐２‐オキソ‐１‐オキサ‐３，８‐ジアザスピロ［４．５］デカン‐３‐イル｝メチル）‐Ｎ‐［（テトラヒドロフラン‐２‐イル）メチル］シクロヘキサンカルボキサミド（化合物番号２３５）の製造

実施例３で得られた、（１ｒ，４ｒ）‐４‐［（２‐オキソ‐１‐オキサ‐３，８‐ジアザスピロ［４．５］デカン‐３‐イル）メチル］‐Ｎ‐［（テトラヒドロフラン‐２‐イル）メチル］シクロヘキサンカルボキサミド一塩酸塩（２０．８ｍｇ、０．０５ｍｍｏｌ）をメタノール／酢酸（１０／１）の混合溶媒（２．０ｍＬ）に溶解し、室温にて３，５‐ビス（トリフルオロメチル）ベンズアルデヒド（市販）（１１．５μＬ、０．０７ｍｍｏｌ）とボラン‐２-ピコリンコンプレックス（純正化学社より購入）（７．５ｍｇ、０．０７ｍｍｏｌ）を加えて、室温で１日間かき混ぜた。反応終了後、反応液を減圧留去した後、得られた反応残渣をシリカゲルカラムクロマトグラフィー［充填剤：富士シリシア社製ＦＬ１００Ｄ、展開溶媒：クロロホルム／メタノール＝２０／１］にて精製し、（１ｒ，４ｒ）‐４‐（｛８‐［３，５‐ビス（トリフルオロメチル）ベンジル］‐２‐オキソ‐１‐オキサ‐３，８‐ジアザスピロ［４．５］デカン‐３‐イル｝メチル）‐Ｎ‐［（テトラヒドロフラン‐２‐イル）メチル］シクロヘキサンカルボキサミド（２３．３ｍｇ、収率７７％）を白色粉末として得た。

^１Ｈ−ＮＭＲ（３００ＭＨｚ，ＣＤＣｌ_３）δ：１．０２（２Ｈ，ｄｑ，Ｊ＝３．０，１２．６Ｈｚ），１．３６−１．６９（４Ｈ，ｍ），１．６９−２．１５（１２Ｈ，ｍ），２．５３−２．６８（４Ｈ，ｂｒ ｍ），３．１０（２Ｈ，ｄ，Ｊ＝７．３Ｈｚ），３．１１（１Ｈ，ｄｄｄ，Ｊ＝１３．９，７．３，４．６Ｈｚ），３．２７（２Ｈ，ｓ），３．５８（１Ｈ，ｄｄｄ，Ｊ＝１３．９，６．９，３．３Ｈｚ），３．６３（２Ｈ，ｓ），３．７５（１Ｈ，ｄｔ，Ｊ＝８．３，６．８Ｈｚ），３．８５（１Ｈ，ｄｔ，Ｊ＝８．３，６．６Ｈｚ），３．９４（１Ｈ，ｄｑ，Ｊ＝３．３，７．１Ｈｚ），５．８２（１Ｈ，ｂｒ ｔ，Ｊ＝５．６Ｈｚ），７．７８（１Ｈ，ｂｒ ｓ），７．８０（２Ｈ，ｂｒ ｓ）．

ＬＣ／ＭＳ［条件１］：保持時間３．６０分；ｍ／ｚ６０６．０[Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ６４０．２［Ｍ＋Ｃｌ］⁻、６５０．２［Ｍ＋ＨＣＯＯ］⁻（ＥＳＩ負イオンモード）

Example 235
(1r, 4r) -4-({8- [3,5-bis (trifluoromethyl) benzyl] -2-oxo-1-oxa-3,8-diazaspiro [4.5] decan-3-yl} Preparation of methyl) -N-[(tetrahydrofuran-2-yl) methyl] cyclohexanecarboxamide (Compound No. 235)

(1r, 4r) -4-[(2-oxo-1-oxa-3,8-diazaspiro [4.5] decan-3-yl) methyl] -N-[(tetrahydrofuran) obtained in Example 3 -2-yl) methyl] cyclohexanecarboxamide monohydrochloride (20.8 mg, 0.05 mmol) was dissolved in a mixed solvent of methanol / acetic acid (10/1) (2.0 mL) and 3,5-bis at room temperature. (Trifluoromethyl) benzaldehyde (commercially available) (11.5 μL, 0.07 mmol) and borane-2-picoline complex (purchased from Junsei Co., Ltd.) (7.5 mg, 0.07 mmol) were added and stirred at room temperature for 1 day It was. After completion of the reaction, the reaction solution was distilled off under reduced pressure, and the resulting reaction residue was purified by silica gel column chromatography [filler: FL100D manufactured by Fuji Silysia Ltd., developing solvent: chloroform / methanol = 20/1] ( 1r, 4r) -4-({8- [3,5-bis (trifluoromethyl) benzyl] -2-oxo-1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl ) -N-[(Tetrahydrofuran-2-yl) methyl] cyclohexanecarboxamide (23.3 mg, 77% yield) was obtained as a white powder.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.02 (2H, dq, J = 3.0, 12.6 Hz), 1.36 to 1.69 (4H, m), 1.69-2. 15 (12H, m), 2.53-2.68 (4H, br m), 3.10 (2H, d, J = 7.3 Hz), 3.11 (1H, ddd, J = 13.9, 7.3, 4.6 Hz), 3.27 (2H, s), 3.58 (1 H, ddd, J = 13.9, 6.9, 3.3 Hz), 3.63 (2H, s), 3.75 (1H, dt, J = 8.3, 6.8 Hz), 3.85 (1H, dt, J = 8.3, 6.6 Hz), 3.94 (1H, dq, J = 3. 3, 7.1 Hz), 5.82 (1 H, br t, J = 5.6 Hz), 7.78 (1 H, br s), 7.80 (2 H, br s).

LC / MS [condition 1]: retention time 3.60 minutes; m / z 606.0 [M + H] ⁺ (ESI positive ion mode), m / z 640.2 [M + Cl] ⁻ , 650.2 [M + HCOO] ⁻ (ESI Negative ion mode)

実施例２３６
（１ｒ，４ｒ）‐４‐［（２‐オキソ‐８‐｛［６‐（トリフルオロメチル）ピリジン‐３‐イル］メチル｝‐１‐オキサ‐３，８‐ジアザスピロ［４．５］デカン‐３‐イル）メチル］‐Ｎ‐［（テトラヒドロフラン‐２‐イル）メチル］シクロヘキサンカルボキサミド（化合物番号２３６）の製造
３，５‐ビス（トリフルオロメチル）ベンズアルデヒドの代わりに、６‐（トリフルオロメチル）ピリジン‐３‐ピリジンカルボキシアルデヒド（市販）を用いること以外は実質的に実施例２３５と同様に反応を行なって、表題化合物（１１．７ｍｇ、収率４３％）を白色粉末として得た。

^１Ｈ−ＮＭＲ（３００ＭＨｚ，ＣＤＣｌ_３）δ：１．０２（２Ｈ，ｄｑ，Ｊ＝３．７，１２．８Ｈｚ），１．３９−１．６５（４Ｈ，ｍ），１．６９−１．８４（４Ｈ，ｍ），１．８４−２．１２（８Ｈ，ｍ），２．４６−２．７０（４Ｈ，ｂｒ ｍ），３．０９（２Ｈ，ｄ，Ｊ＝７．４Ｈｚ），３．１１（１Ｈ，ｄｄｄ，Ｊ＝１３．９，７．４，４．５Ｈｚ），３．２６（２Ｈ，ｓ），３．５８（１Ｈ，ｄｄｄ，Ｊ＝１３．９，６．５，３．３Ｈｚ），３．６１（２Ｈ，ｓ），３．７４（１Ｈ，ｄｔ，Ｊ＝８．２，６．５Ｈｚ），３．８５（１Ｈ，ｄｔ，Ｊ＝８．２，６．５Ｈｚ），３．９４（１Ｈ，ｄｑ，Ｊ＝３．３，７．１Ｈｚ），５．８０（１Ｈ，ｂｒ ｔ，Ｊ＝５．３Ｈｚ），７．６５（１Ｈ，ｄ，Ｊ＝７．８Ｈｚ），７．８５（１Ｈ，ｂｒ ｄ，Ｊ＝７．８Ｈｚ），８．６８（１Ｈ，ｓ）．

ＬＣ／ＭＳ［条件１］：保持時間３．００分；ｍ／ｚ５３８．９[Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ５７３．１［Ｍ＋Ｃｌ］⁻、５８３．２［Ｍ＋ＨＣＯＯ］⁻（ＥＳＩ負イオンモード）

Example 236
(1r, 4r) -4-[(2-oxo-8-{[6- (trifluoromethyl) pyridin-3-yl] methyl} -1-oxa-3,8-diazaspiro [4.5] decane- Preparation of 3-yl) methyl] -N-[(tetrahydrofuran-2-yl) methyl] cyclohexanecarboxamide (Compound No. 236) Instead of 3,5-bis (trifluoromethyl) benzaldehyde, 6- (trifluoromethyl) The reaction was carried out substantially in the same manner as in Example 235 except that pyridine-3-pyridinecarboxaldehyde (commercially available) was used to obtain the title compound (11.7 mg, yield 43%) as a white powder.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.02 (2H, dq, J = 3.7, 12.8 Hz), 1.39-1.65 (4H, m), 1.69-1. 84 (4H, m), 1.84-2.12 (8H, m), 2.46-2.70 (4H, br m), 3.09 (2H, d, J = 7.4 Hz), 3 .11 (1H, ddd, J = 13.9, 7.4, 4.5 Hz), 3.26 (2H, s), 3.58 (1H, ddd, J = 13.9, 6.5, 3 .3 Hz), 3.61 (2H, s), 3.74 (1 H, dt, J = 8.2, 6.5 Hz), 3.85 (1 H, dt, J = 8.2, 6.5 Hz) 3.94 (1H, dq, J = 3.3, 7.1 Hz), 5.80 (1H, brt, J = 5.3 Hz), 7.65 (1H, d, J = 7.8 Hz) , 7.85 (1 H, br d, J = 7.8 Hz), 8.68 (1H, s).

LC / MS [Condition 1]: Retention time 3.00 minutes; m / z 538.9 [M + H] ⁺ (ESI positive ion mode), m / z 573.1 [M + Cl] ⁻ , 583.2 [M + HCOO] ⁻ (ESI Negative ion mode)

参考例２３７
３−［４−（４−ベンゾイルピペリジン−１−カルボニル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−２−オン塩酸塩の製造
２−オキソ−３−［（（１ｒ，４ｒ）−４−｛［（テトラヒドロフラン−２−イル）メチル］カルバモイル｝シクロヘキシル）メチル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−８−カルボン酸ｔ−ブチルの代わりに、実施例１５８で得られた３−［４−（４−ベンゾイルピペリジン−１−カルボニル）ベンジル］−２−オキソ−１−オキサ−３，８−ジアザスピロ［４．５］デカン−８−カルボン酸ｔ−ブチルを用いること以外は実質的に実施例３と同様に反応を行って表題化合物（１．１ｇ、定量的）を無色無定形物として得た。

^１Ｈ−ＮＭＲ（３００ＭＨｚ、ＣＤＣｌ_３）δ：１．７０−２．１４（６Ｈ，ｍ），２．２５（２Ｈ，ｔ，Ｊ＝９．８Ｈｚ），２．９２−４．０２（１０Ｈ，ｍ），４．４４（２Ｈ，ｓ），４．６７（１Ｈ，ｂｒ ｓ），７．３０（２Ｈ，ｄ，Ｊ＝７．４Ｈｚ），７．３６−７．５４（４Ｈ，ｍ），７．５９（１Ｈ，ｔ，Ｊ＝７．４Ｈｚ），７．９４（２Ｈ，ｄ，Ｊ＝７．０Ｈｚ），９．７０（１Ｈ，ｓ）．
ＬＣ／ＭＳ［条件１］：保持時間３．１６分；ｍ／ｚ４６１．９［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）

Reference Example 237
Preparation of 3- [4- (4-benzoylpiperidine-1-carbonyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-2-one hydrochloride 2-oxo-3-[(( 1r, 4r) -4-{[(Tetrahydrofuran-2-yl) methyl] carbamoyl} cyclohexyl) methyl] -1-oxa-3,8-diazaspiro [4.5] decan-8-carboxyl instead of t-butyl 3- [4- (4-benzoylpiperidine-1-carbonyl) benzyl] -2-oxo-1-oxa-3,8-diazaspiro [4.5] decane-8-carvone obtained in Example 158 The reaction was carried out substantially in the same manner as in Example 3 except for using t-butyl acid to obtain the title compound (1.1 g, quantitative) as a colorless amorphous product.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.70-2.14 (6H, m), 2.25 (2H, t, J = 9.8 Hz), 2.92-4.02 (10H, m), 4.44 (2H, s), 4.67 (1H, br s), 7.30 (2H, d, J = 7.4 Hz), 7.36-7.54 (4H, m), 7.59 (1H, t, J = 7.4 Hz), 7.94 (2H, d, J = 7.0 Hz), 9.70 (1H, s).
LC / MS [Condition 1]: Retention time 3.16 minutes; m / z 461.9 [M + H] ⁺ (ESI positive ion mode)

実施例２３７
３‐［４‐（４‐ベンゾイル‐ピペリジン‐１‐カルボニル）‐ベンジル］‐８‐（４‐ニトロ‐ベンジル）‐１‐オキサ‐３，８‐ジアザ‐スピロ［４．５］デカン‐２‐オン（化合物番号２３７）の製造
参考例２３７で得られた、３‐［４‐（４‐ベンゾイルピペリジン‐１‐カルボニル）ベンジル］‐１‐オキサ‐３，８‐ジアザ‐スピロ［４．５］デカン‐２‐オン塩酸塩（２４．９ｍｇ、０．０５ｍｍｏｌ）をＮ，Ｎ‐ジメチルホルムアミド（１．０ｍＬ）に溶解し、室温にて４‐ニトロベンジルブロミド（市販）（１５．１ｍｇ、０．０７ｍｍｏｌ）とトリエチルアミン（２０．９μＬ、０．１５ｍｍｏｌ）を加えて、室温で１日間かき混ぜた。反応終了後、酢酸エチルを加え、水で洗浄し、無水硫酸ナトリウムで乾燥、減圧留去した。得られた反応残渣をシリカゲルカラムクロマトグラフィー［充填剤：富士シリシア社製ＦＬ１００Ｄ、展開溶媒：酢酸エチル／メタノール＝２０／１］にて精製し、３‐［４‐（４‐ベンゾイル‐ピペリジン‐１‐カルボニル）‐ベンジル］‐８‐（４‐ニトロ‐ベンジル）‐１‐オキサ‐３，８‐ジアザスピロ［４．５］デカン‐２‐オン（２０．４ｍｇ、収率６８％）を淡黄色油状物として得た。

^１Ｈ−ＮＭＲ（３００ＭＨｚ，ＣＤＣｌ_３）δ：１．６１−２．１７（８Ｈ，ｍ），２．４０−２．６６（４Ｈ，ｂｒ ｍ），２．９５−３．２９（２Ｈ，ｂｒ ｍ），３．１４（２Ｈ，ｓ），３．４８−３．６２（１Ｈ，ｍ），３．６０（２Ｈ，ｓ），３．６５−４．０７（１Ｈ，ｂｒ ｍ），４．４４（２Ｈ，ｓ），４．４９−４．８５（１Ｈ，ｂｒ ｍ），７．３０（２Ｈ，ｄ，Ｊ＝８．０Ｈｚ），７．４１（２Ｈ，ｄ，Ｊ＝８．０Ｈｚ），７．４９（２Ｈ，ｔ，Ｊ＝８．０Ｈｚ），７．４９（２Ｈ，ｄ，Ｊ＝８．６Ｈｚ），７．５９（１Ｈ，ｔｔ，Ｊ＝７．４，１．２Ｈｚ），７．９４（２Ｈ，ｄ，Ｊ＝８．０Ｈｚ），８．１７（２Ｈ，ｄ，Ｊ＝８．６Ｈｚ）．

ＬＣ／ＭＳ［条件１］：保持時間３．３０分；ｍ／ｚ５９７．１[Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ５９５．４［Ｍ−Ｈ］⁻、６３１．３［Ｍ＋Ｃｌ］⁻（ＥＳＩ負イオンモード）

Example 237
3- [4- (4-Benzoyl-piperidine-1-carbonyl) -benzyl] -8- (4-nitro-benzyl) -1-oxa-3,8-diaza-spiro [4.5] decane-2- Preparation of ON (Compound No. 237) 3- [4- (4-Benzoylpiperidine-1-carbonyl) benzyl] -1-oxa-3,8-diaza-spiro [4.5] obtained in Reference Example 237 Decan-2-one hydrochloride (24.9 mg, 0.05 mmol) was dissolved in N, N-dimethylformamide (1.0 mL) and 4-nitrobenzyl bromide (commercially available) (15.1 mg, 0.1 mL) at room temperature. 07 mmol) and triethylamine (20.9 μL, 0.15 mmol) were added, and the mixture was stirred at room temperature for 1 day. After completion of the reaction, ethyl acetate was added, washed with water, dried over anhydrous sodium sulfate and evaporated under reduced pressure. The obtained reaction residue was purified by silica gel column chromatography [filler: FL100D manufactured by Fuji Silysia Ltd., developing solvent: ethyl acetate / methanol = 20/1], and 3- [4- (4-benzoyl-piperidine-1] was obtained. -Carbonyl) -benzyl] -8- (4-nitro-benzyl) -1-oxa-3,8-diazaspiro [4.5] decan-2-one (20.4 mg, 68% yield) as a pale yellow oil Obtained as a thing.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.61-2.17 (8H, m), 2.40-2.66 (4H, br m), 2.95-3.29 (2H, br m), 3.14 (2H, s), 3.48-3.62 (1H, m), 3.60 (2H, s), 3.65-4.07 (1H, br m), 4. 44 (2H, s), 4.49-4.85 (1H, br m), 7.30 (2H, d, J = 8.0 Hz), 7.41 (2H, d, J = 8.0 Hz) , 7.49 (2H, t, J = 8.0 Hz), 7.49 (2H, d, J = 8.6 Hz), 7.59 (1H, tt, J = 7.4, 1.2 Hz), 7.94 (2H, d, J = 8.0 Hz), 8.17 (2H, d, J = 8.6 Hz).

LC / MS [Condition 1]: Retention time 3.30 minutes; m / z 597.1 [M + H] ⁺ (ESI positive ion mode), m / z 595.4 [M−H] ⁻ , 631.3 [M + Cl] ⁻ (ESI negative ion mode)

実施例２３８
３‐［４‐（４‐ベンゾイル‐ピペリジン‐１‐カルボニル）‐ベンジル］‐８‐（４‐トリフルオロメトキシ‐ベンジル）‐１‐オキサ‐３，８‐ジアザ‐スピロ［４．５］デカン‐２‐オン（化合物番号２３８）の製造
４‐ニトロベンジルブロミドの代わりに、４‐（トリフルオロメトキシ）ベンジルブロミド（市販）を用いること以外は実質的に実施例２３７と同様に反応を行なって、表題化合物（２７．８ｍｇ、収率８７％）を白色粉末として得た。

^１Ｈ−ＮＭＲ（３００ＭＨｚ，ＣＤＣｌ_３）δ：１．６８−２．１３（８Ｈ，ｍ），２．３８−２．６３（４Ｈ，ｂｒ ｍ），２．９５−３．２５（２Ｈ，ｂｒ ｍ），３．１２（２Ｈ，ｓ），３．４９（２Ｈ，ｓ），３．４９−３．６１（１Ｈ，ｍ），３．６５−４．０５（１Ｈ，ｂｒ ｍ），４．４４（２Ｈ，ｓ），４．４７−４．８３（１Ｈ，ｂｒ ｍ），７．１４（２Ｈ，ｄ，Ｊ＝７．８Ｈｚ），７．３０（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ），７．３２（２Ｈ，ｄ，Ｊ＝７．８Ｈｚ），７．４１（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ），７．４８（１Ｈ，ｔ，Ｊ＝７．８Ｈｚ），７．５８（１Ｈ，ｔｔ，Ｊ＝７．４，１．２Ｈｚ），７．９４（２Ｈ，ｄ，Ｊ＝７．８Ｈｚ）．

ＬＣ／ＭＳ［条件１］：保持時間３．５０分；ｍ／ｚ６３６．２[Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ６７０．２［Ｍ＋Ｃl］⁻、６８０．３［Ｍ＋ＨＣＯＯ］⁻（ＥＳＩ負イオンモード）

Example 238
3- [4- (4-Benzoyl-piperidine-1-carbonyl) -benzyl] -8- (4-trifluoromethoxy-benzyl) -1-oxa-3,8-diaza-spiro [4.5] decane- Preparation of 2-one (Compound No. 238) The reaction was carried out in substantially the same manner as in Example 237 except that 4- (trifluoromethoxy) benzyl bromide (commercially available) was used instead of 4-nitrobenzyl bromide. The title compound (27.8 mg, 87% yield) was obtained as a white powder.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.68-2.13 (8H, m), 2.38-2.63 (4H, br m), 2.95-3.25 (2H, br m), 3.12 (2H, s), 3.49 (2H, s), 3.49-3.61 (1H, m), 3.65-4.05 (1H, br m), 4. 44 (2H, s), 4.47-4.83 (1H, br m), 7.14 (2H, d, J = 7.8 Hz), 7.30 (2H, d, J = 8.2 Hz) , 7.32 (2H, d, J = 7.8 Hz), 7.41 (2H, d, J = 8.2 Hz), 7.48 (1H, t, J = 7.8 Hz), 7.58 ( 1H, tt, J = 7.4, 1.2 Hz), 7.94 (2H, d, J = 7.8 Hz).

LC / MS [Condition 1]: Retention time 3.50 minutes; m / z 636.2 [M + H] ⁺ (ESI positive ion mode), m / z 670.2 [M + Cl] ⁻ , 680.3 [M + HCOO] ⁻ (ESI Negative ion mode)

実施例２３９
３‐［４‐（４‐ベンゾイル‐ピペリジン‐１‐カルボニル）‐ベンジル］‐８‐（４‐ブロモ‐ベンジル）‐１‐オキサ‐３，８‐ジアザ‐スピロ［４．５］デカン‐２‐オン（化合物番号２３９）の製造
４‐ニトロベンジルブロミドの代わりに、４‐ブロモベンジルブロミド（市販）を用いること以外は実質的に実施例２３７と同様に反応を行なって、表題化合物（１４９．８ｍｇ、収率９５％）を無色油状物として得た。

^１Ｈ−ＮＭＲ（３００ＭＨｚ，ＣＤＣｌ_３）δ：１．６４−２．１８（８Ｈ，ｍ），２．３６−２．６１（４Ｈ，ｂｒ ｍ），２．９４−３．２７（２Ｈ，ｂｒ ｍ），３．１２（２Ｈ，ｓ），３．４５（２Ｈ，ｓ），３．４８−３．６３（１Ｈ，ｍ），３．６４−４．０５（１Ｈ，ｂｒ ｍ），４．４４（２Ｈ，ｂｒ ｓ），４．４８−４．９２（１Ｈ，ｂｒ ｍ），７．１７（２Ｈ，ｄ，Ｊ＝８．４Ｈｚ），７．３０（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ），７．４１（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ），７．４２（２Ｈ，ｄ，Ｊ＝８．４Ｈｚ），７．４９（２Ｈ，ｔ，Ｊ＝７．８Ｈｚ），７．５９（１Ｈ，ｔｔ，Ｊ＝７．４，１．６Ｈｚ），７．９４（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ）．
ＬＣ／ＭＳ［条件１］：保持時間３．４０分；ｍ／ｚ６３０．１ [Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ６６４．３［Ｍ＋Ｃl］⁻（ＥＳＩ負イオンモード）

Example 239
3- [4- (4-Benzoyl-piperidine-1-carbonyl) -benzyl] -8- (4-bromo-benzyl) -1-oxa-3,8-diaza-spiro [4.5] decane-2- Preparation of ON (Compound No. 239) The reaction was conducted in substantially the same manner as in Example 237 except that 4-bromobenzyl bromide (commercially available) was used instead of 4-nitrobenzyl bromide to give the title compound (149.8 mg Yield 95%) as a colorless oil.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.64-2.18 (8H, m), 2.36-2.61 (4H, br m), 2.94-3.27 (2H, br m), 3.12 (2H, s), 3.45 (2H, s), 3.48-3.63 (1H, m), 3.64-4.05 (1H, br m), 4. 44 (2H, br s), 4.48-4.92 (1H, br m), 7.17 (2H, d, J = 8.4 Hz), 7.30 (2H, d, J = 8.2 Hz) ), 7.41 (2H, d, J = 8.2 Hz), 7.42 (2H, d, J = 8.4 Hz), 7.49 (2H, t, J = 7.8 Hz), 7.59 (1H, tt, J = 7.4, 1.6 Hz), 7.94 (2H, d, J = 8.2 Hz).
LC / MS [Condition 1]: Retention time 3.40 minutes; m / z 630.1 [M + H] ⁺ (ESI positive ion mode), m / z 664.3 [M + Cl] ⁻ (ESI negative ion mode)

実施例２４０
３‐［４‐（４‐ベンゾイル‐ピペリジン‐１‐カルボニル）‐ベンジル］‐８‐（４‐クロロ‐ベンジル）‐１‐オキサ‐３，８‐ジアザ‐スピロ［４．５］デカン‐２‐オン（化合物番号２４０）の製造
４‐ニトロベンジルブロミドの代わりに、４‐クロロベンジルブロミド（市販）を用いること以外は実質的に実施例２３７と同様に反応を行なって、表題化合物（９．５ｍｇ、収率３１％）を淡黄色油状物として得た。

^１Ｈ−ＮＭＲ（３００ＭＨｚ，ＣＤＣｌ_３）δ：１．６４−２．２０（８Ｈ，ｍ），２．３７−２．６５（４Ｈ，ｂｒ ｍ），２．９７−３．２９（２Ｈ，ｂｒ ｍ），３．１２（２Ｈ，ｓ），３．４６（２Ｈ，ｓ），３．４８−３．６５（１Ｈ，ｍ），３．６５−４．０７（１Ｈ，ｂｒ ｍ），４．４４（２Ｈ，ｓ），４．４６−４．８４（１Ｈ，ｂｒ ｍ），７．２２（２Ｈ，ｄ，Ｊ＝８．６Ｈｚ），７．２７（２Ｈ，ｄ，Ｊ＝８．６Ｈｚ），７．３０（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ），７．４１（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ），７．４９（２Ｈ，ｔ，Ｊ＝７．４Ｈｚ），７．５９（１Ｈ，ｔｔ，Ｊ＝７．４，１．６Ｈｚ），７．９４（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ）．

ＬＣ／ＭＳ［条件１］：保持時間３．３８分；ｍ／ｚ５８６．１[Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ６２０．２［Ｍ＋Ｃｌ］⁻（ＥＳＩ負イオンモード）、ｍ／ｚ６３０．３［Ｍ＋ＨＣＯＯ］⁻（ＥＳＩ負イオンモード）

Example 240
3- [4- (4-Benzoyl-piperidine-1-carbonyl) -benzyl] -8- (4-chloro-benzyl) -1-oxa-3,8-diaza-spiro [4.5] decane-2- Preparation of ON (Compound No. 240) The reaction was conducted in substantially the same manner as in Example 237 except that 4-chlorobenzyl bromide (commercially available) was used instead of 4-nitrobenzyl bromide to give the title compound (9.5 mg Yield 31%) as a pale yellow oil.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.64-2.20 (8H, m), 2.37-2.65 (4H, br m), 2.97-3.29 (2H, br m), 3.12 (2H, s), 3.46 (2H, s), 3.48-3.65 (1H, m), 3.65-4.07 (1H, br m), 4. 44 (2H, s), 4.46-4.84 (1H, br m), 7.22 (2H, d, J = 8.6 Hz), 7.27 (2H, d, J = 8.6 Hz) 7.30 (2H, d, J = 8.2 Hz), 7.41 (2H, d, J = 8.2 Hz), 7.49 (2H, t, J = 7.4 Hz), 7.59 ( 1H, tt, J = 7.4, 1.6 Hz), 7.94 (2H, d, J = 8.2 Hz).

LC / MS [Condition 1]: Retention time 3.38 minutes; m / z 586.1 [M + H] ⁺ (ESI positive ion mode), m / z 620.2 [M + Cl] ⁻ (ESI negative ion mode), m / z 630 .3 [M + HCOO] ⁻ (ESI negative ion mode)

実施例２４１
２‐｛３‐［４‐（４‐ベンゾイル‐ピペリジン‐１‐カルボニル）‐ベンジル］‐２‐オキソ‐１‐オキサ‐３，８‐ジアザ‐スピロ［４．５］デク‐８‐イルメチル｝‐ベンゾニトリル（化合物番号２４１）の製造
４‐ニトロベンジルブロミドの代わりに、２‐シアノベンジルブロミド（市販）を用いること以外は実質的に実施例２３７と同様に反応を行なって、表題化合物（２６．５ｍｇ、収率９２％）を淡黄色油状物として得た。

^１Ｈ−ＮＭＲ（３００ＭＨｚ，ＣＤＣｌ_３）δ：１．６７−２．１７（８Ｈ，ｍ），２．４３−２．７２（４Ｈ，ｍ），２．９５−３．２６（２Ｈ，ｂｒ ｍ），３．１３（２Ｈ，ｓ），３．４６−３．６３（１Ｈ，ｍ），３．６７−４．１２（１Ｈ，ｂｒ ｍ），３．６９（２Ｈ，ｓ），４．４４（２Ｈ，ｓ），４．４７−４．８８（１Ｈ，ｂｒ ｍ），７．３０（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ），７．３５（１Ｈ，ｄｔ，Ｊ＝１．２，７．８Ｈｚ），７．４１（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ），７．４４−７．６１（５Ｈ，ｍ），７．６３（１Ｈ，ｄ，Ｊ＝７．８Ｈｚ），７．９４（２Ｈ，ｄ，Ｊ＝７．８Ｈｚ）．

ＬＣ／ＭＳ［条件１］：保持時間３．２８分；ｍ／ｚ５７６．７[Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）

Example 241
2- {3- [4- (4-Benzoyl-piperidine-1-carbonyl) -benzyl] -2-oxo-1-oxa-3,8-diaza-spiro [4.5] dec-8-ylmethyl}- Preparation of benzonitrile (Compound No. 241) The reaction was conducted in substantially the same manner as in Example 237 except that 2-cyanobenzyl bromide (commercially available) was used instead of 4-nitrobenzyl bromide to give the title compound (26. 5 mg, 92% yield) was obtained as a pale yellow oil.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.67-2.17 (8H, m), 2.44-2.72 (4H, m), 2.95-3.26 (2H, br m ), 3.13 (2H, s), 3.46-3.63 (1H, m), 3.67-4.12 (1H, br m), 3.69 (2H, s), 4.44 (2H, s), 4.47-4.88 (1H, br m), 7.30 (2H, d, J = 8.2 Hz), 7.35 (1H, dt, J = 1.2, 7 .8 Hz), 7.41 (2H, d, J = 8.2 Hz), 7.44-7.61 (5H, m), 7.63 (1H, d, J = 7.8 Hz), 7.94 (2H, d, J = 7.8 Hz).

LC / MS [Condition 1]: retention time 3.28 minutes; m / z 576.7 [M + H] ⁺ (ESI positive ion mode)

実施例２４２
３‐｛３‐［４‐（４‐ベンゾイル‐ピペリジン‐１‐カルボニル）‐ベンジル］‐２‐オキソ‐１‐オキサ‐３，８‐ジアザ‐スピロ［４．５］デク‐８‐イルメチル｝‐ベンゾニトリル（化合物番号２４２）の製造
４‐ニトロベンジルブロミドの代わりに、３‐シアノベンジルブロミド（市販）を用いること以外は実質的に実施例２３７と同様に反応を行なって、表題化合物（２１．３ｍｇ、収率７４％）を淡黄色油状物として得た。

^１Ｈ−ＮＭＲ（３００ＭＨｚ，ＣＤＣｌ_３）δ：１．６８−２．１７（８Ｈ，ｍ），２．４０−２．６５（４Ｈ，ｂｒ ｍ），２．９６−３．３０（２Ｈ，ｂｒ ｍ），３．１３（２Ｈ，ｓ），３．４７−３．６２（１Ｈ，ｍ），３．５３（２Ｈ，ｓ），３．６３−４．０５（１Ｈ，ｂｒ ｍ），４．４５（２Ｈ，ｓ），４．５１−４．８７（１Ｈ，ｂｒ ｍ），７．３０（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ），７．４０（１Ｈ，ｔ，Ｊ＝７．４Ｈｚ），７．４１（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ），７．４８（２Ｈ，ｔ，Ｊ＝７．４Ｈｚ），７．５０−７．５７（２Ｈ，ｍ），７．５９（１Ｈ，ｔｔ，Ｊ＝７．４，１．２Ｈｚ），７．６４（１Ｈ，ｂｒ ｓ），７．９４（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ）．

ＬＣ／ＭＳ［条件１］：保持時間３．２８分；ｍ／ｚ５７７．１[Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ６１１．３［Ｍ＋Ｃｌ］⁻、６２１．４［Ｍ＋ＨＣＯＯ］⁻（ＥＳＩ負イオンモード）

Example 242
3- {3- [4- (4-Benzoyl-piperidine-1-carbonyl) -benzyl] -2-oxo-1-oxa-3,8-diaza-spiro [4.5] dec-8-ylmethyl}- Preparation of benzonitrile (Compound No. 242) The reaction was conducted in substantially the same manner as in Example 237 except that 3-cyanobenzyl bromide (commercially available) was used instead of 4-nitrobenzyl bromide to give the title compound (21. 3 mg, 74% yield) was obtained as a pale yellow oil.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.68-2.17 (8H, m), 2.40-2.65 (4H, br m), 2.96-3.30 (2H, br m), 3.13 (2H, s), 3.47-3.62 (1H, m), 3.53 (2H, s), 3.63-4.05 (1H, br m), 4. 45 (2H, s), 4.51-4.87 (1H, br m), 7.30 (2H, d, J = 8.2 Hz), 7.40 (1H, t, J = 7.4 Hz) , 7.41 (2H, d, J = 8.2 Hz), 7.48 (2H, t, J = 7.4 Hz), 7.50-7.57 (2H, m), 7.59 (1H, tt, J = 7.4, 1.2 Hz), 7.64 (1H, brs), 7.94 (2H, d, J = 8.2 Hz).

LC / MS [Condition 1]: Retention time 3.28 minutes; m / z 577.1 [M + H] ⁺ (ESI positive ion mode), m / z 611.3 [M + Cl] ⁻ , 621.4 [M + HCOO] ⁻ (ESI Negative ion mode)

実施例２４３
３‐［４‐（４‐ベンゾイル‐ピペリジン‐１‐カルボニル）‐ベンジル］‐２‐オキソ‐１‐オキサ‐３，８‐ジアザ‐スピロ［４．５］デカン‐８‐チオカルボン酸（４‐シアノ‐フェニル）‐アミド（化合物番号２４３）の製造
４‐ニトロベンジルブロミドの代わりに、４‐シアノフェニルイソチオシアネート（市販）を用いること以外は実質的に実施例２３７と同様に反応を行なって、表題化合物（２７．２ｍｇ、収率８７％）を白色粉末として得た。

^１Ｈ−ＮＭＲ（３００ＭＨｚ，ＣＤＣｌ_３）δ：１．７４−２．１１（８Ｈ，ｍ），２．９５−３．２６（２Ｈ，ｂｒ ｍ），３．１８（２Ｈ，ｓ），３．５４（２Ｈ，ｔ，Ｊ＝１１．９Ｈｚ），３．５５−３．６３（１Ｈ，ｍ），３．６４−３．９９（１Ｈ，ｂｒ ｍ），４．４６（２Ｈ，ｓ），４．４８（１Ｈ，ｂｒ ｄ，Ｊ＝１４．３Ｈｚ），４．５４−４．７８（１Ｈ，ｂｒ ｍ），７．３０（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ），７．３１（２Ｈ，ｄ，Ｊ＝８．５Ｈｚ），７．４０（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ），７．４９（２Ｈ，ｔ，Ｊ＝７．４Ｈｚ），７．５６（２Ｈ，ｄ，Ｊ＝８．５Ｈｚ），７．６０（１Ｈ，ｔｔ，Ｊ＝７．０，１．２Ｈｚ），７．９４（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ），７．９７（１Ｈ，ｂｒ ｓ）．

ＬＣ／ＭＳ［条件１］：保持時間４．３３分；ｍ／ｚ６２２．２[Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ６２０．３［Ｍ−Ｈ］⁻、６５６．２［Ｍ＋Ｃｌ］⁻（ＥＳＩ負イオンモード）

Example 243
3- [4- (4-Benzoyl-piperidine-1-carbonyl) -benzyl] -2-oxo-1-oxa-3,8-diaza-spiro [4.5] decane-8-thiocarboxylic acid (4-cyano -Phenyl) -amide (Compound No. 243) The reaction was conducted in substantially the same manner as in Example 237 except that 4-cyanophenyl isothiocyanate (commercially available) was used instead of 4-nitrobenzyl bromide. The compound (27.2 mg, 87% yield) was obtained as a white powder.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.74-2.11 (8H, m), 2.95-3.26 (2H, br m), 3.18 (2H, s), 3. 54 (2H, t, J = 11.9 Hz), 3.55-3.63 (1H, m), 3.64-3.99 (1H, br m), 4.46 (2H, s), 4 .48 (1H, br d, J = 14.3 Hz), 4.54-4.78 (1 H, br m), 7.30 (2H, d, J = 8.2 Hz), 7.31 (2H, d, J = 8.5 Hz), 7.40 (2H, d, J = 8.2 Hz), 7.49 (2H, t, J = 7.4 Hz), 7.56 (2H, d, J = 8) .5 Hz), 7.60 (1H, tt, J = 7.0, 1.2 Hz), 7.94 (2H, d, J = 8.2 Hz), 7.97 (1H, br s).

LC / MS [Condition 1]: Retention time 4.33 minutes; m / z 622.2 [M + H] ⁺ (ESI positive ion mode), m / z 620.3 [M−H] ⁻ , 656.2 [M + Cl] ⁻ (ESI negative ion mode)

実施例２４４
３‐［４‐（４‐ベンゾイル‐ピペリジン‐１‐カルボニル）‐ベンジル］‐２‐オキソ‐１‐オキサ‐３，８‐ジアザ‐スピロ［４．５］デカン‐８‐カルボン酸（４‐シアノ‐フェニル）‐アミド（化合物番号２４４）の製造
４‐ニトロベンジルブロミドの代わりに、４‐シアノフェニルイソシアネート（市販）を用いること以外は実質的に実施例２３７と同様に反応を行なって、表題化合物（２７．４ｍｇ、収率９０％）を無色油状物として得た。

^１Ｈ−ＮＭＲ（３００ＭＨｚ，ＣＤＣｌ_３）δ：１．６５−２．１４（８Ｈ，ｍ），２．９３−３．２８（２Ｈ，ｂｒ ｍ），３．１６（２Ｈ，ｓ），３．３６（２Ｈ，ｔ，Ｊ＝１２．７Ｈｚ），３．５０−３．６５（１Ｈ，ｍ），３．６９−３．９５（１Ｈ，ｂｒ ｍ），３．９２（２Ｈ，ｂｒ ｄ，Ｊ＝１３．９Ｈｚ），４．４５（２Ｈ，ｓ），４．４８−４．８０（１Ｈ，ｂｒ ｍ），７．３０（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ），７．３４（１Ｈ，ｂｒ ｓ），７．４０（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ），７．４９（２Ｈ，ｔ，Ｊ＝７．８Ｈｚ），７．５０（４Ｈ，ｓ），７．５９（１Ｈ，ｔｔ，Ｊ＝７．８，１．２Ｈｚ），７．９４（２Ｈ，ｄ，Ｊ＝７．８Ｈｚ）．

ＬＣ／ＭＳ［条件１］：保持時間４．０３分；ｍ／ｚ６０６．１[Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ６０４．２［Ｍ−Ｈ］⁻、６４０．２［Ｍ＋Ｃｌ］⁻（ＥＳＩ負イオンモード）

Example 244
3- [4- (4-Benzoyl-piperidine-1-carbonyl) -benzyl] -2-oxo-1-oxa-3,8-diaza-spiro [4.5] decane-8-carboxylic acid (4-cyano -Phenyl) -amide (Compound No. 244) The title compound was reacted in substantially the same manner as in Example 237 except that 4-cyanophenyl isocyanate (commercially available) was used instead of 4-nitrobenzyl bromide. (27.4 mg, 90% yield) was obtained as a colorless oil.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.65-2.14 (8H, m), 2.93-3.28 (2H, br m), 3.16 (2H, s), 3. 36 (2H, t, J = 12.7 Hz), 3.50-3.65 (1H, m), 3.69-3.95 (1H, br m), 3.92 (2H, br d, J = 13.9 Hz), 4.45 (2H, s), 4.48-4.80 (1 H, br m), 7.30 (2 H, d, J = 8.2 Hz), 7.34 (1 H, br s), 7.40 (2H, d, J = 8.2 Hz), 7.49 (2H, t, J = 7.8 Hz), 7.50 (4H, s), 7.59 (1H, tt) , J = 7.8, 1.2 Hz), 7.94 (2H, d, J = 7.8 Hz).

LC / MS [Condition 1]: Retention time 4.03 minutes; m / z 606.1 [M + H] ⁺ (ESI positive ion mode), m / z 604.2 [M−H] ⁻ , 640.2 [M + Cl] ⁻ (ESI negative ion mode)

実施例２４５
３‐［４‐（４‐ベンゾイル‐ピペリジン‐１‐カルボニル）‐ベンジル］‐２‐オキソ‐１‐オキサ‐３，８‐ジアザ‐スピロ［４．５］デカン‐８‐カルボン酸（３‐シアノ‐フェニル）‐アミド（化合物番号２４５）の製造
４‐ニトロベンジルブロミドの代わりに、３‐シアノフェニルイソシアネート（市販）を用いること以外は実質的に実施例２３７と同様に反応を行なって、表題化合物（３８．１ｍｇ、収率１００％）を無色油状物として得た。

^１Ｈ−ＮＭＲ（３００ＭＨｚ，ＣＤＣｌ_３）δ：１．６３−２．１１（８Ｈ，ｍ），２．９８−３．３０（２Ｈ，ｂｒ ｍ），３．１６（２Ｈ，ｓ），３．３６（２Ｈ，ｂｒ ｔ，Ｊ＝１２．７Ｈｚ），３．４９−３．６５（１Ｈ，ｍ），３．７３−４．０５（１Ｈ，ｂｒ ｍ），３．９０（２Ｈ，ｂｒ ｄ，Ｊ＝１３．９Ｈｚ），４．４６（２Ｈ，ｓ），４．５１−４．８１（１Ｈ，ｂｒ ｍ），７．１８（１Ｈ，ｂｒ ｓ），７．２６（１Ｈ，ｄｄｄ，Ｊ＝７．４，１．６，１．２Ｈｚ），７．３１（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ），７．３４（１Ｈ，ｔ，Ｊ＝７．８Ｈｚ），７．４１（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ），７．４９（２Ｈ，ｔ，Ｊ＝７．４Ｈｚ），７．５９（１Ｈ，ｔｔ，Ｊ＝７．４，１．２Ｈｚ），７．６３（２Ｈ，ｄｄｄ，Ｊ＝７．８，２．０，１．２Ｈｚ），７．７０（１Ｈ，ｔ，Ｊ＝１．６Ｈｚ），７．９４（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ）．

ＬＣ／ＭＳ［条件１］：保持時間４．０１分；ｍ／ｚ６０６．２[Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ６０４．２［Ｍ−Ｈ］⁻（ＥＳＩ負イオンモード）

Example 245
3- [4- (4-Benzoyl-piperidine-1-carbonyl) -benzyl] -2-oxo-1-oxa-3,8-diaza-spiro [4.5] decane-8-carboxylic acid (3-cyano -Phenyl) -amide (Compound No. 245) The title compound was reacted in substantially the same manner as in Example 237 except that 3-cyanophenyl isocyanate (commercially available) was used instead of 4-nitrobenzyl bromide. (38.1 mg, 100% yield) was obtained as a colorless oil.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.63-2.11 (8H, m), 2.98-3.30 (2H, br m), 3.16 (2H, s), 3. 36 (2H, br t, J = 12.7 Hz), 3.49-3.65 (1H, m), 3.73-4.05 (1H, br m), 3.90 (2H, br d, J = 13.9 Hz), 4.46 (2H, s), 4.51-4.81 (1H, br m), 7.18 (1 H, br s), 7.26 (1 H, ddd, J = 7.4, 1.6, 1.2 Hz), 7.31 (2H, d, J = 8.2 Hz), 7.34 (1H, t, J = 7.8 Hz), 7.41 (2H, d , J = 8.2 Hz), 7.49 (2H, t, J = 7.4 Hz), 7.59 (1H, tt, J = 7.4, 1.2 Hz), 7.63 (2H, ddd, J = .8,2.0,1.2Hz), 7.70 (1H, t, J = 1.6Hz), 7.94 (2H, d, J = 8.2Hz).

LC / MS [Condition 1]: Retention time 4.01 min; m / z 606.2 [M + H] ⁺ (ESI positive ion mode), m / z 604.2 [MH] ⁻ (ESI negative ion mode)

実施例２４６
３‐［４‐（４‐ベンゾイル‐ピペリジン‐１‐カルボニル）‐ベンジル］‐８‐（２，５‐ジメトキシ‐ベンジル）‐１‐オキサ‐３，８‐ジアザ‐スピロ［４．５］デカン‐２‐オン（化合物番号２４６）の製造
４‐ニトロベンジルブロミドの代わりに、２，５‐ジメトキシベンジルブロミド（市販）を用いること以外は実質的に実施例２３７と同様に反応を行なって、表題化合物（７．７ｍｇ、収率２５％）を無色油状物として得た。

^１Ｈ−ＮＭＲ（３００ＭＨｚ，ＣＤＣｌ_３）δ：１．６７−２．０６（８Ｈ，ｍ），２．４１−２．７２（４Ｈ，ｍ），２．９７−３．２５（２Ｈ，ｂｒ ｍ），３．１２（２Ｈ，ｓ），３．４８−３．６３（１Ｈ，ｍ），３．５４（１Ｈ，ｓ），３．７１−３．９９（１Ｈ，ｂｒ ｍ），３．７７（６Ｈ，ｓ），４．４４（２Ｈ，ｓ），４．５１−４．８４（１Ｈ，ｂｒ ｍ），６．７４（１Ｈ，ｄｄ，Ｊ＝９．０，２．９Ｈｚ），６．７８（１Ｈ，ｄ，Ｊ＝９．０Ｈｚ），６．９３（１Ｈ，ｄ，Ｊ＝２．９Ｈｚ），７．３０（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ），７．４１（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ），７．４８（２Ｈ，ｔ，Ｊ＝８．２Ｈｚ），７．５８（１Ｈ，ｔｔ，Ｊ＝７．４，１．２Ｈｚ），７．９４（２Ｈ，ｄ，Ｊ＝７．８Ｈｚ）．

ＬＣ／ＭＳ［条件１］：保持時間４．０１分；ｍ／ｚ６０６．２[Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ６０４．２［Ｍ−Ｈ］⁻（ＥＳＩ負イオンモード）

Example 246
3- [4- (4-Benzoyl-piperidine-1-carbonyl) -benzyl] -8- (2,5-dimethoxy-benzyl) -1-oxa-3,8-diaza-spiro [4.5] decane- Preparation of 2-one (Compound No. 246) The title compound was obtained by carrying out the reaction in substantially the same manner as in Example 237 except that 2,5-dimethoxybenzyl bromide (commercially available) was used instead of 4-nitrobenzyl bromide. (7.7 mg, 25% yield) was obtained as a colorless oil.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.67-2.06 (8H, m), 2.41-2.72 (4H, m), 2.97-3.25 (2H, br m ), 3.12 (2H, s), 3.48-3.63 (1H, m), 3.54 (1H, s), 3.71-3.99 (1H, br m), 3.77. (6H, s), 4.44 (2H, s), 4.51-4.84 (1H, br m), 6.74 (1H, dd, J = 9.0, 2.9 Hz), 6. 78 (1H, d, J = 9.0 Hz), 6.93 (1H, d, J = 2.9 Hz), 7.30 (2H, d, J = 8.2 Hz), 7.41 (2H, d , J = 8.2 Hz), 7.48 (2H, t, J = 8.2 Hz), 7.58 (1H, tt, J = 7.4, 1.2 Hz), 7.94 (2H, d, J = 7.8 Hz).

LC / MS [Condition 1]: Retention time 4.01 min; m / z 606.2 [M + H] ⁺ (ESI positive ion mode), m / z 604.2 [MH] ⁻ (ESI negative ion mode)

実施例２４７
３‐［４‐（４‐ベンゾイル‐ピペリジン‐１‐カルボニル）‐ベンジル］‐８‐（２‐トリフルオロメチル‐ベンジル）‐１‐オキサ‐３，８‐ジアザ‐スピロ［４．５］デカン‐２‐オン（化合物番号２４７）の製造
４‐ニトロベンジルブロミドの代わりに、２‐トリフルオロメチルベンジルブロミド（市販）を用いること以外は実質的に実施例２３７と同様に反応を行なって、表題化合物（２０．５ｍｇ、収率６６％）を無色油状物として得た。

^１Ｈ−ＮＭＲ（３００ＭＨｚ，ＣＤＣｌ_３）δ：１．７０−２．１３（８Ｈ，ｍ），２．４０−２．５５（２Ｈ，ｂｒ ｍ），２．６３（２Ｈ，ｂｒ ｔ，Ｊ＝９．０Ｈｚ），３．０１−３．３５（２Ｈ，ｂｒ ｍ），３．１５（２Ｈ，ｓ），３．４７−３．６４（１Ｈ，ｍ），３．６５−４．０７（１Ｈ，ｂｒ ｍ），３．６６（２Ｈ，ｓ），４．４５（２Ｈ，ｓ），４．４７−４．９０（１Ｈ，ｂｒ ｍ），７．２７−７．３７（３Ｈ，ｍ），７．４１（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ），７．４４−７．５４（３Ｈ，ｍ），７．５９（１Ｈ，ｔｔ，Ｊ＝７．４，１．６Ｈｚ），７．６１（１Ｈ，ｂｒ ｄ，Ｊ＝７．８Ｈｚ），７．７３（２Ｈ，ｂｒ ｄ，Ｊ＝８．２Ｈｚ），７．９４（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ）．

ＬＣ／ＭＳ［条件１］：保持時間３．４０分；ｍ／ｚ６２０．２[Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ６５４．１［Ｍ＋Ｃl］⁻、６６４．３［Ｍ＋ＨＣＯＯ］⁻（ＥＳＩ負イオンモード）

Example 247
3- [4- (4-Benzoyl-piperidine-1-carbonyl) -benzyl] -8- (2-trifluoromethyl-benzyl) -1-oxa-3,8-diaza-spiro [4.5] decane- Preparation of 2-one (Compound No. 247) The title compound was reacted in substantially the same manner as in Example 237 except that 2-trifluoromethylbenzyl bromide (commercially available) was used instead of 4-nitrobenzyl bromide. (20.5 mg, 66% yield) was obtained as a colorless oil.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.70-2.13 (8H, m), 2.40-2.55 (2H, br m), 2.63 (2H, br t, J = 9.0 Hz), 3.01-3.35 (2H, br m), 3.15 (2H, s), 3.47-3.64 (1H, m), 3.65-4.07 (1H , Br m), 3.66 (2H, s), 4.45 (2H, s), 4.47-4.90 (1H, br m), 7.27-7.37 (3H, m), 7.41 (2H, d, J = 8.2 Hz), 7.44-7.54 (3H, m), 7.59 (1H, tt, J = 7.4, 1.6 Hz), 7.61 (1H, br d, J = 7.8 Hz), 7.73 (2H, br d, J = 8.2 Hz), 7.94 (2H, d, J = 8.2 Hz).

LC / MS [condition 1]: retention time 3.40 minutes; m / z 620.2 [M + H] ⁺ (ESI positive ion mode), m / z 654.1 [M + Cl] ⁻ , 664.3 [M + HCOO] ⁻ (ESI Negative ion mode)

実施例２４８
３‐［４‐（４‐ベンゾイル‐ピペリジン‐１‐カルボニル）‐ベンジル］‐８‐［２‐（４‐トリフルオロメチル‐フェニル）‐エチル］‐１‐オキサ‐３，８‐ジアザ‐スピロ［４．５］デカン‐２‐オン（化合物番号２４８）の製造
４‐ニトロベンジルブロミドの代わりに、４‐トリフルオロメチルフェネチルブロミド（市販）を用いること以外は実質的に実施例２３７と同様に反応を行なって、表題化合物（２０．５ｍｇ、収率６５％）を淡黄色油状物として得た。

^１Ｈ−ＮＭＲ（３００ＭＨｚ，ＣＤＣｌ_３）δ：１．７１−２．１１（６Ｈ，ｂｒ ｍ），２．１３−２．３９（２Ｈ，ｂｒ ｍ），２．８２−３．０２（４Ｈ，ｂｒ ｍ），３．０２−３．２５（６Ｈ，ｂｒ ｍ），３．２２（２Ｈ，ｓ），３．５７（１Ｈ，ｔｔ，Ｊ＝９．８，４．１Ｈｚ），３．６５−４．０５（１Ｈ，ｂｒ ｍ），４．４５（２Ｈ，ｓ），４．４９−４．８７（１Ｈ，ｂｒ ｍ），７．３１（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ），７．３５（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ），７．４３（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ），７．４９（２Ｈ，ｔ，Ｊ＝７．４Ｈｚ），７．５６（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ），７．５９（１Ｈ，ｔｔ，Ｊ＝７．４，１．２Ｈｚ），７．９５（２Ｈ，ｄ，Ｊ＝７．８Ｈｚ）．

ＬＣ／ＭＳ［条件１］：保持時間３．３４分；ｍ／ｚ６３４．３[Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ６６８．４［Ｍ＋Ｃｌ］⁻、６７８．４［Ｍ＋ＨＣＯＯ］⁻（ＥＳＩ負イオンモード）

Example 248
3- [4- (4-Benzoyl-piperidine-1-carbonyl) -benzyl] -8- [2- (4-trifluoromethyl-phenyl) -ethyl] -1-oxa-3,8-diaza-spiro [ 4.5] Preparation of decan-2-one (Compound No. 248) The reaction was carried out in substantially the same manner as in Example 237 except that 4-trifluoromethylphenethyl bromide (commercially available) was used instead of 4-nitrobenzyl bromide. To give the title compound (20.5 mg, 65% yield) as a pale yellow oil.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.71-2.11 (6H, br m), 2.13-2.39 (2H, br m), 2.82-3.02 (4H, br m), 3.02-3.25 (6H, br m), 3.22 (2H, s), 3.57 (1H, tt, J = 9.8, 4.1 Hz), 3.65- 4.05 (1H, br m), 4.45 (2H, s), 4.49-4.87 (1 H, br m), 7.31 (2H, d, J = 8.2 Hz), 7. 35 (2H, d, J = 8.2 Hz), 7.43 (2H, d, J = 8.2 Hz), 7.49 (2H, t, J = 7.4 Hz), 7.56 (2H, d , J = 8.2 Hz), 7.59 (1H, tt, J = 7.4, 1.2 Hz), 7.95 (2H, d, J = 7.8 Hz).

LC / MS [condition 1]: retention time 3.34 minutes; m / z 634.3 [M + H] ⁺ (ESI positive ion mode), m / z 668.4 [M + Cl] ⁻ , 678.4 [M + HCOO] ⁻ (ESI Negative ion mode)

実施例２４９
８‐（４‐アセチル‐ベンジル）‐３‐[４‐（４‐ベンゾイル‐ピペリジン‐１‐カルボニル）‐ベンジル］‐１‐オキサ‐３，８‐ジアザ‐スピロ［４．５］デカン‐２‐オン（化合物番号２４９）の製造
実施例２３９で得られた、３‐［４‐（４‐ベンゾイル‐ピペリジン‐１‐カルボニル）‐ベンジル］‐８‐（４‐ブロモ‐ベンジル）‐１‐オキサ‐３，８‐ジアザスピロ［４．５］デカン‐２‐オン（１０２．３ｍｇ、０．２ｍｍｏｌ）をテトラヒドロフラン（２．０ｍＬ）に溶解し、室温にてトリブチル（１‐エトキシビニル）スズ（アルドリッチ社より購入）（１３５．１μＬ、０．４ｍｍｏｌ）とビス（トリフェニルホスフィン）パラジウム（II）クロライド（７．９ｍｇ、０．０１ｍｍｏｌ）を加えて、加熱還流下、１５時間かき混ぜた。冷却後、、０．１Ｍ塩酸（２．０ｍＬ）を加え、室温で３時間かき混ぜた。反応終了後、酢酸エチルを加え、水で洗浄し、無水硫酸ナトリウムで乾燥、減圧留去した。得られた反応残渣をシリカゲルカラムクロマトグラフィー［充填剤：富士シリシア社製ＦＬ１００Ｄ、展開溶媒：酢酸エチル→酢酸エチル／メタノール＝２０／１］にて精製し、８‐（４‐アセチル‐ベンジル）‐３‐[４‐（４‐ベンゾイル‐ピペリジン‐１‐カルボニル）‐ベンジル］‐１‐オキサ‐３，８‐ジアザ‐スピロ［４．５］デカン‐２‐オン（２８．３ｍｇ、収率２４％）を白色粉末として得た。

^１Ｈ−ＮＭＲ（３００ＭＨｚ，ＣＤＣｌ_３）δ：１．６４−２．２１（８Ｈ，ｍ），２．３５−２．６５（４Ｈ，ｂｒ ｍ），２．５８（３Ｈ，ｓ），２．９３−３．２８（２Ｈ，ｂｒ ｍ），３．１３（２Ｈ，ｓ），３．４９−３．６１（１Ｈ，ｍ），３．５６（２Ｈ，ｓ），３．７０−４．０４（１Ｈ，ｂｒ ｍ），４．４４（２Ｈ，ｓ），４．４９−４．８６（１Ｈ，ｂｒ ｍ），７．３０（２Ｈ，ｄ，Ｊ＝７．８Ｈｚ），７．４０（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ），７．４１（２Ｈ，ｄ，Ｊ＝７．８Ｈｚ），７．４９（２Ｈ，ｔ，Ｊ＝７．８Ｈｚ），７．５９（１Ｈ，ｔｔ，Ｊ＝７．４，１．４Ｈｚ），７．９０（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ），７．９４（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ）．

ＬＣ／ＭＳ［条件１］：保持時間３．２６分；ｍ／ｚ５９４．１[Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ５９２．１［Ｍ−Ｈ］⁻、６２８．２［Ｍ＋Ｃｌ］⁻、６３８．２［Ｍ＋ＨＣＯＯ］⁻（ＥＳＩ負イオンモード）

Example 249
8- (4-Acetyl-benzyl) -3- [4- (4-benzoyl-piperidine-1-carbonyl) -benzyl] -1-oxa-3,8-diaza-spiro [4.5] decane-2- Preparation of ON (Compound No. 249) 3- [4- (4-Benzoyl-piperidine-1-carbonyl) -benzyl] -8- (4-bromo-benzyl) -1-oxa- obtained in Example 239 3,8-diazaspiro [4.5] decan-2-one (102.3 mg, 0.2 mmol) was dissolved in tetrahydrofuran (2.0 mL) and tributyl (1-ethoxyvinyl) tin (from Aldrich) at room temperature. Purchase) (135.1 μL, 0.4 mmol) and bis (triphenylphosphine) palladium (II) chloride (7.9 mg, 0.01 mmol) were added, and the mixture was heated under reflux for 15 And the mixture was stirred between. After cooling, 0.1 M hydrochloric acid (2.0 mL) was added, and the mixture was stirred at room temperature for 3 hours. After completion of the reaction, ethyl acetate was added, washed with water, dried over anhydrous sodium sulfate and evaporated under reduced pressure. The obtained reaction residue was purified by silica gel column chromatography [filler: FL100D manufactured by Fuji Silysia, developing solvent: ethyl acetate → ethyl acetate / methanol = 20/1], and 8- (4-acetyl-benzyl)- 3- [4- (4-Benzoyl-piperidine-1-carbonyl) -benzyl] -1-oxa-3,8-diaza-spiro [4.5] decan-2-one (28.3 mg, 24% yield) ) Was obtained as a white powder.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.64-2.21 (8H, m), 2.35-2.65 (4H, br m), 2.58 (3H, s), 2. 93-3.28 (2H, br m), 3.13 (2H, s), 3.49-3.61 (1H, m), 3.56 (2H, s), 3.70-4.04 (1H, br m), 4.44 (2H, s), 4.49-4.86 (1H, br m), 7.30 (2H, d, J = 7.8 Hz), 7.40 (2H , D, J = 8.2 Hz), 7.41 (2H, d, J = 7.8 Hz), 7.49 (2H, t, J = 7.8 Hz), 7.59 (1H, tt, J = 7.4, 1.4 Hz), 7.90 (2H, d, J = 8.2 Hz), 7.94 (2H, d, J = 8.2 Hz).

LC / MS [condition 1]: retention time 3.26 minutes; m / z 594.1 [M + H] ⁺ (ESI positive ion mode), m / z 592.1 [M−H] ⁻ , 628.2 [M + Cl] ⁻ , 638.2 [M + HCOO] ⁻ (ESI negative ion mode)

実施例２５０
３−｛４−［（ベンゾ［１．３］ジオキソル‐５‐イルメチル）‐カルバモイル］−ベンジル｝‐２‐オキソ‐１‐オキサ‐３，８−ジアザ‐スピロ［４．５］デカン‐８‐カルボン酸ｔ−ブチル（化合物番号２５０）の製造
４‐ベンゾイルピペリジン塩酸塩の代わりに、ピペロニルアミンを用いること以外は実質的に実施例１５８と同様に反応を行なって、表題化合物（９０５．２ｍｇ、収率７０％）を無色油状物として得た。

^１Ｈ−ＮＭＲ（３００ＭＨｚ，ＣＤＣｌ_３）δ：１．４３（９Ｈ，ｓ），１．５２−１．６６（２Ｈ，ｍ），１．８３（２Ｈ，ｂｒ ｄ，Ｊ＝１３．９Ｈｚ），３．１０（２Ｈ，ｓ），３．２６（２Ｈ，ｄｄｄ，Ｊ＝１３．９，１１．５，２．５Ｈｚ），３．７８（２Ｈ，ｂｒ ｄ，Ｊ＝１３．５Ｈｚ），４．４５（２Ｈ，ｓ），４．５４（２Ｈ，ｄ，Ｊ＝５．７Ｈｚ），５．９４（２Ｈ，ｓ），６．４２（１Ｈ，ｂｒ ｓ），６．７７（１Ｈ，ｄ，Ｊ＝７．８Ｈｚ），６．８１（１Ｈ，ｄｄ，Ｊ＝７．８，１．６Ｈｚ），６．８４（１Ｈ，ｄ，Ｊ＝１．６Ｈｚ），７．３２（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ），７．７７（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ）．

ＬＣ／ＭＳ［条件１］：保持時間４．１０分；ｍ／ｚ４２４．１[Ｍ−isobutene−ＣＯ２＋Ｈ］^＋、４６８．１[Ｍ-isobutene＋Ｈ］^＋、５２４．２[Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ５２２．２［Ｍ−Ｈ］⁻、５６８．２［Ｍ＋ＨＣＯＯ］⁻（ＥＳＩ負イオンモード）

Example 250
3- {4-[(Benzo [1.3] dioxol-5-ylmethyl) -carbamoyl] -benzyl} -2-oxo-1-oxa-3,8-diaza-spiro [4.5] decane-8- Preparation of t-butyl carboxylate (Compound No. 250) The reaction was conducted in substantially the same manner as in Example 158 except that piperonylamine was used instead of 4-benzoylpiperidine hydrochloride to give the title compound (905.2 mg, yield). 70%) was obtained as a colorless oil.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.43 (9H, s), 1.52-1.66 (2H, m), 1.83 (2H, br d, J = 13.9 Hz), 3.10 (2H, s), 3.26 (2H, ddd, J = 13.9, 11.5, 2.5 Hz), 3.78 (2H, br d, J = 13.5 Hz), 4. 45 (2H, s), 4.54 (2H, d, J = 5.7 Hz), 5.94 (2H, s), 6.42 (1H, br s), 6.77 (1H, d, J = 7.8 Hz), 6.81 (1H, dd, J = 7.8, 1.6 Hz), 6.84 (1H, d, J = 1.6 Hz), 7.32 (2H, d, J = 8.2 Hz), 7.77 (2H, d, J = 8.2 Hz).

LC / MS [Condition 1]: Retention time 4.10 minutes; m / z 424.1 [M-isobutene-CO2 + H] ⁺ , 468.1 [M-isobutene + H] ⁺ , 524.2 [M + H] ⁺ (ESI positive ion Mode), m / z 522.2 [M−H] ⁻ , 568.2 [M + HCOO] ⁻ (ESI negative ion mode)

実施例２５１
３−（４−｛４−［ヒドロキシ（フェニル）メチル］ピペリジン−１−カルボニル｝ベンジル）−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−２−オン（化合物番号２５１）の製造
実施例５５で得られた、３−［４−（４−ベンゾイルピペリジン−１−カルボニル）ベンジル］−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−２−オン（２０ｍｇ、０．０３２ｍｍｏｌ）のメタノール（１．０ｍＬ）溶液に水素化ホウ素ナトリウム（２．０ｍｇ、０．０４８ｍｍｏｌ）を加えて、室温で３０分間攪拌したのち、酢酸（５μＬ、０．０９ｍｍｏｌ）を加えて、減圧下濃縮乾固した。残留物に水（１ｍL）と酢酸エチル（２ｍＬ）を加えて有機層を分離、減圧下濃縮乾固して、表題化合物（１８ｍｇ、収率９０％）を無色無定形物として得た。

^１Ｈ−ＮＭＲ（３００ＭＨｚ，ＣＤＣｌ_３）δ：１．１０−１．５２（３Ｈ，ｂｒ ｍ），１．７２（２Ｈ，ｄｄｄ，Ｊ＝１３．９，７．８，６．１Ｈｚ），１．８０−２．２１（５Ｈ，ｂｒ ｍ），２．４２−２．６０（４Ｈ，ｂｒ ｍ），２．６０−２．８２（１Ｈ，ｂｒ ｍ），２．８２−３．０７（１Ｈ，ｂｒ ｍ），３．１１（２Ｈ，ｓ），３．５５（２Ｈ，ｓ），３．５５−３．９０（１Ｈ，ｂｒ ｍ），４．３６−４．５２（３Ｈ，ｍ），４．５２−４．９２（１Ｈ，ｂｒ ｍ），７．２４−７．４０（９Ｈ，ｍ），７．４２（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ），７．５６（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ）．

ＬＣ／ＭＳ［条件１］：保持時間３．６６分；ｍ／ｚ６２２．０［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ６６６．２［Ｍ＋ＨＣＯＯ］⁻（ＥＳＩ負イオンモード）

Example 251
3- (4- {4- [Hydroxy (phenyl) methyl] piperidine-1-carbonyl} benzyl) -8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5 Preparation of decan-2-one (Compound No. 251) 3- [4- (4-Benzoylpiperidine-1-carbonyl) benzyl] -8- [4- (trifluoromethyl) benzyl obtained in Example 55 ] Sodium borohydride (2.0 mg, 0.048 mmol) in a solution of 1-oxa-3,8-diazaspiro [4.5] decan-2-one (20 mg, 0.032 mmol) in methanol (1.0 mL) After stirring at room temperature for 30 minutes, acetic acid (5 μL, 0.09 mmol) was added, and the mixture was concentrated to dryness under reduced pressure. Water (1 mL) and ethyl acetate (2 mL) were added to the residue, the organic layer was separated and concentrated to dryness under reduced pressure to give the title compound (18 mg, yield 90%) as a colorless amorphous product.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.10-1.52 (3H, br m), 1.72 (2H, ddd, J = 13.9, 7.8, 6.1 Hz), 1 80-2.21 (5H, br m), 2.42-2.60 (4H, br m), 2.60-2.82 (1H, br m), 2.82-3.07 (1H , Br m), 3.11 (2H, s), 3.55 (2H, s), 3.55-3.90 (1H, br m), 4.36-4.52 (3H, m), 4.52-4.92 (1H, br m), 7.24-7.40 (9H, m), 7.42 (2H, d, J = 8.2 Hz), 7.56 (2H, d, J = 8.2 Hz).

LC / MS [Condition 1]: Retention time 3.66 minutes; m / z 622.0 [M + H] ⁺ (ESI positive ion mode), m / z 666.2 [M + HCOO] ⁻ (ESI negative ion mode)

実施例２５２
３−｛［（１ｒ，４ｒ）−４−（４−ベンゾイルピペリジン−１−カルボニル）シクロヘキシル］メチル｝−２−オキソ−１−オキサ−３，８−ジアザスピロ［４．５］デカン−８−カルボン酸ｔ−ブチル（化合物番号２５２）の製造
参考例２−３で得られた、（１ｒ，４ｒ）−４−｛［８−（ｔ−ブトキシカルボニル）−２−オキソ−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル］メチル｝シクロヘキサンカルボン酸（１．６３ｇ、４．１１ｍｍｏｌ）、１−ヒドロキシベンゾトリアゾール（０．１７ｇ、１．２ｍｍｏｌ）及び４−ベンゾイルピペリジン塩酸塩（市販）（１．０ｇ、４．５ｍｍｏｌ）のクロロホルム（５０ｍＬ）溶液に、トリエチルアミン（１．１ｍＬ，８２ｍｍｏｌ）及び１−エチル−３−（３−ジメチルアミノプロピル）カルボジイミド塩酸塩（１．２ｇ、６．２ｍｍｏｌ）を加えて、室温で２日間静置したのち、水（５０ｍＬ）を加えて２時間激しくかき混ぜた。有機層を分離し、クエン酸（０．８０ｇ）の水（５０ｍＬ）溶液で洗浄したのち、減圧下濃縮乾固して、表題化合物（２．５ｇ、収率定量的）を無色無定形物として得た。

^１Ｈ−ＮＭＲ（３００ＭＨｚ，ＣＤＣｌ_３）δ：１．０５（２Ｈ，ｂｒ ｑ，Ｊ＝１２．７Ｈｚ），１．４６（９Ｈ，ｓ），１．４９−１．９９（１５Ｈ，ｍ），２．４７（１Ｈ，ｔｔ，Ｊ＝１１．９，２．９Ｈｚ），２．８２（１Ｈ，ｂｒ ｔ，Ｊ＝１２．７Ｈｚ），３．１２（２Ｈ，ｄ，Ｊ＝７．４Ｈｚ），３．２１（１Ｈ，ｂｒ ｔ，Ｊ＝１３．１Ｈｚ），３．２６（２Ｈ，ｓ），３．２８（２Ｈ，ｂｒ ｔ，Ｊ＝１３．０Ｈｚ），３．５１（１Ｈ，ｔｔ，Ｊ＝１０．６，４．１Ｈｚ），３．８５（２Ｈ，ｂｒ ｄ，Ｊ＝１３．０Ｈｚ），３．９８（１Ｈ，ｂｒ ｄ，Ｊ＝１３．５Ｈｚ），４．５９（１Ｈ，ｂｒ ｄ，Ｊ＝１３．１Ｈｚ），７．４９（２Ｈ，ｔ，Ｊ＝７．４Ｈｚ），７．５９（１Ｈ，ｔ，Ｊ＝７．４Ｈｚ），７．９４（２Ｈ，ｄ，Ｊ＝７．４Ｈｚ）．

ＬＣ／ＭＳ［条件１］：保持時間４．４７分；ｍ／ｚ５９０．１［Ｍ＋Ｎａ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ６１２．４［Ｍ＋ＨＣＯＯ］⁻（ＥＳＩ負イオンモード）

Example 252
3-{[(1r, 4r) -4- (4-Benzoylpiperidine-1-carbonyl) cyclohexyl] methyl} -2-oxo-1-oxa-3,8-diazaspiro [4.5] decane-8-carvone Production of t-butyl acid (Compound No. 252) (1r, 4r) -4-{[8- (t-butoxycarbonyl) -2-oxo-1-oxa-3, obtained in Reference Example 2-3 8-Diazaspiro [4.5] decan-3-yl] methyl} cyclohexanecarboxylic acid (1.63 g, 4.11 mmol), 1-hydroxybenzotriazole (0.17 g, 1.2 mmol) and 4-benzoylpiperidine hydrochloride (Commercially available) (1.0 g, 4.5 mmol) in chloroform (50 mL) was added to triethylamine (1.1 mL, 82 mmol) and 1-ethyl-3- (3-di It added Chill aminopropyl) carbodiimide hydrochloride (1.2 g, 6.2 mmol), then was allowed to stand 2 days at room temperature, add water (50 mL) 2 hours stirring vigorously. The organic layer was separated, washed with a solution of citric acid (0.80 g) in water (50 mL), and concentrated to dryness under reduced pressure to give the title compound (2.5 g, quantitative yield) as a colorless amorphous product. Obtained.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.05 (2H, br q, J = 12.7 Hz), 1.46 (9H, s), 1.49-1.99 (15H, m), 2.47 (1H, tt, J = 11.9, 2.9 Hz), 2.82 (1H, br t, J = 12.7 Hz), 3.12 (2H, d, J = 7.4 Hz), 3.21 (1H, br t, J = 13.1 Hz), 3.26 (2H, s), 3.28 (2H, br t, J = 13.0 Hz), 3.51 (1 H, tt, J = 10.6, 4.1 Hz), 3.85 (2H, br d, J = 13.0 Hz), 3.98 (1 H, br d, J = 13.5 Hz), 4.59 (1 H, br d , J = 13.1 Hz), 7.49 (2H, t, J = 7.4 Hz), 7.59 (1H, t, J = 7.4 Hz), 7.94 (2H, , J = 7.4Hz).

LC / MS [Condition 1]: retention time 4.47 minutes; m / z 590.1 [M + Na] ⁺ (ESI positive ion mode), m / z 612.4 [M + HCOO] ⁻ (ESI negative ion mode)

実施例２５３
３−［４−（４−ベンジルピペリジン−１−カルボニル）ベンジル］−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−２−オン（化合物番号２５３）の製造
参考例２１で得られた、４−（｛２−オキソ−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）安息香酸（２２ｍｇ、０．０４９ｍｍｏｌ）、１−ヒドロキシベンゾトリアゾール（２ｍｇ、０．０１ｍｍｏｌ）及び４−ベンジルピペリジン（市販）（１１μＬ、０．０６４ｍｍｏｌ）をクロロホルム（１ｍＬ）に溶解し、１−エチル−３−（３−ジメチルアミノプロピル）カルボジイミド塩酸塩（１４ｍｇ、０．０７４ｍｍｏｌ）を加えて、室温で７日間静置したのち、クエン酸（３ｍｇ）の水（２ｍＬ）溶液を加えた。有機層を分離し、減圧下濃縮乾固して、表題化合物（３３ｍｇ、収率定量的）を薄オレンジ色無定形物として得た。

^１Ｈ−ＮＭＲ（３００ＭＨｚ，ＣＤＣｌ_３）δ：１．０２−１．４２（２Ｈ，ｂｒ ｍ），１．６３−１．８７（５Ｈ，ｍ），１．９１（２Ｈ，ｂｒ ｄ，Ｊ＝１３．５Ｈｚ），２．４４−２．６４（４Ｈ，ｂｒ ｍ），２．５４（２Ｈ，ｄ，Ｊ＝７．４Ｈｚ），２．６０−２．８５（１Ｈ，ｂｒ ｍ），２．８０−３．０５（１Ｈ，ｂｒ ｍ），３．１２（２Ｈ，ｓ），３．５３−３．８３（１Ｈ，ｂｒ ｍ），３．５６（２Ｈ，ｓ），４．４３（２Ｈ，ｓ），４．５２−４．８４（１Ｈ，ｂｒ ｍ），７．１３（２Ｈ，ｄｄ，Ｊ＝７．４，１．６Ｈｚ），７．２０（１Ｈ，ｔｔ，Ｊ＝７．４，１．６Ｈｚ），７．２５−７．３４（４Ｈ，ｍ），７．３７（２Ｈ，ｄ，Ｊ＝７．８Ｈｚ），７．４２（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ），７．５６（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ）．

ＬＣ／ＭＳ［条件１］：保持時間３．５２分；ｍ／ｚ６０６．２［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ６５０．２［Ｍ＋ＨＣＯＯ］⁻（ＥＳＩ負イオンモード）

Example 253
3- [4- (4-Benzylpiperidine-1-carbonyl) benzyl] -8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-2-one 4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] obtained in Production Reference Example 21 of (Compound No. 253) Decan-3-yl} methyl) benzoic acid (22 mg, 0.049 mmol), 1-hydroxybenzotriazole (2 mg, 0.01 mmol) and 4-benzylpiperidine (commercially available) (11 μL, 0.064 mmol) in chloroform (1 mL) 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (14 mg, 0.074 mmol) was added and dissolved at room temperature for 7 days. After standing, water was added (2 mL) solution of citric acid (3 mg). The organic layer was separated and concentrated to dryness under reduced pressure to give the title compound (33 mg, quantitative yield) as a light orange amorphous product.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.02-1.42 (2H, br m), 1.63-1.87 (5H, m), 1.91 (2H, br d, J = 13.5 Hz), 2.44-2.64 (4 H, br m), 2.54 (2 H, d, J = 7.4 Hz), 2.60-2.85 (1 H, br m), 2. 80-3.05 (1H, br m), 3.12 (2H, s), 3.53-3.83 (1H, br m), 3.56 (2H, s), 4.43 (2H, s), 4.52-4.84 (1H, br m), 7.13 (2H, dd, J = 7.4, 1.6 Hz), 7.20 (1H, tt, J = 7.4) 1.6 Hz), 7.25-7.34 (4 H, m), 7.37 (2 H, d, J = 7.8 Hz), 7.42 (2 H, d, J = 8.2 Hz), 7. 56 (2H, , J = 8.2Hz).

LC / MS [Condition 1]: Retention time 3.52 min; m / z 606.2 [M + H] ⁺ (ESI positive ion mode), m / z 650.2 [M + HCOO] ⁻ (ESI negative ion mode)

実施例２５４
４−［４−（｛２−オキソ−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）ベンズアミド］ピペリジン−１−カルボン酸エチル（化合物番号２５４）の製造
４−ベンジルピペリジンの代わりに、４−アミノピペリジン−１−カルボン酸エチル（市販）を用いること以外は実質的に実施例２５３と同様に反応を行なって、表題化合物(２９ｍｇ、収率定量的)を白色固体として得た。

^１Ｈ−ＮＭＲ（３００ＭＨｚ，ＣＤＣｌ_３）δ：１．２７（３Ｈ，ｔ，Ｊ＝７．４Ｈｚ），１．４３（２Ｈ，ｄｑ，Ｊ＝４．１，１１．５Ｈｚ），１．７１（２Ｈ，ｄｄｄ，Ｊ＝１４．３，８．２，６．１Ｈｚ），１．９０（２Ｈ，ｂｒ ｄ，Ｊ＝１２．７Ｈｚ），２．０５（２Ｈ，ｂｒ ｄ，Ｊ＝１２．７Ｈｚ），２．４２−２．６４（４Ｈ，ｂｒ ｍ），２．９６（２Ｈ，ｂｒ ｔ，Ｊ＝１２．７Ｈｚ），３．１１（２Ｈ，ｓ），３．５５（２Ｈ，ｓ），４．０１−４．２９（３Ｈ，ｂｒ ｍ），４．１４（２Ｈ，ｑ，Ｊ＝７．４Ｈｚ），４．４６（２Ｈ，ｓ），５．９６（１Ｈ，ｂｒ ｄ，Ｊ＝７．８Ｈｚ），７．３３（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ），７．４２（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ），７．５６（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ），７．７４（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ）．

ＬＣ／ＭＳ［条件１］：保持時間３．１２分；ｍ／ｚ６０３．２［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ６０１．３［Ｍ−Ｈ］⁻（ＥＳＩ負イオンモード）

Example 254
4- [4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl) benzamide] piperidine- Preparation of ethyl 1-carboxylate (Compound No. 254) The reaction was carried out in substantially the same manner as in Example 253, except that ethyl 4-aminopiperidine-1-carboxylate (commercially available) was used instead of 4-benzylpiperidine. To give the title compound (29 mg, quantitative yield) as a white solid.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.27 (3H, t, J = 7.4 Hz), 1.43 (2H, dq, J = 4.1, 11.5 Hz), 1.71 ( 2H, ddd, J = 14.3, 8.2, 6.1 Hz), 1.90 (2H, br d, J = 12.7 Hz), 2.05 (2H, br d, J = 12.7 Hz) , 2.42-2.64 (4H, br m), 2.96 (2H, br t, J = 12.7 Hz), 3.11 (2H, s), 3.55 (2H, s), 4 .01-4.29 (3H, br m), 4.14 (2H, q, J = 7.4 Hz), 4.46 (2H, s), 5.96 (1H, br d, J = 7. 8 Hz), 7.33 (2H, d, J = 8.2 Hz), 7.42 (2H, d, J = 8.2 Hz), 7.56 (2H, d, J = 8.2 Hz), 7. 4 (2H, d, J = 8.2Hz).

LC / MS [Condition 1]: Retention time 3.12 minutes; m / z 603.2 [M + H] ⁺ (ESI positive ion mode), m / z 601.3 [M−H] ⁻ (ESI negative ion mode)

参考例２５５
３−｛［（１ｒ，４ｒ）−４−（４−ベンゾイルピペリジン−１−カルボニル）シクロヘキシル］メチル｝−１−オキサ−３，８−ジアザスピロ［４．５］デカン−２−オン塩酸塩の製造
２−オキソ−３−［（（１ｒ，４ｒ）−４−｛［（テトラヒドロフラン−２−イル）メチル］カルバモイル｝シクロヘキシル）メチル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−８−カルボン酸ｔ−ブチルの代わりに、実施例２５２で得られた３−｛［（１ｒ，４ｒ）−４−（４−ベンゾイルピペリジン−１−カルボニル）シクロヘキシル］メチル｝−２−オキソ−１−オキサ−３，８−ジアザスピロ［４．５］デカン−８−カルボン酸ｔ−ブチルを用いること以外は実質的に実施例３と同様に反応を行って表題化合物（２０ｇ、定量的）を白色粉末として得た。

^１Ｈ−ＮＭＲ（ＣＤ_３ＯＤ）δ：１．１０（２Ｈ，ｑ，Ｊ＝１１．２Ｈｚ），１．３６−２．２２（１５Ｈ，ｍ），２．６８（１Ｈ，ｔ，Ｊ＝１１．２Ｈｚ），２．８８（１Ｈ，ｔ，Ｊ＝１３．２Ｈｚ），３．１１（２Ｈ，ｄ，Ｊ＝８．１Ｈｚ），３．２８−３．３８（１Ｈ，ｍ），３．４８（２Ｈ，ｓ），３．６７−３．８０（１Ｈ，ｍ），４．１１（１Ｈ，ｄ，Ｊ＝１１．９Ｈｚ），４．５３（１Ｈ，ｄ，Ｊ＝１３．９Ｈｚ），７．５２（１Ｈ，ｔ，Ｊ＝７．９Ｈｚ），７．６２（１Ｈ，ｔ，Ｊ＝７．９Ｈｚ），８．０１（２Ｈ，ｄ，Ｊ＝７．９Ｈｚ）．

ＬＣ／ＭＳ［条件１］：保持時間２．８２分；ｍ／ｚ４６７．９［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ５０２．１［Ｍ＋Ｃｌ］⁻（ＥＳＩ負イオンモード）

Reference Example 255
Preparation of 3-{[(1r, 4r) -4- (4-benzoylpiperidine-1-carbonyl) cyclohexyl] methyl} -1-oxa-3,8-diazaspiro [4.5] decan-2-one hydrochloride 2-Oxo-3-[((1r, 4r) -4-{[(tetrahydrofuran-2-yl) methyl] carbamoyl} cyclohexyl) methyl] -1-oxa-3,8-diazaspiro [4.5] decane- 3-{[(1r, 4r) -4- (4-benzoylpiperidine-1-carbonyl) cyclohexyl] methyl} -2-oxo-1 obtained in Example 252 instead of t-butyl 8-carboxylate The title compound (20 g, quantitative) was prepared by carrying out the reaction in substantially the same manner as in Example 3 except that t-butyl oxa-3,8-diazaspiro [4.5] decane-8-carboxylate was used. It was obtained as a white powder.

¹ H-NMR (CD ₃ OD) δ: 1.10 (2H, q, J = 11.2 Hz), 1.36-2.22 (15H, m), 2.68 (1H, t, J = 11) .2 Hz), 2.88 (1 H, t, J = 13.2 Hz), 3.11 (2 H, d, J = 8.1 Hz), 3.28-3.38 (1 H, m), 3.48. (2H, s), 3.67-3.80 (1H, m), 4.11 (1H, d, J = 11.9 Hz), 4.53 (1H, d, J = 13.9 Hz), 7 .52 (1H, t, J = 7.9 Hz), 7.62 (1H, t, J = 7.9 Hz), 8.01 (2H, d, J = 7.9 Hz).

LC / MS [Condition 1]: Retention time 2.82 minutes; m / z 467.9 [M + H] ⁺ (ESI positive ion mode), m / z 502.1 [M + Cl] ⁻ (ESI negative ion mode)

実施例２５５
３−｛［（１ｒ，４ｒ）−４−（４−ベンゾイルピペリジン−１−カルボニル）シクロヘキシル］メチル｝−８−［２，４−ビス（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−２−オン（化合物番号２５５）の製造
（１ｒ，４ｒ）−４−［（２−オキソ−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル）メチル］−Ｎ−［（テトラヒドロフラン−２−イル）メチル］シクロヘキサンカルボキサミド塩酸塩の代わりに、参考例２５５で得られた、３−｛［（１ｒ，４ｒ）−４−（４−ベンゾイルピペリジン−１−カルボニル）シクロヘキシル］メチル｝−１−オキサ−３，８−ジアザスピロ［４．５］デカン−２−オン塩酸塩を用いることと、３−（ブロモメチル）ピリジン臭化水素酸塩の代わりに、１−（ブロモメチル）−２，４−ビス（トリフルオロメチル）ベンゼン（市販）を用いること以外は実質的に実施例４と同様に反応を行なって、表題化合物（１４ｍｇ、収率２５％）を白色粉末として得た。

^１Ｈ−ＮＭＲ（ＣＤＣｌ_３）δ：１．０６（２Ｈ，ｑ，Ｊ＝１２．７Ｈｚ），１．４４−２．０２（１５Ｈ，ｍ），２．４７（１Ｈ，ｔ，Ｊ＝１１．９Ｈｚ），２．５０−２．７１（４Ｈ，ｂｒ ｍ），２．８２（１Ｈ，ｔ，Ｊ＝１１．５Ｈｚ），３．１１（２Ｈ，ｄ，Ｊ＝６．５Ｈｚ），３．２０（１Ｈ，ｔ，Ｊ＝１３．０Ｈｚ），３．２８（２Ｈ，ｓ），３．４３−３．５９（１Ｈ，ｍ），３．７３（２Ｈ，ｓ），３．９８（１Ｈ，ｄ，Ｊ＝１３．１Ｈｚ），４．６０（１Ｈ，ｄ，Ｊ＝１２．７Ｈｚ），７．４９（２Ｈ，ｔ，Ｊ＝７．４Ｈｚ），７．５９（１Ｈ，ｔ，Ｊ＝７．４Ｈｚ），７．７８（１Ｈ，ｄ，Ｊ＝７．８Ｈｚ），７．８８（１Ｈ，ｂｒ ｓ），７．９４（２Ｈ，ｄ，Ｊ＝７．４Ｈｚ），７．９７（１Ｈ，ｄ，Ｊ＝７．８Ｈｚ）．

ＬＣ／ＭＳ［条件１］：保持時間４．０１分；ｍ／ｚ６９４．０［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ７３８．０［Ｍ＋ＨＣＯＯ］⁻（ＥＳＩ負イオンモード）

Example 255
3-{[(1r, 4r) -4- (4-Benzoylpiperidine-1-carbonyl) cyclohexyl] methyl} -8- [2,4-bis (trifluoromethyl) benzyl] -1-oxa-3,8 Preparation of diazaspiro [4.5] decan-2-one (Compound No. 255) (1r, 4r) -4-[(2-oxo-1-oxa-3,8-diazaspiro [4.5] decane-3 3-{[(1r, 4r) -4- (4-benzoyl) obtained in Reference Example 255 instead of -yl) methyl] -N-[(tetrahydrofuran-2-yl) methyl] cyclohexanecarboxamide hydrochloride Using piperidine-1-carbonyl) cyclohexyl] methyl} -1-oxa-3,8-diazaspiro [4.5] decan-2-one hydrochloride and 3- (bromomethyl) pyridine bromide The reaction was conducted in substantially the same manner as in Example 4 except that 1- (bromomethyl) -2,4-bis (trifluoromethyl) benzene (commercially available) was used instead of the acid salt to give the title compound (14 mg Yield 25%) as a white powder.

¹ H-NMR (CDCl ₃ ) δ: 1.06 (2H, q, J = 12.7 Hz), 1.44 to 2.02 (15H, m), 2.47 (1H, t, J = 11.1. 9 Hz), 2.50-2.71 (4 H, br m), 2.82 (1 H, t, J = 11.5 Hz), 3.11 (2 H, d, J = 6.5 Hz), 3.20 (1H, t, J = 13.0 Hz), 3.28 (2H, s), 3.43-3.59 (1H, m), 3.73 (2H, s), 3.98 (1H, d , J = 13.1 Hz), 4.60 (1H, d, J = 12.7 Hz), 7.49 (2H, t, J = 7.4 Hz), 7.59 (1H, t, J = 7. 4 Hz), 7.78 (1 H, d, J = 7.8 Hz), 7.88 (1 H, br s), 7.94 (2 H, d, J = 7.4 Hz), 7.97 (1 H, d , J = 7.8H z).

LC / MS [Condition 1]: Retention time 4.01 min; m / z 694.0 [M + H] ⁺ (ESI positive ion mode), m / z 738.0 [M + HCOO] ⁻ (ESI negative ion mode)

実施例２５６
４−［（３−｛［（１ｒ，４ｒ）−４−（４−ベンゾイルピペリジン−１−カルボニル）シクロヘキシル］メチル｝−２−オキソ−１−オキサ−３，８−ジアザスピロ［４．５］デカン−８−イル）メチル］−３−フルオロベンゾニトリル（化合物番号２５６）の製造
１−（ブロモメチル）−２，４−ビス（トリフルオロメチル）ベンゼンの代わりに、４−（ブロモメチル）−３−フルオロベンゾニトリル（市販）を用いること以外は実質的に実施例２５５と同様に反応を行なって、表題化合物（２３ｍｇ、収率５５％）を白色粉末として得た。

^１Ｈ−ＮＭＲ（ＣＤＣｌ_３）δ：１．０５（２Ｈ，ｑ，Ｊ＝１１．６Ｈｚ），１．３９−２．０２（１５Ｈ，ｍ），２．４７（１Ｈ，ｔ，Ｊ＝１０．９Ｈｚ），２．５４−２．６９（４Ｈ，ｂｒ ｍ），２．８１（１Ｈ，ｔ，Ｊ＝１２．５Ｈｚ），３．１１（２Ｈ，ｄ，Ｊ＝５．９Ｈｚ），３．２０（１Ｈ，ｔ，Ｊ＝１２．２Ｈｚ），３．２６（２Ｈ，ｓ），３．４５−３．５８（１Ｈ，ｍ），３．６４（２Ｈ，ｓ），３．９８（１Ｈ，ｄ，Ｊ＝１１．９Ｈｚ），４．６０（１Ｈ，ｄ，Ｊ＝１２．９Ｈｚ），７．３４（１Ｈ，ｄ，Ｊ＝９．２Ｈｚ），７．４４（１Ｈ，ｄ，Ｊ＝９．２Ｈｚ），７．４９（２Ｈ，ｔ，Ｊ＝７．３Ｈｚ），７．５１−７．５８（１Ｈ，ｍ），７．５９（１Ｈ，ｔ，Ｊ＝７．３Ｈｚ），７．９５（２Ｈ，ｄ，Ｊ＝７．３Ｈｚ）．

ＬＣ／ＭＳ［条件１］：保持時間３．１６分；ｍ／ｚ６０１．０［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ６４５．１［Ｍ＋ＨＣＯＯ］⁻（ＥＳＩ負イオンモード）

Example 256
4-[(3-{[(1r, 4r) -4- (4-Benzoylpiperidine-1-carbonyl) cyclohexyl] methyl} -2-oxo-1-oxa-3,8-diazaspiro [4.5] decane Preparation of -8-yl) methyl] -3-fluorobenzonitrile (Compound No. 256) 4- (Bromomethyl) -3-fluoro instead of 1- (bromomethyl) -2,4-bis (trifluoromethyl) benzene The reaction was carried out substantially in the same manner as in Example 255 except that benzonitrile (commercially available) was used, and the title compound (23 mg, yield 55%) was obtained as a white powder.

¹ H-NMR (CDCl ₃ ) δ: 1.05 (2H, q, J = 11.6 Hz), 1.39-2.02 (15H, m), 2.47 (1H, t, J = 10. 9 Hz), 2.54-2.69 (4 H, br m), 2.81 (1 H, t, J = 12.5 Hz), 3.11 (2 H, d, J = 5.9 Hz), 3.20 (1H, t, J = 12.2 Hz), 3.26 (2H, s), 3.45-3.58 (1H, m), 3.64 (2H, s), 3.98 (1H, d , J = 11.9 Hz), 4.60 (1H, d, J = 12.9 Hz), 7.34 (1H, d, J = 9.2 Hz), 7.44 (1H, d, J = 9. 2 Hz), 7.49 (2H, t, J = 7.3 Hz), 7.51-7.58 (1H, m), 7.59 (1H, t, J = 7.3 Hz), 7.95 ( 2H, d, J = 7 3Hz).

LC / MS [Condition 1]: Retention time 3.16 minutes; m / z 601.0 [M + H] ⁺ (ESI positive ion mode), m / z 645.1 [M + HCOO] ⁻ (ESI negative ion mode)

実施例２５７
３−［（３−｛［（１ｒ，４ｒ）−４−（４−ベンゾイルピペリジン−１−カルボニル）シクロヘキシル］メチル｝−２−オキソ−１−オキサ−３，８−ジアザスピロ［４．５］デカン−８−イル）メチル］ベンゾニトリル（化合物番号２５７）の製造
参考例２５５で得られた、３−｛［（１ｒ，４ｒ）−４−（４−ベンゾイルピペリジン−１−カルボニル）シクロヘキシル］メチル｝−１−オキサ−３，８−ジアザスピロ［４．５］デカン−２−オン塩酸塩（１６ｍｇ、０．０３２ｍｍｏｌ）のＮ，Ｎ−ジメチルホルムアミド（０．５０ｍＬ）懸濁液にトリエチルアミン（１１μＬ、０．０７９ｍｍｏｌ）と３−（ブロモメチル）ベンゾニトリル（市販）（７ｍｇ、０．０３５ｍｍｏｌ）を加えた。室温で２日間静置したのち、水（０．５ｍＬ）を加えた。生じた固体をろ取して、表題化合物（１７ｍｇ、収率９４％）を白色固体として得た。

^１Ｈ−ＮＭＲ（３００ＭＨｚ，ＣＤＣｌ_３）δ：１．０５（２Ｈ，ｄｑ，Ｊ＝４．１，１２．３Ｈｚ），１．４９−１．７１（４Ｈ，ｂｒ ｍ），１．７１−１．８７（７Ｈ，ｂｒ ｍ），１．８７−２．０１（４Ｈ，ｂｒ ｍ），２．４７（１Ｈ，ｔｔ，Ｊ＝１１．５，２．９Ｈｚ），２．４９−２．６５（４Ｈ，ｍ），２．８２（１Ｈ，ｂｒ ｔ，Ｊ＝１１．５Ｈｚ），３．１１（２Ｈ，ｄ，Ｊ＝７．４Ｈｚ），３．２１（１Ｈ，ｂｒ ｔ，Ｊ＝１３．９Ｈｚ），３．２７（２Ｈ，ｓ），３．５１（１Ｈ，ｔｔ，Ｊ＝１０．６，３．７Ｈｚ），３．５５（２Ｈ，ｓ），３．９８（１Ｈ，ｂｒ ｄ，Ｊ＝１２．７Ｈｚ），４．５９（１Ｈ，ｂｒ ｄ，Ｊ＝１３．１Ｈｚ），７．３６−７．６３（６Ｈ，ｍ），７．６６（１Ｈ，ｂｒ ｓ），７．９４（２Ｈ，ｄ，Ｊ＝７．８Ｈｚ）．

ＬＣ／ＭＳ［条件２］：保持時間３．５８分；ｍ／ｚ５８３．６［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ６２７．６［Ｍ＋ＨＣＯＯ］⁻（ＥＳＩ負イオンモード）

Example 257
3-[(3-{[(1r, 4r) -4- (4-Benzoylpiperidine-1-carbonyl) cyclohexyl] methyl} -2-oxo-1-oxa-3,8-diazaspiro [4.5] decane Preparation of -8-yl) methyl] benzonitrile (Compound No. 257) 3-{[(1r, 4r) -4- (4-benzoylpiperidine-1-carbonyl) cyclohexyl] methyl} obtained in Reference Example 255 Triethylamine (11 μL, 0) was added to a suspension of -1-oxa-3,8-diazaspiro [4.5] decan-2-one hydrochloride (16 mg, 0.032 mmol) in N, N-dimethylformamide (0.50 mL). 0.079 mmol) and 3- (bromomethyl) benzonitrile (commercially available) (7 mg, 0.035 mmol) were added. After standing at room temperature for 2 days, water (0.5 mL) was added. The resulting solid was collected by filtration to give the title compound (17 mg, yield 94%) as a white solid.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.05 (2H, dq, J = 4.1, 12.3 Hz), 1.49-1.71 (4H, br m), 1.71-1 .87 (7H, br m), 1.87-2.01 (4H, br m), 2.47 (1H, tt, J = 11.5, 2.9 Hz), 2.49-2.65 ( 4H, m), 2.82 (1H, br t, J = 11.5 Hz), 3.11 (2H, d, J = 7.4 Hz), 3.21 (1H, br t, J = 13.9 Hz) ), 3.27 (2H, s), 3.51 (1H, tt, J = 10.6, 3.7 Hz), 3.55 (2H, s), 3.98 (1H, br d, J = 12.7 Hz), 4.59 (1 H, br d, J = 13.1 Hz), 7.36-7.63 (6 H, m), 7.66 (1 H, br s), 7.94 ( 2H, d, J = 7.8 Hz).

LC / MS [Condition 2]: retention time 3.58 min; m / z 583.6 [M + H] ⁺ (ESI positive ion mode), m / z 627.6 [M + HCOO] ⁻ (ESI negative ion mode)

実施例２５８
２−［（３−｛［（１ｒ，４ｒ）−４−（４−ベンゾイルピペリジン−１−カルボニル）シクロヘキシル］メチル｝−２−オキソ−１−オキサ−３，８−ジアザスピロ［４．５］デカン−８−イル）メチル］ベンゾニトリル（化合物番号２５８）の製造
３−（ブロモメチル）ベンゾニトリルの代わりに、２−（ブロモメチル）ベンゾニトリル（市販）を用いること以外は実質的に実施例２５７と同様に反応を行なって、表題化合物（１９ｍｇ、収率定量的）を白色固体として得た。

^１Ｈ−ＮＭＲ（３００ＭＨｚ，ＣＤＣｌ_３）δ：１．０５（２Ｈ，ｄｑ，Ｊ＝４．１，１１．９Ｈｚ），１．４８−１．７０（４Ｈ，ｂｒ ｍ），１．７０−１．８７（７Ｈ，ｂｒ ｍ），１．８７−２．０１（４Ｈ，ｂｒ ｍ），２．４６（１Ｈ，ｔｔ，Ｊ＝１１．５，２．９Ｈｚ），２．５４−２．７４（４Ｈ，ｂｒ ｍ），２．８２（１Ｈ，ｂｒ ｔ，Ｊ＝１１．９Ｈｚ），３．１１（２Ｈ，ｄ，Ｊ＝７．４Ｈｚ），３．２０（１Ｈ，ｂｒ ｔ，Ｊ＝１１．９Ｈｚ），３．２６（２Ｈ，ｓ），３．５１（１Ｈ，ｔｔ，Ｊ＝１０．２，３．７Ｈｚ），３．７２（２Ｈ，ｓ），３．９７（１Ｈ，ｂｒ ｄ，Ｊ＝１４．３Ｈｚ），４．５９（１Ｈ，ｂｒ ｄ，Ｊ＝１３．９Ｈｚ），７．３６（１Ｈ，ｄｔ，Ｊ＝１．２，７．４Ｈｚ），７．４１−７．６２（５Ｈ，ｍ），７．６５（１Ｈ，ｄ，Ｊ＝７．８Ｈｚ），７．９４（２Ｈ，ｄ，Ｊ＝８．６Ｈｚ）．

ＬＣ／ＭＳ［条件２］：保持時間３．５６分；ｍ／ｚ５８３．６［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ６２７．６［Ｍ＋ＨＣＯＯ］⁻（ＥＳＩ負イオンモード）

Example 258
2-[(3-{[(1r, 4r) -4- (4-benzoylpiperidine-1-carbonyl) cyclohexyl] methyl} -2-oxo-1-oxa-3,8-diazaspiro [4.5] decane Preparation of -8-yl) methyl] benzonitrile (Compound No. 258) Substantially the same as Example 257, except that 2- (bromomethyl) benzonitrile (commercially available) was used instead of 3- (bromomethyl) benzonitrile. The title compound (19 mg, quantitative yield) was obtained as a white solid.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.05 (2H, dq, J = 4.1, 11.9 Hz), 1.48-1.70 (4H, br m), 1.70-1 .87 (7H, br m), 1.87-2.01 (4H, br m), 2.46 (1H, tt, J = 11.5, 2.9 Hz), 2.54-2.74 ( 4H, br m), 2.82 (1H, br t, J = 11.9 Hz), 3.11 (2H, d, J = 7.4 Hz), 3.20 (1H, br t, J = 1.11. 9 Hz), 3.26 (2 H, s), 3.51 (1 H, tt, J = 10.2, 3.7 Hz), 3.72 (2 H, s), 3.97 (1 H, br d, J = 14.3 Hz), 4.59 (1H, br d, J = 13.9 Hz), 7.36 (1H, dt, J = 1.2, 7.4 Hz), 7.41-7.6. 2 (5H, m), 7.65 (1H, d, J = 7.8 Hz), 7.94 (2H, d, J = 8.6 Hz).

LC / MS [Condition 2]: retention time 3.56 minutes; m / z 583.6 [M + H] ⁺ (ESI positive ion mode), m / z 627.6 [M + HCOO] ⁻ (ESI negative ion mode)

実施例２５９
4-{3-[4-({2-オキソ-8-[4-(トリフルオロメチル)ベンジル]-1-オキサ-3,8-ジアザスピロ[4.5]デカン-3-イル}メチル)フェニル]ウレイド}ピペリジン-1-カルボン酸エチル（化合物番号２５９）の製造
参考例２１で得られた４−（｛２−オキソ−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）安息香酸（１００ｍｇ、０．２２ｍｍｏｌ）のクロロホルム（２ｍＬ）溶液に、トリエチルアミン（６２μＬ、０．４５ｍｍｏｌ）とジフェニルホスホリルアジド（７２μＬ、０．３３ｍｍｏｌ）を加えて、室温で１８時間静置したのち、水（２ｍＬ）を加えて有機層を分離した。その有機層を３分の１の容積まで減圧下濃縮し、トルエン（２ｍＬ）を加えて１１０℃で２時間攪拌したのち、４−アミノピペリジン−１−カルボン酸エチル（市販）（５７μＬ、０．３３ｍｍｏｌ）を加えて室温まで放冷した。反応混合物に水（２ｍＬ）を加えたのち、有機層を分離し、減圧下濃縮乾固した。残留物をシリカゲルカラムクロマトグラフィー［充填剤：富士シリシア社製ＦＬ１００Ｄ、展開溶媒：クロロホルム／２−プロパノール＝１０／１］にて精製し、表題化合物（６４ｍｇ、収率４７％）を白色固体として得た。

^１Ｈ−ＮＭＲ（３００ＭＨｚ，ＣＤＣｌ_３）δ：１．２５（３Ｈ，ｔ，Ｊ＝７．０Ｈｚ），１．３１（２Ｈ，ｄｑ，Ｊ＝４．１，１１．５Ｈｚ），１．７１（２Ｈ，ｄｔ，Ｊ＝１３．５，７．４Ｈｚ），１．８３−２．０４（４Ｈ，ｂｒ ｍ），２．４１−２．６１（４Ｈ，ｂｒ ｍ），２．９５（２Ｈ，ｂｒ ｔ，Ｊ＝１２．３Ｈｚ），３．１５（２Ｈ，ｓ），３．５４（２Ｈ，ｓ），３．７７−３．９５（１Ｈ，ｍ），３．９８−４．１３（２Ｈ，ｂｒ ｍ），４．１２（２Ｈ，ｑ，Ｊ＝７．０Ｈｚ），４．３５（２Ｈ，ｓ），４．８９（１Ｈ，ｂｒ ｄ，Ｊ＝７．８Ｈｚ），６．７２（１Ｈ，ｂｒ ｓ），７．１５（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ），７．２８（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ），７．４２（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ），７．５６（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ）．

ＬＣ／ＭＳ［条件２］：保持時間３．５２分；ｍ／ｚ６１８．５［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ６１６．６［Ｍ−Ｈ］⁻（ＥＳＩ負イオンモード）

Example 259
4- {3- [4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl) phenyl] ureido } Production of ethyl piperidine-1-carboxylate (Compound No. 259) 4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8 obtained in Reference Example 21 -To a solution of diazaspiro [4.5] decan-3-yl} methyl) benzoic acid (100 mg, 0.22 mmol) in chloroform (2 mL), triethylamine (62 μL, 0.45 mmol) and diphenylphosphoryl azide (72 μL, 0.33 mmol). ) And allowed to stand at room temperature for 18 hours, and then water (2 mL) was added to separate the organic layer. The organic layer was concentrated under reduced pressure to 1/3 volume, toluene (2 mL) was added and stirred at 110 ° C. for 2 hours, and then ethyl 4-aminopiperidine-1-carboxylate (commercially available) (57 μL, 0. 33 mmol) was added and allowed to cool to room temperature. After adding water (2 mL) to the reaction mixture, the organic layer was separated and concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography [filler: FL100D manufactured by Fuji Silysia Ltd., developing solvent: chloroform / 2-propanol = 10/1] to obtain the title compound (64 mg, yield 47%) as a white solid. It was.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.25 (3H, t, J = 7.0 Hz), 1.31 (2H, dq, J = 4.1, 11.5 Hz), 1.71 ( 2H, dt, J = 13.5, 7.4 Hz), 1.83 to 2.04 (4H, br m), 2.41-2.61 (4H, br m), 2.95 (2H, br t, J = 12.3 Hz), 3.15 (2H, s), 3.54 (2H, s), 3.77-3.95 (1H, m), 3.98-4.13 (2H, br m), 4.12 (2H, q, J = 7.0 Hz), 4.35 (2H, s), 4.89 (1H, br d, J = 7.8 Hz), 6.72 (1H, br s), 7.15 (2H, d, J = 8.2 Hz), 7.28 (2H, d, J = 8.2 Hz), 7.42 (2H, d, J = 8.2 Hz), 7 .56 2H, d, J = 8.2Hz).

LC / MS [Condition 2]: retention time 3.52 minutes; m / z 618.5 [M + H] ⁺ (ESI positive ion mode), m / z 616.6 [M−H] ⁻ (ESI negative ion mode)

参考例２６０−１
２−（４−｛［８−（ｔ−ブトキシカルボニル）−２−オキソ−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル］メチル｝フェニル）酢酸の製造
参考例１１１−１で得られた、２−オキソ−１−オキサ−３，８−ジアザスピロ［４．５］デカン−８−カルボン酸ｔ−ブチル（２０ｍｇ、０．０７８ｍｍｏｌ）のＮ，Ｎ−ジメチルホルムアミド（０．６０ｍＬ）溶液にナトリウムｔ−ブトキシド（１９ｍｇ、０．２０ｍｍｏｌ）を加えて、室温で３０分間攪拌した。反応混合物に２−｛４−（ブロモメチル）フェニル｝酢酸（市販）（１８ｍｇ、０．０７８ｍｍｏｌ）を加えて室温で４日間攪拌したのち、水（２ｍＬ）、１Ｍ塩酸（０．１２ｍＬ）及び酢酸エチル（２ｍＬ）を加えて有機層を分離した。その有機層に、炭酸水素ナトリウム（３３ｍｇ）の水（２．４ｍＬ）溶液を加えて水層を分離した。その水層に１Ｍ塩酸（０．５０ｍＬ）と酢酸エチル（３ｍＬ）を加えたのち、有機層を分離し、減圧下濃縮乾固して、表題化合物（２４ｍｇ、収率７５％）を無色無定形物として得た。

^１Ｈ−ＮＭＲ（３００ＭＨｚ，ＣＤＣｌ_３）δ：１．４４（９Ｈ，ｓ），１．５９（２Ｈ，ｄｄｄ，Ｊ＝１３．１，１０．２，４．９Ｈｚ），１．８５（２Ｈ，ｂｒ ｄ，Ｊ＝１３．１Ｈｚ），３．１２（２Ｈ，ｓ），３．２８（２Ｈ，ｂｒ ｔ，Ｊ＝１１．９Ｈｚ），３．６５（２Ｈ，ｓ），３．７９（２Ｈ，ｂｒ ｄ，Ｊ＝１１．９Ｈｚ），４．４１（２Ｈ，ｓ），７．２２（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ），７．２８（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ）．

ＬＣ／ＭＳ［条件２］：保持時間４．０２分；ｍ／ｚ４２７．３［Ｍ＋Ｎａ］^＋、３４９．３［Ｍ−ｉｓｏｂｕｔｅｎｅ＋Ｈ］^＋、３０５．３［Ｍ−ｉｓｏｂｕｔｅｎｅ−ＣＯ２＋Ｈ］^＋（ＥＳＩ正イオンモード）

Reference Example 260-1
Preparation of 2- (4-{[8- (t-butoxycarbonyl) -2-oxo-1-oxa-3,8-diazaspiro [4.5] decan-3-yl] methyl} phenyl) acetic acid Reference Example 111 -1,2-oxo-1-oxa-3,8-diazaspiro [4.5] decane-8-carboxylate t-butyl (20 mg, 0.078 mmol), N, N-dimethylformamide (0 Sodium t-butoxide (19 mg, 0.20 mmol) was added to the solution and stirred at room temperature for 30 minutes. 2- {4- (Bromomethyl) phenyl} acetic acid (commercially available) (18 mg, 0.078 mmol) was added to the reaction mixture and stirred at room temperature for 4 days, and then water (2 mL), 1M hydrochloric acid (0.12 mL), and ethyl acetate were added. (2 mL) was added and the organic layer was separated. A solution of sodium bicarbonate (33 mg) in water (2.4 mL) was added to the organic layer, and the aqueous layer was separated. After adding 1M hydrochloric acid (0.50 mL) and ethyl acetate (3 mL) to the aqueous layer, the organic layer was separated and concentrated to dryness under reduced pressure to give the title compound (24 mg, 75% yield) as colorless amorphous. Obtained as a thing.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.44 (9H, s), 1.59 (2H, ddd, J = 13.1, 10.2, 4.9 Hz), 1.85 (2H, brd, J = 13.1 Hz), 3.12 (2H, s), 3.28 (2H, br t, J = 11.9 Hz), 3.65 (2H, s), 3.79 (2H, br d, J = 11.9 Hz), 4.41 (2H, s), 7.22 (2H, d, J = 8.2 Hz), 7.28 (2H, d, J = 8.2 Hz).

LC / MS [condition 2]: retention time 4.02 min; m / z 427.3 [M + Na] ⁺ , 349.3 [M-isobutene + H] ⁺ , 305.3 [M-isobutene-CO 2 + H] ⁺ (ESI positive ion mode)

参考例２６０−２
２−オキソ−３−（４−｛２−オキソ−２−［（テトラヒドロフラン−２−イル）メチルアミノ］エチル｝ベンジル）−１−オキサ−３，８−ジアザスピロ［４．５］デカン−８−カルボン酸ｔ−ブチルの製造
参考例２６０−１で得られた、２−（４−｛［８−（ｔ−ブトキシカルボニル）−２−オキソ−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル］メチル｝フェニル）酢酸（２４ｍｇ、０．０５９ｍｍｏｌ）、１−ヒドロキシベンゾトリアゾール（３ｍｇ、０．０２ｍｍｏｌ）及びテトラヒドロフルフリルアミン（市販）（１２μＬ、０．１２ｍｍｏｌ）のクロロホルム（１ｍＬ）溶液に、１−エチル−３−（３−ジメチルアミノプロピル）カルボジイミド塩酸塩（１７ｍｇ、０．０８９ｍｍｏｌ）を加えて、室温で８日間静置したのち、水（1ｍＬ）を加えて有機層を分離した。その有機層をクエン酸（３ｍｇ）の水（２ｍＬ）溶液で洗浄したのち、減圧下濃縮乾固して、表題化合物（２６ｍｇ、収率９０％）を無色油状物として得た。

^１Ｈ−ＮＭＲ（３００ＭＨｚ，ＣＤＣｌ_３）δ：１．４１−１．５３（１Ｈ，ｍ），１．４５（９Ｈ，ｓ），１．５３−１．６８（２Ｈ，ｍ），１．７４−２．０１（５Ｈ，ｍ），３．１３（２Ｈ，ｓ），３．１４（１Ｈ，ｄｄｄ，Ｊ＝１３．５，７．４，５．３Ｈｚ），３．２８（２Ｈ，ｄｄｄ，Ｊ＝１３．９，１１．０，２．９Ｈｚ），３．５４（１Ｈ，ｄｄｄ，Ｊ＝１３．５，６．５，３．３Ｈｚ），３．５６（２Ｈ，ｓ），３．６３−３．８０（２Ｈ，ｍ），３．８０（２Ｈ，ｂｒ ｄ，Ｊ＝１２．３Ｈｚ），３．９１（１Ｈ，ｄｑ，Ｊ＝３．３，７．０Ｈｚ），４．４２（２Ｈ，ｓ），５．６７−５．８８（１Ｈ，ｂｒ ｍ），７．２３（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ），７．２７（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ）．

ＬＣ／ＭＳ［条件１］：保持時間３．９９分；ｍ／ｚ５１０．０［Ｍ＋Ｎａ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ４８６．３［Ｍ−Ｈ］⁻（ＥＳＩ負イオンモード）

Reference Example 260-2
2-Oxo-3- (4- {2-oxo-2-[(tetrahydrofuran-2-yl) methylamino] ethyl} benzyl) -1-oxa-3,8-diazaspiro [4.5] decane-8- Production of t-butyl carboxylate 2- (4-{[8- (t-butoxycarbonyl) -2-oxo-1-oxa-3,8-diazaspiro [4.5] obtained in Reference Example 260-1. ] Decan-3-yl] methyl} phenyl) acetic acid (24 mg, 0.059 mmol), 1-hydroxybenzotriazole (3 mg, 0.02 mmol) and tetrahydrofurfurylamine (commercially available) (12 μL, 0.12 mmol) in chloroform (1 mL ) To the solution was added 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (17 mg, 0.089 mmol) at room temperature. After standing days, and the organic layer was separated by adding water (1 mL). The organic layer was washed with a solution of citric acid (3 mg) in water (2 mL) and then concentrated to dryness under reduced pressure to give the title compound (26 mg, yield 90%) as a colorless oil.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.41-1.53 (1H, m), 1.45 (9H, s), 1.53-1.68 (2H, m), 1.74 -2.01 (5H, m), 3.13 (2H, s), 3.14 (1H, ddd, J = 13.5, 7.4, 5.3 Hz), 3.28 (2H, ddd, J = 13.9, 11.0, 2.9 Hz), 3.54 (1H, ddd, J = 13.5, 6.5, 3.3 Hz), 3.56 (2H, s), 3.63 -3.80 (2H, m), 3.80 (2H, brd, J = 12.3 Hz), 3.91 (1H, dq, J = 3.3, 7.0 Hz), 4.42 (2H , S), 5.67-5.88 (1H, br m), 7.23 (2H, d, J = 8.2 Hz), 7.27 (2H, d, J = 8.2 Hz).

LC / MS [Condition 1]: Retention time 3.99 minutes; m / z 510.0 [M + Na] ⁺ (ESI positive ion mode), m / z 486.3 [M−H] ⁻ (ESI negative ion mode)

実施例２６０
２−［４−（｛２−オキソ−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）フェニル］−Ｎ−［（テトラヒドロフラン−２−イル）メチル］アセトアミド（化合物番号２６０）の製造
参考例２６０−２で得られた、２−オキソ−３−（４−｛２−オキソ−２−［（テトラヒドロフラン−２−イル）メチルアミノ］エチル｝ベンジル）−１−オキサ−３，８−ジアザスピロ［４．５］デカン−８−カルボン酸ｔ−ブチル（２６ｍｇ、０．０５３ｍｍｏｌ）の１，４−ジオキサン（１．３ｍＬ）に１０質量％塩化水素メタノール溶液（０．１３ｍＬ）を加えて、室温で１６時間静置したのち、減圧下濃縮乾固した。残留物をＮ，Ｎ−ジメチルホルムアミド（１ｍＬ）に溶解し、トリエチルアミン（２２μＬ）及び４−（トリフルオロメチル）ベンジルブロミド（９μＬ）を加えて、室温で４日間静置した。反応混合物に水（３ｍＬ）と酢酸エチル（４ｍＬ）を加えて、有機層を分離し、減圧下濃縮乾固した。残留物をシリカゲルカラムクロマトグラフィー［充填剤：富士シリシア社製ＦＬ１００Ｄ、展開溶媒：クロロホルム／アセトン＝３／１］にて精製し、表題化合物（１２ｍｇ、収率５２％）を白色固体として得た。

^１Ｈ−ＮＭＲ（３００ＭＨｚ，ＣＤＣｌ_３）δ：１．４２−１．５６（１Ｈ，ｍ），１．６５−２．０１（７Ｈ，ｍ），２．４３−２．６１（４Ｈ，ｂｒ ｍ），３．１３（２Ｈ，ｓ），３．１４（１Ｈ，ｄｄｄ，Ｊ＝１３．５，７．４，４．９Ｈｚ），３．５３（１Ｈ，ｄｄｄ，Ｊ＝１３．９，６．５，３．３Ｈｚ），３．５５（４Ｈ，ｓ），３．６３−３．７８（２Ｈ，ｍ），３．９１（１Ｈ，ｄｑ，Ｊ＝３．７，７．０Ｈｚ），４．４１（２Ｈ，ｓ），５．７８（１Ｈ，ｂｒ ｍ），７．２３（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ），７．２６（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ），７．４２（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ），７．５６（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ）．

ＬＣ／ＭＳ［条件１］：保持時間２．８６分；ｍ／ｚ５４６．０［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ５９０．２［Ｍ＋ＨＣＯＯ］⁻（ＥＳＩ負イオンモード）

Example 260
2- [4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl) phenyl] -N Preparation of-[(Tetrahydrofuran-2-yl) methyl] acetamide (Compound No. 260) 2-Oxo-3- (4- {2-oxo-2-[(tetrahydrofuran-2 ) obtained in Reference Example 260-2 -Yl) methylamino] ethyl} benzyl) -1-oxa-3,8-diazaspiro [4.5] decane-8-carboxylate t-butyl (26 mg, 0.053 mmol) of 1,4-dioxane (1. (3 mL) was added a 10 mass% hydrogen chloride methanol solution (0.13 mL), allowed to stand at room temperature for 16 hours, and then concentrated to dryness under reduced pressure. The residue was dissolved in N, N-dimethylformamide (1 mL), triethylamine (22 μL) and 4- (trifluoromethyl) benzyl bromide (9 μL) were added, and the mixture was allowed to stand at room temperature for 4 days. Water (3 mL) and ethyl acetate (4 mL) were added to the reaction mixture, the organic layer was separated, and concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography [filler: FL100D manufactured by Fuji Silysia Ltd., developing solvent: chloroform / acetone = 3/1] to obtain the title compound (12 mg, yield 52%) as a white solid.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.42-1.56 (1 H, m), 1.65 to 2.01 (7 H, m), 2.43-2.61 (4 H, br m ), 3.13 (2H, s), 3.14 (1H, ddd, J = 13.5, 7.4, 4.9 Hz), 3.53 (1H, ddd, J = 13.9, 6. 5, 3.3 Hz), 3.55 (4 H, s), 3.63-3.78 (2 H, m), 3.91 (1 H, dq, J = 3.7, 7.0 Hz), 4. 41 (2H, s), 5.78 (1H, br m), 7.23 (2H, d, J = 8.2 Hz), 7.26 (2H, d, J = 8.2 Hz), 7.42 (2H, d, J = 8.2 Hz), 7.56 (2H, d, J = 8.2 Hz).

LC / MS [Condition 1]: Retention time 2.86 minutes; m / z 546.0 [M + H] ⁺ (ESI positive ion mode), m / z 590.2 [M + HCOO] ⁻ (ESI negative ion mode)

実施例２６１
４−（｛３−［（（１ｒ，４ｒ）−４−｛４−［ヒドロキシ（フェニル）メチル］ピペリジン−１−カルボニル｝シクロヘキシル）メチル］−２−オキソ−１−オキサ−３，８−ジアザスピロ［４．５］デカン−８−イル｝メチル）ベンゾニトリル（化合物番号２６１）の製造
実施例１５４で得られた、４−［（３−｛［（１ｒ，４ｒ）−４−（４−ベンゾイルピペリジン−１−カルボニル）シクロヘキシル］メチル｝−２−オキソ−１−オキサ−３，８−ジアザスピロ［４．５］デカン−８−イル）メチル］ベンゾニトリル（３０ｍｇ、０．０５１ｍｍｏｌ）のメタノール（１．０ｍＬ）−テトラヒドロフラン（０．５ｍＬ）溶液に、水素化ホウ素ナトリウム（２．０ｍｇ、０．０５１ｍｍｏｌ）を加えて、室温で３０分間攪拌したのち、酢酸（６μＬ）を加えて、減圧下濃縮乾固した。残留物にメタノール（１ｍＬ）を加えて減圧下濃縮乾固した。残留物にシクロペンチルメチルエーテル（２ｍＬ）と水（１ｍＬ）を加えて有機層を分離し、減圧下濃縮乾固した。残留物をシリカゲルカラムクロマトグラフィー［充填剤：富士シリシア社製ＮＨ−ＤＭ１０２０、展開溶媒：クロロホルム／酢酸エチル＝１／１］にて精製し、表題化合物（２１ｍｇ、収率７０％）を無色無定形物として得た。

^１Ｈ−ＮＭＲ（３００ＭＨｚ，ＣＤＣｌ_３）δ：０．８７−１．４０（５Ｈ，ｍ），１．４０−２．１３（１３Ｈ，ｍ），２．２７−２．５１（２Ｈ，ｍ），２．４７−２．６５（４Ｈ，ｂｒ ｍ），２．８９（０．５Ｈ，ｂｒ ｔ，Ｊ＝１２．７Ｈｚ），２．９６（０．５Ｈ，ｂｒ ｔ，Ｊ＝１３．５Ｈｚ），３．０３−３．１４（２Ｈ，ｍ），３．２５（２Ｈ，ｓ），３．５７（２Ｈ，ｓ），３．８２（０．５Ｈ，ｂｒ ｄ，Ｊ＝１３．５Ｈｚ），３．９３（０．５Ｈ，ｂｒ ｄ，Ｊ＝１３．１Ｈｚ），４．３９（１Ｈ，ｄ，Ｊ＝７．４Ｈｚ），４．５８（０．５Ｈ，ｂｒ ｄ，Ｊ＝１３．５Ｈｚ），４．６９（０．５Ｈ，ｂｒ ｄ，Ｊ＝１３．１Ｈｚ），７．２６−７．４０（５Ｈ，ｍ），７．４４（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ），７．６１（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ）．

ＬＣ／ＭＳ［条件１］：保持時間２．９８分；ｍ／ｚ５８５．０［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ６２９．２［Ｍ＋ＨＣＯＯ］⁻（ＥＳＩ負イオンモード）

Example 261
4-({3-[((1r, 4r) -4- {4- [hydroxy (phenyl) methyl] piperidine-1-carbonyl} cyclohexyl) methyl] -2-oxo-1-oxa-3,8-diazaspiro Preparation of [4.5] decan-8-yl} methyl) benzonitrile (Compound No. 261) 4-[(3-{[(1r, 4r) -4- (4-Benzoyl) obtained in Example 154 Piperidine-1-carbonyl) cyclohexyl] methyl} -2-oxo-1-oxa-3,8-diazaspiro [4.5] decan-8-yl) methyl] benzonitrile (30 mg, 0.051 mmol) in methanol (1 0.0 mL) -tetrahydrofuran (0.5 mL) solution, sodium borohydride (2.0 mg, 0.051 mmol) was added and stirred at room temperature for 30 minutes, By adding an acid (6 [mu] L), concentrated to dryness under reduced pressure. Methanol (1 mL) was added to the residue, and the mixture was concentrated to dryness under reduced pressure. Cyclopentyl methyl ether (2 mL) and water (1 mL) were added to the residue, the organic layer was separated, and concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography [filler: NH-DM1020 manufactured by Fuji Silysia Co., Ltd., developing solvent: chloroform / ethyl acetate = 1/1], and the title compound (21 mg, yield 70%) was colorless and amorphous. Obtained as a thing.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 0.87-1.40 (5H, m), 1.40-2.13 (13H, m), 2.27-2.51 (2H, m) 2.47-2.65 (4H, br m), 2.89 (0.5 H, br t, J = 12.7 Hz), 2.96 (0.5 H, br t, J = 13.5 Hz) , 3.03-3.14 (2H, m), 3.25 (2H, s), 3.57 (2H, s), 3.82 (0.5H, br d, J = 13.5 Hz), 3.93 (0.5 H, br d, J = 13.1 Hz), 4.39 (1 H, d, J = 7.4 Hz), 4.58 (0.5 H, br d, J = 13.5 Hz) 4.69 (0.5 H, br d, J = 13.1 Hz), 7.26-7.40 (5 H, m), 7.44 (2 H, d, J = 8.2 Hz), 7.61 ( H, d, J = 8.2Hz).

LC / MS [Condition 1]: Retention time 2.98 minutes; m / z 585.0 [M + H] ⁺ (ESI positive ion mode), m / z 629.2 [M + HCOO] ⁻ (ESI negative ion mode)

実施例２６２
（１ｒ，４ｒ）−Ｎ−（４−シアノベンジル）−４−（｛２−オキソ−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）シクロヘキサンカルボキサミド（化合物番号２６２）の製造
参考例６−３で得られた、（１ｒ，４ｒ）−４−（｛２−オキソ−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）シクロヘキサンカルボン酸（２０ｍｇ、０．０４４ｍｍｏｌ）、１−ヒドロキシベンゾトリアゾール（２ｍｇ、０．０１ｍｍｏｌ）及び４−（アミノメチル）ベンゾニトリル塩酸塩（市販）（９．０ｍｇ、０．０５３ｍｍｏｌ）をクロロホルム（１ｍＬ）に溶解し、トリエチルアミン（１２μＬ，０．０８８ｍｍｏｌ）及び１−エチル−３−（３−ジメチルアミノプロピル）カルボジイミド塩酸塩（１３ｍｇ、０．０６６ｍｍｏｌ）を加えて、室温で８日間静置した。反応混合物に水（１ｍＬ）を加えて有機層を分離し、減圧下濃縮乾固した。残留物をシリカゲルカラムクロマトグラフィー［充填剤：富士シリシア製ＦＬ１００Ｄ、展開溶媒：クロロホルム／アセトン＝２／１］にて精製し、表題化合物（２３ｍｇ、収率９２％）を無色無定形物として得た。

^１Ｈ−ＮＭＲ（３００ＭＨｚ，ＣＤＣｌ_３）δ：１．０３（２Ｈ，ｄｑ，Ｊ＝２．９，１２．７Ｈｚ），１．４４−１．６６（３Ｈ，ｍ），１．７０−１．８５（４Ｈ，ｍ），１．８６−２．００（４Ｈ，ｍ），２．０９（１Ｈ，ｔｔ，Ｊ＝１２．３，２．９Ｈｚ），２．４６−２．６３（４Ｈ，ｂｒ ｍ），３．１０（２Ｈ，ｄ，Ｊ＝７．４Ｈｚ），３．２５（２Ｈ，ｓ），３．５７（２Ｈ，ｓ），４．４９（２Ｈ，ｄ，Ｊ＝６．１Ｈｚ），５．８７（１Ｈ，ｂｒ ｔ，Ｊ＝５．７Ｈｚ），７．３６（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ），７．４３（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ），７．５７（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ），７．６１（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ）．

ＬＣ／ＭＳ［条件１］：保持時間３．０８分；ｍ／ｚ５６９．１［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ６０３．２［Ｍ＋Ｃｌ］⁻（ＥＳＩ負イオンモード）

Example 262
(1r, 4r) -N- (4-cyanobenzyl) -4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] Production of Decan-3-yl} methyl) cyclohexanecarboxamide (Compound No. 262) (1r, 4r) -4-({2-oxo-8- [4- (trifluoromethyl) obtained in Reference Example 6-3 ) Benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl) cyclohexanecarboxylic acid (20 mg, 0.044 mmol), 1-hydroxybenzotriazole (2 mg, 0.01 mmol) and 4- (Aminomethyl) benzonitrile hydrochloride (commercially available) (9.0 mg, 0.053 mmol) was dissolved in chloroform (1 mL) and triethylamine (12 μL) was dissolved. 0.088 mmol) and 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (13 mg, 0.066 mmol) was added and allowed to stand at room temperature for 8 days. Water (1 mL) was added to the reaction mixture, the organic layer was separated, and concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography [filler: FL100D manufactured by Fuji Silysia, developing solvent: chloroform / acetone = 2/1] to obtain the title compound (23 mg, yield 92%) as a colorless amorphous product. .

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.03 (2H, dq, J = 2.9, 12.7 Hz), 1.44 to 1.66 (3H, m), 1.70-1. 85 (4H, m), 1.86-2.00 (4H, m), 2.09 (1H, tt, J = 12.3, 2.9 Hz), 2.46-2.63 (4H, br m), 3.10 (2H, d, J = 7.4 Hz), 3.25 (2H, s), 3.57 (2H, s), 4.49 (2H, d, J = 6.1 Hz) , 5.87 (1H, br t, J = 5.7 Hz), 7.36 (2H, d, J = 8.2 Hz), 7.43 (2H, d, J = 8.2 Hz), 7.57 (2H, d, J = 8.2 Hz), 7.61 (2H, d, J = 8.2 Hz).

LC / MS [Condition 1]: Retention time 3.08 minutes; m / z 569.1 [M + H] ⁺ (ESI positive ion mode), m / z 603.2 [M + Cl] ⁻ (ESI negative ion mode)

実施例２６３
（１ｒ，４ｒ）−Ｎ−（４−シアノベンジル）−４−｛［８−（４−シアノベンジル）−２−オキソ−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル］メチル｝シクロヘキサンカルボキサミド（化合物番号２６３）の製造
参考例１７−２で得られた、（１ｒ，４ｒ）−４−｛［８−（４−シアノベンジル）−２−オキソ−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル］メチル｝シクロヘキサンカルボン酸（０．１０ｇ、０．２４ｍｍｏｌ）のＮ，Ｎ−ジメチルホルムアミド（２ｍＬ）懸濁液に、トリエチルアミン（０．１０ｍＬ、０．７２ｍｍｏｌ）、１−ヒドロキシベンゾトリアゾール（１０ｍｇ、０．０７２ｍｍｏｌ）、４−（アミノメチル）ベンゾニトリル塩酸塩（市販）（４８ｍｇ、０．２９ｍｍｏｌ）及び１−エチル−３−（３−ジメチルアミノプロピル）カルボジイミド塩酸塩（６９ｍｇ、０．３６ｍｍｏｌ）を加えて、室温で５日間攪拌した。反応混合物に水（４ｍＬ）とクロロホルム（６ｍＬ）を加えて、有機層を水（５ｍＬ×２）で洗浄したのち、減圧下濃縮乾固した。残留物をシリカゲルカラムクロマトグラフィー［充填剤：富士シリシア社製ＦＬ１００Ｄ、展開溶媒：クロロホルム／アセトン＝２／１］にて精製し、表題化合物（２６ｍｇ、収率２０％）を無色無定形物として得た。

^１Ｈ−ＮＭＲ（３００ＭＨｚ，ＣＤＣｌ_３）δ：１．０３（２Ｈ，ｄｑ，Ｊ＝３．３，１２．５Ｈｚ），１．５２（２Ｈ，ｄｑ，Ｊ＝３．３，１２．５Ｈｚ），１．５６−１．６６（１Ｈ，ｍ），１．６９−１．８５（４Ｈ，ｍ），１．８６−２．００（４Ｈ，ｍ），２．１０（１Ｈ，ｔｔ，Ｊ＝１１．９，３．３Ｈｚ），２．４４−２．６４（４Ｈ，ｂｒ ｍ），３．０９（２Ｈ，ｄ，Ｊ＝７．８Ｈｚ），３．２６（２Ｈ，ｓ），３．５７（２Ｈ，ｓ），４．４８（２Ｈ，ｄ，Ｊ＝６．０Ｈｚ），６．０２（１Ｈ，ｂｒ ｔ，Ｊ＝６．０Ｈｚ），７．３６（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ），７．４４（２Ｈ，ｄ，Ｊ＝７．８Ｈｚ），７．６１（４Ｈ，ｄ，Ｊ＝８．６Ｈｚ）．

ＬＣ／ＭＳ［条件１］：保持時間２．６１分；ｍ／ｚ５２６．１［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ５２４．２［Ｍ−Ｈ］⁻（ＥＳＩ負イオンモード）

Example 263
(1r, 4r) -N- (4-cyanobenzyl) -4-{[8- (4-cyanobenzyl) -2-oxo-1-oxa-3,8-diazaspiro [4.5] decane-3- Preparation of (yl) methyl} cyclohexanecarboxamide (Compound No. 263) (1r, 4r) -4-{[8- (4-cyanobenzyl) -2-oxo-1-oxa-] obtained in Reference Example 17-2 To a suspension of 3,8-diazaspiro [4.5] decan-3-yl] methyl} cyclohexanecarboxylic acid (0.10 g, 0.24 mmol) in N, N-dimethylformamide (2 mL) was added triethylamine (0.10 mL). , 0.72 mmol), 1-hydroxybenzotriazole (10 mg, 0.072 mmol), 4- (aminomethyl) benzonitrile hydrochloride (commercially available) (48 mg, 0.29 m ol) and 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (69 mg, 0.36 mmol) was added and stirred at room temperature for 5 days. Water (4 mL) and chloroform (6 mL) were added to the reaction mixture, and the organic layer was washed with water (5 mL × 2) and then concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography [filler: FL100D manufactured by Fuji Silysia Ltd., developing solvent: chloroform / acetone = 2/1] to obtain the title compound (26 mg, yield 20%) as a colorless amorphous product. It was.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.03 (2H, dq, J = 3.3, 12.5 Hz), 1.52 (2H, dq, J = 3.3, 12.5 Hz), 1.56-1.66 (1H, m), 1.69-1.85 (4H, m), 1.86-2.00 (4H, m), 2.10 (1H, tt, J = 11) .9, 3.3 Hz), 2.44-2.64 (4H, br m), 3.09 (2H, d, J = 7.8 Hz), 3.26 (2H, s), 3.57 ( 2H, s), 4.48 (2H, d, J = 6.0 Hz), 6.02 (1H, brt, J = 6.0 Hz), 7.36 (2H, d, J = 8.2 Hz) 7.44 (2H, d, J = 7.8 Hz), 7.61 (4H, d, J = 8.6 Hz).

LC / MS [Condition 1]: Retention time 2.61 minutes; m / z 526.1 [M + H] ⁺ (ESI positive ion mode), m / z 524.2 [M−H] ⁻ (ESI negative ion mode)

参考例２６４−１
４−（４−シアノフェノキシ）ピペリジン−１−カルボン酸ｔ−ブチルの製造
ＷＯ２００７／１０６７０５記載の方法を用いて合成した。

^１Ｈ−ＮＭＲ（３００ＭＨｚ，ＣＤＣｌ_３）δ：１．４７（９Ｈ，ｓ），１．６４−１．８６（２Ｈ，ｍ），１．８６−２．０１（２Ｈ，ｍ），３．３６（２Ｈ，ｄｄｄ，Ｊ＝１３．５，８．０，４．０Ｈｚ），３．６９（２Ｈ，ｄｄｄ，Ｊ＝１３．５，７．６，３．６Ｈｚ），４．５５（１Ｈ，ｔｔ，Ｊ＝７．４，３．３Ｈｚ），６．９５（２Ｈ，ｄ，Ｊ＝９．０Ｈｚ），７．５８（２Ｈ，ｄ，Ｊ＝９．０Ｈｚ）．

ＬＣ／ＭＳ［条件１］：保持時間４．４９分；ｍ／ｚ２４７．２［Ｍ−ｉｓｏｂｕｔｅｎｅ＋Ｈ］^＋、２０３．２［Ｍ−ｉｓｏｂｕｔｅｎｅ−ＣＯ２＋Ｈ］^＋（ＥＳＩ正イオンモード）

Reference Example 264-1
Production of t-butyl 4- (4-cyanophenoxy) piperidine-1-carboxylate Synthesized using the method described in WO2007 / 106705.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.47 (9H, s), 1.64-1.86 (2H, m), 1.86-2.01 (2H, m), 3.36 (2H, ddd, J = 13.5, 8.0, 4.0 Hz), 3.69 (2H, ddd, J = 13.5, 7.6, 3.6 Hz), 4.55 (1H, tt , J = 7.4, 3.3 Hz), 6.95 (2H, d, J = 9.0 Hz), 7.58 (2H, d, J = 9.0 Hz).

LC / MS [Condition 1]: Retention time 4.49 minutes; m / z 247.2 [M-isobutene + H] ⁺ , 203.2 [M-isobutene-CO2 + H] ⁺ (ESI positive ion mode)

参考例２６４−２
４−（ピペリジン−４−イルオキシ）ベンゾニトリル塩酸塩の製造
ＷＯ２００７／１０６７０５記載の方法を用いて合成した。

^１Ｈ−ＮＭＲ（３００ＭＨｚ，ＣＤＣｌ_３）δ：２．０６−２．２５（２Ｈ，ｂｒ ｍ），２．２６−２．４８（２Ｈ，ｂｒ ｍ），３．１８−３．５２（４Ｈ，ｂｒ ｍ），４．６８−４．８１（１Ｈ，ｂｒ ｍ），６．９６（２Ｈ，ｄ，Ｊ＝９．０Ｈｚ），７．６２（２Ｈ，ｄ，Ｊ＝９．０Ｈｚ），９．７４（２Ｈ，ｂｒ ｓ）．

ＬＣ／ＭＳ［条件１］：保持時間０．４９分；ｍ／ｚ２０３．２［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）

Reference Example 264-2
Preparation of 4- (piperidin-4-yloxy) benzonitrile hydrochloride The compound was synthesized using the method described in WO2007 / 106705.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 2.06-2.25 (2H, br m), 2.26-2.48 (2H, br m), 3.18-3.52 (4H, br m), 4.68-4.81 (1H, br m), 6.96 (2H, d, J = 9.0 Hz), 7.62 (2H, d, J = 9.0 Hz), 9. 74 (2H, brs).

LC / MS [Condition 1]: Retention time 0.49 min; m / z 203.2 [M + H] ⁺ (ESI positive ion mode)

実施例２６４
４−｛１−［４−（｛２−オキソ−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）ベンゾイル］ピペリジン−４−イルオキシ｝ベンゾニトリル（化合物番号２６４）の製造
４−ベンジルピペリジンの代わりに、参考例２６４−２で得られた４−（ピペリジン−４−イルオキシ）ベンゾニトリル塩酸塩を用いること以外は実質的に実施例２５３と同様に反応を行なって、表題化合物（２０ｍｇ、収率６８％）を無色無定形物として得た。

^１Ｈ−ＮＭＲ（３００ＭＨｚ，ＣＤＣｌ_３）δ：１．７３（２Ｈ，ｄｄｄ，Ｊ＝１３．５，８．６，６．１Ｈｚ），１．７４−２．１３（４Ｈ，ｂｒ ｍ），１．９２（２Ｈ，ｂｒ ｄ，Ｊ＝１３．５Ｈｚ），２．４０−２．６５（４Ｈ，ｂｒ ｍ），３．１４（２Ｈ，ｓ），３．２６−４．０３（４Ｈ，ｂｒ ｍ），３．５５（２Ｈ，ｓ），４．４５（２Ｈ，ｓ），４．６７（１Ｈ，ｔｔ，Ｊ＝６．１，３．３Ｈｚ），６．９６（２Ｈ，ｄ，Ｊ＝８．６Ｈｚ），７．３２（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ），７．４１（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ），７．４２（２Ｈ，ｄ，Ｊ＝８．６Ｈｚ），７．５５（２Ｈ，ｄ，Ｊ＝８．６Ｈｚ），７．５９（２Ｈ，ｄ，Ｊ＝８．６Ｈｚ）．

ＬＣ／ＭＳ［条件１］：保持時間３．３２分；ｍ／ｚ６３３．１［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ６７７．２［Ｍ＋ＨＣＯＯ］⁻（ＥＳＩ負イオンモード）

Example 264
4- {1- [4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl) benzoyl Preparation of piperidin-4-yloxy} benzonitrile (Compound No. 264) Other than using 4- (piperidin-4-yloxy) benzonitrile hydrochloride obtained in Reference Example 264-2 instead of 4-benzylpiperidine Was carried out in substantially the same manner as in Example 253 to give the title compound (20 mg, yield 68%) as a colorless amorphous product.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.73 (2H, ddd, J = 13.5, 8.6, 6.1 Hz), 1.74-2.13 (4H, br m), 1 .92 (2H, br d, J = 13.5 Hz), 2.40-2.65 (4H, br m), 3.14 (2H, s), 3.26-4.03 (4H, br m ), 3.55 (2H, s), 4.45 (2H, s), 4.67 (1H, tt, J = 6.1, 3.3 Hz), 6.96 (2H, d, J = 8) .6 Hz), 7.32 (2H, d, J = 8.2 Hz), 7.41 (2H, d, J = 8.2 Hz), 7.42 (2H, d, J = 8.6 Hz), 7 .55 (2H, d, J = 8.6 Hz), 7.59 (2H, d, J = 8.6 Hz).

LC / MS [Condition 1]: Retention time 3.32 minutes; m / z 633.1 [M + H] ⁺ (ESI positive ion mode), m / z 677.2 [M + HCOO] ⁻ (ESI negative ion mode)

実施例２６５
４−｛１−［（１ｒ，４ｒ）−４−（｛２−オキソ−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）シクロヘキサンカルボニル］ピペリジン−４−イルオキシ｝ベンゾニトリル（化合物番号２６５）の製造
４−（アミノメチル）ベンゾニトリル塩酸塩の代わりに、参考例２６４−２で得られた４−（ピペリジン−４−イルオキシ）ベンゾニトリル塩酸塩を用いること以外は実質的に実施例２６２と同様に反応を行なって、表題化合物（１５ｍｇ、収率５４％）を無色無定形物として得た。

^１Ｈ−ＮＭＲ（３００ＭＨｚ，ＣＤＣｌ_３）δ：１．０５（２Ｈ，ｄｑ，Ｊ＝２．９，１１．９Ｈｚ），１．４６−１．６８（３Ｈ，ｂｒ ｍ），１．６９−１．８７（８Ｈ，ｂｒ ｍ），１．８７−２．０２（４Ｈ，ｂｒ ｍ），２．４６（１Ｈ，ｔｔ，Ｊ＝１１．５，３．３Ｈｚ），２．５２−２．６７（４Ｈ，ｂｒ ｍ），３．１０（２Ｈ，ｄ，Ｊ＝７．４Ｈｚ），３．２６（２Ｈ，ｓ），３．３７−３．５３（１Ｈ，ｂｒ ｍ），３．５９（２Ｈ，ｓ），３．６０−３．８３（３Ｈ，ｂｒ ｍ），４．６２（１Ｈ，ｔｔ，Ｊ＝６．１，３．３Ｈｚ），６．９５（２Ｈ，ｄ、Ｊ＝８．６Ｈｚ），７．４４（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ），７．５２−７．６３（４Ｈ，ｍ）．

ＬＣ／ＭＳ［条件１］：保持時間３．３８分；ｍ／ｚ６３９．２［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ６８３．３［Ｍ＋ＨＣＯＯ］⁻（ＥＳＩ負イオンモード）

Example 265
4- {1-[(1r, 4r) -4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decane-3 Preparation of -yl} methyl) cyclohexanecarbonyl] piperidin-4-yloxy} benzonitrile (Compound No. 265) Instead of 4- (aminomethyl) benzonitrile hydrochloride, 4- (piperidine obtained in Reference Example 264-2 The reaction was carried out substantially in the same manner as in Example 262 except that -4-yloxy) benzonitrile hydrochloride was used to give the title compound (15 mg, yield 54%) as a colorless amorphous product.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.05 (2H, dq, J = 2.9, 11.9 Hz), 1.46 to 1.68 (3H, br m), 1.69-1 .87 (8H, br m), 1.87-2.02 (4H, br m), 2.46 (1H, tt, J = 11.5, 3.3 Hz), 2.52-2.67 ( 4H, br m), 3.10 (2H, d, J = 7.4 Hz), 3.26 (2H, s), 3.37-3.53 (1H, br m), 3.59 (2H, s), 3.60-3.83 (3H, br m), 4.62 (1H, tt, J = 6.1, 3.3 Hz), 6.95 (2H, d, J = 8.6 Hz) , 7.44 (2H, d, J = 8.2 Hz), 7.52-7.63 (4H, m).

LC / MS [Condition 1]: Retention time 3.38 minutes; m / z 639.2 [M + H] ⁺ (ESI positive ion mode), m / z 683.3 [M + HCOO] ⁻ (ESI negative ion mode)

実施例２６６
４−［１−（（１ｒ，４ｒ）−４−｛［８−（４−シアノベンジル）−２−オキソ−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル］メチル｝シクロヘキサンカルボニル）ピペリジン−４−イルオキシ］ベンゾニトリル（化合物番号２６６）の製造
４−（アミノメチル）ベンゾニトリル塩酸塩の代わりに、参考例２６４−２で得られた４−（ピペリジン−４−イルオキシ）ベンゾニトリル塩酸塩を用いること以外は実質的に実施例２６３と同様に反応を行なって、表題化合物（３１ｍｇ、収率４３％）を無色無定形物として得た。

^１Ｈ−ＮＭＲ（３００ＭＨｚ，ＣＤＣｌ_３）δ：１．０５（２Ｈ，ｄｑ，Ｊ＝３．３，１２．３Ｈｚ），１．５０−１．６７（３Ｈ，ｂｒ ｍ），１．７０−１．８７（８Ｈ，ｂｒ ｍ），１．８７−２．０１（４Ｈ，ｂｒ ｍ），２．４７（１Ｈ，ｔｔ，Ｊ＝１１．５，２．９Ｈｚ），２．４９−２．６４（４Ｈ，ｂｒ ｍ），３．１１（２Ｈ，ｄ，Ｊ＝７．４Ｈｚ），３．２６（２Ｈ，ｓ），３．３８−３．５３（１Ｈ，ｂｒ ｍ），３．５７（２Ｈ，ｓ），３．５８−３．８５（３Ｈ，ｂｒ ｍ），４．６３（１Ｈ，ｔｔ，Ｊ＝６．５，３．３Ｈｚ），６．９５（２Ｈ，ｄ，Ｊ＝８．６Ｈｚ），７．４４（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ），７．５９（２Ｈ，ｄ，Ｊ＝８．６Ｈｚ），７．６１（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ）．

ＬＣ／ＭＳ［条件１］：保持時間３．１４分；ｍ／ｚ５９６．１［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ６４０．２［Ｍ＋ＨＣＯＯ］⁻（ＥＳＩ負イオンモード）

Example 266
4- [1-((1r, 4r) -4-{[8- (4-cyanobenzyl) -2-oxo-1-oxa-3,8-diazaspiro [4.5] decan-3-yl] methyl } Cyclohexanecarbonyl) piperidin-4-yloxy] benzonitrile (Compound No. 266) 4- (piperidin-4-yloxy) obtained in Reference Example 264-2 instead of 4- (aminomethyl) benzonitrile hydrochloride ) The reaction was carried out in substantially the same manner as in Example 263 except that benzonitrile hydrochloride was used to obtain the title compound (31 mg, yield 43%) as a colorless amorphous product.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.05 (2H, dq, J = 3.3, 12.3 Hz), 1.50-1.67 (3H, br m), 1.70-1. .87 (8H, br m), 1.87-2.01 (4H, br m), 2.47 (1H, tt, J = 11.5, 2.9 Hz), 2.49-2.64 ( 4H, br m), 3.11 (2H, d, J = 7.4 Hz), 3.26 (2H, s), 3.38-3.53 (1H, br m), 3.57 (2H, s), 3.58-3.85 (3H, br m), 4.63 (1H, tt, J = 6.5, 3.3 Hz), 6.95 (2H, d, J = 8.6 Hz) 7.44 (2H, d, J = 8.2 Hz), 7.59 (2H, d, J = 8.6 Hz), 7.61 (2H, d, J = 8.2 Hz).

LC / MS [Condition 1]: Retention time 3.14 minutes; m / z 596.1 [M + H] ⁺ (ESI positive ion mode), m / z 640.2 [M + HCOO] ⁻ (ESI negative ion mode)

実施例２６７
４−［（３−｛［（１ｒ，４ｒ）−４−（４−ベンゾイルピペリジン−１−カルボニル）シクロヘキシル］メチル｝−２−オキソ−１−オキサ−３，８−ジアザスピロ［４．５］デカン−８−イル）メチル］−３，５−ジフルオロベンゾニトリル（化合物番号２６７）の製造
参考例２５５で得られた３−｛［（１ｒ，４ｒ）−４−（４−ベンゾイルピペリジン−１−カルボニル）シクロヘキシル］メチル｝−１−オキサ−３，８−ジアザスピロ［４．５］デカン−２−オン塩酸塩（２０ｍｇ、０．０４０ｍｍｏｌ）と、３，５−ジフルオロ−４−ホルミルベンゾニトリル（市販）（８．０ｍｇ，０．０４６ｍｍｏｌ）のメタノール（１ｍＬ）溶液に酢酸（８０μＬ）とボラン−２−ピコリン錯体（５ｍｇ、０．０５ｍｍｏｌ）を加えて、室温で３日間攪拌したのち、ボラン−２−ピコリン錯体（２ｍｇ、０．０２ｍｍｏｌ）を加えて、さらに２６日間攪拌した。その後、反応混合物を減圧下濃縮乾固して、得られた残留物をメタノール（１ｍＬ）に溶解し、減圧下濃縮乾固した。残留物にクロロホルム（１ｍＬ）と水（１ｍＬ）を加えたのち、有機層を分離し、減圧下濃縮乾固した。得られた残留物をシリカゲルカラムクロマトグラフィー［充填剤：富士シリシア社製ＦＬ１００Ｄ、展開溶媒：クロロホルム／アセトン＝４／１］にて精製し、表題化合物（１８ｍｇ、収率７２％）を無色無定形物として得た。

^１Ｈ−ＮＭＲ（３００ＭＨｚ，ＣＤＣｌ_３）δ：１．０４（２Ｈ，ｂｒ ｑ，Ｊ＝１２．３Ｈｚ），１．４３−１．６８（４Ｈ，ｂｒ ｍ），１．６８−１．８６（７Ｈ，ｂｒ ｍ），１．８６−２．００（４Ｈ，ｂｒ ｍ），２．４６（１Ｈ，ｔｔ，Ｊ＝１１．９，２．５Ｈｚ），２．５３−２．７２（４Ｈ，ｂｒ ｍ），２．８１（１Ｈ，ｂｒ ｔ，Ｊ＝１２．３Ｈｚ），３．０９（２Ｈ，ｄ，Ｊ＝７．４Ｈｚ），３．２０（１Ｈ，ｂｒ ｔ，Ｊ＝１２．３Ｈｚ），３．２２（２Ｈ，ｓ），３．５１（１Ｈ，ｔｔ，Ｊ＝１０．６，３．７Ｈｚ），３．７５（２Ｈ，ｓ），３．９８（１Ｈ，ｂｒ ｄ，Ｊ＝１３．５Ｈｚ），４．６０（１Ｈ，ｂｒ ｄ，Ｊ＝１３．１Ｈｚ），７．２２（２Ｈ，ｄ，Ｊ＝６．１Ｈｚ），７．４９（２Ｈ，ｄｄ，Ｊ＝８．２，７．４Ｈｚ），７．５９（１Ｈ，ｔ，Ｊ＝７．４Ｈｚ），７．９４（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ）．

ＬＣ／ＭＳ［条件１］：保持時間３．２６分；ｍ／ｚ６１９．０［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ６６３．１［Ｍ＋ＨＣＯＯ］⁻（ＥＳＩ負イオンモード）

Example 267
4-[(3-{[(1r, 4r) -4- (4-Benzoylpiperidine-1-carbonyl) cyclohexyl] methyl} -2-oxo-1-oxa-3,8-diazaspiro [4.5] decane Preparation of -8-yl) methyl] -3,5-difluorobenzonitrile (Compound No. 267) 3-{[(1r, 4r) -4- (4-benzoylpiperidine-1-carbonyl] obtained in Reference Example 255 ) Cyclohexyl] methyl} -1-oxa-3,8-diazaspiro [4.5] decan-2-one hydrochloride (20 mg, 0.040 mmol) and 3,5-difluoro-4-formylbenzonitrile (commercially available) Acetic acid (80 μL) and borane-2-picoline complex (5 mg, 0.05 mmol) were added to a methanol (1 mL) solution of (8.0 mg, 0.046 mmol) at room temperature. After stirring for 3 days, it added borane-2-picoline complex (2 mg, 0.02 mmol), and stirred for an additional 26 days. Thereafter, the reaction mixture was concentrated to dryness under reduced pressure, and the resulting residue was dissolved in methanol (1 mL) and concentrated to dryness under reduced pressure. After adding chloroform (1 mL) and water (1 mL) to the residue, the organic layer was separated and concentrated to dryness under reduced pressure. The obtained residue was purified by silica gel column chromatography [filler: FL100D manufactured by Fuji Silysia Ltd., developing solvent: chloroform / acetone = 4/1], and the title compound (18 mg, yield 72%) was colorless and amorphous. Obtained as a thing.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.04 (2H, br q, J = 12.3 Hz), 1.43-1.68 (4H, br m), 1.68-1.86 ( 7H, br m), 1.86-2.00 (4H, br m), 2.46 (1H, tt, J = 11.9, 2.5 Hz), 2.53-2.72 (4H, br m), 2.81 (1H, br t, J = 12.3 Hz), 3.09 (2 H, d, J = 1.4 Hz), 3.20 (1 H, br t, J = 12.3 Hz), 3.22 (2H, s), 3.51 (1H, tt, J = 10.6, 3.7 Hz), 3.75 (2H, s), 3.98 (1H, br d, J = 13. 5 Hz), 4.60 (1H, br d, J = 13.1 Hz), 7.22 (2H, d, J = 6.1 Hz), 7.49 (2H, dd, J = 8. , 7.4Hz), 7.59 (1H, t, J = 7.4Hz), 7.94 (2H, d, J = 8.2Hz).

LC / MS [condition 1]: retention time 3.26 minutes; m / z 619.0 [M + H] ⁺ (ESI positive ion mode), m / z 663.1 [M + HCOO] ⁻ (ESI negative ion mode)

実施例２６８
３−（｛（１ｒ，４ｒ）−４−［４−（４−シアノフェノキシ）ピペリジン−１−カルボニル］シクロヘキシル｝メチル）−２−オキソ−１−オキサ−３，８−ジアザスピロ［４．５］デカン−８−カルボン酸ｔ−ブチル（化合物番号２６８）の製造
４−ベンゾイルピペリジン塩酸塩の代わりに、参考例２６４−２で得られた４−（ピペリジン−４−イルオキシ）ベンゾニトリル塩酸塩を用いること以外は実質的に実施例２５２と同様に反応を行なって、表題化合物(５８ｍｇ、収率定量的)を白色固体として得た。

^１Ｈ−ＮＭＲ（ＣＤＣｌ_３）δ：１．０６（２Ｈ，ｑ，Ｊ＝１２．７Ｈｚ），１．４６（９Ｈ，ｓ），１．４７−１．７３（５Ｈ，ｍ），１．７３−２．０９（１０Ｈ，ｍ），２．４７（１Ｈ，ｂｒ ｔ，Ｊ＝１１．１Ｈｚ），３．０７−３．１８（２Ｈ，ｍ），３．２６（２Ｈ，ｓ），３．２８（２Ｈ，ｂｒ ｔ，Ｊ＝１１．５Ｈｚ），３．４０−３．５７（１Ｈ，ｂｒ ｍ），３．５６−４．０４（５Ｈ，ｂｒ ｍ），４．６３（１Ｈ，ｔｔ，Ｊ＝６．１，３．３Ｈｚ），６．９６（２Ｈ，ｄ，Ｊ＝９．０Ｈｚ），７．６０（２Ｈ，ｄ，Ｊ＝９．０Ｈｚ）．

ＬＣ／ＭＳ［条件１］：保持時間４．３３ 分；ｍ／ｚ６０３．０［Ｍ＋Ｎａ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ６２５．２［Ｍ＋ＨＣＯＯ］⁻（ＥＳＩ負イオンモード）

Example 268
3-({(1r, 4r) -4- [4- (4-cyanophenoxy) piperidine-1-carbonyl] cyclohexyl} methyl) -2-oxo-1-oxa-3,8-diazaspiro [4.5] Preparation of t-butyl decane-8-carboxylate (Compound No. 268) Instead of 4-benzoylpiperidine hydrochloride, 4- (piperidin-4-yloxy) benzonitrile hydrochloride obtained in Reference Example 264-2 was used. Except for the above, the reaction was carried out in substantially the same manner as in Example 252 to obtain the title compound (58 mg, quantitative yield) as a white solid.

¹ H-NMR (CDCl ₃ ) δ: 1.06 (2H, q, J = 12.7 Hz), 1.46 (9H, s), 1.47-1.73 (5H, m), 1.73 -2.09 (10H, m), 2.47 (1H, brt, J = 11.1 Hz), 3.07-3.18 (2H, m), 3.26 (2H, s), 3. 28 (2H, br t, J = 11.5 Hz), 3.40-3.57 (1H, br m), 3.56-4.04 (5H, br m), 4.63 (1H, tt, J = 6.1, 3.3 Hz), 6.96 (2H, d, J = 9.0 Hz), 7.60 (2H, d, J = 9.0 Hz).

LC / MS [Condition 1]: Retention time 4.33 min; m / z 603.0 [M + Na] ⁺ (ESI positive ion mode), m / z 625.2 [M + HCOO] ⁻ (ESI negative ion mode)

実施例２６９
３−｛［（１ｒ，４ｒ）−４−（４−シアノベンジルカルバモイル）シクロヘキシル］メチル｝−２−オキソ−１−オキサ−３，８−ジアザスピロ［４．５］デカン−８−カルボン酸ｔ−ブチル（化合物番号２６９）の製造
４−ベンゾイルピペリジン塩酸塩の代わりに、４−（アミノメチル）ベンゾニトリル塩酸塩（市販）を用いること以外は実質的に実施例２５２と同様に反応を行なって、表題化合物(５５ｍｇ、収率定量的)を白色固体として得た。

^１Ｈ−ＮＭＲ（ＣＤＣｌ_３）δ：１．０４（２Ｈ，ｄｑ，Ｊ＝３．３，１２．３Ｈｚ），１．４６（９Ｈ，ｓ），１．４９−１．７３（５Ｈ，ｍ），１．７３−２．０２（６Ｈ，ｍ），２．１０（１Ｈ，ｔｔ，Ｊ＝１２．３，３．３Ｈｚ），３．１１（２Ｈ，ｄ，Ｊ＝７．８Ｈｚ），３．２６（２Ｈ，ｓ），３．２７（２Ｈ，ｂｒ ｔ，Ｊ＝１２．０Ｈｚ），３．８６（２Ｈ，ｂｒ ｄ，Ｊ＝１２．０Ｈｚ），４．４９（２Ｈ，ｄ，Ｊ＝６．１Ｈｚ），５．８８（１Ｈ，ｂｒ ｔ，Ｊ＝６．１Ｈｚ），７．３６（２Ｈ，ｄ，Ｊ＝７．８Ｈｚ），７．６２（２Ｈ，ｄ，Ｊ＝７．８Ｈｚ）．

ＬＣ／ＭＳ［条件１］：保持時間４．０３分；ｍ／ｚ５３２．９［Ｍ＋Ｎａ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ５０９．１［Ｍ−Ｈ］⁻、５５５．１［Ｍ＋ＨＣＯＯ］⁻（ＥＳＩ負イオンモード）

Example 269
3-{[(1r, 4r) -4- (4-cyanobenzylcarbamoyl) cyclohexyl] methyl} -2-oxo-1-oxa-3,8-diazaspiro [4.5] decane-8-carboxylic acid t- Preparation of butyl (Compound No. 269) The reaction was carried out in substantially the same manner as in Example 252, except that 4- (aminomethyl) benzonitrile hydrochloride (commercially available) was used instead of 4-benzoylpiperidine hydrochloride. The title compound (55 mg, quantitative yield) was obtained as a white solid.

¹ H-NMR (CDCl ₃ ) δ: 1.04 (2H, dq, J = 3.3, 12.3 Hz), 1.46 (9H, s), 1.49-1.73 (5H, m) , 1.73-2.02 (6H, m), 2.10 (1H, tt, J = 12.3, 3.3 Hz), 3.11 (2H, d, J = 7.8 Hz), 3. 26 (2H, s), 3.27 (2H, br t, J = 12.0 Hz), 3.86 (2H, br d, J = 12.0 Hz), 4.49 (2H, d, J = 6) .1 Hz), 5.88 (1H, br t, J = 6.1 Hz), 7.36 (2H, d, J = 7.8 Hz), 7.62 (2H, d, J = 7.8 Hz).

LC / MS [Condition 1]: Retention time 4.03 minutes; m / z 532.9 [M + Na] ⁺ (ESI positive ion mode), m / z 509.1 [M−H] ⁻ , 555.1 [M + HCOO] ⁻ (ESI negative ion mode)

実施例２７０
１−［（１ｒ，４ｒ）−４−（｛２−オキソ−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）シクロヘキサンカルボニル］−４−フェニルピペリジン−４−カルボニトリル（化合物番号２７０）の製造
４−（アミノメチル）ベンゾニトリル塩酸塩の代わりに、４−フェニルピペリジン−４−カルボニトリル塩酸塩（市販）を用いること以外は実質的に実施例２６２と同様に反応を行なって、表題化合物（２６ｍｇ、収率９６％）を無色無定形物として得た。

^１Ｈ−ＮＭＲ（ＣＤＣｌ_３）δ：１．０７（２Ｈ，ｑ，Ｊ＝１２．３Ｈｚ），１．４４−１．６９（３Ｈ，ｍ），１．７２−２．０４（１０Ｈ，ｍ），２．１９（２Ｈ，ｂｒ ｔ，Ｊ＝１２．３Ｈｚ），２．４６−２．６８（４Ｈ，ｂｒ ｍ），２．４９（１Ｈ，ｂｒ ｔ，Ｊ＝１１．９Ｈｚ），３．０２（１Ｈ，ｂｒ ｔ，Ｊ＝１３．１Ｈｚ），３．１１（２Ｈ，ｄ，Ｊ＝７．４Ｈｚ），３．２６（２Ｈ，ｓ），３．５５（１Ｈ，ｂｒ ｔ，Ｊ＝１３．５Ｈｚ），３．５８（２Ｈ，ｓ），４．０５（１Ｈ，ｂｒ ｄ，Ｊ＝１４．７Ｈｚ），４．８５（１Ｈ，ｂｒ ｄ，Ｊ＝１４．３Ｈｚ），７．３２−７．５１（７Ｈ，ｍ），７．５７（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ）．

ＬＣ／ＭＳ［条件１］：保持時間３．４０分；ｍ／ｚ６２３．１［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ６６７．１［Ｍ＋ＨＣＯＯ］⁻（ＥＳＩ負イオンモード）

Example 270
1-[(1r, 4r) -4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} Preparation of methyl) cyclohexanecarbonyl] -4-phenylpiperidine-4-carbonitrile (Compound No. 270) Instead of 4- (aminomethyl) benzonitrile hydrochloride, 4-phenylpiperidine-4-carbonitrile hydrochloride (commercially available) The title compound (26 mg, yield 96%) was obtained as a colorless amorphous product in substantially the same manner as in Example 262 except that was used.

¹ H-NMR (CDCl ₃ ) δ: 1.07 (2H, q, J = 12.3 Hz), 1.44-1.69 (3H, m), 1.72-2.04 (10H, m) 2.19 (2H, br t, J = 12.3 Hz), 2.46-2.68 (4 H, br m), 2.49 (1 H, br t, J = 11.9 Hz), 3.02 (1H, br t, J = 13.1 Hz), 3.11 (2H, d, J = 7.4 Hz), 3.26 (2H, s), 3.55 (1H, br t, J = 13. 5 Hz), 3.58 (2H, s), 4.05 (1 H, br d, J = 14.7 Hz), 4.85 (1 H, br d, J = 14.3 Hz), 7.32-7. 51 (7H, m), 7.57 (2H, d, J = 8.2 Hz).

LC / MS [Condition 1]: Retention time 3.40 minutes; m / z 623.1 [M + H] ⁺ (ESI positive ion mode), m / z 667.1 [M + HCOO] ⁻ (ESI negative ion mode)

実施例２７１
１−（（１ｒ，４ｒ）−４−｛［８−（４−シアノベンジル）−２−オキソ−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル］メチル｝シクロヘキサンカルボニル）−４−フェニルピペリジン−４−カルボニトリル（化合物番号２７１）の製造
４−（アミノメチル）ベンゾニトリル塩酸塩の代わりに、４−フェニルピペリジン−４−カルボニトリル塩酸塩（市販）を用いること以外は実質的に実施例２６３と同様に反応を行なって、表題化合物（５２ｍｇ、収率９３％）を無色無定形物として得た。

^１Ｈ−ＮＭＲ（ＣＤＣｌ_３）δ：１．０６（２Ｈ，ｑ，Ｊ＝１１．９Ｈｚ），１．４６−１．７０（３Ｈ，ｍ），１．７１−２．０１（１０Ｈ，ｍ），２．１９（２Ｈ，ｂｒ ｔ，Ｊ＝１１．９Ｈｚ），２．４４−２．６８（４Ｈ，ｂｒ ｍ），２．４８（１Ｈ，ｂｒ ｔ，Ｊ＝１１．９Ｈｚ），３．０２（１Ｈ，ｂｒ ｔ，Ｊ＝１３．１Ｈｚ），３．１１（２Ｈ，ｄ，Ｊ＝７．４Ｈｚ），３．２６（２Ｈ，ｓ），３．５５（１Ｈ，ｂｒ ｔ，Ｊ＝１３．９Ｈｚ），３．５７（２Ｈ，ｓ），４．０５（１Ｈ，ｄ，Ｊ＝１４．３Ｈｚ），４．８６（１Ｈ，ｂｒ ｄ，Ｊ＝１３．５Ｈｚ），７．３１−７．５０（７Ｈ，ｍ），７．６１（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ）．

ＬＣ／ＭＳ［条件１］：保持時間３．１８分；ｍ／ｚ５８０．０［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ６２４．１［Ｍ＋ＨＣＯＯ］⁻（ＥＳＩ負イオンモード）

Example 271
1-((1r, 4r) -4-{[8- (4-cyanobenzyl) -2-oxo-1-oxa-3,8-diazaspiro [4.5] decan-3-yl] methyl} cyclohexanecarbonyl ) Preparation of 4-phenylpiperidine-4-carbonitrile (Compound No. 271) Instead of using 4- (aminomethyl) benzonitrile hydrochloride, 4-phenylpiperidine-4-carbonitrile hydrochloride (commercially available) was used. Was carried out in substantially the same manner as in Example 263 to obtain the title compound (52 mg, yield 93%) as a colorless amorphous product.

¹ H-NMR (CDCl ₃ ) δ: 1.06 (2H, q, J = 11.9 Hz), 1.46-1.70 (3H, m), 1.71-2.01 (10H, m) 2.19 (2H, br t, J = 11.9 Hz), 2.44-2.68 (4H, br m), 2.48 (1 H, br t, J = 11.9 Hz), 3.02 (1H, br t, J = 13.1 Hz), 3.11 (2H, d, J = 7.4 Hz), 3.26 (2H, s), 3.55 (1H, br t, J = 13. 9 Hz), 3.57 (2H, s), 4.05 (1 H, d, J = 14.3 Hz), 4.86 (1 H, br d, J = 13.5 Hz), 7.31-7.50. (7H, m), 7.61 (2H, d, J = 8.2 Hz).

LC / MS [Condition 1]: Retention time 3.18 minutes; m / z 580.0 [M + H] ⁺ (ESI positive ion mode), m / z 624.1 [M + HCOO] ⁻ (ESI negative ion mode)

参考例２７２−１
４−［（シクロヘキシルメチルアミノ）メチル］−４−ヒドロキシピペリジン−１−カルボン酸ｔ−ブチルの製造
参考例１−１で得られた、１−オキサ−６−アザスピロ［２．５］オクタン−６−カルボン酸ｔ−ブチル（０．７０ｇ、０．３３ｍｍｏｌ）のメタノール（１．５ｍＬ）溶液にシクロヘキシルメチルアミン（市販）（８５μＬ、０．６６ｍｍｏｌ）と水（１．５ｍＬ）を加えて室温で８日間攪拌した。反応液を減圧下濃縮してメタノールを除去したのちに、クロロホルム（３ｍＬ）を加えて有機層を分離し、減圧下濃縮乾固した。残留物をシリカゲルカラムクロマトグラフィー［充填剤：富士シリシア社製ＦＬ１００Ｄ、展開溶媒：クロロホルム／２−プロパノール＝１０／１］にて精製し、表題化合物（２５ｍｇ、収率２３％）を無色油状物として得た。

^１Ｈ−ＮＭＲ（ＣＤＣｌ_３）δ：０．９０（２Ｈ，ｑ，Ｊ＝１１．５Ｈｚ），１．０９−１．６１（７Ｈ，ｍ），１．４５（９Ｈ，ｓ），１．６１−１．８１（６Ｈ，ｍ），２．４８（２Ｈ，ｄ，Ｊ＝６．５Ｈｚ），２．４９（２Ｈ，ｓ），３．１６（２Ｈ，ｂｒ ｔ，Ｊ＝１１．９Ｈｚ），３．７５−３．９７（２Ｈ，ｂｒ ｍ）．

Reference Example 272-1
Production of t-butyl 4-[(cyclohexylmethylamino) methyl] -4-hydroxypiperidine-1-carboxylate 1-oxa-6-azaspiro [2.5] octane-6 obtained in Reference Example 1-1 -Add cyclohexylmethylamine (commercially available) (85 μL, 0.66 mmol) and water (1.5 mL) to a solution of t-butyl carboxylate (0.70 g, 0.33 mmol) in methanol (1.5 mL) at room temperature. Stir for days. The reaction solution was concentrated under reduced pressure to remove methanol, and then chloroform (3 mL) was added to separate the organic layer, followed by concentration to dryness under reduced pressure. The residue was purified by silica gel column chromatography [filler: FL100D manufactured by Fuji Silysia Ltd., developing solvent: chloroform / 2-propanol = 10/1] to give the title compound (25 mg, yield 23%) as a colorless oil. Obtained.

¹ H-NMR (CDCl ₃ ) δ: 0.90 (2H, q, J = 11.5 Hz), 1.09-1.61 (7H, m), 1.45 (9H, s), 1.61 −1.81 (6H, m), 2.48 (2H, d, J = 6.5 Hz), 2.49 (2H, s), 3.16 (2H, brt, J = 11.9 Hz), 3.75-3.97 (2H, br m).

参考例２７２−２
３−（シクロヘキシルメチル）−２−オキソ−１−オキサ−３，８−ジアザスピロ［４．５］デカン−８−カルボン酸ｔ−ブチルの製造
参考例２７２−１で得られた、４−［（シクロヘキシルメチルアミノ）メチル］−４−ヒドロキシピペリジン−１−カルボン酸ｔ−ブチル（８６ｍｇ、０．２６ｍｍｏｌ）の１，４−ジオキサン（３ｍＬ）溶液に１，１’−カルボニルジイミダゾール（０．１３ｇ、０．７８ｍｍｏｌ）を加えて、反応混合物を９０℃で１５時間静置したのち減圧下濃縮乾固した。残留物に水（２ｍＬ）、ｎ−ヘキサン（２ｍＬ）及び酢酸エチル（２ｍＬ）を加えて、有機層を分離し、減圧下濃縮乾固した。残留物を再結晶（ｎ−ヘキサン−酢酸エチル）により精製して、表題化合物（６２ｍｇ、収率６７％）を白色固体として得た。

^１Ｈ−ＮＭＲ（ＣＤＣｌ_３）δ：０．９６（２Ｈ，ｑ，Ｊ＝１１．５Ｈｚ），１．１１−１．３２（３Ｈ，ｍ），１．５４−１．８０（８Ｈ，ｍ），１．８８（２Ｈ，ｂｒ ｄ，Ｊ＝１３．５Ｈｚ），３．０８（２Ｈ，ｄ，Ｊ＝７．４Ｈｚ），３．２５（２Ｈ，ｓ），３．２８（２Ｈ，ｔ，Ｊ＝１１．９Ｈｚ），３．８５（２Ｈ，ｂｒ ｄ，Ｊ＝１２．７Ｈｚ）．

Reference Example 272-2
Production of t-butyl 3- (cyclohexylmethyl) -2-oxo-1-oxa-3,8-diazaspiro [4.5] decane-8-carboxylate 4-[( Cyclohexylmethylamino) methyl] -4-hydroxypiperidine-1-carboxylate t-butyl (86 mg, 0.26 mmol) in 1,4-dioxane (3 mL) in 1,1′-carbonyldiimidazole (0.13 g, 0.78 mmol) was added, and the reaction mixture was allowed to stand at 90 ° C. for 15 hours, and then concentrated to dryness under reduced pressure. Water (2 mL), n-hexane (2 mL) and ethyl acetate (2 mL) were added to the residue, and the organic layer was separated and concentrated to dryness under reduced pressure. The residue was purified by recrystallization (n-hexane-ethyl acetate) to give the title compound (62 mg, 67% yield) as a white solid.

¹ H-NMR (CDCl ₃ ) δ: 0.96 (2H, q, J = 11.5 Hz), 1.11-1.32 (3H, m), 1.54-1.80 (8H, m) , 1.88 (2H, br d, J = 13.5 Hz), 3.08 (2H, d, J = 7.4 Hz), 3.25 (2H, s), 3.28 (2H, t, J = 11.9 Hz), 3.85 (2H, br d, J = 12.7 Hz).

参考例２７２−３
３−（シクロヘキシルメチル）−１−オキサ−３，８−ジアザスピロ［４．５］デカン−２−オン塩酸塩の製造
参考例２７２−２で得られた、３−（シクロヘキシルメチル）−２−オキソ−１−オキサ−３，８−ジアザスピロ［４．５］デカン−８−カルボン酸ｔ−ブチル（５９ｍｇ、０．１７ｍｍｏｌ）のメタノール（３ｍＬ）溶液に、１０質量％塩化水素メタノール溶液（０．４０ｍＬ）を加えたのち、反応混合物を室温で４２時間、４０℃で６時間静置した。その後、反応混合物を減圧下濃縮乾固して、表題化合物（５３ｍｇ、収率定量的）を黄色固体として得た。

ＬＣ／ＭＳ［条件２］：保持時間０．８２分；ｍ／ｚ２５３．１［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）

Reference Example 272-3
Production of 3- (cyclohexylmethyl) -1-oxa-3,8-diazaspiro [4.5] decan-2-one hydrochloride 3- (cyclohexylmethyl) -2-oxo obtained in Reference Example 272-2 To a solution of tert-butyl-1-oxa-3,8-diazaspiro [4.5] decane-8-carboxylate (59 mg, 0.17 mmol) in methanol (3 mL), a 10% by mass hydrogen chloride methanol solution (0.40 mL). ) Was added, and the reaction mixture was allowed to stand at room temperature for 42 hours and at 40 ° C. for 6 hours. The reaction mixture was then concentrated to dryness under reduced pressure to give the title compound (53 mg, quantitative yield) as a yellow solid.

LC / MS [Condition 2]: Retention time 0.82 minutes; m / z 253.1 [M + H] ⁺ (ESI positive ion mode)

実施例２７２
３−｛４−［３−（シクロヘキシルメチル）−２−オキソ−１−オキサ−３，８−ジアザスピロ［４．５］デカン−８−カルボニル］ベンジル｝−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−２−オン（化合物番号２７２）の製造
４−ベンジルピペリジンの代わりに、参考例２７２−３で得られた３−（シクロヘキシルメチル）−１−オキサ−３，８−ジアザスピロ［４．５］デカン−２−オン塩酸塩を用いること以外は実質的に実施例２５３と同様に反応を行なって、表題化合物(１９ｍｇ、収率９０％)を無色無定形物として得た。

^１Ｈ−ＮＭＲ（ＣＤＣｌ_３）δ：０．９６（２Ｈ，ｑ，Ｊ＝１１．５Ｈｚ），１．０８−１．３５（３Ｈ，ｍ），１．５０−２．１５（１３Ｈ，ｍ），２．３９−２．６８（４Ｈ，ｂｒ ｍ），３．０９（２Ｈ，ｄ，Ｊ＝７．４Ｈｚ），３．１４（２Ｈ，ｓ），３．２２−３．７６（３Ｈ，ｂｒ ｍ），３．２９（２Ｈ，ｓ），３．５６（２Ｈ，ｓ），４．３６−４．６５（１Ｈ，ｂｒ ｍ），４．４５（２Ｈ，ｂｒ ｓ），７．３１（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ），７．４０（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ），７．４３（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ），７．５７（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ）．

ＬＣ／ＭＳ［条件１］：保持時間３．４２分；ｍ／ｚ６８３．２［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ７２７．２［Ｍ＋ＨＣＯＯ］⁻（ＥＳＩ負イオンモード）

Example 272
3- {4- [3- (cyclohexylmethyl) -2-oxo-1-oxa-3,8-diazaspiro [4.5] decan-8-carbonyl] benzyl} -8- [4- (trifluoromethyl) Preparation of [benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-2-one (Compound No. 272) Instead of 4-benzylpiperidine, 3- (cyclohexyl) obtained in Reference Example 272-3 Methyl) -1-oxa-3,8-diazaspiro [4.5] decan-2-one hydrochloride was used in the substantially same manner as in Example 253 except that the title compound (19 mg, yield) was obtained. 90%) was obtained as a colorless amorphous product.

¹ H-NMR (CDCl ₃ ) δ: 0.96 (2H, q, J = 11.5 Hz), 1.08-1.35 (3H, m), 1.50-2.15 (13H, m) 2.39-2.68 (4H, br m), 3.09 (2H, d, J = 7.4 Hz), 3.14 (2H, s), 3.22-3.76 (3H, br) m), 3.29 (2H, s), 3.56 (2H, s), 4.36-4.65 (1H, br m), 4.45 (2H, br s), 7.31 (2H) , D, J = 8.2 Hz), 7.40 (2H, d, J = 8.2 Hz), 7.43 (2H, d, J = 8.2 Hz), 7.57 (2H, d, J = 8.2 Hz).

LC / MS [condition 1]: retention time 3.42 minutes; m / z 683.2 [M + H] ⁺ (ESI positive ion mode), m / z 727.2 [M + HCOO] ⁻ (ESI negative ion mode)

参考例２７３−１
１−オキサ−３，８−ジアザスピロ［４．５］デカン−２−オン塩酸塩の製造
参考例１１１−１で得られた、２−オキソ−１−オキサ−３，８−ジアザスピロ［４．５］デカン−８−カルボン酸ｔ−ブチル（９５ｍｇ、０．３７ｍｍｏｌ）のメタノール（２ｍＬ）溶液に、１０質量％塩化水素メタノール溶液（１ｍＬ）を加えたのち、反応混合物を室温で３日間静置した。その後、反応混合物を減圧下濃縮乾固して、表題化合物（７５ｍｇ、収率定量的）を白色固体として得た。

^１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ_６）δ：１．８５−２．０６（４Ｈ，ｍ），２．９８−３．１３（２Ｈ，ｍ），３．１３−３．２４（２Ｈ，ｍ），３．３２（２Ｈ，ｓ），７．６５（１Ｈ，ｂｒ ｓ），８．８２（２Ｈ，ｂｒ ｓ）．

Reference Example 273-1
Production of 1-oxa-3,8-diazaspiro [4.5] decan-2-one hydrochloride 2-oxo- 1-oxa-3,8-diazaspiro [4.5] obtained in Reference Example 111-1. ] To a solution of t-butyl decane-8-carboxylate (95 mg, 0.37 mmol) in methanol (2 mL) was added 10 mass% hydrogen chloride methanol solution (1 mL), and the reaction mixture was allowed to stand at room temperature for 3 days. . The reaction mixture was then concentrated to dryness under reduced pressure to give the title compound (75 mg, quantitative yield) as a white solid.

¹ H-NMR (DMSO-d ₆ ) δ: 1.85-2.06 (4H, m), 2.98-3.13 (2H, m), 3.13-3.24 (2H, m) , 3.32 (2H, s), 7.65 (1H, br s), 8.82 (2H, br s).

参考例２７３−２
３−［４−（２−オキソ−１−オキサ−３，８−ジアザスピロ［４．５］デカン−８−カルボニル）ベンジル］−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−２−オンの製造
参考例２１で得られた、４−（｛２−オキソ−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）安息香酸（５１ｍｇ、０．１１ｍｍｏｌ）、１−ヒドロキシベンゾトリアゾール（５ｍｇ、０．０３ｍｍｏｌ）及び参考例２７３−１で得られた１−オキサ−３，８−ジアザスピロ［４．５］デカン−２−オン塩酸塩（２４ｍｇ、０．１２ｍｍｏｌ）をクロロホルム（１ｍＬ）に懸濁し、トリエチルアミン（６３μＬ、０．４５ｍｍｏｌ）及び１−エチル−３−（３−ジメチルアミノプロピル）カルボジイミド塩酸塩（３３ｍｇ、０．１７ｍｍｏｌ）を加えて、室温で２１日間攪拌した。反応混合物に水（２ｍＬ）を加えたのち、有機層を分離し、減圧下濃縮乾固した。残留物をシリカゲルカラムクロマトグラフィー［充填剤：富士シリシア社製ＦＬ１００Ｄ、展開溶媒：クロロホルム／２−プロパノール＝５／１］にて精製し、表題化合物(５４ｍｇ、収率８２％)を無色無定形物として得た。

^１Ｈ−ＮＭＲ（ＣＤＣｌ_３）δ：１．５４−２．２２（４Ｈ，ｂｒ ｍ），１．７３（２Ｈ，ｄｔ，Ｊ＝１３．５，７．０Ｈｚ），１．９２（２Ｈ，ｄ，Ｊ＝１３．１Ｈｚ），２．４１−２．６５（４Ｈ，ｂｒ ｍ），３．１４（２Ｈ，ｓ），３．２６−３．８０（３Ｈ，ｂｒ ｍ），３．３９（２Ｈ，ｂｒ ｓ），３．５５（２Ｈ，ｓ），４．３３−４．６２（１Ｈ，ｂｒ ｍ），４．４５（２Ｈ，ｂｒ ｓ），５．１０（１Ｈ，ｂｒ ｓ），７．３２（２Ｈ，ｄ，Ｊ＝７．８Ｈｚ），７．４０（２Ｈ，ｄ，Ｊ＝７．８Ｈｚ），７．４３（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ），７．５７（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ）．

ＬＣ／ＭＳ［条件１］：保持時間１．９〜２．４分；ｍ／ｚ５８７．０［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ６３１．０［Ｍ＋ＨＣＯＯ］⁻、５８５．１［Ｍ−Ｈ］⁻（ＥＳＩ負イオンモード）

Reference Example 273-2
3- [4- (2-Oxo-1-oxa-3,8-diazaspiro [4.5] decane-8-carbonyl) benzyl] -8- [4- (trifluoromethyl) benzyl] -1-oxa- Production of 3,8-diazaspiro [4.5] decan-2-one 4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1- oxa- obtained in Reference Example 21 3,8-diazaspiro [4.5] decan-3-yl} methyl) benzoic acid (51 mg, 0.11 mmol), 1-hydroxybenzotriazole (5 mg, 0.03 mmol) and obtained in Reference Example 273-1 1-oxa-3,8-diazaspiro [4.5] decan-2-one hydrochloride (24 mg, 0.12 mmol) was suspended in chloroform (1 mL) and triethylamine (63 μL, 0.45 mmol). And 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (33 mg, 0.17 mmol) was added and stirred at room temperature for 21 days. After adding water (2 mL) to the reaction mixture, the organic layer was separated and concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography [filler: FL100D manufactured by Fuji Silysia Ltd., developing solvent: chloroform / 2-propanol = 5/1], and the title compound (54 mg, yield 82%) was colorless and amorphous. Got as.

¹ H-NMR (CDCl ₃ ) δ: 1.54-2.22 (4H, br m), 1.73 (2H, dt, J = 13.5, 7.0 Hz), 1.92 (2H, d , J = 13.1 Hz), 2.41-2.65 (4H, br m), 3.14 (2H, s), 3.26-3.80 (3H, br m), 3.39 (2H , Br s), 3.55 (2H, s), 4.33-4.62 (1H, br m), 4.45 (2H, br s), 5.10 (1H, br s), 7. 32 (2H, d, J = 7.8 Hz), 7.40 (2H, d, J = 7.8 Hz), 7.43 (2H, d, J = 8.2 Hz), 7.57 (2H, d , J = 8.2 Hz).

LC / MS [Condition 1]: Retention time 1.9 to 2.4 minutes; m / z 587.0 [M + H] ⁺ (ESI positive ion mode), m / z 631.0 [M + HCOO] ⁻ , 585.1 [M -H] ^- (ESI negative ion mode)

実施例２７３
３−［４−（３−エチル−２−オキソ−１−オキサ−３，８−ジアザスピロ［４．５］デカン−８−カルボニル）ベンジル］−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−２−オン（化合物番号２７３）の製造
参考例２７３−２で得られた、３−［４−（２−オキソ−１−オキサ−３，８−ジアザスピロ［４．５］デカン−８−カルボニル）ベンジル］−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−２−オン（２０ｍｇ、０．０３４ｍｍｏｌ）のＮ，Ｎ−ジメチルホルムアミド（１ｍＬ）溶液にカリウムｔ−ブトキシド（５ｍｇ、０．０５ｍｍｏｌ）を加えて、室温で１．５時間攪拌した。その後、ヨウ化エチル（４μＬ）を加えて室温で、４時間攪拌した。酢酸（６μＬ）、水（２ｍＬ）及びクロロホルム（４ｍＬ）を加えて、有機層を分離し、減圧下濃縮乾固した。残留物に水（１ｍＬ）と酢酸エチル（２ｍＬ）を加えて、有機層を分離し、減圧下濃縮乾固した。残留物をシリカゲルカラムクロマトグラフィー［充填剤：富士シリシア社製ＮＨ−ＤＭ１０２０、展開溶媒：クロロホルム／酢酸エチル＝２／１］にて精製し、表題化合物（１０ｍｇ、収率４８％）を白色固体として得た。

^１Ｈ−ＮＭＲ（ＣＤＣｌ_３）δ：１．７３（２Ｈ，ｄｔ，Ｊ＝１３．１，７．０Ｈｚ），１．７４−２．１６（４Ｈ，ｂｒ ｍ），１．９２（２Ｈ，ｂｒ ｄ，Ｊ＝１３．１Ｈｚ），２．４３−２．６５（４Ｈ，ｂｒ ｍ），３．１４（２Ｈ，ｓ），３．２６−３．７６（３Ｈ，ｂｒ ｍ），３．３０（２Ｈ，ｓ），３．３４（２Ｈ，ｑ，Ｊ＝７．４Ｈｚ），３．５６（２Ｈ，ｓ），４．３３−４．６２（１Ｈ，ｂｒ ｍ），４．４５（２Ｈ，ｂｒ ｓ），７．３２（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ），７．４０（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ），７．４３（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ），７．５７（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ）

ＬＣ／ＭＳ［条件１］：保持時間２．９６分；ｍ／ｚ６１５．０［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ６５９．１［Ｍ＋ＨＣＯＯ］⁻（ＥＳＩ負イオンモード）

Example 273
3- [4- (3-Ethyl-2-oxo-1-oxa-3,8-diazaspiro [4.5] decan-8-carbonyl) benzyl] -8- [4- (trifluoromethyl) benzyl]- Production of 1-oxa-3,8-diazaspiro [4.5] decan-2-one (Compound No. 273) 3- [4- (2-oxo-1-oxa- ) obtained in Reference Example 273-2 3,8-diazaspiro [4.5] decan-8-carbonyl) benzyl] -8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-2- To a solution of ON (20 mg, 0.034 mmol) in N, N-dimethylformamide (1 mL) was added potassium t-butoxide (5 mg, 0.05 mmol), and the mixture was stirred at room temperature for 1.5 hours. Then, ethyl iodide (4 μL) was added and stirred at room temperature for 4 hours. Acetic acid (6 μL), water (2 mL) and chloroform (4 mL) were added, and the organic layer was separated and concentrated to dryness under reduced pressure. Water (1 mL) and ethyl acetate (2 mL) were added to the residue, the organic layer was separated, and concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography [filler: NH-DM1020 manufactured by Fuji Silysia Ltd., developing solvent: chloroform / ethyl acetate = 2/1] to give the title compound (10 mg, 48% yield) as a white solid. Obtained.

¹ H-NMR (CDCl ₃ ) δ: 1.73 (2H, dt, J = 13.1, 7.0 Hz), 1.74-2.16 (4H, br m), 1.92 (2H, br d, J = 13.1 Hz), 2.43-2.65 (4H, br m), 3.14 (2H, s), 3.26-3.76 (3H, br m), 3.30 ( 2H, s), 3.34 (2H, q, J = 7.4 Hz), 3.56 (2H, s), 4.33-4.62 (1H, br m), 4.45 (2H, br) s), 7.32 (2H, d, J = 8.2 Hz), 7.40 (2H, d, J = 8.2 Hz), 7.43 (2H, d, J = 8.2 Hz), 7. 57 (2H, d, J = 8.2 Hz)

LC / MS [Condition 1]: Retention time 2.96 minutes; m / z 615.0 [M + H] ⁺ (ESI positive ion mode), m / z 659.1 [M + HCOO] ⁻ (ESI negative ion mode)

実施例２７４
４−（３−｛［（１ｒ，４ｒ）−４−（４−ベンゾイルピペリジン−１−カルボニル）シクロヘキシル］メチル｝−２−オキソ−１−オキサ−３，８−ジアザスピロ［４．５］デカン−８−イル）−３−ニトロベンゾニトリル（化合物番号２７４）の製造
参考例２５５で得られた３−｛［（１ｒ，４ｒ）−４−（４−ベンゾイルピペリジン−１−カルボニル）シクロヘキシル］メチル｝−１−オキサ−３，８−ジアザスピロ［４．５］デカン−２−オン塩酸塩（２０ｍｇ、０．０４０ｍｍｏｌ）と４−クロロ−３−ニトロベンゾニトリル（７ｍｇ、０．０４０ｍｍｏｌ）の１，４−ジオキサン（１ｍＬ）懸濁液にＮ，Ｎ−ジイソプロピルエチルアミン（２１μＬ，０．１２ｍｍｏｌ）を加えたのち、反応混合物を１００℃で２０時間撹拌し、減圧下濃縮乾固した。残留物に酢酸エチル（２ｍＬ）と水（２ｍＬ）を加えたのち、有機層を分離し、減圧下濃縮乾固した。残留物をシリカゲルカラムクロマトグラフィー［充填剤：富士シリシア社製ＦＬ１００Ｄ、展開溶媒：クロロホルム／アセトン＝３／１］にて精製し、表題化合物（２３ｍｇ、収率９６％）を黄色固体として得た。

^１Ｈ−ＮＭＲ（ＣＤＣｌ_３）δ：１．０７（２Ｈ，ｑ，Ｊ＝１２．７Ｈｚ），１．５１−１．７２（３Ｈ，ｍ），１．７３−２．１１（１２Ｈ，ｍ），２．４８（１Ｈ，ｂｒ ｔ，Ｊ＝１１．１Ｈｚ），２．８２（１Ｈ，ｂｒ ｔ，Ｊ＝１１．９Ｈｚ），３．１４（２Ｈ，ｄ，Ｊ＝７．４Ｈｚ），３．１９−３．３１（３Ｈ，ｍ），３．３５（２Ｈ，ｓ），３．３６−３．４７（２Ｈ，ｍ），３．５２（１Ｈ，ｔｔ，Ｊ＝１０．６，３．７Ｈｚ），３．９９（１Ｈ，ｂｒ ｄ，Ｊ＝１３．５Ｈｚ），４．６１（１Ｈ，ｂｒ ｄ，Ｊ＝１３．１Ｈｚ），７．１４（１Ｈ，ｄ，Ｊ＝９．０Ｈｚ），７．４９（２Ｈ，ｔ，Ｊ＝７．４Ｈｚ），７．５９（１Ｈ，ｔｔ，Ｊ＝７．４，１．２Ｈｚ），７．６８（１Ｈ，ｄｄ，Ｊ＝８．６，２．０Ｈｚ），７．９５（２Ｈ，ｄ，Ｊ＝７．４Ｈｚ），８．１２（１Ｈ，ｄ，Ｊ＝２．０Ｈｚ）．

ＬＣ／ＭＳ［条件１］：保持時間４．３１分；ｍ／ｚ６１４．１［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ６５８．２［Ｍ＋ＨＣＯＯ］⁻（ＥＳＩ負イオンモード）

Example 274
4- (3-{[(1r, 4r) -4- (4-benzoylpiperidine-1-carbonyl) cyclohexyl] methyl} -2-oxo-1-oxa-3,8-diazaspiro [4.5] decane- Preparation of 8-yl) -3-nitrobenzonitrile (Compound No. 274) 3-{[(1r, 4r) -4- (4-benzoylpiperidine-1-carbonyl) cyclohexyl] methyl} obtained in Reference Example 255 1,4-Oxa-3,8-diazaspiro [4.5] decan-2-one hydrochloride (20 mg, 0.040 mmol) and 4-chloro-3-nitrobenzonitrile (7 mg, 0.040 mmol) After adding N, N-diisopropylethylamine (21 μL, 0.12 mmol) to the dioxane (1 mL) suspension, the reaction mixture was stirred at 100 ° C. for 20 hours, Was solidified pressure concentrated to dryness. After adding ethyl acetate (2 mL) and water (2 mL) to the residue, the organic layer was separated and concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography [filler: FL100D manufactured by Fuji Silysia Ltd., developing solvent: chloroform / acetone = 3/1] to obtain the title compound (23 mg, yield 96%) as a yellow solid.

¹ H-NMR (CDCl ₃ ) δ: 1.07 (2H, q, J = 12.7 Hz), 1.51-1.72 (3H, m), 1.73-2.11 (12H, m) 2.48 (1H, br t, J = 11.1 Hz), 2.82 (1 H, br t, J = 11.9 Hz), 3.14 (2H, d, J = 7.4 Hz), 3. 19-3.31 (3H, m), 3.35 (2H, s), 3.36-3.47 (2H, m), 3.52 (1H, tt, J = 10.6, 3.7 Hz) ), 3.99 (1H, brd, J = 13.5 Hz), 4.61 (1H, brd, J = 13.1 Hz), 7.14 (1H, d, J = 9.0 Hz), 7 .49 (2H, t, J = 7.4 Hz), 7.59 (1H, tt, J = 7.4, 1.2 Hz), 7.68 (1H, dd, J = 8.6, 2.0 Hz) ), 7. 5 (2H, d, J = 7.4Hz), 8.12 (1H, d, J = 2.0Hz).

LC / MS [Condition 1]: Retention time 4.31 min; m / z 614.1 [M + H] ⁺ (ESI positive ion mode), m / z 658.2 [M + HCOO] ⁻ (ESI negative ion mode)

実施例２７５
３−（４−｛２−［４−（４−シアノフェノキシ）ピペリジン−１−イル］−２−オキソエチル｝ベンジル）−２−オキソ−１−オキサ−３，８−ジアザスピロ［４．５］デカン−８−カルボン酸ｔ−ブチル（化合物番号２７５）の製造
参考例２６０−１で得られた、２−（４−｛［８−（ｔ−ブトキシカルボニル）−２−オキソ−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル］メチル｝フェニル）酢酸（６０ｍｇ、０．１５ｍｍｏｌ）、１−ヒドロキシベンゾトリアゾール（６ｍｇ、０．０５ｍｍｏｌ）及び参考例２６４−２で得られた、４−（ピペリジン−４−イルオキシ）ベンゾニトリル塩酸塩（３５ｍｇ、０．１５ｍｍｏｌ）のクロロホルム懸濁液に、トリエチルアミン（６２μＬ、０．４５ｍｍｏｌ）及び１−エチル−３−（３−ジメチルアミノプロピル）カルボジイミド塩酸塩（４３ｍｇ、０．２２ｍｍｏｌ）を加えて、室温で１９日間攪拌した。その後、水（２ｍＬ）を加えたのち、有機層を分離し、減圧下濃縮乾固した。残留物をシリカゲルカラムクロマトグラフィー［充填剤：富士シリシア製ＦＬ１００Ｄ、展開溶媒：クロロホルム／アセトン＝５／１］にて精製し、表題化合物（５５ｍｇ、収率６３％）を無色無定形物として得た。

^１Ｈ−ＮＭＲ（ＣＤＣｌ_３）δ：１．４４（９Ｈ，ｓ），１．５９−１．９９（８Ｈ，ｍ），３．１３（２Ｈ，ｓ），３．２７（２Ｈ，ｔ，Ｊ＝１２．３Ｈｚ），３．４０−３．５２（１Ｈ，ｍ），３．６７（１Ｈ，ｄｄｄ，Ｊ＝１３．９，７．８，４．１Ｈｚ），３．７０−３．９１（４Ｈ，ｍ），３．７５（２Ｈ，ｓ），４．４１（２Ｈ，ｓ），４．５９（１Ｈ，ｔｔ，Ｊ＝６．１，３．３Ｈｚ），６．９３（２Ｈ，ｄ，Ｊ＝９．０Ｈｚ），７．２２（２Ｈ，ｄ，Ｊ＝８．６Ｈｚ），７．２５（２Ｈ，ｄ，Ｊ＝８．６Ｈｚ），７．５８（２Ｈ，ｄ，Ｊ＝９．０Ｈｚ）．

ＬＣ／ＭＳ［条件１］：保持時間４．２７分；ｍ／ｚ６１０．８［Ｍ＋Ｎａ］^＋、５３２．９［Ｍ−ｉｓｏｂｕｔｅｎｅ＋Ｈ］^＋、４８８．９［Ｍ−ｉｓｏｂｕｔｅｎｅ−ＣＯ２＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ６３３．１［Ｍ＋ＨＣＯＯ］⁻（ＥＳＩ負イオンモード）

Example 275
3- (4- {2- [4- (4-Cyanophenoxy) piperidin-1-yl] -2-oxoethyl} benzyl) -2-oxo-1-oxa-3,8-diazaspiro [4.5] decane 2- (4-{[8- (t-Butoxycarbonyl) -2-oxo-1-oxa-3] obtained in Production Reference Example 260-1 of t-butyl -8-carboxylate (Compound No. 275) , 8-diazaspiro [4.5] decan-3-yl] methyl} phenyl) acetic acid (60 mg, 0.15 mmol), 1-hydroxybenzotriazole (6 mg, 0.05 mmol) and Reference Example 264-2. , 4- (piperidin-4-yloxy) benzonitrile hydrochloride (35 mg, 0.15 mmol) in chloroform suspension was added triethylamine (62 μL, 0.45 mmol) and 1- Chill-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (43 mg, 0.22 mmol) was added and stirred for 19 days at room temperature. Then, after adding water (2 mL), the organic layer was separated and concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography [filler: FL100D manufactured by Fuji Silysia, developing solvent: chloroform / acetone = 5/1] to obtain the title compound (55 mg, yield 63%) as a colorless amorphous product. .

¹ H-NMR (CDCl ₃ ) δ: 1.44 (9H, s), 1.59-1.99 (8H, m), 3.13 (2H, s), 3.27 (2H, t, J = 12.3 Hz), 3.40-3.52 (1H, m), 3.67 (1H, ddd, J = 13.9, 7.8, 4.1 Hz), 3.70-3.91 ( 4H, m), 3.75 (2H, s), 4.41 (2H, s), 4.59 (1H, tt, J = 6.1, 3.3 Hz), 6.93 (2H, d, J = 9.0 Hz), 7.22 (2H, d, J = 8.6 Hz), 7.25 (2H, d, J = 8.6 Hz), 7.58 (2H, d, J = 9.0 Hz) ).

LC / MS [Condition 1]: Retention time 4.27 min; m / z 610.8 [M + Na] ⁺ , 532.9 [M-isobutene + H] ⁺ , 488.9 [M-isobutene-CO2 + H] ⁺ (ESI positive ion Mode), m / z 633.1 [M + HCOO] ⁻ (ESI negative ion mode)

実施例２７６
（１ｒ，４ｒ）−Ｎ−（ベンゾ［ｄ］［１，３］ジオキソル−５−イルメチル）−４−（｛２−オキソ−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）シクロヘキサンカルボキサミド（化合物番号２７６）の製造
４−（アミノメチル）ベンゾニトリル塩酸塩の代わりに、ベンゾ［ｄ］［１，３］ジオキソール−５−イルメタンアミン（市販）を用いること以外は実質的に実施例２６２と同様に反応を行なって、表題化合物（１７ｍｇ、収率６５％）を無色無定形物として得た。

^１Ｈ−ＮＭＲ（ＣＤＣｌ_３）δ：１．０１（２Ｈ，ｂｒ ｑ，Ｊ＝１２．９Ｈｚ），１．４１−１．６７（３Ｈ，ｍ），１．６９−１．８７（４Ｈ，ｍ），１．８７−２．１４（５Ｈ，ｍ），２．４３−２．６６（４Ｈ，ｍ），３．０９（２Ｈ，ｄ，Ｊ＝７．４Ｈｚ），３．２５（２Ｈ，ｓ），３．５７（２Ｈ，ｓ），４．３３（２Ｈ，ｄ，Ｊ＝５．７Ｈｚ），５．６５（１Ｈ，ｂｒ ｔ，Ｊ＝５．３Ｈｚ），５．９５（２Ｈ，ｓ），６．６７−６．８１（３Ｈ，ｍ），７．４４（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ），７．５７（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ）．

ＬＣ／ＭＳ［条件１］：保持時間３．１８分；ｍ／ｚ５８７．９［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ６３２．１［Ｍ＋ＨＣＯＯ］⁻（ＥＳＩ負イオンモード）

Example 276
(1r, 4r) -N- (Benzo [d] [1,3] dioxol-5-ylmethyl) -4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa- Preparation of 3,8-diazaspiro [4.5] decan-3-yl} methyl) cyclohexanecarboxamide (Compound No. 276) Instead of 4- (aminomethyl) benzonitrile hydrochloride, benzo [d] [1,3] The reaction was carried out substantially in the same manner as in Example 262 except that dioxol-5-ylmethanamine (commercially available) was used, and the title compound (17 mg, yield 65%) was obtained as a colorless amorphous product.

¹ H-NMR (CDCl ₃ ) δ: 1.01 (2H, br q, J = 12.9 Hz), 1.41-1.67 (3H, m), 1.69-1.87 (4H, m ), 1.87-2.14 (5H, m), 2.43-2.66 (4H, m), 3.09 (2H, d, J = 7.4 Hz), 3.25 (2H, s) ), 3.57 (2H, s), 4.33 (2H, d, J = 5.7 Hz), 5.65 (1H, br t, J = 5.3 Hz), 5.95 (2H, s) 6.67-6.81 (3H, m), 7.44 (2H, d, J = 8.2 Hz), 7.57 (2H, d, J = 8.2 Hz).

LC / MS [Condition 1]: Retention time 3.18 minutes; m / z 587.9 [M + H] ⁺ (ESI positive ion mode), m / z 632.1 [M + HCOO] ⁻ (ESI negative ion mode)

参考例２７７−１
４−ヒドロキシ−４−（｛［（１ｒ，４ｒ）−４−（メトキシカルボニル）シクロヘキシル］メチルアミノ｝メチル）ピペリジン−１−カルボン酸ｔ−ブチルの製造
参考例２−１で得られた、（１ｒ，４ｒ）−４−（アミノメチル）シクロヘキサンカルボン酸メチル塩酸塩（０．１０ｇ、０．４８ｍｍｏｌ）及び参考例１−１で得られた、１−オキサ−６−アザスピロ［２．５］オクタン−６−カルボン酸ｔ−ブチル（０．１０ｇ、０．４８ｍｍｏｌ）のメタノール（１．５ｍＬ）−水（１．０ｍＬ）溶液に１Ｍ水酸化ナトリウム水溶液（０．４８ｍＬ）を加えて、反応混合物を室温で５日間攪拌した。不溶物をろ過にて除去したのち、ろ液を減圧下濃縮して、メタノールを除去した。残留物にクロロホルムを加えて、有機層を分離し、水層をクロロホルムで抽出した。合わせた有機層を減圧下濃縮乾固して、表題化合物（０．１２ｇ、収率６３％）を無色油状物として得た。

^１Ｈ−ＮＭＲ（ＣＤＣｌ_３）δ：０．９５（２Ｈ，ｄｑ，Ｊ＝３．３，１２．３Ｈｚ），１．３２−１．５６（３Ｈ，ｍ），１．４６（９Ｈ，ｓ），１．８６（２Ｈ，ｂｒ ｄ，Ｊ＝１２．７Ｈｚ），１．９２−２．１５（６Ｈ，ｍ），２．２４（１Ｈ，ｔｔ，Ｊ＝１２．３，３．３Ｈｚ），２．４４−２．５６（４Ｈ，ｍ），３．１６（２Ｈ，ｂｒ ｔ，Ｊ＝１１．９Ｈｚ），３．６７（３Ｈ，ｓ），３．７５−３．９９（２Ｈ，ｂｒ ｍ）．

Reference Example 277-1
Preparation of 4-hydroxy-4-({[(1r, 4r) -4- (methoxycarbonyl) cyclohexyl] methylamino} methyl) piperidine-1-carboxylate obtained in Reference Example 2-1 ( 1r, 4r) -4- (aminomethyl) cyclohexanecarboxylic acid methyl hydrochloride (0.10 g, 0.48 mmol) and 1-oxa-6-azaspiro [2.5] octane obtained in Reference Example 1-1 To a solution of t-butyl-6-carboxylate (0.10 g, 0.48 mmol) in methanol (1.5 mL) -water (1.0 mL) was added 1M aqueous sodium hydroxide solution (0.48 mL), and the reaction mixture was Stir at room temperature for 5 days. Insoluble matter was removed by filtration, and the filtrate was concentrated under reduced pressure to remove methanol. Chloroform was added to the residue, the organic layer was separated, and the aqueous layer was extracted with chloroform. The combined organic layers were concentrated to dryness under reduced pressure to give the title compound (0.12 g, yield 63%) as a colorless oil.

¹ H-NMR (CDCl ₃ ) δ: 0.95 (2H, dq, J = 3.3, 12.3 Hz), 1.32-1.56 (3H, m), 1.46 (9H, s) , 1.86 (2H, br d, J = 12.7 Hz), 1.92-2.15 (6H, m), 2.24 (1H, tt, J = 12.3, 3.3 Hz), 2 .44-2.56 (4H, m), 3.16 (2H, br t, J = 11.9 Hz), 3.67 (3H, s), 3.75-3.99 (2H, br m) .

参考例２７７−２
３−｛［（１ｒ，４ｒ）−４−（メトキシカルボニル）シクロヘキシル］メチル｝−２−チオキソ−１−オキサ−３，８−ジアザスピロ［４．５］デカン−８−カルボン酸ｔ−ブチルの製造
参考例２７７−１で得られた、４−ヒドロキシ−４−（｛［（１ｒ，４ｒ）−４−（メトキシカルボニル）シクロヘキシル］メチルアミノ｝メチル）ピペリジン−１−カルボン酸ｔ−ブチル（０．１０ｇ、０．２６ｍｍｏｌ）の１，４−ジオキサン（２ｍＬ）溶液に、１，１’−チオカルボニルジイミダゾール（０．１２ｇ、０．６８ｍｍｏｌ）を加えて、反応混合物を９０℃で４３時間静置したのち、減圧下濃縮乾固した。残留物にヘキサン（２ｍＬ）、酢酸エチル（２ｍＬ）及び水（２ｍＬ）を加えて、有機層を分離し、減圧下濃縮乾固した。残留物をシリカゲルカラムクロマトグラフィー［充填剤：富士シリシア社製ＦＬ１００Ｄ、展開溶媒：クロロホルム／酢酸エチル＝６／１］にて精製し、表題化合物（６８ｍｇ、収率６１％）を白色固体として得た。

^１Ｈ−ＮＭＲ（ＣＤＣｌ_３）δ：１．１２（２Ｈ，ｄｑ，Ｊ＝３．３，１２．３Ｈｚ），１．４２（２Ｈ，ｄｑ，Ｊ＝３．７，１３．１Ｈｚ），１．４６（９Ｈ，ｓ），１．６３−１．８５（５Ｈ，ｍ），１．９５（２Ｈ，ｂｒ ｄ，Ｊ＝１３．１Ｈｚ），２．０４（２Ｈ，ｂｒ ｄ，Ｊ＝１３．５Ｈｚ），２．２７（１Ｈ，ｔｔ，Ｊ＝１１．９，３．７Ｈｚ），３．３７（２Ｈ，ｂｒ ｔ，Ｊ＝１１．９Ｈｚ），３．４６（２Ｈ，ｓ），３．５１（２Ｈ，ｄ，Ｊ＝７．０Ｈｚ），３．６７（３Ｈ，ｓ），３．８２（２Ｈ，ｂｒ ｄ，Ｊ＝１１．９Ｈｚ）．

ＬＣ／ＭＳ［条件２］：保持時間４．６１分；ｍ／ｚ４４９．２［Ｍ＋Ｎａ］^＋、４２７．２［Ｍ＋Ｈ］^＋、３７１．１［Ｍ−ｉｓｏｂｕｔｅｎｅ＋Ｈ］^＋（ＥＳＩ正イオンモード）

Reference Example 277-2
Preparation of tert-butyl 3-{[(1r, 4r) -4- (methoxycarbonyl) cyclohexyl] methyl} -2-thioxo-1-oxa-3,8-diazaspiro [4.5] decane-8-carboxylate 4-hydroxy-4-({[(1r, 4r) -4- (methoxycarbonyl) cyclohexyl] methylamino} methyl) piperidine-1-carboxylate t-butyl (0. 0) obtained in Reference Example 277-1. 1,1′-thiocarbonyldiimidazole (0.12 g, 0.68 mmol) was added to a solution of 10 g, 0.26 mmol) in 1,4-dioxane (2 mL), and the reaction mixture was allowed to stand at 90 ° C. for 43 hours. After that, it was concentrated to dryness under reduced pressure. Hexane (2 mL), ethyl acetate (2 mL) and water (2 mL) were added to the residue, and the organic layer was separated and concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography [filler: FL100D manufactured by Fuji Silysia Ltd., developing solvent: chloroform / ethyl acetate = 6/1] to obtain the title compound (68 mg, 61% yield) as a white solid. .

¹ H-NMR (CDCl ₃ ) δ: 1.12 (2H, dq, J = 3.3, 12.3 Hz), 1.42 (2H, dq, J = 3.7, 13.1 Hz), 1. 46 (9H, s), 1.63-1.85 (5H, m), 1.95 (2H, br d, J = 13.1 Hz), 2.04 (2H, br d, J = 13.5 Hz) ), 2.27 (1H, tt, J = 11.9, 3.7 Hz), 3.37 (2H, br t, J = 11.9 Hz), 3.46 (2H, s), 3.51 ( 2H, d, J = 7.0 Hz), 3.67 (3H, s), 3.82 (2H, br d, J = 11.9 Hz).

LC / MS [Condition 2]: Retention time 4.61 min; m / z 449.2 [M + Na] ⁺ , 427.2 [M + H] ⁺ , 371.1 [M-isobutene + H] ⁺ (ESI positive ion mode)

参考例２７７−３
（１ｒ，４ｒ）−４−｛［８−（ｔ−ブトキシカルボニル）−２−チオキソ−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル］メチル｝シクロヘキサンカルボン酸の製造
参考例２７７−２で得られた、３−｛［（１ｒ，４ｒ）−４−（メトキシカルボニル）シクロヘキシル］メチル｝−２−チオキソ−１−オキサ−３，８−ジアザスピロ［４．５］デカン−８−カルボン酸ｔ−ブチル（６８ｍｇ、０．１６ｍｍｏｌ）の１，４−ジオキサン（１．４ｍＬ）溶液に、水（０．５０ｍＬ）と１Ｍ水酸化ナトリウム水溶液（０．１８ｍＬ）を加えて、室温で１日間攪拌した。酢酸（１０μＬ）を加えてｐＨを７に調節したのち、反応混合物を減圧下濃縮乾固した。残留物に水（２ｍＬ）とクロロホルム（４ｍＬ）とクエン酸（６１ｍｇ）を加えて、有機層を分離し、減圧下濃縮乾固して、表題化合物（６５ｍｇ、収率９８％）を白色固体として得た。

ＬＣ／ＭＳ［条件１］：保持時間５．５６分；ｍ／ｚ４３５．０［Ｍ＋Ｎａ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ４１１．０［Ｍ−Ｈ］⁻（ＥＳＩ負イオンモード）

Reference Example 277-3
Preparation of (1r, 4r) -4-{[8- (t-butoxycarbonyl) -2-thioxo-1-oxa-3,8-diazaspiro [4.5] decan-3-yl] methyl} cyclohexanecarboxylic acid 3-{[(1r, 4r) -4- (methoxycarbonyl) cyclohexyl] methyl} -2-thioxo-1-oxa-3,8-diazaspiro [4.5] decane obtained in Reference Example 277-2 To a solution of t-butyl -8-carboxylate (68 mg, 0.16 mmol) in 1,4-dioxane (1.4 mL), water (0.50 mL) and 1M aqueous sodium hydroxide solution (0.18 mL) were added. Stir at room temperature for 1 day. Acetic acid (10 μL) was added to adjust the pH to 7, and then the reaction mixture was concentrated to dryness under reduced pressure. Water (2 mL), chloroform (4 mL) and citric acid (61 mg) were added to the residue, the organic layer was separated and concentrated to dryness under reduced pressure to give the title compound (65 mg, 98% yield) as a white solid. Obtained.

LC / MS [Condition 1]: Retention time 5.56 minutes; m / z 435.0 [M + Na] ⁺ (ESI positive ion mode), m / z 411.0 [M−H] ⁻ (ESI negative ion mode)

実施例２７７
３−（｛（１ｒ，４ｒ）−４−［４−（４−シアノフェノキシ）ピペリジン−１−カルボニル］シクロヘキシル｝メチル）−２−チオキソ−１−オキサ−３，８−ジアザスピロ［４．５］デカン−８−カルボン酸ｔ−ブチル（化合物番号２７７）の製造
参考例２７７−３で得られた、（１ｒ，４ｒ）−４−｛［８−（ｔ−ブトキシカルボニル）−２−チオキソ−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル］メチル｝シクロヘキサンカルボン酸（６５ｍｇ、０．１６ｍｍｏｌ）、１−ヒドロキシベンゾトリアゾール（６ｍｇ、０．０５ｍｍｏｌ）及び参考例２６４−２で得られた、４−（ピペリジン−４−イルオキシ）ベンゾニトリル塩酸塩（４１ｍｇ、０．１７ｍｍｏｌ）のクロロホルム懸濁液に、トリエチルアミン（６６μＬ、０．４７ｍｍｏｌ）及び１−エチル−３−（３−ジメチルアミノプロピル）カルボジイミド塩酸塩（４５ｍｇ、０．２４ｍｍｏｌ）を加えて、室温で２６日間静置した。その後、水（３ｍＬ）を加えたのち、有機層を分離し、減圧下濃縮乾固した。残留物をシリカゲルカラムクロマトグラフィー［充填剤：富士シリシア製ＦＬ１００Ｄ、展開溶媒：クロロホルム／アセトン＝５／１］にて精製し、表題化合物（９６ｍｇ、収率定量的）を無色無定形物として得た。

^１Ｈ−ＮＭＲ（ＣＤＣｌ_３）δ：１．１８（２Ｈ，ｑ，Ｊ＝１２．７Ｈｚ），１．４６（９Ｈ，ｓ），１．４９−２．１０（１５Ｈ，ｍ），２．５０（１Ｈ，ｂｒ ｔ，Ｊ＝１１．９Ｈｚ），３．２８−３．５４（３Ｈ，ｍ），３．４５（２Ｈ，ｓ），３．５５（２Ｈ，ｄ，Ｊ＝７．０Ｈｚ），３．５９−３．９５（５Ｈ，ｍ），４．５７−４．６９（１Ｈ，ｍ），６．９６（２Ｈ，ｄ，Ｊ＝８．６Ｈｚ），７．６０（２Ｈ，ｄ，Ｊ＝８．６Ｈｚ）．

ＬＣ／ＭＳ［条件１］：保持時間４．５１分；ｍ／ｚ５９７．０［Ｍ＋Ｈ］^＋、６１９．１［Ｍ＋Ｎａ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ６４１．１［Ｍ＋ＨＣＯＯ］⁻（ＥＳＩ負イオンモード）

Example 277
3-({(1r, 4r) -4- [4- (4-cyanophenoxy) piperidine-1-carbonyl] cyclohexyl} methyl) -2-thioxo-1-oxa-3,8-diazaspiro [4.5] Production of t-butyl decane-8-carboxylate (Compound No. 277) (1r, 4r) -4-{[8- (t-butoxycarbonyl) -2-thioxo-1 obtained in Reference Example 277-3 -Oxa-3,8-diazaspiro [4.5] decan-3-yl] methyl} cyclohexanecarboxylic acid (65 mg, 0.16 mmol), 1-hydroxybenzotriazole (6 mg, 0.05 mmol) and Reference Example 264-2 Into a chloroform suspension of 4- (piperidin-4-yloxy) benzonitrile hydrochloride (41 mg, 0.17 mmol) obtained in (3) above, triethylamine ( 6 [mu] L, 0.47 mmol) and 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (45 mg, 0.24 mmol) was added and allowed to stand 26 days at room temperature. Then, after adding water (3 mL), the organic layer was separated and concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography [filler: FL100D manufactured by Fuji Silysia, developing solvent: chloroform / acetone = 5/1] to obtain the title compound (96 mg, quantitative yield) as a colorless amorphous product. .

¹ H-NMR (CDCl ₃ ) δ: 1.18 (2H, q, J = 12.7 Hz), 1.46 (9H, s), 1.49-2.10 (15H, m), 2.50 (1H, br t, J = 11.9 Hz), 3.28-3.54 (3H, m), 3.45 (2H, s), 3.55 (2H, d, J = 7.0 Hz), 3.59-3.95 (5H, m), 4.57-4.69 (1H, m), 6.96 (2H, d, J = 8.6 Hz), 7.60 (2H, d, J = 8.6 Hz).

LC / MS [Condition 1]: Retention time 4.51 min; m / z 597.0 [M + H] ⁺ , 619.1 [M + Na] ⁺ (ESI positive ion mode), m / z 641.1 [M + HCOO] ⁻ (ESI Negative ion mode)

参考例２７８−１
４−（キノリン−４−イル）ピペラジン−１−カルボン酸ｔ−ブチルの製造
４−クロロキノリン（０．２０ｇ、１．２ｍｍｏｌ）、ピペラジン−１−カルボン酸ｔ−ブチル（０．３４ｇ、１．８ｍｍｏｌ）のＮ，Ｎ−ジメチルホルムアミド（２ｍＬ）溶液にＮ，Ｎ−ジイソプロピルエチルアミン（０．４３ｍＬ，２．４ｍｍｏｌ）を加えて、反応混合物を１００℃で２２時間静置したのち減圧下濃縮乾固した。残留物に酢酸エチル（２ｍＬ）と水（２ｍＬ）を加えて有機層を減圧下濃縮乾固した。残留物をシリカゲルカラムクロマトグラフィー［充填剤：富士シリシア製ＦＬ１００Ｄ、展開溶媒：クロロホルム／酢酸エチル＝２／３］にて精製し、表題化合物（０．２７ｇ、収率７１％）をこはく色油状物として得た。

^１Ｈ−ＮＭＲ（ＣＤＣｌ_３）δ：１．５１（９Ｈ，ｓ），３．１３−３．２５（４Ｈ，ｍ），３．６８−３．７８（４Ｈ，ｍ），６．８５（１Ｈ，ｄ，Ｊ＝４．９Ｈｚ），７．５１（１Ｈ，ｄｄｄ，Ｊ＝８．２，７．０，１．２Ｈｚ），７．６８（１Ｈ，ｄｄｄ，Ｊ＝８．２，７．０，１．６Ｈｚ），８．０２（１Ｈ，ｄｄ，Ｊ＝８．２，１．２Ｈｚ），８．０７（１Ｈ，ｄ，Ｊ＝８．２Ｈｚ），８．７５（１Ｈ，ｄ，Ｊ＝４．９Ｈｚ）．

Reference Example 278-1
Preparation of 4- (quinolin-4-yl) piperazine-1-carboxylate t-butyl 4-chloroquinoline (0.20 g, 1.2 mmol), t-butyl piperazine-1-carboxylate (0.34 g, 1. 8 mmol) in N, N-dimethylformamide (2 mL) was added N, N-diisopropylethylamine (0.43 mL, 2.4 mmol), and the reaction mixture was allowed to stand at 100 ° C. for 22 hours, and then concentrated to dryness under reduced pressure. did. Ethyl acetate (2 mL) and water (2 mL) were added to the residue, and the organic layer was concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography [filler: FL100D manufactured by Fuji Silysia, developing solvent: chloroform / ethyl acetate = 2/3] to give the title compound (0.27 g, yield 71%) as an amber oily substance. Got as.

¹ H-NMR (CDCl ₃ ) δ: 1.51 (9H, s), 3.13-3.25 (4H, m), 3.68-3.78 (4H, m), 6.85 (1H , D, J = 4.9 Hz), 7.51 (1H, ddd, J = 8.2, 7.0, 1.2 Hz), 7.68 (1H, ddd, J = 8.2, 7.0). , 1.6 Hz), 8.02 (1H, dd, J = 8.2, 1.2 Hz), 8.07 (1H, d, J = 8.2 Hz), 8.75 (1H, d, J = 4.9 Hz).

参考例２７８−２
４−（ピペラジン−１−イル）キノリン二塩酸塩の製造
参考例２７８−１で得られた、４−（キノリン−４−イル）ピペラジン−１−カルボン酸ｔ−ブチル（０．２７ｇ、０．８６ｍｍｏｌ）のメタノール（６ｍＬ）溶液に、１０質量％塩化水素メタノール溶液（２ｍＬ）を加えたのち、反応混合物を５５℃で３時間静置し、減圧下濃縮乾固して、表題化合物（０．２５ｇ、収率定量的）を白色固体として得た。

ＬＣ／ＭＳ［条件１］：保持時間０．４５分；ｍ／ｚ２１４．１［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）

Reference Example 278-2
Production of 4- (piperazin-1-yl) quinoline dihydrochloride t-butyl 4- (quinolin-4-yl) piperazine-1-carboxylate (0.27 g, 0. 1) obtained in Reference Example 278-1. 86 mmol) in methanol (6 mL) was added a 10% by mass hydrogen chloride methanol solution (2 mL), and the reaction mixture was allowed to stand at 55 ° C. for 3 hours, and concentrated to dryness under reduced pressure to give the title compound (0. 25 g, quantitative yield) was obtained as a white solid.

LC / MS [Condition 1]: retention time 0.45 minutes; m / z 214.1 [M + H] ⁺ (ESI positive ion mode)

実施例２７８
４−｛［２−オキソ−３−（｛（１ｒ，４ｒ）−４−［４−（キノリン−４−イル）ピペラジン−１−カルボニル）シクロヘキシル］メチル｝−１−オキサ−３，８−ジアザスピロ［４．５］デカン−８−イル）メチル］ベンゾニトリル（化合物番号２７８）の製造
４−（アミノメチル）ベンゾニトリル塩酸塩の代わりに、参考例２７８−２で得られた４−（ピペラジン−１−イル）キノリン二塩酸塩を用いること以外は実質的に実施例２６３と同様に反応を行なって、表題化合物（２５ｍｇ、収率８６％）を無色無定形物として得た。

^１Ｈ−ＮＭＲ（ＣＤＣｌ_３）δ：１．０８（２Ｈ，ｑ，Ｊ＝１２．３Ｈｚ），１．５３−１．６５（１Ｈ，ｍ），１．６１（２Ｈ，ｑ，Ｊ＝１３．１Ｈｚ），１．７１−１．９０（６Ｈ，ｍ），１．９５（２Ｈ，ｂｒ ｄ，Ｊ＝１３．５Ｈｚ），２．４３−２．６９（５Ｈ，ｍ），３．１２（２Ｈ，ｄ，Ｊ＝７．４Ｈｚ），３．１５−３．３２（６Ｈ，ｍ），３．２７（２Ｈ，ｓ），３．５７（２Ｈ，ｓ），３．７２−３．８５（２Ｈ，ｍ），３．８５−３．９９（２Ｈ，ｍ），６．８５（１Ｈ，ｄ，Ｊ＝４．９Ｈｚ），７．４５（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ），７．５３（１Ｈ，ｔ，Ｊ＝７．０Ｈｚ），７．６１（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ），７．６９（１Ｈ，ｄｔ，Ｊ＝１．２，７．６Ｈｚ），８．０３（１Ｈ，ｄ，Ｊ＝８．２Ｈｚ），８．０８（１Ｈ，ｄ，Ｊ＝８．２Ｈｚ），８．７７（１Ｈ，ｄ，Ｊ＝４．９Ｈｚ）．

ＬＣ／ＭＳ［条件１］：保持時間０．５１分；ｍ／ｚ６０６．９［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ６５１．１［Ｍ＋ＨＣＯＯ］⁻（ＥＳＩ負イオンモード）

Example 278
4-{[2-oxo-3-({(1r, 4r) -4- [4- (quinolin-4-yl) piperazin-1-carbonyl) cyclohexyl] methyl} -1-oxa-3,8-diazaspiro Preparation of [4.5] decan-8-yl) methyl] benzonitrile (Compound No. 278) Instead of 4- (aminomethyl) benzonitrile hydrochloride, 4- (piperazine-) obtained in Reference Example 278-2 The reaction was carried out in substantially the same manner as in Example 263 except that 1-yl) quinoline dihydrochloride was used to give the title compound (25 mg, yield 86%) as a colorless amorphous product.

¹ H-NMR (CDCl ₃ ) δ: 1.08 (2H, q, J = 12.3 Hz), 1.53-1.65 (1H, m), 1.61 (2H, q, J = 13. 1 Hz), 1.71-1.90 (6H, m), 1.95 (2H, br d, J = 13.5 Hz), 2.43-2.69 (5H, m), 3.12 (2H) , D, J = 7.4 Hz), 3.15-3.32 (6H, m), 3.27 (2H, s), 3.57 (2H, s), 3.72-3.85 (2H) M), 3.85-3.99 (2H, m), 6.85 (1H, d, J = 4.9 Hz), 7.45 (2H, d, J = 8.2 Hz), 7.53 (1H, t, J = 7.0 Hz), 7.61 (2H, d, J = 8.2 Hz), 7.69 (1H, dt, J = 1.2, 7.6 Hz), 8.03 ( 1H, d, J = 8.2Hz) 8.08 (1H, d, J = 8.2Hz), 8.77 (1H, d, J = 4.9Hz).

LC / MS [Condition 1]: retention time 0.51 minutes; m / z 606.9 [M + H] ⁺ (ESI positive ion mode), m / z 651.1 [M + HCOO] ⁻ (ESI negative ion mode)

実施例２７９
３−｛４−［４−（６−フルオロベンゾ［ｄ］イソキサゾル−３−イル）ピペリジン−１−カルボニル］ベンジル｝−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−２−オン（化合物番号２７９）の製造
４−ベンジルピペリジンの代わりに、６−フルオロ−３−（ピペリジン−４−イル）ベンゾ［ｄ］イソキサゾール（市販）を用いること以外は実質的に実施例２５３と同様に反応を行なって、表題化合物(３０ｍｇ、収率定量的)を無色無定形物として得た。

^１Ｈ−ＮＭＲ（ＣＤＣｌ_３）δ：１．７３（２Ｈ，ｄｔ，Ｊ＝１３．６，７．０Ｈｚ），１．９２（２Ｈ，ｂｒ ｄ，Ｊ＝１３．５Ｈｚ），１．９６−２．３５（４Ｈ，ｂｒ ｍ），２．３７−２．６９（４Ｈ，ｂｒ ｍ），３．０３−３．３２（２Ｈ，ｂｒ ｍ），３．１４（２Ｈ，ｓ），３．３８（１Ｈ，ｔｔ，Ｊ＝１１．１，４．１Ｈｚ），３．５６（２Ｈ，ｓ），３．７１−４．１３（１Ｈ，ｂｒ ｍ），４．４６（２Ｈ，ｓ），４．５５−４．９４（１Ｈ，ｂｒ ｍ），７．０９（１Ｈ，ｄｔ，Ｊ＝２．０，８．６Ｈｚ），７．２７（２Ｈ，ｄｄ，Ｊ＝２．０，８．６Ｈｚ），７．３３（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ），７．４３（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ），７．４４（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ），７．５６（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ），７．６４（１Ｈ，ｄｄ，Ｊ＝８．６，５．３Ｈｚ）．

ＬＣ／ＭＳ［条件１］：保持時間３．４６分；ｍ／ｚ６５０．９［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ６９５．０［Ｍ＋ＨＣＯＯ］⁻（ＥＳＩ負イオンモード）

Example 279
3- {4- [4- (6-Fluorobenzo [d] isoxazol-3-yl) piperidin-1-carbonyl] benzyl} -8- [4- (trifluoromethyl) benzyl] -1-oxa-3, Preparation of 8-diazaspiro [4.5] decan-2-one (Compound No. 279) Instead of 4-benzylpiperidine, 6-fluoro-3- (piperidin-4-yl) benzo [d] isoxazole (commercially available) The reaction was carried out in substantially the same manner as in Example 253 except for using, to give the title compound (30 mg, quantitative yield) as a colorless amorphous product.

¹ H-NMR (CDCl ₃ ) δ: 1.73 (2H, dt, J = 13.6, 7.0 Hz), 1.92 (2H, br d, J = 13.5 Hz), 1.96-2 .35 (4H, br m), 2.37-2.69 (4H, br m), 3.03-3.32 (2H, br m), 3.14 (2H, s), 3.38 ( 1H, tt, J = 11.1, 4.1 Hz), 3.56 (2H, s), 3.71-4.13 (1H, br m), 4.46 (2H, s), 4.55 -4.94 (1H, br m), 7.09 (1H, dt, J = 2.0, 8.6 Hz), 7.27 (2H, dd, J = 2.0, 8.6 Hz), 7 .33 (2H, d, J = 8.2 Hz), 7.43 (2H, d, J = 8.2 Hz), 7.44 (2H, d, J = 8.2 Hz), 7.56 (2H, d, J = 8.2 z), 7.64 (1H, dd, J = 8.6,5.3Hz).

LC / MS [Condition 1]: Retention time 3.46 minutes; m / z 650.9 [M + H] ⁺ (ESI positive ion mode), m / z 695.0 [M + HCOO] ⁻ (ESI negative ion mode)

実施例２８０
４−｛［３−（｛（１ｒ，４ｒ）−４−［４−（６−フルオロベンゾ［ｄ］イソキサゾル−３−イル）ピペリジン−１−カルボニル］シクロヘキシル｝メチル）−２−オキソ−１−オキサ−３，８−ジアザスピロ［４．５］デカン−８−イル］メチル｝ベンゾニトリル（化合物番号２８０）の製造
４−（アミノメチル）ベンゾニトリル塩酸塩の代わりに、６−フルオロ−３−（ピペリジン−４−イル）ベンゾ［ｄ］イソキサゾール（市販）を用いること以外は実質的に実施例２６３と同様に反応を行なって、表題化合物（４１ｍｇ、収率９１％）を無色無定形物として得た。

^１Ｈ−ＮＭＲ（ＣＤＣｌ_３）δ：１．０７（２Ｈ，ｑ，Ｊ＝１１．９Ｈｚ），１．４９−１．６９（３Ｈ，ｍ），１．７１−２．０４（１０Ｈ，ｍ），２．０８−２．２５（２Ｈ，ｂｒ ｍ），２．４７−２．６８（４Ｈ，ｂｒ ｍ），２．５０（１Ｈ，ｂｒ ｔ，Ｊ＝１１．５Ｈｚ），２．８８（１Ｈ，ｂｒ ｔ，Ｊ＝１１．５Ｈｚ），３．１１（２Ｈ，ｄ，Ｊ＝７．８Ｈｚ），３．１８−３．３１（１Ｈ，ｂｒ ｍ），３．２７（２Ｈ，ｓ），３．３３（１Ｈ，ｔｔ，Ｊ＝１１．５，３．７Ｈｚ），３．５７（２Ｈ，ｓ），４．０５（１Ｈ，ｄ，Ｊ＝１３．９Ｈｚ），４．６７（１Ｈ，ｂｒ ｄ，Ｊ＝１３．９Ｈｚ），７．０８（１Ｈ，ｄｔ，Ｊ＝２．０，８．６Ｈｚ），７．２７（１Ｈ，ｄｄ，Ｊ＝８．２，２．５Ｈｚ），７．４５（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ），７．６１（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ），７．６３（１Ｈ，ｄ，Ｊ＝８．６Ｈｚ）．

ＬＣ／ＭＳ［条件１］：保持時間３．２４分；ｍ／ｚ６１４．０［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ６５８．１［Ｍ＋ＨＣＯＯ］⁻（ＥＳＩ負イオンモード）

Example 280
4-{[3-({(1r, 4r) -4- [4- (6-Fluorobenzo [d] isoxazol-3-yl) piperidin-1-carbonyl] cyclohexyl} methyl) -2-oxo-1- Preparation of Oxa-3,8-diazaspiro [4.5] decan-8-yl] methyl} benzonitrile (Compound No. 280) Instead of 4- (aminomethyl) benzonitrile hydrochloride, 6-fluoro-3- ( The reaction is carried out in substantially the same manner as in Example 263 except that piperidin-4-yl) benzo [d] isoxazole (commercially available) is used to obtain the title compound (41 mg, yield 91%) as a colorless amorphous product. It was.

¹ H-NMR (CDCl ₃ ) δ: 1.07 (2H, q, J = 11.9 Hz), 1.49-1.69 (3H, m), 1.71-2.04 (10H, m) , 2.08-2.25 (2H, br m), 2.47-2.68 (4H, br m), 2.50 (1H, br t, J = 11.5 Hz), 2.88 (1H , Br t, J = 11.5 Hz), 3.11 (2H, d, J = 7.8 Hz), 3.18-3.31 (1H, br m), 3.27 (2H, s), 3 .33 (1H, tt, J = 11.5, 3.7 Hz), 3.57 (2H, s), 4.05 (1H, d, J = 13.9 Hz), 4.67 (1H, br d , J = 13.9 Hz), 7.08 (1H, dt, J = 2.0, 8.6 Hz), 7.27 (1H, dd, J = 8.2, 2.5 Hz), 7.45 ( 2H, , J = 8.2Hz), 7.61 (2H, d, J = 8.2Hz), 7.63 (1H, d, J = 8.6Hz).

LC / MS [Condition 1]: retention time 3.24 minutes; m / z 614.0 [M + H] ⁺ (ESI positive ion mode), m / z 658.1 [M + HCOO] ⁻ (ESI negative ion mode)

参考例２８１−１
４−（３−シアノフェノキシ）ピペリジン−１−カルボン酸ｔ−ブチルの製造
ＷＯ２００７／１０６７０５記載の方法を用いて合成した。

^１Ｈ−ＮＭＲ（ＣＤＣｌ_３）δ：１．４７（９Ｈ，ｓ），１．６７−１．８１（２Ｈ，ｍ），１．８７−１．９９（２Ｈ，ｍ），３．３５（２Ｈ，ｄｄｄ，Ｊ＝１３．５，７．８，３．７Ｈｚ），３．７０（２Ｈ，ｄｄｄ，Ｊ＝１３．５，７．０，３．７Ｈｚ），４．４９（１Ｈ，ｔｔ，Ｊ＝７．４，３．３Ｈｚ），７．１０−７．１８（２Ｈ，ｍ），７．２４（１Ｈ，ｄｔ，Ｊ＝７．４，０．８Ｈｚ），７．３８（１Ｈ，ｔｄ，Ｊ＝７．８，０．８Ｈｚ）．

ＬＣ／ＭＳ［条件１］：保持時間４．５９分；ｍ／ｚ２４７．０［Ｍ−ｉｓｏｂｕｔｅｎｅ＋Ｈ］^＋、２０３．０［Ｍ−ｉｓｏｂｕｔｅｎｅ−ＣＯ２＋Ｈ］^＋（ＥＳＩ正イオンモード）

Reference Example 281-1
Production of t-butyl 4- (3-cyanophenoxy) piperidine-1-carboxylate Synthesized using the method described in WO2007 / 106705.

¹ H-NMR (CDCl ₃ ) δ: 1.47 (9H, s), 1.67-1.81 (2H, m), 1.87-1.99 (2H, m), 3.35 (2H , Ddd, J = 13.5, 7.8, 3.7 Hz), 3.70 (2H, ddd, J = 13.5, 7.0, 3.7 Hz), 4.49 (1H, tt, J = 7.4, 3.3 Hz), 7.10-7.18 (2H, m), 7.24 (1H, dt, J = 7.4, 0.8 Hz), 7.38 (1H, td, J = 7.8, 0.8 Hz).

LC / MS [Condition 1]: Retention time 4.59 minutes; m / z 247.0 [M-isobutene + H] ⁺ , 203.0 [M-isobutene-CO2 + H] ⁺ (ESI positive ion mode)

参考例２８１−２
３−（ピペリジン−４−イルオキシ）ベンゾニトリル塩酸塩の製造
ＷＯ２００７／１０６７０５記載の方法を用いて合成した。

^１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ_６）δ：１．７４−１．９１（２Ｈ，ｍ），２．０３−２．１９（２Ｈ，ｍ），２．９７−３．１４（２Ｈ，ｍ），３．１６−３．３２（２Ｈ，ｍ），４．７４（１Ｈ，ｔｔ，Ｊ＝７．８，３．７Ｈｚ），７．３５（１Ｈ，ｄ，Ｊ＝７．８Ｈｚ），７．４３（１Ｈ，ｄ，Ｊ＝７．８Ｈｚ），７．５１（１Ｈ，ｔ，Ｊ＝７．８Ｈｚ），７．５４−７．５６（１Ｈ，ｍ），８．８８（２Ｈ，ｂｒ ｓ）．

ＬＣ／ＭＳ［条件１］：保持時間０．５５分；ｍ／ｚ２０３．１［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）

Reference Example 281-2
Preparation of 3- (piperidin-4-yloxy) benzonitrile hydrochloride The compound was synthesized using the method described in WO2007 / 106705.

¹ H-NMR (DMSO-d ₆ ) δ: 1.74-1.91 (2H, m), 2.03-2.19 (2H, m), 2.97-3.14 (2H, m) 3.16-3.32 (2H, m), 4.74 (1H, tt, J = 7.8, 3.7 Hz), 7.35 (1H, d, J = 7.8 Hz), 7. 43 (1H, d, J = 7.8 Hz), 7.51 (1H, t, J = 7.8 Hz), 7.54-7.56 (1H, m), 8.88 (2H, br s) .

LC / MS [Condition 1]: Retention time 0.55 min; m / z 203.1 [M + H] ⁺ (ESI positive ion mode)

実施例２８１
３−｛１−［４−（｛２−オキソ−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）ベンゾイル］ピペリジン−４−イルオキシ｝ベンゾニトリル（化合物番号２８１）の製造
４−ベンジルピペリジンの代わりに、参考例２８１−２で得られた３−（ピペリジン−４−イルオキシ）ベンゾニトリル塩酸塩を用いること以外は実質的に実施例２５３と同様に反応を行なって、表題化合物(３０ｍｇ、収率定量的)を無色無定形物として得た。

^１Ｈ−ＮＭＲ（ＣＤＣｌ_３）δ：１．６５−２．１７（８Ｈ，ｍ），２．３９−２．６４（４Ｈ，ｍ），３．１４（２Ｈ，ｓ），３．２９−３．５２（１Ｈ，ｍ），３．５６（２Ｈ，ｓ），３．５８−４．０６（３Ｈ，ｍ），４．４５（２Ｈ，ｓ），４．５６−４．６６（１Ｈ，ｍ），７．１１−７．１８（２Ｈ，ｍ），７．２２−７．２９（１Ｈ，ｍ，ｏｖｅｒｌａｐｐｅｄｂｙＣＨＣｌ３），７．３２（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ），７．３９（１Ｈ，ｔ，Ｊ＝８．２Ｈｚ），７．４１（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ），７．４２（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ），７．５７（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ）．

ＬＣ／ＭＳ［条件１］：保持時間３．４２分；ｍ／ｚ６３３．０［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ６７７．０［Ｍ＋ＨＣＯＯ］⁻（ＥＳＩ負イオンモード）

Example 281
3- {1- [4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl) benzoyl Preparation of piperidin-4-yloxy} benzonitrile (Compound No. 281) Other than using 3- (piperidin-4-yloxy) benzonitrile hydrochloride obtained in Reference Example 281-2 instead of 4-benzylpiperidine Was carried out in substantially the same manner as in Example 253 to obtain the title compound (30 mg, quantitative yield) as a colorless amorphous product.

¹ H-NMR (CDCl ₃ ) δ: 1.65-2.17 (8H, m), 2.39-2.64 (4H, m), 3.14 (2H, s), 3.29-3 .52 (1H, m), 3.56 (2H, s), 3.58-4.06 (3H, m), 4.45 (2H, s), 4.56-4.66 (1H, m) ), 7.11-7.18 (2H, m), 7.22-7.29 (1H, m, overlappedbyCHCl3), 7.32 (2H, d, J = 8.2 Hz), 7.39 (1H , T, J = 8.2 Hz), 7.41 (2H, d, J = 8.2 Hz), 7.42 (2H, d, J = 8.2 Hz), 7.57 (2H, d, J = 8.2 Hz).

LC / MS [Condition 1]: retention time 3.42 minutes; m / z 633.0 [M + H] ⁺ (ESI positive ion mode), m / z 677.0 [M + HCOO] ⁻ (ESI negative ion mode)

実施例２８２
３−｛１−［（１ｒ，４ｒ）−４−（｛２−オキソ−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）シクロヘキサンカルボニル］ピペリジン−４−イルオキシ｝ベンゾニトリル（化合物番号２８２）の製造
４−（アミノメチル）ベンゾニトリル塩酸塩の代わりに、参考例２８１−２で得られた３−（ピペリジン−４−イルオキシ）ベンゾニトリル塩酸塩を用いること以外は実質的に実施例２６２と同様に反応を行なって、表題化合物（３２ｍｇ、収率定量的）を無色無定形物として得た。

^１Ｈ−ＮＭＲ（ＣＤＣｌ_３）δ：１．０６（２Ｈ，ｂｒ ｑ，Ｊ＝１２．７Ｈｚ），１．４７−１．６９（２Ｈ，ｍ，ｏｖｅｒｌａｐｐｅｄｂｙＨ２Ｏ），１．６９−１．８７（８Ｈ，ｍ），１．８７−２．０６（４Ｈ，ｍ），２．４７（１Ｈ，ｔｔ，Ｊ＝１１．９，２．９Ｈｚ），２．４９−２．６５（４Ｈ，ｍ），３．１１（２Ｈ，ｄ，Ｊ＝７．４Ｈｚ），３．２６（２Ｈ，ｓ），３．３８−３．５１（１Ｈ，ｍ），３．５２−３．８９（３Ｈ，ｍ），３．５７（２Ｈ，ｓ），４．５０−４．６２（１Ｈ，ｍ），７．１０−７．１８（２Ｈ，ｍ），７．２３−７．２９（１Ｈ，ｍ，ｏｖｅｒｌａｐｐｅｄｂｙＣＨＣｌ３），７．３９（１Ｈ，ｔ，Ｊ＝８．２Ｈｚ），７．４４（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ），７．５７（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ）．

ＬＣ／ＭＳ［条件１］：保持時間３．４２分；ｍ／ｚ６３９．０［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ６８３．１［Ｍ＋ＨＣＯＯ］⁻（ＥＳＩ負イオンモード）

Example 282
3- {1-[(1r, 4r) -4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decane-3 Preparation of -yl} methyl) cyclohexanecarbonyl] piperidin-4-yloxy} benzonitrile (Compound No. 282) Instead of 4- (aminomethyl) benzonitrile hydrochloride, 3- (piperidine obtained in Reference Example 281-2 The reaction was carried out in substantially the same manner as in Example 262, except that -4-yloxy) benzonitrile hydrochloride was used, and the title compound (32 mg, quantitative yield) was obtained as a colorless amorphous product.

¹ H-NMR (CDCl ₃ ) δ: 1.06 (2H, br q, J = 12.7 Hz), 1.47-1.69 (2H, m, overlappedby H 2 O), 1.69-1.87 (8H) M), 1.87-2.06 (4H, m), 2.47 (1H, tt, J = 11.9, 2.9 Hz), 2.49-2.65 (4H, m), 3 .11 (2H, d, J = 7.4 Hz), 3.26 (2H, s), 3.38-3.51 (1H, m), 3.52-3.89 (3H, m), 3 .57 (2H, s), 4.50-4.62 (1H, m), 7.10-7.18 (2H, m), 7.23-7.29 (1H, m, overlappedbyCHCl3), 7 .39 (1H, t, J = 8.2 Hz), 7.44 (2H, d, J = 8.2 Hz), 7.57 (2H, d, J = 8) 2Hz).

LC / MS [Condition 1]: retention time 3.42 minutes; m / z 639.0 [M + H] ⁺ (ESI positive ion mode), m / z 683.1 [M + HCOO] ⁻ (ESI negative ion mode)

実施例２８３
６−（３−｛［（１ｒ，４ｒ）−４−（４−ベンゾイルピペリジン−１−カルボニル）シクロヘキシル］メチル｝−２−オキソ−１−オキサ−３，８−ジアザスピロ［４．５］デカン−８−イル）ニコチノニトリル（化合物番号２８３）の製造
参考例２５５で得られた３−｛［（１ｒ，４ｒ）−４−（４−ベンゾイルピペリジン−１−カルボニル）シクロヘキシル］メチル｝−１−オキサ−３，８−ジアザスピロ［４．５］デカン−２−オン塩酸塩（２０ｍｇ、０．０４０ｍｍｏｌ）と６−クロロニコチノニトリル（市販）（７ｍｇ、０．０５ｍｍｏｌ）のエタノール（１ｍＬ）懸濁液にトリエチルアミン（２２μＬ、０．１６ｍｍｏｌ）を加えたのち、反応混合物を７０℃で３３時間攪拌し、減圧下濃縮乾固した。残留物をシリカゲルカラムクロマトグラフィー［充填剤：富士シリシア製ＦＬ１００Ｄ、展開溶媒：クロロホルム／アセトン＝３／１］にて精製し、表題化合物（１６ｍｇ、収率７０％）を白色固体として得た。

^１Ｈ−ＮＭＲ（ＣＤＣｌ_３）δ：１．０７（２Ｈ，ｑ，Ｊ＝１２．３Ｈｚ），１．４９−１．６８（３Ｈ，ｍ），１．６８−１．８８（８Ｈ，ｍ），１．９４（２Ｈ，ｂｒ ｄ，Ｊ＝１４．３Ｈｚ），２．０２（２Ｈ，ｂｒ ｄ，Ｊ＝１３．９Ｈｚ），２．４８（１Ｈ，ｂｒ ｔ，Ｊ＝１１．９Ｈｚ），２．８２（１Ｈ，ｂｒ ｔ，Ｊ＝１１．９Ｈｚ），３．１３（２Ｈ，ｄ，Ｊ＝７．０Ｈｚ），３．２１（１Ｈ，ｂｒ ｔ，Ｊ＝１２．４Ｈｚ），３．２９（２Ｈ，ｓ），３．４２−３．６１（３Ｈ，ｍ），３．９９（１Ｈ，ｂｒ ｄ，Ｊ＝１３．９Ｈｚ），４．２５（２Ｈ，ｂｒ ｄ，Ｊ＝１３．５Ｈｚ），４．６１（１Ｈ，ｂｒ ｄ，Ｊ＝１３．９Ｈｚ），６．６５（１Ｈ，ｄ，Ｊ＝９．０Ｈｚ），７．４９（２Ｈ，ｔ，Ｊ＝７．４Ｈｚ），７．６０（１Ｈ，ｔ，Ｊ＝７．４Ｈｚ），７．６２（１Ｈ，ｄｄ，Ｊ＝９．０，２．５Ｈｚ），７．９５（２Ｈ，ｄ，Ｊ＝７．８Ｈｚ），８．４１（１Ｈ，ｄ，Ｊ＝２．０Ｈｚ）．

ＬＣ／ＭＳ［条件１］：保持時間４．１１分；ｍ／ｚ５６９．９［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ６１４．０［Ｍ＋ＨＣＯＯ］⁻（ＥＳＩ負イオンモード）

Example 283
6- (3-{[(1r, 4r) -4- (4-Benzoylpiperidine-1-carbonyl) cyclohexyl] methyl} -2-oxo-1-oxa-3,8-diazaspiro [4.5] decane- Preparation of 8-yl) nicotinonitrile (Compound No. 283) 3-{[(1r, 4r) -4- (4-benzoylpiperidine-1-carbonyl) cyclohexyl] methyl} -1- obtained in Reference Example 255 Suspension of oxa-3,8-diazaspiro [4.5] decan-2-one hydrochloride (20 mg, 0.040 mmol) and 6-chloronicotinonitrile (commercially available) (7 mg, 0.05 mmol) in ethanol (1 mL) Triethylamine (22 μL, 0.16 mmol) was added to the solution, and then the reaction mixture was stirred at 70 ° C. for 33 hours and concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography [filler: FL100D manufactured by Fuji Silysia, developing solvent: chloroform / acetone = 3/1] to obtain the title compound (16 mg, yield 70%) as a white solid.

¹ H-NMR (CDCl ₃ ) δ: 1.07 (2H, q, J = 12.3 Hz), 1.49-1.68 (3H, m), 1.68-1.88 (8H, m) 1.94 (2H, br d, J = 14.3 Hz), 2.02 (2 H, br d, J = 13.9 Hz), 2.48 (1 H, br t, J = 11.9 Hz), 2 .82 (1H, br t, J = 11.9 Hz), 3.13 (2H, d, J = 17.0 Hz), 3.21 (1 H, br t, J = 12.4 Hz), 3.29 ( 2H, s), 3.42-3.61 (3H, m), 3.99 (1H, br d, J = 13.9 Hz), 4.25 (2H, br d, J = 13.5 Hz), 4.61 (1H, br d, J = 13.9 Hz), 6.65 (1H, d, J = 9.0 Hz), 7.49 (2H, t, J = 7.4 Hz), 7.6 0 (1H, t, J = 7.4 Hz), 7.62 (1H, dd, J = 9.0, 2.5 Hz), 7.95 (2H, d, J = 7.8 Hz), 8.41 (1H, d, J = 2.0 Hz).

LC / MS [Condition 1]: Retention time 4.11 min; m / z 569.9 [M + H] ⁺ (ESI positive ion mode), m / z 614.0 [M + HCOO] ⁻ (ESI negative ion mode)

参考例２８４
（１ｒ，４ｒ）−Ｎ−（４−シアノベンジル）−４−［２−オキソ−１−オキサ−３，８−ジアザスピロ［４．５］デカンー３−イル）メチル］シクロヘキサンカルボキサミド塩酸塩の製造
実施例２６９で得られた、３−｛［（１ｒ，４ｒ）−４−（４−シアノベンジルカルバモイル）シクロヘキシル］メチル｝−２−オキソ−１−オキサ−３，８−ジアザスピロ［４．５］デカン−８−カルボン酸ｔ−ブチル（５１ｍｇ、０．１０ｍｍｏｌ）のジオキサン（１ｍＬ）−アセトニトリル（１ｍＬ）溶液に、１０質量％塩化水素メタノール溶液（０．２０ｍＬ）を加えて、室温で１日間静置したのち、減圧下濃縮乾固して、表題化合物（５５ｍｇ、収率定量的）を白色固体として得た。

^１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ_６）δ：０．９１（２Ｈ，ｑ，Ｊ＝１２．３Ｈｚ），１．３７（２Ｈ，ｑ，Ｊ＝１３．１Ｈｚ），１．４６−１．６１（１Ｈ，ｍ），１．６９（２Ｈ，ｂｒ ｄ，Ｊ＝１２．３Ｈｚ），１．７９（２Ｈ，ｂｒ ｄ，Ｊ＝１３．５Ｈ），１．８９−２．０７（４Ｈ，ｍ），２．１６（１Ｈ，ｔｔ，Ｊ＝１１．９，２．９Ｈｚ），２．９９（２Ｈ，ｄ，Ｊ＝７．４Ｈｚ），３．０２−３．２４（４Ｈ，ｂｒ ｍ），３．４０（２Ｈ，ｓ），４．３２（２Ｈ，ｄ，Ｊ＝５．７Ｈｚ），７．４０（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ），７．７９（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ），８．４２（１Ｈ，ｔ，Ｊ＝５．７Ｈｚ），８．９２（２Ｈ，ｂｒ ｓ）．

ＬＣ／ＭＳ［条件１］：保持時間０．５〜１．１分；ｍ／ｚ４１０．９［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ４５４．９［Ｍ＋ＨＣＯＯ］⁻（ＥＳＩ負イオンモード）

Reference Example 284
Production of (1r, 4r) -N- (4-cyanobenzyl) -4- [2-oxo-1-oxa-3,8-diazaspiro [4.5] decan-3-yl) methyl] cyclohexanecarboxamide hydrochloride 3-{[(1r, 4r) -4- (4-cyanobenzylcarbamoyl) cyclohexyl] methyl} -2-oxo-1-oxa-3,8-diazaspiro [4.5] decane obtained in Example 269 To a solution of tert-butyl-8-carboxylate (51 mg, 0.10 mmol) in dioxane (1 mL) -acetonitrile (1 mL) was added a 10% by mass hydrogen chloride methanol solution (0.20 mL) and left at room temperature for 1 day. Then, it was concentrated to dryness under reduced pressure to give the title compound (55 mg, quantitative yield) as a white solid.

¹ H-NMR (DMSO-d ₆ ) δ: 0.91 (2H, q, J = 12.3 Hz), 1.37 (2H, q, J = 13.1 Hz), 1.46-1.61 ( 1H, m), 1.69 (2H, brd, J = 12.3 Hz), 1.79 (2H, brd, J = 13.5H), 1.89-2.07 (4H, m), 2.16 (1H, tt, J = 11.9, 2.9 Hz), 2.99 (2H, d, J = 7.4 Hz), 3.02-3.24 (4H, br m), 3. 40 (2H, s), 4.32 (2H, d, J = 5.7 Hz), 7.40 (2H, d, J = 8.2 Hz), 7.79 (2H, d, J = 8.2 Hz) ), 8.42 (1H, t, J = 5.7 Hz), 8.92 (2H, br s).

LC / MS [Condition 1]: retention time 0.5 to 1.1 minutes; m / z 410.9 [M + H] ⁺ (ESI positive ion mode), m / z 454.9 [M + HCOO] ⁻ (ESI negative ion mode)

実施例２８４
（１ｒ，４ｒ）−４−｛［８−（４−シアノ−２，６−ジフルオロベンジル）−２−オキソ−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル］メチル｝−Ｎ−（４−シアノベンジル）シクロヘキサンカルボキサミド（化合物番号２８４）の製造
３−｛［（１ｒ，４ｒ）−４−（４−ベンゾイルピペリジン−１−カルボニル）シクロヘキシル］メチル｝−１−オキサ−３，８−ジアザスピロ［４．５］デカン−２−オン塩酸塩の代わりに、参考例２８４で得られた（１ｒ，４ｒ）−Ｎ−（４−シアノベンジル）−４−［（２−オキソ−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル）メチル］シクロヘキサンカルボキサミド塩酸塩を用いること以外は実質的に実施例２６７と同様に反応を行なって、表題化合物（３ｍｇ、収率１３％）を白色固体として得た。

^１Ｈ−ＮＭＲ（ＣＤＣｌ_３）δ：１．０２（２Ｈ，ｄｑ，Ｊ＝２．９，１２．３Ｈｚ），１．５２（２Ｈ，ｄｑ，Ｊ＝２．９，１３．５Ｈｚ），１．５７−１．６６（１Ｈ，ｍ），１．６９−１．８４（４Ｈ，ｍ），１．８５−２．０１（４Ｈ，ｍ），２．０９（１Ｈ，ｔｔ，Ｊ＝１２．３，２．９Ｈｚ），２．５０−２．７４（４Ｈ，ｍ），３．０８（２Ｈ，ｄ，Ｊ＝７．８Ｈｚ），３．２２（２Ｈ，ｓ），３．７５（２Ｈ，ｓ），４．４９（２Ｈ，ｄ，Ｊ＝６．１Ｈｚ），５．８７（１Ｈ，ｂｒ ｔ，Ｊ＝６．１Ｈｚ），７．２２（２Ｈ，ｄ，Ｊ＝６．１Ｈｚ），７．３６（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ），７．６２（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ）．

ＬＣ／ＭＳ［条件１］：保持時間２．８６分；ｍ／ｚ５６１．９［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚｍ／ｚ５６０．０［Ｍ−Ｈ］⁻、６０６．１［Ｍ＋ＨＣＯＯ］⁻（ＥＳＩ負イオンモード）

Example 284
(1r, 4r) -4-{[8- (4-Cyano-2,6-difluorobenzyl) -2-oxo-1-oxa-3,8-diazaspiro [4.5] decan-3-yl] methyl } -N- (4-Cyanobenzyl) cyclohexanecarboxamide (Compound No. 284) 3-{[(1r, 4r) -4- (4-Benzoylpiperidine-1-carbonyl) cyclohexyl] methyl} -1-oxa- (1r, 4r) -N- (4-cyanobenzyl) -4-[(2-oxo) obtained in Reference Example 284 instead of 3,8-diazaspiro [4.5] decan-2-one hydrochloride -1-oxa-3,8-diazaspiro [4.5] decan-3-yl) methyl] cyclohexanecarboxamide hydrochloride was used in substantially the same manner as in Example 267 to obtain the title compound. The (3 mg, 13% yield) as a white solid.

¹ H-NMR (CDCl ₃ ) δ: 1.02 (2H, dq, J = 2.9, 12.3 Hz), 1.52 (2H, dq, J = 2.9, 13.5 Hz), 1. 57-1.66 (1H, m), 1.69-1.84 (4H, m), 1.85-2.01 (4H, m), 2.09 (1H, tt, J = 12.3) , 2.9 Hz), 2.50-2.74 (4 H, m), 3.08 (2 H, d, J = 7.8 Hz), 3.22 (2 H, s), 3.75 (2 H, s) ), 4.49 (2H, d, J = 6.1 Hz), 5.87 (1H, brt, J = 6.1 Hz), 7.22 (2H, d, J = 6.1 Hz), 7. 36 (2H, d, J = 8.2 Hz), 7.62 (2H, d, J = 8.2 Hz).

LC / MS [Condition 1]: Retention time 2.86 minutes; m / z 561.9 [M + H] ⁺ (ESI positive ion mode), m / zm / z 560.0 [M−H] ⁻ , 606.1 [M + HCOO] ] ^- (ESI negative ion mode)

参考例２８５
４−（１−｛（１ｒ，４ｒ）−４−［（２−オキソ−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル）メチル］シクロヘキサンカルボニル｝ピペリジン−４−イルオキシ）ベンゾニトリル塩酸塩の製造
実施例２６８で得られた、３−（｛（１ｒ，４ｒ）−４−［４−（４−シアノフェノキシ）ピペリジン−１−カルボニル］シクロヘキシル｝メチル）−２−オキソ−１−オキサ−３，８−ジアザスピロ［４．５］デカン−８−カルボン酸ｔ−ブチル（５４ｍｇ、０．093ｍｍｏｌ）のアセトニトリル（２ｍＬ）溶液に、１０質量％塩化水素メタノール溶液（０．２０ｍＬ）を加えて、室温で１日間静置したのち、減圧下濃縮乾固した。残留物を酢酸エチル（２ｍＬ）で洗浄して、表題化合物（５６ｍｇ、収率定量的）を白色固体として得た。

^１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ_６）δ：０．９９（２Ｈ，ｑ，Ｊ＝１１．９Ｈｚ），１．３６（２Ｈ，ｑ，Ｊ＝１１．５Ｈｚ），１．４４−１．７５（７Ｈ，ｍ），１．８５−２．０７（６Ｈ，ｍ），２．５８（１Ｈ，ｂｒ ｔ，Ｊ＝１２．３Ｈｚ），２．９８−３．２８（６Ｈ，ｍ），２．９８（２Ｈ，ｄ，Ｊ＝７．０Ｈｚ），３．４０（２Ｈ，ｓ），３．７１−３．９６（２Ｈ，ｍ），４．７２−４．８４（１Ｈ，ｍ），７．１６（２Ｈ，ｄ，Ｊ＝８．６Ｈｚ），７．７７（２Ｈ，ｄ，Ｊ＝８．６Ｈｚ），８．９８（２Ｈ，ｂｒ ｓ）．

ＬＣ／ＭＳ［条件１］：保持時間２．８８分；ｍ／ｚ４８０．９［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ５２５．０［Ｍ＋ＨＣＯＯ］⁻（ＥＳＩ負イオンモード）

Reference Example 285
4- (1-{(1r, 4r) -4-[(2-oxo-1-oxa-3,8-diazaspiro [4.5] decan-3-yl) methyl] cyclohexanecarbonyl} piperidin-4-yloxy ) Preparation of benzonitrile hydrochloride 3-({(1r, 4r) -4- [4- (4-cyanophenoxy) piperidine-1-carbonyl] cyclohexyl} methyl) -2-oxo obtained in Example 268 To a solution of tert-butyl-1-oxa-3,8-diazaspiro [4.5] decane-8-carboxylate (54 mg, 0.093 mmol) in acetonitrile (2 mL), a 10 mass% hydrogen chloride methanol solution (0.20 mL). ) And left at room temperature for 1 day, and then concentrated to dryness under reduced pressure. The residue was washed with ethyl acetate (2 mL) to give the title compound (56 mg, quantitative yield) as a white solid.

¹ H-NMR (DMSO-d ₆ ) δ: 0.99 (2H, q, J = 11.9 Hz), 1.36 (2H, q, J = 11.5 Hz), 1.4-1.75 ( 7H, m), 1.85-2.07 (6H, m), 2.58 (1H, br t, J = 12.3 Hz), 2.98-3.28 (6H, m), 2.98 (2H, d, J = 7.0 Hz), 3.40 (2H, s), 3.71-3.96 (2H, m), 4.72-4.84 (1H, m), 7.16 (2H, d, J = 8.6 Hz), 7.77 (2H, d, J = 8.6 Hz), 8.98 (2H, br s).

LC / MS [Condition 1]: Retention time 2.88 minutes; m / z 480.9 [M + H] ⁺ (ESI positive ion mode), m / z 525.0 [M + HCOO] ⁻ (ESI negative ion mode)

実施例２８５
４−｛［３−（｛（１ｒ，４ｒ）−４−［４−（４−シアノフェノキシ）ピペリジン−１−カルボニル）シクロヘキシル］メチル｝−２−オキソ−１−オキサ−３，８−ジアザスピロ［４．５］デカン−８−イル）メチル］−３，５−ジフルオロベンゾニトリル（化合物番号２８５）の製造
３−｛［（１ｒ，４ｒ）−４−（４−ベンゾイルピペリジン−１−カルボニル）シクロヘキシル］メチル｝−１−オキサ−３，８−ジアザスピロ［４．５］デカン−２−オン塩酸塩の代わりに、参考例２８５で得られた４−（１−｛（１ｒ，４ｒ）−４−［（２−オキソ−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル）メチル］シクロヘキサンカルボニル｝ピペリジン−４−イルオキシ）ベンゾニトリル塩酸塩を用いること以外は実質的に実施例２６７と同様に反応を行なって、表題化合物（１４ｍｇ、収率５８％）を白色固体として得た。

^１Ｈ−ＮＭＲ（ＣＤＣｌ_３）δ：１．０４（２Ｈ，ｑ，Ｊ＝１２．７Ｈｚ），１．４５−１．６７（３Ｈ，ｍ），１．６７−２．０２（１２Ｈ，ｍ），２．４６（１Ｈ，ｂｒ ｔ，Ｊ＝１１．５Ｈｚ），２．５４−２．７８（４Ｈ，ｍ），３．０９（２Ｈ，ｄ，Ｊ＝７．０Ｈｚ），３．２３（２Ｈ，ｓ），３．３７−３．５５（１Ｈ，ｂｒ ｍ），３．５６−３．８６（３Ｈ，ｍ），３．７６（２Ｈ，ｓ），４．５６−４．６９（１Ｈ，ｍ），６．９６（２Ｈ，ｄ，Ｊ＝８．６Ｈｚ），７．２３（２Ｈ，ｄ，Ｊ＝６．１Ｈｚ），７．５９（２Ｈ，ｄ，Ｊ＝８．６Ｈｚ）．

ＬＣ／ＭＳ［条件１］：保持時間３．３０分；ｍ／ｚ６３２．０［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ６７６．１［Ｍ＋ＨＣＯＯ］⁻（ＥＳＩ負イオンモード）

Example 285
4-{[3-({(1r, 4r) -4- [4- (4-cyanophenoxy) piperidine-1-carbonyl) cyclohexyl] methyl} -2-oxo-1-oxa-3,8-diazaspiro [ 4.5] Preparation of decan-8-yl) methyl] -3,5-difluorobenzonitrile (Compound No. 285) 3-{[(1r, 4r) -4- (4-benzoylpiperidine-1-carbonyl) cyclohexyl ] Instead of methyl} -1-oxa-3,8-diazaspiro [4.5] decan-2-one hydrochloride, 4- (1-{(1r, 4r) -4- obtained in Reference Example 285 was obtained. Except using [(2-oxo-1-oxa-3,8-diazaspiro [4.5] decan-3-yl) methyl] cyclohexanecarbonyl} piperidin-4-yloxy) benzonitrile hydrochloride. To perform the reaction in the same manner as in Example 267 to give the title compound (14 mg, 58% yield) as a white solid.

¹ H-NMR (CDCl ₃ ) δ: 1.04 (2H, q, J = 12.7 Hz), 1.45 to 1.67 (3H, m), 1.67 to 2.02 (12H, m) , 2.46 (1H, br t, J = 11.5 Hz), 2.54-2.78 (4H, m), 3.09 (2H, d, J = 7.0 Hz), 3.23 (2H , S), 3.37-3.55 (1H, br m), 3.56-3.86 (3H, m), 3.76 (2H, s), 4.56-4.69 (1H, m), 6.96 (2H, d, J = 8.6 Hz), 7.23 (2H, d, J = 6.1 Hz), 7.59 (2H, d, J = 8.6 Hz).

LC / MS [Condition 1]: retention time 3.30 minutes; m / z 632.0 [M + H] ⁺ (ESI positive ion mode), m / z 676.1 [M + HCOO] ⁻ (ESI negative ion mode)

参考例２８６−１
４−（２−クロロフェニルアミノ）ピペリジン−１−カルボン酸ｔ−ブチルの製造
４−オキソピペリジン−１−カルボン酸ｔ−ブチル（０．３８ｇ、１．９ｍｍｏｌ）の１，２−ジクロロエタン（４ｍＬ）溶液に２−クロロアニリン（０．１０ｍＬ、０．９５ｍｍｏｌ）、酢酸（０．１６ｍＬ、２．８ｍｍｏｌ）及びトリアセトキシ水素化ホウ素ナトリウム（０．６０ｇ、２．８ｍｍｏｌ）を加えて、反応混合物を室温で１日間攪拌した。その後、反応混合物に飽和炭酸水素ナトリウム水溶液（５ｍＬ）を加えて、さらに３０分間攪拌したのち静置した。有機層を分離して減圧下濃縮乾固し、残留物をシリカゲルカラムクロマトグラフィー［充填剤：富士シリシア製ＦＬ１００Ｄ、展開溶媒：ｎ−ヘキサン／酢酸エチル＝３／１］にて精製し、表題化合物（０．２９ｇ、収率定量的）を無色油状物として得た。

^１Ｈ−ＮＭＲ（ＣＤＣｌ_３）δ：１．３５−１．５１（２Ｈ，ｍ），１．４６（９Ｈ，ｓ），１．９６−２．１１（２Ｈ，ｍ），２．９７（２Ｈ，ｔ，Ｊ＝１１．９Ｈｚ），３．３８−３．５５（１Ｈ，ｍ），３．９１−４．１３（２Ｈ，ｂｒ ｍ），４．２０（１Ｈ，ｂｒ ｄ，Ｊ＝６．９Ｈｚ），６．６２（１Ｈ，ｔｄ，Ｊ＝７．３，１．３Ｈｚ），６．６８（１Ｈ，ｄ，Ｊ＝７．９Ｈｚ），７．１２（１Ｈ，ｄｄｄ，Ｊ＝７．９，７．３，１．３Ｈｚ），７．２５（１Ｈ，ｄｄ，Ｊ＝７．６，１．７Ｈｚ）．

ＬＣ／ＭＳ［条件２］：保持時間４．８３分；ｍ／ｚ３１０．９［Ｍ＋Ｈ］^＋、２５４．９［Ｍ−ｉｓｏｂｕｔｅｎｅ＋Ｈ］^＋（ＥＳＩ正イオンモード）

Reference Example 286-1
Preparation of 4- (2-chlorophenylamino) piperidine-1-carboxylate t-butyl 4-oxopiperidine-1-carboxylate t-butyl (0.38 g, 1.9 mmol) in 1,2-dichloroethane (4 mL) 2-chloroaniline (0.10 mL, 0.95 mmol), acetic acid (0.16 mL, 2.8 mmol) and sodium triacetoxyborohydride (0.60 g, 2.8 mmol) were added to the reaction mixture at room temperature. Stir for 1 day. Thereafter, a saturated aqueous sodium hydrogen carbonate solution (5 mL) was added to the reaction mixture, and the mixture was further stirred for 30 minutes and allowed to stand. The organic layer was separated and concentrated to dryness under reduced pressure, and the residue was purified by silica gel column chromatography [filler: FL100D manufactured by Fuji Silysia, developing solvent: n-hexane / ethyl acetate = 3/1] to give the title compound. (0.29 g, quantitative yield) was obtained as a colorless oil.

¹ H-NMR (CDCl ₃ ) δ: 1.35 to 1.51 (2H, m), 1.46 (9H, s), 1.96-2.11 (2H, m), 2.97 (2H , T, J = 11.9 Hz), 3.38-3.55 (1H, m), 3.91-4.13 (2H, br m), 4.20 (1H, br d, J = 6. 9 Hz), 6.62 (1H, td, J = 7.3, 1.3 Hz), 6.68 (1H, d, J = 7.9 Hz), 7.12 (1H, ddd, J = 7.9) , 7.3, 1.3 Hz), 7.25 (1H, dd, J = 7.6, 1.7 Hz).

LC / MS [Condition 2]: Retention time 4.83 minutes; m / z 310.9 [M + H] ⁺ , 254.9 [M-isobutene + H] ⁺ (ESI positive ion mode)

参考例２８６−２
Ｎ−（２−クロロフェニル）ピペリジン−４−アミン二塩酸塩の製造
４−（キノリン−４−イル）ピペラジン−１−カルボン酸ｔ−ブチルの代わりに、参考例２８６−１で得られた４−（２−クロロフェニルアミノ）ピペリジン−１−カルボン酸ｔ−ブチルを用いること以外は実質的に参考例２７８−２と同様に反応を行なって、表題化合物（０．２７ｇ、収率定量的）を白色固体として得た。

ＬＣ／ＭＳ［条件２］：保持時間１．７4分；ｍ／ｚ２１１．０［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）

Reference Example 286-2
Preparation of N- (2-chlorophenyl) piperidin-4-amine dihydrochloride 4- (quinolin-4-yl) piperazine-1-carboxylate obtained in Reference Example 286-1 instead of t-butyl 4- The reaction was carried out in substantially the same manner as in Reference Example 278-2 except that t-butyl (2-chlorophenylamino) piperidine-1-carboxylate was used, and the title compound (0.27 g, quantitative yield) was white. Obtained as a solid.

LC / MS [Condition 2]: Retention time 1.74 minutes; m / z 211.0 [M + H] ⁺ (ESI positive ion mode)

実施例２８６
４−｛［３−（｛（１ｒ，４ｒ）−４−［４−（２−クロロフェニルアミノ）ピペリジン−１−カルボニル］シクロヘキシル｝メチル）−２−オキソ−１−オキサ−３，８−ジアザスピロ［４．５］デカン−８−イル］メチル｝ベンゾニトリル（化合物番号２８６）の製造
４−（アミノメチル）ベンゾニトリル塩酸塩の代わりに、参考例２８６−２で得られた、Ｎ−（２−クロロフェニル）ピペリジン−４−アミン二塩酸塩を用いること以外は実質的に実施例２６３と同様に反応を行なって、表題化合物（２４ｍｇ、収率８３％）を無色無定形物として得た。

^１Ｈ−ＮＭＲ（ＣＤＣｌ_３）δ：１．０５（２Ｈ，ｑ，Ｊ＝１１．５Ｈｚ），１．３２−１．６９（５Ｈ，ｍ），１．７０−１．８７（６Ｈ，ｍ），１．９４（２Ｈ，ｄ，Ｊ＝１２．７Ｈｚ），２．０３−２．２１（２Ｈ，ｍ），２．４７−２．６６（４Ｈ，ｂｒ ｍ），２．４７（１Ｈ，ｔｔ，Ｊ＝１１．９，２．９Ｈｚ），２．９２（１Ｈ，ｂｒ ｔ，Ｊ＝１１．９Ｈｚ），３．１１（２Ｈ，ｄ，Ｊ＝７．８Ｈｚ），３．２２（１Ｈ，ｂｒ ｔ，Ｊ＝１２．３Ｈｚ），３．２６（２Ｈ，ｓ），３．４７−３．６３（１Ｈ，ｍ），３．５７（２Ｈ，ｓ），３．８８（１Ｈ，ｂｒ ｄ，Ｊ＝１３．５Ｈｚ），４．２１（１Ｈ，ｄ，Ｊ＝７．８Ｈｚ），４．４６（１Ｈ，ｂｒ ｄ，Ｊ＝１３．５Ｈｚ），６．６４（１Ｈ，ｄｔ，Ｊ＝１．２，７．８Ｈｚ），６．６８（１Ｈ，ｄ，Ｊ＝８．６Ｈｚ），７．１４（１Ｈ，ｄｔ，Ｊ＝１．２，７．８Ｈｚ），７．２６（１Ｈ，ｄｄ，Ｊ＝１．６，７．８Ｈｚ），７．４４（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ），７．６１（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ）．

ＬＣ／ＭＳ［条件１］：保持時間３．３６分；ｍ／ｚ６０３．８［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ６４８．０［Ｍ＋ＨＣＯＯ］⁻（ＥＳＩ負イオンモード）

Example 286
4-{[3-({(1r, 4r) -4- [4- (2-chlorophenylamino) piperidine-1-carbonyl] cyclohexyl} methyl) -2-oxo-1-oxa-3,8-diazaspiro [ 4.5] Preparation of decan-8-yl] methyl} benzonitrile (Compound No. 286) In place of 4- (aminomethyl) benzonitrile hydrochloride, N- (2- The reaction was carried out in substantially the same manner as in Example 263, except that (chlorophenyl) piperidin-4-amine dihydrochloride was used, to give the title compound (24 mg, yield 83%) as a colorless amorphous product.

¹ H-NMR (CDCl ₃ ) δ: 1.05 (2H, q, J = 11.5 Hz), 1.32-1.69 (5H, m), 1.70-1.87 (6H, m) 1.94 (2H, d, J = 12.7 Hz), 2.03-2.21 (2H, m), 2.47-2.66 (4H, br m), 2.47 (1H, tt , J = 11.9, 2.9 Hz), 2.92 (1H, br t, J = 11.9 Hz), 3.11 (2H, d, J = 7.8 Hz), 3.22 (1H, br t, J = 12.3 Hz), 3.26 (2H, s), 3.47-3.63 (1H, m), 3.57 (2H, s), 3.88 (1H, br d, J = 13.5 Hz), 4.21 (1 H, d, J = 7.8 Hz), 4.46 (1 H, br d, J = 13.5 Hz), 6.64 (1 H, dt, J = 1.2) , 7.8H z), 6.68 (1H, d, J = 8.6 Hz), 7.14 (1H, dt, J = 1.2, 7.8 Hz), 7.26 (1H, dd, J = 1.6) , 7.8 Hz), 7.44 (2H, d, J = 8.2 Hz), 7.61 (2H, d, J = 8.2 Hz).

LC / MS [Condition 1]: Retention time 3.36 minutes; m / z 603.8 [M + H] ⁺ (ESI positive ion mode), m / z 648.0 [M + HCOO] ⁻ (ESI negative ion mode)

参考例２８７−１
４−（６−クロロピリミジン−４−ｙｌ）ピペラジン−１−カルボン酸ｔ−ブチルの製造
４，６−ジクロロピリミジン（０．５０ｇ、３．４ｍｍｏｌ）のアセトニトリル（２５ｍＬ）溶液にピペラジン−１−カルボン酸ｔ−ブチル（０．６３ｇ、３．４ｍｍｏｌ）とトリエチルアミン（１．４ｍＬ，１０．１ｍｍｏｌ）を加えて、反応混合物を８０℃で４時間攪拌したのち減圧下濃縮乾固した。残留物に酢酸エチル（５ｍＬ）と水（５ｍＬ）を加えて有機層を分離したのち、その有機層を水（５ｍＬ）と飽和炭酸水素ナトリウム水溶液（１０ｍＬ）で洗浄し、減圧下濃縮乾固して、表題化合物（０．６４ｇ、収率６４％）を白色固体として得た。

^１Ｈ−ＮＭＲ（ＣＤＣｌ_３）δ：１．４９（９Ｈ，ｓ），３．４８−３．５９（４Ｈ，ｍ），３．５９−３．７０（４Ｈ，ｍ），６．５０（１Ｈ，ｓ），８．３９（１Ｈ，ｓ）．

Reference Example 287-1
Preparation of t-butyl 4- (6-chloropyrimidine-4-yl) piperazine-1-carboxylate Piperazine-1-carboxylic acid was added to a solution of 4,6-dichloropyrimidine (0.50 g, 3.4 mmol) in acetonitrile (25 mL). T-Butyl acid (0.63 g, 3.4 mmol) and triethylamine (1.4 mL, 10.1 mmol) were added, and the reaction mixture was stirred at 80 ° C. for 4 hours and then concentrated to dryness under reduced pressure. Ethyl acetate (5 mL) and water (5 mL) were added to the residue to separate the organic layer, and the organic layer was washed with water (5 mL) and saturated aqueous sodium hydrogen carbonate solution (10 mL), and concentrated to dryness under reduced pressure. The title compound (0.64 g, 64% yield) was obtained as a white solid.

¹ H-NMR (CDCl ₃ ) δ: 1.49 (9H, s), 3.48-3.59 (4H, m), 3.59-3.70 (4H, m), 6.50 (1H , S), 8.39 (1H, s).

参考例２８７−２
４−（ピリミジン−４−イル）ピペラジン−１−カルボン酸ｔ−ブチルの製造
参考例２８７−１で得られた、４−（６−クロロピリミジン−４−ｙｌ）ピペラジン−１−カルボン酸ｔ−ブチル（０．３０ｇ、１．０ｍｍｏｌ）のエタノール（１５ｍＬ）溶液に、窒素雰囲気下、１０質量％パラジウム炭素（６０ｍｇ）、トリエチルアミン（２．１ｍＬ、１５ｍｍｏｌ）及びギ酸（０．２８ｍＬ、７．５ｍｍｏｌ）を加えて、室温で１日間かき混ぜたのち、触媒をろ過にて除去し、ろ液を減圧下濃縮乾固した。残留物に酢酸エチル（１０ｍＬ）と飽和炭酸水素ナトリウム水溶液（１０ｍＬ）を加えて、有機層を分離し、その有機層を減圧下濃縮乾固して、表題化合物（０．２５ｇ、収率６４９１％）を白色固体として得た。

Reference Example 287-2
Production of t-butyl 4- (pyrimidin-4-yl) piperazine-1-carboxylate 4- (6-chloropyrimidine-4-yl) piperazine-1-carboxylic acid t-obtained in Reference Example 287-1 To a solution of butyl (0.30 g, 1.0 mmol) in ethanol (15 mL) under nitrogen atmosphere, 10% by mass palladium carbon (60 mg), triethylamine (2.1 mL, 15 mmol) and formic acid (0.28 mL, 7.5 mmol) After stirring at room temperature for 1 day, the catalyst was removed by filtration, and the filtrate was concentrated to dryness under reduced pressure. Ethyl acetate (10 mL) and saturated aqueous sodium hydrogen carbonate solution (10 mL) were added to the residue, the organic layer was separated, and the organic layer was concentrated to dryness under reduced pressure to give the title compound (0.25 g, yield 6491%). ) Was obtained as a white solid.

参考例２８７−３
４−（ピペラジン−１−イル）ピリミジン二塩酸塩の製造
４−（キノリン−４−イル）ピペラジン−１−カルボン酸ｔ−ブチルの代わりに、参考例２８７−２で得られた４−（ピリミジン−４−イル）ピペラジン−１−カルボン酸ｔ−ブチルを用いること以外は実質的に参考例２７８−２と同様に反応を行なって、表題化合物（７６ｍｇ、収率定量的）を白色固体として得た。

^１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ_６）δ：３．１８−３．３０（４Ｈ，ｂｒ ｍ），３．９９−４．１９（４Ｈ，ｍ），７．２７（１Ｈ，ｄ，Ｊ＝７．６Ｈｚ），８．４４（１Ｈ，ｄ，Ｊ＝７．３Ｈｚ），８．９０（１Ｈ，ｓ），９．６５（２Ｈ，ｂｒ ｓ）．

Reference Example 287-3
Preparation of 4- (piperazin-1-yl) pyrimidine dihydrochloride 4- (pyrimidine obtained in Reference Example 287-2 instead of t-butyl 4- (quinolin-4-yl) piperazine-1-carboxylate The reaction was carried out in substantially the same manner as in Reference Example 278-2 except that t-butyl-4-yl) piperazine-1-carboxylate was used to obtain the title compound (76 mg, quantitative yield) as a white solid. It was.

¹ H-NMR (DMSO-d ₆ ) δ: 3.18-3.30 (4H, br m), 3.99-4.19 (4H, m), 7.27 (1H, d, J = 7) .6 Hz), 8.44 (1 H, d, J = 7.3 Hz), 8.90 (1 H, s), 9.65 (2 H, br s).

実施例２８７
３−（｛（１ｒ，４ｒ）−４−［４−（ピリミジン−４−イル）ピペラジン−１−カルボニル］シクロヘキシル｝メチル）−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−２−オン（化合物番号２８７）の製造
４−（アミノメチル）ベンゾニトリル塩酸塩の代わりに、参考例２８７−３で得られた４−（ピペラジン−１−イル）ピリミジン二塩酸塩を用いること以外は実質的に実施例２６３と同様に反応を行なって、表題化合物（１９ｍｇ、収率８７％）を白色固体として得た。

^１Ｈ−ＮＭＲ（ＣＤＣｌ_３）δ：１．０７（２Ｈ，ｑ，Ｊ＝１２．７Ｈｚ），１．４９−１．７０（３Ｈ，ｍ），１．７０−１．８８（６Ｈ，ｍ），１．９４（２Ｈ，ｂｒ ｄ，Ｊ＝１３．１Ｈｚ），２．４７（１Ｈ，ｔｔ，Ｊ＝１１．９，２．９Ｈｚ），２．４８−２．６８（４Ｈ，ｂｒ ｍ），３．１２（２Ｈ，ｄ，Ｊ＝７．８Ｈｚ），３．２７（２Ｈ，ｓ），３．５５−３．６７（４Ｈ，ｂｒ ｍ），３．５７（２Ｈ，ｓ），３．６６−３．８２（４Ｈ，ｂｒ ｍ），６．５２（１Ｈ，ｄｄ，Ｊ＝６．１，１．５Ｈｚ），７．４４（２Ｈ，ｄ，Ｊ＝７．８Ｈｚ），７．５７（２Ｈ，ｄ，Ｊ＝７．８Ｈｚ），８．２５（１Ｈ，ｄ，Ｊ＝６．１Ｈｚ），８．６３（１Ｈ，ｂｒ ｓ）．

ＬＣ／ＭＳ［条件１］：保持時間０．９２分；ｍ／ｚ６００．８［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ６４５．１［Ｍ＋ＨＣＯＯ］⁻（ＥＳＩ負イオンモード）

Example 287
3-({(1r, 4r) -4- [4- (pyrimidin-4-yl) piperazine-1-carbonyl] cyclohexyl} methyl) -8- [4- (trifluoromethyl) benzyl] -1-oxa- Preparation of 3,8-diazaspiro [4.5] decan-2-one (Compound No. 287) Instead of 4- (aminomethyl) benzonitrile hydrochloride, 4- (piperazine-) obtained in Reference Example 287-3 The reaction was carried out in substantially the same manner as in Example 263 except that 1-yl) pyrimidine dihydrochloride was used to obtain the title compound (19 mg, yield 87%) as a white solid.

¹ H-NMR (CDCl ₃ ) δ: 1.07 (2H, q, J = 12.7 Hz), 1.49-1.70 (3H, m), 1.70-1.88 (6H, m) 1.94 (2H, br d, J = 13.1 Hz), 2.47 (1 H, tt, J = 11.9, 2.9 Hz), 2.48-2.68 (4H, br m), 3.12 (2H, d, J = 7.8 Hz), 3.27 (2H, s), 3.55 to 3.67 (4H, br m), 3.57 (2H, s), 3.66 -3.82 (4H, br m), 6.52 (1H, dd, J = 6.1, 1.5 Hz), 7.44 (2H, d, J = 7.8 Hz), 7.57 (2H , D, J = 7.8 Hz), 8.25 (1H, d, J = 6.1 Hz), 8.63 (1H, br s).

LC / MS [Condition 1]: Retention time 0.92 minutes; m / z 600.8 [M + H] ⁺ (ESI positive ion mode), m / z 645.1 [M + HCOO] ⁻ (ESI negative ion mode)

参考例２８８
４−クロロ−６−（ピペラジン−１−イル）ピリミジン二塩酸塩の製造
４−（キノリン−４−イル）ピペラジン−１−カルボン酸ｔ−ブチルの代わりに、参考例２８７−１で得られた４−（６−クロロピリミジン−４−ｙｌ）ピペラジン−１−カルボン酸ｔ−ブチルを用いること以外は実質的に参考例２７８−２と同様に反応を行なって、表題化合物（０．２１ｇ、収率定量的）を白色固体として得た。

^１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ_６）δ：３．０８−３．２１（４Ｈ，ｍ），３．８４−３．９５（４Ｈ，ｍ），７．０９（１Ｈ，ｓ），８．４２（１Ｈ，ｓ），９．３３（２Ｈ，ｓ）．

Reference Example 288
Preparation of 4-chloro-6- (piperazin-1-yl) pyrimidine dihydrochloride Obtained in Reference Example 287-1 instead of t-butyl 4- (quinolin-4-yl) piperazine-1-carboxylate The reaction was carried out in substantially the same manner as in Reference Example 278-2 except that t-butyl 4- (6-chloropyrimidine-4-yl) piperazine-1-carboxylate was used, and the title compound (0.21 g, yield) was obtained. Was obtained as a white solid.

¹ H-NMR (DMSO-d ₆ ) δ: 3.08-3.21 (4H, m), 3.84-3.95 (4H, m), 7.09 (1H, s), 8.42 (1H, s), 9.33 (2H, s).

実施例２８８
３−（｛（１ｒ，４ｒ）−４−［４−（６−クロロピリミジン−４−イル）ピペラジン−１−カルボニル］シクロヘキシル｝メチル）−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−２−オン（化合物番号２８８）の製造
４−（アミノメチル）ベンゾニトリル塩酸塩の代わりに、参考例２８８で得られた４−クロロ−６−（ピペラジン−１−イル）ピリミジン二塩酸塩を用いること以外は実質的に実施例２６３と同様に反応を行なって、表題化合物（２０ｍｇ、収率９１％）を白色固体として得た。

^１Ｈ−ＮＭＲ（ＣＤＣｌ_３）δ：１．０７（２Ｈ，ｑ，Ｊ＝１１．５Ｈｚ），１．５２−１．７０（３Ｈ，ｍ），１．７０−１．８８（６Ｈ，ｍ），１．９５（２Ｈ，ｂｒ ｄ，Ｊ＝１３．１Ｈｚ），２．４６（１Ｈ，ｂｒ ｔ，Ｊ＝１２．７Ｈｚ），２．４８−２．６８（４Ｈ，ｂｒ ｍ），３．１２（２Ｈ，ｄ，Ｊ＝７．４Ｈｚ），３．２７（２Ｈ，ｓ），３．４９−３．７１（４Ｈ，ｂｒ ｍ），３．５８（２Ｈ，ｓ），３．６４−３．８７（４Ｈ，ｂｒ ｍ），６．５２（１Ｈ，ｓ），７．４４（２Ｈ，ｄ，Ｊ＝７．４Ｈｚ），７．５７（２Ｈ，ｄ，Ｊ＝７．４Ｈｚ），８．４１（１Ｈ，ｓ）．

ＬＣ／ＭＳ［条件１］：保持時間３．１２分；ｍ／ｚ６３４．８［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ６７８．９［Ｍ＋ＨＣＯＯ］⁻（ＥＳＩ負イオンモード）

Example 288
3-({(1r, 4r) -4- [4- (6-chloropyrimidin-4-yl) piperazine-1-carbonyl] cyclohexyl} methyl) -8- [4- (trifluoromethyl) benzyl] -1 Preparation of Oxa-3,8-diazaspiro [4.5] decan-2-one (Compound No. 288) 4-Chloro- obtained in Reference Example 288 instead of 4- (aminomethyl) benzonitrile hydrochloride The reaction was carried out substantially in the same manner as in Example 263 except that 6- (piperazin-1-yl) pyrimidine dihydrochloride was used to obtain the title compound (20 mg, yield 91%) as a white solid.

¹ H-NMR (CDCl ₃ ) δ: 1.07 (2H, q, J = 11.5 Hz), 1.52-1.70 (3H, m), 1.70-1.88 (6H, m) 1.95 (2H, br d, J = 13.1 Hz), 2.46 (1 H, br t, J = 12.7 Hz), 2.48-2.68 (4H, br m), 3.12. (2H, d, J = 7.4 Hz), 3.27 (2H, s), 3.49-3.71 (4H, br m), 3.58 (2H, s), 3.64-3. 87 (4H, br m), 6.52 (1H, s), 7.44 (2H, d, J = 7.4 Hz), 7.57 (2H, d, J = 7.4 Hz), 8.41 (1H, s).

LC / MS [Condition 1]: Retention time 3.12 minutes; m / z 634.8 [M + H] ⁺ (ESI positive ion mode), m / z 678.9 [M + HCOO] ⁻ (ESI negative ion mode)

参考例２８９
４−［１−（２−｛４−［（２−オキソ−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル）メチル］フェニル｝アセチル）ピペリジン−４−イルオキシ］ベンゾニトリル塩酸塩の製造
実施例２７５で得られた、３−（４−｛２−［４−（４−シアノフェノキシ）ピペリジン−１−イル］−２−オキソエチル｝ベンジル）−２−オキソ−１−オキサ−３，８−ジアザスピロ［４．５］デカン−８−カルボン酸ｔ−ブチル（２８ｍｇ、０．０４８ｍｍｏｌ）のメタノール（１ｍＬ）溶液に、１０質量％塩化水素メタノール溶液（９５μＬ）を加えたのち、反応混合物を室温で１０日間静置し、減圧下濃縮乾固して、表題化合物（２４ｍｇ、収率定量的）を白色固体として得た。

^１Ｈ−ＮＭＲ（ＣＤＣｌ_３）δ：１．６５−２．３９（８Ｈ，ｂｒ ｍ），２．９９−４．００（１２Ｈ，ｂｒ ｍ），４．４２（２Ｈ，ｂｒ ｓ），４．５０−４．６９（１Ｈ，ｂｒ ｍ），６．９４（２Ｈ，ｄ，Ｊ＝８．０Ｈｚ），７．１８−７．３１（４Ｈ，ｍ），７．５９（２Ｈ，ｄ，Ｊ＝８．０Ｈｚ），９．４３−９．９９（２Ｈ，ｂｒ ｍ）．

ＬＣ／ＭＳ［条件１］：保持時間２．９４分；ｍ／ｚ４８８．７［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ５３２．９［Ｍ＋ＨＣＯＯ］⁻、４８７．０［Ｍ−Ｈ］⁻（ＥＳＩ負イオンモード）

Reference Example 289
4- [1- (2- {4-[(2-oxo-1-oxa-3,8-diazaspiro [4.5] decan-3-yl) methyl] phenyl} acetyl) piperidin-4-yloxy] benzo Preparation of nitrile hydrochloride 3- (4- {2- [4- (4-cyanophenoxy) piperidin-1-yl] -2-oxoethyl} benzyl) -2-oxo-1- obtained in Example 275 After adding a 10 mass% hydrogen chloride methanol solution (95 μL) to a methanol (1 mL) solution of t-butyl oxa-3,8-diazaspiro [4.5] decane-8-carboxylate (28 mg, 0.048 mmol). The reaction mixture was allowed to stand at room temperature for 10 days and concentrated to dryness under reduced pressure to give the title compound (24 mg, quantitative yield) as a white solid.

¹ H-NMR (CDCl ₃ ) δ: 1.65-2.39 (8H, br m), 2.99-4.00 (12H, br m), 4.42 (2H, br s), 4. 50-4.69 (1H, br m), 6.94 (2H, d, J = 8.0 Hz), 7.18-7.31 (4H, m), 7.59 (2H, d, J = 8.0 Hz), 9.43-9.99 (2H, br m).

LC / MS [Condition 1]: Retention time 2.94 minutes; m / z 488.7 [M + H] ⁺ (ESI positive ion mode), m / z 532.9 [M + HCOO] ⁻ , 487.0 [M−H] ⁻ (ESI negative ion mode)

実施例２８９
３−（４−｛２−［４−（４−シアノフェノキシ）ピペリジン−１−イル］−２−オキソエチル｝ベンジル）−２−オキソ−１−オキサ−３，８−ジアザスピロ［４．５］デカン−８−カルボン酸エチル（化合物番号２８９）の製造
参考例２８９で得られた、４−［１−（２−｛４−［（２−オキソ−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル）メチル］フェニル｝アセチル）ピペリジン−４−イルオキシ］ベンゾニトリル塩酸塩（２４ｍｇ、０．０４６ｍｍｏｌ）のクロロホルム（１ｍＬ）溶液にトリエチルアミン（３２μＬ、０．２３ｍｍｏｌ）を加えて、０℃でクロロギ酸エチル（５μＬ，０．０５ｍｍｏｌ）を加えた。氷浴を外して、３日間静置したのち、クエン酸（４４ｍｇ）の水（１ｍＬ）溶液を加えて、有機層を分離し、減圧下濃縮乾固した。残留物をシリカゲルカラムクロマトグラフィー［充填剤：富士シリシア社製ＦＬ１００Ｄ、展開溶媒：クロロホルム／アセトン＝４／１］にて精製し、表題化合物（１６ｍｇ、収率６２％）を無色無定形物として得た。

^１Ｈ−ＮＭＲ（ＣＤＣｌ_３）δ：１．２５（３Ｈ，ｔ，Ｊ＝７．０Ｈｚ），１．５３−２．０１（８Ｈ，ｍ），３．１４（２Ｈ，ｓ），３．３１（１Ｈ，ｂｒ ｔ，Ｊ＝１１．９Ｈｚ），３．４６（１Ｈ，ｄｄｄ，Ｊ＝１３．５，６．１，４．１Ｈｚ），３．６７（１Ｈ，ｄｄｄ，Ｊ＝１３．５，８．２，３．７Ｈｚ），３．７０−３．８０（２Ｈ，ｍ），３．７５（２Ｈ，ｓ），３．７８−４．０１（２Ｈ，ｂｒ ｍ），４．１３（２Ｈ，ｑ，Ｊ＝７．０Ｈｚ），４．４２（２Ｈ，ｓ），４．５９（１Ｈ，ｔｔ，Ｊ＝６．５，４．１Ｈｚ），６．９３（２Ｈ，ｄ，Ｊ＝９．０Ｈｚ），７．２２（２Ｈ，ｄ，Ｊ＝９．０Ｈｚ），７．２６（２Ｈ，ｄ，Ｊ＝９．０Ｈｚ），７．５８（２Ｈ，ｄ，Ｊ＝９．０Ｈｚ）．

ＬＣ／ＭＳ［条件１］：保持時間４．０１分；ｍ／ｚ５６０．８［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ６０５．０［Ｍ＋ＨＣＯＯ］⁻（ＥＳＩ負イオンモード）

Example 289
3- (4- {2- [4- (4-Cyanophenoxy) piperidin-1-yl] -2-oxoethyl} benzyl) -2-oxo-1-oxa-3,8-diazaspiro [4.5] decane Preparation of ethyl -8-carboxylate (Compound No. 289) 4- [1- (2- {4-[(2-oxo-1-oxa-3,8-diazaspiro [4. 5) Decan-3-yl) methyl] phenyl} acetyl) piperidin-4-yloxy] benzonitrile hydrochloride (24 mg, 0.046 mmol) in chloroform (1 mL) was added triethylamine (32 μL, 0.23 mmol), Ethyl chloroformate (5 μL, 0.05 mmol) was added at 0 ° C. After removing the ice bath and allowing to stand for 3 days, a solution of citric acid (44 mg) in water (1 mL) was added, the organic layer was separated, and concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography [filler: FL100D manufactured by Fuji Silysia Ltd., developing solvent: chloroform / acetone = 4/1] to obtain the title compound (16 mg, yield 62%) as a colorless amorphous product. It was.

¹ H-NMR (CDCl ₃ ) δ: 1.25 (3H, t, J = 7.0 Hz), 1.53-2.01 (8H, m), 3.14 (2H, s), 3.31 (1H, br t, J = 11.9 Hz), 3.46 (1H, ddd, J = 13.5, 6.1, 4.1 Hz), 3.67 (1H, ddd, J = 13.5, 8.2, 3.7 Hz), 3.70-3.80 (2H, m), 3.75 (2H, s), 3.78-4.01 (2H, br m), 4.13 (2H , Q, J = 7.0 Hz), 4.42 (2H, s), 4.59 (1H, tt, J = 6.5, 4.1 Hz), 6.93 (2H, d, J = 9. 0 Hz), 7.22 (2H, d, J = 9.0 Hz), 7.26 (2H, d, J = 9.0 Hz), 7.58 (2H, d, J = 9.0 Hz).

LC / MS [Condition 1]: Retention time 4.01 min; m / z 560.8 [M + H] ⁺ (ESI positive ion mode), m / z 605.0 [M + HCOO] ⁻ (ESI negative ion mode)

参考例２９０
４−（１−｛（１ｒ，４ｒ）−４−［（２−チオキソ−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル）メチル］シクロヘキサンカルボニル｝ピペリジン−４−イルオキシ）ベンゾニトリル塩酸塩の製造
実施例２７７で得られた、３−（｛（１ｒ，４ｒ）−４−［４−（４−シアノフェノキシ）ピペリジン−１−カルボニル］シクロヘキシル｝メチル）−２−チオキソ−１−オキサ−３，８−ジアザスピロ［４．５］デカン−８−カルボン酸ｔ−ブチル（８２ｍｇ、０．１４ｍｍｏｌ）のメタノール（２ｍＬ）−クロロホルム（０．５ｍＬ）溶液に、１０質量％塩化水素メタノール溶液（０．３ｍＬ）を加えたのち、反応混合物を室温で３日間静置し、減圧下濃縮乾固して、表題化合物（７９ｍｇ、収率定量的）を白色固体として得た。

^１Ｈ−ＮＭＲ（ＣＤＣｌ_３）δ：１．０８−１．２９（２Ｈ，ｍ），１．４８−１．６８（２Ｈ，ｍ），１．６８−２．０５（９Ｈ，ｍ），２．１６（２Ｈ，ｂｒ ｄ，Ｊ＝１２．７Ｈｚ），２．２９−２．５８（３Ｈ，ｍ），３．２３−３．８４（１２Ｈ，ｍ），４．５９−４．６９（１Ｈ，ｍ），６．９６（２Ｈ，ｄ，Ｊ＝９．０Ｈｚ），７．６０（２Ｈ，ｄ，Ｊ＝９．０Ｈｚ），９．６４−１０．１６（２Ｈ，ｂｒ ｍ）．

ＬＣ／ＭＳ［条件１］：保持時間分３．１２；ｍ／ｚ４９６．８［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ５４０．９［Ｍ＋ＨＣＯＯ］⁻（ＥＳＩ負イオンモード）

Reference Example 290
4- (1-{(1r, 4r) -4-[(2-Thioxo-1-oxa-3,8-diazaspiro [4.5] decan-3-yl) methyl] cyclohexanecarbonyl} piperidin-4-yloxy ) Preparation of benzonitrile hydrochloride 3-({(1r, 4r) -4- [4- (4-cyanophenoxy) piperidine-1-carbonyl] cyclohexyl} methyl) -2-thioxo obtained in Example 277 -1-Oxa-3,8-diazaspiro [4.5] decane-8-carboxylate t-butyl (82 mg, 0.14 mmol) in methanol (2 mL) -chloroform (0.5 mL) in 10% by mass chloride. After adding hydrogen methanol solution (0.3 mL), the reaction mixture was allowed to stand at room temperature for 3 days and concentrated to dryness under reduced pressure to give the title compound (79 mg, quantitative yield) as a white solid It was obtained.

¹ H-NMR (CDCl ₃ ) δ: 1.08-1.29 (2H, m), 1.48-1.68 (2H, m), 1.68-2.05 (9H, m), 2 .16 (2H, br d, J = 12.7 Hz), 2.29-2.58 (3H, m), 3.23-3.84 (12H, m), 4.59-4.69 (1H M), 6.96 (2H, d, J = 9.0 Hz), 7.60 (2H, d, J = 9.0 Hz), 9.64-10.16 (2H, br m).

LC / MS [Condition 1]: retention time minute 3.12; m / z 496.8 [M + H] ⁺ (ESI positive ion mode), m / z 540.9 [M + HCOO] ⁻ (ESI negative ion mode)

実施例２９０
３−（｛（１ｒ，４ｒ）−４−［４−（４−シアノフェノキシ）ピペリジン−１−カルボニル］シクロヘキシル｝メチル）−２−チオキソ−１−オキサ−３，８−ジアザスピロ［４．５］デカン−８−カルボン酸エチル（化合物番号２９０）の製造
参考例２９０で得られた、４−（１−｛（１ｒ，４ｒ）−４−［（２−チオキソ−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル）メチル］シクロヘキサンカルボニル｝ピペリジン−４−イルオキシ）ベンゾニトリル塩酸塩（２０ｍｇ、０．０３８ｍｍｏｌ）のクロロホルム（１ｍＬ）懸濁液にトリエチルアミン（２６μＬ、０．１９ｍｍｏｌ）を加えて、０℃でクロロギ酸エチル（４μＬ，０．０４ｍｍｏｌ）を加えた。氷浴を外して、３日間静置したのち、クエン酸（３７ｍｇ）の水（１ｍＬ）溶液を加えて、有機層を分離し、減圧下濃縮乾固して、表題化合物（２２ｍｇ、収率定量的）を白色固体として得た。

^１Ｈ−ＮＭＲ（ＣＤＣｌ_３）δ：１．１８（２Ｈ，ｑ，Ｊ＝１２．３Ｈｚ），１．２７（３Ｈ，ｔ，Ｊ＝７．０Ｈｚ），１．４５−１．６６（３Ｈ，ｍ），１．６６−１．８９（８Ｈ，ｍ），１．９７（２Ｈ，ｂｒ ｄ，Ｊ＝１４．０Ｈｚ），２．４１−２．５８（１Ｈ，ｍ），３．３７−３．５２（１Ｈ，ｂｒ ｍ），３．４１（２Ｈ，ｔ，Ｊ＝１１．１Ｈｚ），３．４６（２Ｈ，ｓ），３．５６（２Ｈ，ｄ，Ｊ＝７．４Ｈｚ），３．５９−３．８３（３Ｈ，ｍ），３．８１−４．０１（２Ｈ，ｂｒ ｍ），４．１５（２Ｈ，ｑ，Ｊ＝７．０Ｈｚ），４．６３（１Ｈ，ｔｔ，Ｊ＝６．１，３．３Ｈｚ），６．９６（２Ｈ，ｄ，Ｊ＝８．６Ｈｚ），７．５９（２Ｈ，ｄ，Ｊ＝８．６Ｈｚ）．

ＬＣ／ＭＳ［条件１］：保持時間４．２３分；ｍ／ｚ５６８．８［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ６１２．９［Ｍ＋ＨＣＯＯ］⁻（ＥＳＩ負イオンモード）

Example 290
3-({(1r, 4r) -4- [4- (4-cyanophenoxy) piperidine-1-carbonyl] cyclohexyl} methyl) -2-thioxo-1-oxa-3,8-diazaspiro [4.5] Preparation of ethyl decane-8-carboxylate (Compound No. 290) 4- (1-{(1r, 4r) -4-[(2-thioxo-1-oxa-3,8-) obtained in Reference Example 290 To a suspension of diazaspiro [4.5] decan-3-yl) methyl] cyclohexanecarbonyl} piperidin-4-yloxy) benzonitrile hydrochloride (20 mg, 0.038 mmol) in chloroform (1 mL) is triethylamine (26 μL, 0.19 mmol). ) And ethyl chloroformate (4 μL, 0.04 mmol) was added at 0 ° C. After removing the ice bath and allowing to stand for 3 days, a solution of citric acid (37 mg) in water (1 mL) was added, the organic layer was separated and concentrated to dryness under reduced pressure to give the title compound (22 mg, quantitative yield). Was obtained as a white solid.

¹ H-NMR (CDCl ₃ ) δ: 1.18 (2H, q, J = 12.3 Hz), 1.27 (3H, t, J = 7.0 Hz), 1.45 to 1.66 (3H, m), 1.6-1.89 (8H, m), 1.97 (2H, br d, J = 14.0 Hz), 2.41-2.58 (1H, m), 3.37-3 .52 (1H, br m), 3.41 (2H, t, J = 11.1 Hz), 3.46 (2H, s), 3.56 (2H, d, J = 7.4 Hz), 3. 59-3.83 (3H, m), 3.81-4.01 (2H, br m), 4.15 (2H, q, J = 7.0 Hz), 4.63 (1H, tt, J = 6.1, 3.3 Hz), 6.96 (2H, d, J = 8.6 Hz), 7.59 (2H, d, J = 8.6 Hz).

LC / MS [Condition 1]: Retention time 4.23 minutes; m / z 568.8 [M + H] ⁺ (ESI positive ion mode), m / z 612.9 [M + HCOO] ⁻ (ESI negative ion mode)

実施例２９１
４−［１−（（１ｒ，４ｒ）−４−｛［８−（４−シアノベンジル）−２−チオキソ−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル］メチル｝シクロヘキサンカルボニル）ピペリジン−４−イルオキシ］ベンゾニトリル（化合物番号２９１）の製造
参考例２９０で得られた、４−（１−｛（１ｒ，４ｒ）−４−［（２−チオキソ−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル）メチル］シクロヘキサンカルボニル｝ピペリジン−４−イルオキシ）ベンゾニトリル塩酸塩（２０ｍｇ、０．０３８ｍｍｏｌ）のＮ，Ｎ−ジメチルホルムアミド（０．６０ｍＬ）懸濁液に、トリエチルアミン（１６μＬ、０．１１ｍｍｏｌ）と４−（ブロモメチル）ベンゾニトリル（市販）（８ｍｇ、０．０４１ｍｍｏｌ）を加えた。室温で３日間攪拌したのち、水（１ｍＬ）を加えた。生じた固体をろ取して、表題化合物（１７ｍｇ、収率７４％）を白色固体として得た。

^１Ｈ−ＮＭＲ（ＣＤＣｌ_３）δ：１．１７（２Ｈ，ｑ，Ｊ＝１２．７Ｈｚ），１．４７−１．６７（２Ｈ，ｍ），１．６６−２．１１（１３Ｈ，ｍ），２．４１−２．７４（５Ｈ，ｍ），３．３９−３．８３（４Ｈ，ｂｒ ｍ），３．４５（２Ｈ，ｓ），３．５４（２Ｈ，ｄ，Ｊ＝７．４Ｈｚ），３．５８（２Ｈ，ｓ），４．５６−４．６８（１Ｈ，ｍ），６．９５（２Ｈ，ｄ，Ｊ＝８．６Ｈｚ），７．４４（２Ｈ，ｄ，Ｊ＝７．８Ｈｚ），７．６０（２Ｈ，ｄ，Ｊ＝８．６Ｈｚ），７．６２（２Ｈ，ｄ，Ｊ＝７．８Ｈｚ）．

ＬＣ／ＭＳ［条件１］：保持時間３．３４分；ｍ／ｚ６１１．９［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ６５６．０［Ｍ＋ＨＣＯＯ］⁻（ＥＳＩ負イオンモード）

Example 291
4- [1-((1r, 4r) -4-{[8- (4-cyanobenzyl) -2-thioxo-1-oxa-3,8-diazaspiro [4.5] decan-3-yl] methyl } Cyclohexanecarbonyl) piperidin-4-yloxy] benzonitrile (Compound No. 291) 4- (1-{(1r, 4r) -4-[(2-thioxo-1-oxa) obtained in Reference Example 290 −3,8-diazaspiro [4.5] decan-3-yl) methyl] cyclohexanecarbonyl} piperidin-4-yloxy) benzonitrile hydrochloride (20 mg, 0.038 mmol) in N, N-dimethylformamide (0.60 mL) ) To the suspension, triethylamine (16 μL, 0.11 mmol) and 4- (bromomethyl) benzonitrile (commercially available) (8 mg, 0.041 mmol) were added. I was painting. After stirring at room temperature for 3 days, water (1 mL) was added. The resulting solid was collected by filtration to give the title compound (17 mg, yield 74%) as a white solid.

¹ H-NMR (CDCl ₃ ) δ: 1.17 (2H, q, J = 12.7 Hz), 1.47-1.67 (2H, m), 1.66-2.11 (13H, m) , 2.41-2.74 (5H, m), 3.39-3.83 (4H, br m), 3.45 (2H, s), 3.54 (2H, d, J = 7.4 Hz) ), 3.58 (2H, s), 4.56-4.68 (1H, m), 6.95 (2H, d, J = 8.6 Hz), 7.44 (2H, d, J = 7) .8 Hz), 7.60 (2H, d, J = 8.6 Hz), 7.62 (2H, d, J = 7.8 Hz).

LC / MS [condition 1]: retention time 3.34 minutes; m / z 611.9 [M + H] ⁺ (ESI positive ion mode), m / z 656.0 [M + HCOO] ⁻ (ESI negative ion mode)

参考例２９２−１
４−（２−メトキシフェニルアミノ）ピペリジン−１−カルボン酸ｔ−ブチルの製造
４−オキソピペリジン−１−カルボン酸ｔ−ブチル（０．３８ｇ、１．９ｍｍｏｌ）の１，２−ジクロロエタン（４ｍＬ）溶液に２−メトキシアニリン（０．１１ｍＬ、０．９５ｍｍｏｌ）、酢酸（０．１６ｍＬ、２．８ｍｍｏｌ）及びトリアセトキシ水素化ホウ素ナトリウム（０．６０ｇ、２．８ｍｍｏｌ）を加えて、反応混合物を室温で２時間攪拌した。その後、反応混合物に飽和炭酸水素ナトリウム水溶液（５ｍＬ）を加えて、さらに３０分間攪拌したのち静置した。有機層を分離して減圧下濃縮乾固し、残留物をシリカゲルカラムクロマトグラフィー［充填剤：富士シリシア製ＦＬ１００Ｄ、展開溶媒：ｎ−ヘキサン／酢酸エチル＝３／１］にて精製し、表題化合物（０．３１ｇ、収率定量的）を白色固体として得た。

^１Ｈ−ＮＭＲ（ＣＤＣｌ_３）δ：１．３６（２Ｈ，ｄｄｄ，Ｊ＝１３．０，１０．９，４．３Ｈｚ），１．４７（９Ｈ，ｓ），２．０４（２Ｈ，ｂｒ ｄｄ，Ｊ＝１２．６，３．３Ｈｚ），２．９５（２Ｈ，ｔ，Ｊ＝１２．６Ｈｚ），３．３６−３．５０（１Ｈ，ｍ），３．８４（３Ｈ，ｓ），３．９４−４．１２（２Ｈ，ｂｒ ｍ），４．１１−４．１７（１Ｈ，ｂｒ ｍ），６．６３（１Ｈ，ｔｄ，Ｊ＝７．９，１．５Ｈｚ），６．６７（１Ｈ，ｄｄ，Ｊ＝７．６，１．５Ｈｚ），６．７８（１Ｈ，ｄｄ，Ｊ＝７．９，１．５Ｈｚ），６．８６（１Ｈ，ｔｄ，Ｊ＝７．６，１．５Ｈｚ）．

ＬＣ／ＭＳ［条件２］：保持時間２．８１分；ｍ／ｚ３０７．０［Ｍ＋Ｈ］^＋、２５１．０［Ｍ−ｉｓｏｂｕｔｅｎｅ＋Ｈ］^＋（ＥＳＩ正イオンモード）

Reference Example 292-1
Preparation of t-butyl 4- (2-methoxyphenylamino) piperidine-1-carboxylate t-butyl 4-oxopiperidine-1-carboxylate (0.38 g, 1.9 mmol) 1,2-dichloroethane (4 mL) To the solution was added 2-methoxyaniline (0.11 mL, 0.95 mmol), acetic acid (0.16 mL, 2.8 mmol) and sodium triacetoxyborohydride (0.60 g, 2.8 mmol) and the reaction mixture was allowed to cool to room temperature. For 2 hours. Thereafter, a saturated aqueous sodium hydrogen carbonate solution (5 mL) was added to the reaction mixture, and the mixture was further stirred for 30 minutes and allowed to stand. The organic layer was separated and concentrated to dryness under reduced pressure, and the residue was purified by silica gel column chromatography [filler: FL100D manufactured by Fuji Silysia, developing solvent: n-hexane / ethyl acetate = 3/1] to give the title compound. (0.31 g, quantitative yield) was obtained as a white solid.

¹ H-NMR (CDCl ₃ ) δ: 1.36 (2H, ddd, J = 13.0, 10.9, 4.3 Hz), 1.47 (9H, s), 2.04 (2H, br dd , J = 12.6, 3.3 Hz), 2.95 (2H, t, J = 12.6 Hz), 3.36-3.50 (1H, m), 3.84 (3H, s), 3 .94-4.12 (2H, br m), 4.11-4.17 (1 H, br m), 6.63 (1 H, td, J = 7.9, 1.5 Hz), 6.67 ( 1H, dd, J = 7.6, 1.5 Hz), 6.78 (1H, dd, J = 7.9, 1.5 Hz), 6.86 (1H, td, J = 7.6, 1. 5 Hz).

LC / MS [Condition 2]: Retention time 2.81 minutes; m / z 307.0 [M + H] ⁺ , 251.0 [M-isobutene + H] ⁺ (ESI positive ion mode)

参考例２９２−２
Ｎ−（２−メトキシフェニル）ピペリジン−４−アミン二塩酸塩の製造
４−（キノリン−４−イル）ピペラジン−１−カルボン酸ｔ−ブチルの代わりに、参考例２９２−１で得られた４−（２−メトキシフェニルアミノ）ピペリジン−１−カルボン酸ｔ−ブチルを用いること以外は実質的に参考例２７８−２と同様に反応を行なって、表題化合物（０．２９ｇ、収率定量的）を灰色固体として得た。

ＬＣ／ＭＳ［条件２］：保持時間０．５５分；ｍ／ｚ２０７．０［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）

Reference Example 292-2
Preparation of N- (2-methoxyphenyl) piperidin-4-amine dihydrochloride 4 obtained in Reference Example 292-1 instead of t-butyl 4- (quinolin-4-yl) piperazine-1-carboxylate The reaction was carried out in substantially the same manner as in Reference Example 278-2 except that t-butyl-(2-methoxyphenylamino) piperidine-1-carboxylate was used, and the title compound (0.29 g, quantitative yield) Was obtained as a gray solid.

LC / MS [Condition 2]: retention time 0.55 minutes; m / z 207.0 [M + H] ⁺ (ESI positive ion mode)

実施例２９２
４−｛［３−（｛（１ｒ，４ｒ）−４−［４−（２−メトキシフェニルアミノ）ピペリジン−１−カルボニル］シクロヘキシル｝メチル）−２−オキソ−１−オキサ−３，８−ジアザスピロ［４．５］デカン−８−イル］メチル｝ベンゾニトリル（化合物番号２９２）の製造
４−（アミノメチル）ベンゾニトリル塩酸塩の代わりに、参考例２９２−２で得られた、Ｎ−（２−メトキシフェニル）ピペリジン−４−アミン二塩酸塩を用いること以外は実質的に実施例２６３と同様に反応を行なって、表題化合物（２９ｍｇ、収率定量的）を白色固体として得た。

^１Ｈ−ＮＭＲ（ＣＤＣｌ_３）δ：１．０５（２Ｈ，ｑ，Ｊ＝１２．７Ｈｚ），１．３１−１．４７（２Ｈ，ｂｒ ｍ），１．４７−１．６９（３Ｈ，ｍ），１．６９−１．８７（６Ｈ，ｍ），１．９４（２Ｈ，ｂｒ ｄ，Ｊ＝１３．９Ｈｚ），２．００−２．２２（２Ｈ，ｍ），２．４７（１Ｈ，ｔ，Ｊ＝１１．１Ｈｚ），２．４８−２．６６（４Ｈ，ｍ），２．８９（２Ｈ，ｂｒ ｔ，Ｊ＝１２．３Ｈｚ），３．１１（２Ｈ，ｄ，Ｊ＝７．４Ｈｚ），３．２０（２Ｈ，ｂｒ ｔ，Ｊ＝１２．３Ｈｚ），３．２６（２Ｈ，ｓ），３．４３−３．６２（１Ｈ，ｂｒ ｍ），３．５７（２Ｈ，ｓ），３．８３（３Ｈ，ｓ），３．８７（１Ｈ，ｂｒ ｄ，Ｊ＝１３．５Ｈｚ），４．０９−４．１９（１Ｈ，ｂｒ ｍ），４．４６（１Ｈ，ｂｒ ｄ，Ｊ＝１３．５Ｈｚ），６．６３（１Ｈ，ｄｄ，Ｊ＝７．８，１．２Ｈｚ），６．６７（１Ｈ，ｄｔ，Ｊ＝１．２，７．８Ｈｚ），６．７８（１Ｈ，ｄｄ，Ｊ＝７．８，１．２Ｈｚ），６．８６（１Ｈ，ｄｔ，Ｊ＝１．２，７．８Ｈｚ），７．４４（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ），７．６１（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ）．

ＬＣ／ＭＳ［条件１］：保持時間２．８６分；ｍ／ｚ５９９．８［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ６４４．０［Ｍ＋ＨＣＯＯ］⁻（ＥＳＩ負イオンモード）

Example 292
4-{[3-({(1r, 4r) -4- [4- (2-methoxyphenylamino) piperidine-1-carbonyl] cyclohexyl} methyl) -2-oxo-1-oxa-3,8-diazaspiro Preparation of [4.5] decan-8-yl] methyl} benzonitrile (Compound No. 292) N- (2) obtained in Reference Example 292-2 instead of 4- (aminomethyl) benzonitrile hydrochloride The reaction was carried out in substantially the same manner as in Example 263 except that -methoxyphenyl) piperidin-4-amine dihydrochloride was used to obtain the title compound (29 mg, quantitative yield) as a white solid.

¹ H-NMR (CDCl ₃ ) δ: 1.05 (2H, q, J = 12.7 Hz), 1.31-1.47 (2H, br m), 1.47-1.69 (3H, m ), 1.69-1.87 (6H, m), 1.94 (2H, br d, J = 13.9 Hz), 2.00-2.22 (2H, m), 2.47 (1H, t, J = 11.1 Hz), 2.48-2.66 (4H, m), 2.89 (2H, br t, J = 12.3 Hz), 3.11 (2H, d, J = 7. 4 Hz), 3.20 (2 H, br t, J = 12.3 Hz), 3.26 (2 H, s), 3.43-3.62 (1 H, br m), 3.57 (2 H, s) 3.83 (3H, s), 3.87 (1H, br d, J = 13.5 Hz), 4.09-4.19 (1 H, br m), 4.46 (1 H, br d, J = 13. 5 Hz), 6.63 (1H, dd, J = 7.8, 1.2 Hz), 6.67 (1H, dt, J = 1.2, 7.8 Hz), 6.78 (1H, dd, J = 7.8, 1.2 Hz), 6.86 (1H, dt, J = 1.2, 7.8 Hz), 7.44 (2H, d, J = 8.2 Hz), 7.61 (2H, d, J = 8.2 Hz).

LC / MS [Condition 1]: Retention time 2.86 minutes; m / z 599.8 [M + H] ⁺ (ESI positive ion mode), m / z 644.0 [M + HCOO] ⁻ (ESI negative ion mode)

参考例２９３−１
４−（５−シアノピリジン−２−イルオキシ）ピペリジン−１−カルボン酸ｔ−ブチルの製造
４−ヒドロキシピペリジン−１−カルボン酸ｔ−ブチル（市販）（０．２０ｇ、０．９９ｍｍｏｌ）のテトラヒドロフラン（２．０ｍＬ）溶液に室温下、水素化ナトリウム（５５質量％、流動パラフィン分散）（４４ｍｇ、０．９９ｍｍｏｌ）を１３分かけて加えた。室温で２０分間攪拌したのち、６−クロロニコチノニトリル（市販）（０．１１ｇ、０．７９ｍｍｏｌ）のテトラヒドロフラン（２．０ｍＬ）溶液を加えて、３時間攪拌した。酢酸（２３μＬ）を加えて減圧下濃縮乾固した。残留物に酢酸エチル（２ｍＬ）と水（１ｍＬ）を加えたのち、有機層を分離して、減圧下濃縮乾固した。残留物をシリカゲルカラムクロマトグラフィー［充填剤：富士シリシア製ＦＬ１００Ｄ、展開溶媒：クロロホルム／酢酸エチル＝１０／１］にて精製し、表題化合物（０．２７ｇ、収率定量的）を白色固体として得た。

^１Ｈ−ＮＭＲ（ＣＤＣｌ_３）δ：１．４７（９Ｈ，ｓ），１．７５（２Ｈ，ｄｄｄｄ，Ｊ＝１３．１，８．６，８．２，３．７Ｈｚ），１．９２−２．０４（２Ｈ，ｍ），３．２８（２Ｈ，ｄｄｄ，Ｊ＝１３．９，８．６，３．７Ｈｚ），３．７０−３．８５（２Ｈ，ｍ），５．２９（１Ｈ，ｔｔ，Ｊ＝８．２，４．１Ｈｚ），６．７９（１Ｈ，ｄ，Ｊ＝９．０Ｈｚ），７．７８（１Ｈ，ｄｄ，Ｊ＝９．０，２．５Ｈｚ），８．４５（１Ｈ，ｄ，Ｊ＝２．５Ｈｚ）．

Reference Example 293-1
Preparation of 4- (5-cyanopyridin-2-yloxy) piperidine-1-carboxylate t-butyl 4-hydroxypiperidine-1-carboxylate (commercially available) (0.20 g, 0.99 mmol) in tetrahydrofuran (0.20 g, 0.99 mmol) 2.0 mL) solution was added sodium hydride (55 mass%, liquid paraffin dispersion) (44 mg, 0.99 mmol) at room temperature over 13 minutes. After stirring at room temperature for 20 minutes, a solution of 6-chloronicotinonitrile (commercially available) (0.11 g, 0.79 mmol) in tetrahydrofuran (2.0 mL) was added and stirred for 3 hours. Acetic acid (23 μL) was added and concentrated to dryness under reduced pressure. After adding ethyl acetate (2 mL) and water (1 mL) to the residue, the organic layer was separated and concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography [filler: FL100D manufactured by Fuji Silysia, developing solvent: chloroform / ethyl acetate = 10/1] to obtain the title compound (0.27 g, quantitative yield) as a white solid. It was.

¹ H-NMR (CDCl ₃ ) δ: 1.47 (9H, s), 1.75 (2H, dddd, J = 13.1, 8.6, 8.2, 3.7 Hz), 1.92- 2.04 (2H, m), 3.28 (2H, ddd, J = 13.9, 8.6, 3.7 Hz), 3.70-3.85 (2H, m), 5.29 (1H , Tt, J = 8.2, 4.1 Hz), 6.79 (1H, d, J = 9.0 Hz), 7.78 (1H, dd, J = 9.0, 2.5 Hz), 8. 45 (1H, d, J = 2.5 Hz).

参考例２９３−２
６−（ピペリジン−４−イルオキシ）ニコチノニトリル塩酸塩の製造
参考例２９３−１で得られた、４−（５−シアノピリジン−２−イルオキシ）ピペリジン−１−カルボン酸ｔ−ブチル（０．２６ｇ、０．８６ｍｍｏｌ）をメタノール（２ｍL）に溶解し、１０質量％塩化水素メタノール溶液（２ｍＬ）を加えて、５０℃で４時間静置したのち、反応溶液を減圧下濃縮乾固して、表題化合物（０．２２ｇ、収率定量的）を白色固体として得た。

^１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ_６）δ：１．７９−１．９８（２Ｈ，ｍ），２．０６−２．２２（２Ｈ，ｍ），３．１１（２Ｈ，ｄｄｄ，Ｊ＝１２．７，９．０，３．７Ｈｚ），３．２５（２Ｈ，ｄｄｄ，Ｊ＝１２．７，６．５，３．７Ｈｚ），５．３２（１Ｈ，ｔｔ，Ｊ＝７．８，３．７Ｈｚ），７．０３（１Ｈ，ｄ，Ｊ＝９．０Ｈｚ），８．１９（１Ｈ，ｄｄ，Ｊ＝９．０，２．５Ｈｚ），８．７０（１Ｈ，ｄ，Ｊ＝２．５Ｈｚ），８．７７（２Ｈ，ｂｒ ｓ）．

ＬＣ／ＭＳ［条件１］：保持時間０．５４分；ｍ／ｚ２０４．１［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）

Reference Example 293-2
Preparation of 6- (piperidin-4-yloxy) nicotinonitrile hydrochloride t-butyl 4- (5-cyanopyridin-2-yloxy) piperidine-1-carboxylate (0. 0) obtained in Reference Example 293-1. 26 g, 0.86 mmol) was dissolved in methanol (2 mL), 10 mass% hydrogen chloride methanol solution (2 mL) was added, and the mixture was allowed to stand at 50 ° C. for 4 hours. The reaction solution was concentrated to dryness under reduced pressure, The title compound (0.22 g, quantitative yield) was obtained as a white solid.

¹ H-NMR (DMSO-d ₆ ) δ: 1.79-1.98 (2H, m), 2.06-2.22 (2H, m), 3.11 (2H, ddd, J = 1.12. 7, 9.0, 3.7 Hz), 3.25 (2H, ddd, J = 12.7, 6.5, 3.7 Hz), 5.32 (1H, tt, J = 7.8, 3. 7 Hz), 7.03 (1 H, d, J = 9.0 Hz), 8.19 (1 H, dd, J = 9.0, 2.5 Hz), 8.70 (1 H, d, J = 2.5 Hz) ), 8.77 (2H, br s).

LC / MS [Condition 1]: Retention time 0.54 min; m / z 204.1 [M + H] ⁺ (ESI positive ion mode)

実施例２９３
６−｛１−［（１ｒ，４ｒ）−４−（｛２−オキソ−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）シクロヘキサンカルボニル］ピペリジン−４−イルオキシ｝ニコチノニトリル（化合物番号２９３）の製造
４−（アミノメチル）ベンゾニトリル塩酸塩の代わりに、参考例２９３−２で得られた６−（ピペリジン−４−イルオキシ）ニコチノニトリル塩酸塩を用いること以外は実質的に実施例２６３と同様に反応を行なって、表題化合物（２６ｍｇ、収率９３％）を白色固体として得た。

^１Ｈ−ＮＭＲ（ＣＤＣｌ_３）δ：１．０６（２Ｈ，ｑ，Ｊ＝１１．９Ｈｚ），１．４６−１．６８（３Ｈ，ｍ），１．６８−１．８７（８Ｈ，ｍ），１．９２−２．１３（２Ｈ，ｂｒ ｍ），１．９４（２Ｈ，ｂｒ ｄ，Ｊ＝１３．５Ｈｚ），２．４５−２．６９（４Ｈ，ｂｒ ｍ），２．４７（１Ｈ，ｔｔ，Ｊ＝１１．９，２．９Ｈｚ），３．１１（２Ｈ，ｄ，Ｊ＝７．４Ｈｚ），３．２６（２Ｈ，ｓ），３．３２−３．５２（２Ｈ，ｂｒ ｍ），３．５７（２Ｈ，ｓ），３．６７−３．８３（１Ｈ，ｂｒ ｍ），３．８９−４．０５（１Ｈ，ｂｒ ｍ），５．３６（１Ｈ，ｔｔ，Ｊ＝７．８，３．７Ｈｚ），６．８０（１Ｈ，ｄ，Ｊ＝９．０Ｈｚ），７．４４（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ），７．５７（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ），７．７９（１Ｈ，ｄｄ，Ｊ＝８．８，２．５Ｈｚ），８．４６（１Ｈ，ｄ，Ｊ＝２．５Ｈｚ）．

ＬＣ／ＭＳ［条件１］：保持時間３．３０分；ｍ／ｚ６３９．９［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ６８４．１［Ｍ＋ＨＣＯＯ］⁻（ＥＳＩ負イオンモード）

Example 293
6- {1-[(1r, 4r) -4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decane-3 Preparation of -yl} methyl) cyclohexanecarbonyl] piperidin-4-yloxy} nicotinonitrile (Compound No. 293) Instead of 4- (aminomethyl) benzonitrile hydrochloride, 6- (obtained in Reference Example 293-2 The reaction was carried out substantially in the same manner as in Example 263 except that piperidin-4-yloxy) nicotinonitrile hydrochloride was used to obtain the title compound (26 mg, yield 93%) as a white solid.

¹ H-NMR (CDCl ₃ ) δ: 1.06 (2H, q, J = 11.9 Hz), 1.46-1.68 (3H, m), 1.68-1.87 (8H, m) 1.92-2.13 (2H, br m), 1.94 (2H, br d, J = 13.5 Hz), 2.45-2.69 (4H, br m), 2.47 (1H , Tt, J = 11.9, 2.9 Hz), 3.11 (2H, d, J = 7.4 Hz), 3.26 (2H, s), 3.32-3.52 (2H, br m ), 3.57 (2H, s), 3.67-3.83 (1H, br m), 3.89-4.05 (1 H, br m), 5.36 (1 H, tt, J = 7) .8, 3.7 Hz), 6.80 (1H, d, J = 9.0 Hz), 7.44 (2H, d, J = 8.2 Hz), 7.57 (2H, d, J = 8. 2Hz), 7.79 1H, dd, J = 8.8,2.5Hz), 8.46 (1H, d, J = 2.5Hz).

LC / MS [Condition 1]: Retention time 3.30 minutes; m / z 639.9 [M + H] ⁺ (ESI positive ion mode), m / z 684.1 [M + HCOO] ⁻ (ESI negative ion mode)

実施例２９４
６−｛１−［４−（｛２−オキソ−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）ベンゾイル］ピペリジン−４−イルオキシ｝ニコチノニトリル（化合物番号２９４）の製造
４−ベンジルピペリジンの代わりに、参考例２９３−２で得られた６−（ピペリジン−４−イルオキシ）ニコチノニトリル塩酸塩とトリエチルアミンを用いること以外は実質的に実施例２５３と同様に反応を行なって、表題化合物(２９ｍｇ、収率定量的)を無色無定形物として得た。

^１Ｈ−ＮＭＲ（ＣＤＣｌ_３）δ：１．７２−２．２９（４Ｈ，ｂｒ ｍ），１．７３（２Ｈ，ｄｔ，Ｊ＝１３．５，７．０Ｈｚ），１．９２（２Ｈ，ｂｒ ｄ，Ｊ＝１３．５Ｈｚ），２．３９−２．６４（４Ｈ，ｂｒ ｍ），３．１４（２Ｈ，ｓ），３．２４−３．５１（１Ｈ，ｂｒ ｍ），３．４８−３．８５（２Ｈ，ｂｒ ｍ），３．５６（２Ｈ，ｓ），３．８８−４．２２（１Ｈ，ｂｒ ｍ），４．４５（２Ｈ，ｓ），５．４０（１Ｈ，ｔｔ，Ｊ＝７．０，３．７Ｈｚ），６．８１（１Ｈ，ｄ，Ｊ＝９．０Ｈｚ），７．３２（２Ｈ，ｄ，Ｊ＝７．８Ｈｚ），７．４２（２Ｈ，ｄ，Ｊ＝７．８Ｈｚ），７．４２（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ），７．５６（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ），７．８０（１Ｈ，ｄｄ，Ｊ＝９．０，２．０Ｈｚ），８．４５（１Ｈ，ｄ，Ｊ＝２．０Ｈｚ）．

ＬＣ／ＭＳ［条件１］：保持時間３．２６分；ｍ／ｚ６３３．９［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ６７７．９［Ｍ＋ＨＣＯＯ］⁻（ＥＳＩ負イオンモード）

Example 294
6- {1- [4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl) benzoyl Preparation of piperidin-4-yloxy} nicotinonitrile (Compound No. 294) Instead of 4-benzylpiperidine, 6- (piperidin-4-yloxy) nicotinonitrile hydrochloride and triethylamine obtained in Reference Example 293-2 The title compound (29 mg, quantitative yield) was obtained as a colorless amorphous substance by carrying out the reaction substantially in the same manner as in Example 253 except that was used.

¹ H-NMR (CDCl ₃ ) δ: 1.72-2.29 (4H, br m), 1.73 (2H, dt, J = 13.5, 7.0 Hz), 1.92 (2H, br d, J = 13.5 Hz), 2.39-2.64 (4H, br m), 3.14 (2H, s), 3.24-3.51 (1 H, br m), 3.48- 3.85 (2H, br m), 3.56 (2H, s), 3.88-4.22 (1 H, br m), 4.45 (2H, s), 5.40 (1 H, tt, J = 7.0, 3.7 Hz), 6.81 (1H, d, J = 9.0 Hz), 7.32 (2H, d, J = 7.8 Hz), 7.42 (2H, d, J = 7.8 Hz), 7.42 (2H, d, J = 8.2 Hz), 7.56 (2H, d, J = 8.2 Hz), 7.80 (1H, dd, J = 9.0, 2.0 Hz), 8. 5 (1H, d, J = 2.0Hz).

LC / MS [Condition 1]: Retention time 3.26 minutes; m / z 633.9 [M + H] ⁺ (ESI positive ion mode), m / z 677.9 [M + HCOO] ⁻ (ESI negative ion mode)

実施例２９５
３−［１−（（１ｒ，４ｒ）−４−｛［８−（４−シアノベンジル）−２−オキソ−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル］メチル｝シクロヘキサンカルボニル）ピペリジン−４−イルオキシ］ベンゾニトリル（化合物番号２９５）の製造
４−（アミノメチル）ベンゾニトリル塩酸塩の代わりに、参考例２８１−２で得られた３−（ピペリジン−４−イルオキシ）ベンゾニトリル塩酸塩を用いること以外は実質的に実施例２６３と同様に反応を行なって、表題化合物（２３ｍｇ、収率７９％）を白色固体として得た。

^１Ｈ−ＮＭＲ（ＣＤＣｌ_３）δ：１．０５（２Ｈ，ｑ，Ｊ＝１３．１Ｈｚ），１．４５−１．６８（３Ｈ，ｍ），１．７０−１．８７（８Ｈ，ｍ），１．８７−２．０３（４Ｈ，ｍ），２．４７（１Ｈ，ｂｒ ｔ，Ｊ＝１１．１Ｈｚ），２．４９−２．６２（４Ｈ，ｂｒ ｍ），３．１１（２Ｈ，ｄ，Ｊ＝７．４Ｈｚ），３．２６（２Ｈ，ｓ），３．３７−３．５１（１Ｈ，ｍ），３．５２−３．８６（３Ｈ，ｍ），３．５７（２Ｈ，ｓ），４．５６（１Ｈ，ｔｔ，Ｊ＝６．５，３．３Ｈｚ），７．１０−７．１９（２Ｈ，ｍ），７．２２−７．２８（１Ｈ，ｍ），７．３９（１Ｈ，ｔ，Ｊ＝７．８Ｈｚ），７．４５（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ），７．６１（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ）．

ＬＣ／ＭＳ［条件１］：保持時間３．１８分；ｍ／ｚ５９５．９［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ６４０．０［Ｍ＋ＨＣＯＯ］⁻（ＥＳＩ負イオンモード）

Example 295
3- [1-((1r, 4r) -4-{[8- (4-Cyanobenzyl) -2-oxo-1-oxa-3,8-diazaspiro [4.5] decan-3-yl] methyl } Preparation of cyclohexanecarbonyl) piperidin-4-yloxy] benzonitrile (Compound No. 295) Instead of 4- (aminomethyl) benzonitrile hydrochloride, 3- (piperidin-4-yloxy) obtained in Reference Example 281-2 ) The reaction was carried out in substantially the same manner as in Example 263 except that benzonitrile hydrochloride was used to obtain the title compound (23 mg, yield 79%) as a white solid.

¹ H-NMR (CDCl ₃ ) δ: 1.05 (2H, q, J = 13.1 Hz), 1.45 to 1.68 (3H, m), 1.70-1.87 (8H, m) 1.87-2.03 (4H, m), 2.47 (1H, br t, J = 11.1 Hz), 2.49-2.62 (4H, br m), 3.11 (2H, d, J = 7.4 Hz), 3.26 (2H, s), 3.37-3.51 (1H, m), 3.52-3.86 (3H, m), 3.57 (2H, s), 4.56 (1H, tt, J = 6.5, 3.3 Hz), 7.10-7.19 (2H, m), 7.22-7.28 (1H, m), 7. 39 (1H, t, J = 7.8 Hz), 7.45 (2H, d, J = 8.2 Hz), 7.61 (2H, d, J = 8.2 Hz).

LC / MS [Condition 1]: Retention time 3.18 minutes; m / z 595.9 [M + H] ⁺ (ESI positive ion mode), m / z 640.0 [M + HCOO] ⁻ (ESI negative ion mode)

実施例２９６
４−｛［３−（｛（１ｒ，４ｒ）−４−［４−（４−シアノフェノキシ）ピペリジン−１−カルボニル］シクロヘキシル｝メチル）−２−チオキソ−１−オキサ−３，８−ジアザスピロ［４．５］デカン−８−イル］メチル｝−３，５−ジフルオロベンゾニトリル（化合物番号２９６）の製造
３−｛［（１ｒ，４ｒ）−４−（４−ベンゾイルピペリジン−１−カルボニル）シクロヘキシル］メチル｝−１−オキサ−３，８−ジアザスピロ［４．５］デカン−２−オン塩酸塩の代わりに、参考例２９０で得られた４−（１−｛（１ｒ，４ｒ）−４−［（２−チオキソ−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル）メチル］シクロヘキサンカルボニル｝ピペリジン−４−イルオキシ）ベンゾニトリル塩酸塩を用いること以外は実質的に実施例２６７と同様に反応を行なって、表題化合物（２３ｍｇ、収率９４％）を白色固体として得た。

^１Ｈ−ＮＭＲ（ＣＤＣｌ_３）δ：１．０７−１．２８（２Ｈ，ｍ），１．４０−２．０９（１５Ｈ，ｍ），２．４９（１Ｈ，ｔ，Ｊ＝１１．５Ｈｚ），２．５３−２．８２（４Ｈ，ｍ），３．４０−３．５９（１Ｈ，ｂｒ ｍ），３．４１（２Ｈ，ｓ），３．５２（２Ｈ，ｄ，Ｊ＝７．０Ｈｚ），３．５９−３．９０（３Ｈ，ｂｒ ｍ），３．７５（２Ｈ，ｓ），４．５６−４．６９（１Ｈ，ｍ），６．９５（２Ｈ，ｄ，Ｊ＝８．６Ｈｚ），７．２３（２Ｈ，ｄ，Ｊ＝５．７Ｈｚ），７．６０（２Ｈ，ｄ，Ｊ＝８．６Ｈｚ）．

ＬＣ／ＭＳ［条件１］：保持時間３．５６分；ｍ／ｚ６４７．９［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ６９２．０［Ｍ＋ＨＣＯＯ］⁻（ＥＳＩ負イオンモード）

Example 296
4-{[3-({(1r, 4r) -4- [4- (4-cyanophenoxy) piperidine-1-carbonyl] cyclohexyl} methyl) -2-thioxo-1-oxa-3,8-diazaspiro [ 4.5] Preparation of decan-8-yl] methyl} -3,5-difluorobenzonitrile (Compound No. 296) 3-{[(1r, 4r) -4- (4-Benzoylpiperidine-1-carbonyl) cyclohexyl ] 4- (1-{(1r, 4r) -4-] obtained in Reference Example 290 instead of methyl} -1-oxa-3,8-diazaspiro [4.5] decan-2-one hydrochloride Other than using [(2-Thioxo-1-oxa-3,8-diazaspiro [4.5] decan-3-yl) methyl] cyclohexanecarbonyl} piperidin-4-yloxy) benzonitrile hydrochloride By performing the same reaction as substantially Example 267 to give the title compound (23 mg, 94% yield) as a white solid.

¹ H-NMR (CDCl ₃ ) δ: 1.07-1.28 (2H, m), 1.40-2.09 (15 H, m), 2.49 (1 H, t, J = 11.5 Hz) 2.53-2.82 (4H, m), 3.40-3.59 (1H, br m), 3.41 (2H, s), 3.52 (2H, d, J = 7.0 Hz) ), 3.59-3.90 (3H, br m), 3.75 (2H, s), 4.56-4.69 (1H, m), 6.95 (2H, d, J = 8. 6 Hz), 7.23 (2H, d, J = 5.7 Hz), 7.60 (2H, d, J = 8.6 Hz).

LC / MS [Condition 1]: Retention time 3.56 minutes; m / z 647.9 [M + H] ⁺ (ESI positive ion mode), m / z 692.0 [M + HCOO] ⁻ (ESI negative ion mode)

実施例２９７
３−（｛５−［４−（３−イソプロピル−１，２，４−オキサジアゾール−５−イル）ピペリジン−１−カルボニル］ピリジン−２−イル｝メチル）−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−２−オン（化合物番号２９７）の製造
テトラヒドロフルフリルアミンの代わりに参考例１９５で得られた３−イソプロピル−５−（ピペリジン−４−イル）−１，２，４−オキサジアゾール塩酸塩とトリエチルアミンを用いること以外は実質的に実施例１１１と同様に反応を行って、表題化合物（２５ｍｇ、定量的）を無色油状物として得た。

^１Ｈ−ＮＭＲ（ＣＤＣｌ_３）δ：１．３４（６Ｈ，ｄ，Ｊ＝６．０Ｈｚ），１．６６−１．８５（２Ｈ，ｍ），１．８８−２．０３（４Ｈ，ｍ），２．０６−２．２６（２Ｈ，ｍ），２．４５−２．６４（４Ｈ，ｍ），３．０１−３．１５（１Ｈ，ｓｅｐｔｅｔ，Ｊ＝６．０Ｈｚ），３．１７−３．３０（３Ｈ，ｍ），３．３５（２Ｈ，ｓ），３．５７（２Ｈ，ｓ），３．６９−３．８８（１Ｈ，ｂｒｍ），４．５０−４．６１（１Ｈ，ｂｒｍ），４．５８（２Ｈ，ｓ），７．３７（１Ｈ，ｄ，Ｊ＝７．８Ｈｚ），７．４４（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ），７．５７（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ），７．７６（１Ｈ，ｄｄ，Ｊ＝７．８，２．０Ｈｚ），８．６１（１Ｈ，ｄ，Ｊ＝２．０Ｈｚ）．

ＬＣ／ＭＳ［条件１］：保持時間３．１９分；ｍ／ｚ６２７．０［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ６７１．１［Ｍ＋ＨＣＯＯ］^―（ＥＳＩ負イオンモード）

Example 297
3-({5- [4- (3-Isopropyl-1,2,4-oxadiazol-5-yl) piperidin-1-carbonyl] pyridin-2-yl} methyl) -8- [4- (tri Preparation of fluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-2-one (Compound No. 297) 3-isopropyl-5 obtained in Reference Example 195 instead of tetrahydrofurfurylamine The reaction was carried out in substantially the same manner as in Example 111 except that-(piperidin-4-yl) -1,2,4-oxadiazole hydrochloride and triethylamine were used to give the title compound (25 mg, quantitative). Obtained as a colorless oil.

¹ H-NMR (CDCl ₃ ) δ: 1.34 (6H, d, J = 6.0 Hz), 1.6-1.85 (2H, m), 1.88-2.03 (4H, m) 2.06-2.26 (2H, m), 2.45-2.64 (4H, m), 3.01-3.15 (1H, septet, J = 6.0 Hz), 3.17- 3.30 (3H, m), 3.35 (2H, s), 3.57 (2H, s), 3.69-3.88 (1H, brm), 4.50-4.61 (1H, brm), 4.58 (2H, s), 7.37 (1H, d, J = 7.8 Hz), 7.44 (2H, d, J = 8.2 Hz), 7.57 (2H, d, J = 8.2 Hz), 7.76 (1H, dd, J = 7.8, 2.0 Hz), 8.61 (1H, d, J = 2.0 Hz).

LC / MS [Condition 1]: Retention time 3.19 minutes; m / z 627.0 [M + H] ⁺ (ESI positive ion mode), m / z 671.1 [M + HCOO] ⁻ (ESI negative ion mode)

実施例２９８
Ｎ−（４−シアノベンジル）−６−（｛２−オキソ−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）ニコチンアミド（化合物番号２９８）の製造
テトラヒドロフルフリルアミンの代わりに４−（アミノメチル）ベンゾニトリル塩酸塩とトリエチルアミンを用いること以外は実質的に実施例１１１と同様に反応を行って、表題化合物（２５ｍｇ、定量的）を無色油状物として得た。

^１Ｈ−ＮＭＲ（ＣＤＣｌ_３）δ：１．６９−１．８３（２Ｈ，ｍ），１．９０−２．０１（２Ｈ，ｍ），２．４７−２．５９（４Ｈ，ｍ），３．３４（２Ｈ，ｓ），３．５６（２Ｈ，ｓ），４．５７（２Ｈ，ｓ），４．７２（２Ｈ，ｄ，Ｊ＝６．１Ｈｚ），６．７９−６．９８（１Ｈ，ｂｒｍ），７．３７（１Ｈ，ｄ，Ｊ＝７．８Ｈｚ），７．４３（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ），７．４７（２Ｈ，ｄ，Ｊ＝８．５Ｈｚ），７．５７（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ），７．６４（２Ｈ，ｄ，Ｊ＝８．５Ｈｚ），８．１３（１Ｈ，ｄｄ，Ｊ＝７．８，２．４Ｈｚ），８．９６（１Ｈ，ｄ，Ｊ＝２．４Ｈｚ）．

ＬＣ／ＭＳ［条件１］：保持時間３．０６分；ｍ／ｚ５６３．９［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ５６２．１［Ｍ−Ｈ］^―（ＥＳＩ負イオンモード）

Example 298
N- (4-cyanobenzyl) -6-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} Preparation of methyl) nicotinamide (Compound No. 298) The title compound was reacted in substantially the same manner as in Example 111 except that 4- (aminomethyl) benzonitrile hydrochloride and triethylamine were used instead of tetrahydrofurfurylamine. (25 mg, quantitative) was obtained as a colorless oil.

¹ H-NMR (CDCl ₃ ) δ: 1.69-1.83 (2H, m), 1.90-2.01 (2H, m), 2.47-2.59 (4H, m), 3 .34 (2H, s), 3.56 (2H, s), 4.57 (2H, s), 4.72 (2H, d, J = 6.1 Hz), 6.79-6.98 (1H , Brm), 7.37 (1H, d, J = 7.8 Hz), 7.43 (2H, d, J = 8.2 Hz), 7.47 (2H, d, J = 8.5 Hz), 7 .57 (2H, d, J = 8.2 Hz), 7.64 (2H, d, J = 8.5 Hz), 8.13 (1H, dd, J = 7.8, 2.4 Hz), 8. 96 (1H, d, J = 2.4 Hz).

LC / MS [Condition 1]: Retention time 3.06 minutes; m / z 563.9 [M + H] ⁺ (ESI positive ion mode), m / z 562.1 [MH] ⁻ (ESI negative ion mode)

実施例２９９
４−［５−（｛２−オキソ−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）チアゾール−２−カルボキサミド］ピペリジン−１−カルボン酸メチル（化合物番号２９９）の製造
４−ベンゾイルピペリジン塩酸塩の代わりに参考例１３５で得られた４−アミノピペリジン−１−カルボン酸メチル塩酸塩を用いること以外は実質的に実施例１４２と同様に反応を行って、表題化合物（９．１ｍｇ、収率６９％）を油状物として得た。

^１Ｈ−ＮＭＲ（ＣＤＣｌ_３）δ：１．４３−１．５４（２Ｈ，ｍ），１．７０−１．８４（２Ｈ，ｍ），１．８８−２．１０（４Ｈ，ｍ），２．４９−２．６４（４Ｈ，ｍ），２．９８（２Ｈ，ｔ，Ｊ＝１２．１Ｈｚ），３．２８（２Ｈ，ｓ），３．５７（２Ｈ，ｓ），３．７１（３Ｈ，ｓ），４．０１−４．２７（３Ｈ，ｍ），４．５６（２Ｈ，ｓ），７．０７（１Ｈ，ｄ，Ｊ＝８．０Ｈｚ），７．４２（１Ｈ，ｓ），７．４４（２Ｈ，ｄ，Ｊ＝８．０Ｈｚ），７．５７（２Ｈ，ｄ，Ｊ＝８．０Ｈｚ）．

ＬＣ／ＭＳ［条件１］：保持時間３．０２分；ｍ／ｚ５９５．９［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ５９４．０［Ｍ−Ｈ］^―（ＥＳＩ負イオンモード）

Example 299
4- [5-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl) thiazole-2- Carboxamide] Preparation of methyl piperidine-1-carboxylate (Compound No. 299) Substantially except that 4-aminopiperidine-1-carboxylic acid methyl hydrochloride obtained in Reference Example 135 was used instead of 4-benzoylpiperidine hydrochloride The reaction was carried out in the same manner as in Example 142 to obtain the title compound (9.1 mg, yield 69%) as an oil.

¹ H-NMR (CDCl ₃ ) δ: 1.43-1.54 (2H, m), 1.70-1.84 (2H, m), 1.88-2.10 (4H, m), 2 49-2.64 (4H, m), 2.98 (2H, t, J = 12.1 Hz), 3.28 (2H, s), 3.57 (2H, s), 3.71 (3H) , S), 4.01-4.27 (3H, m), 4.56 (2H, s), 7.07 (1H, d, J = 8.0 Hz), 7.42 (1H, s), 7.44 (2H, d, J = 8.0 Hz), 7.57 (2H, d, J = 8.0 Hz).

LC / MS [Condition 1]: Retention time 3.02 minutes; m / z 595.9 [M + H] ⁺ (ESI positive ion mode), m / z 594.0 [M−H] ⁻ (ESI negative ion mode)

実施例３００
Ｎ−（４−シアノベンジル）−５−（｛２−オキソ−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）チアゾール−２−カルボキサミド（化合物番号３００）の製造
４−ベンゾイルピペリジン塩酸塩の代わりに４−（アミノメチル）ベンゾニトリル塩酸塩を用いること以外は実質的に実施例１４２と同様に反応を行って、表題化合物（７．９ｍｇ、収率６４％）を白色固体として得た。

^１Ｈ−ＮＭＲ（ＣＤＣｌ_３）δ：１．６８−１．８１（２Ｈ，ｍ），１．８７−１．９８（２Ｈ，ｍ），２．４５−２．６２（４Ｈ，ｍ），３．２５（２Ｈ，ｓ），３．５６（２Ｈ，ｓ），４．５６（２Ｈ，ｓ），４．６９（２Ｈ，ｄ，Ｊ＝６．３Ｈｚ），７．４３（２Ｈ，ｄ，Ｊ＝８．３Ｈｚ），７．４６（１Ｈ，ｓ），７．４６（２Ｈ，ｄ，Ｊ＝８．０Ｈｚ），７．５７（２Ｈ，ｄ，Ｊ＝８．３Ｈｚ），７．６１−７．６８（１Ｈ，ｍ），７．６４（２Ｈ，ｄ，Ｊ＝８．０Ｈｚ）．

ＬＣ／ＭＳ［条件１］：保持時間３．１９分；ｍ／ｚ５６９．８［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ５６８．０［Ｍ−Ｈ］^―（ＥＳＩ負イオンモード）

Example 300
N- (4-cyanobenzyl) -5-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} Preparation of methyl) thiazole-2-carboxamide (Compound No. 300) The reaction was carried out in substantially the same manner as in Example 142 except that 4- (aminomethyl) benzonitrile hydrochloride was used instead of 4-benzoylpiperidine hydrochloride. To give the title compound (7.9 mg, 64% yield) as a white solid.

¹ H-NMR (CDCl ₃ ) δ: 1.68-1.81 (2H, m), 1.87-1.98 (2H, m), 2.45-2.62 (4H, m), 3 .25 (2H, s), 3.56 (2H, s), 4.56 (2H, s), 4.69 (2H, d, J = 6.3 Hz), 7.43 (2H, d, J = 8.3 Hz), 7.46 (1H, s), 7.46 (2H, d, J = 8.0 Hz), 7.57 (2H, d, J = 8.3 Hz), 7.61-7 .68 (1H, m), 7.64 (2H, d, J = 8.0 Hz).

LC / MS [Condition 1]: Retention time 3.19 minutes; m / z 569.8 [M + H] ⁺ (ESI positive ion mode), m / z 568.0 [M−H] ⁻ (ESI negative ion mode)

実施例３０１
５−（｛２−オキソ−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）−Ｎ−［（テトラヒドロフラン−２−イル）メチル］チアゾール−２−カルボキサミド（化合物番号３０１）の製造
４−ベンゾイルピペリジン塩酸塩とトリエチルアミンの代わりにテトラヒドロフルフリルアミンを用いること以外は実質的に実施例１４２と同様に反応を行って、表題化合物（８．０ｍｇ、収率６８％）を油状物として得た。

^１Ｈ−ＮＭＲ（ＣＤＣｌ_３）δ：１．６０−１．６７（１Ｈ，ｍ），１．７０−１．８３（２Ｈ，ｍ），１．８６−２．１０（５Ｈ，ｍ），２．４８−２．６０（４Ｈ，ｍ），３．３２（２Ｈ，ｓ），３．３４−３．４３（１Ｈ，ｍ），３．５７（２Ｈ，ｓ），３．６８−３．８０（２Ｈ，ｍ），３．８３−３．９３（１Ｈ，ｍ），４．０１−４．１２（１Ｈ，ｍ），４．５６（２Ｈ，ｓ），７．４０−７．５２（１Ｈ，ｍ），７．４２（１Ｈ，ｓ），７．４３（２Ｈ，ｄ，Ｊ＝８．０Ｈｚ），７．５７（２Ｈ，ｄ，Ｊ＝８．０Ｈｚ）．

ＬＣ／ＭＳ［条件１］：保持時間２．９１分；ｍ／ｚ５３８．９［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ５３７．０［Ｍ−Ｈ］^―（ＥＳＩ負イオンモード）

Example 301
5-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl) -N-[(tetrahydrofuran- Preparation of 2-yl) methyl] thiazole-2-carboxamide (Compound No. 301) The reaction was carried out in substantially the same manner as in Example 142 except that tetrahydrofurfurylamine was used instead of 4-benzoylpiperidine hydrochloride and triethylamine. The title compound (8.0 mg, 68% yield) was obtained as an oil.

¹ H-NMR (CDCl ₃ ) δ: 1.60-1.67 (1H, m), 1.70-1.83 (2H, m), 1.86-2.10 (5H, m), 2 .48-2.60 (4H, m), 3.32 (2H, s), 3.34-3.43 (1H, m), 3.57 (2H, s), 3.68-3.80 (2H, m), 3.83-3.93 (1H, m), 4.01-4.12 (1H, m), 4.56 (2H, s), 7.40-7.52 (1H M), 7.42 (1H, s), 7.43 (2H, d, J = 8.0 Hz), 7.57 (2H, d, J = 8.0 Hz).

LC / MS [Condition 1]: Retention time 2.91 minutes; m / z 538.9 [M + H] ⁺ (ESI positive ion mode), m / z 537.0 [M−H] ⁻ (ESI negative ion mode)

実施例３０２
４−｛１−［６−（｛２−オキソ−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）ニコチノイル］ピペリジン−４−イルオキシ｝ベンゾニトリル（化合物番号３０２）の製造
テトラヒドロフルフリルアミンの代わりに４−（ピペリジン−４−イルオキシ）ベンゾニトリル塩酸塩とトリエチルアミンを用いること以外は実質的に実施例１１１と同様に反応を行って、表題化合物（１４ｍｇ、９６％）を無色油状物として得た。

^１Ｈ−ＮＭＲ（ＣＤＣｌ_３）δ：１．７１−２．１３（８Ｈ，ｂｒｍ），２．４５−２．６６（４Ｈ，ｍ），３．２９−４．００（４Ｈ，ｂｒｍ），３．３５（２Ｈ，ｓ），３．５７（２Ｈ，ｓ），４．５８（２Ｈ，ｓ），４．６６−４．７７（１Ｈ，ｍ），６．９７（２Ｈ，ｄ，Ｊ＝８．９Ｈｚ），７．３７（１Ｈ，ｄ，Ｊ＝７．８Ｈｚ），７．４３（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ），７．５７（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ），７．６０（２Ｈ，ｄ，Ｊ＝８．９Ｈｚ），７．７６（１Ｈ，ｄｄ，Ｊ＝７．８，２．０Ｈｚ），８．６２（１Ｈ，ｄ，Ｊ＝２．０Ｈｚ）．

ＬＣ／ＭＳ［条件１］：保持時間３．２６分；ｍ／ｚ６３４．０［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ６７８．１［Ｍ＋ＨＣＯＯ］^―（ＥＳＩ負イオンモード）

Example 302
4- {1- [6-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl) nicotinoyl Preparation of piperidin-4-yloxy} benzonitrile (Compound No. 302) Substantially the same as Example 111, except that 4- (piperidin-4-yloxy) benzonitrile hydrochloride and triethylamine were used in place of tetrahydrofurfurylamine. The title compound (14 mg, 96%) was obtained as a colorless oil.

¹ H-NMR (CDCl ₃ ) δ: 1.71-2.13 (8H, brm), 2.45-2.66 (4H, m), 3.29-4.00 (4H, brm), 3 .35 (2H, s), 3.57 (2H, s), 4.58 (2H, s), 4.66-4.77 (1H, m), 6.97 (2H, d, J = 8) .9 Hz), 7.37 (1H, d, J = 7.8 Hz), 7.43 (2H, d, J = 8.2 Hz), 7.57 (2H, d, J = 8.2 Hz), 7 .60 (2H, d, J = 8.9 Hz), 7.76 (1H, dd, J = 7.8, 2.0 Hz), 8.62 (1H, d, J = 2.0 Hz).

LC / MS [Condition 1]: retention time 3.26 minutes; m / z 634.0 [M + H] ⁺ (ESI positive ion mode), m / z 678.1 [M + HCOO] ⁻ (ESI negative ion mode)

実施例３０３
４−｛１−［５−（｛２−オキソ−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）チアゾール−２−カルボニル］ピペリジン−４−イルオキシ｝ベンゾニトリル（化合物番号３０３）の製造
４−ベンゾイルピペリジン塩酸塩の代わりに４−（ピペリジン−４−イルオキシ）ベンゾニトリル塩酸塩を用いること以外は実質的に実施例１４２と同様に反応を行って、表題化合物（５．８ｍｇ、収率４１％）を無色油状物として得た。

^１Ｈ−ＮＭＲ（ＣＤＣｌ_３）δ：１．６９−１．８２（２Ｈ，ｍ），１．８６−２．１３（６Ｈ，ｍ），２．４４−２．５９（４Ｈ，ｍ），３．２８（２Ｈ，ｓ），３．５５（２Ｈ，ｓ），３．８３−３．９５（２Ｈ，ｂｒｍ），４．３３−４．４９（２Ｈ，ｂｒｍ），４．５６（２Ｈ，ｓ），４．６７−４．７５（１Ｈ，ｍ），６．９７（２Ｈ，ｄ，Ｊ＝８．９Ｈｚ），７．３９（１Ｈ，ｓ），７．４３（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ），７．５７（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ），７．６１（２Ｈ，ｄ，Ｊ＝８．９Ｈｚ）．

ＬＣ／ＭＳ［条件１］：保持時間３．３９分；ｍ／ｚ６４０．０［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ６８４．０［Ｍ＋ＨＣＯＯ］^―（ＥＳＩ負イオンモード）

Example 303
4- {1- [5-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl) thiazole Preparation of 2-carbonyl] piperidin-4-yloxy} benzonitrile (Compound No. 303) Substantially except that 4- (piperidin-4-yloxy) benzonitrile hydrochloride is used instead of 4-benzoylpiperidine hydrochloride The reaction was carried out in the same manner as in Example 142 to obtain the title compound (5.8 mg, yield 41%) as a colorless oil.

¹ H-NMR (CDCl ₃ ) δ: 1.69-1.82 (2H, m), 1.86-2.13 (6H, m), 2.44-2.59 (4H, m), 3 .28 (2H, s), 3.55 (2H, s), 3.83-3.95 (2H, brm), 4.33-4.49 (2H, brm), 4.56 (2H, s) ), 4.67-4.75 (1H, m), 6.97 (2H, d, J = 8.9 Hz), 7.39 (1H, s), 7.43 (2H, d, J = 8) .2 Hz), 7.57 (2H, d, J = 8.2 Hz), 7.61 (2H, d, J = 8.9 Hz).

LC / MS [Condition 1]: Retention time 3.39 minutes; m / z 640.0 [M + H] ⁺ (ESI positive ion mode), m / z 684.0 [M + HCOO] ⁻ (ESI negative ion mode)

参考例３０４−１
４−［（２−オキソ−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル）メチル］安息香酸メチルの製造
参考例１−２で得られた、３−［４−（メトキシカルボニル）ベンジル］−２−オキソ−１−オキサ−３，８−ジアザスピロ［４．５］デカン−８−カルボン酸ｔ−ブチル（１６０ｍｇ、０．４０ｍｍｏｌ）をメタノール（０．４０ｍＬ）に溶解し、４Ｍ塩化水素−ジオキサン溶液（２．０ｍＬ）を加え、室温にて１時間かき混ぜた。減圧下、反応混合物を濃縮乾固した後、得られた固体をクロロホルムに溶解し、炭酸水素ナトリウム水溶液を加えて中和した。有機層を分離した後、飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥した。減圧下、溶媒を留去した後、得られた固体を酢酸エチルに溶解し、ヘキサンで再度析出させることで、表題化合物（９３ｍｇ、収率７６％）を白色固体として得た。

Reference Example 304-1
Production of methyl 4-[(2-oxo-1-oxa-3,8-diazaspiro [4.5] decan-3-yl) methyl] benzoate 3- [4- (Methoxycarbonyl) benzyl] -2-oxo-1-oxa-3,8-diazaspiro [4.5] decane-8-carboxylate t-butyl (160 mg, 0.40 mmol) dissolved in methanol (0.40 mL) 4M hydrogen chloride-dioxane solution (2.0 mL) was added, and the mixture was stirred at room temperature for 1 hr. The reaction mixture was concentrated to dryness under reduced pressure, and then the resulting solid was dissolved in chloroform and neutralized with an aqueous sodium hydrogen carbonate solution. The organic layer was separated, washed with saturated brine, and dried over anhydrous sodium sulfate. After evaporating the solvent under reduced pressure, the obtained solid was dissolved in ethyl acetate and precipitated again with hexane to obtain the title compound (93 mg, yield 76%) as a white solid.

参考例３０４−２
１−［４−（トリフルオロメチル）フェニル］エタノールの製造
１−［４−（トリフルオロメチル）フェニル］エタノン（市販試薬）（１９０ｍｇ、１．０ｍｍｏｌ）をメタノール（５．０ｍＬ）に溶解し、水素化ホウ素ナトリウム（３８ｍｇ、１．０ｍｍｏｌ）を加え、室温にて３０分間かき混ぜた。反応混合物に水と塩化アンモニウムを加えた後、酢酸エチルを加えた。有機層を分離し、水と飽和食塩水で洗浄した後、無水硫酸ナトリウムで乾燥した。有機層を減圧下濃縮し、表題化合物（１８０ｍｇ、収率９２％）を無色油状物として得た。
^１Ｈ−ＮＭＲ（ＣＤＣｌ_３）δ：１．５１（３Ｈ，ｄ，Ｊ＝６．８Ｈｚ），１．９１（１Ｈ，ｂｒｓ），４．９７（１Ｈ，ｑ，Ｊ＝６．８Ｈｚ），７．４９（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ），７．６１（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ）．

Reference Example 304-2
Preparation of 1- [4- (trifluoromethyl) phenyl] ethanol 1- [4- (trifluoromethyl) phenyl] ethanone (commercial reagent) (190 mg, 1.0 mmol) was dissolved in methanol (5.0 mL), Sodium borohydride (38 mg, 1.0 mmol) was added and stirred at room temperature for 30 minutes. Water and ammonium chloride were added to the reaction mixture, and then ethyl acetate was added. The organic layer was separated, washed with water and saturated brine, and dried over anhydrous sodium sulfate. The organic layer was concentrated under reduced pressure to give the title compound (180 mg, yield 92%) as a colorless oil.
¹ H-NMR (CDCl ₃ ) δ: 1.51 (3H, d, J = 6.8 Hz), 1.91 (1H, brs), 4.97 (1H, q, J = 6.8 Hz), 7 .49 (2H, d, J = 8.2 Hz), 7.61 (2H, d, J = 8.2 Hz).

参考例３０４−３
４−［（２−オキソ−８−｛１−［４−（トリフルオロメチル）フェニル］エチル｝−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル）メチル］安息香酸メチルの製造
参考例３０４−２で得られた１−［４−（トリフルオロメチル）フェニル］エタノール（３０ｍｇ、０．１６ｍｍｏｌ）をテトラヒドロフラン（２．０ｍＬ）に溶解し、氷冷下、塩化メタンスルホニル（０．０１４ｍＬ、０．１７ｍｍｏｌ）とトリエチルアミン（０．０２４ｍＬ、０．１７ｍｍｏｌ）を加えた後、３０分間かき混ぜた。さらに室温で１５分間かき混ぜた後、反応混合物を氷冷し、酢酸エチルと水を加え、有機層を分離した。有機層を水と飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥した後、減圧下濃縮してメタンスルホン酸１−［４−（トリフルオロメチル）フェニル］エチルを淡黄色油状物として得た。参考例３０４−１で得られた４−［（２−オキソ−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル）メチル］安息香酸メチル（５２ｍｇ、０．１７ｍｍｏｌ）をＮ，Ｎ−ジメチルホルムアミド（１．０ｍＬ）に溶解した後、氷冷下、上記で得られたメタンスルホン酸１−［４−（トリフルオロメチル）フェニル］エチルとトリエチルアミン（１７ｍｇ、０．１７ｍｍｏｌ）を加え、室温で１日間かき混ぜた。反応混合物に水を加えた後、析出した白色固体をろ取し、減圧下、５０度で１時間乾燥することで、表題化合物（２７ｍｇ、収率３４％）を白色固体として得た。

^１Ｈ−ＮＭＲ（ＣＤＣｌ_３）δ：１．３４（３Ｈ，ｄ，Ｊ＝６．５Ｈｚ），１．４９−１．９５（４Ｈ，ｍ），２．３８−２．６３（４Ｈ，ｍ），３．１０（２Ｈ，ｓ），３．４９（１Ｈ，ｑ，Ｊ＝６．５Ｈｚ），３．９２（３Ｈ，ｓ），４．４７（２Ｈ，ｓ），７．３３（２Ｈ，ｄ，Ｊ＝８．３Ｈｚ），７．４２（２Ｈ，ｄ，Ｊ＝８．３Ｈｚ），７．５６（２Ｈ，ｄ，Ｊ＝８．３Ｈｚ），８．０２（２Ｈ，ｄ，Ｊ＝８．３Ｈｚ）．

ＬＣ／ＭＳ［条件１］：保持時間３．１４分；ｍ／ｚ４７６．９［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）

Reference Example 304-3
4-[(2-oxo-8- {1- [4- (trifluoromethyl) phenyl] ethyl} -1-oxa-3,8-diazaspiro [4.5] decan-3-yl) methyl] benzoic acid Production of methyl 1- [4- (trifluoromethyl) phenyl] ethanol (30 mg, 0.16 mmol) obtained in Reference Example 304-2 was dissolved in tetrahydrofuran (2.0 mL), and methanesulfonyl chloride was cooled with ice. (0.014 mL, 0.17 mmol) and triethylamine (0.024 mL, 0.17 mmol) were added, followed by stirring for 30 minutes. After further stirring at room temperature for 15 minutes, the reaction mixture was ice-cooled, ethyl acetate and water were added, and the organic layer was separated. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give 1- [4- (trifluoromethyl) phenyl] ethyl methanesulfonate as a pale yellow oil. Methyl 4-[(2-oxo-1-oxa-3,8-diazaspiro [4.5] decan-3-yl) methyl] benzoate (52 mg, 0.17 mmol) obtained in Reference Example 304-1 After dissolving in N, N-dimethylformamide (1.0 mL), 1- [4- (trifluoromethyl) phenyl] ethyl methanesulfonate and triethylamine (17 mg, 0.17 mmol) obtained above under ice cooling And stirred at room temperature for 1 day. Water was added to the reaction mixture, and the precipitated white solid was collected by filtration and dried at 50 ° C. for 1 hour under reduced pressure to obtain the title compound (27 mg, yield 34%) as a white solid.

¹ H-NMR (CDCl ₃ ) δ: 1.34 (3H, d, J = 6.5 Hz), 1.49-1.95 (4H, m), 2.38-2.63 (4H, m) 3.10 (2H, s), 3.49 (1H, q, J = 6.5 Hz), 3.92 (3H, s), 4.47 (2H, s), 7.33 (2H, d) , J = 8.3 Hz), 7.42 (2H, d, J = 8.3 Hz), 7.56 (2H, d, J = 8.3 Hz), 8.02 (2H, d, J = 8. 3 Hz).

LC / MS [Condition 1]: Retention time 3.14 minutes; m / z 476.9 [M + H] ⁺ (ESI positive ion mode)

参考例３０４−４
４−［（２−オキソ−８−｛１−［４−（トリフルオロメチル）フェニル］エチル｝−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル）メチル］安息香酸の製造
３−（｛２−オキソ−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）安息香酸メチルの代わりに参考例３０４−３で得られた４−［（２−オキソ−８−｛１−［４−（トリフルオロメチル）フェニル］エチル｝−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル）メチル］安息香酸メチルを用いること以外は実質的に参考例１０８−３と同様に反応を行って、表題化合物（１９ｍｇ、収率７３％）を無色油状物として得た。

^１Ｈ−ＮＭＲ（ＣＤＣｌ_３）δ：１．７７（３Ｈ，ｄ，Ｊ＝６．１Ｈｚ），１．８６−２．０５（２Ｈ，ｍ），２．２７−２．５９（２Ｈ，ｍ），２．７６−２．９６（２Ｈ，ｍ），３．００−３．１４（１Ｈ，ｍ），３．１７（２Ｈ，ｓ），３．４１−３．５９（１Ｈ，ｍ），４．０６（１Ｈ，ｑ，Ｊ＝６．１Ｈｚ），４．４２（１Ｈ，ｄ，Ｊ＝１５．１Ｈｚ），４．５０（１Ｈ，ｄ，Ｊ＝１５．１Ｈｚ），７．３２（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ），７．６１−７．７２（４Ｈ，ｍ），８．０３（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ）．

ＬＣ／ＭＳ［条件１］：保持時間２．８４分；ｍ／ｚ４６２．８［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ４６１．０［Ｍ−Ｈ］^―（ＥＳＩ負イオンモード）

Reference Example 304-4
4-[(2-oxo-8- {1- [4- (trifluoromethyl) phenyl] ethyl} -1-oxa-3,8-diazaspiro [4.5] decan-3-yl) methyl] benzoic acid Preparation of 3-({2-Oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl) methylbenzoate 4-[(2-oxo-8- {1- [4- (trifluoromethyl) phenyl] ethyl} -1-oxa-3,8-diazaspiro [4.5] obtained in Reference Example 304-3. The reaction was carried out in substantially the same manner as in Reference Example 108-3 except that methyl (decan-3-yl) methyl] benzoate was used to give the title compound (19 mg, yield 73%) as a colorless oil.

¹ H-NMR (CDCl ₃ ) δ: 1.77 (3H, d, J = 6.1 Hz), 1.86-2.05 (2H, m), 2.27-2.59 (2H, m) , 2.76-2.96 (2H, m), 3.00-3.14 (1H, m), 3.17 (2H, s), 3.41-3.59 (1H, m), 4 .06 (1H, q, J = 6.1 Hz), 4.42 (1H, d, J = 15.1 Hz), 4.50 (1H, d, J = 15.1 Hz), 7.32 (2H, d, J = 8.2 Hz), 7.61-7.72 (4H, m), 8.03 (2H, d, J = 8.2 Hz).

LC / MS [Condition 1]: Retention time 2.84 minutes; m / z 462.8 [M + H] ⁺ (ESI positive ion mode), m / z 461.0 [M−H] ⁻ (ESI negative ion mode)

実施例３０４
３−［４−（４−ベンゾイルピペリジン−１−カルボニル）ベンジル］−８−｛１−［４−（トリフルオロメチル）フェニル］エチル｝−１−オキサ−３，８−ジアザスピロ［４．５］デカン−２−オン（化合物番号３０４）の製造
６−（｛２−オキソ−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）ニコチン酸の代わりに参考例３０４−４で得られた４−［（２−オキソ−８−｛１−［４−（トリフルオロメチル）フェニル］エチル｝−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル）メチル］安息香酸を、テトラヒドロフルフリルアミンの代わりに４−ベンゾイルピペリジン塩酸塩とトリエチルアミンを用いること以外は実質的に実施例１１１と同様に反応を行って、表題化合物（６．０ｍｇ、収率５０％）を得た。

^１Ｈ−ＮＭＲ（ＣＤＣｌ_３）δ：１．３５（３Ｈ，ｄ，Ｊ＝６．８Ｈｚ），１．６２−２．０７（８Ｈ，ｍ），２．３４−２．６４（４Ｈ，ｍ），３．００−３．２２（２Ｈ，ｂｒｍ），３．１０（２Ｈ，ｓ），３．４４−３．６２（１Ｈ，ｂｒｍ），３．５０（１Ｈ，ｑ，Ｊ＝６．８Ｈｚ），３．７３−３．９６（１Ｈ，ｂｒｍ），４．４４（２Ｈ，ｓ），４．５８−４．７７（１Ｈ，ｂｒｍ），７．３０（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ），７．３７−７．４５（４Ｈ，ｍ），７．４６−７．６３（５Ｈ，ｍ），７．９５（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ）．

ＬＣ／ＭＳ［条件１］：保持時間３．３９分；ｍ／ｚ６３３．７［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ６７８．０［Ｍ＋ＨＣＯＯ］^―（ＥＳＩ負イオンモード）

Example 304
3- [4- (4-Benzoylpiperidine-1-carbonyl) benzyl] -8- {1- [4- (trifluoromethyl) phenyl] ethyl} -1-oxa-3,8-diazaspiro [4.5] Preparation of decan-2-one (Compound No. 304) 6-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decane-3 4-[(2-oxo-8- {1- [4- (trifluoromethyl) phenyl] ethyl} -1-oxa-3 obtained in Reference Example 304-4 instead of -yl} methyl) nicotinic acid , 8-diazaspiro [4.5] decan-3-yl) methyl] benzoic acid is substantially as described in Example 11 except that 4-benzoylpiperidine hydrochloride and triethylamine are used in place of tetrahydrofurfurylamine. The reaction was carried out similarly to give the title compound (6.0 mg, 50% yield).

¹ H-NMR (CDCl ₃ ) δ: 1.35 (3H, d, J = 6.8 Hz), 1.62-2.07 (8H, m), 2.34-2.64 (4H, m) 3.00-3.22 (2H, brm), 3.10 (2H, s), 3.44-3.62 (1H, brm), 3.50 (1H, q, J = 6.8 Hz) , 3.73-3.96 (1H, brm), 4.44 (2H, s), 4.58-4.77 (1H, brm), 7.30 (2H, d, J = 8.2 Hz) 7.37-7.45 (4H, m), 7.46-7.63 (5H, m), 7.95 (2H, d, J = 8.2 Hz).

LC / MS [Condition 1]: Retention time 3.39 minutes; m / z 633.7 [M + H] ⁺ (ESI positive ion mode), m / z 678.0 [M + HCOO] ⁻ (ESI negative ion mode)

実施例３０５
４−（１−｛４−［（２−オキソ−８−｛１−［４−（トリフルオロメチル）フェニル］エチル｝−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル）メチル］ベンゾイル｝ピペリジン−４−イルオキシ）ベンゾニトリル（化合物番号３０５）の製造
６−（｛２−オキソ−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）ニコチン酸の代わりに考例３０４−４で得られた４−［（２−オキソ−８−｛１−［４−（トリフルオロメチル）フェニル］エチル｝−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル）メチル］安息香酸を、テトラヒドロフルフリルアミンの代わりに４−（ピペリジン−４−イルオキシ）ベンゾニトリル塩酸塩とトリエチルアミンを用いること以外は実質的に実施例１１１と同様に反応を行って、表題化合物（７．５ｍｇ、収率６１％）を得た。

^１Ｈ−ＮＭＲ（ＣＤＣｌ_３）δ：１．３５（３Ｈ，ｄ，Ｊ＝６．５Ｈｚ），１．６２−２．０７（８Ｈ，ｍ），２．３５−２．６３（４Ｈ，ｍ），３．１１（２Ｈ，ｓ），３．３６−３．９２（４Ｈ，ｂｒ ｍ），３．５０（１Ｈ，ｑ，Ｊ＝６．５Ｈｚ），４．４４（２Ｈ，ｓ），４．６３−４．７３（１Ｈ，ｍ），６．９６（２Ｈ，ｄ，Ｊ＝８．９Ｈｚ），７．３１（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ），７．４０（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ），７．４２（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ），７．５６（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ），７．５９（２Ｈ，ｄ，Ｊ＝８．９Ｈｚ）．

ＬＣ／ＭＳ［条件１］：保持時間３．４４分；ｍ／ｚ６４７．０［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ６９１．０［Ｍ＋ＨＣＯＯ］^―（ＥＳＩ負イオンモード）

Example 305
4- (1- {4-[(2-oxo-8- {1- [4- (trifluoromethyl) phenyl] ethyl} -1-oxa-3,8-diazaspiro [4.5] decane-3- Yl) methyl] benzoyl} piperidin-4-yloxy) benzonitrile (Compound No. 305) 6-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8- 4-[(2-oxo-8- {1- [4- (trifluoromethyl) phenyl] obtained in Example 304-4 instead of diazaspiro [4.5] decan-3-yl} methyl) nicotinic acid ] Ethyl} -1-oxa-3,8-diazaspiro [4.5] decan-3-yl) methyl] benzoic acid with 4- (piperidin-4-yloxy) benzonitrile hydrochloride instead of tetrahydrofurfurylamine Except using triethylamine is carried out the same reaction as substantially Example 111 to give the title compound (7.5 mg, 61% yield).

¹ H-NMR (CDCl ₃ ) δ: 1.35 (3H, d, J = 6.5 Hz), 1.62-2.07 (8H, m), 2.35-2.63 (4H, m) , 3.11 (2H, s), 3.36-3.92 (4H, br m), 3.50 (1H, q, J = 6.5 Hz), 4.44 (2H, s), 4. 63-4.73 (1H, m), 6.96 (2H, d, J = 8.9 Hz), 7.31 (2H, d, J = 8.2 Hz), 7.40 (2H, d, J = 8.2 Hz), 7.42 (2H, d, J = 8.2 Hz), 7.56 (2H, d, J = 8.2 Hz), 7.59 (2H, d, J = 8.9 Hz) .

LC / MS [Condition 1]: Retention time 3.44 minutes; m / z 647.0 [M + H] ⁺ (ESI positive ion mode), m / z 691.0 [M + HCOO] ⁻ (ESI negative ion mode)

参考例３０６−１
４−［（４−ブロモフェネチルアミノ）メチル］−４−ヒドロキシピペリジン−１−カルボン酸ｔ−ブチルの製造
参考例１−１で得られた１−オキサ−６−アザスピロ［２．５］オクタン−６−カルボン酸ｔ−ブチル（１ｇ、４．７ｍｍｏｌ）をメタノール（１０ｍＬ）と水（１０ｍＬ）に懸濁した後、４−ブロモフェネチルアミン（市販）（９４０ｍｇ、４．７ｍｍｏｌ）を加え、室温で４５時間かき混ぜた。反応混合物にクロロホルムを加えた後、有機層を分離し、飽和塩化アンモニウム水溶液と飽和食塩水で洗浄した。有機層を無水硫酸ナトリウムで乾燥した後、減圧下濃縮した。得られた残留物を少量の酢酸エチルに溶解した後、ヘキサンを加え結晶化した。得られた白色固体を減圧下、５０度で乾燥させ、表題化合物（１．６ｇ、収率８１％）を得た。

^１Ｈ−ＮＭＲ（ＣＤＣｌ_３）δ：１．２８−１．５２（４Ｈ，ｍ），１．４５（９Ｈ，ｓ），２．５２（２Ｈ，ｓ），２．７３（２Ｈ，ｔ，Ｊ＝７．０Ｈｚ），２．９０（２Ｈ，ｔ，Ｊ＝７．０Ｈｚ），３．０３−３．３４（２Ｈ，ｍ），３．６９−４．０２（２Ｈ，ｍ），７．０６（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ），７．４２（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ）．
（ＮＨ、ＯＨ ｉｎｖｉｓｉｂｌｅ）

ＬＣ／ＭＳ［条件１］：保持時間３．２２分；ｍ／ｚ４１２．９、４１４．８［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、保持時間３．８１分；ｍ／ｚ４４６．９、４４９．２［Ｍ＋ＨＣＯＯ］^―（ＥＳＩ負イオンモード）

Reference Example 306-1
Production of t-butyl 4-[(4-bromophenethylamino) methyl] -4-hydroxypiperidine-1-carboxylate 1-oxa-6-azaspiro [2.5] octane- obtained in Reference Example 1-1 After 6-carboxylate t-butyl (1 g, 4.7 mmol) was suspended in methanol (10 mL) and water (10 mL), 4-bromophenethylamine (commercially available) (940 mg, 4.7 mmol) was added, and the mixture was stirred at room temperature. Stir for hours. After adding chloroform to the reaction mixture, the organic layer was separated and washed with saturated aqueous ammonium chloride and saturated brine. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained residue was dissolved in a small amount of ethyl acetate, and hexane was added for crystallization. The obtained white solid was dried at 50 ° C. under reduced pressure to obtain the title compound (1.6 g, yield 81%).

¹ H-NMR (CDCl ₃ ) δ: 1.28-1.52 (4H, m), 1.45 (9H, s), 2.52 (2H, s), 2.73 (2H, t, J = 7.0 Hz), 2.90 (2H, t, J = 7.0 Hz), 3.03-3.34 (2H, m), 3.69-4.02 (2H, m), 7.06 (2H, d, J = 8.2 Hz), 7.42 (2H, d, J = 8.2 Hz).
(NH, OH invisible)

LC / MS [Condition 1]: Retention time 3.22 minutes; m / z 412.9, 414.8 [M + H] ⁺ (ESI positive ion mode), retention time 3.81 minutes; m / z 446.9, 449. 2 [M + HCOO] ^- (ESI negative ion mode)

参考例３０６−２
３−（４−ブロモフェネチル）−２−オキソ−１−オキサ−３，８−ジアザスピロ［４．５］デカン−８−カルボン酸ｔ−ブチルの製造
参考例３０６−１で得られた４−［（４−ブロモフェネチルアミノ）メチル］−４−ヒドロキシピペリジン−１−カルボン酸ｔ−ブチル（１．５ｇ、３．６ｍｍｏｌ）をテトラヒドロフラン（２０ｍＬ）に溶解した後、１，１’−カルボニルジイミダゾール（１．２ｇ、７．３ｍｍｏｌ）を加え、室温で４８時間かき混ぜた。反応混合物に水を加えた後、発泡が収まるまで１時間かき混ぜた。反応混合物に酢酸エチルを加えた後、有機層を分離し、水と飽和食塩水で洗浄した。有機層を無水硫酸ナトリウムで乾燥した後、減圧下濃縮した。得られた残留物を少量の酢酸エチルに溶解した後、ヘキサンを加えて結晶化した。得られた白色固体を回収し、減圧下、５０度で乾燥することで表題化合物（９７０ｍｇ、収率６１％）を得た。

^１Ｈ−ＮＭＲ（ＣＤＣｌ_３）δ：１．４５（９Ｈ，ｓ），１．５０−１．６３（２Ｈ，ｍ），１．７０−１．８４（２Ｈ，ｍ），２．８４（２Ｈ，ｔ，Ｊ＝７．２Ｈｚ），３．０９（２Ｈ，ｓ），３．１７−３．３２（２Ｈ，ｍ），３．５０（２Ｈ，ｔ，Ｊ＝７．２Ｈｚ），３．６７−３．８７（２Ｈ，ｍ），７．０９（２Ｈ，ｄ，Ｊ＝８．５Ｈｚ），７．４３（２Ｈ，ｄ，Ｊ＝８．５Ｈｚ）．

ＬＣ／ＭＳ［条件１］：保持時間４．６５分；ｍ／ｚ４６０．７、４６２．７［Ｍ＋Ｎａ］^＋（ＥＳＩ正イオンモード）

Reference Example 306-2
Production of t-butyl 3- (4-bromophenethyl) -2-oxo-1-oxa-3,8-diazaspiro [4.5] decane-8-carboxylate 4- [obtained in Reference Example 306-1 (4-Bromophenethylamino) methyl] -4-hydroxypiperidine-1-carboxylate t-butyl (1.5 g, 3.6 mmol) was dissolved in tetrahydrofuran (20 mL), and 1,1′-carbonyldiimidazole ( 1.2 g, 7.3 mmol) was added and stirred at room temperature for 48 hours. Water was added to the reaction mixture, and the mixture was stirred for 1 hour until foaming stopped. After adding ethyl acetate to the reaction mixture, the organic layer was separated and washed with water and saturated brine. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained residue was dissolved in a small amount of ethyl acetate and crystallized by adding hexane. The resulting white solid was collected and dried at 50 ° C. under reduced pressure to give the title compound (970 mg, 61% yield).

¹ H-NMR (CDCl ₃ ) δ: 1.45 (9H, s), 1.50-1.63 (2H, m), 1.70-1.84 (2H, m), 2.84 (2H , T, J = 7.2 Hz), 3.09 (2H, s), 3.17-3.32 (2H, m), 3.50 (2H, t, J = 7.2 Hz), 3.67 -3.87 (2H, m), 7.09 (2H, d, J = 8.5 Hz), 7.43 (2H, d, J = 8.5 Hz).

LC / MS [Condition 1]: Retention time 4.65 minutes; m / z 460.7, 462.7 [M + Na] ⁺ (ESI positive ion mode)

参考例３０６−３
２−オキソ−３−（４−ビニルフェネチル）−１−オキサ−３，８−ジアザスピロ［４．５］デカン−８−カルボン酸ｔ−ブチルの製造
参考例３０６−２で得られた３−（４−ブロモフェネチル）−２−オキソ−１−オキサ−３，８−ジアザスピロ［４．５］デカン−８−カルボン酸ｔ−ブチル（１００ｍｇ、０．２３ｍｍｏｌ）、トリブチル（ビニル）スズ（８７ｍｇ、０．２７ｍｍｏｌ）とテトラキス（トリフェニルホスフィン）パラジウム錯体（２７ｍｇ、０．０２３ｍｍｏｌ）をトルエンに懸濁させた後、１１０度で３時間かき混ぜた。反応混合物を室温まで冷却した後、５％フッ化カリウム水溶液を加え、室温で１時間かき混ぜた。反応混合物に酢酸エチルを加えた後、セライトでろ過し、不溶物を除去した。ろ液の有機層を分離し、水と飽和食塩水で洗浄した後、無水硫酸ナトリウムで乾燥した。減圧下、有機層を濃縮乾固した後、得られた残留物をシリカゲルカラムクロマトグラフィー［昭光サイエンティフィック社製プリフパックＳＩ６０μｍ、展開溶媒：ヘキサン−酢酸エチル］にて精製し、表題化合物（５４ｍｇ、収率６２％）を白色固体として得た。

^１Ｈ−ＮＭＲ（ＣＤＣｌ_３）δ：１．４５（９Ｈ，ｓ），１．５０−１．５９（２Ｈ，ｍ），１．７２−１．８１（２Ｈ，ｍ），２．８８（２Ｈ，ｔ，Ｊ＝７．２Ｈｚ），３．０７（２Ｈ，ｓ），３．１７−３．３１（２Ｈ，ｍ），３．５２（２Ｈ，ｔ，Ｊ＝７．２Ｈｚ），３．６６−３．８４（２Ｈ，ｂｒ ｍ），５．２４（１Ｈ，ｄ，Ｊ＝１０．９Ｈｚ），５．７３（１Ｈ，ｄ，Ｊ＝１７．４Ｈｚ），６．６９（１Ｈ，ｄｄ，Ｊ＝１７．４，１０．９Ｈｚ），７．１８（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ），７．３６（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ）．

ＬＣ／ＭＳ［条件１］：保持時間４．４７分；ｍ／ｚ４０８．８［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）

Reference Example 306-3
Preparation of 2-oxo-3- (4-vinylphenethyl) -1-oxa-3,8-diazaspiro [4.5] decane-8-carboxylate 3-butyl obtained in Reference Example 306-2 4-Bromophenethyl) -2-oxo-1-oxa-3,8-diazaspiro [4.5] decane-8-carboxylate t-butyl (100 mg, 0.23 mmol), tributyl (vinyl) tin (87 mg, 0 .27 mmol) and tetrakis (triphenylphosphine) palladium complex (27 mg, 0.023 mmol) were suspended in toluene, and then stirred at 110 degrees for 3 hours. The reaction mixture was cooled to room temperature, 5% aqueous potassium fluoride solution was added, and the mixture was stirred at room temperature for 1 hr. Ethyl acetate was added to the reaction mixture, followed by filtration through celite to remove insolubles. The organic layer of the filtrate was separated, washed with water and saturated brine, and dried over anhydrous sodium sulfate. The organic layer was concentrated to dryness under reduced pressure, and the obtained residue was purified by silica gel column chromatography [Prefpack SI 60 μm, developed by Shoko Scientific Co., Ltd., developing solvent: hexane-ethyl acetate] to give the title compound (54 mg, Yield 62%) was obtained as a white solid.

¹ H-NMR (CDCl ₃ ) δ: 1.45 (9H, s), 1.50-1.59 (2H, m), 1.72-1.81 (2H, m), 2.88 (2H , T, J = 7.2 Hz), 3.07 (2H, s), 3.17-3.31 (2H, m), 3.52 (2H, t, J = 7.2 Hz), 3.66 -3.84 (2H, br m), 5.24 (1H, d, J = 10.9 Hz), 5.73 (1H, d, J = 17.4 Hz), 6.69 (1H, dd, J = 17.4, 10.9 Hz), 7.18 (2H, d, J = 8.2 Hz), 7.36 (2H, d, J = 8.2 Hz).

LC / MS [Condition 1]: Retention time 4.47 minutes; m / z 408.8 [M + H] ⁺ (ESI positive ion mode)

参考例３０６−４
３−（４−ホルミルフェネチル）−２−オキソ−１−オキサ−３，８−ジアザスピロ［４．５］デカン−８−カルボン酸ｔ−ブチルの製造
参考例３０６−３で得られた２−オキソ−３−（４−ビニルフェネチル）−１−オキサ−３，８−ジアザスピロ［４．５］デカン−８−カルボン酸ｔ−ブチル（５０ｍｇ、０．１３ｍｍｏｌ）をテトラヒドロフラン（２．０ｍＬ）に溶解した後、四酸化オスミウム（マイクロカプセル化、含有率１０重量％。和光純薬社より購入。）（４６ｍｇ、０．１０ｍｍｏｌ）、水（１．０ｍＬ）と過ヨウ素酸ナトリウム（８３ｍｇ、０．３９ｍｍｏｌ）を加え、室温でかき混ぜた。反応混合物にチオ硫酸ナトリウム水溶液を加えた後、室温で１０分間かき混ぜた。酢酸エチルを加えた後、不溶物を除去し、ろ液の有機層を分離した。有機層を飽和食塩水で洗浄した後、無水硫酸ナトリウムで乾燥し、減圧下、濃縮乾固し、表題化合物（６０ｍｇ）を白色固体として得た。得られた固体は、未精製のまま次の反応に使用した。

^１Ｈ−ＮＭＲ（ＣＤＣｌ_３）δ：１．４５（９Ｈ，ｓ），１．５０−１．６１（２Ｈ，ｍ），１．７０−１．８３（２Ｈ，ｍ），２．９８（２Ｈ，ｔ，Ｊ＝７．２Ｈｚ），３．１１（２Ｈ，ｓ），３．１７−３．２９（２Ｈ，ｍ），３．５８（２Ｈ，ｔ，Ｊ＝７．２Ｈｚ），３．７２−３．８９（２Ｈ，ｍ），７．４０（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ），７．８５（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ），１０．００（１Ｈ，ｓ）．

ＬＣ／ＭＳ［条件１］：保持時間４．０２分；ｍ／ｚ４１０．９［Ｍ＋Ｎａ］^＋（ＥＳＩ正イオンモード）

Reference Example 306-4
Preparation of t-butyl 3- (4-formylphenethyl) -2-oxo-1-oxa-3,8-diazaspiro [4.5] decane-8-carboxylate 2-oxo obtained in Reference Example 306-3 -3- (4-Vinylphenethyl) -1-oxa-3,8-diazaspiro [4.5] decane-8-carboxylate t-butyl (50 mg, 0.13 mmol) was dissolved in tetrahydrofuran (2.0 mL). Thereafter, osmium tetroxide (microencapsulation, content 10% by weight, purchased from Wako Pure Chemical Industries, Ltd.) (46 mg, 0.10 mmol), water (1.0 mL) and sodium periodate (83 mg, 0.39 mmol) Was added and stirred at room temperature. An aqueous sodium thiosulfate solution was added to the reaction mixture, and the mixture was stirred at room temperature for 10 minutes. After adding ethyl acetate, insoluble matters were removed, and the organic layer of the filtrate was separated. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to dryness under reduced pressure to give the title compound (60 mg) as a white solid. The obtained solid was used for the next reaction without purification.

¹ H-NMR (CDCl ₃ ) δ: 1.45 (9H, s), 1.50-1.61 (2H, m), 1.70-1.83 (2H, m), 2.98 (2H , T, J = 7.2 Hz), 3.11 (2H, s), 3.17-3.29 (2H, m), 3.58 (2H, t, J = 7.2 Hz), 3.72. -3.89 (2H, m), 7.40 (2H, d, J = 8.2 Hz), 7.85 (2H, d, J = 8.2 Hz), 10.00 (1H, s).

LC / MS [Condition 1]: Retention time 4.02 min; m / z 410.9 [M + Na] ⁺ (ESI positive ion mode)

参考例３０６−５
４−｛２−［８−（ｔ−ブトキシカルボニル）−２−オキソ−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル］エチル｝安息香酸の製造
参考例３０６−４で得られた３−（４−ホルミルフェネチル）−２−オキソ−１−オキサ−３，８−ジアザスピロ［４．５］デカン−８−カルボン酸ｔ−ブチル（６０ｍｇ）をｔ−ブチルアルコール（１．５ｍＬ）と水（１．０ｍＬ）に懸濁し、２−メチル−２−ブテン（０．１４ｍＬ、１．３ｍｍｏｌ）、リン酸二水素ナトリウム（７８ｍｇ、０．６５ｍｍｏｌ）と過塩素酸ナトリウム（３５ｍｇ、０．３９ｍｍｏｌ）を加え、室温で２４時間かき混ぜた。反応混合物にジメチルスルホキシド（０．５０ｍＬ）を加え、さらに室温で２４時間かき混ぜた。反応混合物に過塩素酸ナトリウム（３５ｍｇ、０．３９ｍｍｏｌ）、リン酸二水素ナトリウム（７８ｍｇ、０．６５ｍｍｏｌ）と２−メチル−２−ブテン（０．１４ｍＬ、１．３ｍｍｏｌ）を加えた後、クロロホルム（１．５ｍＬ）を加え、室温で２４時間かき混ぜた。反応混合物を減圧下濃縮した後、クロロホルムと水を加えて振とうし、有機層を分離し、水層をクロロホルムで２回抽出した。合わせた有機層を飽和食塩水で洗浄した後、分離した水層を再びクロロホルムで１回抽出した。合わせた有機層を無水硫酸ナトリウムで乾燥した後、減圧下濃縮乾固した。残留物にジエチルエーテルを加えて、析出した白色固体を回収し、減圧下、３０度で１時間乾燥することで、表題化合物（２８ｍｇ、収率５３％（２段階））を得た。

ＬＣ／ＭＳ［条件１］：保持時間３．８１分；ｍ／ｚ４０３．０［Ｍ−Ｈ］^―（ＥＳＩ負イオンモード）

Reference Example 306-5
Preparation of 4- {2- [8- (t-butoxycarbonyl) -2-oxo-1-oxa-3,8-diazaspiro [4.5] decan-3-yl] ethyl} benzoic acid Reference Example 306-4 3- (4-formylphenethyl) -2-oxo-1-oxa-3,8-diazaspiro [4.5] decane-8-carboxylate t-butyl (60 mg) obtained in 1 above was added to t-butyl alcohol (1 0.5 mL) and water (1.0 mL), 2-methyl-2-butene (0.14 mL, 1.3 mmol), sodium dihydrogen phosphate (78 mg, 0.65 mmol) and sodium perchlorate (35 mg). , 0.39 mmol) was added and stirred at room temperature for 24 hours. Dimethyl sulfoxide (0.50 mL) was added to the reaction mixture, and the mixture was further stirred at room temperature for 24 hours. After adding sodium perchlorate (35 mg, 0.39 mmol), sodium dihydrogen phosphate (78 mg, 0.65 mmol) and 2-methyl-2-butene (0.14 mL, 1.3 mmol) to the reaction mixture, chloroform was added. (1.5 mL) was added and stirred at room temperature for 24 hours. The reaction mixture was concentrated under reduced pressure, chloroform and water were added and shaken, the organic layer was separated, and the aqueous layer was extracted twice with chloroform. The combined organic layers were washed with saturated brine, and the separated aqueous layer was extracted once again with chloroform. The combined organic layers were dried over anhydrous sodium sulfate and then concentrated to dryness under reduced pressure. Diethyl ether was added to the residue, and the precipitated white solid was collected, and dried under reduced pressure at 30 ° C. for 1 hour to obtain the title compound (28 mg, yield 53% (2 steps)).

LC / MS [Condition 1]: Retention time 3.81 minutes; m / z 403.0 [M−H] ⁻ (ESI negative ion mode)

参考例３０６−６
３−｛４−［４−（４−シアノフェノキシ）ピペリジン−１−カルボニル］フェネチル｝−２−オキソ−１−オキサ−３，８−ジアザスピロ［４．５］デカン−８−カルボン酸ｔ−ブチルの製造
参考例３０６−５で得られた４−｛２−［８−（ｔ−ブトキシカルボニル）−２−オキソ−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル］エチル｝安息香酸（２５ｍｇ、０．０６２ｍｍｏｌ）、参考例２６４−２で得られた４−（ピペリジン−４−イルオキシ）ベンゾニトリル塩酸塩（１５ｍｇ、０．０６２ｍｍｏｌ）と１−ヒドロキシベンゾトリアゾール（２．５ｍｇ、０．０１９ｍｍｏｌ）をクロロホルム（２．０ｍＬ）に溶解した後、トリエチルアミン（０．００９０ｍＬ、０．０６２ｍｍｏｌ）と１−エチル−３−（３−ジメチルアミノプロピル）カルボジイミド塩酸塩（１２ｍｇ、０．０６２ｍｍｏｌ）を加え、室温で２０時間かき混ぜた。水を加えた後、振とうし、有機層を分離した。有機層をクエン酸水溶液、１．０Ｍ水酸化ナトリウム水溶液、水と飽和食塩水で洗浄した後、無水硫酸ナトリウムで乾燥し、減圧下濃縮乾固した。残留物を分取用薄層クロマトグラフィー［メルク社製ＰＬＣガラスプレートシリカゲル６０Ｆ_２５４、展開溶媒：クロロホルム／メタノール＝１０／１］にて精製し、表題化合物（２２ｍｇ、収率６０％）を白色固体として得た。

^１Ｈ−ＮＭＲ（ＣＤＣｌ_３）δ：１．４５（９Ｈ，ｓ），１．５３−１．６２（２Ｈ，ｍ），１．７３−２．１１（６Ｈ，ｍ），２．９２（２Ｈ，ｔ，Ｊ＝７．２Ｈｚ），３．１３（２Ｈ，ｓ），３．１７−３．３０（２Ｈ，ｍ），３．４８−３．９６（６Ｈ，ｍ），３．５３（２Ｈ，ｔ，Ｊ＝７．２Ｈｚ），４．６２−４．７２（１Ｈ，ｍ），６．９６（２Ｈ，ｄ，Ｊ＝９．２Ｈｚ），７．２７（２Ｈ，ｄ，Ｊ＝８．０Ｈｚ），７．３８（２Ｈ，ｄ，Ｊ＝８．０Ｈｚ），７．５９（２Ｈ，ｄ，Ｊ＝９．２Ｈｚ）．

ＬＣ／ＭＳ［条件１］：保持時間４．３４分；ｍ／ｚ６１０．８［Ｍ＋Ｎａ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ６３３．０［Ｍ＋ＨＣＯＯ］^―（ＥＳＩ負イオンモード）

Reference Example 306-6
3- {4- [4- (4-Cyanophenoxy) piperidine-1-carbonyl] phenethyl} -2-oxo-1-oxa-3,8-diazaspiro [4.5] decane-8-carboxylate t-butyl obtained in the reference example 306-5 4- {2- [8- (t- butoxycarbonyl) -2-oxo-1-oxa-3,8-diazaspiro [4.5] decan-3-yl] Ethyl} benzoic acid (25 mg, 0.062 mmol), 4- (piperidin-4-yloxy) benzonitrile hydrochloride (15 mg, 0.062 mmol) obtained in Reference Example 264-2 and 1-hydroxybenzotriazole (2. 5 mg, 0.019 mmol) was dissolved in chloroform (2.0 mL), then triethylamine (0.0090 mL, 0.062 mmol) and 1-ethyl-3- (3 Dimethylaminopropyl) carbodiimide hydrochloride (12 mg, 0.062 mmol) and the mixture was stirred at room temperature for 20 hours. After adding water, the mixture was shaken to separate the organic layer. The organic layer was washed with aqueous citric acid solution, 1.0 M aqueous sodium hydroxide solution, water and saturated brine, dried over anhydrous sodium sulfate, and concentrated to dryness under reduced pressure. The residue was purified by preparative thin layer chromatography [Merck PLC glass plate silica gel 60F ₂₅₄ , developing solvent: chloroform / methanol = 10/1] to give the title compound (22 mg, yield 60%) as a white solid. Got as.

¹ H-NMR (CDCl ₃ ) δ: 1.45 (9H, s), 1.53-1.62 (2H, m), 1.73-2.11 (6H, m), 2.92 (2H , T, J = 7.2 Hz), 3.13 (2H, s), 3.17-3.30 (2H, m), 3.48-3.96 (6H, m), 3.53 (2H , T, J = 7.2 Hz), 4.62-4.72 (1H, m), 6.96 (2H, d, J = 9.2 Hz), 7.27 (2H, d, J = 8. 0 Hz), 7.38 (2H, d, J = 8.0 Hz), 7.59 (2H, d, J = 9.2 Hz).

LC / MS [Condition 1]: Retention time 4.34 minutes; m / z 610.8 [M + Na] ⁺ (ESI positive ion mode), m / z 633.0 [M + HCOO] ⁻ (ESI negative ion mode)

参考例３０６−７
４−（１−｛４−［２−（２−オキソ−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル）エチル］ベンゾイル｝ピペリジン−４−イルオキシ）ベンゾニトリルの製造
参考例３０６−６で得られた３−｛４−［４−（４−シアノフェノキシ）ピペリジン−１−カルボニル］フェネチル｝−２−オキソ−１−オキサ−３，８−ジアザスピロ［４．５］デカン−８−カルボン酸ｔ−ブチル（２２ｍｇ、０．０３７ｍｍｏｌ）をジオキサン（１．０ｍＬ）に浸した後、４Ｍ塩化水素−ジオキサン溶液（２．０ｍＬ）を加え、室温で３時間かき混ぜた。さらに反応溶液を５０度で４時間かき混ぜた後、室温まで冷却し、メタノール（０．１０ｍＬ）を加え、室温で１２時間かき混ぜた。その後、反応溶液に４Ｍ塩化水素−ジオキサン溶液（０．０２０ｍＬ）を加えた後、５０度で４時間かき混ぜた。減圧下濃縮乾固した後、クロロホルムと飽和炭酸水素ナトリウム水溶液を加え、振とうした。有機層を分離した後、飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥した。減圧下濃縮乾固し、主成分として表題化合物（１５ｍｇ）を含む白色固体を得た。得られた白色固体は、未精製のまま次の反応に用いた。

ＬＣ／ＭＳ［条件１］：保持時間２．９４分；ｍ／ｚ４８８．８［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ５３２．９［Ｍ＋ＨＣＯＯ］^―（ＥＳＩ負イオンモード）

Reference Example 306-7
Preparation of 4- (1- {4- [2- (2-oxo-1-oxa-3,8-diazaspiro [4.5] decan-3-yl) ethyl] benzoyl} piperidin-4-yloxy) benzonitrile 3- {4- [4- (4-Cyanophenoxy) piperidine-1-carbonyl] phenethyl} -2-oxo-1-oxa-3,8-diazaspiro [4.5] obtained in Reference Example 306-6 After immersing decane-8-carboxylate t-butyl (22 mg, 0.037 mmol) in dioxane (1.0 mL), 4M hydrogen chloride-dioxane solution (2.0 mL) was added, and the mixture was stirred at room temperature for 3 hours. The reaction solution was further stirred at 50 ° C. for 4 hours, cooled to room temperature, methanol (0.10 mL) was added, and the mixture was stirred at room temperature for 12 hours. Thereafter, a 4M hydrogen chloride-dioxane solution (0.020 mL) was added to the reaction solution, and the mixture was stirred at 50 degrees for 4 hours. After concentration to dryness under reduced pressure, chloroform and saturated aqueous sodium hydrogen carbonate solution were added and shaken. The organic layer was separated, washed with saturated brine, and dried over anhydrous sodium sulfate. Concentration to dryness under reduced pressure gave a white solid containing the title compound (15 mg) as the main component. The obtained white solid was used for the next reaction without purification.

LC / MS [Condition 1]: Retention time 2.94 minutes; m / z 488.8 [M + H] ⁺ (ESI positive ion mode), m / z 532.9 [M + HCOO] ⁻ (ESI negative ion mode)

実施例３０６
４−［（３−｛４−［４−（４−シアノフェノキシ）ピペリジン−１−カルボニル］フェネチル｝−２−オキソ−１−オキサ−３，８−ジアザスピロ［４．５］デカン−８−イル）メチル］−３，５−ジフルオロベンゾニトリル（化合物番号３０６）の製造
実施例３０６−７で得られた４−（１−｛４−［２−（２−オキソ−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル）エチル］ベンゾイル｝ピペリジン−４−イルオキシ）ベンゾニトリル（１５ｍｇ）と３，５−ジフルオロ−４−ホルミルベンゾニトリル（５．５ｍｇ、０．０３３ｍｍｏｌ）をジクロロメタン（１．０ｍＬ）に溶解し、トリアセトキシ水素化ホウ素ナトリウム（９．５ｍｇ、０．０４５ｍｍｏｌ）を加えて、室温で１０分間かき混ぜた。分析用薄層クロマトグラフィー［メルク社製ＴＬＣガラスプレートシリカゲル６０Ｆ_２５４、展開溶媒：クロロホルム／メタノール＝１０／１］で原料が消失するまで、トリアセトキシ水素化ホウ素ナトリウムと３，５−ジフルオロ−４−ホルミルベンゾニトリルを加え、室温でかき混ぜた。原料が消失するのを確認した後、反応混合物に飽和炭酸水素ナトリウム水溶液と水を加えた後、クロロホルムを加え、激しく振とうした。有機層を分離した後、飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥した。有機層を減圧下濃縮乾固し、得られた残留物を分取用薄層クロマトグラフィー［メルク社製ＰＬＣガラスプレートシリカゲル６０Ｆ_２５４、展開溶媒：クロロホルム／メタノール＝１０／１］にて精製し、表題化合物を主として含む粗生成物（２７ｍｇ）を得た。この粗生成物をジエチルエーテルで再結晶し、析出した固体を回収して減圧下室温で３時間乾燥することで、表題化合物（９．７ｍｇ、収率４０％、２段階）を白色固体として得た。

^１Ｈ−ＮＭＲ（ＣＤＣｌ_３）δ：１．５９−２．０９（８Ｈ，ｍ），２．５０−２．６７（４Ｈ，ｍ），２．８９（２Ｈ，ｔ，Ｊ＝７．０Ｈｚ），３．１２（２Ｈ，ｓ），３．３６−３．９８（４Ｈ，ｍ），３．５０（２Ｈ，ｔ，Ｊ＝７．０Ｈｚ），３．７１（２Ｈ，ｓ），４．６０−４．７３（１Ｈ，ｍ），６．９６（２Ｈ，ｄ，Ｊ＝８．８Ｈｚ），７．１８−７．２８（４Ｈ，ｍ），７．３６（２Ｈ，ｄ，Ｊ＝７．７Ｈｚ），７．６０（２Ｈ，ｄ，Ｊ＝８．８Ｈｚ）

ＬＣ／ＭＳ［条件１］：保持時間３．２９分；ｍ／ｚ６４０．０［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ６８４．２［Ｍ＋ＨＣＯＯ］^―（ＥＳＩ負イオンモード）

Example 306
4-[(3- {4- [4- (4-Cyanophenoxy) piperidine-1-carbonyl] phenethyl} -2-oxo-1-oxa-3,8-diazaspiro [4.5] decan-8-yl ) Preparation of methyl] -3,5-difluorobenzonitrile (Compound No. 306) 4- (1- {4- [2- (2-oxo-1-oxa-3,8 ) obtained in Example 306-7 -Diazaspiro [4.5] decan-3-yl) ethyl] benzoyl} piperidin-4-yloxy) benzonitrile (15 mg) and 3,5-difluoro-4-formylbenzonitrile (5.5 mg, 0.033 mmol). It melt | dissolved in the dichloromethane (1.0 mL), sodium triacetoxyborohydride (9.5 mg, 0.045 mmol) was added, and it stirred at room temperature for 10 minutes. Analytical thin layer chromatography [Merck TLC glass plate silica gel 60F ₂₅₄ , developing solvent: chloroform / methanol = 10/1] until the raw material disappears and sodium triacetoxyborohydride and 3,5-difluoro-4- Formylbenzonitrile was added and stirred at room temperature. After confirming disappearance of the raw materials, a saturated aqueous sodium hydrogen carbonate solution and water were added to the reaction mixture, chloroform was added, and the mixture was shaken vigorously. The organic layer was separated, washed with saturated brine, and dried over anhydrous sodium sulfate. The organic layer was concentrated to dryness under reduced pressure, and the obtained residue was purified by preparative thin layer chromatography [Merck PLC glass plate silica gel 60F ₂₅₄ , developing solvent: chloroform / methanol = 10/1], A crude product (27 mg) mainly containing the title compound was obtained. The crude product was recrystallized from diethyl ether, and the precipitated solid was collected and dried at room temperature under reduced pressure for 3 hours to obtain the title compound (9.7 mg, yield 40%, 2 steps) as a white solid. It was.

¹ H-NMR (CDCl ₃ ) δ: 1.59-2.09 (8H, m), 2.50-2.67 (4H, m), 2.89 (2H, t, J = 7.0 Hz) , 3.12 (2H, s), 3.36-3.98 (4H, m), 3.50 (2H, t, J = 7.0 Hz), 3.71 (2H, s), 4.60. -4.73 (1H, m), 6.96 (2H, d, J = 8.8 Hz), 7.18-7.28 (4H, m), 7.36 (2H, d, J = 7. 7 Hz), 7.60 (2H, d, J = 8.8 Hz)

LC / MS [Condition 1]: Retention time 3.29 minutes; m / z 640.0 [M + H] ⁺ (ESI positive ion mode), m / z 684.2 [M + HCOO] ⁻ (ESI negative ion mode)

参考例３０７
１，２，５−オキサジアゼパン−５−カルボン酸メチル塩酸塩の製造
ピペリジン−４−イルカルバミン酸ｔ−ブチルの代わりに渡辺化学社より購入した１，２，５−オキサジアゼパン−２−カルボン酸ｔ−ブチル塩酸塩（２３０ｍｇ、０．９７ｍｍｏｌ）を使うこと以外は実質的に参考例１３５と同様に反応を行なって、表題化合物（１００ｍｇ、収率５４％）を淡黄色無定形固体として得た。
^１Ｈ−ＮＭＲ（ＣＤＣｌ_３）δ：３．５７−３．６８（２Ｈ，ｂｒ ｍ），３．７８（３Ｈ，ｓ），３．８０−４．０２（４Ｈ，ｂｒ ｍ），４．４８−４．６１（２Ｈ，ｂｒ ｍ），１２．５６（２Ｈ，ｂｒｓ）．
ＬＣ／ＭＳ［条件１］：保持時間０．５９分；ｍ／ｚ１６０．９［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）

Reference Example 307
Preparation of 1,2,5-oxadiazepan-5-carboxylic acid methyl hydrochloride 1,2,5-oxadiazepan-2-carboxylic acid t-purchased from Watanabe Chemical Co. instead of t-butyl piperidin-4-ylcarbamate The reaction was carried out in substantially the same manner as in Reference Example 135 except that butyl hydrochloride (230 mg, 0.97 mmol) was used to give the title compound (100 mg, yield 54%) as a pale yellow amorphous solid.
¹ H-NMR (CDCl ₃ ) δ: 3.57-3.68 (2H, br m), 3.78 (3H, s), 3.80-4.02 (4H, br m), 4.48 -4.61 (2H, br m), 12.56 (2H, brs).
LC / MS [Condition 1]: Retention time 0.59 minutes; m / z 160.9 [M + H] ⁺ (ESI positive ion mode)

実施例３０７
２−［（１ｒ，４ｒ）−４−（｛２−オキソ−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）シクロヘキサンカルボニル］−１，２，５−オキサジアゼパン−５−カルボン酸メチル（化合物番号３０７）の製造
テトラヒドロフルフリルアミンの代わりに参考例３０７で得られた１，２，５−オキサジアゼパン−５−カルボン酸メチル塩酸塩とトリエチルアミンを用いること以外は実質的に実施例１０と同様に反応を行って、表題化合物（８．３ｍｇ、収率２１％）を無色固体として得た。

^１Ｈ−ＮＭＲ（ＣＤＣｌ_３）δ：１．０５（２Ｈ，ｄｑ，Ｊ＝３．３，１２．３Ｈｚ），１．３６−２．４１（１２Ｈ，ｂｒ ｍ），２．５１−３．０４（４Ｈ，ｂｒ ｍ），３．１０（２Ｈ，ｄ，Ｊ＝７．４Ｈｚ），３．２９（２Ｈ，ｓ），３．５４−３．９６（８Ｈ，ｍ），３．７２（３Ｈ，ｓ），３．９５−４．０８（２Ｈ，ｂｒ ｍ），７．５１−７．６７（４Ｈ，ｂｒ ｍ）．
ＬＣ／ＭＳ［条件１］：保持時間３．０９分；ｍ／ｚ５９６．９［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ６４１．０［Ｍ＋ＨＣＯＯ］^―（ＥＳＩ負イオンモード）

Example 307
2-[(1r, 4r) -4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} Methyl) cyclohexanecarbonyl] -1,2,5-oxadiazepane-5 Preparation of methyl 5-carboxylate (Compound No. 307) 1,2,5-oxadiazepane-5-carboxylic acid obtained in Reference Example 307 instead of tetrahydrofurfurylamine The reaction was carried out in substantially the same manner as in Example 10 except that acid methyl hydrochloride and triethylamine were used to obtain the title compound (8.3 mg, yield 21%) as a colorless solid.

¹ H-NMR (CDCl ₃ ) δ: 1.05 (2H, dq, J = 3.3, 12.3 Hz), 1.36-2.41 (12H, br m), 2.51-3.04 (4H, br m), 3.10 (2H, d, J = 7.4 Hz), 3.29 (2H, s), 3.54-3.96 (8H, m), 3.72 (3H, s), 3.95-4.08 (2H, br m), 7.51-7.67 (4H, br m).
LC / MS [Condition 1]: Retention time 3.09 minutes; m / z 596.9 [M + H] ⁺ (ESI positive ion mode), m / z 641.0 [M + HCOO] ⁻ (ESI negative ion mode)

実施例３０８
５−［（１ｒ，４ｒ）−４−（｛２−オキソ−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）シクロヘキサンカルボニル］−１，２，５−オキサジアゼパン−２−カルボン酸ｔ−ブチル（化合物番号３０８）の製造
テトラヒドロフルフリルアミンの代わりに渡辺化学社で購入した１，２，５−オキサジアゼパン−２−カルボン酸t−ブチル塩酸塩とトリエチルアミンを用いること以外は実質的に実施例１０と同様に反応を行って、表題化合物（８９ｍｇ、収率９４％）を無色固体として得た。

^１Ｈ−ＮＭＲ（ＣＤＣｌ_３）δ：０．９５−１．１４（２Ｈ，ｂｒ ｍ），１．４８（９Ｈ，ｓ），１．３７−２．０３（１１Ｈ，ｂｒ ｍ），２．３１−２．４９（１Ｈ，ｍ），２．４９−２．７８（４Ｈ，ｂｒ ｍ），３．１０（２Ｈ，ｄ，Ｊ＝７．４Ｈｚ），３．２７（２Ｈ，ｓ），３．５３−３．８２（８Ｈ，ｍ），３．９４−４．０５（２Ｈ，ｍ），７．４８（２Ｈ，ｂｒ ｄ，Ｊ＝７．８Ｈｚ），７．５９（２Ｈ，ｄ，Ｊ＝７．８Ｈｚ）．

ＬＣ／ＭＳ［条件１］：保持時間３．３２分；ｍ／ｚ６３９．０［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ６８３．１［Ｍ＋ＨＣＯＯ］^―（ＥＳＩ負イオンモード）

Example 308
5-[(1r, 4r) -4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} Preparation of t-butyl (methyl) cyclohexanecarbonyl] -1,2,5-oxadiazepan-2-carboxylate (Compound No. 308) 1,2,5-oxadiazepan-2- purchased from Watanabe Chemical Co. instead of tetrahydrofurfurylamine The reaction was carried out substantially in the same manner as in Example 10 except that t-butyl hydrochloride and triethylamine were used to obtain the title compound (89 mg, yield 94%) as a colorless solid.

¹ H-NMR (CDCl ₃ ) δ: 0.95-1.14 (2H, br m), 1.48 (9 H, s), 1.37-2.03 (11 H, br m), 2.31 -2.49 (1H, m), 2.49-2.78 (4H, br m), 3.10 (2H, d, J = 7.4 Hz), 3.27 (2H, s), 3. 53-3.82 (8H, m), 3.94-4.05 (2H, m), 7.48 (2H, br d, J = 7.8 Hz), 7.59 (2H, d, J = 7.8 Hz).

LC / MS [Condition 1]: Retention time 3.32 minutes; m / z 639.0 [M + H] ⁺ (ESI positive ion mode), m / z 683.1 [M + HCOO] ⁻ (ESI negative ion mode)

実施例３０９
３−｛４−［４−（３−イソプロピル−１，２，４−オキサジアゾール−５−イル）ピペリジン−１−カルボニル］ベンジル｝−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−２−オン（化合物番号３０９）の製造
４−（アミノメチル）ベンゾニトリル塩酸塩の代わりに参考例１９５で得られた３−イソプロピル−５−（ピペリジン−４−イル）−１，２，４−オキサジアゾール塩酸塩を用いること以外は実質的に実施例１８０と同様に反応を行って、表題化合物（１４ｍｇ、収率１９％）を無色無定形物として得た。

^１Ｈ−ＮＭＲ（３００ＭＨｚ、ＣＤＣｌ_３）δ：１．３４（６Ｈ，ｄ，Ｊ＝７．０Ｈｚ），１．６５−１．８０（２Ｈ，ｂｒ ｍ），１．８２−１．９９（４Ｈ，ｂｒ ｍ），２．１３（２Ｈ，ｂｒ ｓ），２．５２（４Ｈ，ｂｒ ｓ），２．９９−３．２８（４Ｈ，ｍ），３．１３（２Ｈ，ｓ），３．５５（２Ｈ，ｓ），３．７９（１Ｈ，ｂｒ ｓ），４．４５（２Ｈ，ｓ），４．５７（１Ｈ，ｂｒ ｓ），７．３１（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ），７．３６−７．４６（４Ｈ，ｍ），７．５６（２Ｈ，ｄ，Ｊ＝８．４Ｈｚ）．

ＬＣ／ＭＳ［条件１］：保持時間３．０２分；ｍ／ｚ６２６．０［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ６７０．１［Ｍ＋ＨＣＯＯ］^―（ＥＳＩ負イオンモード）

Example 309
3- {4- [4- (3-Isopropyl-1,2,4-oxadiazol-5-yl) piperidin-1-carbonyl] benzyl} -8- [4- (trifluoromethyl) benzyl] -1 Preparation of Oxa-3,8-diazaspiro [4.5] decan-2-one (Compound No. 309) 3-Isopropyl-5 obtained in Reference Example 195 instead of 4- (aminomethyl) benzonitrile hydrochloride The reaction was carried out in substantially the same manner as in Example 180 except that-(piperidin-4-yl) -1,2,4-oxadiazole hydrochloride was used to give the title compound (14 mg, yield 19%). Obtained as a colorless amorphous product.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.34 (6H, d, J = 7.0 Hz), 1.65 to 1.80 (2H, br m), 1.82-1.99 (4H , Br m), 2.13 (2H, br s), 2.52 (4H, br s), 2.99-3.28 (4H, m), 3.13 (2H, s), 3.55 (2H, s), 3.79 (1H, br s), 4.45 (2H, s), 4.57 (1H, br s), 7.31 (2H, d, J = 8.2 Hz), 7.36-7.46 (4H, m), 7.56 (2H, d, J = 8.4 Hz).

LC / MS [Condition 1]: Retention time 3.02 minutes; m / z 626.0 [M + H] ⁺ (ESI positive ion mode), m / z 670.1 [M + HCOO] ⁻ (ESI negative ion mode)

参考例３１０
1-[4-({2-オキソ-8-[4-(トリフルオロメチル)ベンジル]-1-オキサ-3,8-ジアザスピロ[4.5]デカン-3-イル}メチル)ベンゾイル]ピペリジン-4-カルボン酸の製造
実施例７６で得られた１−［４−（｛２−オキソ−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）ベンゾイル］ピペリジン−４−カルボン酸メチル（０．１３ｇ、０．２３ｍｍｏｌ）を１，４−ジオキサン（１．５ｍｌ）に溶解した後、１Ｍ水酸化ナトリウム水溶液（０．３５ｍＬ、０．３５ｍｍｏｌ）を加え、室温にて４時間かき混ぜた。反応終了後、減圧下濃縮して１，４−ジオキサンを留去した後、残留反応混合物に１Ｍ塩酸（０．３０ｍＬ）とクロロホルム（３ｍＬ）を加えて有機層を分離した。得られた有機層を減圧下濃縮乾固して、表題化合物（０．１５ｇ、定量的）を無色無定形物として得た。

ＬＣ／ＭＳ［条件１］：保持時間２．７８分；ｍ／ｚ５６０．０［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ５５８．１［Ｍ−Ｈ］^―（ＥＳＩ負イオンモード）

Reference Example 310
1- [4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl) benzoyl] piperidine-4- Preparation of carboxylic acid 1- [4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decane obtained in Example 76 -3-yl} methyl) benzoyl] piperidine-4-carboxylate (0.13 g, 0.23 mmol) was dissolved in 1,4-dioxane (1.5 ml) and then 1M aqueous sodium hydroxide solution (0.35 mL). 0.35 mmol), and the mixture was stirred at room temperature for 4 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to distill off 1,4-dioxane, and then 1M hydrochloric acid (0.30 mL) and chloroform (3 mL) were added to the residual reaction mixture to separate the organic layer. The obtained organic layer was concentrated to dryness under reduced pressure to give the title compound (0.15 g, quantitative) as a colorless amorphous product.

LC / MS [Condition 1]: Retention time 2.78 minutes; m / z 560.0 [M + H] ⁺ (ESI positive ion mode), m / z 558.1 [M−H] ⁻ (ESI negative ion mode)

実施例３１０
３−｛４−［４−（ピペリジン−１−カルボニル）ピペリジン−１−カルボニル］ベンジル｝−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−２−オン（化合物番号３１０）の製造
参考例３１０で得られた１−［４−（｛２−オキソ−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）ベンゾイル］ピペリジン−４−カルボン酸（２９ｍｇ、０．０５２ｍｍｏｌ）とピペリジン（０．０１０ｍＬ、０．１０ｍｍｏｌ）、１−ヒドロキシベンゾトリアゾール（７．０ｍｇ、０．０５２ｍｍｏｌ）、そしてトリエチルアミン（０．０２２ｍＬ、０．１６ｍｍｏｌ）をクロロホルム（１．０ｍＬ）に溶解した後、室温にて１−エチル−３−（３−ジメチルアミノプロピル）カルボジイミド塩酸塩（２０ｍｇ、０．１０ｍｍｏｌ）を加え、室温で１日間かき混ぜた。その後、反応混合物にクロロホルム（２．０ｍＬ）と水（２．０ｍＬ）を加えて有機層を分離した。有機層を無水硫酸マグネシウムで乾燥した後、減圧下濃縮した。得られた残留物をシリカゲルカラムクロマトグラフィー［充填剤：株式会社山善製ＨＩ−ＦＬＡＳＨ（登録商標）ＣＯＬＵＭＮｓｉｌｉｃａｇｅｌ４０μｍ、展開溶媒：酢酸エチル／メタノール＝１０／１］にて精製し、表題化合物（６．４ｍｇ、収率１９％）を無色無定形物として得た。

^１Ｈ−ＮＭＲ（３００ＭＨｚ、ＣＤＣｌ_３）δ：１．４７−１．９７（１４Ｈ，ｍ），２．５３（４Ｈ，ｂｒ ｓ），２．７１−２．８４（１Ｈ，ｍ），２．９６（２Ｈ，ｂｒ ｓ），３．１３（２Ｈ，ｓ），３．３８−３．４９（２Ｈ，ｂｒ ｍ），３．５６（４Ｈ，ｓ），３．７９（１Ｈ，ｂｒ ｓ），４．４４（２Ｈ，ｓ），４．６８（１Ｈ，ｂｒ ｓ），７．２９（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ），７．３５−７．４６（４Ｈ，ｍ），７．５６（２Ｈ，ｄ，Ｊ＝７．８Ｈｚ）．

ＬＣ／ＭＳ［条件１］：保持時間２．８４分；ｍ／ｚ６２７．０［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ６７１．１［Ｍ＋ＨＣＯＯ］^―（ＥＳＩ負イオンモード）

Example 310
3- {4- [4- (piperidine-1-carbonyl) piperidine-1-carbonyl] benzyl} -8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5 Preparation of decan-2-one (Compound No. 310) 1- [4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3, obtained in Reference Example 310, 8-diazaspiro [4.5] decan-3-yl} methyl) benzoyl] piperidine-4-carboxylic acid (29 mg, 0.052 mmol) and piperidine (0.010 mL, 0.10 mmol), 1-hydroxybenzotriazole (7 0.0 mg, 0.052 mmol) and triethylamine (0.022 mL, 0.16 mmol) in chloroform (1.0 mL), The Te 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (20 mg, 0.10 mmol) was added and stirred at room temperature for 1 day. Thereafter, chloroform (2.0 mL) and water (2.0 mL) were added to the reaction mixture to separate the organic layer. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography [filler: HI-FLASH (registered trademark) COLUMNsilica gel 40 μm, manufactured by Yamazen Co., Ltd., developing solvent: ethyl acetate / methanol = 10/1] to give the title compound (6.4 mg Yield 19%) was obtained as a colorless amorphous product.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.47-1.97 (14H, m), 2.53 (4H, br s), 2.71-2.84 (1H, m), 2. 96 (2H, brs), 3.13 (2H, s), 3.38-3.49 (2H, br m), 3.56 (4H, s), 3.79 (1H, br s), 4.44 (2H, s), 4.68 (1H, br s), 7.29 (2H, d, J = 8.2 Hz), 7.35-7.46 (4H, m), 7.56 (2H, d, J = 7.8 Hz).

LC / MS [Condition 1]: Retention time 2.84 minutes; m / z 627.0 [M + H] ⁺ (ESI positive ion mode), m / z 671.1 [M + HCOO] ⁻ (ESI negative ion mode)

実施例３１１
３−｛４−［４−（１−メチル−１Ｈ−イミダゾール−５−イル）ピペリジン−１−カルボニル］ベンジル｝−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−２−オン（化合物番号３１１）の製造
４−（アミノメチル）ベンゾニトリル塩酸塩の代わりに４−（１−メチル−１Ｈ−イミダゾール−５−イル）ピペリジン（市販）を用いること以外は実質的に実施例１８０と同様に反応を行って、表題化合物（２７ｍｇ、収率５２％）を無色油状物として得た。

^１Ｈ−ＮＭＲ（３００ＭＨｚ、ＣＤＣｌ_３）δ：１．４３−２．０９（８Ｈ，ｍ），２．６０（４Ｈ，ｂｒ ｓ），２．７８（１Ｈ，ｔｔ，Ｊ＝１１．９，２．５Ｈｚ），２．８８−３．１７（２Ｈ，ｂｒ ｍ），３．１５（２Ｈ，ｓ），３．６１（５Ｈ，ｓ），３．８５（１Ｈ，ｂｒ ｓ），４．４５（２Ｈ，ｓ），４．８０（１Ｈ，ｂｒ ｓ），６．８１（１Ｈ，ｓ），７．３１（２Ｈ，ｄ，Ｊ＝７．８Ｈｚ），７．３７−７．４９（５Ｈ，ｍ），７．５７（２Ｈ，ｄ，Ｊ＝７．４Ｈｚ）．

ＬＣ／ＭＳ［条件１］：保持時間０．５１分；ｍ／ｚ２９８．６［Ｍ＋２Ｈ］^２＋、５９５．９［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ６４０．１［Ｍ＋ＨＣＯＯ］^―（ＥＳＩ負イオンモード）

Example 311
3- {4- [4- (1-Methyl-1H-imidazol-5-yl) piperidin-1-carbonyl] benzyl} -8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8 Preparation of diazaspiro [4.5] decan-2-one (Compound No. 311) 4- (1-methyl-1H-imidazol-5-yl) piperidine (commercially available) instead of 4- (aminomethyl) benzonitrile hydrochloride ) Was used substantially in the same manner as in Example 180 to obtain the title compound (27 mg, 52% yield) as a colorless oil.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.43 to 2.09 (8H, m), 2.60 (4H, br s), 2.78 (1H, tt, J = 11.9, 2 .5Hz), 2.88-3.17 (2H, br m), 3.15 (2H, s), 3.61 (5H, s), 3.85 (1H, br s), 4.45 ( 2H, s), 4.80 (1H, br s), 6.81 (1H, s), 7.31 (2H, d, J = 7.8 Hz), 7.37-7.49 (5H, m ), 7.57 (2H, d, J = 7.4 Hz).

LC / MS [Condition 1]: retention time 0.51 min; m / z 298.6 [M + 2H] ²⁺ , 595.9 [M + H] ⁺ (ESI positive ion mode), m / z 640.1 [M + HCOO] ⁻ (ESI Negative ion mode)

実施例３１２
Ｎ−（４−ニトロベンジル）−４−（｛２−オキソ−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）ベンズアミド（化合物番号３１２）の製造
４−（アミノメチル）ベンゾニトリル塩酸塩の代わりに（４−ニトロフェニル）メタンアミン塩酸塩（市販）を用いること以外は実質的に実施例１８０と同様に反応を行って、表題化合物（２７ｍｇ、収率５２％）を黄色無定形物として得た。

^１Ｈ−ＮＭＲ（３００ＭＨｚ、ＣＤＣｌ_３）δ：１．６４−１．８０（２Ｈ，ｂｒ ｍ），１．８４−１．９６（２Ｈ，ｂｒ ｍ），２．５２（４Ｈ，ｂｒ ｓ），３．１３（２Ｈ，ｓ），３．５５（２Ｈ，ｓ），４．４６（２Ｈ，ｓ），４．７５（２Ｈ，ｄ，Ｊ＝５．７Ｈｚ），６．７３（１Ｈ，ｔ，Ｊ＝６．１Ｈｚ），７．３５（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ），７．３７−７．６０（６Ｈ，ｍ），７．８１（２Ｈ，ｄ，Ｊ＝８．６Ｈｚ），８．１９（２Ｈ，ｄ，Ｊ＝８．６Ｈｚ）．

ＬＣ／ＭＳ［条件１］：保持時間２．８６分；ｍ／ｚ５８２．９［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ５８１．０［Ｍ−Ｈ］^―、６２７．０［Ｍ＋ＨＣＯＯ］^―（ＥＳＩ負イオンモード）

Example 312
N- (4-nitrobenzyl) -4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} Preparation of methyl) benzamide (Compound No. 312) The reaction was substantially the same as Example 180 except that (4-nitrophenyl) methanamine hydrochloride (commercially available) was used instead of 4- (aminomethyl) benzonitrile hydrochloride. To give the title compound (27 mg, 52% yield) as a yellow amorphous.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.64-1.80 (2H, br m), 1.84-1.96 (2H, br m), 2.52 (4H, br s), 3.13 (2H, s), 3.55 (2H, s), 4.46 (2H, s), 4.75 (2H, d, J = 5.7 Hz), 6.73 (1H, t, J = 6.1 Hz), 7.35 (2H, d, J = 8.2 Hz), 7.37-7.60 (6H, m), 7.81 (2H, d, J = 8.6 Hz), 8.19 (2H, d, J = 8.6 Hz).

LC / MS [Condition 1]: Retention time 2.86 minutes; m / z 582.9 [M + H] ⁺ (ESI positive ion mode), m / z 581.0 [M−H] ⁻ , 627.0 [M + HCOO] ⁻ (ESI negative ion mode)

実施例３１３
Ｎ−［４−（メチルスルホニル）ベンジル］−４−（｛２−オキソ−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）ベンズアミド（化合物番号３１３）の製造
４−（アミノメチル）ベンゾニトリル塩酸塩の代わりに［４−（メチルスルホニル）フェニル］メタンアミン塩酸塩（市販）を用いること以外は実質的に実施例１８０と同様に反応を行って、表題化合物（３３ｍｇ、収率５９％）を白色粉末として得た。

^１Ｈ−ＮＭＲ（３００ＭＨｚ、ＣＤＣｌ_３）δ：１．７４（２Ｈ，ｂｒ ｓ），１．８４−１．９６（２Ｈ，ｂｒ ｍ），２．５５（４Ｈ，ｂｒ ｓ），３．０４（３Ｈ，ｓ），３．１３（２Ｈ，ｓ），３．５８（２Ｈ，ｓ），４．４６（２Ｈ，ｓ），４．７４（２Ｈ，ｄ，Ｊ＝５．７Ｈｚ），６．６４（１Ｈ，ｔ，Ｊ＝６．１Ｈｚ），７．３５（２Ｈ，ｄ，Ｊ＝８．６Ｈｚ），７．４３（２Ｈ，ｄ，Ｊ＝７．４Ｈｚ），７．５１−７．６０（４Ｈ，ｍ），７．８０（２Ｈ，ｄｔ，Ｊ＝８．２，１．６Ｈｚ），７．９１（２Ｈ，ｄｔ，Ｊ＝８．６，２．０Ｈｚ）．

ＬＣ／ＭＳ［条件１］：保持時間２．６５分；ｍ／ｚ６１６．０［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ６１４．１［Ｍ−Ｈ］^―、６６０．１［Ｍ＋ＨＣＯＯ］^―（ＥＳＩ負イオンモード）

Example 313
N- [4- (methylsulfonyl) benzyl] -4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decane-3 Preparation of -yl} methyl) benzamide (Compound No. 313) Substantially carried out except that [4- (methylsulfonyl) phenyl] methanamine hydrochloride (commercially available) is used instead of 4- (aminomethyl) benzonitrile hydrochloride The reaction was carried out in the same manner as in Example 180 to obtain the title compound (33 mg, yield 59%) as a white powder.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.74 (2H, br s), 1.84-1.96 (2H, br m), 2.55 (4H, br s), 3.04 ( 3H, s), 3.13 (2H, s), 3.58 (2H, s), 4.46 (2H, s), 4.74 (2H, d, J = 5.7 Hz), 6.64 (1H, t, J = 6.1 Hz), 7.35 (2H, d, J = 8.6 Hz), 7.43 (2H, d, J = 7.4 Hz), 7.51-7.60 ( 4H, m), 7.80 (2H, dt, J = 8.2, 1.6 Hz), 7.91 (2H, dt, J = 8.6, 2.0 Hz).

LC / MS [Condition 1]: Retention time 2.65 minutes; m / z 616.0 [M + H] ⁺ (ESI positive ion mode), m / z 614.1 [M−H] ⁻ , 660.1 [M + HCOO] ⁻ (ESI negative ion mode)

実施例３１４
４−（｛２−オキソ−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）−Ｎ−［３−（トリフルオロメチル）ベンジル］ベンズアミド（化合物番号３１４）の製造
４−（アミノメチル）ベンゾニトリル塩酸塩の代わりに[3-(トリフルオロメチル)フェニル]メタンアミン（市販）を用いること以外は実質的に実施例１８０と同様に反応を行って、表題化合物（28ｍｇ、収率51％）を黄色無定形物として得た。

^１Ｈ−ＮＭＲ（３００ＭＨｚ、ＣＤＣｌ_３）δ：１．７２−１．９６（４Ｈ，ｂｒ ｍ），２．５１−２．７２（４Ｈ，ｂｒ ｍ），３．１３（２Ｈ，ｓ），３．６３（２Ｈ，ｓ），４．４６（２Ｈ，ｓ），４．７１（２Ｈ，ｄ，Ｊ＝６．１Ｈｚ），６．５２（１Ｈ，ｔ，Ｊ＝５．９Ｈｚ），７．３３（２Ｈ，ｄ，Ｊ＝８．６Ｈｚ），７．４０−７．５０（３Ｈ，ｍ），７．５２−７．６２（５Ｈ，ｍ），７．７９（２Ｈ，ｄ，Ｊ＝８．６Ｈｚ）．

ＬＣ／ＭＳ［条件１］：保持時間３．２２分；ｍ／ｚ６０５．９［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ６０４．１［Ｍ−Ｈ］^―、６５０．１［Ｍ＋ＨＣＯＯ］^―（ＥＳＩ負イオンモード）

Example 314
4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl) -N- [3- ( Preparation of ( trifluoromethyl) benzyl] benzamide (Compound No. 314) Substantially carried out except using [3- (trifluoromethyl) phenyl] methanamine (commercially available) instead of 4- (aminomethyl) benzonitrile hydrochloride The reaction was carried out in the same manner as in Example 180 to obtain the title compound (28 mg, yield 51%) as a yellow amorphous product.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.72-1.96 (4H, br m), 2.51-2.72 (4H, br m), 3.13 (2H, s), 3 .63 (2H, s), 4.46 (2H, s), 4.71 (2H, d, J = 6.1 Hz), 6.52 (1H, t, J = 5.9 Hz), 7.33 (2H, d, J = 8.6 Hz), 7.40-7.50 (3H, m), 7.52-7.62 (5H, m), 7.79 (2H, d, J = 8. 6 Hz).

LC / MS [condition 1]: retention time 3.22 minutes; m / z 605.9 [M + H] ⁺ (ESI positive ion mode), m / z 604.1 [M−H] ⁻ , 650.1 [M + HCOO] ⁻ (ESI negative ion mode)

実施例３１５
４−（｛２−オキソ−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）−Ｎ−［２−（トリフルオロメチル）ベンジル］ベンズアミド（化合物番号３１５）の製造
４−（アミノメチル）ベンゾニトリル塩酸塩の代わりに［２−（トリフルオロメチル）フェニル］メタンアミン（市販）を用いること以外は実質的に実施例１８０と同様に反応を行って、表題化合物（３２ｍｇ、収率５９％）を無色無定形物として得た。

^１Ｈ−ＮＭＲ（３００ＭＨｚ、ＣＤＣｌ_３）δ：１．７２−１．９８（４Ｈ，ｂｒ ｍ），２．６２（４Ｈ，ｂｒ ｓ），３．１２（２Ｈ，ｓ），３．６３（２Ｈ，ｓ），４．４５（２Ｈ，ｓ），４．８２（２Ｈ，ｄ，Ｊ＝６．１Ｈｚ），６．４６（１Ｈ，ｔ，Ｊ＝５．９Ｈｚ），７．３２（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ），７．３６−７．４８（３Ｈ，ｍ），７．４９−７．６１（３Ｈ，ｍ），７．６６（２Ｈ，ｔ，Ｊ＝８．０Ｈｚ），７．７５（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ）．

ＬＣ／ＭＳ［条件１］：保持時間３．２２分；ｍ／ｚ６０５．９［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ６０４．１［Ｍ−Ｈ］^―、６５０．１［Ｍ＋ＨＣＯＯ］^―（ＥＳＩ負イオンモード）

Example 315
4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl) -N- [2- ( Preparation of ( trifluoromethyl) benzyl] benzamide (Compound No. 315) Substantially carried out except that [2- (trifluoromethyl) phenyl] methanamine (commercially available) is used instead of 4- (aminomethyl) benzonitrile hydrochloride. The reaction was carried out in the same manner as in Example 180 to obtain the title compound (32 mg, yield 59%) as a colorless amorphous product.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.72-1.98 (4H, br m), 2.62 (4H, br s), 3.12 (2H, s), 3.63 (2H , S), 4.45 (2H, s), 4.82 (2H, d, J = 6.1 Hz), 6.46 (1H, t, J = 5.9 Hz), 7.32 (2H, d) , J = 8.2 Hz), 7.36-7.48 (3H, m), 7.49-7.61 (3H, m), 7.66 (2H, t, J = 8.0 Hz), 7 .75 (2H, d, J = 8.2 Hz).

LC / MS [condition 1]: retention time 3.22 minutes; m / z 605.9 [M + H] ⁺ (ESI positive ion mode), m / z 604.1 [M−H] ⁻ , 650.1 [M + HCOO] ⁻ (ESI negative ion mode)

実施例３１６
Ｎ−（４−ｔ−ブチルベンジル）−４−（｛２−オキソ−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）ベンズアミド（化合物番号３１６）の製造
４−（アミノメチル）ベンゾニトリル塩酸塩の代わりに（４−ｔ−ブチルフェニル）メタンアミン（市販）を用いること以外は実質的に実施例１８０と同様に反応を行って、表題化合物（３７ｍｇ、収率６９％）を白色粉末として得た。

^１Ｈ−ＮＭＲ（３００ＭＨｚ、ＣＤＣｌ_３）δ：１．３１（９Ｈ，ｓ），１．６３−１．７７（２Ｈ，ｂｒ ｍ），１．８５−１．９５（２Ｈ，ｂｒ ｍ），２．５１（４Ｈ，ｂｒ ｓ），３．１１（２Ｈ，ｓ），３．５５（２Ｈ，ｓ），４．４５（２Ｈ，ｓ），４．６１（２Ｈ，ｄ，Ｊ＝５．３Ｈｚ），６．３１（１Ｈ，ｔ，Ｊ＝５．１Ｈｚ），７．２９（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ），７．３２（２Ｈ，ｄ，Ｊ＝７．４Ｈｚ），７．３８（２Ｈ，ｄｔ，Ｊ＝８．２，２．０Ｈｚ），７．４１（２Ｈ，ｄ，Ｊ＝７．０Ｈｚ），７．５５（２Ｈ，ｄ，Ｊ＝７．８Ｈｚ），７．７６（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ）．

ＬＣ／ＭＳ［条件１］：保持時間３．４６分；ｍ／ｚ５９４．０［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ５９２．２［Ｍ−Ｈ］^―、６３８．１［Ｍ＋ＨＣＯＯ］^―（ＥＳＩ負イオンモード）

Example 316
N- (4-t-butylbenzyl) -4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decane-3- Il} methyl) Preparation of benzamide (Compound No. 316) Substantially the same as Example 180, except that (4-tert-butylphenyl) methanamine (commercially available) was used instead of 4- (aminomethyl) benzonitrile hydrochloride. The title compound (37 mg, 69% yield) was obtained as a white powder.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.31 (9H, s), 1.63-1.77 (2H, br m), 1.85-1.95 (2H, br m), 2 .51 (4H, br s), 3.11 (2H, s), 3.55 (2H, s), 4.45 (2H, s), 4.61 (2H, d, J = 5.3 Hz) , 6.31 (1H, t, J = 5.1 Hz), 7.29 (2H, d, J = 8.2 Hz), 7.32 (2H, d, J = 7.4 Hz), 7.38 ( 2H, dt, J = 8.2, 2.0 Hz), 7.41 (2H, d, J = 7.0 Hz), 7.55 (2H, d, J = 7.8 Hz), 7.76 (2H , D, J = 8.2 Hz).

LC / MS [Condition 1]: Retention time 3.46 minutes; m / z 594.0 [M + H] ⁺ (ESI positive ion mode), m / z 592.2 [M−H] ⁻ , 638.1 [M + HCOO] ⁻ (ESI negative ion mode)

実施例３１７
４−（｛２−オキソ−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）−Ｎ−［４−（トリフルオロメトキシ）ベンジル］ベンズアミド（化合物番号３１７）の製造
４−（アミノメチル）ベンゾニトリル塩酸塩とトリエチルアミンの代わりに［４−（トリフルオロメトキシ）フェニル］メタンアミン（市販）を用いること以外は実質的に実施例１８０と同様に反応を行って、表題化合物（２８ｍｇ、収率５２％）を黄色粉末として得た。

^１Ｈ−ＮＭＲ（３００ＭＨｚ、ＣＤＣｌ_３）δ：１．６５−１．９８（４Ｈ，ｂｒ ｍ），２．５７（４Ｈ，ｂｒ ｓ），３．１２（２Ｈ，ｓ），３．６０（２Ｈ，ｓ），４．４６（２Ｈ，ｓ），４．６５（２Ｈ，ｄ，Ｊ＝５．７Ｈｚ），６．４５（１Ｈ，ｔ，Ｊ＝５．５Ｈｚ），７．１９（２Ｈ，ｄ，Ｊ＝８．６Ｈｚ），７．３０−７．５０（６Ｈ，ｍ），７．５７（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ），７．７８（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ）．

ＬＣ／ＭＳ［条件１］：保持時間３．２８分；ｍ／ｚ６２１．９［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ６２０．１［Ｍ−Ｈ］^―、６６６．２［Ｍ＋ＨＣＯＯ］^―（ＥＳＩ負イオンモード）

Example 317
4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl) -N- [4- ( Preparation of ( trifluoromethoxy) benzyl] benzamide (Compound No. 317) Substantially except that [4- (trifluoromethoxy) phenyl] methanamine (commercially available) is used instead of 4- (aminomethyl) benzonitrile hydrochloride and triethylamine. Was reacted in the same manner as in Example 180 to give the title compound (28 mg, yield 52%) as a yellow powder.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.65-1.98 (4H, br m), 2.57 (4H, br s), 3.12 (2H, s), 3.60 (2H , S), 4.46 (2H, s), 4.65 (2H, d, J = 5.7 Hz), 6.45 (1H, t, J = 5.5 Hz), 7.19 (2H, d). , J = 8.6 Hz), 7.30-7.50 (6H, m), 7.57 (2H, d, J = 8.2 Hz), 7.78 (2H, d, J = 8.2 Hz) .

LC / MS [Condition 1]: Retention time 3.28 minutes; m / z 621.9 [M + H] ⁺ (ESI positive ion mode), m / z 620.1 [M−H] ⁻ , 666.2 [M + HCOO] ⁻ (ESI negative ion mode)

実施例３１８
Ｎ−［３，５−ビス（トリフルオロメチル）ベンジル］−４−（｛２−オキソ−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）ベンズアミド（化合物番号３１８）の製造
４−（アミノメチル）ベンゾニトリル塩酸塩とトリエチルアミンの代わりに［３，５−ビス（トリフルオロメチル）フェニル］メタンアミン（市販）を用いること以外は実質的に実施例１８０と同様に反応を行って、表題化合物（３０ｍｇ、収率５０％）を無色無定形物として得た。

^１Ｈ−ＮＭＲ（３００ＭＨｚ、ＣＤＣｌ_３）δ：１．７２−１．９７（４Ｈ，ｂｒ ｍ），２．６２（４Ｈ，ｂｒ ｓ），３．１４（２Ｈ，ｓ），３．６３（２Ｈ，ｓ），４．４６（２Ｈ，ｓ），４．７７（２Ｈ，ｄ，Ｊ＝６．１Ｈｚ），６．６８（１Ｈ，ｔ，Ｊ＝５．９Ｈｚ），７．３５（２Ｈ，ｄ，Ｊ＝８．６Ｈｚ），７．４５（２Ｈ，ｄ，Ｊ＝７．８Ｈｚ），７．５８（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ），７．７７−７．８３（５Ｈ，ｍ）．

ＬＣ／ＭＳ［条件１］：保持時間３．５２分；ｍ／ｚ６７４．０［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ６７２．０［Ｍ−Ｈ］^―、７１８．１［Ｍ＋ＨＣＯＯ］^―（ＥＳＩ負イオンモード）

Example 318
N- [3,5-bis (trifluoromethyl) benzyl] -4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5 Preparation of decan-3-yl} methyl) benzamide (Compound No. 318) [3,5-bis (trifluoromethyl) phenyl] methanamine (commercially available) instead of 4- (aminomethyl) benzonitrile hydrochloride and triethylamine The reaction was carried out substantially in the same manner as in Example 180 except for using, and the title compound (30 mg, yield 50%) was obtained as a colorless amorphous product.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.72-1.97 (4H, br m), 2.62 (4H, br s), 3.14 (2H, s), 3.63 (2H , S), 4.46 (2H, s), 4.77 (2H, d, J = 6.1 Hz), 6.68 (1H, t, J = 5.9 Hz), 7.35 (2H, d) , J = 8.6 Hz), 7.45 (2H, d, J = 7.8 Hz), 7.58 (2H, d, J = 8.2 Hz), 7.77-7.83 (5H, m) .

LC / MS [condition 1]: retention time 3.52 minutes; m / z 674.0 [M + H] ⁺ (ESI positive ion mode), m / z 672.0 [M−H] ⁻ , 718.1 [M + HCOO] ⁻ (ESI negative ion mode)

実施例３１９
Ｎ−（４−クロロベンジル）−４−（｛２−オキソ−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）ベンズアミド（化合物番号３１９）の製造
４−（アミノメチル）ベンゾニトリル塩酸塩とトリエチルアミンの代わりに（４−クロロフェニル）メタンアミン（市販）を用いること以外は実質的に実施例１８０と同様に反応を行って、表題化合物（３１ｍｇ、収率６１％）を白色粉末として得た。

^１Ｈ−ＮＭＲ（３００ＭＨｚ、ＣＤＣｌ_３）δ：１．６３−１．７９（２Ｈ，ｂｒ ｍ），１．８２−１．９８（２Ｈ，ｂｒ ｍ），２．５１（４Ｈ，ｂｒ ｓ），３．１１（２Ｈ，ｓ），３．５５（２Ｈ，ｓ），４．４６（２Ｈ，ｓ），４．６１（２Ｈ，ｄ，Ｊ＝５．７Ｈｚ），６．４１（１Ｈ，ｔ，Ｊ＝５．１Ｈｚ），７．２２−７．３６（６Ｈ，ｍ），７．４１（２Ｈ，ｄ，Ｊ＝７．４Ｈｚ），７．５６（２Ｈ，ｄ，Ｊ＝７．８Ｈｚ），７．７７（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ）．

ＬＣ／ＭＳ［条件１］：保持時間３．１２分；ｍ／ｚ５７１．９［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ５７０．１［Ｍ−Ｈ］^―、６１６．１［Ｍ＋ＨＣＯＯ］^―（ＥＳＩ負イオンモード）

Example 319
N- (4-chlorobenzyl) -4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} Preparation of methyl) benzamide (Compound No. 319) The reaction was carried out in substantially the same manner as in Example 180 except that (4-chlorophenyl) methanamine (commercially available) was used instead of 4- (aminomethyl) benzonitrile hydrochloride and triethylamine. Performed to give the title compound (31 mg, 61% yield) as a white powder.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.63-1.79 (2H, br m), 1.82-1.98 (2H, br m), 2.51 (4H, br s), 3.11 (2H, s), 3.55 (2H, s), 4.46 (2H, s), 4.61 (2H, d, J = 5.7 Hz), 6.41 (1H, t, J = 5.1 Hz), 7.22-7.36 (6H, m), 7.41 (2H, d, J = 7.4 Hz), 7.56 (2H, d, J = 7.8 Hz), 7.77 (2H, d, J = 8.2 Hz).

LC / MS [Condition 1]: Retention time 3.12 minutes; m / z 571.9 [M + H] ⁺ (ESI positive ion mode), m / z 570.1 [M−H] ⁻ , 616.1 [M + HCOO] ⁻ (ESI negative ion mode)

実施例３２０
Ｎ−（４−メチルベンジル）−４−（｛２−オキソ−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）ベンズアミド（化合物番号３２０）の製造
４−（アミノメチル）ベンゾニトリル塩酸塩とトリエチルアミンの代わりにｐ−トリルメタンアミン（市販）を用いること以外は実質的に実施例１８０と同様に反応を行って、表題化合物（３１ｍｇ、収率６３％）を白色粉末として得た。

^１Ｈ−ＮＭＲ（３００ＭＨｚ、ＣＤＣｌ_３）δ：１．６２−１．７７（２Ｈ，ｂｒ ｍ），１．８３−１．９６（２Ｈ，ｂｒ ｍ），２．３５（３Ｈ，ｓ），２．５１（４Ｈ，ｂｒ ｓ），３．１０（２Ｈ，ｓ），３．５４（２Ｈ，ｓ），４．４５（２Ｈ，ｓ），４．６０（２Ｈ，ｄ，Ｊ＝５．７Ｈｚ），６．２９（１Ｈ，ｔ，Ｊ＝４．５Ｈｚ），７．１６（２Ｈ，ｄ，Ｊ＝７．８Ｈｚ），７．２４（２Ｈ，ｄ，Ｊ＝７．０Ｈｚ），７．３２（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ），７．４１（２Ｈ，ｄ，Ｊ＝７．８Ｈｚ），７．５５（２Ｈ，ｄ，Ｊ＝７．８Ｈｚ），７．７６（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ）．

ＬＣ／ＭＳ［条件１］：保持時間３．０２分；ｍ／ｚ５５２．０［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ５５０．１［Ｍ−Ｈ］^―、５９６．１［Ｍ＋ＨＣＯＯ］^―（ＥＳＩ負イオンモード）

Example 320
N- (4-methylbenzyl) -4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} Preparation of methyl) benzamide (Compound No. 320) The reaction was carried out in substantially the same manner as in Example 180, except that 4- (aminomethyl) benzonitrile hydrochloride and p-tolylmethanamine (commercially available) were used instead of triethylamine. The title compound (31 mg, 63% yield) was obtained as a white powder.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.62-1.77 (2H, br m), 1.83-1.96 (2H, br m), 2.35 (3H, s), 2 .51 (4H, br s), 3.10 (2H, s), 3.54 (2H, s), 4.45 (2H, s), 4.60 (2H, d, J = 5.7 Hz) 6.29 (1H, t, J = 4.5 Hz), 7.16 (2H, d, J = 7.8 Hz), 7.24 (2H, d, J = 7.0 Hz), 7.32 ( 2H, d, J = 8.2 Hz), 7.41 (2H, d, J = 7.8 Hz), 7.55 (2H, d, J = 7.8 Hz), 7.76 (2H, d, J = 8.2 Hz).

LC / MS [Condition 1]: Retention time 3.02 minutes; m / z 552.0 [M + H] ⁺ (ESI positive ion mode), m / z 550.1 [M−H] ⁻ , 596.1 [M + HCOO] ⁻ (ESI negative ion mode)

実施例３２１
Ｎ−（４−メトキシベンジル）−４−（｛２−オキソ−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）ベンズアミド（化合物番号３２１）の製造
４−（アミノメチル）ベンゾニトリル塩酸塩とトリエチルアミンの代わりに（４−メトキシフェニル）メタンアミン（市販）を用いること以外は実質的に実施例１８０と同様に反応を行って、表題化合物（２４ｍｇ、収率４７％）を白色粉末として得た。

^１Ｈ−ＮＭＲ（３００ＭＨｚ、ＣＤＣｌ_３）δ：１．６２−１．７９（２Ｈ，ｂｒ ｍ），１．８３−１．９７（２Ｈ，ｂｒ ｍ），２．５１（４Ｈ，ｂｒ ｓ），３．１１（２Ｈ，ｓ），３．５４（２Ｈ，ｓ），３．８０（３Ｈ，ｓ），４．４５（２Ｈ，ｓ），４．５７（２Ｈ，ｄ，Ｊ＝５．７Ｈｚ），６．２９（１Ｈ，ｔ，Ｊ＝４．９Ｈｚ），６．８８（２Ｈ，ｄｔ，Ｊ＝８．６，２．５Ｈｚ），７．２３−７．３５（４Ｈ，ｍ），７．４１（２Ｈ，ｄ，Ｊ＝７．８Ｈｚ），７．５５（２Ｈ，ｄ，Ｊ＝７．８Ｈｚ），７．７６（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ）．

ＬＣ／ＭＳ［条件１］：保持時間２．８６分；ｍ／ｚ５６８．０［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ５６６．１［Ｍ−Ｈ］^―、６１２．１［Ｍ＋ＨＣＯＯ］^―（ＥＳＩ負イオンモード）

Example 321
N- (4-methoxybenzyl) -4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} Preparation of methyl) benzamide (Compound No. 321) Reaction substantially in the same manner as in Example 180 except that 4- (aminomethyl) benzonitrile hydrochloride and (4-methoxyphenyl) methanamine (commercially available) were used instead of triethylamine. To give the title compound (24 mg, 47% yield) as a white powder.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.62-1.79 (2H, br m), 1.83-1.97 (2H, br m), 2.51 (4H, br s), 3.11 (2H, s), 3.54 (2H, s), 3.80 (3H, s), 4.45 (2H, s), 4.57 (2H, d, J = 5.7 Hz) 6.29 (1H, t, J = 4.9 Hz), 6.88 (2H, dt, J = 8.6, 2.5 Hz), 7.23-7.35 (4H, m), 7. 41 (2H, d, J = 7.8 Hz), 7.55 (2H, d, J = 7.8 Hz), 7.76 (2H, d, J = 8.2 Hz).

LC / MS [Condition 1]: Retention time 2.86 minutes; m / z 568.0 [M + H] ⁺ (ESI positive ion mode), m / z 566.1 [M−H] ⁻ , 612.1 [M + HCOO] ⁻ (ESI negative ion mode)

実施例３２２
Ｎ−（３，４−ジメトキシベンジル）−４−（｛２−オキソ−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）ベンズアミド（化合物番号３２２）の製造
４−（アミノメチル）ベンゾニトリル塩酸塩とトリエチルアミンの代わりに（３，４−ジメトキシフェニル）メタンアミン（市販）を用いること以外は実質的に実施例１８０と同様に反応を行って、表題化合物（１６ｍｇ、収率３０％）を白色粉末として得た。

^１Ｈ−ＮＭＲ（３００ＭＨｚ、ＣＤＣｌ_３）δ：１．６３−１．７８（２Ｈ，ｂｒ ｍ），１．８３−１．９７（２Ｈ，ｂｒ ｍ），２．５１（４Ｈ，ｂｒ ｓ），３．１１（２Ｈ，ｓ），３．５４（２Ｈ，ｓ），３．８８（６Ｈ，ｓ），４．４５（２Ｈ，ｓ），４．５８（２Ｈ，ｄ，Ｊ＝５．３Ｈｚ），６．３１（１Ｈ，ｔ，Ｊ＝４．９Ｈｚ），６．７８−６．９４（３Ｈ，ｍ），７．３２（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ），７．４１（２Ｈ，ｄ，Ｊ＝７．４Ｈｚ），７．５５（２Ｈ，ｄ，Ｊ＝７．８Ｈｚ），７．７６（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ）．

ＬＣ／ＭＳ［条件１］：保持時間２．７１分；ｍ／ｚ５９７．９［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ５９６．１［Ｍ−Ｈ］^―、６４２．１［Ｍ＋ＨＣＯＯ］^―（ＥＳＩ負イオンモード）

Example 322
N- (3,4-dimethoxybenzyl) -4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decane-3- Il} methyl) benzamide (Compound No. 322) Example 180 substantially except that (3,4-dimethoxyphenyl) methanamine (commercially available) was used instead of 4- (aminomethyl) benzonitrile hydrochloride and triethylamine. The title compound (16 mg, yield 30%) was obtained as a white powder.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.63-1.78 (2H, br m), 1.83-1.97 (2H, br m), 2.51 (4H, br s), 3.11 (2H, s), 3.54 (2H, s), 3.88 (6H, s), 4.45 (2H, s), 4.58 (2H, d, J = 5.3 Hz) , 6.31 (1H, t, J = 4.9 Hz), 6.78-6.94 (3H, m), 7.32 (2H, d, J = 8.2 Hz), 7.41 (2H, d, J = 7.4 Hz), 7.55 (2H, d, J = 7.8 Hz), 7.76 (2H, d, J = 8.2 Hz).

LC / MS [Condition 1]: Retention time 2.71 minutes; m / z 597.9 [M + H] ⁺ (ESI positive ion mode), m / z 596.1 [M−H] ⁻ , 642.1 [M + HCOO] ⁻ (ESI negative ion mode)

実施例３２３
Ｎ−［（２，３−ジヒドロベンゾ［ｂ］［１，４］ジオキシン−６−イル）メチル］−４−（｛２−オキソ−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）ベンズアミド（化合物番号３２３）の製造
４−（アミノメチル）ベンゾニトリル塩酸塩とトリエチルアミンの代わりに（２，３−ジヒドロベンゾ［ｂ］［１，４］ジオキシン−６−イル）メタンアミン（市販）を用いること以外は実質的に実施例１８０と同様に反応を行って、表題化合物（１６ｍｇ、収率２９％）を白色粉末として得た。

^１Ｈ−ＮＭＲ（３００ＭＨｚ、ＣＤＣｌ_３）δ：１．６３−１．７９（２Ｈ，ｂｒ ｍ），１．８４−１．９７（２Ｈ，ｂｒ ｍ），２．５１（４Ｈ，ｂｒ ｓ），３．１０（２Ｈ，ｓ），３．５５（２Ｈ，ｓ），４．２５（４Ｈ，ｓ），４．４５（２Ｈ，ｓ），４．５３（２Ｈ，ｄ，Ｊ＝５．７Ｈｚ），６．２７（１Ｈ，ｔ，Ｊ＝４．９Ｈｚ），６．７６−６．８８（３Ｈ，ｍ），７．３１（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ），７．４１（２Ｈ，ｄ，Ｊ＝７．８Ｈｚ），７．５５（２Ｈ，ｄ，Ｊ＝７．８Ｈｚ），７．７６（２Ｈ，ｄ，Ｊ＝８．６Ｈｚ）．

ＬＣ／ＭＳ［条件１］：保持時間２．８０分；ｍ／ｚ５９５．９［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ５９４．１［Ｍ−Ｈ］^―、６４０．１［Ｍ＋ＨＣＯＯ］^―（ＥＳＩ負イオンモード）

Example 323
N-[(2,3-dihydrobenzo [b] [1,4] dioxin-6-yl) methyl] -4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1- Preparation of Oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl) benzamide (Compound No. 323) 4- (Aminomethyl) benzonitrile hydrochloride and (2,3-dihydrobenzoic acid instead of triethylamine [B] [1,4] dioxin-6-yl) methanamine (commercially available) was used in the same manner as in Example 180 to give the title compound (16 mg, 29% yield) as a white powder. Got as.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.63-1.79 (2H, br m), 1.84-1.97 (2H, br m), 2.51 (4H, br s), 3.10 (2H, s), 3.55 (2H, s), 4.25 (4H, s), 4.45 (2H, s), 4.53 (2H, d, J = 5.7 Hz) , 6.27 (1H, t, J = 4.9 Hz), 6.76-6.88 (3H, m), 7.31 (2H, d, J = 8.2 Hz), 7.41 (2H, d, J = 7.8 Hz), 7.55 (2H, d, J = 7.8 Hz), 7.76 (2H, d, J = 8.6 Hz).

LC / MS [Condition 1]: Retention time 2.80 minutes; m / z 595.9 [M + H] ⁺ (ESI positive ion mode), m / z 594.1 [M−H] ⁻ , 640.1 [M + HCOO] ⁻ (ESI negative ion mode)

実施例３２４
Ｎ−（フラン−２−イルメチル）−４−（｛２−オキソ−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）ベンズアミド（化合物番号３２４）の製造
４−（アミノメチル）ベンゾニトリル塩酸塩とトリエチルアミンの代わりにフラン−２−イルメタンアミン（市販）を用いること以外は実質的に実施例１８０と同様に反応を行って、表題化合物（２０ｍｇ、収率４１％）を白色粉末として得た。

^１Ｈ−ＮＭＲ（３００ＭＨｚ、ＣＤＣｌ_３）δ：１．６２−１．７９（２Ｈ，ｂｒ ｍ），１．８４−１．９７（２Ｈ，ｂｒ ｍ），２．５１（４Ｈ，ｂｒ ｓ），３．１１（２Ｈ，ｓ），３．５５（２Ｈ，ｓ），４．４６（２Ｈ，ｓ），４．６４（２Ｈ，ｄ，Ｊ＝５．３Ｈｚ），６．２７−６．３６（２Ｈ，ｍ），６．３６（１Ｈ，ｔ，Ｊ＝４．９Ｈｚ），７．３２（２Ｈ，ｄ，Ｊ＝８．６Ｈｚ），７．３６−７．３９（１Ｈ，ｍ），７．４１（２Ｈ，ｄ，Ｊ＝７．０Ｈｚ），７．５５（２Ｈ，ｄ，Ｊ＝７．８Ｈｚ），７．７７（２Ｈ，ｄ，Ｊ＝８．６Ｈｚ）．

ＬＣ／ＭＳ［条件１］：保持時間２．６３分；ｍ／ｚ５２７．８［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ５２６．０［Ｍ−Ｈ］^―、５７１．９［Ｍ＋ＨＣＯＯ］^―（ＥＳＩ負イオンモード）

Example 324
N- (furan-2-ylmethyl) -4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl } Preparation of methyl) benzamide (Compound No. 324) Substantially the same as Example 180, except that 4- (aminomethyl) benzonitrile hydrochloride and triethylamine were replaced by furan-2-ylmethanamine (commercially available). The reaction was performed to give the title compound (20 mg, 41% yield) as a white powder.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.62-1.79 (2H, br m), 1.84-1.97 (2H, br m), 2.51 (4H, br s), 3.11 (2H, s), 3.55 (2H, s), 4.46 (2H, s), 4.64 (2H, d, J = 5.3 Hz), 6.27-6.36 ( 2H, m), 6.36 (1H, t, J = 4.9 Hz), 7.32 (2H, d, J = 8.6 Hz), 7.36-7.39 (1H, m), 7. 41 (2H, d, J = 7.0 Hz), 7.55 (2H, d, J = 7.8 Hz), 7.77 (2H, d, J = 8.6 Hz).

LC / MS [Condition 1]: Retention time 2.63 minutes; m / z 527.8 [M + H] ⁺ (ESI positive ion mode), m / z 526.0 [M−H] ⁻ , 571.9 [M + HCOO] ⁻ (ESI negative ion mode)

実施例３２５
４−（｛２−オキソ−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）−Ｎ−（テトラヒドロ−２Ｈ−ピラン−４−イル）ベンズアミド（化合物番号３２５）の製造
４−（アミノメチル）ベンゾニトリル塩酸塩の代わりにテトラヒドロ−２Ｈ−ピラン−４−アミン塩酸塩（市販）を用いること以外は実質的に実施例１８０と同様に反応を行って、表題化合物（２８ｍｇ、収率５９％）を白色粉末として得た。

^１Ｈ−ＮＭＲ（３００ＭＨｚ、ＣＤＣｌ_３）δ：１．４８−１．８０（４Ｈ，ｂｒ ｍ），１．８３−２．０８（４Ｈ，ｂｒ ｍ），２．５２（４Ｈ，ｂｒ ｓ），３．１２（２Ｈ，ｓ），３．４５−３．６２（４Ｈ，ｍ），３．９４−４．０５（２Ｈ，ｂｒ ｍ），４．１１−４．２８（１Ｈ，ｍ），４．４６（２Ｈ，ｓ），５．９５（１Ｈ，ｄ，Ｊ＝７．０Ｈｚ），７．３３（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ），７．４１（２Ｈ，ｄ，Ｊ＝８．６Ｈｚ），７．５６（２Ｈ，ｄ，Ｊ＝７．４Ｈｚ），７．７４（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ）．

ＬＣ／ＭＳ［条件１］：保持時間２．３７分；ｍ／ｚ５３１．９［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ５３０．１［Ｍ−Ｈ］^―、５７６．１［Ｍ＋ＨＣＯＯ］^―（ＥＳＩ負イオンモード）

Example 325
4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl) -N- (tetrahydro-2H Preparation of -pyran-4-yl) benzamide (Compound No. 325) Substantially except that tetrahydro-2H-pyran-4-amine hydrochloride (commercially available) is used instead of 4- (aminomethyl) benzonitrile hydrochloride. The reaction was carried out in the same manner as in Example 180 to obtain the title compound (28 mg, yield 59%) as a white powder.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.48-1.80 (4H, br m), 1.83 to 2.08 (4H, br m), 2.52 (4H, br s), 3.12 (2H, s), 3.45-3.62 (4H, m), 3.94-4.05 (2H, br m), 4.11-4.28 (1H, m), 4 .46 (2H, s), 5.95 (1H, d, J = 7.0 Hz), 7.33 (2H, d, J = 8.2 Hz), 7.41 (2H, d, J = 8. 6 Hz), 7.56 (2H, d, J = 7.4 Hz), 7.74 (2H, d, J = 8.2 Hz).

LC / MS [Condition 1]: Retention time 2.37 minutes; m / z 531.9 [M + H] ⁺ (ESI positive ion mode), m / z 530.1 [M−H] ⁻ , 576.1 [M + HCOO] ⁻ (ESI negative ion mode)

実施例３２６
３−｛４−［３−（４−クロロベンゾイル）ピペリジン−１−カルボニル］ベンジル｝−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−２−オン（化合物番号３２６）の製造
４−（アミノメチル）ベンゾニトリル塩酸塩の代わりに（４−クロロフェニル）（ピペリジン−３−イル）メタノン塩酸塩（市販）を用いること以外は実質的に実施例１８０と同様に反応を行って、表題化合物（４９ｍｇ、収率８４％）を無色無定形物として得た。

^１Ｈ−ＮＭＲ（３００ＭＨｚ、ＣＤＣｌ_３）δ：１．３９−２．２１（８Ｈ，ｂｒ ｍ），２．５３（４Ｈ，ｂｒ ｓ），２．８１−３．１９（２Ｈ，ｂｒ ｍ），３．１４（２Ｈ，ｓ），３．３１（１Ｈ，ｂｒ ｓ），３．５６（２Ｈ，ｓ），３．６７−３．９３（１Ｈ，ｂｒ ｍ），４．４５（２Ｈ，ｓ），４．５５−４．９２（１Ｈ，ｂｒ ｍ），７．３１（２Ｈ，ｄ，Ｊ＝６．５Ｈｚ），７．３５−７．５１（６Ｈ，ｍ），７．５６（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ），７．６１−８．０６（２Ｈ，ｂｒ ｍ）．

ＬＣ／ＭＳ［条件１］：保持時間３．５０分；ｍ／ｚ６５３．９［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ６５２．１［Ｍ−Ｈ］^―、６９８．１［Ｍ＋ＨＣＯＯ］^―（ＥＳＩ負イオンモード）

Example 326
3- {4- [3- (4-Chlorobenzoyl) piperidine-1-carbonyl] benzyl} -8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] Preparation of decan-2-one (Compound No. 326) Substantially except that (4-chlorophenyl) (piperidin-3-yl) methanone hydrochloride (commercially available) is used instead of 4- (aminomethyl) benzonitrile hydrochloride Was reacted in the same manner as in Example 180 to obtain the title compound (49 mg, yield 84%) as a colorless amorphous product.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.39-2.21 (8H, br m), 2.53 (4H, br s), 2.81-3.19 (2H, br m), 3.14 (2H, s), 3.31 (1H, br s), 3.56 (2H, s), 3.67-3.93 (1H, br m), 4.45 (2H, s) 4.55-4.92 (1H, br m), 7.31 (2H, d, J = 6.5 Hz), 7.35-7.51 (6H, m), 7.56 (2H, d , J = 8.2 Hz), 7.61-8.06 (2H, br m).

LC / MS [Condition 1]: Retention time 3.50 minutes; m / z 653.9 [M + H] ⁺ (ESI positive ion mode), m / z 652.1 [M−H] ⁻ , 698.1 [M + HCOO] ⁻ (ESI negative ion mode)

実施例３２７
１−［４−（｛２−オキソ−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）ベンゾイル］−４−フェニルピペリジン−４−カルボニトリル（化合物番号３２７）の製造
４−（アミノメチル）ベンゾニトリル塩酸塩の代わりに４−フェニルピペリジン−４−カルボニトリル塩酸塩（市販）を用いること以外は実質的に実施例１８０と同様に反応を行って、表題化合物（４１ｍｇ、収率７５％）を無色無定形物として得た。

^１Ｈ−ＮＭＲ（３００ＭＨｚ、ＣＤＣｌ_３）δ：１．６３−２．３４（８Ｈ，ｂｒ ｍ），２．５３（４Ｈ，ｂｒ ｓ），３．１４（２Ｈ，ｓ），３．２８（１Ｈ，ｂｒ ｓ），３．５５（３Ｈ，ｓ），３．９１（１Ｈ，ｂｒ ｓ），４．４５（２Ｈ，ｓ），４．９３（１Ｈ，ｂｒ ｓ），７．２８−７．５０（１１Ｈ，ｍ），７．５６（２Ｈ，ｄ，Ｊ＝７．８Ｈｚ）．

ＬＣ／ＭＳ［条件１］：保持時間３．４２分；ｍ／ｚ６１７．０［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ６６１．１［Ｍ＋ＨＣＯＯ］^―（ＥＳＩ負イオンモード）

Example 327
1- [4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl) benzoyl] -4 -Preparation of phenylpiperidine-4-carbonitrile (Compound No. 327) Substantially except that 4-phenylpiperidine-4-carbonitrile hydrochloride (commercially available) is used instead of 4- (aminomethyl) benzonitrile hydrochloride The reaction was carried out in the same manner as in Example 180 to obtain the title compound (41 mg, yield 75%) as a colorless amorphous product.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.63-2.34 (8H, br m), 2.53 (4H, br s), 3.14 (2H, s), 3.28 (1H , Br s), 3.55 (3H, s), 3.91 (1H, br s), 4.45 (2H, s), 4.93 (1H, br s), 7.28-7.50. (11H, m), 7.56 (2H, d, J = 7.8 Hz).

LC / MS [Condition 1]: retention time 3.42 minutes; m / z 617.0 [M + H] ⁺ (ESI positive ion mode), m / z 661.1 [M + HCOO] ⁻ (ESI negative ion mode)

実施例３２８
３−｛４−［４−（３，５−ジメチル−１Ｈ−ピラゾール−１−イル）ピペリジン−１−カルボニル］ベンジル｝−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−２−オン（化合物番号３２８）の製造
４−（アミノメチル）ベンゾニトリル塩酸塩とトリエチルアミンの代わりに４−（３，５−ジメチル−１Ｈ−ピラゾール−１−イル）ピペリジン（市販）を用いること以外は実質的に実施例１８０と同様に反応を行って、表題化合物（４２ｍｇ、収率７６％）を白色粉末として得た。

^１Ｈ−ＮＭＲ（３００ＭＨｚ、ＣＤＣｌ_３）δ：１．６４−１．８１（２Ｈ，ｂｒ ｍ），１．８３−２．００（４Ｈ，ｂｒ ｍ），２．１４−２．３１（２Ｈ，ｍ），２．２２（３Ｈ，ｓ），２．２５（３Ｈ，ｓ），２．５３（４Ｈ，ｂｒ ｓ），２．８０−３．１５（２Ｈ，ｂｒ ｍ），３．１３（２Ｈ，ｓ），３．５５（２Ｈ，ｓ），３．９１（１Ｈ，ｂｒ ｓ），４．１３（１Ｈ，ｔｔ，Ｊ＝１１．４，４．１Ｈｚ），４．４４（２Ｈ，ｓ），４．８４（１Ｈ，ｂｒ ｓ），５．７９（１Ｈ，ｓ），７．２９（２Ｈ，ｄ，Ｊ＝７．８Ｈｚ），７．３６−７．４７（４Ｈ，ｍ），７．５６（２Ｈ，ｄ，Ｊ＝７．８Ｈｚ）．

ＬＣ／ＭＳ［条件１］：保持時間３．１６分；ｍ／ｚ３０５．６［Ｍ＋２Ｈ］^２＋、６１０．０［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ６５４．１［Ｍ＋ＨＣＯＯ］^―（ＥＳＩ負イオンモード）

Example 328
3- {4- [4- (3,5-Dimethyl-1H-pyrazol-1-yl) piperidin-1-carbonyl] benzyl} -8- [4- (trifluoromethyl) benzyl] -1-oxa-3 , 8-Diazaspiro [4.5] decan-2-one (Compound No. 328) 4- (3,5-dimethyl-1H-pyrazole-1 instead of 4- (aminomethyl) benzonitrile hydrochloride and triethylamine -Ill) The reaction was carried out in substantially the same manner as in Example 180 except that piperidine (commercially available) was used to obtain the title compound (42 mg, yield 76%) as a white powder.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.64 to 1.81 (2H, br m), 1.83 to 2.00 (4H, br m), 2.14 to 2.31 (2H, m), 2.22 (3H, s), 2.25 (3H, s), 2.53 (4H, br s), 2.80-3.15 (2H, br m), 3.13 (2H) , S), 3.55 (2H, s), 3.91 (1H, br s), 4.13 (1H, tt, J = 11.4, 4.1 Hz), 4.44 (2H, s) 4.84 (1H, br s), 5.79 (1 H, s), 7.29 (2H, d, J = 7.8 Hz), 7.36-7.47 (4H, m), 7. 56 (2H, d, J = 7.8 Hz).

LC / MS [Condition 1]: Retention time 3.16 minutes; m / z 305.6 [M + 2H] ²⁺ , 610.0 [M + H] ⁺ (ESI positive ion mode), m / z 654.1 [M + HCOO] ⁻ (ESI Negative ion mode)

実施例３２９
３−｛４−［４−（モルホリン−４−カルボニル）ピペリジン−１−カルボニル］ベンジル｝−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−２−オン（化合物番号３２９）の製造
ピペリジンの代わりにモルホリン（市販）を用いること以外は実質的に実施例３１０と同様に反応を行って、表題化合物（２０ｍｇ、収率５９％）を無色無定形物として得た。

^１Ｈ−ＮＭＲ（３００ＭＨｚ、ＣＤＣｌ_３）δ：１．６１−２．００（８Ｈ，ｂｒ ｍ），２．５３（４Ｈ，ｂｒ ｓ），２．６６−２．８３（１Ｈ，ｂｒ ｍ），２．８３−３．１５（２Ｈ，ｂｒ ｍ），３．１３（２Ｈ，ｓ），３．４４−３．７５（１０Ｈ，ｍ），３．８１（１Ｈ，ｂｒ ｓ），４．４４（２Ｈ，ｓ），４．６８（１Ｈ，ｂｒ ｓ），７．２９（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ），７．３４−７．４７（４Ｈ，ｍ），７．５６（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ）．

ＬＣ／ＭＳ［条件１］：保持時間２．９０分；ｍ／ｚ６２９．１［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ６７３．２［Ｍ＋ＨＣＯＯ］^―（ＥＳＩ負イオンモード）

Example 329
3- {4- [4- (morpholine-4-carbonyl) piperidine-1-carbonyl] benzyl} -8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5 Production of decan-2-one (Compound No. 329) The reaction was conducted in substantially the same manner as in Example 310 except that morpholine (commercially available) was used instead of piperidine to give the title compound (20 mg, yield 59%). Was obtained as a colorless amorphous product.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.61-2.00 (8H, br m), 2.53 (4H, br s), 2.66-2.83 (1H, br m), 2.83-3.15 (2H, br m), 3.13 (2H, s), 3.44-3.75 (10H, m), 3.81 (1H, br s), 4.44 ( 2H, s), 4.68 (1H, br s), 7.29 (2H, d, J = 8.2 Hz), 7.34-7.47 (4H, m), 7.56 (2H, d , J = 8.2 Hz).

LC / MS [Condition 1]: Retention time 2.90 minutes; m / z 629.1 [M + H] ⁺ (ESI positive ion mode), m / z 673.2 [M + HCOO] ⁻ (ESI negative ion mode)

実施例３３０
Ｎ−シクロヘキシル−１−［４−（｛２−オキソ−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）ベンゾイル］ピペリジン−４−カルボキサミド（化合物番号３３０）の製造
ピペリジンの代わりにシクロヘキサンアミン（市販）を用いること以外は実質的に実施例３１０と同様に反応を行って、表題化合物（２１ｍｇ、収率５９％）を無色無定形物として得た。

^１Ｈ−ＮＭＲ（３００ＭＨｚ、ＣＤＣｌ_３）δ：１．１０（２Ｈ，ｄｑ，Ｊ＝２．５，１１．４Ｈｚ），１．２０−１．４６（２Ｈ，ｍ），１．４９−１．９９（１４Ｈ，ｂｒ ｍ），２．３０（１Ｈ，ｔｔ，Ｊ＝１１．４，３．７Ｈｚ），２．５２（４Ｈ，ｂｒ ｓ），２．７６−３．１１（２Ｈ，ｂｒ ｍ），３．１３（２Ｈ，ｓ），３．５５（２Ｈ，ｓ），３．６７−３．８７（２Ｈ，ｍ），４．４４（２Ｈ，ｓ），４．６７（１Ｈ，ｂｒ ｓ），５．２９（１Ｈ，ｄ，Ｊ＝７．８Ｈｚ），７．２９（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ），７．３３−７．４７（４Ｈ，ｍ），７．５６（２Ｈ，ｄ，Ｊ＝７．４Ｈｚ）．

ＬＣ／ＭＳ［条件１］：保持時間３．２２分；ｍ／ｚ６４１．０［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ６８５．２［Ｍ＋ＨＣＯＯ］^―（ＥＳＩ負イオンモード）

Example 330
N-cyclohexyl-1- [4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl) Preparation of benzoyl] piperidine-4-carboxamide (Compound No. 330) The reaction was conducted in substantially the same manner as in Example 310 except that cyclohexaneamine (commercially available) was used instead of piperidine to give the title compound (21 mg, yield 59 %) As a colorless amorphous product.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.10 (2H, dq, J = 2.5, 11.4 Hz), 1.20-1.46 (2H, m), 1.49-1. 99 (14H, br m), 2.30 (1H, tt, J = 11.4, 3.7 Hz), 2.52 (4H, br s), 2.76-3.11 (2H, br m) , 3.13 (2H, s), 3.55 (2H, s), 3.67-3.87 (2H, m), 4.44 (2H, s), 4.67 (1H, br s) , 5.29 (1H, d, J = 7.8 Hz), 7.29 (2H, d, J = 8.2 Hz), 7.33-7.47 (4H, m), 7.56 (2H, d, J = 7.4 Hz).

LC / MS [Condition 1]: Retention time 3.22 minutes; m / z 641.0 [M + H] ⁺ (ESI positive ion mode), m / z 685.2 [M + HCOO] ⁻ (ESI negative ion mode)

実施例３３１
Ｎ−ｔ−ブチル−１−［４−（｛２−オキソ−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）ベンゾイル］ピペリジン−４−カルボキサミド（化合物番号３３１）の製造
ピペリジンの代わりに２−メチルプロパン−２−アミン（市販）を用いること以外は実質的に実施例３１０と同様に反応を行って、表題化合物（２１ｍｇ、収率６２％）を無色無定形物として得た。

^１Ｈ−ＮＭＲ（３００ＭＨｚ、ＣＤＣｌ_３）δ：１．３５（９Ｈ，ｓ），１．６１−１．９９（８Ｈ，ｂｒ ｍ），２．２４（１Ｈ，ｔｔ，Ｊ＝１１．０，３．７Ｈｚ），２．５２（４Ｈ，ｂｒ ｓ），２．７８−３．０７（２Ｈ，ｂｒ ｍ），３．１３（２Ｈ，ｓ），３．５５（２Ｈ，ｓ），３．７６（１Ｈ，ｂｒ ｓ），４．４４（２Ｈ，ｓ），４．６７（１Ｈ，ｂｒ ｓ），５．２５（１Ｈ，ｓ），７．２９（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ），７．３３−７．４８（４Ｈ，ｍ），７．５６（２Ｈ，ｄ，Ｊ＝８．０Ｈｚ）．

ＬＣ／ＭＳ［条件１］：保持時間３．１２分；ｍ／ｚ６１５．１［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ６５９．２［Ｍ＋ＨＣＯＯ］^―（ＥＳＩ負イオンモード）

Example 331
Nt-butyl-1- [4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} Preparation of methyl) benzoyl] piperidine-4-carboxamide (Compound No. 331) The reaction was carried out in substantially the same manner as in Example 310 except that 2-methylpropan-2-amine (commercially available) was used instead of piperidine. The title compound (21 mg, 62% yield) was obtained as a colorless amorphous product.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.35 (9H, s), 1.61-1.99 (8H, br m), 2.24 (1H, tt, J = 11.0, 3 .7Hz), 2.52 (4H, br s), 2.78-3.07 (2H, br m), 3.13 (2H, s), 3.55 (2H, s), 3.76 ( 1H, brs), 4.44 (2H, s), 4.67 (1H, brs), 5.25 (1H, s), 7.29 (2H, d, J = 8.2 Hz), 7 .33-7.48 (4H, m), 7.56 (2H, d, J = 8.0 Hz).

LC / MS [Condition 1]: Retention time 3.12 minutes; m / z 615.1 [M + H] ⁺ (ESI positive ion mode), m / z 659.2 [M + HCOO] ⁻ (ESI negative ion mode)

実施例３３２
Ｎ−（フラン−３−イルメチル）−４−（｛２−オキソ−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）ベンズアミド（化合物番号３３２）の製造
４−（アミノメチル）ベンゾニトリル塩酸塩とトリエチルアミンの代わりにフラン−３−イルメタンアミン（市販）を用いること以外は実質的に実施例１８０と同様に反応を行って、表題化合物（３７ｍｇ、収率７８％）を白色粉末として得た。

^１Ｈ−ＮＭＲ（３００ＭＨｚ、ＣＤＣｌ_３）δ：１．６１−１．７９（２Ｈ，ｂｒ ｍ），１．８２−１．９８（２Ｈ，ｂｒ ｍ），２．５１（４Ｈ，ｂｒ ｓ），３．１１（２Ｈ，ｓ），３．５５（２Ｈ，ｓ），４．４６（２Ｈ，ｓ），４．４９（２Ｈ，ｄ，Ｊ＝５．３Ｈｚ），６．２１（１Ｈ，ｔ，Ｊ＝４．５Ｈｚ），６．４２（１Ｈ，ｓ），７．３２（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ），７．３６−７．４６（４Ｈ，ｍ），７．５６（２Ｈ，ｄ，Ｊ＝７．８Ｈｚ），７．７５（２Ｈ，ｄｔ，Ｊ＝８．６，２．０Ｈｚ）．

ＬＣ／ＭＳ［条件１］：保持時間３．０４分；ｍ／ｚ５２７．８［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ５２６．０［Ｍ−Ｈ］^―、５７２．０［Ｍ＋ＨＣＯＯ］^―（ＥＳＩ負イオンモード）

Example 332
N- (furan-3-ylmethyl) -4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl } Preparation of methyl) benzamide (Compound No. 332) Substantially the same as Example 180 except that 4- (aminomethyl) benzonitrile hydrochloride and triethylamine were used instead of furan-3-ylmethanamine (commercially available). The reaction was performed to give the title compound (37 mg, yield 78%) as a white powder.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.61-1.79 (2H, br m), 1.82-1.98 (2H, br m), 2.51 (4H, br s), 3.11 (2H, s), 3.55 (2H, s), 4.46 (2H, s), 4.49 (2H, d, J = 5.3 Hz), 6.21 (1H, t, J = 4.5 Hz), 6.42 (1H, s), 7.32 (2H, d, J = 8.2 Hz), 7.36-7.46 (4H, m), 7.56 (2H, d, J = 7.8 Hz), 7.75 (2H, dt, J = 8.6, 2.0 Hz).

LC / MS [Condition 1]: Retention time 3.04 minutes; m / z 527.8 [M + H] ⁺ (ESI positive ion mode), m / z 526.0 [M−H] ⁻ , 572.0 [M + HCOO] ⁻ (ESI negative ion mode)

参考例３３３−１
４−（４−ｔ−ブチルベンゾイル）ピペリジン−１−カルボン酸ｔ−ブチルの製造
１．１Ｍ臭化メチルマグネシウム−テトラヒドロフラン溶液の代わりに２．０Ｍ（４−ｔ−ブチルフェニル）マグネシウムブロミド−ジエチルエーテル溶液（市販）を用いること以外は実質的に参考例１６８−２と同様に反応を行って、表題化合物（８１ｍｇ、収率７１％）を無色油状物として得た。

ＬＣ／ＭＳ［条件１］：保持時間５．３８分；ｍ／ｚ２９０．０［Ｍ−ｉｓｏｂｕｔｅｎｅ＋Ｈ］^＋（ＥＳＩ正イオンモード）

Reference Example 333-1
Preparation of t-butyl 4- (4-tert-butylbenzoyl) piperidine-1-carboxylate 2.0 M (4-tert-butylphenyl) magnesium bromide-diethyl ether instead of 1.1 M methylmagnesium bromide-tetrahydrofuran solution The reaction was carried out substantially in the same manner as in Reference Example 168-2 except that a solution (commercially available) was used, and the title compound (81 mg, yield 71%) was obtained as a colorless oil.

LC / MS [Condition 1]: Retention time 5.38 minutes; m / z 290.0 [M-isobutene + H] ⁺ (ESI positive ion mode)

参考例３３３−２
（４−ｔ−ブチルフェニル）（ピペリジン−４−イル）メタノン塩酸塩の製造
４−アセチルピペリジン−１−カルボン酸ｔ−ブチルの代わりに参考例３３３−１で得られた４−（４−ｔ−ブチルベンゾイル）ピペリジン−１−カルボン酸ｔ−ブチルを用いること以外は実質的に参考例１６８−３と同様に反応を行って、表題化合物（６１ｍｇ、定量的）を紫色粉末として得た。

ＬＣ／ＭＳ［条件１］：保持時間２．８２分；ｍ／ｚ２４６．１［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）

Reference Example 333-2
Preparation of (4-t-butylphenyl) (piperidin-4-yl) methanone hydrochloride 4- (4-t) obtained in Reference Example 333-1 instead of t-butyl 4-acetylpiperidine-1-carboxylate Reaction was carried out in substantially the same manner as in Reference Example 168-3 except that t-butyl-butylbenzoyl) piperidine-1-carboxylate was used to obtain the title compound (61 mg, quantitative) as a purple powder.

LC / MS [Condition 1]: Retention time 2.82 minutes; m / z 246.1 [M + H] ⁺ (ESI positive ion mode)

実施例３３３
３−｛４−［４−（４−ｔ−ブチルベンゾイル）ピペリジン−１−カルボニル］ベンジル｝−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−２−オン（化合物番号３３３）の製造
４−（アミノメチル）ベンゾニトリル塩酸塩の代わりに参考例３３３−２で得られた（４−ｔ−ブチルフェニル）（ピペリジン−４−イル）メタノン塩酸塩を用いること以外は実質的に実施例１８０と同様に反応を行って、表題化合物（５７ｍｇ、収率９５％）を無色無定形物として得た。

^１Ｈ−ＮＭＲ（３００ＭＨｚ、ＣＤＣｌ_３）δ：１．３５（９Ｈ，ｓ），１．６３−２．０８（８Ｈ，ｂｒ ｍ），２．５２（４Ｈ，ｂｒ ｓ），２．９６−３．２５（２Ｈ，ｂｒ ｍ），３．１３（２Ｈ，ｓ），３．４６−３．６１（１Ｈ，ｂｒ ｍ），３．５５（２Ｈ，ｓ），３．８２（１Ｈ，ｂｒ ｓ），４．４４（２Ｈ，ｓ），４．６６（１Ｈ，ｂｒ ｓ），７．３０（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ），７．３６−７．４５（４Ｈ，ｍ），７．４９（２Ｈ，ｄｔ，Ｊ＝８．６，１．６Ｈｚ），７．５６（２Ｈ，ｄ，Ｊ＝７．４Ｈｚ），７．８９（２Ｈ，ｄｔ，Ｊ＝８．６，１．６Ｈｚ）．

ＬＣ／ＭＳ［条件１］：保持時間３．７０分；ｍ／ｚ３３８．６［Ｍ＋２Ｈ］^２＋、６７６．１［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ７２０．３［Ｍ＋ＨＣＯＯ］^―（ＥＳＩ負イオンモード）

Example 333
3- {4- [4- (4-t-butylbenzoyl) piperidine-1-carbonyl] benzyl} -8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4. 5] Preparation of decan-2-one (Compound No. 333) (4-tert-butylphenyl) (piperidin-4-yl) obtained in Reference Example 333-2 instead of 4- (aminomethyl) benzonitrile hydrochloride ) The reaction was carried out in substantially the same manner as in Example 180 except that methanone hydrochloride was used to obtain the title compound (57 mg, yield 95%) as a colorless amorphous product.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.35 (9H, s), 1.63 to 2.08 (8H, br m), 2.52 (4H, br s), 2.96-3 .25 (2H, br m), 3.13 (2H, s), 3.46-3.61 (1H, br m), 3.55 (2H, s), 3.82 (1H, br s) 4.44 (2H, s), 4.66 (1 H, br s), 7.30 (2H, d, J = 8.2 Hz), 7.36-7.45 (4H, m), 7. 49 (2H, dt, J = 8.6, 1.6 Hz), 7.56 (2H, d, J = 7.4 Hz), 7.89 (2H, dt, J = 8.6, 1.6 Hz) .

LC / MS [Condition 1]: Retention time 3.70 minutes; m / z 338.6 [M + 2H] ²⁺ , 676.1 [M + H] ⁺ (ESI positive ion mode), m / z 720.3 [M + HCOO] ⁻ (ESI Negative ion mode)

参考例３３４−１
４−（シクロヘキサンカルボニル）ピペリジン−１−カルボン酸ｔ−ブチルの製造
１．１Ｍ臭化メチルマグネシウム−テトラヒドロフラン溶液の代わりに１．０Ｍシクロヘキシルマグネシウムブロミド−テトラヒドロフラン溶液（市販）を用いること以外は実質的に参考例１６８−２と同様に反応を行って、表題化合物（１７ｍｇ、収率１５％）を無色油状物として得た。

ＬＣ／ＭＳ［条件１］：保持時間４．８７分；ｍ／ｚ２４０．１［Ｍ−ｉｓｏｂｕｔｅｎｅ＋Ｈ］^＋（ＥＳＩ正イオンモード）

Reference Example 334-1
Preparation of t-butyl 4- (cyclohexanecarbonyl) piperidine-1-carboxylate Substantially except that a 1.0 M cyclohexylmagnesium bromide-tetrahydrofuran solution (commercially available) was used instead of the 1.1 M methylmagnesium bromide-tetrahydrofuran solution. The reaction was performed in the same manner as in Reference Example 168-2 to give the title compound (17 mg, yield 15%) as a colorless oil.

LC / MS [Condition 1]: Retention time 4.87 min; m / z 240.1 [M-isobutene + H] ⁺ (ESI positive ion mode)

参考例３３４−２
シクロヘキシル（ピペリジン−４−イル）メタノン塩酸塩の製造
４−アセチルピペリジン−１−カルボン酸ｔ−ブチルの代わりに参考例３３４−１で得られた４−（シクロヘキサンカルボニル）ピペリジン−１−カルボン酸ｔ−ブチルを用いること以外は実質的に参考例１６８−３と同様に反応を行って、表題化合物（１３ｍｇ、定量的）を白色粉末として得た。

ＬＣ／ＭＳ［条件１］：保持時間０．７４分；ｍ／ｚ１９６．１［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）

Reference Example 334-2
Preparation of cyclohexyl (piperidin-4-yl) methanone hydrochloride 4- (cyclohexanecarbonyl) piperidine-1-carboxylic acid t obtained in Reference Example 334-1 in place of t-butyl 4-acetylpiperidine-1-carboxylate The reaction was carried out substantially in the same manner as in Reference Example 168-3 except that -butyl was used to give the title compound (13 mg, quantitative) as a white powder.

LC / MS [Condition 1]: Retention time 0.74 minutes; m / z 196.1 [M + H] ⁺ (ESI positive ion mode)

実施例３３４
３−｛４−［４−（シクロヘキサンカルボニル）ピペリジン−１−カルボニル］ベンジル｝−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−２−オン（化合物番号３３４）の製造
４−（アミノメチル）ベンゾニトリル塩酸塩の代わりに参考例３３４−２で得られたシクロヘキシル（ピペリジン−４−イル）メタノン塩酸塩を用いること以外は実質的に実施例１８０と同様に反応を行って、表題化合物（２２ｍｇ、収率８０％）を白色粉末として得た。

^１Ｈ−ＮＭＲ（３００ＭＨｚ、ＣＤＣｌ_３）δ：１．１１−１．４２（６Ｈ，ｂｒ ｍ），１．４７−２．００（１２Ｈ，ｂｒ ｍ），２．４０−２．６４（５Ｈ，ｂｒ ｍ），２．６８−２．８３（１Ｈ，ｍ），２．９６（２Ｈ，ｂｒ ｓ），３．１３（２Ｈ，ｓ），３．５７（２Ｈ，ｓ），３．７４（１Ｈ，ｂｒ ｓ），４．４４（２Ｈ，ｓ），４．６５（１Ｈ，ｂｒ ｓ），７．２９（２Ｈ，ｄ，Ｊ＝７．８Ｈｚ），７．３８（２Ｈ，ｄ，Ｊ＝７．８Ｈｚ），７．４３（２Ｈ，ｄ，Ｊ＝７．０Ｈｚ），７．５６（２Ｈ，ｄ，Ｊ＝７．８Ｈｚ）．

ＬＣ／ＭＳ［条件１］：保持時間３．４８分；ｍ／ｚ６２６．０［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ６７０．１［Ｍ＋ＨＣＯＯ］^―（ＥＳＩ負イオンモード）

Example 334
3- {4- [4- (Cyclohexanecarbonyl) piperidine-1-carbonyl] benzyl} -8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decane- Preparation of 2-one (Compound No. 334) Substantially except that cyclohexyl (piperidin-4-yl) methanone hydrochloride obtained in Reference Example 334-2 was used instead of 4- (aminomethyl) benzonitrile hydrochloride Was reacted in the same manner as in Example 180 to obtain the title compound (22 mg, yield: 80%) as a white powder.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.11-1.42 (6H, br m), 1.47-2.00 (12H, br m), 2.40-2.64 (5H, br m), 2.68-2.83 (1H, m), 2.96 (2H, br s), 3.13 (2H, s), 3.57 (2H, s), 3.74 (1H) , Br s), 4.44 (2H, s), 4.65 (1H, br s), 7.29 (2H, d, J = 7.8 Hz), 7.38 (2H, d, J = 7). .8 Hz), 7.43 (2H, d, J = 7.0 Hz), 7.56 (2H, d, J = 7.8 Hz).

LC / MS [Condition 1]: retention time 3.48 minutes; m / z 626.0 [M + H] ⁺ (ESI positive ion mode), m / z 670.1 [M + HCOO] ⁻ (ESI negative ion mode)

実施例３３５
３−｛４−［４−（４−クロロベンゾイル）ピペリジン−１−カルボニル］ベンジル｝−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−２−オン（化合物番号３３５）の製造
４−（アミノメチル）ベンゾニトリル塩酸塩の代わりに（４−クロロフェニル）（ピペリジン−４−イル）メタノン塩酸塩（市販）を用いること以外は実質的に実施例１８０と同様に反応を行って、表題化合物（５２ｍｇ、収率８９％）を白色粉末として得た。

^１Ｈ−ＮＭＲ（３００ＭＨｚ、ＣＤＣｌ_３）δ：１．６４−２．０８（８Ｈ，ｂｒ ｍ），２．５２（４Ｈ，ｂｒ ｓ），２．９６−３．２８（２Ｈ，ｂｒ ｍ），３．１３（２Ｈ，ｓ），３．４２−３．５７（１Ｈ，ｍ），３．５５（２Ｈ，ｓ），３．８３（１Ｈ，ｂｒ ｓ），４．４４（２Ｈ，ｓ），４．６７（１Ｈ，ｂｒ ｓ），７．３０（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ），７．３５−７．５０（６Ｈ，ｍ），７．５６（２Ｈ，ｄ，Ｊ＝８．６Ｈｚ），７．８８（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ）．

ＬＣ／ＭＳ［条件１］：保持時間３．５０分；ｍ／ｚ６５３．９［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ６９８．０［Ｍ＋ＨＣＯＯ］^―（ＥＳＩ負イオンモード）

Example 335
3- {4- [4- (4-Chlorobenzoyl) piperidine-1-carbonyl] benzyl} -8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] Preparation of decan-2-one (Compound No. 335) Substantially except that (4-chlorophenyl) (piperidin-4-yl) methanone hydrochloride (commercially available) is used instead of 4- (aminomethyl) benzonitrile hydrochloride Was reacted in the same manner as in Example 180 to give the title compound (52 mg, yield 89%) as a white powder.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.64-2.08 (8H, br m), 2.52 (4H, br s), 2.96-3.28 (2H, br m), 3.13 (2H, s), 3.42-3.57 (1H, m), 3.55 (2H, s), 3.83 (1H, br s), 4.44 (2H, s), 4.67 (1H, br s), 7.30 (2H, d, J = 8.2 Hz), 7.35-7.50 (6H, m), 7.56 (2H, d, J = 8. 6 Hz), 7.88 (2H, d, J = 8.2 Hz).

LC / MS [Condition 1]: Retention time 3.50 minutes; m / z 653.9 [M + H] ⁺ (ESI positive ion mode), m / z 698.0 [M + HCOO] ⁻ (ESI negative ion mode)

参考例３３６−１
４−（４−メトキシベンゾイル）ピペリジン−１−カルボン酸ｔ−ブチルの製造
１．１Ｍ臭化メチルマグネシウム−テトラヒドロフラン溶液の代わりに１．０Ｍ（４−メトキシフェニル）マグネシウムブロミド−テトラヒドロフラン溶液（市販）を用いること以外は実質的に参考例１６８−２と同様に反応を行って、表題化合物（１１３ｍｇ、収率８８％）を無色油状物として得た。

ＬＣ／ＭＳ［条件１］：保持時間４．４５分；ｍ／ｚ２６４．０［Ｍ−ｉｓｏｂｕｔｅｎｅ＋Ｈ］^＋（ＥＳＩ正イオンモード）

Reference Example 336-1
Preparation of t-butyl 4- (4-methoxybenzoyl) piperidine-1-carboxylate The reaction was carried out in substantially the same manner as in Reference Example 168-2 except that the title compound (113 mg, yield 88%) was obtained as a colorless oil.

LC / MS [Condition 1]: Retention time 4.45 min; m / z 264.0 [M-isobutene + H] ⁺ (ESI positive ion mode)

参考例３３６−２
（４−メトキシフェニル）（ピペリジン−４−イル）メタノン塩酸塩の製造
４−アセチルピペリジン−１−カルボン酸ｔ−ブチルの代わりに参考例３３６−１で得られた４−（４−メトキシベンゾイル）ピペリジン−１−カルボン酸ｔ−ブチルを用いること以外は実質的に参考例１６８−３と同様に反応を行って、表題化合物（83ｍｇ、定量的）を青色無定形物として得た。

ＬＣ／ＭＳ［条件１］：保持時間０．５３分；ｍ／ｚ２２０．０［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）

Reference Example 336-2
Preparation of (4-methoxyphenyl) (piperidin-4-yl) methanone hydrochloride 4- (4-methoxybenzoyl) obtained in Reference Example 336-1 instead of t-butyl 4-acetylpiperidine-1-carboxylate The reaction was carried out substantially in the same manner as in Reference Example 168-3 except that t-butyl piperidine-1-carboxylate was used, and the title compound (83 mg, quantitative) was obtained as a blue amorphous product.

LC / MS [Condition 1]: Retention time 0.53 minutes; m / z 220.0 [M + H] ⁺ (ESI positive ion mode)

実施例３３６
３−｛４−［４−（４−メトキシベンゾイル）ピペリジン−１−カルボニル］ベンジル｝−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−２−オン（化合物番号３３６）の製造
４−（アミノメチル）ベンゾニトリル塩酸塩の代わりに参考例３３６−２で得られた（４−メトキシフェニル）（ピペリジン−４−イル）メタノン塩酸塩を用いること以外は実質的に実施例１８０と同様に反応を行って、表題化合物（５９ｍｇ、収率７０％）を無色無定形物として得た。

^１Ｈ−ＮＭＲ（３００ＭＨｚ、ＣＤＣｌ_３）δ：１．６４−２．１０（８Ｈ，ｂｒ ｍ），２．５２（４Ｈ，ｂｒ ｓ），２．９５−３．２５（２Ｈ，ｂｒ ｍ），３．１３（２Ｈ，ｓ），３．４３−３．５７（１Ｈ，ｍ），３．５５（２Ｈ，ｓ），３．８４（１Ｈ，ｂｒ ｓ），３．８８（３Ｈ，ｓ），４．４４（２Ｈ，ｓ），４．６８（１Ｈ，ｂｒ ｓ），６．９５（２Ｈ，ｄｔ，Ｊ＝９．０，２．０Ｈｚ），７．３０（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ），７．３６−７．４６（４Ｈ，ｍ），７．５６（２Ｈ，ｄ，Ｊ＝７．８Ｈｚ），７．９４（２Ｈ，ｄｔ，Ｊ＝９．０，２．０Ｈｚ）．

ＬＣ／ＭＳ［条件１］：保持時間３．３２分；ｍ／ｚ６４９．９［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ６９４．０［Ｍ＋ＨＣＯＯ］^―（ＥＳＩ負イオンモード）

Example 336
3- {4- [4- (4-Methoxybenzoyl) piperidine-1-carbonyl] benzyl} -8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] Preparation of decan-2-one (Compound No. 336) (4-Methoxyphenyl) (piperidin-4-yl) methanone hydrochloride obtained in Reference Example 336-2 instead of 4- (aminomethyl) benzonitrile hydrochloride The title compound (59 mg, yield 70%) was obtained as a colorless amorphous product in substantially the same manner as in Example 180 except that was used.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.64-2.10 (8H, br m), 2.52 (4H, br s), 2.95-3.25 (2H, br m), 3.13 (2H, s), 3.43-3.57 (1H, m), 3.55 (2H, s), 3.84 (1H, br s), 3.88 (3H, s), 4.44 (2H, s), 4.68 (1H, br s), 6.95 (2H, dt, J = 9.0, 2.0 Hz), 7.30 (2H, d, J = 8. 2 Hz), 7.36-7.46 (4H, m), 7.56 (2H, d, J = 7.8 Hz), 7.94 (2H, dt, J = 9.0, 2.0 Hz).

LC / MS [Condition 1]: Retention time 3.32 minutes; m / z 649.9 [M + H] ⁺ (ESI positive ion mode), m / z 694.0 [M + HCOO] ⁻ (ESI negative ion mode)

参考例３３７−１
４−（２−メチルベンゾイル）ピペリジン−１−カルボン酸ｔ−ブチルの製造
１．１Ｍ臭化メチルマグネシウム−テトラヒドロフラン溶液の代わりに１．０Ｍｏ−トリルマグネシウムブロミド−テトラヒドロフラン溶液（市販）を用いること以外は実質的に参考例１６８−２と同様に反応を行って、表題化合物（２０ｍｇ、収率２７％）を無色油状物として得た。

ＬＣ／ＭＳ［条件１］：保持時間４．６３分；ｍ／ｚ２４８．０［Ｍ−ｉｓｏｂｕｔｅｎｅ＋Ｈ］^＋（ＥＳＩ正イオンモード）

Reference Example 337-1
Production of t-butyl 4- (2-methylbenzoyl) piperidine-1-carboxylate A 1.0 Mo-tolylmagnesium bromide-tetrahydrofuran solution (commercially available) was used in place of the 1.1 M methylmagnesium bromide-tetrahydrofuran solution. The reaction was carried out substantially in the same manner as in Reference Example 168-2 to give the title compound (20 mg, yield 27%) as a colorless oil.

LC / MS [Condition 1]: Retention time 4.63 minutes; m / z 248.0 [M-isobutene + H] ⁺ (ESI positive ion mode)

参考例３３７−２
ピペリジン−４−イル（ｏ−トリル）メタノン塩酸塩の製造
４−アセチルピペリジン−１−カルボン酸ｔ−ブチルの代わりに参考例３３７−１で得られた４−（２−メチルベンゾイル）ピペリジン−１−カルボン酸ｔ−ブチルを用いること以外は実質的に参考例１６８−３と同様に反応を行って、表題化合物（１６ｍｇ、定量的）を白色粉末として得た。

ＬＣ／ＭＳ［条件１］：保持時間０．６８分；ｍ／ｚ２０４．１［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）

Reference Example 337-2
Preparation of piperidin-4-yl (o-tolyl) methanone hydrochloride 4- (2-methylbenzoyl) piperidine-1 obtained in Reference Example 337-1 in place of t-butyl 4-acetylpiperidine-1-carboxylate -The reaction was carried out in substantially the same manner as in Reference Example 168-3 except that t-butyl carboxylate was used to obtain the title compound (16 mg, quantitative) as a white powder.

LC / MS [Condition 1]: Retention time 0.68 min; m / z 204.1 [M + H] ⁺ (ESI positive ion mode)

実施例３３７
３−｛４−［４−（２−メチルベンゾイル）ピペリジン−１−カルボニル］ベンジル｝−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−２−オン（化合物番号３３７）の製造
４−（アミノメチル）ベンゾニトリル塩酸塩の代わりに参考例３３７−２で得られたピペリジン−４−イル（ｏ−トリル）メタノン塩酸塩を用いること以外は実質的に実施例１８０と同様に反応を行って、表題化合物（２６ｍｇ、収率６９％）を無色無定形物として得た。

^１Ｈ−ＮＭＲ（３００ＭＨｚ、ＣＤＣｌ_３）δ：１．６２−２．０９（８Ｈ，ｂｒ ｍ），２．４３（３Ｈ，ｓ），２．５２（４Ｈ，ｂｒ ｓ），２．８９−３．２０（２Ｈ，ｂｒ ｍ），３．１３（２Ｈ，ｓ），３．２６−３．４３（１Ｈ，ｍ），３．５５（２Ｈ，ｓ），３．８１（１Ｈ，ｂｒ ｓ），４．４４（２Ｈ，ｓ），４．６４（１Ｈ，ｂｒ ｓ），７．２１−７．３２（４Ｈ，ｍ），７．３３−７．４６（５Ｈ，ｍ），７．４８−７．５９（３Ｈ，ｍ）．

ＬＣ／ＭＳ［条件１］：保持時間３．４２分；ｍ／ｚ６３４．０［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ６７８．１［Ｍ＋ＨＣＯＯ］^―（ＥＳＩ負イオンモード）

Example 337
3- {4- [4- (2-Methylbenzoyl) piperidine-1-carbonyl] benzyl} -8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] Preparation of decan-2-one (Compound No. 337) Instead of 4- (aminomethyl) benzonitrile hydrochloride, use piperidin-4-yl (o-tolyl) methanone hydrochloride obtained in Reference Example 337-2. The title compound (26 mg, yield 69%) was obtained as a colorless amorphous product in substantially the same manner as in Example 180 except for the above.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.62-2.09 (8H, br m), 2.43 (3H, s), 2.52 (4H, br s), 2.89-3 .20 (2H, br m), 3.13 (2H, s), 3.26-3.43 (1H, m), 3.55 (2H, s), 3.81 (1H, br s), 4.44 (2H, s), 4.64 (1H, br s), 7.21-7.32 (4H, m), 7.33-7.46 (5H, m), 7.48-7 .59 (3H, m).

LC / MS [condition 1]: retention time 3.42 minutes; m / z 634.0 [M + H] ⁺ (ESI positive ion mode), m / z 678.1 [M + HCOO] ⁻ (ESI negative ion mode)

参考例３３８−１
ピペラジン−１，４−ジカルボン酸（１−ｔ−ブチル）４−メチルの製造
ピペラジン−１−カルボン酸ｔ−ブチル（４．１ｇ、２２ｍｍｏｌ）をクロロホルム（１２ｍＬ）に溶解し、０℃にてトリエチルアミン（９．２ｍＬ、６６ｍｍｏｌ）を加えた後、クロロホルム（８．０ｍＬ）に溶解したクロロギ酸メチル（３．４ｍＬ、６６ｍｍｏｌ）を０℃にてゆっくりと滴下し、室温まで昇温した後、１２時間かき混ぜた。その後、水（４０ｍＬ）とクロロホルム（４０ｍＬ）を加えて、有機層を分離し、無水硫酸ナトリウムで乾燥した後、減圧下濃縮乾固して、表題化合物（５．３ｇ、収率９８％）を白色粉末として得た。

^１Ｈ−ＮＭＲ（３００ＭＨｚ、ＣＤＣｌ_３）δ：１．４７（９Ｈ，ｓ），３．３５−３．４８（８Ｈ，ｂｒ ｍ），３．７１（３Ｈ，ｓ）．

ＬＣ／ＭＳ［条件１］：保持時間３．６６分；ｍ／ｚ１４５．０［Ｍ−ｉｓｏｂｕｔｅｎｅ−ＣＯ_２＋Ｈ］^＋（ＥＳＩ正イオンモード）

Reference Example 338-1
Preparation of piperazine- 1,4-dicarboxylic acid (1-t-butyl) 4-methyl Piperazine-1-carboxylate t-butyl (4.1 g, 22 mmol) was dissolved in chloroform (12 mL) and triethylamine was obtained at 0 ° C. (9.2 mL, 66 mmol) was added, methyl chloroformate (3.4 mL, 66 mmol) dissolved in chloroform (8.0 mL) was slowly added dropwise at 0 ° C., and the mixture was warmed to room temperature, then 12 hours. Stir. Then, water (40 mL) and chloroform (40 mL) were added, the organic layer was separated, dried over anhydrous sodium sulfate, and then concentrated to dryness under reduced pressure to give the title compound (5.3 g, yield 98%). Obtained as a white powder.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.47 (9H, s), 3.35-3.48 (8H, br m), 3.71 (3H, s).

LC / MS [Condition 1]: Retention time 3.66 minutes; m / z 145.0 [M-isobutene-CO ₂ + H] ⁺ (ESI positive ion mode)

参考例３３８−２
ピペラジン−１−カルボン酸メチル塩酸塩の製造
４−アセチルピペリジン−１−カルボン酸ｔ−ブチルの代わりに参考例３３８−１で得られたピペラジン−１，４−ジカルボン酸（１−ｔ−ブチル）４−メチルを用いること以外は実質的に参考例１６８−３と同様に反応を行って、表題化合物（３．９ｇ、定量的）を白色粉末として得た。

ＬＣ／ＭＳ［条件１］：保持時間０．５１分；ｍ／ｚ１４５．０［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）

Reference Example 338-2
Preparation of Piperazine-1-carboxylic Acid Methyl Hydrochloride Piperazine-1,4-dicarboxylic acid (1-t-butyl) obtained in Reference Example 338-1 instead of 4-acetylpiperidine-1-carboxylate t-butyl The reaction was carried out substantially in the same manner as in Reference Example 168-3, except that 4-methyl was used, to give the title compound (3.9 g, quantitative) as a white powder.

LC / MS [Condition 1]: Retention time 0.51 min; m / z 145.0 [M + H] ⁺ (ESI positive ion mode)

実施例３３８
４−［４−（｛２−オキソ−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）ベンゾイル］ピペラジン−１−カルボン酸メチル（化合物番号３３８）の製造
４−（アミノメチル）ベンゾニトリル塩酸塩の代わりに参考例３３８−２で得られたピペラジン−１−カルボン酸メチル塩酸塩を用いること以外は実質的に実施例１８０と同様に反応を行って、表題化合物（４９ｍｇ、収率５７％）を無色無定形物として得た。

^１Ｈ−ＮＭＲ（３００ＭＨｚ、ＣＤＣｌ_３）δ：１．６５−１．８１（２Ｈ，ｂｒ ｍ），１．８５−２．００（２Ｈ，ｂｒ ｍ），２．５２（４Ｈ，ｂｒ ｓ），３．１３（２Ｈ，ｓ），３．２９−３．８６（８Ｈ，ｂｒ ｍ），３．５５（２Ｈ，ｓ），３．７３（３Ｈ，ｓ），４．４５（２Ｈ，ｓ），７．３１（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ），７．３９（２Ｈ，ｄ，Ｊ＝８．６Ｈｚ），７．４２（２Ｈ，ｄ，Ｊ＝６．５Ｈｚ），７．５６（２Ｈ，ｄ，Ｊ＝７．８Ｈｚ）．

ＬＣ／ＭＳ［条件１］：保持時間２．９６分；ｍ／ｚ５７４．９［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ６１９．０［Ｍ＋ＨＣＯＯ］^―（ＥＳＩ負イオンモード）

Example 338
4- [4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl) benzoyl] piperazine- Preparation of methyl 1-carboxylate (Compound No. 338) Substantially except that piperazine-1-carboxylic acid methyl hydrochloride obtained in Reference Example 338-2 was used instead of 4- (aminomethyl) benzonitrile hydrochloride Was reacted in the same manner as in Example 180 to obtain the title compound (49 mg, yield 57%) as a colorless amorphous product.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.65 to 1.81 (2H, br m), 1.85 to 2.00 (2H, br m), 2.52 (4H, br s), 3.13 (2H, s), 3.29-3.86 (8H, br m), 3.55 (2H, s), 3.73 (3H, s), 4.45 (2H, s), 7.31 (2H, d, J = 8.2 Hz), 7.39 (2H, d, J = 8.6 Hz), 7.42 (2H, d, J = 6.5 Hz), 7.56 (2H , D, J = 7.8 Hz).

LC / MS [Condition 1]: Retention time 2.96 minutes; m / z 574.9 [M + H] ⁺ (ESI positive ion mode), m / z 619.0 [M + HCOO] ⁻ (ESI negative ion mode)

実施例３３９
４−（（１ｒ，４ｒ）−４−｛［８−（４−シアノベンジル）−２−オキソ−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル］メチル｝シクロヘキサンカルボニル）ピペラジン−１−カルボン酸メチル（化合物番号３３９）の製造
４−（｛２−オキソ−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）安息香酸の代わりに参考例１７−２で得られた（１ｒ，４ｒ）−４−｛［８−（４−シアノベンジル）−２−オキソ−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル］メチル｝シクロヘキサンカルボン酸を、４−（アミノメチル）ベンゾニトリル塩酸塩の代わりに参考例３３８−２で得られたピペラジン−１−カルボン酸メチル塩酸塩を用いること以外は実質的に実施例１８０と同様に反応を行って、表題化合物（１４ｍｇ、収率３４％）を白色粉末として得た。

^１Ｈ−ＮＭＲ（３００ＭＨｚ、ＣＤＣｌ_３）δ：１．０５（２Ｈ，ｑ，Ｊ＝１１．４Ｈｚ），１．４５−１．６８（３Ｈ，ｂｒ ｍ），１．６９−１．８６（６Ｈ，ｂｒ ｍ），１．８７−２．００（２Ｈ，ｂｒ ｍ），２．４３（１Ｈ，ｔ，Ｊ＝１１．７Ｈｚ），２．５６（４Ｈ，ｂｒ ｓ），３．１１（２Ｈ，ｄ，Ｊ＝７．４Ｈｚ），３．２６（２Ｈ，ｓ），３．４０−３．６４（８Ｈ，ｂｒ ｍ），３．５７（２Ｈ，ｓ），３．７２（３Ｈ，ｓ），７．４４（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ），７．６１（２Ｈ，ｄ，Ｊ＝７．８Ｈｚ）．

ＬＣ／ＭＳ［条件１］：保持時間１．４０分；ｍ／ｚ５３７．９［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ５８２．１［Ｍ＋ＨＣＯＯ］^―（ＥＳＩ負イオンモード）

Example 339
4-((1r, 4r) -4-{[8- (4-cyanobenzyl) -2-oxo-1-oxa-3,8-diazaspiro [4.5] decan-3-yl] methyl} cyclohexanecarbonyl ) Preparation of methyl piperazine-1-carboxylate (Compound No. 339) 4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] (1r, 4r) -4-{[8- (4-Cyanobenzyl) -2-oxo-1-oxa-3] obtained in Reference Example 17-2 instead of (decan-3-yl} methyl) benzoic acid , 8-Diazaspiro [4.5] decan-3-yl] methyl} cyclohexanecarboxylic acid, instead of 4- (aminomethyl) benzonitrile hydrochloride, piperazine-1-carboxylic acid obtained in Reference Example 338-2 Methyl salt Except using salt The reaction was carried out in the same manner as substantially Example 180 to give the title compound (14 mg, 34% yield) as a white powder.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.05 (2H, q, J = 11.4 Hz), 1.45 to 1.68 (3H, br m), 1.69 to 1.86 (6H) , Br m), 1.87-2.00 (2H, br m), 2.43 (1H, t, J = 11.7 Hz), 2.56 (4H, br s), 3.11 (2H, d, J = 7.4 Hz), 3.26 (2H, s), 3.40-3.64 (8H, br m), 3.57 (2H, s), 3.72 (3H, s), 7.44 (2H, d, J = 8.2 Hz), 7.61 (2H, d, J = 7.8 Hz).

LC / MS [Condition 1]: Retention time 1.40 minutes; m / z 537.9 [M + H] ⁺ (ESI positive ion mode), m / z 582.1 [M + HCOO] ⁻ (ESI negative ion mode)

実施例３４０
４−（４−｛［８−（４−シアノベンジル）−２−オキソ−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル］メチル｝ベンズアミド）ピペリジン−１−カルボン酸エチル（化合物番号３４０）の製造
４−（｛２−オキソ−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）安息香酸の代わりに参考例１７１−２で得られた４−｛［８−（４−シアノベンジル）−２−オキソ−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル］メチル｝安息香酸を、４−（アミノメチル）ベンゾニトリル塩酸塩の代わりに４−アミノピペリジン−１−カルボン酸エチル（市販）を用いること以外は実質的に実施例１８０と同様に反応を行って、表題化合物（２４ｍｇ、収率５７％）を白色粉末として得た。

^１Ｈ−ＮＭＲ（３００ＭＨｚ、ＣＤＣｌ_３）δ：１．２７（３Ｈ，ｔ，Ｊ＝７．２Ｈｚ），１．４２（２Ｈ，ｄｑ，Ｊ＝３．３，１２．１Ｈｚ），１．６３−１．７８（２Ｈ，ｂｒ ｍ），１．８３−１．９６（２Ｈ，ｂｒ ｍ），１．９８−２．１０（２Ｈ，ｂｒ ｍ），２．４０−６０（４Ｈ，ｂｒ ｍ），２．９６（２Ｈ，ｔ，Ｊ＝１２．５Ｈｚ），３．１１（２Ｈ，ｓ），３．５５（２Ｈ，ｓ），４．０４−４．２６（３Ｈ，ｂｒ ｍ），４．１４（２Ｈ，ｑ，Ｊ＝７．１Ｈｚ），４．４６（２Ｈ，ｓ），５．９６（１Ｈ，ｄ，Ｊ＝７．８Ｈｚ），７．３３（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ），７．４２（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ），７．５９（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ），７．７３（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ）．

ＬＣ／ＭＳ［条件１］：保持時間２．７８分；ｍ／ｚ５５９．９［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ５５８．１［Ｍ−Ｈ］^―、６０４．１［Ｍ＋ＨＣＯＯ］^―（ＥＳＩ負イオンモード）

Example 340
4- (4-{[8- (4-Cyanobenzyl) -2-oxo-1-oxa-3,8-diazaspiro [4.5] decan-3-yl] methyl} benzamido) piperidine-1-carboxylic acid Preparation of ethyl (Compound No. 340) 4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl ) 4-{[8- (4-Cyanobenzyl) -2-oxo-1-oxa-3,8-diazaspiro [4.5] decane-3- obtained in Reference Example 171-2 instead of benzoic acid Yl] methyl} benzoic acid in substantially the same manner as in Example 180 except that ethyl 4-aminopiperidine-1-carboxylate (commercially available) is used instead of 4- (aminomethyl) benzonitrile hydrochloride. Go to the title compound The (24 mg, 57% yield) as a white powder.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.27 (3H, t, J = 7.2 Hz), 1.42 (2H, dq, J = 3.3, 12.1 Hz), 1.63- 1.78 (2H, br m), 1.83-1.96 (2H, br m), 1.98-2.10 (2H, br m), 2.40-60 (4H, br m), 2.96 (2H, t, J = 12.5 Hz), 3.11 (2H, s), 3.55 (2H, s), 4.04-4.26 (3H, br m), 4.14 (2H, q, J = 7.1 Hz), 4.46 (2H, s), 5.96 (1H, d, J = 7.8 Hz), 7.33 (2H, d, J = 8.2 Hz) 7.42 (2H, d, J = 8.2 Hz), 7.59 (2H, d, J = 8.2 Hz), 7.73 (2H, d, J = 8.2 Hz).

LC / MS [Condition 1]: Retention time 2.78 minutes; m / z 559.9 [M + H] ⁺ (ESI positive ion mode), m / z 558.1 [M−H] ⁻ , 604.1 [M + HCOO] ⁻ (ESI negative ion mode)

実施例３４１
４−（（１ｒ，４ｒ）−４−｛［８−（４−シアノベンジル）−２−オキソ−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル］メチル｝シクロヘキサンカルボキサミド）ピペリジン−１−カルボン酸エチル（化合物番号３４１）の製造
ピペラジン−１−カルボン酸メチル塩酸塩の代わりに４−アミノピペリジン−１−カルボン酸エチル（市販）を用いること以外は実質的に実施例３３９と同様に反応を行って、表題化合物（３０ｍｇ、収率６３％）を白色粉末として得た。

^１Ｈ−ＮＭＲ（３００ＭＨｚ、ＣＤＣｌ_３）δ：１．０１（２Ｈ，ｄｑ，Ｊ＝２．９，１２．７Ｈｚ），１．２５（３Ｈ，ｔ，Ｊ＝７．０Ｈｚ），１．２８（２Ｈ，ｄｑ，Ｊ＝４．１，１１．９Ｈｚ），１．４８（２Ｈ，ｄｑ，Ｊ＝２．９，１２．３Ｈｚ），１．４８−１．６５（１Ｈ，ｂｒ ｍ），１．７０−２．０５（１１Ｈ，ｂｒ ｍ），２．５５（４Ｈ，ｂｒ ｓ），２．８９（２Ｈ，ｔ，Ｊ＝１２．３Ｈｚ），３．０９（２Ｈ，ｄ，Ｊ＝７．４Ｈｚ），３．２５（２Ｈ，ｓ），３．５６（３Ｈ，ｓ），３．８４−３．９８（１Ｈ，ｍ），４．０１−４．２０（２Ｈ，ｂｒ ｍ），４．１２（２Ｈ，ｑ，Ｊ＝７．１Ｈｚ），５．２９（１Ｈ，ｄ，Ｊ＝８．２Ｈｚ），７．４４（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ），７．６０（２Ｈ，ｔ，Ｊ＝４．１Ｈｚ）．

ＬＣ／ＭＳ［条件１］：保持時間２．８２分；ｍ／ｚ５６５．９［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ５６４．１［Ｍ−Ｈ］^―、６１０．１［Ｍ＋ＨＣＯＯ］^―（ＥＳＩ負イオンモード）

Example 341
4-((1r, 4r) -4-{[8- (4-cyanobenzyl) -2-oxo-1-oxa-3,8-diazaspiro [4.5] decan-3-yl] methyl} cyclohexanecarboxamide ) Preparation of Piperidine-1-Carboxylate (Compound No. 341) Substantially Examples except that ethyl 4-aminopiperidine-1-carboxylate (commercially available) was used instead of piperazine-1-carboxylate methyl hydrochloride The reaction was conducted in the same manner as in 339 to give the title compound (30 mg, yield 63%) as a white powder.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.01 (2H, dq, J = 2.9, 12.7 Hz), 1.25 (3H, t, J = 7.0 Hz), 1.28 ( 2H, dq, J = 4.1, 11.9 Hz), 1.48 (2H, dq, J = 2.9, 12.3 Hz), 1.48-1.65 (1H, br m), 1. 70-2.05 (11H, br m), 2.55 (4H, br s), 2.89 (2H, t, J = 12.3 Hz), 3.09 (2H, d, J = 7.4 Hz) ), 3.25 (2H, s), 3.56 (3H, s), 3.84-3.98 (1H, m), 4.01-4.20 (2H, br m), 4.12 (2H, q, J = 7.1 Hz), 5.29 (1H, d, J = 8.2 Hz), 7.44 (2H, d, J = 8.2 Hz), 7.60 (2H, t, J = 4 1Hz).

LC / MS [Condition 1]: Retention time 2.82 minutes; m / z 565.9 [M + H] ⁺ (ESI positive ion mode), m / z 564.1 [M−H] ⁻ , 610.1 [M + HCOO] ⁻ (ESI negative ion mode)

実施例３４２
３−｛［（１ｒ，４ｒ）−４−（３，５−ジメチルピペリジン−１−カルボニル）シクロヘキシル］メチル｝−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−２−オン（化合物番号３４２）の製造
４−（｛２−オキソ−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）安息香酸の代わりに参考例６−３で得られた（１ｒ，４ｒ）−４−（｛２−オキソ−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）シクロヘキサンカルボン酸を、４−（アミノメチル）ベンゾニトリル塩酸塩の代わりに３，５−ジメチルピペリジン（市販）を用いること以外は実質的に実施例１８０と同様に反応を行って、表題化合物（２２ｍｇ、収率６１％）を白色粉末として得た。

^１Ｈ−ＮＭＲ（３００ＭＨｚ、ＣＤＣｌ_３）δ：０．８４−０．９４（６Ｈ，ｍ），１．０５（２Ｈ，ｑ，Ｊ＝１２．４Ｈｚ），１．４０−１．６５（６Ｈ，ｂｒ ｍ），１．６９−１．８７（７Ｈ，ｂｒ ｍ），１．８８−２．００（３Ｈ，ｂｒ ｍ），２．３８−２．５６（１．８５Ｈ，ｍ），２．５６（４Ｈ，ｂｒ ｓ），３．１０（２Ｈ，ｄ，Ｊ＝７．８Ｈｚ），３．１７（０．１５Ｈ，ｄｄ，Ｊ＝１３．１，７．４Ｈｚ），３．２６（２Ｈ，ｓ），３．４２（０．１５Ｈ，ｄｄ，Ｊ＝１３．１，３．７Ｈｚ），３．５７（２Ｈ，ｓ），３．６４（０．１５Ｈ，ｄｄ，Ｊ＝１３．９，３．７Ｈｚ），３．７３（０．８５Ｈ，ｄ，Ｊ＝１２．７Ｈｚ），４．５８（０．８５Ｈ，ｄ，Ｊ＝１２．７Ｈｚ），７．４３（２Ｈ，ｄ，Ｊ＝７．８Ｈｚ），７．５７（２Ｈ，ｄ，Ｊ＝７．６Ｈｚ）．

ＬＣ／ＭＳ［条件１］：保持時間３．４０分；ｍ／ｚ５４９．８［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ５９３．９［Ｍ＋ＨＣＯＯ］^―（ＥＳＩ負イオンモード）

Example 342
3-{[(1r, 4r) -4- (3,5-dimethylpiperidine-1-carbonyl) cyclohexyl] methyl} -8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8- Preparation of diazaspiro [4.5] decan-2-one (Compound No. 342) 4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4 .5] Decan-3-yl} methyl) benzoic acid instead of (1r, 4r) -4-({2-oxo-8- [4- (trifluoromethyl) benzyl] obtained in Reference Example 6-3 ] 1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl) cyclohexanecarboxylic acid was converted to 3,5-dimethylpiperidine (commercially available) instead of 4- (aminomethyl) benzonitrile hydrochloride. ) It except by performing the reaction as a substantially Example 180 to give the title compound (22 mg, 61% yield) as a white powder.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 0.84-0.94 (6H, m), 1.05 (2H, q, J = 12.4 Hz), 1.40-1.65 (6H, br m), 1.69-1.87 (7H, br m), 1.88-2.00 (3H, br m), 2.38-2.56 (1.85 H, m), 2.56 (4H, br s), 3.10 (2H, d, J = 7.8 Hz), 3.17 (0.15H, dd, J = 13.1, 7.4 Hz), 3.26 (2H, s ), 3.42 (0.15H, dd, J = 13.1, 3.7 Hz), 3.57 (2H, s), 3.64 (0.15H, dd, J = 13.9, 3. 7 Hz), 3.73 (0.85 H, d, J = 12.7 Hz), 4.58 (0.85 H, d, J = 12.7 Hz), 7.43 (2 H, d, J = 7.8 H) ), 7.57 (2H, d, J = 7.6Hz).

LC / MS [Condition 1]: Retention time 3.40 minutes; m / z 549.8 [M + H] ⁺ (ESI positive ion mode), m / z 593.9 [M + HCOO] ⁻ (ESI negative ion mode)

実施例３４３
３−｛［（１ｒ，４ｒ）−４−（４−イソプロピルピペリジン−１−カルボニル）シクロヘキシル］メチル｝−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−２−オン（化合物番号３４３）の製造
３，５−ジメチルピペリジンの代わりに４−イソプロピルピペリジン（市販）を用いること以外は実質的に実施例３４２と同様に反応を行って、表題化合物（２７ｍｇ、収率７３％）を白色粉末として得た。

^１Ｈ−ＮＭＲ（３００ＭＨｚ、ＣＤＣｌ_３）δ：０．８８（６Ｈ，ｄ，Ｊ＝６．５Ｈｚ），０．９４−１．３３（６Ｈ，ｍ），１．３６−１．８５（１１Ｈ，ｂｒ ｍ），１．８６−２．００（２Ｈ，ｂｒ ｍ），２．３７−２．５１（２Ｈ，ｍ），２．５５（４Ｈ，ｂｒ ｓ），２．９４（１Ｈ，ｔ，Ｊ＝１１．７Ｈｚ），３．１０（２Ｈ，ｄ，Ｊ＝７．４Ｈｚ），３．２５（２Ｈ，ｓ），３．５７（２Ｈ，ｓ），３．８９（１Ｈ，ｄ，Ｊ＝１３．１Ｈｚ），４．６６（１Ｈ，ｄ，Ｊ＝１３．１Ｈｚ），７．４３（２Ｈ，ｄ，Ｊ＝７．８Ｈｚ），７．５７（２Ｈ，ｄ，Ｊ＝７．６Ｈｚ）．

ＬＣ／ＭＳ［条件１］：保持時間３．５４分；ｍ／ｚ５６３．９［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ６０８．０［Ｍ＋ＨＣＯＯ］^―（ＥＳＩ負イオンモード）

Example 343
3-{[(1r, 4r) -4- (4-Isopropylpiperidine-1-carbonyl) cyclohexyl] methyl} -8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [ 4.5] Preparation of decan-2-one (Compound No. 343) The reaction was carried out in substantially the same manner as in Example 342, except that 4-isopropylpiperidine (commercially available) was used instead of 3,5-dimethylpiperidine. The title compound (27 mg, 73% yield) was obtained as a white powder.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 0.88 (6H, d, J = 6.5 Hz), 0.94-1.33 (6H, m), 1.36-1.85 (11H, br m), 1.86-2.00 (2H, br m), 2.37-2.51 (2H, m), 2.55 (4H, br s), 2.94 (1H, t, J = 11.7 Hz), 3.10 (2H, d, J = 7.4 Hz), 3.25 (2H, s), 3.57 (2H, s), 3.89 (1H, d, J = 13) .1 Hz), 4.66 (1H, d, J = 13.1 Hz), 7.43 (2H, d, J = 7.8 Hz), 7.57 (2H, d, J = 7.6 Hz).

LC / MS [Condition 1]: Retention time 3.54 minutes; m / z 563.9 [M + H] ⁺ (ESI positive ion mode), m / z 608.0 [M + HCOO] ⁻ (ESI negative ion mode)

実施例３４４
３−｛［（１ｒ，４ｒ）−４−（デカヒドロイソキノリン−２−カルボニル）シクロヘキシル］メチル｝−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−２−オン（化合物番号３４４）の製造
３，５−ジメチルピペリジンの代わりにデカヒドロイソキノリン（市販）を用いること以外は実質的に実施例３４２と同様に反応を行って、表題化合物（２６ｍｇ、収率６８％）を白色粉末として得た。

^１Ｈ−ＮＭＲ（３００ＭＨｚ、ＣＤＣｌ_３）δ：０．９２−１．１６（３Ｈ，ｂｒ ｍ），１．１９−２．１５（２２Ｈ，ｂｒ ｍ），２．３６−２．５５（１Ｈ，ｂｒ ｍ），２．５６（４Ｈ，ｓ），２．８１−３．２８（２Ｈ，ｂｒ ｍ），３．１０（２Ｈ，ｄ，Ｊ＝７．４Ｈｚ），３．２５（２Ｈ，ｓ），３．４８−４．７４（２Ｈ，ｂｒ ｍ），３．５７（２Ｈ，ｓ），７．４３（２Ｈ，ｄ，Ｊ＝７．８Ｈｚ），７．５７（２Ｈ，ｄ，Ｊ＝７．６Ｈｚ）．

ＬＣ／ＭＳ［条件１］：保持時間３．５２分；ｍ／ｚ５７５．９［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ６２０．１［Ｍ＋ＨＣＯＯ］^―（ＥＳＩ負イオンモード）

Example 344
3-{[(1r, 4r) -4- (decahydroisoquinoline-2-carbonyl) cyclohexyl] methyl} -8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4 .5] Preparation of decan-2-one (Compound No. 344) The reaction was conducted in substantially the same manner as in Example 342 except that decahydroisoquinoline (commercially available) was used instead of 3,5-dimethylpiperidine. The compound (26 mg, yield 68%) was obtained as a white powder.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 0.92-1.16 (3H, br m), 1.19-2.15 (22H, br m), 2.36-2.55 (1H, br m), 2.56 (4H, s), 2.81-3.28 (2H, br m), 3.10 (2H, d, J = 7.4 Hz), 3.25 (2H, s) 3.48-4.74 (2H, br m), 3.57 (2H, s), 7.43 (2H, d, J = 7.8 Hz), 7.57 (2H, d, J = 7) .6 Hz).

LC / MS [Condition 1]: Retention time 3.52 minutes; m / z 575.9 [M + H] ⁺ (ESI positive ion mode), m / z 620.1 [M + HCOO] ⁻ (ESI negative ion mode)

実施例３４５
８−［４−（トリフルオロメチル）ベンジル］−３−（｛（１ｒ，４ｒ）−４−［４−（トリフルオロメチル）ピペリジン−１−カルボニル］シクロヘキシル｝メチル）−１−オキサ−３，８−ジアザスピロ［４．５］デカン−２−オン（化合物番号３４５）の製造
３，５−ジメチルピペリジンの代わりに４−（トリフルオロメチル）ピペリジン塩酸塩（市販）を用いること以外は実質的に実施例３４２と同様に反応を行って、表題化合物（３０ｍｇ、収率７７％）を白色粉末として得た。

^１Ｈ−ＮＭＲ（３００ＭＨｚ、ＣＤＣｌ_３）δ：１．０４（２Ｈ，ｑ，Ｊ＝１２．０Ｈｚ），１．３５−１．６８（５Ｈ，ｂｒ ｍ），１．６９−１．８５（６Ｈ，ｂｒ ｍ），１．８５−２．０１（４Ｈ，ｂｒ ｍ），２．１５−２．３５（１Ｈ，ｍ），２．３６−２．５４（２Ｈ，ｂｒ ｍ），２．５５（４Ｈ，ｂｒ ｓ），３．０２（１Ｈ，ｔ，Ｊ＝１２．９Ｈｚ），３．１０（２Ｈ，ｄ，Ｊ＝７．４Ｈｚ），３．２６（２Ｈ，ｓ），３．５７（２Ｈ，ｓ），３．９９（１Ｈ，ｄ，Ｊ＝１３．１Ｈｚ），４．７５（１Ｈ，ｄ，Ｊ＝１３．１Ｈｚ），７．４３（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ），７．５７（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ）．

ＬＣ／ＭＳ［条件１］：保持時間３．３６分；ｍ／ｚ５８９．８［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ６３４．０［Ｍ＋ＨＣＯＯ］^―（ＥＳＩ負イオンモード）

Example 345
8- [4- (trifluoromethyl) benzyl] -3-({(1r, 4r) -4- [4- (trifluoromethyl) piperidine-1-carbonyl] cyclohexyl} methyl) -1-oxa-3, Preparation of 8-diazaspiro [4.5] decan-2-one (Compound No. 345) Substantially except that 4- (trifluoromethyl) piperidine hydrochloride (commercially available) is used instead of 3,5-dimethylpiperidine. The reaction was conducted in the same manner as in Example 342 to give the title compound (30 mg, yield 77%) as a white powder.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.04 (2H, q, J = 12.0 Hz), 1.35 to 1.68 (5H, br m), 1.69-1.85 (6H) , Br m), 1.85-2.01 (4H, br m), 2.15-2.35 (1H, m), 2.36-2.54 (2H, br m), 2.55 ( 4H, br s), 3.02 (1H, t, J = 12.9 Hz), 3.10 (2H, d, J = 7.4 Hz), 3.26 (2H, s), 3.57 (2H) , S), 3.99 (1H, d, J = 13.1 Hz), 4.75 (1H, d, J = 13.1 Hz), 7.43 (2H, d, J = 8.2 Hz), 7 .57 (2H, d, J = 8.2 Hz).

LC / MS [Condition 1]: Retention time 3.36 minutes; m / z 589.8 [M + H] ⁺ (ESI positive ion mode), m / z 634.0 [M + HCOO] ⁻ (ESI negative ion mode)

実施例３４６
３−（｛（１ｒ，４ｒ）−４−［４−（２−ヒドロキシプロパン−２−イル）ピペリジン−１−カルボニル］シクロヘキシル｝メチル）−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−２−オン（化合物番号３４６）の製造
３，５−ジメチルピペリジンの代わりに２−（ピペリジン−４−イル）プロパン−２−オール（市販）を用いること以外は実質的に実施例３４２と同様に反応を行って、表題化合物（３０ｍｇ、収率７８％）を白色粉末として得た。

^１Ｈ−ＮＭＲ（３００ＭＨｚ、ＣＤＣｌ_３）δ：１．０４（２Ｈ，ｑ，Ｊ＝１２．３Ｈｚ），１．１７（３Ｈ，ｓ），１．１９（３Ｈ，ｓ），１．２０−１．６８（６Ｈ，ｂｒ ｍ），１．６８−２．００（１０Ｈ，ｂｒ ｍ），２．３６−２．５２（２Ｈ，ｍ），２．５５（４Ｈ，ｂｒ ｓ），２．９６（１Ｈ，ｔ，Ｊ＝１２．１Ｈｚ），３．１０（２Ｈ，ｄ，Ｊ＝７．４Ｈｚ），３．２６（２Ｈ，ｓ），３．５７（２Ｈ，ｓ），３．９６（１Ｈ，ｄ，Ｊ＝１２．３Ｈｚ），４．７４（１Ｈ，ｄ，Ｊ＝１３．９Ｈｚ），７．４３（２Ｈ，ｄ，Ｊ＝７．８Ｈｚ），７．５７（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ）．

ＬＣ／ＭＳ［条件１］：保持時間３．０４分；ｍ／ｚ５７９．９［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ６２４．０［Ｍ＋ＨＣＯＯ］^―（ＥＳＩ負イオンモード）

Example 346
3-({(1r, 4r) -4- [4- (2-hydroxypropan-2-yl) piperidin-1-carbonyl] cyclohexyl} methyl) -8- [4- (trifluoromethyl) benzyl] -1 -Preparation of oxa-3,8-diazaspiro [4.5] decan-2-one (Compound No. 346) 2- (piperidin-4-yl) propan-2-ol (commercially available) instead of 3,5-dimethylpiperidine ) Was used substantially in the same manner as in Example 342 to obtain the title compound (30 mg, yield 78%) as a white powder.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.04 (2H, q, J = 12.3 Hz), 1.17 (3H, s), 1.19 (3H, s), 1.20-1 .68 (6H, br m), 1.68-2.00 (10H, br m), 2.36-2.52 (2H, m), 2.55 (4H, br s), 2.96 ( 1H, t, J = 12.1 Hz), 3.10 (2H, d, J = 7.4 Hz), 3.26 (2H, s), 3.57 (2H, s), 3.96 (1H, d, J = 12.3 Hz), 4.74 (1H, d, J = 13.9 Hz), 7.43 (2H, d, J = 7.8 Hz), 7.57 (2H, d, J = 8) .2 Hz).

LC / MS [Condition 1]: Retention time 3.04 minutes; m / z 579.9 [M + H] ⁺ (ESI positive ion mode), m / z 624.0 [M + HCOO] ⁻ (ESI negative ion mode)

実施例３４７
４−［（１ｒ，４ｒ）−４−（｛２−オキソ−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）シクロヘキサンカルボニル］ピペラジン−１−カルボン酸エチル（化合物番号３４７）の製造
３，５−ジメチルピペリジンの代わりにピペラジン−１−カルボン酸エチル（市販）を用いること以外は実質的に実施例３４２と同様に反応を行って、表題化合物（３２ｍｇ、収率８１％）を白色粉末として得た。

^１Ｈ−ＮＭＲ（３００ＭＨｚ、ＣＤＣｌ_３）δ：１．０４（２Ｈ，ｑ，Ｊ＝１１．７Ｈｚ），１．２７（３Ｈ，ｔ，Ｊ＝７．１Ｈｚ），１．４６−１．６８（３Ｈ，ｂｒ ｍ），１．７０−１．８６（６Ｈ，ｂｒ ｍ），１．８７−２．００（２Ｈ，ｂｒ ｍ），２．４２（１Ｈ，ｔ，Ｊ＝１１．７Ｈｚ），２．５５（４Ｈ，ｂｒ ｓ），３．１０（２Ｈ，ｄ，Ｊ＝７．４Ｈｚ），３．２５（２Ｈ，ｓ），３．４７（６Ｈ，ｂｒ ｓ），３．５７（４Ｈ，ｂｒ ｓ），４．１６（２Ｈ，ｑ，Ｊ＝７．４Ｈｚ），７．４３（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ），７．５６（２Ｈ，ｄ，Ｊ＝７．２Ｈｚ）．

ＬＣ／ＭＳ［条件１］：保持時間３．１２分；ｍ／ｚ５９４．７［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ６３９．０［Ｍ＋ＨＣＯＯ］^―（ＥＳＩ負イオンモード）

Example 347
4-[(1r, 4r) -4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} Methyl) cyclohexanecarbonyl] Preparation of ethyl piperazine-1-carboxylate (Compound No. 347) Example 342 was substantially the same as that of Example 3, except that ethyl piperazine-1-carboxylate (commercially available) was used instead of 3,5-dimethylpiperidine. The reaction was performed in the same manner to obtain the title compound (32 mg, yield 81%) as a white powder.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.04 (2H, q, J = 11.7 Hz), 1.27 (3H, t, J = 7.1 Hz), 1.46 to 1.68 ( 3H, br m), 1.70-1.86 (6H, br m), 1.87-2.00 (2H, br m), 2.42 (1 H, t, J = 11.7 Hz), 2 .55 (4H, br s), 3.10 (2H, d, J = 7.4 Hz), 3.25 (2H, s), 3.47 (6H, br s), 3.57 (4H, br) s), 4.16 (2H, q, J = 7.4 Hz), 7.43 (2H, d, J = 8.2 Hz), 7.56 (2H, d, J = 7.2 Hz).

LC / MS [Condition 1]: Retention time 3.12 minutes; m / z 594.7 [M + H] ⁺ (ESI positive ion mode), m / z 639.0 [M + HCOO] ⁻ (ESI negative ion mode)

実施例３４８
４−［（１ｒ，４ｒ）−４−（｛２−オキソ−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）シクロヘキサンカルボニル］−１，４−ジアゼパン−１−カルボン酸ｔ−ブチル（化合物番号３４８）の製造
３，５−ジメチルピペリジンの代わりに１，４−ジアゼパン−１−カルボン酸ｔ−ブチル（市販）を用いること以外は実質的に実施例３４２と同様に反応を行って、表題化合物（３７ｍｇ、収率８９％）を白色粉末として得た。

^１Ｈ−ＮＭＲ（３００ＭＨｚ、ＣＤＣｌ_３）δ：１．０４（２Ｈ，ｑ，Ｊ＝１２．３Ｈｚ），１．３８−１．４８（９Ｈ，ｍ），１．４８−１．６８（３Ｈ，ｂｒ ｍ），１．６８−１．８８（８Ｈ，ｂｒ ｍ），１．８７−２．０１（２Ｈ，ｂｒ ｍ），２．４０（１Ｈ，ｔ，Ｊ＝１２．３Ｈｚ），２．５５（４Ｈ，ｂｒ ｓ），３．０５−３．１４（２Ｈ，ｂｒ ｍ），３．２５（２Ｈ，ｓ），３．２８−３．６６（８Ｈ，ｂｒ ｍ），３．５７（２Ｈ，ｓ），７．４３（２Ｈ，ｄ，Ｊ＝７．４Ｈｚ），７．５７（２Ｈ，ｄ，Ｊ＝７．６Ｈｚ）．

ＬＣ／ＭＳ［条件１］：保持時間３．３２分；ｍ／ｚ６３６．８［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ６８１．０［Ｍ＋ＨＣＯＯ］^―（ＥＳＩ負イオンモード）

Example 348
4-[(1r, 4r) -4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} Preparation of t-butyl methyl) cyclohexanecarbonyl] -1,4-diazepane-1-carboxylate (Compound No. 348) t-butyl 1,4-diazepane-1-carboxylate instead of 3,5-dimethylpiperidine (commercially available) The title compound (37 mg, 89% yield) was obtained as a white powder in substantially the same manner as in Example 342 except that was used.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.04 (2H, q, J = 12.3 Hz), 1.38-1.48 (9H, m), 1.48-1.68 (3H, br m), 1.68-1.88 (8H, br m), 1.87-2.01 (2H, br m), 2.40 (1 H, t, J = 12.3 Hz), 2.55 (4H, br s), 3.05-3.14 (2H, br m), 3.25 (2H, s), 3.28-3.66 (8H, br m), 3.57 (2H, s), 7.43 (2H, d, J = 7.4 Hz), 7.57 (2H, d, J = 7.6 Hz).

LC / MS [Condition 1]: Retention time 3.32 minutes; m / z 636.8 [M + H] ⁺ (ESI positive ion mode), m / z 681.0 [M + HCOO] ⁻ (ESI negative ion mode)

参考例３４９
１，４−ジアゼパン−１−カルボン酸メチル塩酸塩の製造
ピペリジン−４−イルカルバミン酸ｔ−ブチルの代わりに１，４−ジアゼパン−１−カルボン酸ｔ−ブチル塩酸塩（５０３ｍｇ、２．５１ｍｍｏｌ）を使うこと以外は実質的に参考例１３５と同様に反応を行なって、表題化合物（５２４ｍｇ、定量的）を淡黄色固体として得た。

^１Ｈ−ＮＭＲ（ＣＤＣｌ_３）δ：２．１７−２．３７（２Ｈ，ｂｒ ｍ），３．１６−３．３７（４Ｈ，ｂｒ ｍ），３．５７−３．６９（２Ｈ，ｍ），３．７４−３．８６（２Ｈ，ｍ），３．７４（３Ｈ，ｓ），９．８１（２Ｈ，ｂｒ ｓ）．
ＬＣ／ＭＳ［条件１］：保持時間０．４９分；ｍ／ｚ１５９．０［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）

Reference Example 349
Preparation of methyl 1,4-diazepan-1-carboxylate hydrochloride t-butyl 1,4-diazepan-1-carboxylate (503 mg, 2.51 mmol) instead of t-butyl piperidin-4-ylcarbamate The title compound (524 mg, quantitative) was obtained as a pale yellow solid in substantially the same manner as in Reference Example 135 except that was used.

¹ H-NMR (CDCl ₃ ) δ: 2.17-2.37 (2H, br m), 3.16-3.37 (4H, br m), 3.57-3.69 (2H, m) 3.74-3.86 (2H, m), 3.74 (3H, s), 9.81 (2H, br s).
LC / MS [Condition 1]: Retention time 0.49 min; m / z 159.0 [M + H] ⁺ (ESI positive ion mode)

実施例３４９
４−［（１ｒ，４ｒ）−４−（｛２−オキソ−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）シクロヘキサンカルボニル］−１，４−ジアゼパン−１−カルボン酸メチル（化合物番号３４９）の製造
３，５−ジメチルピペリジンの代わりに、参考例３４９で得られた１，４−ジアゼパン−１−カルボン酸メチル塩酸塩を用いること以外は実質的に実施例３４２と同様に反応を行って、表題化合物（１７ｍｇ、収率４３％）を白色粉末として得た。

^１Ｈ−ＮＭＲ（３００ＭＨｚ、ＣＤＣｌ_３）δ：１．０４（２Ｈ，ｑ，Ｊ＝１１．７Ｈｚ），１．４６−１．６９（３Ｈ，ｂｒ ｍ），１．６９−２．００（１０Ｈ，ｂｒ ｍ），２．４１（１Ｈ，ｔ，Ｊ＝１１．７Ｈｚ），２．５８（４Ｈ，ｂｒ ｓ），３．１０（２Ｈ，ｄ，Ｊ＝７．４Ｈｚ），３．２５（２Ｈ，ｓ），３．３４−３．６５（８Ｈ，ｍ），３．５８（２Ｈ，ｓ），３．６６−３．７２（３Ｈ，ｍ），７．４４（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ），７．５６（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ）．

ＬＣ／ＭＳ［条件１］：保持時間３．０２分；ｍ／ｚ５９４．７［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ６３８．９［Ｍ＋ＨＣＯＯ］^―（ＥＳＩ負イオンモード）

Example 349
4-[(1r, 4r) -4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} Methyl) cyclohexanecarbonyl] -1,4-diazepane-1-carboxylate methyl ester (Compound No. 349) 1,4-diazepane-1-carboxyl obtained in Reference Example 349 instead of 3,5-dimethylpiperidine The reaction was carried out substantially in the same manner as in Example 342 except for using acid methyl hydrochloride to obtain the title compound (17 mg, yield 43%) as a white powder.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.04 (2H, q, J = 11.7 Hz), 1.46-1.69 (3H, br m), 1.69-2.00 (10H , Br m), 2.41 (1H, t, J = 11.7 Hz), 2.58 (4H, br s), 3.10 (2H, d, J = 7.4 Hz), 3.25 (2H , S), 3.34-3.65 (8H, m), 3.58 (2H, s), 3.66-3.72 (3H, m), 7.44 (2H, d, J = 8) .2 Hz), 7.56 (2H, d, J = 8.2 Hz).

LC / MS [Condition 1]: Retention time 3.02 minutes; m / z 594.7 [M + H] ⁺ (ESI positive ion mode), m / z 638.9 [M + HCOO] ⁻ (ESI negative ion mode)

実施例３５０
４−［（１ｒ，４ｒ）−４−（｛２−オキソ−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）シクロヘキサンカルボニル］ピペラジン−１−カルボン酸２−メトキシエチル（化合物番号３５０）の製造
クロロギ酸メチルの代わりにクロロギ酸２−メトキシエチル（市販）を用いること以外は実質的に実施例１４９と同様に反応を行って、表題化合物（６．４ｍｇ、収率２２％）を白色粉末として得た。

^１Ｈ−ＮＭＲ（３００ＭＨｚ、ＣＤＣｌ_３）δ：１．０４（２Ｈ，ｑ，Ｊ＝１１．０Ｈｚ），１．４６−１．６９（３Ｈ，ｂｒ ｍ），１．７１−１．８７（６Ｈ，ｂｒ ｍ），１．８８−２．００（２Ｈ，ｂｒ ｍ），２．４２（１Ｈ，ｔ，Ｊ＝１１．９Ｈｚ），２．５６（４Ｈ，ｂｒ ｓ），３．１０（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ），３．２６（２Ｈ，ｓ），３．３８（３Ｈ，ｓ），３．４１−３．５４（６Ｈ，ｂｒ ｍ），３．５３−３．６６（６Ｈ，ｍ），４．２２−４．３１（２Ｈ，ｍ），７．４３（２Ｈ，ｄ，Ｊ＝７．８Ｈｚ），７．５７（２Ｈ，ｄ，Ｊ＝７．８Ｈｚ）．

ＬＣ／ＭＳ［条件１］：保持時間３．０２分；ｍ／ｚ６２４．９［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ６６９．０［Ｍ＋ＨＣＯＯ］^―（ＥＳＩ負イオンモード）

Example 350
4-[(1r, 4r) -4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} Preparation of 2-methoxyethyl (methyl) cyclohexanecarbonyl] piperazine-1-carboxylate (Compound No. 350) Substantially the same as Example 149, except that 2-methoxyethyl chloroformate (commercially available) was used instead of methyl chloroformate. The title compound (6.4 mg, 22% yield) was obtained as a white powder.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.04 (2H, q, J = 11.0 Hz), 1.46-1.69 (3H, br m), 1.71-1.87 (6H , Br m), 1.88-2.00 (2H, br m), 2.42 (1H, t, J = 11.9 Hz), 2.56 (4H, br s), 3.10 (2H, d, J = 8.2 Hz), 3.26 (2H, s), 3.38 (3H, s), 3.41-3.54 (6H, br m), 3.53-3.66 (6H) M), 4.22-4.31 (2H, m), 7.43 (2H, d, J = 7.8 Hz), 7.57 (2H, d, J = 7.8 Hz).

LC / MS [Condition 1]: Retention time 3.02 minutes; m / z 624.9 [M + H] ⁺ (ESI positive ion mode), m / z 669.0 [M + HCOO] ⁻ (ESI negative ion mode)

実施例３５１
４−［（１ｒ，４ｒ）−４−（｛２−オキソ−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）シクロヘキサンカルボニル］ピペラジン−１−カルボン酸イソプロピル（化合物番号３５１）の製造
クロロギ酸メチルの代わりにクロロギ酸イソプロピル（市販）を用いること以外は実質的に実施例１４９と同様に反応を行って、表題化合物（７．３ｍｇ、収率２７％）を白色粉末として得た。

^１Ｈ−ＮＭＲ（３００ＭＨｚ、ＣＤＣｌ_３）δ：１．０４（２Ｈ，ｑ，Ｊ＝１１．９Ｈｚ），１．２５（６Ｈ，ｄ，Ｊ＝６．１Ｈｚ），１．４３−１．６７（３Ｈ，ｂｒ ｍ），１．７０−１．８６（６Ｈ，ｂｒ ｍ），１．８７−２．０２（２Ｈ，ｂｒ ｍ），２．４３（１Ｈ，ｔ，Ｊ＝１２．１Ｈｚ），２．５６（４Ｈ，ｂｒ ｓ），３．１０（２Ｈ，ｄ，Ｊ＝７．４Ｈｚ），３．２６（２Ｈ，ｓ），３．４７（６Ｈ，ｂｒ ｓ），３．５７（４Ｈ，ｂｒ ｓ），４．９４（１Ｈ，ｑｑ，Ｊ＝６．１，６．１Ｈｚ），７．４３（２Ｈ，ｄ，Ｊ＝７．８Ｈｚ），７．５７（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ）．

ＬＣ／ＭＳ［条件１］：保持時間３．２２分；ｍ／ｚ６０８．８［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ６５３．０［Ｍ＋ＨＣＯＯ］^―（ＥＳＩ負イオンモード）

Example 351
4-[(1r, 4r) -4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} (Methyl) cyclohexanecarbonyl] piperazine-1-carboxylate (Compound No. 351) Preparation The reaction was carried out in substantially the same manner as in Example 149 except that isopropyl chloroformate (commercially available) was used instead of methyl chloroformate. The title compound (7.3 mg, 27% yield) was obtained as a white powder.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.04 (2H, q, J = 11.9 Hz), 1.25 (6H, d, J = 6.1 Hz), 1.43-1.67 ( 3H, br m), 1.70-1.86 (6H, br m), 1.87-2.02 (2H, br m), 2.43 (1 H, t, J = 12.1 Hz), 2 .56 (4H, br s), 3.10 (2H, d, J = 7.4 Hz), 3.26 (2H, s), 3.47 (6H, br s), 3.57 (4H, br) s), 4.94 (1H, qq, J = 6.1, 6.1 Hz), 7.43 (2H, d, J = 7.8 Hz), 7.57 (2H, d, J = 8.2 Hz) ).

LC / MS [Condition 1]: Retention time 3.22 minutes; m / z 608.8 [M + H] ⁺ (ESI positive ion mode), m / z 653.0 [M + HCOO] ⁻ (ESI negative ion mode)

実施例３５２
３−（｛（１ｒ，４ｒ）−４−［４−（メチルスルホニル）ピペラジン−１−カルボニル］シクロヘキシル｝メチル）−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−２−オン（化合物番号３５２）の製造
クロロギ酸メチルの代わりに塩化メタンスルホニル（市販）を用いること以外は実質的に実施例１４９と同様に反応を行って、表題化合物（１８ｍｇ、収率７０％）を白色粉末として得た。

^１Ｈ−ＮＭＲ（３００ＭＨｚ、ＣＤＣｌ_３）δ：１．０５（２Ｈ，ｑ，Ｊ＝１１．９Ｈｚ），１．４７−１．６８（３Ｈ，ｂｒ ｍ），１．７１−１．８５（６Ｈ，ｂｒ ｍ），１．８７−２．０１（２Ｈ，ｂｒ ｍ），２．４２（１Ｈ，ｔ，Ｊ＝１１．９Ｈｚ），２．５６（４Ｈ，ｂｒ ｓ），２．７９（３Ｈ，ｓ），３．１１（２Ｈ，ｄ，Ｊ＝７．４Ｈｚ），３．２２（４Ｈ，ｂｒ ｓ），３．２６（２Ｈ，ｓ），３．５７（２Ｈ，ｓ），３．６０（２Ｈ，ｂｒ ｓ），３．７３（２Ｈ，ｂｒ ｓ），７．４３（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ），７．５７（２Ｈ，ｄ，Ｊ＝９．４Ｈｚ）．

ＬＣ／ＭＳ［条件１］：保持時間２．９２分；ｍ／ｚ６００．８［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ６４５．０［Ｍ＋ＨＣＯＯ］^―（ＥＳＩ負イオンモード）

Example 352
3-({(1r, 4r) -4- [4- (methylsulfonyl) piperazine-1-carbonyl] cyclohexyl} methyl) -8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8 -Preparation of diazaspiro [4.5] decan-2-one (Compound No. 352) The reaction was conducted in substantially the same manner as in Example 149 except that methanesulfonyl chloride (commercially available) was used instead of methyl chloroformate The title compound (18 mg, 70% yield) was obtained as a white powder.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.05 (2H, q, J = 11.9 Hz), 1.47-1.68 (3H, br m), 1.71-1.85 (6H , Br m), 1.87-2.01 (2H, br m), 2.42 (1H, t, J = 11.9 Hz), 2.56 (4H, br s), 2.79 (3H, s), 3.11 (2H, d, J = 7.4 Hz), 3.22 (4H, br s), 3.26 (2H, s), 3.57 (2H, s), 3.60 ( 2H, br s), 3.73 (2H, br s), 7.43 (2H, d, J = 8.2 Hz), 7.57 (2H, d, J = 9.4 Hz).

LC / MS [Condition 1]: Retention time 2.92 minutes; m / z 600.8 [M + H] ⁺ (ESI positive ion mode), m / z 645.0 [M + HCOO] ⁻ (ESI negative ion mode)

実施例３５３
３−オキソ−３−｛４−［（１ｒ，４ｒ）−４−（｛２−オキソ−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）シクロヘキサンカルボニル］ピペラジン−１−イル｝プロパンニトリル（化合物番号３５３）の製造
参考例１４９で得られた３−｛［（１ｒ，４ｒ）−４−（ピペラジン−１−カルボニル）シクロヘキシル］メチル｝−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−２−オン二塩酸塩（２８ｍｇ、０．０４７ｍｍｏｌ）と、２−シアノ酢酸（市販）（６．０ｍｇ、０．０７１ｍｍｏｌ）、１−ヒドロキシベンゾトリアゾール（３．０ｍｇ、０．０２４ｍｏｌ）、そしてトリエチルアミン（０．０３３ｍＬ、０．２４ｍｍｏｌ）をクロロホルム（１．０ｍＬ）に溶解し、室温にて１−エチル−３−（３−ジメチルアミノプロピル）カルボジイミド塩酸塩（１４ｍｇ、０．０７１ｍｍｏｌ）を加え、室温で１日間かき混ぜた。その後、反応混合物にクロロホルム（２．０ｍＬ）と水（２．０ｍＬ）を加えて有機層を分離した。有機層を無水硫酸マグネシウムで乾燥した後、減圧下濃縮した。得られた残留物をシリカゲルカラムクロマトグラフィー［充填剤：株式会社山善製ＨＩ−ＦＬＡＳＨ（登録商標）ＣＯＬＵＭＮｓｉｌｉｃａｇｅｌ４０μｍ、展開溶媒：酢酸エチル／メタノール＝１０／１］にて精製し、表題化合物（２０ｍｇ、収率７１％）を白色粉末として得た。

^１Ｈ−ＮＭＲ（３００ＭＨｚ、ＣＤＣｌ_３）δ：１．０５（２Ｈ，ｑ，Ｊ＝１１．６Ｈｚ），１．５７（２Ｈ，ｑ，Ｊ＝１２．７Ｈｚ），１．５６−１．７１（１Ｈ，ｂｒ ｍ），１．７２−１．８６（６Ｈ，ｂｒ ｍ），１．８８−２．００（２Ｈ，ｂｒ ｍ），２．４４（１Ｈ，ｔ，Ｊ＝１０．０Ｈｚ），２．５７（４Ｈ，ｂｒ ｓ），３．１１（２Ｈ，ｄ，Ｊ＝７．０Ｈｚ），３．２６（２Ｈ，ｓ），３．３８−３．７７（１２Ｈ，ｂｒ ｍ），７．４３（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ），７．５６（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ）．

ＬＣ／ＭＳ［条件１］：保持時間２．７５分；ｍ／ｚ５８９．８［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ５８７．９［Ｍ−Ｈ］^―（ＥＳＩ負イオンモード）

Example 353
3-oxo-3- {4-[(1r, 4r) -4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5 ] Decan-3-yl} methyl) cyclohexanecarbonyl] piperazin-1-yl} propanenitrile (Compound No. 353) 3-{[(1r, 4r) -4- (piperazine-1) obtained in Reference Example 149 -Carbonyl) cyclohexyl] methyl} -8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-2-one dihydrochloride (28 mg, 0.047 mmol) 2-cyanoacetic acid (commercially available) (6.0 mg, 0.071 mmol), 1-hydroxybenzotriazole (3.0 mg, 0.024 mol), and triethylamine (0. 33 mL, 0.24 mmol) was dissolved in chloroform (1.0 mL), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (14 mg, 0.071 mmol) was added at room temperature, and one day at room temperature. Stir. Thereafter, chloroform (2.0 mL) and water (2.0 mL) were added to the reaction mixture to separate the organic layer. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography [filler: HI-FLASH (registered trademark) COLUMNsilica gel 40 μm, manufactured by Yamazen Co., Ltd., developing solvent: ethyl acetate / methanol = 10/1], and the title compound (20 mg, 71%) was obtained as a white powder.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.05 (2H, q, J = 11.6 Hz), 1.57 (2H, q, J = 12.7 Hz), 1.56-1.71 ( 1H, br m), 1.72-1.86 (6H, br m), 1.88-2.00 (2H, br m), 2.44 (1 H, t, J = 10.0 Hz), 2 .57 (4H, br s), 3.11 (2H, d, J = 7.0 Hz), 3.26 (2H, s), 3.38-3.77 (12 H, br m), 7.43 (2H, d, J = 8.2 Hz), 7.56 (2H, d, J = 8.2 Hz).

LC / MS [Condition 1]: Retention time 2.75 minutes; m / z 589.8 [M + H] ⁺ (ESI positive ion mode), m / z 587.9 [M−H] ⁻ (ESI negative ion mode)

実施例３５４
１−｛４−［（１ｒ，４ｒ）−４−（｛２−オキソ−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）シクロヘキサンカルボニル］ピペラジン−１−カルボニル｝シクロプロパンカルボニトリル（化合物番号３５４）の製造
２−シアノ酢酸の代わりに１−シアノシクロプロパンカルボン酸（市販）を用いること以外は、実質的に実施例３５３と同様に反応を行って、表題化合物（１８ｍｇ、収率６１％）を白色粉末として得た。

^１Ｈ−ＮＭＲ（３００ＭＨｚ、ＣＤＣｌ_３）δ：１．０５（２Ｈ，ｑ，Ｊ＝１１．６Ｈｚ），１．４８−１．６８（７Ｈ，ｍ），１．７１−１．８６（６Ｈ，ｂｒ ｍ），１．８６−２．０２（２Ｈ，ｂｒ ｍ），２．４４（１Ｈ，ｔ，Ｊ＝１１．９Ｈｚ），２．５６（４Ｈ，ｂｒ ｓ），３．１１（２Ｈ，ｄ，Ｊ＝７．４Ｈｚ），３．２６（２Ｈ，ｓ），３．４３−３．９３（８Ｈ，ｂｒ ｍ），３．５７（２Ｈ，ｓ），７．４３（２Ｈ，ｄ，Ｊ＝７．８Ｈｚ），７．５７（２Ｈ，ｄ，Ｊ＝７．８Ｈｚ）．

ＬＣ／ＭＳ［条件１］：保持時間３．００分；ｍ／ｚ６１５．８［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ６５９．９［Ｍ＋ＨＣＯＯ］^―（ＥＳＩ負イオンモード）

Example 354
1- {4-[(1r, 4r) -4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decane-3 Preparation of -yl} methyl) cyclohexanecarbonyl] piperazine-1-carbonyl} cyclopropanecarbonitrile (Compound No. 354) Substantially except that 1-cyanocyclopropanecarboxylic acid (commercially available) is used instead of 2-cyanoacetic acid Was reacted in the same manner as in Example 353 to give the title compound (18 mg, yield 61%) as a white powder.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.05 (2H, q, J = 11.6 Hz), 1.48-1.68 (7H, m), 1.71-1.86 (6H, br m), 1.86-2.02 (2H, br m), 2.44 (1H, t, J = 11.9 Hz), 2.56 (4H, br s), 3.11 (2H, d , J = 7.4 Hz), 3.26 (2H, s), 3.43-3.93 (8H, br m), 3.57 (2H, s), 7.43 (2H, d, J = 7.8 Hz), 7.57 (2H, d, J = 7.8 Hz).

LC / MS [Condition 1]: Retention time 3.00 minutes; m / z 615.8 [M + H] ⁺ (ESI positive ion mode), m / z 659.9 [M + HCOO] ⁻ (ESI negative ion mode)

参考例３５５−１
５−（ヒドロキシメチル）チオフェン−２−カルボン酸メチルの製造
５−（メトキシカルボニル）チオフェン−２−カルボン酸（ＵＳ２６０９４６９４記載の方法を用いて合成）（１２０ｍｇ、０．６２ｍｍｏｌ）をテトラヒドロフラン（２．０ｍＬ）に溶解し、氷冷下１Ｍボランテトラヒドロフラン溶液（１．２ｍＬ、１．２ｍｍｏｌ）を加え、その後６０℃で３時間かき混ぜた。室温まで冷却した後、反応混合物に酢酸エチルと水を加え、有機層を分離した。得られた有機層を無水硫酸マグネシウムで乾燥した後、減圧下濃縮した。得られた粗生成物をシリカゲルカラムクロマトグラフィー［充填剤：Ｍｅｒｃｋ ＧＭＢＨ製シリカゲル６０（０．０４０−０．０６３ｍｍ）、展開溶媒：ヘキサン／酢酸エチル＝２／１］にて精製し、表題化合物（１１０ｍｇ、収率９８％）を無色油状物として得た。

^１Ｈ−ＮＭＲ（３００ＭＨｚ，ＣＤＣｌ_３）δ：２．００（１Ｈ，ｔ，Ｊ＝６．１Ｈｚ），３．８８（３Ｈ，ｓ），４．８６（２Ｈ，ｄ，Ｊ＝５．７Ｈｚ），６．９９（１Ｈ，ｄｔ，Ｊ＝３．７，０．８Ｈｚ），７．６８（１Ｈ，ｄ，Ｊ＝３．７Ｈｚ）．

Reference Example 355-1
Preparation of methyl 5- (hydroxymethyl) thiophene-2-carboxylate 5- (methoxycarbonyl) thiophene-2-carboxylic acid (synthesized using the method described in US26094469) (120 mg, 0.62 mmol) in tetrahydrofuran (2.0 mL) 1 M borane tetrahydrofuran solution (1.2 mL, 1.2 mmol) was added under ice cooling, and the mixture was stirred at 60 ° C. for 3 hours. After cooling to room temperature, ethyl acetate and water were added to the reaction mixture, and the organic layer was separated. The obtained organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography [filler: silica gel 60 (0.040-0.063 mm) manufactured by Merck GMBH, developing solvent: hexane / ethyl acetate = 2/1], and the title compound ( 110 mg, 98% yield) was obtained as a colorless oil.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 2.00 (1H, t, J = 6.1 Hz), 3.88 (3H, s), 4.86 (2H, d, J = 5.7 Hz) , 6.99 (1H, dt, J = 3.7, 0.8 Hz), 7.68 (1H, d, J = 3.7 Hz).

参考例３５５−２
５−（クロロメチル）チオフェン−２−カルボン酸メチルの製造
参考例３５５−１で得た５−（ヒドロキシメチル）チオフェン−２−カルボン酸メチルをジクロロメタン（１．０ｍＬ）に溶解し、氷冷下、トリエチルアミン（０．０６６ｍＬ、０．４８ｍｍｏｌ）と塩化メタンスルホニル（０．０４２ｍＬ、０．５２ｍｍｏｌ）を加え、室温で２時間半攪拌した。さらに氷冷下でトリエチルアミン（０．０６６ｍＬ、０．４８ｍｍｏｌ）と塩化メタンスルホニル（０．０４２ｍＬ、０．５２ｍｍｏｌ）を加え、室温で一晩攪拌した。反応混合物に水とクロロホルムを加え、有機層を分離した後、無水硫酸マグネシウムで乾燥し、減圧下濃縮した。得られた残留物をシリカゲルカラムクロマトグラフィー［充填剤：Ｍｅｒｃｋ ＧＭＢＨ製シリカゲル６０（０．０４０−０．０６３ｍｍ）、展開溶媒：ヘキサン／酢酸エチル＝４／１］にて精製し、表題化合物（３５ｍｇ、収率４７％）を無色油状物として得た。

^１Ｈ−ＮＭＲ（３００ＭＨｚ，ＣＤＣｌ_３）δ：３．８８（３Ｈ，ｓ），４．７６（２Ｈ，ｓ），７．０７（１Ｈ，ｄ，Ｊ＝３．７Ｈｚ），７．６５（１Ｈ，ｄ，Ｊ＝４．１Ｈｚ）．

Reference Example 355-2
Preparation of methyl 5- (chloromethyl) thiophene-2-carboxylate Methyl 5- (hydroxymethyl) thiophene-2-carboxylate obtained in Reference Example 355-1 was dissolved in dichloromethane (1.0 mL) and cooled with ice. , Triethylamine (0.066 mL, 0.48 mmol) and methanesulfonyl chloride (0.042 mL, 0.52 mmol) were added, and the mixture was stirred at room temperature for 2.5 hours. Further, triethylamine (0.066 mL, 0.48 mmol) and methanesulfonyl chloride (0.042 mL, 0.52 mmol) were added under ice cooling, and the mixture was stirred overnight at room temperature. Water and chloroform were added to the reaction mixture, and the organic layer was separated, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography [filler: silica gel 60 (0.040-0.063 mm) manufactured by Merck GMBH, developing solvent: hexane / ethyl acetate = 4/1], and the title compound (35 mg Yield 47%) as a colorless oil.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 3.88 (3H, s), 4.76 (2H, s), 7.07 (1H, d, J = 3.7 Hz), 7.65 (1H , D, J = 4.1 Hz).

参考例３５５−３
３−｛［５−（メトキシカルボニル）チオフェン−２−イル］メチル｝−２−オキソ−１−オキサ−３，８−ジアザスピロ［４．５］デカン−８−カルボン酸ｔ−ブチルの製造
参考例１１１−１で得られた２−オキソ−１−オキサ−３，８−ジアザスピロ［４．５］デカン−８−カルボン酸ｔ−ブチル（７１ｍｇ、０．２８ｍｍｏｌ）をＮ，Ｎ−ジメチルホルムアミド（２．０ｍＬ）に溶かし、ナトリウムｔ−ブトキシド（３０ｍｇ、０．３１ｍｍｏｌ）を加えて３０分撹拌した後、参考例３５５−２で得られた５−（クロロメチル）チオフェン−２−カルボン酸メチル（３５ｍｇ、０．１９ｍｍｏｌ）のＮ，Ｎ−ジメチルホルムアミド（２．０ｍＬ）溶液を加え、３時間かき混ぜた。その後、水と酢酸エチルを加えて有機層を分離し、有機層を飽和食塩水で２回洗浄した。有機層を無水硫酸マグネシウムで乾燥した後、減圧下濃縮し、得られた残留物をシリカゲルカラムクロマトグラフィー［充填剤：Ｍｅｒｃｋ ＧＭＢＨ製シリカゲル６０（０．０４０−０．０６３ｍｍ）、展開溶媒：ヘキサン／酢酸エチル＝１／１］にて精製することにより、表題化合物（２０ｍｇ、収率２６％）を白色固体として得た。

^１Ｈ−ＮＭＲ（３００ＭＨｚ，ＣＤＣｌ_３）δ：１．４５（９Ｈ，ｓ），１．５８−１．７０（２Ｈ，ｍ），１．８８（２Ｈ，ｄ，Ｊ＝１３．１Ｈｚ），３．２４（２Ｈ，ｓ），３．２９（２Ｈ，ｄ，Ｊ＝１０．６Ｈｚ），３．８３（２Ｈ，ｄ，Ｊ＝１４．３Ｈｚ），３．８８（３Ｈ，ｓ），４．６２（２Ｈ，ｓ），６．９９（１Ｈ，ｄ，Ｊ＝３．７Ｈｚ），７．６８（１Ｈ，ｄ，Ｊ＝３．７Ｈｚ）．

ＬＣ／ＭＳ［条件１］：保持時間４．１１分；ｍ／ｚ４３２．９［Ｍ＋Ｎａ］^＋（ＥＳＩ正イオンモード）

Reference Example 355-3
Reference example for production of t-butyl 3-{[5- (methoxycarbonyl) thiophen-2-yl] methyl} -2-oxo-1-oxa-3,8-diazaspiro [4.5] decane-8-carboxylate 2-Oxo-1-oxa-3,8-diazaspiro [4.5] decane-8-carboxylate t-butyl (71 mg, 0.28 mmol) obtained in 111-1 was converted to N, N-dimethylformamide (2 0.0 mL), sodium t-butoxide (30 mg, 0.31 mmol) was added, and the mixture was stirred for 30 minutes, and then methyl 5- (chloromethyl) thiophene-2-carboxylate (35 mg) obtained in Reference Example 355-2. 0.19 mmol) in N, N-dimethylformamide (2.0 mL) was added and stirred for 3 hours. Thereafter, water and ethyl acetate were added to separate the organic layer, and the organic layer was washed twice with saturated brine. The organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography [filler: silica gel 60 (0.040-0.063 mm) manufactured by Merck GMBH, developing solvent: hexane / Purification by ethyl acetate = 1/1] gave the title compound (20 mg, 26% yield) as a white solid.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.45 (9H, s), 1.58-1.70 (2H, m), 1.88 (2H, d, J = 13.1 Hz), 3 .24 (2H, s), 3.29 (2H, d, J = 10.6 Hz), 3.83 (2H, d, J = 14.3 Hz), 3.88 (3H, s), 4.62 (2H, s), 6.99 (1H, d, J = 3.7 Hz), 7.68 (1H, d, J = 3.7 Hz).

LC / MS [Condition 1]: Retention time 4.11 min; m / z 432.9 [M + Na] ⁺ (ESI positive ion mode)

参考例３５５−４
５−［（２−オキソ−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル）メチル］チオフェン−２−カルボン酸メチル塩酸塩の製造
［（テトラヒドロフラン−２−イル）メチル］カルバミン酸ｔ−ブチルの代わりに３−｛［５−（メトキシカルボニル）チオフェン−２−イル］メチル｝−２−オキソ−１−オキサ−３，８−ジアザスピロ［４．５］デカン−８−カルバミン酸ｔ−ブチルを用いること以外は実質的に参考例１８２−３と同様に反応を行って、表題化合物（１７ｍｇ、収率定量的）を白色固体として得た。

^１Ｈ−ＮＭＲ（３００ＭＨｚ，ＣＤ_３ＯＤ）δ：２．０５−１．９１（３Ｈ，ｍ），２．１５（２Ｈ，ｄ，Ｊ＝１４．３Ｈｚ），３．４４（２Ｈ，ｓ），３．８６（３Ｈ，ｓ），４．６６（２Ｈ，ｓ），７．１１（１Ｈ，ｄ，Ｊ＝３．７Ｈｚ），７．７０（１Ｈ，ｄ，Ｊ＝３．７Ｈｚ）．

ＬＣ／ＭＳ［条件１］：保持時間０．５９分；ｍ／ｚ３１１．０［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）

Reference Example 355-4
Preparation of 5-[(2-oxo-1-oxa-3,8-diazaspiro [4.5] decan-3-yl) methyl] thiophene-2-carboxylic acid methyl hydrochloride [(tetrahydrofuran-2-yl) methyl ] Instead of t-butyl carbamate, 3-{[5- (methoxycarbonyl) thiophen-2-yl] methyl} -2-oxo-1-oxa-3,8-diazaspiro [4.5] decan-8- The reaction was performed in substantially the same manner as in Reference Example 182-3 except that t-butyl carbamate was used to give the title compound (17 mg, quantitative yield) as a white solid.

¹ H-NMR (300 MHz, CD ₃ OD) δ: 2.05-1.91 (3H, m), 2.15 (2H, d, J = 14.3 Hz), 3.44 (2H, s), 3.86 (3H, s), 4.66 (2H, s), 7.11 (1H, d, J = 3.7 Hz), 7.70 (1H, d, J = 3.7 Hz).

LC / MS [Condition 1]: Retention time 0.59 minutes; m / z 311.0 [M + H] ⁺ (ESI positive ion mode)

参考例３５５−５
５−（｛２−オキソ−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）チオフェン−２−カルボン酸メチルの製造
参考例３５５−４で得られた５−［（２−オキソ−１−オキサ−３，８−ジアザスピロ［４．５］デカン−イル）メチル］チオフェン−２−カルボン酸メチル塩酸塩（１７ｍｇ、０．０４９ｍｍｏｌ）をＮ，Ｎ−ジメチルホルムアミド（２．０ｍＬ）に懸濁し、トリエチルアミン（０．０２０ｍＬ、０．１５ｍｍｏｌ）と４−（トリフルオロメチル）ベンジルブロミド（１４ｍｇ、０．０５８ｍｍｏｌ）を加え、室温で１時間かき混ぜた。水と酢酸エチルを加えて有機層を分離し、有機層を飽和食塩水で洗浄した。有機層を無水硫酸ナトリウムで乾燥した後、減圧下濃縮した。得られた残留物をシリカゲルカラムクロマトグラフィー［充填剤：富士シリシア社製アミンシリカＮＨ−ＤＭ１０２０、展開溶媒：ヘキサン／酢酸エチル＝１／１］にて精製し、表題化合物（２５ｍｇ、収率定量的）を白色固体として得た。

^１Ｈ−ＮＭＲ（３００ＭＨｚ，ＣＤＣｌ_３）δ：１．６９−１．８４（２Ｈ，ｍ），１．９３（２Ｈ，ｄ，Ｊ＝１２．９Ｈｚ），２．６１−２．４９（４Ｈ，ｂｒｍ），３．２４（２Ｈ，ｓ），３．５６（２Ｈ，ｓ），３．８８（３Ｈ，ｓ），４．６１（２Ｈ，ｓ），６．９８（１Ｈ，ｄ，Ｊ＝４．０Ｈｚ），７．４３（２Ｈ，ｄ，Ｊ＝８．３Ｈｚ），７．５７（２Ｈ，ｄ，Ｊ＝８．３Ｈｚ），７．６８（１Ｈ，ｄ，Ｊ＝３．６Ｈｚ）．

ＬＣ／ＭＳ［条件１］：保持時間３．０４分；ｍ／ｚ４６８．８［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）

Reference Example 355-5
5-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl) thiophene-2-carboxylate methyl 5 obtained in reference example 355-4 of - [(2-oxo-1-oxa-3,8-diazaspiro [4.5] decane - yl) methyl] thiophene-2-carboxylic acid methyl hydrochloride (17 mg , 0.049 mmol) was suspended in N, N-dimethylformamide (2.0 mL), and triethylamine (0.020 mL, 0.15 mmol) and 4- (trifluoromethyl) benzyl bromide (14 mg, 0.058 mmol) were added. Stir at room temperature for 1 hour. Water and ethyl acetate were added to separate the organic layer, and the organic layer was washed with saturated brine. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography [filler: amine silica NH-DM1020 manufactured by Fuji Silysia Ltd., developing solvent: hexane / ethyl acetate = 1/1], and the title compound (25 mg, quantitative yield). Was obtained as a white solid.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.69-1.84 (2H, m), 1.93 (2H, d, J = 12.9 Hz), 2.61-2.49 (4H, brm), 3.24 (2H, s), 3.56 (2H, s), 3.88 (3H, s), 4.61 (2H, s), 6.98 (1H, d, J = 4). .0 Hz), 7.43 (2H, d, J = 8.3 Hz), 7.57 (2H, d, J = 8.3 Hz), 7.68 (1H, d, J = 3.6 Hz).

LC / MS [Condition 1]: Retention time 3.04 minutes; m / z 468.8 [M + H] ⁺ (ESI positive ion mode)

参考例３５５−６
５−（｛２−オキソ−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）チオフェン−２−カルボン酸の製造
参考例３５５−５で得られた５−（｛２−オキソ−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）チオフェン−２−カルボン酸メチル（２５ｍｇ、０．０５２ｍｍｏｌ）をメタノール（２．０ｍＬ）に懸濁し、６０℃に加熱して溶かした後、１Ｍ水酸化ナトリウム水溶液（０．２６ｍＬ、０．２６ｍｍｏｌ）を加え、６０℃で３時間かき混ぜた。反応終了後、反応混合物を室温まで冷却した後、１Ｍ塩酸（０．２６ｍＬ、０．２６ｍｍｏｌ）を滴下した。さらに飽和食塩水と酢酸エチルを加え、有機層を分離した後、有機層を無水硫酸マグネシウムで乾燥した。有機層を減圧下濃縮乾固し、表題化合物（２０ｍｇ、収率８３％）を白色固体として得た。

^１Ｈ−ＮＭＲ（３００ＭＨｚ，ＣＤＣｌ_３）δ：１．８８−２．０３（４Ｈ，ｍ），２．６５−３．２３（６Ｈ，ｍ），３．９３（２Ｈ，ｓ），４．５７（２Ｈ，ｓ），６．９３（１Ｈ，ｂｒｓ），７．６９−７．４４（６Ｈ，ｍ）．
ＬＣ／ＭＳ［条件１］：保持時間２．５３分；ｍ／ｚ４５４．８［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ４５３．０［Ｍ−Ｈ］^―（ＥＳＩ負イオンモード）

Reference Example 355-6
Of 5-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl) thiophene-2-carboxylic acid 5-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl obtained in Preparation Reference Example 355-5 } Methyl) methyl thiophene-2-carboxylate (25 mg, 0.052 mmol) was suspended in methanol (2.0 mL), dissolved by heating to 60 ° C., and then 1M aqueous sodium hydroxide solution (0.26 mL, 0.2 mL). 26 mmol) was added, and the mixture was stirred at 60 ° C. for 3 hours. After completion of the reaction, the reaction mixture was cooled to room temperature, and 1M hydrochloric acid (0.26 mL, 0.26 mmol) was added dropwise. Further, saturated brine and ethyl acetate were added to separate the organic layer, and the organic layer was dried over anhydrous magnesium sulfate. The organic layer was concentrated to dryness under reduced pressure to give the title compound (20 mg, 83% yield) as a white solid.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.88-2.03 (4H, m), 2.65-3.23 (6H, m), 3.93 (2H, s), 4.57 (2H, s), 6.93 (1H, brs), 7.69-7.44 (6H, m).
LC / MS [Condition 1]: Retention time 2.53 minutes; m / z 454.8 [M + H] ⁺ (ESI positive ion mode), m / z 453.0 [M−H] ⁻ (ESI negative ion mode)

実施例３５５
３−（｛５−［４−（４−フロオロベンゾイル）ピペリジン−１−カルボニル］チオフェン−２−イル｝メチル）−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−２−オン（化合物番号３５５）の製造
参考例３５５−６で得た５−（｛２−オキソ−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）チオフェン−２−カルボン酸（４．０ｍｇ、０．００８８ｍｍｏｌ）、４−（４−フルオロベンゾイル）ピペリジン塩酸塩（３．２ｍｇ、０．０１３ｍｍｏｌ）、トリエチルアミン（１．８μＬ、０．０１３ｍｍｏｌ）と１−ヒドロキシベンゾトリアゾール（１．２ｍｇ、０．００８８ｍｍｏｌ）をクロロホルム（１．０ｍＬ）に溶解した後、１−エチル−３−（３−ジメチルアミノプロピル）カルボジイミド塩酸塩（２．５ｍｇ、０．０１３ｍｍｏｌ）を加えて、室温で８４時間かき混ぜた。反応終了後、反応混合物に水を加えて有機層を分離し、無水硫酸ナトリウムで乾燥した後、減圧下濃縮乾固した。得られた残留物を薄層クロマトグラフィー［富士シリシア社製ＰＬＣ０５ Ｐｌａｔｅ ＮＨ、展開溶媒：酢酸エチル］にて精製し、表題化合物（４．１ｍｇ、収率７３％）を白色固体として得た。

^１Ｈ−ＮＭＲ（３００ＭＨｚ，ＣＤＣｌ_３）δ：１．６８−２．００（８Ｈ，ｍ），２．４７−２．５８（４Ｈ，ｂｒｍ），３．１２−３．２８（４Ｈ，ｍ），３．４６−３．５９（３Ｈ，ｍ），４．４４（２Ｈ，ｄ，Ｊ＝１３．３Ｈｚ），４．６０（２Ｈ，ｓ），６．９３（１Ｈ，ｄ，Ｊ＝３．７Ｈｚ），７．１１−７．２４（３Ｈ，ｍ），７．４３（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ），７．５７（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ），８．０２−７．９４（２Ｈ，ｍ）．

ＬＣ／ＭＳ［条件１］：保持時間３．３８分；ｍ／ｚ６４４．０［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ６４２．１［Ｍ−Ｈ］^―（ＥＳＩ負イオンモード）

Example 355
3-({5- [4- (4-Fluorobenzoyl) piperidin-1-carbonyl] thiophen-2-yl} methyl) -8- [4- (trifluoromethyl) benzyl] -1-oxa-3, Preparation of 8-diazaspiro [4.5] decan-2-one (Compound No. 355) 5-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1 obtained in Reference Example 355-6 -Oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl) thiophene-2-carboxylic acid (4.0 mg, 0.0088 mmol), 4- (4-fluorobenzoyl) piperidine hydrochloride (3 0.2 mg, 0.013 mmol), triethylamine (1.8 μL, 0.013 mmol) and 1-hydroxybenzotriazole (1.2 mg, 0.0088 mmol) in chloroform Was dissolved in 1.0 mL), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (2.5 mg, 0.013 mmol) was added and stirred for 84 hours at room temperature. After completion of the reaction, water was added to the reaction mixture to separate the organic layer, dried over anhydrous sodium sulfate, and concentrated to dryness under reduced pressure. The obtained residue was purified by thin layer chromatography [PLC05 Plate NH, manufactured by Fuji Silysia Ltd., developing solvent: ethyl acetate] to obtain the title compound (4.1 mg, yield 73%) as a white solid.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.68-2.00 (8H, m), 2.47-2.58 (4H, brm), 3.12-3.28 (4H, m) , 3.46-3.59 (3H, m), 4.44 (2H, d, J = 13.3 Hz), 4.60 (2H, s), 6.93 (1H, d, J = 3. 7 Hz), 7.11-7.24 (3H, m), 7.43 (2H, d, J = 8.2 Hz), 7.57 (2H, d, J = 8.2 Hz), 8.02- 7.94 (2H, m).

LC / MS [Condition 1]: Retention time 3.38 minutes; m / z 644.0 [M + H] ⁺ (ESI positive ion mode), m / z 642.1 [M−H] ⁻ (ESI negative ion mode)

実施例３５６
４−［５−（｛２−オキソ−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）チオフェン−２−カルボキサミド］ピペリジン−１−カルボン酸メチル（化合物番号３５６）の製造
４−（４−フルオロベンゾイル）ピペリジン塩酸塩の代わりに参考例１３５で得られた４−アミノピペリジン−１−カルボン酸メチル塩酸塩を用いること以外は実質的に実施例３５５と同様に反応を行なって、表題化合物（３．６ｍｇ、収率６９％）を無色油状物として得た。

^１Ｈ−ＮＭＲ（３００ＭＨｚ，ＣＤＣｌ_３）δ：１．４１（２Ｈ，ｑｄ，Ｊ＝１２．３，３．３Ｈｚ），１．７４（２Ｈ，ｄｔ，Ｊ＝１３．５，７．２Ｈｚ），１．９２（２Ｈ，ｄ，Ｊ＝１３．１Ｈｚ），２．０２（２Ｈ，ｄ，Ｊ＝１３．９Ｈｚ），２．４９−２．５７（４Ｈ，ｍ），２．９４（２Ｈ，ｔ，Ｊ＝１２．７Ｈｚ），３．２４（２Ｈ，ｓ），３．５６（２Ｈ，ｓ），３．７０（３Ｈ，ｓ），４．２５−４．００（３Ｈ，ｍ），４．５９（２Ｈ，ｓ），５．７６（１Ｈ，ｄ，Ｊ＝７．４Ｈｚ），６．９６（１Ｈ，ｄ，Ｊ＝３．７Ｈｚ），７．３６（１Ｈ，ｄ，Ｊ＝３．７Ｈｚ），７．４２（２Ｈ，ｄ，Ｊ＝７．８Ｈｚ），７．５７（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ）．

ＬＣ／ＭＳ［条件１］：保持時間２．３１分；ｍ／ｚ５９４．９［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ５９３．０［Ｍ−Ｈ］^―（ＥＳＩ負イオンモード）

Example 356
4- [5-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl) thiophene-2- Carboxamide] Preparation of methyl piperidine-1-carboxylate (Compound No. 356) Instead of 4- (4-fluorobenzoyl) piperidine hydrochloride, 4-aminopiperidine-1-carboxylic acid methyl hydrochloride obtained in Reference Example 135 was used. The reaction was carried out substantially in the same manner as in Example 355, except that the title compound (3.6 mg, yield 69%) was obtained as a colorless oil.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.41 (2H, qd, J = 12.3, 3.3 Hz), 1.74 (2H, dt, J = 13.5, 7.2 Hz), 1.92 (2H, d, J = 13.1 Hz), 2.02 (2H, d, J = 13.9 Hz), 2.49-2.57 (4H, m), 2.94 (2H, t , J = 12.7 Hz), 3.24 (2H, s), 3.56 (2H, s), 3.70 (3H, s), 4.25-4.00 (3H, m), 4. 59 (2H, s), 5.76 (1H, d, J = 7.4 Hz), 6.96 (1H, d, J = 3.7 Hz), 7.36 (1H, d, J = 3.7 Hz) ), 7.42 (2H, d, J = 7.8 Hz), 7.57 (2H, d, J = 8.2 Hz).

LC / MS [Condition 1]: Retention time 2.31 min; m / z 594.9 [M + H] ⁺ (ESI positive ion mode), m / z 593.0 [M−H] ⁻ (ESI negative ion mode)

実施例３５７
Ｎ−（ベンゾ［ｄ］［１，３］ジオキソール−５−イルメチル）−５−（｛２−オキソ−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）チオフェン−２−カルボキサミド（化合物番号３５７）の製造
４−（４−フルオロベンゾイル）ピペリジン塩酸塩の代わりにピペロニルアミンを用いること以外は実質的に実施例３５５と同様に反応を行なって、表題化合物（３．８ｍｇ、収率７４％）を無色油状物として得た。

^１Ｈ−ＮＭＲ（３００ＭＨｚ，ＣＤＣｌ_３）δ：１．７４（２Ｈ，ｄｔ，Ｊ＝１４．１，６．９Ｈｚ），１．９２（２Ｈ，ｄｔ，Ｊ＝１３．５，３．３Ｈｚ），２．４７−２．５７（４Ｈ，ｍ），３．２３（２Ｈ，ｓ），３．５６（２Ｈ，ｓ），４．５０（２Ｈ，ｄ，Ｊ＝５．７Ｈｚ），４．５９（２Ｈ，ｓ），５．９５（２Ｈ，ｓ），６．１２（１Ｈ，ｔ，Ｊ＝５．７Ｈｚ），６．７３−６．８５（３Ｈ，ｍ），６．９６（１Ｈ，ｄ，Ｊ＝４．１Ｈｚ），７．３６（１Ｈ，ｄ，Ｊ＝３．７Ｈｚ），７．４２（２Ｈ，ｄ，Ｊ＝７．８Ｈｚ），７．５７（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ）．

ＬＣ／ＭＳ［条件１］：保持時間３．２２分；ｍ／ｚ５８７．９［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ５８６．０［Ｍ−Ｈ］^―（ＥＳＩ負イオンモード）

Example 357
N- (benzo [d] [1,3] dioxol-5-ylmethyl) -5-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [ 4.5] Preparation of decan-3-yl} methyl) thiophene-2-carboxamide (Compound No. 357) Substantially Example 355 except that piperonylamine was used instead of 4- (4-fluorobenzoyl) piperidine hydrochloride. The title compound (3.8 mg, yield 74%) was obtained as a colorless oil.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.74 (2H, dt, J = 14.1, 6.9 Hz), 1.92 (2H, dt, J = 13.5, 3.3 Hz), 2.47-2.57 (4H, m), 3.23 (2H, s), 3.56 (2H, s), 4.50 (2H, d, J = 5.7 Hz), 4.59 ( 2H, s), 5.95 (2H, s), 6.12 (1H, t, J = 5.7 Hz), 6.73-6.85 (3H, m), 6.96 (1H, d, J = 4.1 Hz), 7.36 (1H, d, J = 3.7 Hz), 7.42 (2H, d, J = 7.8 Hz), 7.57 (2H, d, J = 8.2 Hz) ).

LC / MS [Condition 1]: retention time 3.22 minutes; m / z 587.9 [M + H] ⁺ (ESI positive ion mode), m / z 586.0 [M−H] ⁻ (ESI negative ion mode)

実施例３５８
５−（｛２−オキソ−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）−Ｎ−［（テトラヒドロフラン−２−イル）メチル］チオフェン−２−カルボキサミド（化合物番号３５８）の製造
４−（４−フルオロベンゾイル）ピペリジン塩酸塩の代わりにテトラヒドロフルフリルアミンを用いること以外は実質的に実施例３５５と同様に反応を行なって、表題化合物（２．９ｍｇ、収率６０％）を無色油状物として得た。

^１Ｈ−ＮＭＲ（３００ＭＨｚ，ＣＤＣｌ_３）δ：１．７５（２Ｈ，ｄｔ，Ｊ＝１３．５，７．５Ｈｚ），１．８５−２．０９（６Ｈ，ｍ），２．４６−２．６０（４Ｈ，ｍ），３．２４（２Ｈ，ｓ），３．２９（１Ｈ，ｄｄｄ，Ｊ＝１３．９，７．８，４．９Ｈｚ），３．５６（２Ｈ，ｓ），３．７０−３．８３（２Ｈ，ｍ），３．８９（１Ｈ，ｄｔ，Ｊ＝８．２，７．０Ｈｚ），４．０５（１Ｈ，ｑｄ，Ｊ＝７．４，３．３Ｈｚ），４．５９（２Ｈ，ｓ），６．３０（１Ｈ，ｔ，Ｊ＝５．７Ｈｚ），６．９６（１Ｈ，ｄ，Ｊ＝３．７Ｈｚ），７．３７（１Ｈ，ｄ，Ｊ＝３．７Ｈｚ），７．４３（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ），７．５７（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ）．

ＬＣ／ＭＳ［条件１］：保持時間２．９０分；ｍ／ｚ５３７．８［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ５３６．１［Ｍ−Ｈ］^―（ＥＳＩ負イオンモード）

Example 358
5-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl) -N-[(tetrahydrofuran- Preparation of 2-yl) methyl] thiophene-2-carboxamide (Compound No. 358) Reaction substantially as in Example 355 except that tetrahydrofurfurylamine was used in place of 4- (4-fluorobenzoyl) piperidine hydrochloride. To give the title compound (2.9 mg, 60% yield) as a colorless oil.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.75 (2H, dt, J = 13.5, 7.5 Hz), 1.85 to 2.09 (6H, m), 2.46-2. 60 (4H, m), 3.24 (2H, s), 3.29 (1H, ddd, J = 13.9, 7.8, 4.9 Hz), 3.56 (2H, s), 3. 70-3.83 (2H, m), 3.89 (1H, dt, J = 8.2, 7.0 Hz), 4.05 (1H, qd, J = 7.4, 3.3 Hz), 4 .59 (2H, s), 6.30 (1H, t, J = 5.7 Hz), 6.96 (1H, d, J = 3.7 Hz), 7.37 (1H, d, J = 3. 7 Hz), 7.43 (2H, d, J = 8.2 Hz), 7.57 (2H, d, J = 8.2 Hz).

LC / MS [Condition 1]: Retention time 2.90 minutes; m / z 537.8 [M + H] ⁺ (ESI positive ion mode), m / z 536.1 [M−H] ⁻ (ESI negative ion mode)

実施例３５９
Ｎ−（４−シアノベンジル）−５−（｛２−オキソ−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）チオフェン−２−カルボキサミド（化合物番号３５９）の製造
４−（４−フルオロベンゾイル）ピペリジン塩酸塩の代わりに４−シアノベンジルアミン塩酸塩を用いること以外は実質的に実施例３５５と同様に反応を行なって、表題化合物（２．４ｍｇ、収率４８％）を無色油状物として得た。

^１Ｈ−ＮＭＲ（３００ＭＨｚ，ＣＤＣｌ_３）δ：１．５３−１．８７（２Ｈ，ｍ），１．９３（２Ｈ，ｄ，Ｊ＝１３．１Ｈｚ），２．４８−２．６９（４Ｈ，ｍ），３．２５（２Ｈ，ｓ），３．５９（２Ｈ，ｓ），４．６０（２Ｈ，ｓ），４．６６（２Ｈ，ｄ，Ｊ＝６．１Ｈｚ），６．３６（１Ｈ，ｔ，Ｊ＝５．９Ｈｚ），６．９８（１Ｈ，ｄ，Ｊ＝３．７Ｈｚ），７．４２（１Ｈ，ｄ，Ｊ＝３．７Ｈｚ），７．４４（２Ｈ，ｄ，Ｊ＝８．６Ｈｚ），７．４５（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ），７．５８（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ），７．６４（２Ｈ，ｄ，Ｊ＝８．６Ｈｚ）．

ＬＣ／ＭＳ［条件１］：保持時間３．２０分；ｍ／ｚ５６８．９［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ５６７．０［Ｍ−Ｈ］^―（ＥＳＩ負イオンモード）

Example 359
N- (4-cyanobenzyl) -5-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} Preparation of methyl) thiophene-2-carboxamide (Compound No. 359) Reaction substantially as in Example 355 except that 4-cyanobenzylamine hydrochloride was used instead of 4- (4-fluorobenzoyl) piperidine hydrochloride. To give the title compound (2.4 mg, 48% yield) as a colorless oil.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.53-1.87 (2H, m), 1.93 (2H, d, J = 13.1 Hz), 2.48-2.69 (4H, m), 3.25 (2H, s), 3.59 (2H, s), 4.60 (2H, s), 4.66 (2H, d, J = 6.1 Hz), 6.36 (1H) , T, J = 5.9 Hz), 6.98 (1H, d, J = 3.7 Hz), 7.42 (1H, d, J = 3.7 Hz), 7.44 (2H, d, J = 8.6 Hz), 7.45 (2H, d, J = 8.2 Hz), 7.58 (2H, d, J = 8.2 Hz), 7.64 (2H, d, J = 8.6 Hz).

LC / MS [Condition 1]: Retention time 3.20 minutes; m / z 568.9 [M + H] ⁺ (ESI positive ion mode), m / z 567.0 [M−H] ⁻ (ESI negative ion mode)

実施例３６０
Ｎ−（４−シアノベンジル）−３−（｛２−オキソ−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）ベンズアミド（化合物番号３６０）の製造
４−アミノピペリジン−１−カルボン酸メチル塩酸塩の代わりに、４−シアノベンジルアミン塩酸塩を用いること以外は実質的に実施例２０２と同様に反応を行なって、表題化合物（２３ｍｇ、収率９１％）を白色固体として得た。

^１Ｈ−ＮＭＲ（３００ＭＨｚ，ＣＤＣｌ_３）δ：１．７２（２Ｈ，ｄｔ，Ｊ＝１３．８，６．９Ｈｚ），１．９１（２Ｈ，ｄｔ，Ｊ＝１３．１，３．３Ｈｚ），２．４４−２．６０（４Ｈ，ｍ），３．１５（２Ｈ，ｓ），３．５５（２Ｈ，ｓ），４．４６（２Ｈ，ｓ），４．７１（２Ｈ，ｄ，Ｊ＝６．１Ｈｚ），６．６７（１Ｈ，ｔ，Ｊ＝５．７Ｈｚ），７．３８−７．５０（６Ｈ，ｍ），７．５６（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ），７．６４（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ），７．７０−７．７８（２Ｈ，ｍ）．

ＬＣ／ＭＳ［条件１］：保持時間３．１８分；ｍ／ｚ５６２．９［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ５６１．０［Ｍ−Ｈ］^―（ＥＳＩ負イオンモード）

Example 360
N- (4-cyanobenzyl) -3-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} Preparation of methyl) benzamide (Compound No. 360) The reaction was carried out in substantially the same manner as in Example 202 except that 4-cyanobenzylamine hydrochloride was used instead of methyl 4-aminopiperidine-1-carboxylate. To give the title compound (23 mg, 91% yield) as a white solid.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.72 (2H, dt, J = 13.8, 6.9 Hz), 1.91 (2H, dt, J = 13.1, 3.3 Hz), 2.44-2.60 (4H, m), 3.15 (2H, s), 3.55 (2H, s), 4.46 (2H, s), 4.71 (2H, d, J = 6.1 Hz), 6.67 (1 H, t, J = 5.7 Hz), 7.38-7.50 (6 H, m), 7.56 (2 H, d, J = 8.2 Hz), 7. 64 (2H, d, J = 8.2 Hz), 7.70-7.78 (2H, m).

LC / MS [Condition 1]: Retention time 3.18 minutes; m / z 562.9 [M + H] ⁺ (ESI positive ion mode), m / z 561.0 [M−H] ⁻ (ESI negative ion mode)

実施例３６１
４−｛１−［３−（｛２−オキソ−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）ベンゾイル］ピペリジン−４−イルオキシ｝ベンゾニトリル（化合物番号３６１）の製造
４−アミノピペリジン−１−カルボン酸メチル塩酸塩の代わりに、参考例２６４−２により得られた４−（ピペリジン−４−イルオキシ）ベンゾニトリル塩酸塩を用いること以外は実質的に実施例２０２と同様に反応を行なって、表題化合物（３１ｍｇ、収率定量的）を白色固体として得た。

^１Ｈ−ＮＭＲ（３００ＭＨｚ，ＣＤＣｌ_３）δ：１．６６−２．１１（８Ｈ，ｍ），２．４４−２．６０（４Ｈ，ｍ），３．１５（２Ｈ，ｓ），３．２８−３．９６（４Ｈ，ｂｒｍ），３．５５（２Ｈ，ｓ），４．４５（２Ｈ，ｓ），４．６８（１Ｈ，ｔｔ，Ｊ＝６．１，３．７Ｈｚ），６．９６（２Ｈ，ｄ，Ｊ＝９．３Ｈｚ），７．２９−７．３８（３Ｈ，ｍ），７．４０（１Ｈ，ｄ，Ｊ＝７．９Ｈｚ），７．４２（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ），７．５６（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ），７．６０（２Ｈ，ｄ，Ｊ＝９．０Ｈｚ）．

ＬＣ／ＭＳ［条件１］：保持時間３．３６分；ｍ／ｚ６３３．０［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ６７７．１［Ｍ＋ＨＣＯＯ］^―（ＥＳＩ負イオンモード）

Example 361
4- {1- [3-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl) benzoyl Preparation of piperidin-4-yloxy} benzonitrile (Compound No. 361) 4- (piperidin-4-yloxy) obtained by Reference Example 264-2 instead of 4-aminopiperidine-1-carboxylic acid methyl hydrochloride The reaction was carried out substantially in the same manner as in Example 202 except for using benzonitrile hydrochloride to obtain the title compound (31 mg, quantitative yield) as a white solid.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.66-2.11 (8H, m), 2.44-2.60 (4H, m), 3.15 (2H, s), 3.28 -3.96 (4H, brm), 3.55 (2H, s), 4.45 (2H, s), 4.68 (1H, tt, J = 6.1, 3.7 Hz), 6.96 (2H, d, J = 9.3 Hz), 7.29-7.38 (3H, m), 7.40 (1H, d, J = 7.9 Hz), 7.42 (2H, d, J = 8.2 Hz), 7.56 (2H, d, J = 8.2 Hz), 7.60 (2H, d, J = 9.0 Hz).

LC / MS [Condition 1]: Retention time 3.36 minutes; m / z 633.0 [M + H] ⁺ (ESI positive ion mode), m / z 677.1 [M + HCOO] ⁻ (ESI negative ion mode)

実施例３６２
１−（４−シアノベンジル）−３−［４−（｛２−オキソ−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）フェニル］ウレア（化合物番号３６２）の製造
Ｎ−（ｔ−ブトキシカルボニル）−１，３−ジアミノプロパンの代わりに、４−シアノベンジルアミン（市販の４−シアノベンジルアミン塩酸塩を脱塩酸して得た。）そてを用いること以外は実質的に実施例８３と同様に反応を行って、表題化合物（２４ｍｇ、収率４６％）を無色油状物として得た。

^１Ｈ−ＮＭＲ（３００ＭＨｚ，ＣＤＣｌ_３）δ：１．７２（２Ｈ，ｄｔ，Ｊ＝１３．２，７．５Ｈｚ），１．８９（２Ｈ，ｄｔ，Ｊ＝１３．５，４．１Ｈｚ），２．４４−２．５８（４Ｈ，ｍ），３．１６（２Ｈ，ｓ），３．５４（２Ｈ，ｓ），４．３５（２Ｈ，ｓ），４．５１（２Ｈ，ｄ，Ｊ＝５．７Ｈｚ），５．４３（１Ｈ，ｔ，Ｊ＝６．１Ｈｚ），６．７８（１Ｈ，ｓ），７．１５（２Ｈ，ｄ，Ｊ＝８．６Ｈｚ），７．２８（２Ｈ，ｄ，Ｊ＝８．６Ｈｚ），７．４２（２Ｈ，ｄ，Ｊ＝８．６Ｈｚ），７．４３（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ），７．５７（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ），７．６１（２Ｈ，ｄ，Ｊ＝８．６Ｈｚ）．

ＬＣ／ＭＳ［条件１］：保持時間３．１８分；ｍ／ｚ５７７．９Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ５７６．０［Ｍ−Ｈ］^―（ＥＳＩ負イオンモード）

Example 362
1- (4-Cyanobenzyl) -3- [4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decane-3 -Il} methyl) phenyl] urea (Compound No. 362) Preparation of 4-cyanobenzylamine (commercially available 4-cyanobenzylamine hydrochloride instead of N- (t-butoxycarbonyl) -1,3-diaminopropane The reaction was carried out in substantially the same manner as in Example 83 except that the iron was used to give the title compound (24 mg, yield 46%) as a colorless oil.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.72 (2H, dt, J = 13.2, 7.5 Hz), 1.89 (2H, dt, J = 13.5, 4.1 Hz), 2.44-2.58 (4H, m), 3.16 (2H, s), 3.54 (2H, s), 4.35 (2H, s), 4.51 (2H, d, J = 5.7 Hz), 5.43 (1H, t, J = 6.1 Hz), 6.78 (1H, s), 7.15 (2H, d, J = 8.6 Hz), 7.28 (2H, d, J = 8.6 Hz), 7.42 (2H, d, J = 8.6 Hz), 7.43 (2H, d, J = 8.2 Hz), 7.57 (2H, d, J = 8) .2 Hz), 7.61 (2H, d, J = 8.6 Hz).

LC / MS [Condition 1]: Retention time 3.18 minutes; m / z 577.9 M + H] ⁺ (ESI positive ion mode), m / z 576.0 [M−H] ⁻ (ESI negative ion mode)

実施例３６３
１−［４−（｛２−オキソ−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）フェニル］−３−［（テトラヒドロ−２Ｈ−ピラン−４−イル）メチル］ウレア（化合物番号３６３）の製造
Ｎ−（ｔ−ブトキシカルボニル）−１，３−ジアミノプロパンの代わりに、４−アミノメチルテトラヒドロピランを用いること以外は実質的に実施例８３と同様に反応を行って、表題化合物（３１ｍｇ、収率６３％）を白色固体として得た。

^１Ｈ−ＮＭＲ（３００ＭＨｚ，ＣＤＣｌ_３）δ：１．３２（２Ｈ，ｑｄ，Ｊ＝１２．７，４．５Ｈｚ），１．６０−１．８４（５Ｈ，ｍ），１．９０（２Ｈ，ｄｔ，Ｊ＝１３．１，３．７Ｈｚ），２．４４−２．６１（４Ｈ，ｍ），３．１５（２Ｈ，ｓ），３．１６（２Ｈ，ｔ，Ｊ＝６．１Ｈｚ），３．３７（２Ｈ，ｔｄ，Ｊ＝１１．７，１．９Ｈｚ），３．５５（２Ｈ，ｓ），３．９７（２Ｈ，ｄｄ，Ｊ＝１１．３，３．１Ｈｚ），４．３６（２Ｈ，ｓ），４．９９（１Ｈ，ｔ，Ｊ＝５．７Ｈｚ），６．５８（１Ｈ，ｓ），７．１６（２Ｈ，ｄ，Ｊ＝８．６Ｈｚ），７．２８（２Ｈ，ｄ，Ｊ＝９．４Ｈｚ），７．４２（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ），７．５６（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ）．

ＬＣ／ＭＳ［条件１］：保持時間２．９４分；ｍ／ｚ５６０．９［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ５５９．０［Ｍ−Ｈ］^―（ＥＳＩ負イオンモード）

Example 363
1- [4-({2-Oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl) phenyl] -3 -Preparation of [(tetrahydro-2H-pyran-4-yl) methyl] urea (Compound No. 363) 4-aminomethyltetrahydropyran is used in place of N- (t-butoxycarbonyl) -1,3-diaminopropane Except for the above, the reaction was carried out in substantially the same manner as in Example 83 to obtain the title compound (31 mg, yield: 63%) as a white solid.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.32 (2H, qd, J = 12.7, 4.5 Hz), 1.60-1.84 (5H, m), 1.90 (2H, dt, J = 13.1, 3.7 Hz), 2.44-2.61 (4H, m), 3.15 (2H, s), 3.16 (2H, t, J = 6.1 Hz), 3.37 (2H, td, J = 11.7, 1.9 Hz), 3.55 (2H, s), 3.97 (2H, dd, J = 11.3, 3.1 Hz), 4.36 (2H, s), 4.99 (1H, t, J = 5.7 Hz), 6.58 (1H, s), 7.16 (2H, d, J = 8.6 Hz), 7.28 (2H , D, J = 9.4 Hz), 7.42 (2H, d, J = 8.2 Hz), 7.56 (2H, d, J = 8.2 Hz).

LC / MS [Condition 1]: Retention time 2.94 minutes; m / z 560.9 [M + H] ⁺ (ESI positive ion mode), m / z 559.0 [M−H] ⁻ (ESI negative ion mode)

実施例３６４
１−（フラン−２−イルメチル）−３−［４−（｛２−オキソ−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）フェニル］ウレア（化合物番号３６４）の製造
Ｎ−（ｔ−ブトキシカルボニル）−１，３−ジアミノプロパンの代わりに、フルフリルアミンを用いること以外は実質的に実施例８３と同様に反応を行って、表題化合物（２１ｍｇ、収率４３％）を黄色固体として得た。

^１Ｈ−ＮＭＲ（３００ＭＨｚ，ＣＤＣｌ_３）δ：１．７０（２Ｈ，ｄｔ，Ｊ＝１４．４，６．９Ｈｚ），１．８９（２Ｈ，ｄ，Ｊ＝１３．１Ｈｚ），２．４４−２．５９（４Ｈ，ｍ），３．１２（２Ｈ，ｓ），３．５４（２Ｈ，ｓ），４．３６（２Ｈ，ｓ），４．４４（２Ｈ，ｄ，Ｊ＝５．７Ｈｚ），５．０６（１Ｈ，ｔ，Ｊ＝５．３Ｈｚ），６．２５（１Ｈ，ｄ，Ｊ＝３．３Ｈｚ），６．３２（１Ｈ，ｄｄ，Ｊ＝３．３，１．６Ｈｚ），６．４６（１Ｈ，ｓ），７．１７（２Ｈ，ｄ，Ｊ＝８．６Ｈｚ），７．２９（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ），７．３３−７．３６（１Ｈ，ｍ），７．４２（２Ｈ，ｄ，Ｊ＝７．８Ｈｚ），７．５６（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ）．

ＬＣ／ＭＳ［条件１］：保持時間３．１２分；ｍ／ｚ５４２．９［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ５４１．１［Ｍ−Ｈ］^―（ＥＳＩ負イオンモード）

Example 364
1- (furan-2-ylmethyl) -3- [4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decane- Preparation of 3-yl} methyl) phenyl] urea (Compound No. 364) Substantially the same as Example 83, except that furfurylamine was used instead of N- (t-butoxycarbonyl) -1,3-diaminopropane. The title compound (21 mg, 43% yield) was obtained as a yellow solid.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.70 (2H, dt, J = 14.4, 6.9 Hz), 1.89 (2H, d, J = 13.1 Hz), 2.44 − 2.59 (4H, m), 3.12 (2H, s), 3.54 (2H, s), 4.36 (2H, s), 4.44 (2H, d, J = 5.7 Hz) , 5.06 (1H, t, J = 5.3 Hz), 6.25 (1H, d, J = 3.3 Hz), 6.32 (1H, dd, J = 3.3, 1.6 Hz), 6.46 (1H, s), 7.17 (2H, d, J = 8.6 Hz), 7.29 (2H, d, J = 8.2 Hz), 7.33-7.36 (1H, m ), 7.42 (2H, d, J = 7.8 Hz), 7.56 (2H, d, J = 8.2 Hz).

LC / MS [Condition 1]: Retention time 3.12 minutes; m / z 542.9 [M + H] ⁺ (ESI positive ion mode), m / z 541.1 [M−H] ⁻ (ESI negative ion mode)

実施例３６５
１−（フラン−３−イルメチル）−３−［４−（｛２−オキソ−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）フェニル］ウレア（化合物番号３６５）の製造
Ｎ−（ｔ−ブトキシカルボニル）−１，３−ジアミノプロパンの代わりに、３−フリルメチルアミンを用いること以外は実質的に実施例８３と同様に反応を行って、表題化合物（２１ｍｇ、収率４３％）を淡黄色固体として得た。

^１Ｈ−ＮＭＲ（３００ＭＨｚ，ＣＤＣｌ_３）δ：１．７１（２Ｈ，ｄｔ，Ｊ＝１３．８，７．２Ｈｚ），１．８９（２Ｈ，ｄｔ，Ｊ＝１３．１，４．１Ｈｚ），２．４５−２．５８（４Ｈ，ｍ），３．１３（２Ｈ，ｓ），３．５５（２Ｈ，ｓ），４．３０（２Ｈ，ｄ，Ｊ＝５．３Ｈｚ），４．３６（２Ｈ，ｓ），４．８７−４．９８（１Ｈ，ｍ），
６．４０（１Ｈ，ｓ），６．４８（１Ｈ，ｂｒｓ），７．１７（２Ｈ，ｄ，Ｊ＝８．６Ｈｚ），７．２８（２Ｈ，ｄ，Ｊ＝８．６Ｈｚ），７．３６−７．４２（２Ｈ，ｍ），７．４２（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ），７．５６（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ）．

ＬＣ／ＭＳ［条件１］：保持時間３．０８分；ｍ／ｚ５４２．９［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ５４１．１［Ｍ−Ｈ］^―（ＥＳＩ負イオンモード）

Example 365
1- (furan-3-ylmethyl) -3- [4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decane- Preparation of 3-yl} methyl) phenyl] urea (Compound No. 365) Substantially examples except using 3-furylmethylamine instead of N- (t-butoxycarbonyl) -1,3-diaminopropane The reaction was conducted in the same manner as in 83 to give the title compound (21 mg, yield 43%) as a pale yellow solid.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.71 (2H, dt, J = 13.8, 7.2 Hz), 1.89 (2H, dt, J = 13.1, 4.1 Hz), 2.45-2.58 (4H, m), 3.13 (2H, s), 3.55 (2H, s), 4.30 (2H, d, J = 5.3 Hz), 4.36 ( 2H, s), 4.87-4.98 (1H, m),
6.40 (1H, s), 6.48 (1H, brs), 7.17 (2H, d, J = 8.6 Hz), 7.28 (2H, d, J = 8.6 Hz), 7. 36-7.42 (2H, m), 7.42 (2H, d, J = 8.2 Hz), 7.56 (2H, d, J = 8.2 Hz).

LC / MS [Condition 1]: Retention time 3.08 minutes; m / z 542.9 [M + H] ⁺ (ESI positive ion mode), m / z 541.1 [M−H] ⁻ (ESI negative ion mode)

実施例３６６
（１ｒ，４ｒ）−Ｎ−（３−シアノベンジル）−４−（｛２−オキソ−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）シクロヘキサンカルボキサミド（化合物番号３６６）の製造
テトラヒドロフルフリルアミンの代わりに、３−（アミノメチル）ベンゾニトリル塩酸塩（ＷＯ２００７／００２３１３記載の方法により製造）を用いること以外は実質的に実施例１０と同様に反応を行なって、表題化合物（１９ｍｇ、収率７３％）を白色固体として得た。

^１Ｈ−ＮＭＲ（３００ＭＨｚ，ＣＤＣｌ_３）δ：１．０３（２Ｈ，ｑｄ，Ｊ＝１１．９，２．９Ｈｚ），１．５３（２Ｈ，ｑｄ，Ｊ＝１２．７，２．９Ｈｚ），１．６２−１．６９（１Ｈ，ｍ），１．７９（４Ｈ，ｄ，Ｊ＝１０．６Ｈｚ），１．９５（４Ｈ，ｄ，Ｊ＝１５．１Ｈｚ），２．１０（１Ｈ，ｔｔ，Ｊ＝１１．９，３．７Ｈｚ），２．５１−２．６１（４Ｈ，ｍ），３．１０（２Ｈ，ｄ，Ｊ＝７．４Ｈｚ），３．２６（２Ｈ，ｓ），３．５８（２Ｈ，ｓ），４．４７（２Ｈ，ｄ，Ｊ＝６．１Ｈｚ），５．９１（１Ｈ，ｔ，Ｊ＝５．７Ｈｚ），７．３９−７．６２（８Ｈ，ｍ）．

ＬＣ／ＭＳ［条件１］：保持時間３．１４分；ｍ／ｚ５６８．７［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ６１２．９［Ｍ＋ＨＣＯＯ］^―（ＥＳＩ負イオンモード）

Example 366
(1r, 4r) -N- (3-cyanobenzyl) -4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] Decan-3-yl} methyl) cyclohexanecarboxamide (Compound No. 366) Manufacture substantially except that 3- (aminomethyl) benzonitrile hydrochloride (manufactured by the method described in WO2007 / 002313) is used instead of tetrahydrofurfurylamine. Specifically, the reaction was carried out in the same manner as in Example 10 to obtain the title compound (19 mg, yield 73%) as a white solid.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.03 (2H, qd, J = 11.9, 2.9 Hz), 1.53 (2H, qd, J = 12.7, 2.9 Hz), 1.62-1.69 (1H, m), 1.79 (4H, d, J = 10.6 Hz), 1.95 (4H, d, J = 15.1 Hz), 2.10 (1H, tt , J = 11.9, 3.7 Hz), 2.51-2.61 (4H, m), 3.10 (2H, d, J = 7.4 Hz), 3.26 (2H, s), 3 .58 (2H, s), 4.47 (2H, d, J = 6.1 Hz), 5.91 (1H, t, J = 5.7 Hz), 7.39-7.62 (8H, m) .

LC / MS [Condition 1]: Retention time 3.14 minutes; m / z 568.7 [M + H] ⁺ (ESI positive ion mode), m / z 612.9 [M + HCOO] ⁻ (ESI negative ion mode)

参考例３６７−１
４−［４−（メチルスルホニル）ベンゾイル］ピペリジン−１−カルボン酸ｔ−ブチルの製造
ＷＯ２００５／０５９１０７記載の方法を用いて合成した。

Reference Example 367-1
Production of t-butyl 4- [4- (methylsulfonyl) benzoyl] piperidine-1-carboxylate Synthesized using the method described in WO2005 / 059107.

参考例３６７−２
４−［４−（メチルスルホニル）ベンゾイル］ピペリジン塩酸塩の製造
参考例３６７−１で得られた４−［４−（メチルスルホニル）ベンゾイル］ピペリジン−１−カルボン酸ｔ−ブチル（６８ｍｇ、０．１８ｍｍｏｌ）をメタノール（２．０ｍＬ）に溶解し、４Ｍ塩化水素−ジオキサン溶液（２．０ｍＬ）を加え、室温で３０時間かき混ぜた。反応混合物をろ過し、得られた固体を１，４−ジオキサンで洗浄した後、減圧下乾燥し、表題化合物（３０ｍｇ、収率５３％）を白色固体として得た。

^１Ｈ−ＮＭＲ（３００ＭＨｚ，ＣＤ_３ＯＤ）δ：１．９０（２Ｈ，ｄｔｄ，Ｊ＝１５．１，１１．１，４．１Ｈｚ），２．１４（２Ｈ，ｄｄ，Ｊ＝１４．９，２．７Ｈｚ），３．１５（１Ｈ，ｄｄ，Ｊ＝７．４，４．１Ｈｚ），３．１７（３Ｈ，ｓ），３．２１（１Ｈ，ｄｄ，Ｊ＝１２．３，３．３Ｈｚ），３．４７（２Ｈ，ｄｔ，Ｊ＝１３．１，４．２Ｈｚ），３．８２（１Ｈ，ｔｔ，Ｊ＝１１．１，３．７Ｈｚ），８．１２（２Ｈ，ｄ，Ｊ＝８．６Ｈｚ），８．２４（２Ｈ，ｄ，Ｊ＝９．０Ｈｚ）．

Reference Example 367-2
Production of 4- [4- (methylsulfonyl) benzoyl] piperidine hydrochloride t-butyl 4- [4- (methylsulfonyl) benzoyl] piperidine-1-carboxylate obtained in Reference Example 367-1 (68 mg, 0. 18 mmol) was dissolved in methanol (2.0 mL), 4M hydrogen chloride-dioxane solution (2.0 mL) was added, and the mixture was stirred at room temperature for 30 hr. The reaction mixture was filtered, and the resulting solid was washed with 1,4-dioxane and dried under reduced pressure to give the title compound (30 mg, yield 53%) as a white solid.

¹ H-NMR (300 MHz, CD ₃ OD) δ: 1.90 (2H, dtd, J = 15.1, 11.1, 4.1 Hz), 2.14 (2H, dd, J = 14.9, 2.7 Hz), 3.15 (1 H, dd, J = 7.4, 4.1 Hz), 3.17 (3 H, s), 3.21 (1 H, dd, J = 12.3, 3.3 Hz) ), 3.47 (2H, dt, J = 13.1, 4.2 Hz), 3.82 (1H, tt, J = 11.1, 3.7 Hz), 8.12 (2H, d, J = 8.6 Hz), 8.24 (2H, d, J = 9.0 Hz).

実施例３６７
３−［（（１ｒ，４ｒ）−４−｛４−［４−（メチルスルホニル）ベンゾイル］ピペリジン−１−カルボニル｝シクロヘキシル）メチル］−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−２−オン（化合物番号３６７）の製造
テトラヒドロフルフリルアミンの代わりに、参考例３６７−２で得られた４−［４−（メチルスルホニル）ベンゾイル］ピペリジン塩酸塩を用いること以外は実質的に実施例１０と同様に反応を行なって、表題化合物（３０ｍｇ、収率９７％）を白色固体として得た。

^１Ｈ−ＮＭＲ（３００ＭＨｚ，ＣＤＣｌ_３）δ：１．０５（２Ｈ，ｑ，Ｊ＝１２．７Ｈｚ），１．５６（２Ｈ，ｑ，Ｊ＝１３．１Ｈｚ），１．５６−１．６９（２Ｈ，ｍ），１．７２−１．８７（７Ｈ，ｍ），１．８８−２．００（４Ｈ，ｍ），２．４６（１Ｈ，ｔｔ，Ｊ＝１２．３，３．３Ｈｚ），２．５３−２．６３（４Ｈ，ｍ），２．８４（１Ｈ，ｔ，Ｊ＝１１．９Ｈｚ），３．０９（３Ｈ，ｓ），３．１１（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ），３．２２（１Ｈ，ｔ，Ｊ＝１３．５Ｈｚ），３．２６（２Ｈ，ｓ），３．５１（１Ｈ，ｔｔ，Ｊ＝１０．６，３．７Ｈｚ），３．５７（２Ｈ，ｓ），３．９９（１Ｈ，ｄ，Ｊ＝１３．５Ｈｚ），４．６０（１Ｈ，ｄ，Ｊ＝１３．１Ｈｚ），７．４４（２Ｈ，ｄ，Ｊ＝７．８Ｈｚ），７．５７（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ），８．０７（２Ｈ，ｄ，Ｊ＝８．６Ｈｚ），８．１１（２Ｈ，ｄ，Ｊ＝９．０Ｈｚ）．

ＬＣ／ＭＳ［条件１］：保持時間３．１８分；ｍ／ｚ７０３．８［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ７４７．９［Ｍ＋ＨＣＯＯ］^―（ＥＳＩ負イオンモード）

Example 367
3-[((1r, 4r) -4- {4- [4- (methylsulfonyl) benzoyl] piperidine-1-carbonyl} cyclohexyl) methyl] -8- [4- (trifluoromethyl) benzyl] -1- Preparation of Oxa-3,8-diazaspiro [4.5] decan-2-one (Compound No. 367) 4- [4- (methylsulfonyl) benzoyl obtained in Reference Example 367-2 instead of tetrahydrofurfurylamine The reaction was performed in substantially the same manner as in Example 10 except that piperidine hydrochloride was used to obtain the title compound (30 mg, yield 97%) as a white solid.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.05 (2H, q, J = 12.7 Hz), 1.56 (2H, q, J = 13.1 Hz), 1.56-1.69 ( 2H, m), 1.72-1.87 (7H, m), 1.88-2.00 (4H, m), 2.46 (1H, tt, J = 12.3, 3.3 Hz), 2.53-2.63 (4H, m), 2.84 (1H, t, J = 11.9 Hz), 3.09 (3H, s), 3.11 (2H, d, J = 8.2 Hz) ), 3.22 (1H, t, J = 13.5 Hz), 3.26 (2H, s), 3.51 (1H, tt, J = 10.6, 3.7 Hz), 3.57 (2H , S), 3.99 (1H, d, J = 13.5 Hz), 4.60 (1H, d, J = 13.1 Hz), 7.44 (2H, d, J = 7.8 Hz), 7 .57 ( H, d, J = 8.2Hz), 8.07 (2H, d, J = 8.6Hz), 8.11 (2H, d, J = 9.0Hz).

LC / MS [Condition 1]: Retention time 3.18 minutes; m / z 703.8 [M + H] ⁺ (ESI positive ion mode), m / z 747.9 [M + HCOO] ⁻ (ESI negative ion mode)

実施例３６８
３−｛４−［４−（４−フルオロベンゾイル）ピペリジン−１−イルスルホニル］ベンジル｝−２−オキソ−１−オキサ−３，８−ジアザスピロ［４．５］デカン−８−カルボン酸ｔ−ブチル（化合物番号３６８）の製造
４−（ブロモメチル）ベンゼンスルホニルクロリド（５３０ｍｇ、２．０ｍｍｏｌ）をクロロホルム（５．０ｍＬ）に溶解し、氷冷下、４−（４−フルオロベンゾイル）ピペリジン塩酸塩（４８０ｍｇ、２．０ｍｍｏｌ）とトリエチルアミン（０．５５ｍＬ、４．０ｍｍｏｌ）を加え、室温で２時間かき混ぜた。反応混合物に、水（１０ｍＬ）とクロロホルム（１０ｍＬ）を加えた後、有機層を分離し、ろ過して得られた溶液を減圧下濃縮した。得られた残留物をシリカゲルカラムクロマトグラフィー［充填剤：Ｍｅｒｃｋ ＧＭＢＨ製シリカゲル６０（０．０４０−０．０６３ｍｍ）、展開溶媒：クロロホルム／酢酸エチル＝１０／１］にて精製し、無色油状物（６０ｍｇ）を得た。
参考例１１１−１で得られた２−オキソ−１−オキサ−３，８−ジアザスピロ［４．５］デカン−８−カルボン酸ｔ−ブチル（３５ｍｇ、０．１４ｍｍｏｌ）をＮ，Ｎ−ジメチルホルムアミド（１．０ｍＬ）に溶かし、ナトリウムｔ−ブトキシド（１６ｍｇ、０．１６ｍｍｏｌ）を加えて３０分撹拌した後、先に得られた無色油状物（６０ｍｇ）のＮ，Ｎ−ジメチルホルムアミド（２．０ｍＬ）溶液を加え、５時間かき混ぜた。その後、水と酢酸エチルを加えて有機層を分離した。得られた有機層を水で２回洗浄し、無水硫酸マグネシウムで乾燥した後、減圧下濃縮し、得られた残留物をシリカゲルカラムクロマトグラフィー［充填剤：Ｍｅｒｃｋ ＧＭＢＨ製シリカゲル６０（０．０４０−０．０６３ｍｍ）、展開溶媒：酢酸エチル＝１］にて精製することにより、表題化合物（７５ｍｇ、６％）を白色固体として得た。

^１Ｈ−ＮＭＲ（３００ＭＨｚ，ＣＤＣｌ_３）δ：１．４５（９Ｈ，ｓ），１．５９−１．７２（２Ｈ，ｍ），１．７８−１．９９（６Ｈ，ｍ），２．６１（２Ｈ，ｔｄ，Ｊ＝１０．６，３．７Ｈｚ），３．２０（１Ｈ，ｔｔ，Ｊ＝１０．２，４．５Ｈｚ），３．２１（２Ｈ，ｓ），３．２９（２Ｈ，ｔ，Ｊ＝１１．５Ｈｚ），３．７８（２Ｈ，ｄｔ，Ｊ＝１２．３，３．３Ｈｚ），３．７９−３．９２（２Ｈ，ｍ），４．５３（２Ｈ，ｓ），７．１２（２Ｈ，ｔ，Ｊ＝８．６Ｈｚ），７．４４（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ），７．７９（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ），７．８９（２Ｈ，ｄｄ，Ｊ＝８．８，５．５Ｈｚ）．

ＬＣ／ＭＳ［条件１］：保持時間４．５９分；ｍ／ｚ６１５．８［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ６５９．９［Ｍ＋ＨＣＯＯ］^―（ＥＳＩ負イオンモード）

Example 368
3- {4- [4- (4-Fluorobenzoyl) piperidin-1-ylsulfonyl] benzyl} -2-oxo-1-oxa-3,8-diazaspiro [4.5] decane-8-carboxylic acid t- Preparation of Butyl (Compound No. 368) 4- (Bromomethyl) benzenesulfonyl chloride (530 mg, 2.0 mmol) was dissolved in chloroform (5.0 mL), and 4- (4-fluorobenzoyl) piperidine hydrochloride ( 480 mg, 2.0 mmol) and triethylamine (0.55 mL, 4.0 mmol) were added, and the mixture was stirred at room temperature for 2 hours. After adding water (10 mL) and chloroform (10 mL) to the reaction mixture, the organic layer was separated, and the solution obtained by filtration was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography [filler: silica gel 60 (0.040-0.063 mm) manufactured by Merck GMBH, developing solvent: chloroform / ethyl acetate = 10/1], and colorless oil ( 60 mg) was obtained.
2-Oxo-1-oxa-3,8-diazaspiro [4.5] decane-8-carboxylate t-butyl (35 mg, 0.14 mmol) obtained in Reference Example 111-1 was replaced with N, N-dimethylformamide. (1.0 mL), sodium t-butoxide (16 mg, 0.16 mmol) was added, and the mixture was stirred for 30 minutes, and then the colorless oil (60 mg) obtained above, N, N-dimethylformamide (2.0 mL) was added. ) The solution was added and stirred for 5 hours. Thereafter, water and ethyl acetate were added to separate the organic layer. The obtained organic layer was washed twice with water, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography [filler: silica gel 60 (0.040- from Merck GMBH). 0.063 mm), developing solvent: ethyl acetate = 1] to give the title compound (75 mg, 6%) as a white solid.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.45 (9H, s), 1.59-1.72 (2H, m), 1.78-1.99 (6H, m), 2.61 (2H, td, J = 10.6, 3.7 Hz), 3.20 (1H, tt, J = 10.2, 4.5 Hz), 3.21 (2H, s), 3.29 (2H, t, J = 11.5 Hz), 3.78 (2H, dt, J = 12.3, 3.3 Hz), 3.79-3.92 (2H, m), 4.53 (2H, s), 7.12 (2H, t, J = 8.6 Hz), 7.44 (2H, d, J = 8.2 Hz), 7.79 (2H, d, J = 8.2 Hz), 7.89 (2H , Dd, J = 8.8, 5.5 Hz).

LC / MS [Condition 1]: Retention time 4.59 minutes; m / z 615.8 [M + H] ⁺ (ESI positive ion mode), m / z 659.9 [M + HCOO] ⁻ (ESI negative ion mode)

参考例３６９
３−｛４−［４−（４−フルオロベンゾイル）ピペリジン−１−イルスルホニル］ベンジル｝−１−オキサ−３，８−ジアザスピロ［４．５］デカン−２−オン塩酸塩の製造
実施例３６８で得られた３−｛４−［４−（４−フルオロベンゾイル）ピペリジン−１−イルスルホニル］ベンジル｝−２−オキソ−１−オキサ−３，８−ジアザスピロ［４．５］デカン−８−カルボン酸ｔ−ブチル（６９ｍｇ、０．１１ｍｍｏｌ）を１，４−ジオキサン（２．０ｍＬ）に溶解し、４Ｍ塩化水素−ジオキサン溶液（２．０ｍＬ）を加えて室温で３時間かきまぜた。反応混合物を減圧下濃縮乾固し、表題化合物（６１ｍｇ、収率９８％）を白色固体として得た。

ＬＣ／ＭＳ［条件１］：保持時間３．１０分；ｍ／ｚ５１５．８［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ５１３．８［Ｍ−Ｈ］^―（ＥＳＩ負イオンモード）

Reference Example 369
3- {4- [4- (4-Fluorobenzoyl) piperidin-1-ylsulfonyl] benzyl} -1-oxa-3,8-diazaspiro [4.5] decan-2-one hydrochloride Preparation Example 368 3- {4- [4- (4-Fluorobenzoyl) piperidin-1-ylsulfonyl] benzyl} -2-oxo-1-oxa-3,8-diazaspiro [4.5] decane-8- T-butyl carboxylate (69 mg, 0.11 mmol) was dissolved in 1,4-dioxane (2.0 mL), 4M hydrogen chloride-dioxane solution (2.0 mL) was added, and the mixture was stirred at room temperature for 3 hr. The reaction mixture was concentrated to dryness under reduced pressure to give the title compound (61 mg, yield 98%) as a white solid.

LC / MS [Condition 1]: Retention time 3.10 minutes; m / z 515.8 [M + H] ⁺ (ESI positive ion mode), m / z 513.8 [MH] ⁻ (ESI negative ion mode)

実施例３６９
３，５−ジフルオロ−４−［（３−｛４−［４−（４−フルオロベンゾイル）ピペリジン−１−イルスルホニル］ベンジル｝−２−オキソ−１−オキサ−３，８−ジアザスピロ［４．５］デカン−８−イル）メチル］ベンゾニトリル（化合物番号３６９）の製造
参考例３６９で得られた３−｛４−［４−（４−フルオロベンゾイル）ピペリジン−１−イルスルホニル］ベンジル｝−１−オキサ−３，８−ジアザスピロ［４．５］デカン−２−オン塩酸塩を脱塩し、３−｛４−［４−（４−フルオロベンゾイル）ピペリジン−１−イルスルホニル］ベンジル｝−１−オキサ−３，８−ジアザスピロ［４．５］デカン−２−オンを得た。
得られた３−｛４−［４−（４−フルオロベンゾイル）ピペリジン−１−イルスルホニル］ベンジル｝−１−オキサ−３，８−ジアザスピロ［４．５］デカン−２−オンと３，５−ジフルオロ−４−ホルミルベンゾニトリル（６．９ｍｇ、０．０４１ｍｍｏｌ）をジクロロメタン（２．０ｍＬ）に溶解し、トリアセトキシ水素化ホウ素ナトリウム（１２ｍｇ、０．０５７ｍｍｏｌ）を加え、室温で１時間かき混ぜた。反応混合物に水とクロロホルムを加え、有機層を分離し、無水硫酸マグネシウムで乾燥した後、減圧下濃縮した。得られた残留物を薄層クロマトグラフィー［富士シリシア社製ＰＬＣ０５ Ｐｌａｔｅ ＮＨ、展開溶媒：酢酸エチル］にて精製し、表題化合物（３．０ｍｇ、収率１２％）を白色固体として得た。

^１Ｈ−ＮＭＲ（３００ＭＨｚ，ＣＤＣｌ_３）δ：１．７０−１．８２（２Ｈ，ｍ），１．８２−１．９９（６Ｈ，ｍ），２．５４−２．６７（６Ｈ，ｍ），３．１７（２Ｈ，ｓ），３．１９（１Ｈ，ｔｔ，Ｊ＝９．６，５．０Ｈｚ），３．７４（２Ｈ，ｓ），３．７７（２Ｈ，ｄｔ，Ｊ＝１２．６，３．３Ｈｚ），４．５１（２Ｈ，ｓ），７．１２（２Ｈ，ｔ，Ｊ＝８．６Ｈｚ），７．２２（２Ｈ，ｄ，Ｊ＝６．３Ｈｚ），７．４３（２Ｈ，ｄ，Ｊ＝８．３Ｈｚ），７．７７（２Ｈ，ｄ，Ｊ＝８．３Ｈｚ），７．８９（２Ｈ，ｄｄ，Ｊ＝８．９，５．６Ｈｚ）．

ＬＣ／ＭＳ［条件１］：保持時間３．５８分；ｍ／ｚ６６６．７［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ７１１．０［Ｍ＋ＨＣＯＯ］^―（ＥＳＩ負イオンモード）

Example 369
3,5-Difluoro-4-[(3- {4- [4- (4-fluorobenzoyl) piperidin-1-ylsulfonyl] benzyl} -2-oxo-1-oxa-3,8-diazaspiro [4. 5] Production of decan-8-yl) methyl] benzonitrile (Compound No. 369) 3- {4- [4- (4-fluorobenzoyl) piperidin-1-ylsulfonyl] benzyl}-obtained in Reference Example 369 1-oxa-3,8-diazaspiro [4.5] decan-2-one hydrochloride is desalted to give 3- {4- [4- (4-fluorobenzoyl) piperidin-1-ylsulfonyl] benzyl}- 1-oxa-3,8-diazaspiro [4.5] decan-2-one was obtained.
The resulting 3- {4- [4- (4-fluorobenzoyl) piperidin-1-ylsulfonyl] benzyl} -1-oxa-3,8-diazaspiro [4.5] decan-2-one and 3,5 -Difluoro-4-formylbenzonitrile (6.9 mg, 0.041 mmol) was dissolved in dichloromethane (2.0 mL), sodium triacetoxyborohydride (12 mg, 0.057 mmol) was added, and the mixture was stirred at room temperature for 1 hour. . Water and chloroform were added to the reaction mixture, the organic layer was separated, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by thin layer chromatography [PLC05 Plate NH, manufactured by Fuji Silysia Ltd., developing solvent: ethyl acetate] to obtain the title compound (3.0 mg, yield 12%) as a white solid.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.70-1.82 (2H, m), 1.82-1.99 (6H, m), 2.54-2.67 (6H, m) 3.17 (2H, s), 3.19 (1H, tt, J = 9.6, 5.0 Hz), 3.74 (2H, s), 3.77 (2H, dt, J = 12. 6, 3.3 Hz), 4.51 (2H, s), 7.12 (2H, t, J = 8.6 Hz), 7.22 (2H, d, J = 6.3 Hz), 7.43 ( 2H, d, J = 8.3 Hz), 7.77 (2H, d, J = 8.3 Hz), 7.89 (2H, dd, J = 8.9, 5.6 Hz).

LC / MS [Condition 1]: retention time 3.58 minutes; m / z 666.7 [M + H] ⁺ (ESI positive ion mode), m / z 711.0 [M + HCOO] ⁻ (ESI negative ion mode)

実施例３７０
４−［（３−｛４−［４−（４−フルオロベンゾイル）ピペリジン−１−イルスルホニル］ベンジル｝−２−オキソ−１−オキサ−３，８−ジアザスピロ［４．５］デカン−８−イル）メチル］ベンゾニトリル（化合物番号３７０）の製造
（１ｒ，４ｒ）−Ｎ−（１−ベンジルピペリジン−４−イル）−４−［（２−オキソ−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル）メチル］シクロヘキサンカルボキサミド塩酸塩の代わりに参考例３６９で得られた３−｛４−［４−（４−フルオロベンゾイル）ピペリジン−１−イルスルホニル］ベンジル｝−１−オキサ−３，８−ジアザスピロ［４．５］デカン−２−オン塩酸塩を、ベンジルブロミドの代わりに４−シアノベンジルブロミドを用いること以外は実質的に実施例９８と同様に反応を行って、表題化合物（１２ｍｇ、収率６６％）を淡黄色固体として得た。

^１Ｈ−ＮＭＲ（３００ＭＨｚ，ＣＤＣｌ_３）δ：１．７３−２．０１（８Ｈ，ｍ），２．５０−２．６７（６Ｈ，ｍ），３．１９（１Ｈ，ｔｔ，Ｊ＝９．８，５．３Ｈｚ），３．２０（２Ｈ，ｓ），３．５８（２Ｈ，ｓ），３．７７（２Ｈ，ｄｔ，Ｊ＝１２．３，３．７Ｈｚ），４．５２（２Ｈ，ｓ），７．１１（２Ｈ，ｔ，Ｊ＝８．６Ｈｚ），７．４４（４Ｈ，ｄ，Ｊ＝８．２Ｈｚ），７．６１（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ），７．７８（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ），７．８９（２Ｈ，ｄｄ，Ｊ＝８．６，５．３Ｈｚ）．

ＬＣ／ＭＳ［条件１］：保持時間３．２９分；ｍ／ｚ６３０．９［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ６２９．２［Ｍ−Ｈ］^―（ＥＳＩ負イオンモード）

Example 370
4-[(3- {4- [4- (4-Fluorobenzoyl) piperidin-1-ylsulfonyl] benzyl} -2-oxo-1-oxa-3,8-diazaspiro [4.5] decane-8- Yl) methyl] benzonitrile (Compound No. 370) (1r, 4r) -N- (1-benzylpiperidin-4-yl) -4-[(2-oxo-1-oxa-3,8-diazaspiro [ 4.5] Decan-3-yl) methyl] cyclohexanecarboxamide hydrochloride instead of 3- {4- [4- (4- (4-fluorobenzoyl) piperidin-1-ylsulfonyl] benzyl}-obtained in Reference Example 369 Example 9 substantially except that 1-oxa-3,8-diazaspiro [4.5] decan-2-one hydrochloride is used instead of 4-cyanobenzyl bromide instead of benzyl bromide. The reaction was carried out similarly to give the title compound (12 mg, 66% yield) as a pale yellow solid.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.73-2.01 (8H, m), 2.50-2.67 (6H, m), 3.19 (1H, tt, J = 9. 8, 5.3 Hz), 3.20 (2H, s), 3.58 (2H, s), 3.77 (2H, dt, J = 12.3, 3.7 Hz), 4.52 (2H, s), 7.11 (2H, t, J = 8.6 Hz), 7.44 (4H, d, J = 8.2 Hz), 7.61 (2H, d, J = 8.2 Hz), 7. 78 (2H, d, J = 8.2 Hz), 7.89 (2H, dd, J = 8.6, 5.3 Hz).

LC / MS [Condition 1]: Retention time 3.29 minutes; m / z 630.9 [M + H] ⁺ (ESI positive ion mode), m / z 629.2 [M−H] ⁻ (ESI negative ion mode)

参考例３７１−１
２−（メトキシメトキシ）−４−メチル安息香酸メチルの製造
４−メチルサリチル酸メチル（４２６ｍｇ、２．６ｍｍｏｌ）をＮ，Ｎ−ジメチルホルムアミド（５．０ｍＬ）に溶解し、氷冷下、水素化ナトリウム（５５重量％、流動パラフィン分散）（１７０ｍｇ、３．９ｍｍｏｌ）を加え２０分間かき混ぜた後、クロロメチルメチルエーテル（０．２５ｍＬ、３．３ｍｍｏｌ）を加え、室温で１５時間かき混ぜた。反応混合物に飽和炭酸水素ナトリウム水溶液（１０ｍＬ）と酢酸エチル（１０ｍＬ）を加えた後、有機層を分離し、飽和食塩水で３回洗浄した。有機層を無水硫酸マグネシウムで乾燥した後、減圧下濃縮した。得られた残留物をシリカゲルカラムクロマトグラフィー［充填剤：Ｍｅｒｃｋ ＧＭＢＨ製シリカゲル６０（０．０４０−０．０６３ｍｍ）、展開溶媒：ヘキサン／酢酸エチル＝１０／１］にて精製し、表題化合物を無色油状物（４８０ｍｇ、収率８９％）として得た。

^１Ｈ−ＮＭＲ（３００ＭＨｚ，ＣＤＣｌ_３）δ：２．３７（３Ｈ，ｓ），３．５３（３Ｈ，ｓ），３．８７（３Ｈ，ｓ），５．２５（２Ｈ，ｓ），６．８５（１Ｈ，ｄ，Ｊ＝８．２Ｈｚ），７．００（１Ｈ，ｓ），７．７１（１Ｈ，ｄ，Ｊ＝７．８Ｈｚ）．

Reference Example 371-1
Preparation of methyl 2- (methoxymethoxy) -4-methylbenzoate Methyl 4-methylsalicylate (426 mg, 2.6 mmol) was dissolved in N, N-dimethylformamide (5.0 mL), and sodium hydride was cooled with ice. (55 wt%, liquid paraffin dispersion) (170 mg, 3.9 mmol) was added and stirred for 20 minutes, chloromethyl methyl ether (0.25 mL, 3.3 mmol) was added, and the mixture was stirred at room temperature for 15 hours. A saturated aqueous sodium hydrogen carbonate solution (10 mL) and ethyl acetate (10 mL) were added to the reaction mixture, and the organic layer was separated and washed with saturated brine three times. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography [filler: silica gel 60 (0.040-0.063 mm) manufactured by Merck GMBH, developing solvent: hexane / ethyl acetate = 10/1], and the title compound was colorless. Obtained as an oil (480 mg, 89% yield).

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 2.37 (3H, s), 3.53 (3H, s), 3.87 (3H, s), 5.25 (2H, s), 6. 85 (1H, d, J = 8.2 Hz), 7.00 (1H, s), 7.71 (1H, d, J = 7.8 Hz).

参考例３７１−２
３−［４−（メトキシカルボニル）−３−（メトキシメトキシ）ベンジル］−２−オキソ−１−オキサ−３，８−ジアザスピロ［４．５］デカン−８−カルボン酸ｔ−ブチルの製造
参考例３７１−１で得られた２−（メトキシメトキシ）−４−メチル安息香酸メチル（４８０ｍｇ、２．３ｍｍｏｌ）をクロロホルム（５．０ｍＬ）に溶解し、８０℃に加熱した後、Ｎ−ブロモスクシンイミド（５３４ｍｇ、３．０ｍｍｏｌ）とアゾビスイソブチロニトリル（７５ｍｇ、０．４６ｍｍｏｌ）を加え、８０℃で３時間かき混ぜた。室温まで冷却した後、飽和炭酸水素ナトリウム水溶液（１０ｍＬ）とクロロホルム（１０ｍＬ）を加え、有機層を分離し、無水硫酸マグネシウムで乾燥し、減圧下濃縮した。得られた残留物をシリカゲルカラムクロマトグラフィー［充填剤：Ｍｅｒｃｋ ＧＭＢＨ製シリカゲル６０（０．０４０−０．０６３ｍｍ）、展開溶媒：ヘキサン／酢酸エチル＝５／１］にて精製し、無色油状物（６９４ｍｇ）を得た。
参考例１１１−１で得られた２−オキソ−１−オキサ−３，８−ジアザスピロ［４．５］デカン−８−カルボン酸ｔ−ブチル（５９１ｍｇ、２．３ｍｍｏｌ）をＮ，Ｎ−ジメチルホルムアミド（６．０ｍＬ）に溶かし、ナトリウムｔ−ブトキシド（２２２ｍｇ、２．３ｍｍｏｌ）を加えて３０分撹拌した後、先に得られた無色油状物（６９４ｍｇ）をＮ，Ｎ−ジメチルホルムアミド（４．０ｍＬ）に溶かして加え、２時間かき混ぜた。その後、水と酢酸エチルを加えて有機層を分離し、飽和食塩水で３回洗浄し、無水硫酸マグネシウムで乾燥した後、減圧下濃縮し、得られた残留物をシリカゲルカラムクロマトグラフィー［充填剤：Ｍｅｒｃｋ ＧＭＢＨ製シリカゲル６０（０．０４０−０．０６３ｍｍ）、展開溶媒：ヘキサン／酢酸エチル＝１／１］にて精製することにより、表題化合物（５４２ｍｇ、５１％）を無色油状物として得た。

^１Ｈ−ＮＭＲ（３００ＭＨｚ，ＣＤＣｌ_３）δ：１．４５（９Ｈ，ｓ），１．５８−１．６９（２Ｈ，ｍ），１．８８（２Ｈ，ｄ，Ｊ＝１３．５Ｈｚ），３．１５（２Ｈ，ｓ），３．２９（２Ｈ，ｔ，Ｊ＝１１．１Ｈｚ），３．５１（３Ｈ，ｓ），３．８１（２Ｈ，ｄ，Ｊ＝１２．３Ｈｚ），３．９０（３Ｈ，ｓ），４．４５（２Ｈ，ｓ），５．２５（２Ｈ，ｓ），６．９４（１Ｈ，ｄｄ，Ｊ＝７．８，１．６Ｈｚ），７．０７（１Ｈ，ｄ，Ｊ＝１．２Ｈｚ），７．７７（１Ｈ，ｄ，Ｊ＝８．２Ｈｚ）．

ＬＣ／ＭＳ［条件１］：保持時間４．０９分；ｍ／ｚ４８６．８［Ｍ＋Ｎａ］^＋（ＥＳＩ正イオンモード）

Reference Example 371-2
Reference example for production of t-butyl 3- [4- (methoxycarbonyl) -3- (methoxymethoxy) benzyl] -2-oxo-1-oxa-3,8-diazaspiro [4.5] decane-8-carboxylate Methyl 2- (methoxymethoxy) -4-methylbenzoate (480 mg, 2.3 mmol) obtained in 371-1 was dissolved in chloroform (5.0 mL), heated to 80 ° C., and then N-bromosuccinimide ( 534 mg, 3.0 mmol) and azobisisobutyronitrile (75 mg, 0.46 mmol) were added, and the mixture was stirred at 80 ° C. for 3 hours. After cooling to room temperature, saturated aqueous sodium hydrogen carbonate solution (10 mL) and chloroform (10 mL) were added, the organic layer was separated, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography [filler: silica gel 60 (0.040-0.063 mm) manufactured by Merck GMBH, developing solvent: hexane / ethyl acetate = 5/1], and colorless oil ( 694 mg) was obtained.
2-Oxo-1-oxa-3,8-diazaspiro [4.5] decane-8-carboxylate t-butyl (591 mg, 2.3 mmol) obtained in Reference Example 111-1 was replaced with N, N-dimethylformamide. (6.0 mL), sodium t-butoxide (222 mg, 2.3 mmol) was added, and the mixture was stirred for 30 min. The colorless oil (694 mg) obtained above was then added to N, N-dimethylformamide (4.0 mL). And dissolved for 2 hours. Thereafter, water and ethyl acetate were added to separate the organic layer, washed with saturated brine three times, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography [filler The title compound (542 mg, 51%) was obtained as a colorless oil by purification with silica gel 60 (0.040-0.063 mm) manufactured by Merck GMBH, developing solvent: hexane / ethyl acetate = 1/1. .

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.45 (9H, s), 1.58-1.69 (2H, m), 1.88 (2H, d, J = 13.5 Hz), 3 .15 (2H, s), 3.29 (2H, t, J = 11.1 Hz), 3.51 (3H, s), 3.81 (2H, d, J = 12.3 Hz), 3.90 (3H, s), 4.45 (2H, s), 5.25 (2H, s), 6.94 (1H, dd, J = 7.8, 1.6 Hz), 7.07 (1H, d , J = 1.2 Hz), 7.77 (1H, d, J = 8.2 Hz).

LC / MS [Condition 1]: Retention time 4.09 minutes; m / z 486.8 [M + Na] ⁺ (ESI positive ion mode)

参考例３７１−３
２−ヒドロキシ−４−［（２−オキソ−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル）メチル］安息香酸メチル 塩酸塩の製造
参考例３７１−２で得られた３−［４−（メトキシカルボニル）−３−（メトキシメトキシ）ベンジル］−２−オキソ−１−オキサ−３，８−ジアザスピロ［４．５］デカン−８−カルボン酸ｔ−ブチル（５４２ｍｇ、０．０２９ｍｍｏｌ）をメタノール（５．０ｍＬ）に溶解し、４Ｍ塩化水素−ジオキサン溶液（２．０ｍＬ）を加えて室温で２時間かき混ぜた。その後、ろ過して得られた固体を１，４−ジオキサンで３回洗浄、減圧下乾固し、表題化合物（２２５ｍｇ、収率５４％）を白色固体として得た。

^１Ｈ−ＮＭＲ（３００ＭＨｚ，ＣＤＣｌ_３）δ：２．０６（２Ｈ，ｄ，Ｊ＝１３．５Ｈｚ），２．１７−２．３１（２Ｈ，ｍ），３．２３（２Ｈ，ｓ），３．２８（２Ｈ，ｔ，Ｊ＝１０．２Ｈｚ），３．４５（２Ｈ，ｄ，Ｊ＝１１．９Ｈｚ），３．９６（３Ｈ，ｓ），４．４０（２Ｈ，ｓ），６．７７（１Ｈ，ｄｄ，Ｊ＝８．２，１．６Ｈｚ），６．８４（１Ｈ，ｄ，Ｊ＝１．２Ｈｚ），７．８３（１Ｈ，ｄ，Ｊ＝８．２Ｈｚ），９．７６（２Ｈ，ｂｒｓ），１０．８２（１Ｈ，ｓ）．

ＬＣ／ＭＳ［条件１］：保持時間０．７４分；ｍ／ｚ３２１．０［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）

Reference Example 371-3
Preparation of 2-hydroxy-4-[(2-oxo-1-oxa-3,8-diazaspiro [4.5] decan-3-yl) methyl] benzoic acid hydrochloride Obtained in Reference Example 371-2 3- [4- (methoxycarbonyl) -3- (methoxymethoxy) benzyl] -2-oxo-1-oxa-3,8-diazaspiro [4.5] decane-8-carboxylate t-butyl (542 mg, 0 0.029 mmol) was dissolved in methanol (5.0 mL), 4M hydrogen chloride-dioxane solution (2.0 mL) was added, and the mixture was stirred at room temperature for 2 hr. Thereafter, the solid obtained by filtration was washed with 1,4-dioxane three times and dried under reduced pressure to obtain the title compound (225 mg, yield 54%) as a white solid.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 2.06 (2H, d, J = 13.5 Hz), 2.17-2.31 (2H, m), 3.23 (2H, s), 3 .28 (2H, t, J = 10.2 Hz), 3.45 (2H, d, J = 11.9 Hz), 3.96 (3H, s), 4.40 (2H, s), 6.77 (1H, dd, J = 8.2, 1.6 Hz), 6.84 (1H, d, J = 1.2 Hz), 7.83 (1H, d, J = 8.2 Hz), 9.76 ( 2H, brs), 10.82 (1H, s).

LC / MS [Condition 1]: Retention time 0.74 minutes; m / z 321.0 [M + H] ⁺ (ESI positive ion mode)

参考例３７１−４
２−ヒドロキシ−４−（｛２−オキソ−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）安息香酸メチルの製造
参考例３７１−３で得られた２−ヒドロキシ−４−［（２−オキソ−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル）メチル］安息香酸メチル 塩酸塩（１１０ｍｇ、０．３６ｍｍｏｌ）をＮ，Ｎ−ジメチルホルムアミド（３．０ｍＬ）に懸濁し、トリエチルアミン（０．１５ｍＬ、１．１ｍｍｏｌ）と４−（トリフルオロメチル）ベンジルブロミド（１００ｍｇ、０．４３ｍｍｏｌ）を加え、室温で２時間かき混ぜた。水と酢酸エチルを加えて有機層を分離し、有機層を飽和食塩水で洗浄した。有機層を無水硫酸ナトリウムで乾燥し、減圧下濃縮した。得られた残留物をシリカゲルカラムクロマトグラフィー［充填剤：富士シリシア社製アミンシリカＮＨ−ＤＭ１０２０、展開溶媒：ヘキサン／酢酸エチル＝１／１］にて精製し、表題化合物（１４２ｍｇ、収率８２％）を白色固体として得た。

^１Ｈ−ＮＭＲ（３００ＭＨｚ，ＣＤＣｌ_３）δ：１．６８−１．８０（２Ｈ，ｍ），１．９３（２Ｈ，ｄ，Ｊ＝１３．１Ｈｚ），２．４８−２．６２（４Ｈ，ｍ），３．１５（２Ｈ，ｓ），３．５６（２Ｈ，ｓ），３．９５（３Ｈ，ｓ），４．４０（２Ｈ，ｓ），６．８０（１Ｈ，ｄｄ，Ｊ＝８．２，１．６Ｈｚ），６．８５（１Ｈ，ｄ，Ｊ＝１．６Ｈｚ），７．４２（２Ｈ，ｄ，Ｊ＝７．８Ｈｚ），７．５６（２Ｈ，ｄ，Ｊ＝７．８Ｈｚ），７．８２（１Ｈ，ｄ，Ｊ＝８．２Ｈｚ），１０．８１（１Ｈ，ｓ）．

ＬＣ／ＭＳ［条件１］：保持時間３．１０分；ｍ／ｚ４７８．８［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ４７７．０［Ｍ−Ｈ］^―（ＥＳＩ負イオンモード）

Reference Example 371-4
2-hydroxy-4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl) methyl benzoate of reference example 2-hydroxy obtained in 371-3 4 - [(2-oxo-1-oxa-3,8-diazaspiro [4.5] decan-3-yl) methyl] benzoate hydrochloride (110 mg, 0.36 mmol) was suspended in N, N-dimethylformamide (3.0 mL) and triethylamine (0.15 mL, 1.1 mmol) and 4- (trifluoromethyl) benzyl bromide (100 mg, 0.43 mmol). And stirred at room temperature for 2 hours. Water and ethyl acetate were added to separate the organic layer, and the organic layer was washed with saturated brine. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography [filler: amine silica NH-DM1020 manufactured by Fuji Silysia Ltd., developing solvent: hexane / ethyl acetate = 1/1], and the title compound (142 mg, yield 82%). Was obtained as a white solid.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.68-1.80 (2H, m), 1.93 (2H, d, J = 13.1 Hz), 2.48-2.62 (4H, m), 3.15 (2H, s), 3.56 (2H, s), 3.95 (3H, s), 4.40 (2H, s), 6.80 (1H, dd, J = 8) .2, 1.6 Hz), 6.85 (1H, d, J = 1.6 Hz), 7.42 (2H, d, J = 7.8 Hz), 7.56 (2H, d, J = 7. 8 Hz), 7.82 (1 H, d, J = 8.2 Hz), 10.81 (1 H, s).

LC / MS [Condition 1]: Retention time 3.10 minutes; m / z 478.8 [M + H] ⁺ (ESI positive ion mode), m / z 477.0 [M−H] ⁻ (ESI negative ion mode)

参考例３７１−５
２−ヒドロキシ−４−（｛２−オキソ−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）安息香酸の製造
参考例３７１−４で得られた２−ヒドロキシ−４−（｛２−オキソ−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）安息香酸メチル（８８ｍｇ、０．１８ｍｍｏｌ）をメタノール（５．０ｍＬ）に懸濁し、５０℃に加熱して溶解した後、１Ｍ水酸化ナトリウム水溶液（１．５ｍＬ、１．５ｍｍｏｌ）を加え５０℃で２時間、６０℃で１５時間、室温で１６時間かき混ぜた。その後、１Ｍ塩酸（１．５ｍＬ、１．５ｍｍｏｌ）と水（４．０ｍＬ）を加え、ろ過して得られた固体を減圧下乾燥し、表題化合物（１２２ｍｇ、収率９０％）を白色固体として得た。

^１Ｈ−ＮＭＲ（３００ＭＨｚ，ＣＤ_３ＯＤ）δ：１．８２−１．９６（２Ｈ，ｍ），２．０３（２Ｈ，ｄ，Ｊ＝１４．３Ｈｚ），２．８２−２．９８（４Ｈ，ｍ），３．９８（２Ｈ，ｓ），４．３８（２Ｈ，ｓ），６．７４（２Ｈ，ｄ，Ｊ＝９．４Ｈｚ），７．６１（２Ｈ，ｄ，Ｊ＝８．６Ｈｚ），７．７０（２Ｈ，ｄ，Ｊ＝８．６Ｈｚ），７．８３（１Ｈ，ｄ，Ｊ＝７．８Ｈｚ）．

ＬＣ／ＭＳ［条件１］：保持時間２．８８分；ｍ／ｚ４６４．８［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ４６２．９［Ｍ−Ｈ］^―（ＥＳＩ負イオンモード）

Reference Example 371-5
Of 2-hydroxy-4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl) benzoic acid 2-hydroxy-4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decane obtained in Preparation Reference Example 371-4 -3-yl} methyl) methyl benzoate (88 mg, 0.18 mmol) was suspended in methanol (5.0 mL), dissolved by heating to 50 ° C., and then 1M aqueous sodium hydroxide solution (1.5 mL, 1. mL). 5 mmol) was added, and the mixture was stirred at 50 ° C. for 2 hours, at 60 ° C. for 15 hours, and at room temperature for 16 hours. Thereafter, 1M hydrochloric acid (1.5 mL, 1.5 mmol) and water (4.0 mL) were added, and the solid obtained by filtration was dried under reduced pressure to give the title compound (122 mg, 90% yield) as a white solid. Obtained.

¹ H-NMR (300 MHz, CD ₃ OD) δ: 1.82-1.96 (2H, m), 2.03 (2H, d, J = 14.3 Hz), 2.82-2.98 (4H M), 3.98 (2H, s), 4.38 (2H, s), 6.74 (2H, d, J = 9.4 Hz), 7.61 (2H, d, J = 8.6 Hz). ), 7.70 (2H, d, J = 8.6 Hz), 7.83 (1H, d, J = 7.8 Hz).

LC / MS [Condition 1]: Retention time 2.88 minutes; m / z 464.8 [M + H] ⁺ (ESI positive ion mode), m / z 462.9 [M−H] ⁻ (ESI negative ion mode)

実施例３７１
４−［２−ヒドロキシ−４−（｛２−オキソ−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）ベンゾイル］ピペラジン−１−カルボン酸エチル（化合物番号３７１）の製造
参考例３７１−５で得られた２−ヒドロキシ−４−（｛２−オキソ−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）安息香酸（２０ｍｇ、０．０４３ｍｍｏｌ）、１−ピペラジンカルボン酸エチルエステル（０．００７５ｍＬ、０．０５２ｍｍｏｌ）と１−ヒドロキシベンゾトリアゾール（１．７ｍｇ、０．０３１ｍｍｏｌ）をクロロホルム（１．０ｍＬ）に溶解した後、１−エチル−３−（３−ジメチルアミノプロピル）カルボジイミド塩酸塩（１３ｍｇ、０．０６８ｍｍｏｌ）を加えて、室温で８４時間かき混ぜた。反応終了後、水とクエン酸（６ｍｇ、０．０３１ｍｍｏｌ）を加えて有機層を分離し、減圧下濃縮した後、酢酸エチル、水と炭酸水素ナトリウムを加え、有機層を分離した。有機層を無水硫酸ナトリウムで乾燥した後、減圧下濃縮した。得られた残留物を薄層クロマトグラフィー［富士シリシア社製ＰＬＣ０５ Ｐｌａｔｅ ＮＨ、展開溶媒：酢酸エチル／メタノール＝２５／１］にて精製し、表題化合物（８．５ｍｇ、収率３３％）を白色固体として得た。

^１Ｈ−ＮＭＲ（３００ＭＨｚ，ＣＤＣｌ_３）δ：１．２９（３Ｈ，ｔ，Ｊ＝６．９Ｈｚ），１．７５（２Ｈ，ｄｔ，Ｊ＝１１．１，６．６Ｈｚ），１．９４（２Ｈ，ｄ，Ｊ＝１３．９Ｈｚ），２．４７−２．６４（４Ｈ，ｍ），３．１８（２Ｈ，ｓ），３．５１−３．６２（６Ｈ，ｍ），３．６７−３．７７（４Ｈ，ｍ），４．１８（２Ｈ，ｑ，Ｊ＝６．９Ｈｚ），４．３９（２Ｈ，ｓ），６．７９（１Ｈ，ｄｄ，Ｊ＝７．９，１．３Ｈｚ），６．９０（１Ｈ，ｄ，Ｊ＝１．３Ｈｚ），７．２２（１Ｈ，ｄ，Ｊ＝７．９Ｈｚ），７．４３（２Ｈ，ｄ，Ｊ＝７．９Ｈｚ），７．５７（２Ｈ，ｄ，Ｊ＝８．１Ｈｚ），９．６５（１Ｈ，ｂｒｓ）．

ＬＣ／ＭＳ［条件１］：保持時間３．０６分；ｍ／ｚ６０４．６［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ６０２．９［Ｍ−Ｈ］^―（ＥＳＩ負イオンモード）

Example 371
4- [2-hydroxy-4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl) Preparation of Ethyl benzoyl] piperazine-1-carboxylate (Compound No. 371) 2-Hydroxy-4-({2-oxo-8- [4- (trifluoromethyl) benzyl]-obtained in Reference Example 371-5 1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl) benzoic acid (20 mg, 0.043 mmol), 1-piperazinecarboxylic acid ethyl ester (0.0075 mL, 0.052 mmol) and 1 -Hydroxybenzotriazole (1.7 mg, 0.031 mmol) was dissolved in chloroform (1.0 mL) and 1-ethyl-3- (3-dimethylaminopropyl) was dissolved. Pills) carbodiimide hydrochloride (13 mg, 0.068 mmol) was added and stirred for 84 hours at room temperature. After completion of the reaction, water and citric acid (6 mg, 0.031 mmol) were added to separate the organic layer. After concentration under reduced pressure, ethyl acetate, water and sodium bicarbonate were added to separate the organic layer. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained residue was purified by thin layer chromatography [PLC05 Plate NH, manufactured by Fuji Silysia Ltd., developing solvent: ethyl acetate / methanol = 25/1], and the title compound (8.5 mg, yield 33%) was white. Obtained as a solid.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.29 (3H, t, J = 6.9 Hz), 1.75 (2H, dt, J = 11.1, 6.6 Hz), 1.94 ( 2H, d, J = 13.9 Hz), 2.47-2.64 (4H, m), 3.18 (2H, s), 3.51-3.62 (6H, m), 3.67- 3.77 (4H, m), 4.18 (2H, q, J = 6.9 Hz), 4.39 (2H, s), 6.79 (1H, dd, J = 7.9, 1.3 Hz) ), 6.90 (1H, d, J = 1.3 Hz), 7.22 (1H, d, J = 7.9 Hz), 7.43 (2H, d, J = 7.9 Hz), 7.57 (2H, d, J = 8.1 Hz), 9.65 (1H, brs).

LC / MS [Condition 1]: Retention time 3.06 minutes; m / z 604.6 [M + H] ⁺ (ESI positive ion mode), m / z 602.9 [M−H] ⁻ (ESI negative ion mode)

実施例３７２
３−｛４−［４−（６−クロロピリミジン−４−イル）ピペラジン−１−カルボニル］−３−ヒドロキシベンジル｝−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−２−オン（化合物番号３７２）の製造
１−ピペラジンカルボン酸エチルエステルの代わりに参考例２８８で得られた４−クロロ−６−（ピペラジン−１−イル）ピリミジン二塩酸塩を用いること以外は実質的に実施例３７１と同様に反応を行なって、表題化合物（１１ｍｇ、収率４１％）を白色固体として得た。

^１Ｈ−ＮＭＲ（３００ＭＨｚ，ＣＤＣｌ_３）δ：１．７６（２Ｈ，ｄｔ，Ｊ＝１３．２，６．９Ｈｚ），１．９４（２Ｈ，ｄ，Ｊ＝１２．９Ｈｚ），２．５０−２．６１（４Ｈ，ｍ），３．１９（２Ｈ，ｓ），３．５７（２Ｈ，ｓ），３．７３−３．８１（４Ｈ，ｍ），３．８１−３．９０（４Ｈ，ｍ），４．４１（２Ｈ，ｓ），６．５４（１Ｈ，ｄ，Ｊ＝０．７Ｈｚ），６．８１（１Ｈ，ｄｄ，Ｊ＝７．９，１．７Ｈｚ），６．９１（１Ｈ，ｄ，Ｊ＝１．７Ｈｚ），７．４３（２Ｈ，ｄ，Ｊ＝７．９Ｈｚ），７．５７（２Ｈ，ｄ，Ｊ＝７．９Ｈｚ），８．４２（１Ｈ，ｄ，Ｊ＝０．７Ｈｚ），９．６８（１Ｈ，ｂｒｓ）．

ＬＣ／ＭＳ［条件１］：保持時間３．０８分；ｍ／ｚ６４４．９［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ６４２．９［Ｍ−Ｈ］^―（ＥＳＩ負イオンモード）

Example 372
3- {4- [4- (6-Chloropyrimidin-4-yl) piperazine-1-carbonyl] -3-hydroxybenzyl} -8- [4- (trifluoromethyl) benzyl] -1-oxa-3, Preparation of 8-diazaspiro [4.5] decan-2-one (Compound No. 372) 4-chloro-6- (piperazin-1-yl) obtained in Reference Example 288 instead of 1-piperazinecarboxylic acid ethyl ester The reaction was carried out substantially in the same manner as in Example 371 except that pyrimidine dihydrochloride was used to obtain the title compound (11 mg, yield 41%) as a white solid.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.76 (2H, dt, J = 13.2, 6.9 Hz), 1.94 (2H, d, J = 12.9 Hz), 2.50− 2.61 (4H, m), 3.19 (2H, s), 3.57 (2H, s), 3.73-3.81 (4H, m), 3.81-3.90 (4H, m), 4.41 (2H, s), 6.54 (1H, d, J = 0.7 Hz), 6.81 (1H, dd, J = 7.9, 1.7 Hz), 6.91 ( 1H, d, J = 1.7 Hz), 7.43 (2H, d, J = 7.9 Hz), 7.57 (2H, d, J = 7.9 Hz), 8.42 (1H, d, J = 0.7 Hz), 9.68 (1H, brs).

LC / MS [Condition 1]: Retention time 3.08 minutes; m / z 644.9 [M + H] ⁺ (ESI positive ion mode), m / z 642.9 [M−H] ⁻ (ESI negative ion mode)

実施例３７３
２−ヒドロキシ−４−（｛２−オキソ−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）−Ｎ−［（テトラヒドロフラン−２−イル）メチル］ベンズアミド（化合物番号３７３）の製造
１−ピペラジンカルボン酸エチルエステルの代わりにテトラヒドロフルフリルアミンを用いること以外は実質的に実施例３７１と同様に反応を行なって、表題化合物（２５ｍｇ、収率定量的）を白色固体として得た。

^１Ｈ−ＮＭＲ（３００ＭＨｚ，ＣＤＣｌ_３）δ：１．７３（２Ｈ，ｄｔ，Ｊ＝１３．５，６．９Ｈｚ），１．６７−１．８０（２Ｈ，ｍ），１．８７−２．１２（５Ｈ，ｍ），２．４７−２．６１（４Ｈ，ｍ），３．１５（２Ｈ，ｓ），３．３１（１Ｈ，ｄｄｄ，Ｊ＝１３．９，７．９，４．６Ｈｚ），３．５６（２Ｈ，ｓ），３．７４−３．８４（２Ｈ，ｍ），３．９０（１Ｈ，ｄｔ，Ｊ＝８．６，６．６Ｈｚ），４．０７（１Ｈ，ｄｑ，Ｊ＝３．０，７．３Ｈｚ），４．３８（２Ｈ，ｓ），６．６６（１Ｈ，ｔ，Ｊ＝５．９Ｈｚ），６．７７（１Ｈ，ｄｄ，Ｊ＝８．３，１．７Ｈｚ），６．８４（１Ｈ，ｄ，Ｊ＝１．３Ｈｚ），７．３７（１Ｈ，ｄ，Ｊ＝８．３Ｈｚ），７．４３（２Ｈ，ｄ，Ｊ＝７．９Ｈｚ），７．５６（２Ｈ，ｄ，Ｊ＝８．３Ｈｚ），１２．４５（１Ｈ，ｓ）．

ＬＣ／ＭＳ［条件１］：保持時間３．０６分；ｍ／ｚ５４７．７［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ５４５．９［Ｍ−Ｈ］^―（ＥＳＩ負イオンモード）

Example 373
2-hydroxy-4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl) -N- Preparation of [(tetrahydrofuran-2-yl) methyl] benzamide (Compound No. 373) The reaction was carried out in substantially the same manner as in Example 371 except that tetrahydrofurfurylamine was used instead of 1-piperazinecarboxylic acid ethyl ester. The title compound (25 mg, quantitative yield) was obtained as a white solid.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.73 (2H, dt, J = 13.5, 6.9 Hz), 1.67-1.80 (2H, m), 1.87-2. 12 (5H, m), 2.47-2.61 (4H, m), 3.15 (2H, s), 3.31 (1H, ddd, J = 13.9, 7.9, 4.6 Hz) ), 3.56 (2H, s), 3.74-3.84 (2H, m), 3.90 (1H, dt, J = 8.6, 6.6 Hz), 4.07 (1H, dq) , J = 3.0, 7.3 Hz), 4.38 (2H, s), 6.66 (1H, t, J = 5.9 Hz), 6.77 (1H, dd, J = 8.3). 1.7 Hz), 6.84 (1H, d, J = 1.3 Hz), 7.37 (1H, d, J = 8.3 Hz), 7.43 (2H, d, J = 7.9 Hz), 7.56 (2H, d, = 8.3Hz), 12.45 (1H, s).

LC / MS [Condition 1]: Retention time 3.06 minutes; m / z 547.7 [M + H] ⁺ (ESI positive ion mode), m / z 545.9 [M−H] ⁻ (ESI negative ion mode)

実施例３７４
４−［２−ヒドロキシ−４−（｛２−オキソ−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）ベンゾイル］−１，４−ジアゼパン−１−カルボン酸メチル（化合物番号３７４）の製造
１−ピペラジンカルボン酸エチルエステルの代わりに参考例３４９で得られた１，４−ジアゼパン−１−カルボン酸メチル塩酸塩を用いること以外は実質的に実施例３７１と同様に反応を行なって、表題化合物（９．９ｍｇ、収率３８％）を淡黄色固体として得た。

^１Ｈ−ＮＭＲ（３００ＭＨｚ，ＣＤＣｌ_３）δ：１．７１−２．０３（６Ｈ，ｍ），２．５０−２．６４（４Ｈ，ｍ），３．１８（２Ｈ，ｓ），３．４７−３．８５（１３Ｈ，ｍ），４．３８（２Ｈ，ｓ），６．７８（１Ｈ，ｄ，Ｊ＝７．６Ｈｚ），６．８８（１Ｈ，ｓ），７．２５−７．３２（１Ｈ，ｍ），７．４３（２Ｈ，ｄ，Ｊ＝７．６Ｈｚ），７．５７（２Ｈ，ｄ，Ｊ＝８．９Ｈｚ），９．４７（１Ｈ，ｂｒｓ）．

ＬＣ／ＭＳ［条件１］：保持時間２．８８分；ｍ／ｚ６０４．７［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ６０３．０［Ｍ−Ｈ］^―（ＥＳＩ負イオンモード）

Example 374
4- [2-hydroxy-4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl) Preparation of methyl benzoyl] -1,4-diazepane-1-carboxylate (Compound No. 374) 1,4-diazepane-1-carboxylate methyl hydrochloride obtained in Reference Example 349 instead of 1-piperazinecarboxylic acid ethyl ester The reaction was carried out in substantially the same manner as in Example 371 except that the salt was used to give the title compound (9.9 mg, yield 38%) as a pale yellow solid.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.71-2.03 (6H, m), 2.50-2.64 (4H, m), 3.18 (2H, s), 3.47 -3.85 (13H, m), 4.38 (2H, s), 6.78 (1H, d, J = 7.6 Hz), 6.88 (1H, s), 7.25-7.32. (1H, m), 7.43 (2H, d, J = 7.6 Hz), 7.57 (2H, d, J = 8.9 Hz), 9.47 (1H, brs).

LC / MS [Condition 1]: Retention time 2.88 minutes; m / z 604.7 [M + H] ⁺ (ESI positive ion mode), m / z 603.0 [M−H] ⁻ (ESI negative ion mode)

参考例３７５−１
３−｛４−［４−（４−フルオロベンゾイル）ピペリジン−１−カルボニル］ベンジル｝−２−オキソ−１−オキサ−３，８−ジアザスピロ［４．５］デカン−８−カルボン酸ｔ−ブチルの製造
（１ｒ，４ｒ）−４−｛［８−（ｔ−ブトキシカルボニル）−２−オキソ−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル］メチル｝シクロヘキサンカルボン酸の代わりに参考例１５８で得られた４−｛［８−（ｔ−ブトキシカルボニル）−２−オキソ−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル］メチル｝安息香酸を用いることと、テトラヒドロフルフリルアミンの代わりに（４−フルオロフェニル）（ピペリジン−４−イル）メタノン塩酸塩（市販）とトリエチルアミンを用いること以外は実質的に実施例２と同様に反応を行って表題化合物（１．５ｇ、収率９２％）を白色粉末で得た。

^１Ｈ−ＮＭＲ（ＣＤＣｌ_３）δ：１．４５（９Ｈ，ｓ），１．５４−１．６７（２Ｈ，ｍ），１．７１−２．０９（６Ｈ，ｂｒ ｍ），２．９７−３．２２（２Ｈ，ｍ），３．１４（２Ｈ，ｓ），３．２８（２Ｈ，ｔ，Ｊ＝１１．１Ｈｚ），３．４３−３．６０（１Ｈ，ｍ），３．７４−３．９４（１Ｈ，ｂｒ ｍ），３．８１（２Ｈ，ｄ，Ｊ＝１１．５Ｈｚ），４．４６（２Ｈ，ｓ），４．５２−４．７８（１Ｈ，ｂｒ ｍ），７．１６（２Ｈ，ｔ，Ｊ＝８．６Ｈｚ），７．３１（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ），７．４２（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ），７．９９（２Ｈ，ｄｄ，Ｊ＝８．６，５．３Ｈｚ）．

ＬＣ／ＭＳ［条件１］：保持時間４．３７分；ｍ／ｚ５７９．７［Ｍ＋Ｈ］^＋、５２３．７［Ｍ−ｉｓｏｂｕｔｅｎｅ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ６２４．０［Ｍ＋ＨＣＯＯ］⁻（ＥＳＩ負イオンモード）

Reference Example 375-1
3- {4- [4- (4-Fluorobenzoyl) piperidine-1-carbonyl] benzyl} -2-oxo-1-oxa-3,8-diazaspiro [4.5] decane-8-carboxylate t-butyl manufacturing (1r, 4r) -4 - { [8- (t- butoxycarbonyl) -2-oxo-1-oxa-3,8-diazaspiro [4.5] decan-3-yl] methyl} cyclohexanecarboxylic acid 4-{[8- (t-butoxycarbonyl) -2-oxo-1-oxa-3,8-diazaspiro [4.5] decan-3-yl] methyl} benzoic acid obtained in Reference Example 158 instead of Substantially implemented except using acid and (4-fluorophenyl) (piperidin-4-yl) methanone hydrochloride (commercially available) and triethylamine instead of tetrahydrofurfurylamine The title compound by performing the reaction as in 2 (1.5 g, 92% yield) as a white powder.

¹ H-NMR (CDCl ₃ ) δ: 1.45 (9H, s), 1.54-1.67 (2H, m), 1.71-2.09 (6H, br m), 2.97- 3.22 (2H, m), 3.14 (2H, s), 3.28 (2H, t, J = 11.1 Hz), 3.43-3.60 (1H, m), 3.74- 3.94 (1H, br m), 3.81 (2H, d, J = 11.5 Hz), 4.46 (2H, s), 4.52-4.78 (1 H, br m), 7. 16 (2H, t, J = 8.6 Hz), 7.31 (2H, d, J = 8.2 Hz), 7.42 (2H, d, J = 8.2 Hz), 7.99 (2H, dd) , J = 8.6, 5.3 Hz).

LC / MS [Condition 1]: Retention time 4.37 minutes; m / z 579.7 [M + H] ⁺ , 523.7 [M-isobutene + H] ⁺ (ESI positive ion mode), m / z 624.0 [M + HCOO] ⁻ (ESI negative ion mode)

参考例３７５−２
３−｛４−［４−（４−フルオロベンゾイル）ピペリジン−１−カルボニル］ベンジル｝−１−オキサ−３，８−ジアザスピロ［４．５］デカン−２−オン塩酸塩の製造
２−オキソ−３−［（（１ｒ，４ｒ）−４−｛［（テトラヒドロフラン−２−イル）メチル］カルバモイル｝シクロヘキシル）メチル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−８−カルボン酸ｔ−ブチルの代わりに、参考例３７５−１で得られた３−｛４−［４−（４−フルオロベンゾイル）ピペリジン−１−カルボニル］ベンジル｝−２−オキソ−１−オキサ−３，８−ジアザスピロ［４．５］デカン−８−カルボン酸ｔ−ブチルを用いること以外は実質的に実施例３と同様に反応を行って表題化合物（１．５ｇ、定量的）を白色粉末として得た。

ＬＣ／ＭＳ［条件１］：保持時間２．７３分；ｍ／ｚ４８０．０［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ５１４．０［Ｍ＋Ｃｌ］⁻、５２４．０［Ｍ＋ＨＣＯＯ］⁻（ＥＳＩ負イオンモード）

Reference Example 375-2
Preparation of 3- {4- [4- (4-fluorobenzoyl) piperidine-1-carbonyl] benzyl} -1-oxa-3,8-diazaspiro [4.5] decan-2-one hydrochloride 2-oxo- 3-[((1r, 4r) -4-{[(tetrahydrofuran-2-yl) methyl] carbamoyl} cyclohexyl) methyl] -1-oxa-3,8-diazaspiro [4.5] decane-8-carboxylic acid Instead of t-butyl, 3- {4- [4- (4-fluorobenzoyl) piperidine-1-carbonyl] benzyl} -2-oxo-1-oxa-3,8 obtained in Reference Example 375-1 -The reaction was carried out in substantially the same manner as in Example 3 except that t-butyl diazaspiro [4.5] decane-8-carboxylate was used to obtain the title compound (1.5 g, quantitative) as a white powder. .

LC / MS [Condition 1]: Retention time 2.73 minutes; m / z 480.0 [M + H] ⁺ (ESI positive ion mode), m / z 514.0 [M + Cl] ⁻ , 524.0 [M + HCOO] ⁻ (ESI Negative ion mode)

実施例３７５
３−｛４−［４−（４−フルオロベンゾイル）ピペリジン−１−カルボニル］ベンジル｝−８−［４−（トリフルオロメチルチオ）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−２−オン （化合物番号３７５）の製造
（１ｒ，４ｒ）−４−［（２−オキソ−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル）メチル］−Ｎ−［（テトラヒドロフラン−２−イル）メチル］シクロヘキサンカルボキサミド塩酸塩の代わりに、参考例３７５−２で得られた３−｛４−［４−（４−フルオロベンゾイル）ピペリジン−１−カルボニル］ベンジル｝−１−オキサ−３，８−ジアザスピロ［４．５］デカン−２−オン塩酸塩を用いることと、３−（ブロモメチル）ピリジン臭化水素酸塩の代わりに、［４−（ブロモメチル）フェニル］（トリフルオロメチル）スルファン（市販）を用いること以外は実質的に実施例４と同様に反応を行なって、表題化合物（３５ｍｇ、収率９９％）を白色粉末として得た。

^１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ_６）δ：１．５１（２Ｈ，ｄｑ，Ｊ＝２．９，１１．９Ｈｚ），１．６７−１．９５（６Ｈ，ｍ），２．３２−２．４９（４Ｈ，ｂｒ ｍ），２．８８−３．１０（１Ｈ，ｂｒ ｍ），３．１２−３．３２（２Ｈ，ｂｒ ｍ），３．２３（２Ｈ，ｓ），３．５５（２Ｈ，ｓ），３．５８−３．６９（１Ｈ，ｂｒ ｍ），３．７６（１Ｈ，ｔｔ，Ｊ＝１１．５，３．３Ｈｚ），４．３９（２Ｈ，ｓ），４．４２−４．６１（１Ｈ，ｂｒ ｍ），７．３２（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ），７．３７（２Ｈ，ｔ，Ｊ＝８．６Ｈｚ），７．４０（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ），７．４６（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ），７．６７（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ），８．１０（２Ｈ，ｄｄ，Ｊ＝８．６，４．９Ｈｚ）．

ＬＣ／ＭＳ［条件１］：保持時間３．４８分；ｍ／ｚ６６９．９［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ７０４．０［Ｍ＋Ｃｌ］⁻、７１４．１［Ｍ＋ＨＣＯＯ］⁻（ＥＳＩ負イオンモード）

Example 375
3- {4- [4- (4-Fluorobenzoyl) piperidine-1-carbonyl] benzyl} -8- [4- (trifluoromethylthio) benzyl] -1-oxa-3,8-diazaspiro [4.5] Preparation of decan-2-one (Compound No. 375) (1r, 4r) -4-[(2-oxo-1-oxa-3,8-diazaspiro [4.5] decan-3-yl) methyl] -N 3- [4- [4- (4- (4-Fluorobenzoyl) piperidine-1-carbonyl] benzyl} obtained in Reference Example 375-2 instead of-[(tetrahydrofuran-2-yl) methyl] cyclohexanecarboxamide hydrochloride} Instead of using -1-oxa-3,8-diazaspiro [4.5] decan-2-one hydrochloride, instead of 3- (bromomethyl) pyridine hydrobromide, [4- (bromo The reaction was carried out in substantially the same manner as in Example 4 except that (methyl) phenyl] (trifluoromethyl) sulfane (commercially available) was used to give the title compound (35 mg, yield 99%) as a white powder.

¹ H-NMR (DMSO-d ₆ ) δ: 1.51 (2H, dq, J = 2.9, 11.9 Hz), 1.67-1.95 (6H, m), 2.32-2. 49 (4H, br m), 2.88-3.10 (1H, br m), 3.12-3.32 (2H, br m), 3.23 (2H, s), 3.55 (2H , S), 3.58-3.69 (1H, br m), 3.76 (1H, tt, J = 11.5, 3.3 Hz), 4.39 (2H, s), 4.42- 4.61 (1H, br m), 7.32 (2H, d, J = 8.2 Hz), 7.37 (2H, t, J = 8.6 Hz), 7.40 (2H, d, J = 8.2 Hz), 7.46 (2H, d, J = 8.2 Hz), 7.67 (2H, d, J = 8.2 Hz), 8.10 (2H, dd, J = 8.6, 4 .9 Hz).

LC / MS [Condition 1]: Retention time 3.48 minutes; m / z 669.9 [M + H] ⁺ (ESI positive ion mode), m / z 704.0 [M + Cl] ⁻ , 714.1 [M + HCOO] ⁻ (ESI Negative ion mode)

実施例３７６
３−｛４−［４−（４−フルオロベンゾイル）ピペリジン−１−カルボニル］ベンジル｝−８−［４−（トリフルオロメチル）フェネチル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−２−オン（化合物番号３７６）の製造
［４−（ブロモメチル）フェニル］（トリフルオロメチル）スルファンの代わりに、１−（２−ブロモエチル）−４−（トリフルオロメチル）ベンゼン（市販）を用いること以外は実質的に実施例３７５と同様に反応を行なって、表題化合物（１４ｍｇ、収率４２％）を白色粉末として得た。

^１Ｈ−ＮＭＲ（ＣＤＣｌ_３）δ：１．６４−２．０６（８Ｈ，ｍ），２．４９−２．７１（６Ｈ，ｍ），２．７５−２．９１（２Ｈ，ｍ），２．９８−３．２３（２Ｈ，ｍ），３．１５（２Ｈ，ｓ），３．４４−３．６０（１Ｈ，ｍ），３．７２−３．９８（１Ｈ，ｂｒ ｍ），４．４６（２Ｈ，ｓ），４．５７−４．８２（１Ｈ，ｂｒ ｍ），７．１７（２Ｈ，ｔ，Ｊ＝９．０Ｈｚ），７．３０（２Ｈ，ｄ，Ｊ＝７．８Ｈｚ），７．３２（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ），７．４２（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ），７．５３（２Ｈ，ｄ，Ｊ＝７．８Ｈｚ），７．９９（２Ｈ，ｄｄ，Ｊ＝９．０，５．３Ｈｚ）．

ＬＣ／ＭＳ［条件１］：保持時間３．４０分；ｍ／ｚ６５１．８［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ６８６．１［Ｍ＋Ｃｌ］⁻、６９６．０［Ｍ＋ＨＣＯＯ］⁻（ＥＳＩ負イオンモード）

Example 376
3- {4- [4- (4-Fluorobenzoyl) piperidine-1-carbonyl] benzyl} -8- [4- (trifluoromethyl) phenethyl] -1-oxa-3,8-diazaspiro [4.5] Preparation of decan-2-one (Compound No. 376) Instead of [4- (bromomethyl) phenyl] (trifluoromethyl) sulfane, 1- (2-bromoethyl) -4- (trifluoromethyl) benzene (commercially available) The reaction was carried out substantially in the same manner as in Example 375, except that the title compound (14 mg, yield 42%) was obtained as a white powder.

¹ H-NMR (CDCl ₃ ) δ: 1.64-2.06 (8H, m), 2.49-2.71 (6H, m), 2.75-2.91 (2H, m), 2 .98-3.23 (2H, m), 3.15 (2H, s), 3.44-3.60 (1H, m), 3.72-3.98 (1H, br m), 4. 46 (2H, s), 4.57-4.82 (1H, br m), 7.17 (2H, t, J = 9.0 Hz), 7.30 (2H, d, J = 7.8 Hz) , 7.32 (2H, d, J = 8.2 Hz), 7.42 (2H, d, J = 8.2 Hz), 7.53 (2H, d, J = 7.8 Hz), 7.99 ( 2H, dd, J = 9.0, 5.3 Hz).

LC / MS [Condition 1]: retention time 3.40 minutes; m / z 651.8 [M + H] ⁺ (ESI positive ion mode), m / z 686.1 [M + Cl] ⁻ , 696.0 [M + HCOO] ⁻ (ESI Negative ion mode)

実施例３７７
３−［２−（３−｛４−［４−（４−フルオロベンゾイル）ピペリジン−１−カルボニル］ベンジル｝−２−オキソ−１−オキサ−３，８−ジアザスピロ［４．５］デカン−８−イル）アセチル］ベンゾニトリル（化合物番号３７７）の製造
［４−（ブロモメチル）フェニル］（トリフルオロメチル）スルファンの代わりに、３−（２−ブロモアセチル）ベンゾニトリル（市販）を用いること以外は実質的に実施例３７５と同様に反応を行なって、表題化合物（２．２ｍｇ、収率２．０％）を淡黄色無定形物として得た。

^１Ｈ−ＮＭＲ（ＣＤＣｌ_３）δ：１．７１−２．０９（８Ｈ，ｍ），２．５７−２．８１（４Ｈ，ｂｒ ｍ），２．９９−３．２２（２Ｈ，ｍ），３．１６（２Ｈ，ｓ），３．４４−３．６０（１Ｈ，ｍ），３．７５−３．９６（１Ｈ，ｂｒ ｍ），３．８１（２Ｈ，ｓ），４．４６（２Ｈ，ｓ），４．５５−４．８１（１Ｈ，ｂｒ ｍ），７．１７（２Ｈ，ｔ，Ｊ＝８．６Ｈｚ），７．３２（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ），７．４２（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ），７．６１（１Ｈ，ｔ，Ｊ＝７．８Ｈｚ），７．８５（１Ｈ，ｄ，Ｊ＝７．８Ｈｚ），７．９９（２Ｈ，ｄｄ，Ｊ＝８．６，５．３Ｈｚ），８．２２（１Ｈ，ｄ，Ｊ＝７．８Ｈｚ），８．３１（１Ｈ，ｓ）．

ＬＣ／ＭＳ［条件１］：保持時間３．２０分；ｍ／ｚ６２２．９［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ６２１．１［Ｍ−Ｈ］⁻（ＥＳＩ負イオンモード）

Example 377
3- [2- (3- {4- [4- (4-Fluorobenzoyl) piperidine-1-carbonyl] benzyl} -2-oxo-1-oxa-3,8-diazaspiro [4.5] decane-8 Preparation of -yl) acetyl] benzonitrile (Compound No. 377) Except for using 3- (2-bromoacetyl) benzonitrile (commercially available) instead of [4- (bromomethyl) phenyl] (trifluoromethyl) sulfane The reaction was carried out substantially in the same manner as in Example 375 to give the title compound (2.2 mg, yield 2.0%) as a pale yellow amorphous product.

¹ H-NMR (CDCl ₃ ) δ: 1.71-2.09 (8H, m), 2.57-2.81 (4H, br m), 2.99-3.22 (2H, m), 3.16 (2H, s), 3.44-3.60 (1H, m), 3.75-3.96 (1H, br m), 3.81 (2H, s), 4.46 (2H , S), 4.55-4.81 (1H, br m), 7.17 (2H, t, J = 8.6 Hz), 7.32 (2H, d, J = 8.2 Hz), 7. 42 (2H, d, J = 8.2 Hz), 7.61 (1H, t, J = 7.8 Hz), 7.85 (1H, d, J = 7.8 Hz), 7.99 (2H, dd) , J = 8.6, 5.3 Hz), 8.22 (1H, d, J = 7.8 Hz), 8.31 (1H, s).

LC / MS [Condition 1]: Retention time 3.20 minutes; m / z 622.9 [M + H] ⁺ (ESI positive ion mode), m / z 621.1 [M−H] ⁻ (ESI negative ion mode)

参考例３７８
１−（ブロモメチル）−４−（トリフルオロメチルスルフィニル）ベンゼンおよび１−（ブロモメチル）−４−（トリフルオロメチルスルフォニル）ベンゼンの製造
［４−（ブロモメチル）フェニル］（トリフルオロメチル）スルファン（市販）（０．２７ｇ、１．０ｍｍｏｌ）をアセトニトリル（５．０ｍＬ）に溶解し、七モリブデン酸六アンモニウム四水和物（０．１２ｇ、０．１０ｍｍｏｌ）及び３０％過酸化水素水（０．０４１ｍＬ、４．０ｍｍｏｌ）を加えて、室温にて７時間３０分かき混ぜた。反応終了後、チオ硫酸ナトリウム水溶液（４．０ｍＬ）と酢酸エチル（１０ｍＬ）を加えて、有機層を分離した。得られた有機層を無水硫酸ナトリウムで乾燥、減圧下濃縮乾固した後、シリカゲルカラムクロマトグラフィ−［充填剤：富士シリシア製ＦＬ１００Ｄ、展開溶媒：ヘキサン／酢酸エチル＝１０／１→２／１］にて精製し、１−（ブロモメチル）−４−（トリフルオロメチルスルフィニル）ベンゼン（３０ｍｇ、収率１０％）を無色油状物として、１−（ブロモメチル）−４−（トリフルオロメチルスルフォニル）ベンゼンを（４２ｍｇ、収率１４％）を無色油状物として得た。

１−（ブロモメチル）−４−（トリフルオロメチルスルフィニル）ベンゼンのデータ

^１Ｈ−ＮＭＲ（ＣＤＣｌ_３）δ：４．５３（２Ｈ，ｓ），７．６４（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ），７．７８（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ）．

ＬＣ／ＭＳ［条件１］：保持時間４．０７分；ｍ／ｚ２８６．８［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）

１−（ブロモメチル）−４−（トリフルオロメチルスルフォニル）ベンゼンのデータ

^１Ｈ−ＮＭＲ（ＣＤＣｌ_３）δ：４．５３（２Ｈ，ｓ），７．７０（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ），８．０２（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ）．

Reference Example 378
Preparation of 1- (bromomethyl) -4- (trifluoromethylsulfinyl) benzene and 1- (bromomethyl) -4- (trifluoromethylsulfonyl) benzene [4- (bromomethyl) phenyl] (trifluoromethyl) sulfane (commercially available) (0.27 g, 1.0 mmol) dissolved in acetonitrile (5.0 mL), hexamolybdate hexaammonium tetrahydrate (0.12 g, 0.10 mmol) and 30% aqueous hydrogen peroxide (0.041 mL, 4.0 mmol) was added, and the mixture was stirred at room temperature for 7 hours 30 minutes. After completion of the reaction, an aqueous sodium thiosulfate solution (4.0 mL) and ethyl acetate (10 mL) were added, and the organic layer was separated. The obtained organic layer was dried over anhydrous sodium sulfate and concentrated to dryness under reduced pressure, and then silica gel column chromatography [filler: FL100D manufactured by Fuji Silysia, developing solvent: hexane / ethyl acetate = 10/1 → 2/1]. 1- (bromomethyl) -4- (trifluoromethylsulfinyl) benzene (30 mg, 10% yield) as a colorless oil, 1- (bromomethyl) -4- (trifluoromethylsulfonyl) benzene ( 42 mg, 14% yield) was obtained as a colorless oil.

1- (Bromomethyl) -4- (trifluoromethylsulfinyl) benzene data

¹ H-NMR (CDCl ₃ ) δ: 4.53 (2H, s), 7.64 (2H, d, J = 8.2 Hz), 7.78 (2H, d, J = 8.2 Hz).

LC / MS [Condition 1]: Retention time 4.07 minutes; m / z 286.8 [M + H] ⁺ (ESI positive ion mode)

1- (Bromomethyl) -4- (trifluoromethylsulfonyl) benzene data

¹ H-NMR (CDCl ₃ ) δ: 4.53 (2H, s), 7.70 (2H, d, J = 8.2 Hz), 8.02 (2H, d, J = 8.2 Hz).

実施例３７８
３−｛４−［４−（４−フルオロベンゾイル）ピペリジン−１−カルボニル］ベンジル｝−８−［４−（トリフルオロメチルスルフィニル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−２−オン（化合物番号３７８）の製造

［４−（ブロモメチル）フェニル］（トリフルオロメチル）スルファンの代わりに、参考例３７８で得られた１−（ブロモメチル）−４−（トリフルオロメチルスルフィニル）ベンゼンを用いること以外は実質的に実施例３７５と同様に反応を行なって、表題化合物（１２ｍｇ、収率３４％）を淡橙色無定形物として得た。

^１Ｈ−ＮＭＲ（ＣＤＣｌ_３）δ：１．６６−２．０８（８Ｈ，ｍ），２．４８−２．６４（４Ｈ，ｂｒ ｍ），２．９８−３．２２（２Ｈ，ｂｒ ｍ），３．１４（２Ｈ，ｓ），３．４４−３．５８（１Ｈ，ｍ），３．６０（２Ｈ，ｓ），３．７３−３．９６（１Ｈ，ｂｒ ｍ），４．４５（２Ｈ，ｓ），４．５４−４．７９（１Ｈ，ｂｒ ｍ），７．１６（２Ｈ，ｔ，Ｊ＝８．６Ｈｚ），７．３１（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ），７．４２（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ），７．５７（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ），７．７４（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ），７．９９（２Ｈ，ｄｄ，Ｊ＝８．６，５．３Ｈｚ）．

ＬＣ／ＭＳ［条件１］：保持時間３．２６分；ｍ／ｚ６８６．０［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ７２０．２［Ｍ＋Ｃｌ］、７３０．１［Ｍ＋ＨＣＯＯ］⁻（ＥＳＩ負イオンモード）⁻（ＥＳＩ負イオンモード）

Example 378
3- {4- [4- (4-Fluorobenzoyl) piperidine-1-carbonyl] benzyl} -8- [4- (trifluoromethylsulfinyl) benzyl] -1-oxa-3,8-diazaspiro [4.5 Production of decan-2-one (Compound No. 378)

[Examples] Except for using 1- (bromomethyl) -4- (trifluoromethylsulfinyl) benzene obtained in Reference Example 378 in place of [4- (bromomethyl) phenyl] (trifluoromethyl) sulfane, practical examples were obtained. The reaction was conducted in the same manner as in 375 to give the title compound (12 mg, yield 34%) as a pale orange amorphous product.

¹ H-NMR (CDCl ₃ ) δ: 1.66 to 2.08 (8H, m), 2.48-2.64 (4H, br m), 2.98-3.22 (2H, br m) 3.14 (2H, s), 3.44-3.58 (1H, m), 3.60 (2H, s), 3.73-3.96 (1H, br m), 4.45 ( 2H, s), 4.54-4.79 (1H, br m), 7.16 (2H, t, J = 8.6 Hz), 7.31 (2H, d, J = 8.2 Hz), 7 .42 (2H, d, J = 8.2 Hz), 7.57 (2H, d, J = 8.2 Hz), 7.74 (2H, d, J = 8.2 Hz), 7.99 (2H, dd, J = 8.6, 5.3 Hz).

LC / MS [Condition 1]: Retention time 3.26 minutes; m / z 686.0 [M + H] ⁺ (ESI positive ion mode), m / z 720.2 [M + Cl], 730.1 [M + HCOO] ⁻ (ESI negative Ion mode) ^- (ESI negative ion mode)

実施例３７９
３−｛４−［４−（４−フルオロベンゾイル）ピペリジン−１−カルボニル］ベンジル｝−８−［４−（トリフルオロメチルスルフォニル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−２−オン（化合物番号３７９）の製造

［４−（ブロモメチル）フェニル］（トリフルオロメチル）スルファンの代わりに、参考例３７８で得られた１−（ブロモメチル）−４−（トリフルオロメチルスルフォニル）ベンゼンを用いること以外は実質的に実施例３７５と同様に反応を行なって、表題化合物（２４ｍｇ、収率６９％）を無色無定形物として得た。

^１Ｈ−ＮＭＲ（ＣＤＣｌ_３）δ：１．４８−２．１０（８Ｈ，ｍ），２．４４−２．６７（４Ｈ，ｂｒ ｍ），２．８９−３．２８（２Ｈ，ｂｒ ｍ），３．１５（２Ｈ，ｓ），３．５２（１Ｈ，ｔｔ，Ｊ＝７．３，７．３Ｈｚ），３．６４（２Ｈ，ｓ），３．７１−４．０１（１Ｈ，ｂｒ ｍ），４．４６（２Ｈ，ｓ），４．５５−４．８０（１Ｈ，ｂｒ ｍ），７．１７（２Ｈ，ｔ，Ｊ＝８．６Ｈｚ），７．３２（２Ｈ，ｄ，Ｊ＝７．８Ｈｚ），７．４２（２Ｈ，ｄ，Ｊ＝７．８Ｈｚ），７．６４（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ），７．９８（２Ｈ，ｄ，Ｊ＝８．６Ｈｚ），８．００（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ）．

ＬＣ／ＭＳ［条件１］：保持時間３．４８分；ｍ／ｚ７０２．０［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ７００．１［Ｍ−Ｈ］⁻、７４６．１［Ｍ＋ＨＣＯＯ］⁻（ＥＳＩ負イオンモード）

Example 379
3- {4- [4- (4-Fluorobenzoyl) piperidine-1-carbonyl] benzyl} -8- [4- (trifluoromethylsulfonyl) benzyl] -1-oxa-3,8-diazaspiro [4.5 Production of decan-2-one (Compound No. 379)

[Examples] Except for using 1- (bromomethyl) -4- (trifluoromethylsulfonyl) benzene obtained in Reference Example 378 instead of [4- (bromomethyl) phenyl] (trifluoromethyl) sulfane, practical examples were obtained. The reaction was conducted in the same manner as in 375 to give the title compound (24 mg, yield 69%) as a colorless amorphous product.

¹ H-NMR (CDCl ₃ ) δ: 1.48-2.10 (8H, m), 2.44-2.67 (4H, br m), 2.89-3.28 (2H, br m) 3.15 (2H, s), 3.52 (1H, tt, J = 7.3, 7.3 Hz), 3.64 (2H, s), 3.71-4.01 (1H, br m ), 4.46 (2H, s), 4.55-4.80 (1H, br m), 7.17 (2H, t, J = 8.6 Hz), 7.32 (2H, d, J = 7.8 Hz), 7.42 (2H, d, J = 7.8 Hz), 7.64 (2H, d, J = 8.2 Hz), 7.98 (2H, d, J = 8.6 Hz), 8.00 (2H, d, J = 8.2 Hz).

LC / MS [Condition 1]: retention time 3.48 minutes; m / z 702.0 [M + H] ⁺ (ESI positive ion mode), m / z 700.1 [M−H] ⁻ , 746.1 [M + HCOO] ⁻ (ESI negative ion mode)

参考例３８０
１−（メトキシメチレン）−４−（トリフルオロメチル）シクロヘキサンの製造
（メトキシメチル）トリフェニルホスホニウムクロリド（市販）（１．４ｇ、４．２ｍｍｏｌ）をテトラヒドロフラン（８．０ｍＬ）に溶解し、氷冷下にてｎ−ブチルリチウム（約１５％ヘキサン溶液、２．６ｍＬ、４．０ｍｍｏｌ）を加え、氷冷下にて２０分間撹拌した後、４−（トリフルオロメチル）シクロヘキサノン（市販）（０．４０ｇ、２．４ｍｍｏｌ）を加え、氷冷下にて９０分間かき混ぜた。反応終了後、飽和塩化アンモニウム水溶液（１５ｍＬ）にてクエンチを行なった後、酢酸エチル（３０ｍＬ）を加えて、有機層を分離した。得られた有機層を無水硫酸ナトリウムで乾燥、減圧下濃縮乾固した後、シリカゲルカラムクロマトグラフィ−［充填剤：株式会社山善製ＨＩ−ＦＬＡＳＨ（登録商標）ＣＯＬＵＭＮｓｉｌｉｃａｇｅｌ４０μｍ、展開溶媒：ヘキサン／酢酸エチル＝４／１→１／１］にて精製し、表題化合物（０．３１ｇ、収率６７％）を白色粉末として得た。

^１Ｈ−ＮＭＲ（ＣＤＣｌ_３）δ：１．２８（２Ｈ，ｄｑ，Ｊ＝４．５，１２．３Ｈｚ），１．６５（１Ｈ，ｄｔ，Ｊ＝５．７，１５．１Ｈｚ），１．８２−２．０３（３Ｈ，ｍ），２．０４−２．２８（２Ｈ，ｍ），２．８７（１Ｈ，ｄ，Ｊ＝１３．９Ｈｚ），３．５６（３Ｈ，ｓ），５．８０（１Ｈ，ｓ）．

Reference Example 380
Preparation of 1- (methoxymethylene) -4- (trifluoromethyl) cyclohexane (Methoxymethyl) triphenylphosphonium chloride (commercially available) (1.4 g, 4.2 mmol) was dissolved in tetrahydrofuran (8.0 mL) and ice-cooled. N-Butyllithium (about 15% hexane solution, 2.6 mL, 4.0 mmol) was added and stirred for 20 minutes under ice-cooling, and then 4- (trifluoromethyl) cyclohexanone (commercially available) (0. 40 g, 2.4 mmol) was added, and the mixture was stirred for 90 minutes under ice cooling. After completion of the reaction, the reaction was quenched with a saturated aqueous ammonium chloride solution (15 mL), and then ethyl acetate (30 mL) was added to separate the organic layer. The obtained organic layer was dried over anhydrous sodium sulfate and concentrated to dryness under reduced pressure, followed by silica gel column chromatography [filler: HI-FLASH (registered trademark) COLUMNsilica gel 40 μm manufactured by Yamazen Co., Ltd., developing solvent: hexane / ethyl acetate = 4. / 1 → 1/1] to give the title compound (0.31 g, 67% yield) as a white powder.

¹ H-NMR (CDCl ₃ ) δ: 1.28 (2H, dq, J = 4.5, 12.3 Hz), 1.65 (1H, dt, J = 5.7, 15.1 Hz), 1. 82-2.03 (3H, m), 2.04-2.28 (2H, m), 2.87 (1H, d, J = 13.9 Hz), 3.56 (3H, s), 5. 80 (1H, s).

実施例３８０
３−｛４−［４−（４−フルオロベンゾイル）ピペリジン−１−カルボニル］ベンジル｝−８−｛［４−（トリフルオロメチル）シクロヘキシル］メチル｝−１−オキサ−３，８−ジアザスピロ［４．５］デカン−２−オン（化合物番号３８０）の製造
参考例３８０で得られた、１−（メトキシメチレン）−４−（トリフルオロメチル）シクロヘキサン（０．１２ｇ、０．６２ｍｍｏｌ）をアセトン（２．０ｍＬ）に溶解し、１Ｍ塩酸（０．１９ｍＬ、０．１９ｍｍｏｌ）を加えて、室温にて２時間かき混ぜた。反応終了後、飽和炭酸水素ナトリウム水溶液（１０ｍＬ）を加え、メタノールを減圧下留去した後、残留物にクロロホルム（２０ｍＬ）を加えて有機層を分離した。得られた有機層を無水硫酸ナトリウムで乾燥、減圧下濃縮乾固し、無色油状物（６０ｍｇ）を得た。
この油状物と、参考例３７５−２で得られた３−｛４−［４−（４−フルオロベンゾイル）ピペリジン−１−カルボニル］ベンジル｝−１−オキサ−３，８−ジアザスピロ［４．５］デカン−２−オン塩酸塩（２６ｍｇ、０．０５０ｍｍｏｌ）をメタノール／酢酸（１０／１）（２ｍＬ）に溶解し、室温にてボラン‐２-ピコリン錯体（純正化学（株）より購入）（１１ｍｇ、０．１０ｍｍｏｌ）を加えて、室温で１日間かき混ぜた。反応終了後、反応液を減圧留去した後、得られた反応残渣をシリカゲルカラムクロマトグラフィー［充填剤：富士シリシア製ＮＨ−ＤＭ１０２０、展開溶媒：クロロホルム／メタノール＝２０／１］にて精製し、表題化合物（２４ｍｇ、収率７３％）を淡黄色無定形物として得た。

^１Ｈ−ＮＭＲ（ＣＤＣｌ_３）δ：１．３８−２．０６（１８Ｈ，ｍ），２．２７（１Ｈ，ｄ，Ｊ＝７．０Ｈｚ），２．３６−２．５９（４Ｈ，ｂｒ ｍ），３．００−３．２４（２Ｈ，ｍ），３．１２（２Ｈ，ｓ），３．４５−３．５８（１Ｈ，ｍ），３．７０−３．９９（１Ｈ，ｂｒ ｍ），４．４５（２Ｈ，ｓ），４．５４−４．７９（１Ｈ，ｂｒ ｍ），７．１７（２Ｈ，ｔ，Ｊ＝８．６Ｈｚ），７．３１（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ），７．４２（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ），７．９９（２Ｈ，ｄｄ，Ｊ＝８．６，５．３Ｈｚ）．

ＬＣ／ＭＳ［条件１］：保持時間３．３６分；ｍ／ｚ６４３．９［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ６８８．０［Ｍ＋ＨＣＯＯ］⁻（ＥＳＩ負イオンモード）

Example 380
3- {4- [4- (4-Fluorobenzoyl) piperidine-1-carbonyl] benzyl} -8-{[4- (trifluoromethyl) cyclohexyl] methyl} -1-oxa-3,8-diazaspiro [4 .5] Production of decan-2-one (Compound No. 380) 1- (Methoxymethylene) -4- (trifluoromethyl) cyclohexane (0.12 g, 0.62 mmol) obtained in Reference Example 380 was added to acetone (0.12 g, 0.62 mmol). 2.0M), 1M hydrochloric acid (0.19mL, 0.19mmol) was added, and the mixture was stirred at room temperature for 2 hours. After completion of the reaction, a saturated aqueous sodium hydrogen carbonate solution (10 mL) was added, methanol was distilled off under reduced pressure, and chloroform (20 mL) was added to the residue to separate the organic layer. The obtained organic layer was dried over anhydrous sodium sulfate and concentrated to dryness under reduced pressure to obtain a colorless oil (60 mg).
This oil and 3- {4- [4- (4-fluorobenzoyl) piperidine-1-carbonyl] benzyl} -1-oxa-3,8-diazaspiro [4.5] obtained in Reference Example 375-2. ] Decan-2-one hydrochloride (26 mg, 0.050 mmol) was dissolved in methanol / acetic acid (10/1) (2 mL) and borane-2-picoline complex (purchased from Junsei Co., Ltd.) at room temperature ( 11 mg, 0.10 mmol) was added and stirred at room temperature for 1 day. After completion of the reaction, the reaction solution was distilled off under reduced pressure, and the resulting reaction residue was purified by silica gel column chromatography [filler: NH-DM1020 manufactured by Fuji Silysia, developing solvent: chloroform / methanol = 20/1], The title compound (24 mg, yield 73%) was obtained as a pale yellow amorphous product.

¹ H-NMR (CDCl ₃ ) δ: 1.38-2.06 (18H, m), 2.27 (1H, d, J = 7.0 Hz), 2.36-2.59 (4H, br m ), 3.00-3.24 (2H, m), 3.12 (2H, s), 3.45-3.58 (1H, m), 3.70-3.99 (1H, br m) 4.45 (2H, s), 4.54-4.79 (1H, br m), 7.17 (2H, t, J = 8.6 Hz), 7.31 (2H, d, J = 8) .2 Hz), 7.42 (2H, d, J = 8.2 Hz), 7.99 (2H, dd, J = 8.6, 5.3 Hz).

LC / MS [Condition 1]: Retention time 3.36 minutes; m / z 643.9 [M + H] ⁺ (ESI positive ion mode), m / z 688.0 [M + HCOO] ⁻ (ESI negative ion mode)

参考例３８１−１
３−（５−シアノピリジン−２−イルオキシ）アゼチジン−１−カルボン酸ｔ−ブチル
の製造
３−ヒドロキシアゼチジン−１−カルボン酸ｔ−ブチル（市販）（０．８７ｇ、５．０ｍｍｏｌ）をテトラヒドロフラン（８．０ｍＬ）に溶解し、室温にて水素化ナトリウム（＞５５％、流動パラフィン分散、関東化学（株）より購入）（０．１９ｇ、５．０ｍｍｏｌ）を加えた後、同じ温度で３０分間かき混ぜた後、６−クロロニコチノニトリル（０．６６ｇ、４．８ｍｍｏｌ）を加えた。室温にて１５０分間かき混ぜた後、水（２５ｍＬ）、酢酸エチル（５０ｍＬ）を加えて、有機層を分離した。得られた有機層を無水硫酸ナトリウムで乾燥、減圧下濃縮乾固した後、シリカゲルカラムクロマトグラフィ−［充填剤：株式会社山善製ＨＩ−ＦＬＡＳＨ（登録商標）ＣＯＬＵＭＮｓｉｌｉｃａｇｅｌ４０μｍ、展開溶媒：ヘキサン／酢酸エチル＝４／１→１／１］にて精製し、表題化合物（１．５ｇ、収率定量的）を白色粉末として得た。

^１Ｈ−ＮＭＲ（ＣＤＣｌ_３）δ：１．４５（９Ｈ，ｓ），３．９８（２Ｈ，ｄｄ，Ｊ＝１０．６，４．１Ｈｚ），４．３４（２Ｈ，ｄｄ，Ｊ＝１０．６，６．７Ｈｚ），５．３６（１Ｈ，ｔｔ，Ｊ＝６．５，４．１Ｈｚ），６．８９（１Ｈ，ｄ，Ｊ＝８．８Ｈｚ），７．８３（１Ｈ，ｄｄ，Ｊ＝８．８，２．０Ｈｚ），８．４４（１Ｈ，ｄ，Ｊ＝２．０Ｈｚ）．

ＬＣ／ＭＳ［条件１］：保持時間４．１７分；ｍ／ｚ２７６．０［Ｍ＋Ｈ］^＋、２２０．０［Ｍ−ｉｓｏｂｕｔｅｎｅ＋Ｈ］^＋（ＥＳＩ正イオンモード）

Reference Example 381-1
3- (5-Cyanopyridin-2-yloxy) azetidine-1-carboxylate t-butyl
Preparation of 3-hydroxyazetidine-1-carboxylate t-butyl (commercially available) (0.87 g, 5.0 mmol) dissolved in tetrahydrofuran (8.0 mL) and sodium hydride (> 55%, fluid) at room temperature Paraffin dispersion, purchased from Kanto Chemical Co., Inc.) (0.19 g, 5.0 mmol) was added, and after stirring for 30 minutes at the same temperature, 6-chloronicotinonitrile (0.66 g, 4.8 mmol) was added. added. After stirring at room temperature for 150 minutes, water (25 mL) and ethyl acetate (50 mL) were added, and the organic layer was separated. The obtained organic layer was dried over anhydrous sodium sulfate and concentrated to dryness under reduced pressure, followed by silica gel column chromatography [filler: HI-FLASH (registered trademark) COLUMNsilica gel 40 μm manufactured by Yamazen Co., Ltd., developing solvent: hexane / ethyl acetate = 4. / 1 → 1/1] to give the title compound (1.5 g, quantitative yield) as a white powder.

¹ H-NMR (CDCl ₃ ) δ: 1.45 (9H, s), 3.98 (2H, dd, J = 10.6, 4.1 Hz), 4.34 (2H, dd, J = 10. 6, 6.7 Hz), 5.36 (1 H, tt, J = 6.5, 4.1 Hz), 6.89 (1 H, d, J = 8.8 Hz), 7.83 (1 H, dd, J = 8.8, 2.0 Hz), 8.44 (1H, d, J = 2.0 Hz).

LC / MS [Condition 1]: Retention time 4.17 minutes; m / z 276.0 [M + H] ⁺ , 220.0 [M-isobutene + H] ⁺ (ESI positive ion mode)

参考例３８１−２
６−（アゼチジン−３−イルオキシ）ニコチノニトリルの製造
参考例３８１−１で得られた、３−（５−シアノピリジン−２−イルオキシ）アゼチジン−１−カルボン酸ｔ−ブチル（０．３６ｇ、１．３ｍｍｏｌ）をクロロホルム（２．０ｍＬ）に溶解し、トリフルオロ酢酸（１．０ｍＬ）を加え、室温にて１時間撹拌した。反応終了後、飽和炭酸水素ナトリウム水溶液（３０ｍＬ）にて中和を行なった後、クロロホルム（６０ｍＬ）を加えて、有機層を分離した。得られた有機層を無水硫酸ナトリウムで乾燥、減圧下濃縮乾固し、表題化合物（０．１０ｇ、収率４４％）を白色粉末として得た。

^１Ｈ−ＮＭＲ（ＣＤＣｌ_３）δ：３．７６（２Ｈ，ｄｄ，Ｊ＝１０．２，６．５Ｈｚ），３．９８（２Ｈ，ｄｄ，Ｊ＝１０．２，６．１Ｈｚ），５．５０−５．５２（１Ｈ，ｍ），６．８４（１Ｈ，ｄ，Ｊ＝８．６Ｈｚ），７．８０（１Ｈ，ｄｄ，Ｊ＝８．６，２．５Ｈｚ），８．４３（１Ｈ，ｄ，Ｊ＝２．５Ｈｚ）．

ＬＣ／ＭＳ［条件１］：保持時間０．４９分；ｍ／ｚ１７６．０［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）

Reference Example 381-2
Production of 6- (azetidin-3-yloxy) nicotinonitrile t-butyl 3- (5-cyanopyridin-2-yloxy) azetidine-1-carboxylate (0.36 g, obtained in Reference Example 381-1) 1.3 mmol) was dissolved in chloroform (2.0 mL), trifluoroacetic acid (1.0 mL) was added, and the mixture was stirred at room temperature for 1 hour. After completion of the reaction, the reaction mixture was neutralized with a saturated aqueous sodium hydrogen carbonate solution (30 mL), and chloroform (60 mL) was added to separate the organic layer. The obtained organic layer was dried over anhydrous sodium sulfate and concentrated to dryness under reduced pressure to obtain the title compound (0.10 g, yield 44%) as a white powder.

¹ H-NMR (CDCl ₃ ) δ: 3.76 (2H, dd, J = 10.2, 6.5 Hz), 3.98 (2H, dd, J = 10.2, 6.1 Hz), 5. 50-5.52 (1H, m), 6.84 (1H, d, J = 8.6 Hz), 7.80 (1H, dd, J = 8.6, 2.5 Hz), 8.43 (1H , D, J = 2.5 Hz).

LC / MS [Condition 1]: Retention time 0.49 min; m / z 176.0 [M + H] ⁺ (ESI positive ion mode)

実施例３８１
６−｛１−［４−（｛２−オキソ−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）ベンゾイル］アゼチジン−３−イルオキシ｝ニコチノニトリル（化合物番号３８１）の製造
４−（２−アミノエチル）モルホリンの代わりに参考例３８１−２で得られた６−（アゼチジン−３−イルオキシ）ニコチノニトリルを用いる以外は実質的に実施例４４と同様に反応を行って、表題化合物（１９ｍｇ、収率６１％）を無色無定形物として得た。

^１Ｈ−ＮＭＲ（ＣＤＣｌ_３）δ：１．６６−１．７９（２Ｈ，ｍ），１．８１−１．９８（２Ｈ，ｍ），２．４１−２．６４（４Ｈ，ｂｒ ｍ），３．１３（２Ｈ，ｓ），３．５５（２Ｈ，ｓ），４．２９（２Ｈ，ｄｄ，Ｊ＝１０．７，３．５Ｈｚ），４．４５（２Ｈ，ｓ），４．５６−４．７６（０Ｈ，ｂｒ ｍ），５．４７（１Ｈ，ｔｔ，Ｊ＝６．６，３．９Ｈｚ），６．９１（１Ｈ，ｄ，Ｊ＝８．６Ｈｚ），７．３２（２Ｈ，ｄ，Ｊ＝８．３Ｈｚ），７．４２（２Ｈ，ｄ，Ｊ＝８．３Ｈｚ），７．５６（２Ｈ，ｄ，Ｊ＝８．３Ｈｚ），７．６４（２Ｈ，ｄ，Ｊ＝８．３Ｈｚ），７．８５（１Ｈ，ｄｄ，Ｊ＝８．６，２．３Ｈｚ），８．４３（１Ｈ，ｄ，Ｊ＝２．３Ｈｚ）．

ＬＣ／ＭＳ［条件１］：保持時間３．１６分；ｍ／ｚ６０５．９［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ６４０．０［Ｍ＋Ｃｌ］⁻、６５０．０［Ｍ＋ＨＣＯＯ］⁻（ＥＳＩ負イオンモード）

Example 381
6- {1- [4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl) benzoyl Preparation of azetidin-3-yloxy} nicotinonitrile (Compound No. 381) 6- (azetidin-3-yloxy) nicotinonitrile obtained in Reference Example 381-2 instead of 4- (2-aminoethyl) morpholine The title compound (19 mg, 61% yield) was obtained as a colorless amorphous product by substantially reacting in the same manner as in Example 44 except that was used.

¹ H-NMR (CDCl ₃ ) δ: 1.66-1.79 (2H, m), 1.81-1.98 (2H, m), 2.41-2.64 (4H, br m), 3.13 (2H, s), 3.55 (2H, s), 4.29 (2H, dd, J = 10.7, 3.5 Hz), 4.45 (2H, s), 4.56- 4.76 (0H, br m), 5.47 (1H, tt, J = 6.6, 3.9 Hz), 6.91 (1H, d, J = 8.6 Hz), 7.32 (2H, d, J = 8.3 Hz), 7.42 (2H, d, J = 8.3 Hz), 7.56 (2H, d, J = 8.3 Hz), 7.64 (2H, d, J = 8) .3 Hz), 7.85 (1H, dd, J = 8.6, 2.3 Hz), 8.43 (1H, d, J = 2.3 Hz).

LC / MS [Condition 1]: Retention time 3.16 minutes; m / z 605.9 [M + H] ⁺ (ESI positive ion mode), m / z 640.0 [M + Cl] ⁻ , 650.0 [M + HCOO] ⁻ (ESI Negative ion mode)

実施例３８２
６−｛１−［（１ｒ，４ｒ）−４−（｛２−オキソ−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）シクロヘキサンカルボニル］アゼチジン−３−イルオキシ｝ニコチノニトリル（化合物番号３８２）の製造
ピペリジンの代わりに、参考例３８１−２で得られた６−（アゼチジン−３−イルオキシ）ニコチノニトリルを用いること以外は実質的に実施例１６と同様に反応を行なって、表題化合物（２０ｍｇ、収率６６％）を白色粉末として得た。

^１Ｈ−ＮＭＲ（ＣＤＣｌ_３）δ：１．０１（２Ｈ，ｑ，Ｊ＝１２．８Ｈｚ），１．３９−２．００（２Ｈ，ｍ），２．１２（１Ｈ，ｔｔ，Ｊ＝１３．０，３．３Ｈｚ），２．４０−２．６８（４Ｈ，ｂｒ ｍ），３．０９（２Ｈ，ｄ，Ｊ＝７．４Ｈｚ），３．２５（２Ｈ，ｓ），３．５７（２Ｈ，ｓ），４．０５（１Ｈ，ｄｄ，Ｊ＝１１．３，４．１Ｈｚ），４．１４（１Ｈ，ｄｄ，Ｊ＝１３．９，４．１Ｈｚ），４．４０（１Ｈ，ｄｄ，Ｊ＝１１．３，７．２Ｈｚ），４．５６（１Ｈ，ｄｄ，Ｊ＝９．２，７．２Ｈｚ），５．４２（１Ｈ，ｔｔ，Ｊ＝６．１，４．５Ｈｚ），６．９０（１Ｈ，ｄ，Ｊ＝８．６Ｈｚ），７．４４（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ），７．５７（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ），７．８５（１Ｈ，ｄｄ，Ｊ＝８．６，２．０Ｈｚ），８．４５（１Ｈ，ｄ，Ｊ＝２．０Ｈｚ）．

ＬＣ／ＭＳ［条件１］：保持時間３．１６分；ｍ／ｚ６１１．９［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ６４５．９［Ｍ＋Ｃｌ］⁻、６５６．０［Ｍ＋ＨＣＯＯ］⁻（ＥＳＩ負イオンモード）

Example 382
6- {1-[(1r, 4r) -4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decane-3 Preparation of -yl} methyl) cyclohexanecarbonyl] azetidin-3-yloxy} nicotinonitrile (Compound No. 382) Instead of piperidine, 6- (azetidin-3-yloxy) nicotinonitrile obtained in Reference Example 381-2 The title compound (20 mg, yield 66%) was obtained as a white powder in substantially the same manner as in Example 16 except that was used.

¹ H-NMR (CDCl ₃ ) δ: 1.01 (2H, q, J = 12.8 Hz), 1.39-2.00 (2H, m), 2.12 (1H, tt, J = 13. 0, 3.3 Hz), 2.40-2.68 (4H, br m), 3.09 (2H, d, J = 7.4 Hz), 3.25 (2H, s), 3.57 (2H) , S), 4.05 (1H, dd, J = 11.3, 4.1 Hz), 4.14 (1H, dd, J = 13.9, 4.1 Hz), 4.40 (1H, dd, J = 11.3, 7.2 Hz), 4.56 (1H, dd, J = 9.2, 7.2 Hz), 5.42 (1H, tt, J = 6.1, 4.5 Hz), 6 .90 (1H, d, J = 8.6 Hz), 7.44 (2H, d, J = 8.2 Hz), 7.57 (2H, d, J = 8.2 Hz), 7.85 (1H, dd, J = 8.6 .0Hz), 8.45 (1H, d, J = 2.0Hz).

LC / MS [Condition 1]: Retention time 3.16 minutes; m / z 611.9 [M + H] ⁺ (ESI positive ion mode), m / z 645.9 [M + Cl] ⁻ , 656.0 [M + HCOO] ⁻ (ESI Negative ion mode)

参考例３８３−１
３−（４−シアノフェノキシ）アゼチジン−１−カルボン酸ｔ−ブチルの製造
６−クロロニコチノニトリルの代わりに、４−フルオロベンゾニトリル（市販）を用いること以外は実質的に参考例３８１−１と同様に反応を行なって、表題化合物（１．１ｇ、収率７７％）を白色粉末として得た。

^１Ｈ−ＮＭＲ（ＣＤＣｌ_３）δ：１．４５（９Ｈ，ｓ），４．０１（２Ｈ，ｄｄ，Ｊ＝９．８，４．１Ｈｚ），４．３３（２Ｈ，ｄｄ，Ｊ＝９．８，６．５Ｈｚ），４．９３（１Ｈ，ｔｔ，Ｊ＝６．５，４．１Ｈｚ），６．８１（２Ｈ，ｄ，Ｊ＝９．４Ｈｚ），７．６０（２Ｈ，ｄ，Ｊ＝９．４Ｈｚ）．

ＬＣ／ＭＳ［条件１］：保持時間４．２９分；ｍ／ｚ２１９．０［Ｍ−ｉｓｏｂｕｔｅｎｅ＋Ｈ］^＋（ＥＳＩ正イオンモード）

Reference Example 383-1
Preparation of t-butyl 3- (4-cyanophenoxy) azetidine-1-carboxylate Substantially Reference Example 381-1 except that 4-fluorobenzonitrile (commercially available) was used instead of 6-chloronicotinonitrile. The title compound (1.1 g, yield 77%) was obtained as a white powder.

¹ H-NMR (CDCl ₃ ) δ: 1.45 (9H, s), 4.01 (2H, dd, J = 9.8, 4.1 Hz), 4.33 (2H, dd, J = 9. 8, 6.5 Hz), 4.93 (1H, tt, J = 6.5, 4.1 Hz), 6.81 (2H, d, J = 9.4 Hz), 7.60 (2H, d, J = 9.4 Hz).

LC / MS [Condition 1]: Retention time 4.29 minutes; m / z 219.0 [M-isobutene + H] ⁺ (ESI positive ion mode)

参考例３８３−２
４−（アゼチジン−３−イルオキシ）ベンゾニトリルの製造
３−（５−シアノピリジン−２−イルオキシ）アゼチジン−１−カルボン酸ｔ−ブチルの代わりに、参考例３８３−１で得られた、３−（４−シアノフェノキシ）アゼチジン−１−カルボン酸ｔ−ブチルを用いること以外は実質的に参考例３８１−２と同様に反応を行なって、表題化合物（０．１０ｇ、収率３１％）を白色粉末として得た。

^１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ_６）δ：３．２０（１Ｈ，ｄｄ，Ｊ＝６．１，４．９Ｈｚ），３．６１（１Ｈ，ｔ，Ｊ＝６．１Ｈｚ），４．８７（１Ｈ，ｔｔ，Ｊ＝６．１，４．９Ｈｚ），７．０１（２Ｈ，ｄ，Ｊ＝８．６Ｈｚ），７．７５（２Ｈ，ｄ，Ｊ＝８．６Ｈｚ）．

ＬＣ／ＭＳ［条件１］：保持時間０．５１分；ｍ／ｚ１７５．０［Ｍ−ｉｓｏｂｕｔｅｎｅ＋Ｈ］^＋（ＥＳＩ正イオンモード）

Reference Example 383-2
Preparation of 4- (azetidin-3-yloxy) benzonitrile 3- (5-cyanopyridin-2-yloxy) azetidine-1-carboxylate obtained in Reference Example 383-1 instead of 3- The reaction was carried out in substantially the same manner as in Reference Example 381-2 except that t-butyl (4-cyanophenoxy) azetidine-1-carboxylate was used, and the title compound (0.10 g, yield 31%) was white. Obtained as a powder.

¹ H-NMR (DMSO-d ₆ ) δ: 3.20 (1H, dd, J = 6.1, 4.9 Hz), 3.61 (1H, t, J = 6.1 Hz), 4.87 ( 1H, tt, J = 6.1, 4.9 Hz), 7.01 (2H, d, J = 8.6 Hz), 7.75 (2H, d, J = 8.6 Hz).

LC / MS [Condition 1]: Retention time 0.51 min; m / z 175.0 [M-isobutene + H] ⁺ (ESI positive ion mode)

実施例３８３
４−｛１−［（１ｒ，４ｒ）−４−（｛２−オキソ−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）シクロヘキサンカルボニル］アゼチジン−３−イルオキシ｝ベンゾニトリル（化合物番号３８３）の製造

ピペリジンの代わりに、参考例３８３−２で得られた４−（アゼチジン−３−イルオキシ）ベンゾニトリルを用いること以外は実質的に実施例１６と同様に反応を行なって、表題化合物（６．０ｍｇ、収率２０％）を無色無定形物として得た。

^１Ｈ−ＮＭＲ（ＣＤＣｌ_３）δ：１．０２（２Ｈ，ｑ，Ｊ＝１２．６Ｈｚ），１．４６−１．６２（３Ｈ，ｍ），１．７４−１．８３（６Ｈ，ｍ），１．９４（２Ｈ，ｄ，Ｊ＝１３．１Ｈｚ），２．１３（１Ｈ，ｔｔ，Ｊ＝１２．１，３．１Ｈｚ），２．４２−２．６８（４Ｈ，ｂｒ ｍ），３．１０（２Ｈ，ｄ，Ｊ＝７．４Ｈｚ），３．２５（２Ｈ，ｓ），３．５７（２Ｈ，ｓ），４．０５（１Ｈ，ｄｄ，Ｊ＝１０．８，３．９Ｈｚ），４．２０（１Ｈ，ｄｄ，Ｊ＝９．２，３．５Ｈｚ），４．４０（１Ｈ，ｄｄ，Ｊ＝１０．８，６．３Ｈｚ），４．５５（１Ｈ，ｄｄ，Ｊ＝９．２，６．５Ｈｚ），４．９６−５．０３（１Ｈ，ｍ），６．８２（２Ｈ，ｄ，Ｊ＝９．０Ｈｚ），７．４４（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ），７．５７（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ），７．６２（２Ｈ，ｄ，Ｊ＝９．０Ｈｚ）．

ＬＣ／ＭＳ［条件１］：保持時間３．３２分；ｍ／ｚ６１１．０［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ６４４．９［Ｍ＋Ｃｌ］⁻、６５５．２［Ｍ＋ＨＣＯＯ］⁻（ＥＳＩ負イオンモード）

Example 383
4- {1-[(1r, 4r) -4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decane-3 -Il} methyl) cyclohexanecarbonyl] azetidin-3-yloxy} benzonitrile (Compound No. 383)

The reaction was conducted in substantially the same manner as in Example 16 except that 4- (azetidin-3-yloxy) benzonitrile obtained in Reference Example 383-2 was used instead of piperidine to give the title compound (6.0 mg Yield 20%) as a colorless amorphous product.

¹ H-NMR (CDCl ₃ ) δ: 1.02 (2H, q, J = 12.6 Hz), 1.46-1.62 (3H, m), 1.74-1.83 (6H, m) 1.94 (2H, d, J = 13.1 Hz), 2.13 (1H, tt, J = 12.1, 3.1 Hz), 2.42-2.68 (4H, br m), 3 .10 (2H, d, J = 7.4 Hz), 3.25 (2H, s), 3.57 (2H, s), 4.05 (1H, dd, J = 10.8, 3.9 Hz) 4.20 (1H, dd, J = 9.2, 3.5 Hz), 4.40 (1H, dd, J = 10.8, 6.3 Hz), 4.55 (1H, dd, J = 9) .2, 6.5 Hz), 4.96-5.03 (1 H, m), 6.82 (2 H, d, J = 9.0 Hz), 7.44 (2 H, d, J = 8.2 Hz) 7.57 (2H, d J = 8.2Hz), 7.62 (2H, d, J = 9.0Hz).

LC / MS [Condition 1]: Retention time 3.32 minutes; m / z 611.0 [M + H] ⁺ (ESI positive ion mode), m / z 644.9 [M + Cl] ⁻ , 655.2 [M + HCOO] ⁻ (ESI Negative ion mode)

実施例３８４
３−｛［（１ｒ，４ｒ）−４−（４−ベンゾイルピペリジン−１−カルボニル）シクロヘキシル］メチル｝−８−｛［６−（トリフルオロメチル）ピリジン−３−イル］メチル｝−１−オキサ−３，８−ジアザスピロ［４．５］デカン−２−オン（化合物番号３８４）の製造
（１ｒ，４ｒ）−４−［（２−オキソ−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル）メチル］−Ｎ−［（テトラヒドロフラン−２−イル）メチル］シクロヘキサンカルボキサミド塩酸塩の代わりに、参考例２５５で得られた、３−｛［（１ｒ，４ｒ）−４−（４−ベンゾイルピペリジン−１−カルボニル）シクロヘキシル］メチル｝−１−オキサ−３，８−ジアザスピロ［４．５］デカン−２−オン塩酸塩を用いることと、３，５−ビス（トリフルオロメチル）ベンズアルデヒドの代わりに、６−（トリフルオロメチル）ニコチンアルデヒド（市販）を用いること以外は実質的に実施例２３５と同様に反応を行なって、表題化合物（１４ｍｇ、収率２８％）を無色無定形物として得た。

^１Ｈ−ＮＭＲ（ＣＤＣｌ_３）δ：１．０５（２Ｈ，ｑ，Ｊ＝１１．５Ｈｚ），１．４６−２．０４（１５Ｈ，ｍ），２．４７（１Ｈ，ｔ，Ｊ＝１６．０Ｈｚ），２．５２−２．７１（４Ｈ，ｂｒ ｍ），２．８２（１Ｈ，ｔ，Ｊ＝１１．５Ｈｚ），３．１１（２Ｈ，ｄ，Ｊ＝６．１Ｈｚ），３．２０（１Ｈ，ｔ，Ｊ＝１２．７Ｈｚ），３．２７（２Ｈ，ｓ），３．５２（１Ｈ，ｔｔ，Ｊ＝１１．５，３．７Ｈｚ），３．６２（２Ｈ，ｓ），３．９８（１Ｈ，ｄ，Ｊ＝１３．１Ｈｚ），４．６０（１Ｈ，ｄ，Ｊ＝１２．７Ｈｚ），７．４９（１Ｈ，ｔ，Ｊ＝７．４Ｈｚ），７．５９（１Ｈ，ｔ，Ｊ＝７．４Ｈｚ），７．６５（１Ｈ，ｄ，Ｊ＝８．２Ｈｚ），７．８５（１Ｈ，ｄ，Ｊ＝８．２Ｈｚ），７．９４（２Ｈ，ｄ，Ｊ＝７．４Ｈｚ），８．６８（１Ｈ，ｓ）．

ＬＣ／ＭＳ［条件１］：保持時間３．２８分；ｍ／ｚ６２６．９［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ６６１．４［Ｍ＋Ｃｌ］⁻、６７１．０［Ｍ＋ＨＣＯＯ］⁻（ＥＳＩ負イオンモード）

Example 384
3-{[(1r, 4r) -4- (4-Benzoylpiperidine-1-carbonyl) cyclohexyl] methyl} -8-{[6- (trifluoromethyl) pyridin-3-yl] methyl} -1-oxa Preparation of -3,8-diazaspiro [4.5] decan-2-one (Compound No. 384) (1r, 4r) -4-[(2-oxo-1-oxa-3,8-diazaspiro [4.5 ] Instead of [decane-3-yl) methyl] -N-[(tetrahydrofuran-2-yl) methyl] cyclohexanecarboxamide hydrochloride, 3-{[(1r, 4r) -4-] obtained in Reference Example 255 was obtained. Using (4-benzoylpiperidine-1-carbonyl) cyclohexyl] methyl} -1-oxa-3,8-diazaspiro [4.5] decan-2-one hydrochloride; 3,5-bis (trif The reaction was conducted in substantially the same manner as in Example 235 except that 6- (trifluoromethyl) nicotinaldehyde (commercially available) was used instead of (olomethyl) benzaldehyde to give the title compound (14 mg, yield 28%) as a colorless product. Obtained as an amorphous material.

¹ H-NMR (CDCl ₃ ) δ: 1.05 (2H, q, J = 11.5 Hz), 1.46-2.04 (15H, m), 2.47 (1H, t, J = 16. 0 Hz), 2.52-2.71 (4H, br m), 2.82 (1H, t, J = 11.5 Hz), 3.11 (2H, d, J = 6.1 Hz), 3.20 (1H, t, J = 12.7 Hz), 3.27 (2H, s), 3.52 (1H, tt, J = 11.5, 3.7 Hz), 3.62 (2H, s), 3 .98 (1H, d, J = 13.1 Hz), 4.60 (1 H, d, J = 12.7 Hz), 7.49 (1 H, t, J = 7.4 Hz), 7.59 (1H, t, J = 7.4 Hz), 7.65 (1H, d, J = 8.2 Hz), 7.85 (1H, d, J = 8.2 Hz), 7.94 (2H, d, J = 7) .4Hz), 8 68 (1H, s).

LC / MS [Condition 1]: retention time 3.28 min; m / z 626.9 [M + H] ⁺ (ESI positive ion mode), m / z 661.4 [M + Cl] ⁻ , 671.0 [M + HCOO] ⁻ (ESI Negative ion mode)

実施例３８５
３−｛［（１ｒ，４ｒ）−４−（４−ベンゾイルピペリジン−１−カルボニル）シクロヘキシル］メチル｝−８−［２−フルオロ−４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−２−オン（化合物番号３８５）の製造
１−（ブロモメチル）−２，４−ビス（トリフルオロメチル）ベンゼンの代わりに、１−（ブロモメチル）−２−フルオロ−４−（トリフルオロメチル）ベンゼン（市販）を用いること以外は実質的に実施例２５５と同様に反応を行なって、表題化合物（３４ｍｇ、収率６７％）を白色粉末として得た。

^１Ｈ−ＮＭＲ（ＣＤＣｌ_３）δ：１．０５（２Ｈ，ｑ，Ｊ＝１１．３Ｈｚ），１．４５−２．０２（１５Ｈ，ｍ），２．４６（１Ｈ，ｔ，Ｊ＝１１．５Ｈｚ），２．５３−２．６９（４Ｈ，ｂｒ ｍ），２．８２（１Ｈ，ｔ，Ｊ＝１２．７Ｈｚ），３．１０（２Ｈ，ｄ，Ｊ＝５．７Ｈｚ），３．２０（１Ｈ，ｔ，Ｊ＝１３．５Ｈｚ），３．２５（２Ｈ，ｓ），３．４４−３．５８（１Ｈ，ｍ），３．６４（２Ｈ，ｓ），３．９８（１Ｈ，ｄ，Ｊ＝１２．７Ｈｚ），４．６０（１Ｈ，ｄ，Ｊ＝１４．３Ｈｚ），７．３０（２Ｈ，ｄ，Ｊ＝１０．２Ｈｚ），７．３９（１Ｈ，ｄ，Ｊ＝８．２Ｈｚ），７．４９（２Ｈ，ｔ，Ｊ＝７．６Ｈｚ），７．５２−７．５７（１Ｈ，ｍ），７．５９（１Ｈ，ｔ，Ｊ＝７．６Ｈｚ），７．９４（２Ｈ，ｄ，Ｊ＝７．６Ｈｚ）．

ＬＣ／ＭＳ［条件１］：保持時間３．４２分；ｍ／ｚ６４３．８［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ６７７．９［Ｍ＋Ｃｌ］⁻、６８７．９［Ｍ＋ＨＣＯＯ］⁻（ＥＳＩ負イオンモード）

Example 385
3-{[(1r, 4r) -4- (4-benzoylpiperidine-1-carbonyl) cyclohexyl] methyl} -8- [2-fluoro-4- (trifluoromethyl) benzyl] -1-oxa-3, Preparation of 8-diazaspiro [4.5] decan-2-one (Compound No. 385) 1- (Bromomethyl) -2-fluoro instead of 1- (bromomethyl) -2,4-bis (trifluoromethyl) benzene The reaction was carried out substantially in the same manner as in Example 255 except that -4- (trifluoromethyl) benzene (commercially available) was used to obtain the title compound (34 mg, yield 67%) as a white powder.

¹ H-NMR (CDCl ₃ ) δ: 1.05 (2H, q, J = 11.3 Hz), 1.45-2.02 (15H, m), 2.46 (1H, t, J = 11.1. 5Hz), 2.53-2.69 (4H, br m), 2.82 (1H, t, J = 12.7 Hz), 3.10 (2H, d, J = 5.7 Hz), 3.20 (1H, t, J = 13.5 Hz), 3.25 (2H, s), 3.44-3.58 (1H, m), 3.64 (2H, s), 3.98 (1H, d , J = 12.7 Hz), 4.60 (1H, d, J = 14.3 Hz), 7.30 (2H, d, J = 10.2 Hz), 7.39 (1H, d, J = 8. 2 Hz), 7.49 (2H, t, J = 7.6 Hz), 7.52-7.57 (1 H, m), 7.59 (1 H, t, J = 7.6 Hz), 7.94 ( 2H, d, J = .6Hz).

LC / MS [Condition 1]: Retention time 3.42 minutes; m / z 643.8 [M + H] ⁺ (ESI positive ion mode), m / z 677.9 [M + Cl] ⁻ , 687.9 [M + HCOO] ⁻ (ESI Negative ion mode)

参考例３８６
６−（ブロモメチル）ニコチノニトリルの製造
６−メチルニコチノニトリル（市販）（０．３０ｇ、２．５ｍｍｏｌ）を四塩化炭素（６．０ｍＬ）に溶解し、Ｎ−ブロモコハク酸イミド（０．５０ｇ、２．８ｍｍｏｌ）及びアゾビスイソブチロニトリル（４１ｍｇ、０．２５ｍｍｏｌ）を加えた後、６０℃にて２日間かき混ぜた。反応終了後、チオ硫酸ナトリウム水溶液（８．０ｍＬ）と酢酸エチル（２０ｍＬ）を加えて、有機層を分離した。得られた有機層を無水硫酸ナトリウムで乾燥、減圧下濃縮乾固した後、シリカゲルカラムクロマトグラフィ−［充填剤：株式会社山善製ＨＩ−ＦＬＡＳＨ（登録商標）ＣＯＬＵＭＮｓｉｌｉｃａｇｅｌ４０μｍ、展開溶媒：酢酸エチル／メタノ−ル＝１／０→１／１］にて精製し、表題化合物（５０ｍｇ、収率１０％）を無色油状物として得た。

^１Ｈ−ＮＭＲ（ＣＤＣｌ_３）δ：４．５７（２Ｈ，ｓ），７．６０（１Ｈ，ｄ，Ｊ＝８．２Ｈｚ），７．９９（１Ｈ，ｄｄ，Ｊ＝８．２，２．０Ｈｚ），８．８５（１Ｈ，ｄ，Ｊ＝２．０Ｈｚ）．

ＬＣ／ＭＳ［条件１］：保持時間２．３５分；ｍ／ｚ１９６．８［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）

Reference Example 386
Preparation of 6- (bromomethyl) nicotinonitrile 6-Methylnicotinonitrile (commercially available) (0.30 g, 2.5 mmol) was dissolved in carbon tetrachloride (6.0 mL) and N-bromosuccinimide (0.50 g) 2.8 mmol) and azobisisobutyronitrile (41 mg, 0.25 mmol) were added, followed by stirring at 60 ° C. for 2 days. After completion of the reaction, an aqueous sodium thiosulfate solution (8.0 mL) and ethyl acetate (20 mL) were added, and the organic layer was separated. The obtained organic layer was dried over anhydrous sodium sulfate and concentrated to dryness under reduced pressure, followed by silica gel column chromatography [filler: HI-FLASH (registered trademark) COLUMNsilica gel 40 μm manufactured by Yamazen Co., Ltd., developing solvent: ethyl acetate / methanol. = 1/0 → 1/1] to give the title compound (50 mg, yield 10%) as a colorless oil.

¹ H-NMR (CDCl ₃ ) δ: 4.57 (2H, s), 7.60 (1H, d, J = 8.2 Hz), 7.99 (1H, dd, J = 8.2, 2. 0 Hz), 8.85 (1H, d, J = 2.0 Hz).

LC / MS [Condition 1]: Retention time 2.35 minutes; m / z 196.8 [M + H] ⁺ (ESI positive ion mode)

実施例３８６
６−［（３−｛［（１ｒ，４ｒ）−４−（４−ベンゾイルピペリジン−１−カルボニル）シクロヘキシル］メチル｝−２−オキソ−１−オキサ−３，８−ジアザスピロ［４．５］デカン−８−イル）メチル］ニコチノニトリル（化合物番号３８６）の製造
１−（ブロモメチル）−２，４−ビス（トリフルオロメチル）ベンゼンの代わりに、参考例３８６で得られた、６−（ブロモメチル）ニコチノニトリルを用いること以外は実質的に実施例２５５と同様に反応を行なって、表題化合物（４２ｍｇ、収率９０％）を白色粉末として得た。

^１Ｈ−ＮＭＲ（ＣＤＣｌ_３）δ：１．０５（２Ｈ，ｑ，Ｊ＝１２．１Ｈｚ），１．４７−２．０２（１１Ｈ，ｍ），２．４７（１Ｈ，ｔｔ，Ｊ＝１１．６，３．６Ｈｚ），２．５４−２．７４（４Ｈ，ｂｒ ｍ），２．８１（１Ｈ，ｔｄ，Ｊ＝１３．２，２．３Ｈｚ），３．１１（２Ｈ，ｄ，Ｊ＝７．６Ｈｚ），３．２０（１Ｈ，ｔ，Ｊ＝１３．０Ｈｚ），３．２８（２Ｈ，ｓ），３．５２（１Ｈ，ｔｔ，Ｊ＝１０．６，３．９Ｈｚ），３．７６（２Ｈ，ｓ），３．９８（１Ｈ，ｄ，Ｊ＝１３．２Ｈｚ），４．６０（１Ｈ，ｄ，Ｊ＝１３．２Ｈｚ），７．４９（２Ｈ，ｔ，Ｊ＝７．４Ｈｚ），７．５８（１Ｈ，ｄ，Ｊ＝７．９Ｈｚ），７．５９（１Ｈ，ｔ，Ｊ＝７．４Ｈｚ），７．９０−７．９８（１Ｈ，ｍ），７．９４（１Ｈ，ｄｄ，Ｊ＝７．３，１．６Ｈｚ），８．８４（１Ｈ，ｄ，Ｊ＝１．６Ｈｚ）．

ＬＣ／ＭＳ［条件１］：保持時間３．０４分；ｍ／ｚ５８３．９［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ５８２．１［Ｍ−Ｈ］⁻、６２７．９［Ｍ＋ＨＣＯＯ］⁻（ＥＳＩ負イオンモード）

Example 386
6-[(3-{[(1r, 4r) -4- (4-Benzoylpiperidine-1-carbonyl) cyclohexyl] methyl} -2-oxo-1-oxa-3,8-diazaspiro [4.5] decane Preparation of -8-yl) methyl] nicotinonitrile (Compound No. 386) 6- (Bromomethyl) obtained in Reference Example 386 instead of 1- (bromomethyl) -2,4-bis (trifluoromethyl) benzene ) The reaction was carried out in substantially the same manner as in Example 255 except that nicotinonitrile was used to obtain the title compound (42 mg, yield 90%) as a white powder.

¹ H-NMR (CDCl ₃ ) δ: 1.05 (2H, q, J = 12.1 Hz), 1.47-2.02 (11H, m), 2.47 (1H, tt, J = 1.11. 6, 3.6 Hz), 2.54-2.74 (4H, br m), 2.81 (1H, td, J = 13.2, 2.3 Hz), 3.11 (2H, d, J = 7.6 Hz), 3.20 (1 H, t, J = 13.0 Hz), 3.28 (2 H, s), 3.52 (1 H, tt, J = 10.6, 3.9 Hz), 3. 76 (2H, s), 3.98 (1H, d, J = 13.2 Hz), 4.60 (1H, d, J = 13.2 Hz), 7.49 (2H, t, J = 7.4 Hz) ), 7.58 (1H, d, J = 7.9 Hz), 7.59 (1H, t, J = 7.4 Hz), 7.90-7.98 (1H, m), 7.94 (1H , Dd, J = .3,1.6Hz), 8.84 (1H, d, J = 1.6Hz).

LC / MS [Condition 1]: Retention time 3.04 minutes; m / z 583.9 [M + H] ⁺ (ESI positive ion mode), m / z 582.1 [M−H] ⁻ , 627.9 [M + HCOO] ⁻ (ESI negative ion mode)

参考例３８７
５−（ブロモメチル）ピコリノニトリルの製造
６−メチルニコチノニトリルの代わりに、５−メチルピコリノニトリル（市販）を用いること以外は実質的に参考例３８６と同様に反応を行なって、表題化合物（０．５９ｇ、収率７１％）を白色粉末として得た。

^１Ｈ−ＮＭＲ（ＣＤＣｌ_３）δ：４．５２（２Ｈ，ｓ），７．７２（１Ｈ，ｄ，Ｊ＝８．２Ｈｚ），７．９１（１Ｈ，ｄｄ，Ｊ＝８．２，２．５Ｈｚ），８．７４（１Ｈ，ｄ，Ｊ＝２．５Ｈｚ）．

ＬＣ／ＭＳ［条件１］：保持時間２．９４分；ｍ／ｚ１９６．９［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）

Reference Example 387
Preparation of 5- (bromomethyl) picolinonitrile The title compound was reacted in the same manner as in Reference Example 386 except that 5-methylpicolinonitrile (commercially available) was used instead of 6-methylnicotinonitrile. (0.59 g, 71% yield) was obtained as a white powder.

¹ H-NMR (CDCl ₃ ) δ: 4.52 (2H, s), 7.72 (1H, d, J = 8.2 Hz), 7.91 (1H, dd, J = 8.2, 2. 5 Hz), 8.74 (1H, d, J = 2.5 Hz).

LC / MS [Condition 1]: Retention time 2.94 minutes; m / z 196.9 [M + H] ⁺ (ESI positive ion mode)

実施例３８７
５−［（３−｛［（１ｒ，４ｒ）−４−（４−ベンゾイルピペリジン−１−カルボニル）シクロヘキシル］メチル｝−２−オキソ−１−オキサ−３，８−ジアザスピロ［４．５］デカン−８−イル）メチル］ピコリノニトリル（化合物番号３８７）の製造
１−（ブロモメチル）−２，４−ビス（トリフルオロメチル）ベンゼンの代わりに、参考例３８７で得られた、５−（ブロモメチル）ピコリノニトリルを用いること以外は実質的に実施例２５５と同様に反応を行なって、表題化合物（２５ｍｇ、収率５３％）を白色粉末として得た。

^１Ｈ−ＮＭＲ（ＣＤＣｌ_３）δ：１．０５（２Ｈ，ｑ，Ｊ＝１１．９Ｈｚ），１．４５−２．０１（４Ｈ，ｍ），２．４７（１Ｈ，ｔ，Ｊ＝１１．９Ｈｚ），２．５２−２．６４（４Ｈ，ｂｒ ｍ），２．８１（１Ｈ，ｔ，Ｊ＝１２．９Ｈｚ），３．１１（２Ｈ，ｄ，Ｊ＝６．５Ｈｚ），３．２０（１Ｈ，ｔ，Ｊ＝１２．５Ｈｚ），３．２７（２Ｈ，ｓ），３．５２（１Ｈ，ｔ，Ｊ＝１１．１Ｈｚ），３．６１（２Ｈ，ｓ），３．９８（１Ｈ，ｄ，Ｊ＝１３．５Ｈｚ），４．６０（１Ｈ，ｄ，Ｊ＝１３．５Ｈｚ），７．４９（２Ｈ，ｔ，Ｊ＝７．４Ｈｚ），７．５９（１Ｈ，ｔ，Ｊ＝７．４Ｈｚ），７．６６（１Ｈ，ｄ，Ｊ＝７．８Ｈｚ），７．８１（１Ｈ，ｄ，Ｊ＝７．８Ｈｚ），７．９４（２Ｈ，ｄ，Ｊ＝７．４Ｈｚ），８．６８（１Ｈ，ｓ）．

ＬＣ／ＭＳ［条件１］：保持時間３．１０分；ｍ／ｚ５８３．９［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ６１８．０［Ｍ＋Ｃｌ］⁻、６２７．９［Ｍ＋ＨＣＯＯ］⁻（ＥＳＩ負イオンモード）

Example 387
5-[(3-{[(1r, 4r) -4- (4-benzoylpiperidine-1-carbonyl) cyclohexyl] methyl} -2-oxo-1-oxa-3,8-diazaspiro [4.5] decane Preparation of -8-yl) methyl] picolinonitrile (Compound No. 387) 5- (bromomethyl) obtained in Reference Example 387 instead of 1- (bromomethyl) -2,4-bis (trifluoromethyl) benzene ) The reaction was carried out in substantially the same manner as in Example 255 except that picolinonitrile was used to obtain the title compound (25 mg, yield 53%) as a white powder.

¹ H-NMR (CDCl ₃ ) δ: 1.05 (2H, q, J = 11.9 Hz), 1.45-2.01 (4H, m), 2.47 (1H, t, J = 1.11. 9 Hz), 2.52-2.64 (4 H, br m), 2.81 (1 H, t, J = 12.9 Hz), 3.11 (2 H, d, J = 6.5 Hz), 3.20 (1H, t, J = 12.5 Hz), 3.27 (2H, s), 3.52 (1H, t, J = 11.1 Hz), 3.61 (2H, s), 3.98 (1H , D, J = 13.5 Hz), 4.60 (1H, d, J = 13.5 Hz), 7.49 (2H, t, J = 7.4 Hz), 7.59 (1H, t, J = 7.4 Hz), 7.66 (1H, d, J = 7.8 Hz), 7.81 (1H, d, J = 7.8 Hz), 7.94 (2H, d, J = 7.4 Hz), 8.68 (1H s).

LC / MS [Condition 1]: Retention time 3.10 minutes; m / z 583.9 [M + H] ⁺ (ESI positive ion mode), m / z 618.0 [M + Cl] ⁻ , 627.9 [M + HCOO] ⁻ (ESI Negative ion mode)

実施例３８８
３−｛［（１ｒ，４ｒ）−４−（４−ベンゾイルピペリジン−１−カルボニル）シクロヘキシル］メチル｝−８−［２−メトキシ−４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−２−オン（化合物番号３８８）の製造
６−（トリフルオロメチル）ニコチンアルデヒドの代わりに、２−メトキシ−４−（トリフルオロメチル）ベンズアルデヒド（市販）を用いること以外は実質的に実施例３８４と同様に反応を行なって、表題化合物（１３ｍｇ、収率２４％）を無色無定形物として得た。

^１Ｈ−ＮＭＲ（ＣＤＣｌ_３）δ：１．０５（２Ｈ，ｑ，Ｊ＝１１．９Ｈｚ），１．４５−２．０３（１５Ｈ，ｍ），２．４７（１Ｈ，ｔ，Ｊ＝１１．７Ｈｚ），２．５４−２．７３（４Ｈ，ｂｒ ｍ），２．８１（１Ｈ，ｔ，Ｊ＝１２．２Ｈｚ），３．１１（２Ｈ，ｄ，Ｊ＝７．３Ｈｚ），３．２０（１Ｈ，ｔ，Ｊ＝１１．９Ｈｚ），３．２６（２Ｈ，ｓ），３．５２（１Ｈ，ｔｔ，Ｊ＝１０．９，３．３Ｈｚ），３．６１（２Ｈ，ｓ），３．８７（３Ｈ，ｓ），３．９８（１Ｈ，ｄ，Ｊ＝１４．２Ｈｚ），４．６０（１Ｈ，ｄ，Ｊ＝１３．２Ｈｚ），７．０６（１Ｈ，ｓ），７．２０（１Ｈ，ｄ，Ｊ＝７．６Ｈｚ），７．４９（３Ｈ，ｔ，Ｊ＝７．６Ｈｚ），７．５９（１Ｈ，ｔ，Ｊ＝７．６Ｈｚ），７．９４（２Ｈ，ｄ，Ｊ＝７．６Ｈｚ）．

ＬＣ／ＭＳ［条件１］：保持時間３．３８分；ｍ／ｚ６５５．８［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ６９０．２［Ｍ＋Ｃｌ］⁻、６９９．６［Ｍ＋ＨＣＯＯ］⁻（ＥＳＩ負イオンモード）

Example 388
3-{[(1r, 4r) -4- (4-benzoylpiperidine-1-carbonyl) cyclohexyl] methyl} -8- [2-methoxy-4- (trifluoromethyl) benzyl] -1-oxa-3, Preparation of 8-diazaspiro [4.5] decan-2-one (Compound No. 388) Instead of 6- (trifluoromethyl) nicotinaldehyde, 2-methoxy-4- (trifluoromethyl) benzaldehyde (commercially available) is used. In substantially the same manner as in Example 384, the title compound (13 mg, yield 24%) was obtained as a colorless amorphous product.

¹ H-NMR (CDCl ₃ ) δ: 1.05 (2H, q, J = 11.9 Hz), 1.45-2.03 (15H, m), 2.47 (1H, t, J = 1.11. 7Hz), 2.54-2.73 (4H, br m), 2.81 (1H, t, J = 12.2 Hz), 3.11 (2H, d, J = 7.3 Hz), 3.20 (1H, t, J = 11.9 Hz), 3.26 (2H, s), 3.52 (1H, tt, J = 10.9, 3.3 Hz), 3.61 (2H, s), 3 .87 (3H, s), 3.98 (1H, d, J = 14.2 Hz), 4.60 (1H, d, J = 13.2 Hz), 7.06 (1H, s), 7.20 (1H, d, J = 7.6 Hz), 7.49 (3H, t, J = 7.6 Hz), 7.59 (1H, t, J = 7.6 Hz), 7.94 (2H, d, J = 7.6 Hz .

LC / MS [Condition 1]: Retention time 3.38 minutes; m / z 655.8 [M + H] ⁺ (ESI positive ion mode), m / z 690.2 [M + Cl] ⁻ , 699.6 [M + HCOO] ⁻ (ESI Negative ion mode)

参考例３８９
５−（トリフルオロメチル）ピコリンアルデヒドの製造
５−（トリフルオロメチル）ピコリン酸メチル（市販）（１．０ｇ、４．９ｍｍｏｌ）をジクロロメタン（３０ｍＬ）に溶解し、−７８℃にて水素化ジイソブチルアルミニウム （１７％トルエン溶液、約１．０ｍｏｌ／Ｌ）（１５ｍＬ、１５ｍｍｏｌ）を加えた後、−７８℃にて２０分間かき混ぜた。反応終了後、飽和酒石酸カリウムナトリウム水溶液（５０ｍＬ）とクロロホルム（２５ｍＬ）を加えて、１時間激しく撹拌した後、有機層を分離した。得られた有機層を無水硫酸ナトリウムで乾燥、減圧下濃縮乾固した後、シリカゲルカラムクロマトグラフィ−［充填剤：株式会社山善製ＨＩ−ＦＬＡＳＨ（登録商標）ＣＯＬＵＭＮｓｉｌｉｃａｇｅｌ４０μｍ、展開溶媒：ヘキサン／酢酸エチル＝９／１→１／１］にて精製し、表題化合物（０．２４ｇ、収率２８％）を無色油状物として得た。

^１Ｈ−ＮＭＲ（ＣＤＣｌ_３）δ：８．１０（１Ｈ，ｄ，Ｊ＝８．２Ｈｚ），８．１７（１Ｈ，ｄｄ，Ｊ＝８．２，１．２Ｈｚ），９．０７（１Ｈ，ｄ，Ｊ＝１．２Ｈｚ），１０．１５（１Ｈ，ｓ）．

ＬＣ／ＭＳ［条件１］：保持時間２．６９分；ｍ／ｚ１７５．９［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）

Reference Example 389
Preparation of 5- (trifluoromethyl) picolinaldehyde Methyl 5- (trifluoromethyl) picolinate (commercially available) (1.0 g, 4.9 mmol) was dissolved in dichloromethane (30 mL), and diisobutyl hydride at −78 ° C. Aluminum (17% toluene solution, about 1.0 mol / L) (15 mL, 15 mmol) was added, and the mixture was stirred at −78 ° C. for 20 minutes. After completion of the reaction, a saturated aqueous solution of potassium sodium tartrate (50 mL) and chloroform (25 mL) were added and stirred vigorously for 1 hour, and then the organic layer was separated. The obtained organic layer was dried over anhydrous sodium sulfate and concentrated to dryness under reduced pressure, followed by silica gel column chromatography [filler: HI-FLASH (registered trademark) COLUMNsilica gel 40 μm manufactured by Yamazen Co., Ltd., developing solvent: hexane / ethyl acetate = 9. / 1/1/1] to give the title compound (0.24 g, 28% yield) as a colorless oil.

¹ H-NMR (CDCl ₃ ) δ: 8.10 (1H, d, J = 8.2 Hz), 8.17 (1H, dd, J = 8.2, 1.2 Hz), 9.07 (1H, d, J = 1.2 Hz), 10.15 (1H, s).

LC / MS [Condition 1]: Retention time 2.69 minutes; m / z 175.9 [M + H] ⁺ (ESI positive ion mode)

実施例３８９
３−｛［（１ｒ，４ｒ）−４−（４−ベンゾイルピペリジン−１−カルボニル）シクロヘキシル］メチル｝−８−｛［５−（トリフルオロメチル）ピリジン−２−イル］メチル｝−１−オキサ−３，８−ジアザスピロ［４．５］デカン−２−オン（化合物番号３８９）の製造
６−（トリフルオロメチル）ニコチンアルデヒドの代わりに、参考例３８９で得られた、５−（トリフルオロメチル）ピコリンアルデヒドを用いること以外は実質的に実施例３８４と同様に反応を行なって、表題化合物（１２ｍｇ、収率１９％）を白色粉末として得た。

^１Ｈ−ＮＭＲ（ＣＤＣｌ_３）δ：１．０５（２Ｈ，ｑ，Ｊ＝１１．４Ｈｚ），１．４０−２．０３（１１Ｈ，ｍ），２．４７（１Ｈ，ｔ，Ｊ＝１１．７Ｈｚ），２．５５−２．７３（４Ｈ，ｂｒ ｍ），２．８２（１Ｈ，ｔ，Ｊ＝１１．４Ｈｚ），３．１１（２Ｈ，ｄ，Ｊ＝６．６Ｈｚ），３．２１（１Ｈ，ｔ，Ｊ＝１２．９Ｈｚ），３．２８（２Ｈ，ｓ），３．５２（１Ｈ，ｔｔ，Ｊ＝１０．５，３．６Ｈｚ），３．７６（２Ｈ，ｓ），３．９９（１Ｈ，ｄ，Ｊ＝１２．９Ｈｚ），４．６０（１Ｈ，ｄ，Ｊ＝１３．２Ｈｚ），７．４９（４Ｈ，ｔ，Ｊ＝７．６Ｈｚ），７．５６（１Ｈ，ｄ，Ｊ＝８．３Ｈｚ），７．５９（１Ｈ，ｔ，Ｊ＝７．６Ｈｚ），７．９０（１Ｈ，ｄｄ，Ｊ＝８．３，２．３Ｈｚ），７．９５（２Ｈ，ｄ，Ｊ＝７．６Ｈｚ），８．８３（１Ｈ，ｓ）．

ＬＣ／ＭＳ［条件１］：保持時間３．２２分；ｍ／ｚ６２６．８［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ６６０．８［Ｍ＋Ｃｌ］⁻、６７１．０［Ｍ＋ＨＣＯＯ］⁻（ＥＳＩ負イオンモード）

Example 389
3-{[(1r, 4r) -4- (4-Benzoylpiperidine-1-carbonyl) cyclohexyl] methyl} -8-{[5- (trifluoromethyl) pyridin-2-yl] methyl} -1-oxa Preparation of 3,8-diazaspiro [4.5] decan-2-one (Compound No. 389) Instead of 6- (trifluoromethyl) nicotinaldehyde, 5- (trifluoromethyl) obtained in Reference Example 389 ) The reaction was carried out in substantially the same manner as in Example 384 except that picolinaldehyde was used to obtain the title compound (12 mg, yield 19%) as a white powder.

¹ H-NMR (CDCl ₃ ) δ: 1.05 (2H, q, J = 11.4 Hz), 1.40-2.03 (11H, m), 2.47 (1H, t, J = 1.11. 7 Hz), 2.55-2.73 (4 H, br m), 2.82 (1 H, t, J = 11.4 Hz), 3.11 (2 H, d, J = 6.6 Hz), 3.21 (1H, t, J = 12.9 Hz), 3.28 (2H, s), 3.52 (1H, tt, J = 10.5, 3.6 Hz), 3.76 (2H, s), 3 .99 (1H, d, J = 12.9 Hz), 4.60 (1H, d, J = 13.2 Hz), 7.49 (4H, t, J = 7.6 Hz), 7.56 (1H, d, J = 8.3 Hz), 7.59 (1H, t, J = 7.6 Hz), 7.90 (1H, dd, J = 8.3, 2.3 Hz), 7.95 (2H, d , J = 7.6 z), 8.83 (1H, s).

LC / MS [Condition 1]: retention time 3.22 minutes; m / z 626.8 [M + H] ⁺ (ESI positive ion mode), m / z 660.8 [M + Cl] ⁻ , 671.0 [M + HCOO] ⁻ (ESI Negative ion mode)

参考例３９０−１
３−（３−シアノフェノキシ）アゼチジン−１−カルボン酸ｔ−ブチルの製造
６−クロロニコチノニトリルの代わりに、３−フルオロベンゾニトリル（市販）を用いること以外は実質的に参考例３８１−１と同様に反応を行なって、表題化合物（０．６６ｇ、収率８３％）を無色油状物として得た。

^１Ｈ−ＮＭＲ（ＣＤＣｌ_３）δ：１．４６（９Ｈ，ｓ），４．００（２Ｈ，ｄｄ，Ｊ＝９．８，４．１Ｈｚ），４．３４（２Ｈ，ｄｄ，Ｊ＝９．８，６．５Ｈｚ），４．９０（１Ｈ，ｔｔ，Ｊ＝６．５，４．１Ｈｚ），６．９９（１Ｈ，ｂｒ ｓ），７．００（１Ｈ，ｄｄ，Ｊ＝８．０，２．０Ｈｚ），７．３０（１Ｈ，ｄｄ，Ｊ＝７．４，２．０Ｈｚ），７．４０（１Ｈ，ｔ，Ｊ＝７．４Ｈｚ）．

ＬＣ／ＭＳ［条件１］：保持時間４．２７分；ｍ／ｚ２７４．９［Ｍ＋Ｈ］^＋、２１８．９［Ｍ−ｉｓｏｂｕｔｅｎｅ＋Ｈ］^＋（ＥＳＩ正イオンモード）

Reference Example 390-1
Preparation of t-butyl 3- (3-cyanophenoxy) azetidine-1-carboxylate Substantially Reference Example 381-1 except that 3-fluorobenzonitrile (commercially available) was used instead of 6-chloronicotinonitrile. The title compound (0.66 g, yield 83%) was obtained as a colorless oil.

¹ H-NMR (CDCl ₃ ) δ: 1.46 (9H, s), 4.00 (2H, dd, J = 9.8, 4.1 Hz), 4.34 (2H, dd, J = 9. 8, 6.5 Hz), 4.90 (1 H, tt, J = 6.5, 4.1 Hz), 6.99 (1 H, br s), 7.00 (1 H, dd, J = 8.0, 2.0 Hz), 7.30 (1H, dd, J = 7.4, 2.0 Hz), 7.40 (1H, t, J = 7.4 Hz).

LC / MS [Condition 1]: Retention time 4.27 minutes; m / z 274.9 [M + H] ⁺ , 218.9 [M-isobutene + H] ⁺ (ESI positive ion mode)

参考例３９０−２
３−（アゼチジン−３−イルオキシ）ベンゾニトリル塩酸塩の製造
２−オキソ−３−［（（１ｒ，４ｒ）−４−｛［（テトラヒドロフラン−２−イル）メチル］カルバモイル｝シクロヘキシル）メチル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−８−カルボン酸ｔ−ブチルの代わりに、参考例３９０−１で得られた、３−（３−シアノフェノキシ）アゼチジン−１−カルボン酸ｔ−ブチルを用いること以外は実質的に実施例３と同様に反応を行なって、表題化合物（０．４７ｇ、収率９２％）を白色粉末として得た。

^１Ｈ−ＮＭＲ（ＣＤ_３ＯＤ）δ：４．１６（２Ｈ，ｄｄ，Ｊ＝１２．７，４．５Ｈｚ），４．５８（２Ｈ，ｄｄ，Ｊ＝１２．７，６．１Ｈｚ），５．２１（１Ｈ，ｔｔ，Ｊ＝６．１，４．５Ｈｚ），７．２１（１Ｈ，ｄｄｄ，Ｊ＝８．２，２．５，１．２Ｈｚ），７．２５（１Ｈ，ｄｄ，Ｊ＝２．５，１．２Ｈｚ），７．４１（１Ｈ，ｄｔ，Ｊ＝７．７，１．２Ｈｚ），７．５２（１Ｈ，ｔ，Ｊ＝８．２Ｈｚ）．

ＬＣ／ＭＳ［条件１］：保持時間０．５１分；ｍ／ｚ１７５．０［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）

Reference Example 390-2
Preparation of 3- (azetidin-3-yloxy) benzonitrile hydrochloride 2-oxo-3-[((1r, 4r) -4-{[(tetrahydrofuran-2-yl) methyl] carbamoyl} cyclohexyl) methyl] -1 3- (3-Cyanophenoxy) azetidine-1-carboxylic acid obtained in Reference Example 390-1 instead of t-butyl oxa-3,8-diazaspiro [4.5] decane-8-carboxylate The reaction was carried out substantially in the same manner as in Example 3 except for using t-butyl to obtain the title compound (0.47 g, yield 92%) as a white powder.

¹ H-NMR (CD ₃ OD) δ: 4.16 (2H, dd, J = 12.7, 4.5 Hz), 4.58 (2H, dd, J = 12.7, 6.1 Hz), 5 .21 (1H, tt, J = 6.1, 4.5 Hz), 7.21 (1H, ddd, J = 8.2, 2.5, 1.2 Hz), 7.25 (1H, dd, J = 2.5, 1.2 Hz), 7.41 (1H, dt, J = 7.7, 1.2 Hz), 7.52 (1H, t, J = 8.2 Hz).

LC / MS [Condition 1]: Retention time 0.51 min; m / z 175.0 [M + H] ⁺ (ESI positive ion mode)

実施例３９０
３−｛１−［（１ｒ，４ｒ）−４−（｛２−オキソ−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）シクロヘキサンカルボニル］アゼチジン−３−イルオキシ｝ベンゾニトリル（化合物番号３９０）の製造

ピペリジンの代わりに、参考例３９０−２で得られた３−（アゼチジン−３−イルオキシ）ベンゾニトリル塩酸塩を用いること以外は実質的に実施例１６と同様に反応を行なって、表題化合物（３６ｍｇ、収率７３％）を白色粉末として得た。

^１Ｈ−ＮＭＲ（ＣＤＣｌ_３）δ：１．０２（２Ｈ，ｄｑ，Ｊ＝４．５，１１．９Ｈｚ），１．５３（２Ｈ，ｄｑ，Ｊ＝２．５，１１．５Ｈｚ），１．５８−２．００（９Ｈ，ｍ），２．１４（１Ｈ，ｔｔ，Ｊ＝１１．９，３．３Ｈｚ），２．４３−２．６５（４Ｈ，ｂｒ ｍ），３．１０（２Ｈ，ｄ，Ｊ＝７．４Ｈｚ），３．２５（２Ｈ，ｓ），３．５７（２Ｈ，ｓ），４．０４（１Ｈ，ｄｄ，Ｊ＝１１．３，３．９Ｈｚ），４．１９（１Ｈ，ｄｄ，Ｊ＝９．４，３．９Ｈｚ），４．３９（１Ｈ，ｄｄ，Ｊ＝１０．６，６．５Ｈｚ），４．５５（１Ｈ，ｄｄ，Ｊ＝８．６，６．５Ｈｚ），４．９６（１Ｈ，ｔｔ，Ｊ＝６．５，３．９Ｈｚ），６．９９（１Ｈ，ｄ，Ｊ＝１．２Ｈｚ），７．０１（１Ｈ，ｄｄｄ，Ｊ＝９．０，２．９，０．８Ｈｚ），７．３２（１Ｈ，ｄｔ，Ｊ＝７．８，１．２Ｈｚ），７．４２（１Ｈ，ｔ，Ｊ＝８．６Ｈｚ），７．４４（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ），７．５７（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ）．

ＬＣ／ＭＳ［条件１］：保持時間３．３０分；ｍ／ｚ６１０．７［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ６５４．９［Ｍ＋ＨＣＯＯ］⁻（ＥＳＩ負イオンモード）

Example 390
3- {1-[(1r, 4r) -4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decane-3 -Il} methyl) cyclohexanecarbonyl] azetidin-3-yloxy} benzonitrile (Compound No. 390)

The reaction was conducted in substantially the same manner as in Example 16 except that 3- (azetidin-3-yloxy) benzonitrile hydrochloride obtained in Reference Example 390-2 was used instead of piperidine to give the title compound (36 mg Yield 73%) as a white powder.

¹ H-NMR (CDCl ₃ ) δ: 1.02 (2H, dq, J = 4.5, 11.9 Hz), 1.53 (2H, dq, J = 2.5, 11.5 Hz), 1. 58-2.00 (9H, m), 2.14 (1H, tt, J = 11.9, 3.3 Hz), 2.43-2.65 (4H, br m), 3.10 (2H, d, J = 7.4 Hz), 3.25 (2H, s), 3.57 (2H, s), 4.04 (1H, dd, J = 11.3, 3.9 Hz), 4.19 ( 1H, dd, J = 9.4, 3.9 Hz), 4.39 (1H, dd, J = 10.6, 6.5 Hz), 4.55 (1H, dd, J = 8.6, 6. 5 Hz), 4.96 (1H, tt, J = 6.5, 3.9 Hz), 6.99 (1H, d, J = 1.2 Hz), 7.01 (1H, ddd, J = 9.0) , 2.9, 0.8H ), 7.32 (1H, dt, J = 7.8, 1.2 Hz), 7.42 (1H, t, J = 8.6 Hz), 7.44 (2H, d, J = 8.2 Hz) 7.57 (2H, d, J = 8.2 Hz).

LC / MS [Condition 1]: Retention time 3.30 minutes; m / z 610.7 [M + H] ⁺ (ESI positive ion mode), m / z 654.9 [M + HCOO] ⁻ (ESI negative ion mode)

参考例３９１−１
４−［４−（トリフルオロメチル）フェニルアミノ］ピペリジン−１−カルボン酸ｔ−ブチルの製造
１−（ｔ−ブトキシカルボニル）−４−ピペリドン（１．０ｇ、５．０ｍｍｏｌ）を１，２−ジクロロエタン（１０ｍＬ）に溶解し、室温にて４−（トリフルオロメチル）アニリン（０．９７ｇ、６．０ｍｍｏｌ）及び酢酸（１．２ｍＬ、２０ｍｍｏｌ）を加えた後、８０℃にて９時間かき混ぜた。反応混合物を室温まで放冷した後、ナトリウムトリアセトキシボロヒドリド（１．３ｇ、６．０ｍｍｏｌ）を加え、室温にて１２時間かき混ぜた。反応終了後、水（１０ｍＬ）と飽和炭酸水素ナトリウム水溶液（２０ｍＬ）とクロロホルム（６０ｍＬ）を加えて、有機層を分離した。得られた有機層を無水硫酸ナトリウムで乾燥、減圧下濃縮乾固した後、アセトン（１０ｍＬ）を加え析出した固体をろ取、減圧下乾燥し、表題化合物（１．１ｇ、収率６２％）を白色粉末として得た。

^１Ｈ−ＮＭＲ（ＣＤＣｌ_３）δ：１．３５（３Ｈ，ｄｑ，Ｊ＝４．９，１２．７Ｈｚ），１．４７（９Ｈ，ｓ），２．０４（２Ｈ，ｄｄ，Ｊ＝１２．７，３．３Ｈｚ），２．９４（２Ｈ，ｔ，Ｊ＝１１．７Ｈｚ），３．３９−３．５４（１Ｈ，ｍ），３．８７（１Ｈ，ｄ，Ｊ＝７．４Ｈｚ），４．０７（２Ｈ，ｄ，Ｊ＝１１．９Ｈｚ），６．５９（２Ｈ，ｄ，Ｊ＝８．６Ｈｚ），７．３９（２Ｈ，ｄ，Ｊ＝８．６Ｈｚ）．

ＬＣ／ＭＳ［条件１］：保持時間４．８５分；ｍ／ｚ２８８．９［Ｍ−ｉｓｏｂｕｔｅｎｅ＋Ｈ］^＋（ＥＳＩ正イオンモード）

Reference Example 391-1
Preparation of t-butyl 4- [4- (trifluoromethyl) phenylamino] piperidine-1-carboxylate 1- (t-butoxycarbonyl) -4-piperidone (1.0 g, 5.0 mmol) was converted to 1,2- After dissolving in dichloroethane (10 mL) and adding 4- (trifluoromethyl) aniline (0.97 g, 6.0 mmol) and acetic acid (1.2 mL, 20 mmol) at room temperature, the mixture was stirred at 80 ° C. for 9 hours. . The reaction mixture was allowed to cool to room temperature, sodium triacetoxyborohydride (1.3 g, 6.0 mmol) was added, and the mixture was stirred at room temperature for 12 hr. After completion of the reaction, water (10 mL), saturated aqueous sodium hydrogen carbonate solution (20 mL) and chloroform (60 mL) were added, and the organic layer was separated. The obtained organic layer was dried over anhydrous sodium sulfate and concentrated to dryness under reduced pressure, then acetone (10 mL) was added, and the precipitated solid was collected by filtration and dried under reduced pressure to give the title compound (1.1 g, yield 62%). Was obtained as a white powder.

¹ H-NMR (CDCl ₃ ) δ: 1.35 (3H, dq, J = 4.9, 12.7 Hz), 1.47 (9H, s), 2.04 (2H, dd, J = 12. 7, 3.3 Hz), 2.94 (2H, t, J = 11.7 Hz), 3.39-3.54 (1 H, m), 3.87 (1 H, d, J = 7.4 Hz), 4.07 (2H, d, J = 11.9 Hz), 6.59 (2H, d, J = 8.6 Hz), 7.39 (2H, d, J = 8.6 Hz).

LC / MS [Condition 1]: Retention time 4.85 minutes; m / z 288.9 [M-isobutene + H] ⁺ (ESI positive ion mode)

参考例３９１−２
Ｎ−［４−（トリフルオロメチル）フェニル］ピペリジン−４−アミン二塩酸塩の製造
参考例３９１−１で得られた、４−［４−（トリフルオロメチル）フェニルアミノ］ピペリジン−１−カルボン酸ｔ−ブチル（１．１ｇ、３．１ｍｍｏｌ）をアセトニトリル（２０ｍＬ）に溶解し、室温にて１０％塩化水素−メタノ−ル溶液（６．２ｍＬ）を加え、室温にて３日間かき混ぜた。反応終了後、減圧下濃縮乾固した後、アセトン（１０ｍＬ）を加え析出した固体をろ取、減圧下乾燥し、表題化合物（０．９４ｇ、収率９５％）を白色粉末として得た。

^１Ｈ−ＮＭＲ（ＣＤ_３ＯＤ）δ：１．６５−１．８１（２Ｈ，ｍ），２．２３（２Ｈ，ｄｄ，Ｊ＝１４．３，３．７Ｈｚ），３．１５（２Ｈ，ｔｄ，Ｊ＝１１．９，２．９Ｈｚ），３．４６（２Ｈ，ｄｔ，Ｊ＝１３．０，３．７Ｈｚ），３．７２（１Ｈ，ｔｔ，Ｊ＝１０．２，４．０Ｈｚ），６．８４（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ），７．４３（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ）．

ＬＣ／ＭＳ［条件１］：保持時間１．９２分；ｍ／ｚ２４４．９［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）

Reference Example 391-2
Production of N- [4- (trifluoromethyl) phenyl] piperidin-4-amine dihydrochloride 4- [4- (trifluoromethyl) phenylamino] piperidine-1-carvone obtained in Reference Example 391-1 T-Butyl acid (1.1 g, 3.1 mmol) was dissolved in acetonitrile (20 mL), 10% hydrogen chloride-methanol solution (6.2 mL) was added at room temperature, and the mixture was stirred at room temperature for 3 days. After completion of the reaction, the mixture was concentrated to dryness under reduced pressure, acetone (10 mL) was added, and the precipitated solid was collected by filtration and dried under reduced pressure to give the title compound (0.94 g, yield 95%) as a white powder.

¹ H-NMR (CD ₃ OD) δ: 1.65 to 1.81 (2H, m), 2.23 (2H, dd, J = 14.3, 3.7 Hz), 3.15 (2H, td , J = 11.9, 2.9 Hz), 3.46 (2H, dt, J = 13.0, 3.7 Hz), 3.72 (1H, tt, J = 10.2, 4.0 Hz), 6.84 (2H, d, J = 8.2 Hz), 7.43 (2H, d, J = 8.2 Hz).

LC / MS [Condition 1]: Retention time 1.92 minutes; m / z 244.9 [M + H] ⁺ (ESI positive ion mode)

実施例３９１
８−［４−（トリフルオロメチル）ベンジル］−３−［（（１ｒ，４ｒ）−４−｛４−［４−（トリフルオロメチル）フェニルアミノ］ピペリジン−１−カルボニル｝シクロヘキシル）メチル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−２−オン（化合物番号３９１）の製造
ピペリジンの代わりに、参考例３９１−２で得られたＮ−［４−（トリフルオロメチル）フェニル］ピペリジン−４−アミン二塩酸塩とトリエチルアミンを用いること以外は実質的に実施例１６と同様に反応を行なって、表題化合物（４１ｍｇ、収率７３％）を白色粉末として得た。

^１Ｈ−ＮＭＲ（ＣＤＣｌ_３）δ：１．０５（２Ｈ，ｑ，Ｊ＝１２．２Ｈｚ），１．３６（２Ｈ，ｑ，Ｊ＝１２．６Ｈｚ），１．４６−１．９０（９Ｈ，ｍ），１．９４（２Ｈ，ｄ，Ｊ＝１３．２Ｈｚ），２．１４（２Ｈ，ｄ，Ｊ＝１２．９Ｈｚ），２．４７（１Ｈ，ｔ，Ｊ＝１１．７Ｈｚ），２．５１−２．７０（４Ｈ，ｂｒ ｍ），２．８５（１Ｈ，ｔ，Ｊ＝１１．６Ｈｚ），３．１１（２Ｈ，ｄ，Ｊ＝７．６Ｈｚ），３．２０（１Ｈ，ｔ，Ｊ＝１２．９Ｈｚ），３．２６（２Ｈ，ｓ），３．５１−３．６８（１Ｈ，ｂｒ ｍ），３．５７（２Ｈ，ｓ），３．８０−４．０１（２Ｈ，ｍ），４．５２（１Ｈ，ｄ，Ｊ＝１３．５Ｈｚ），６．６０（２Ｈ，ｄ，Ｊ＝８．６Ｈｚ），７．４０（２Ｈ，ｄ，Ｊ＝８．６Ｈｚ），７．４４（２Ｈ，ｄ，Ｊ＝８．３Ｈｚ），７．５７（２Ｈ，ｄ，Ｊ＝８．３Ｈｚ）．
ＬＣ／ＭＳ［条件１］：保持時間３．６８分；ｍ／ｚ６８０．９［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ７２５．０［Ｍ＋ＨＣＯＯ］⁻（ＥＳＩ負イオンモード）

Example 391
8- [4- (trifluoromethyl) benzyl] -3-[((1r, 4r) -4- {4- [4- (trifluoromethyl) phenylamino] piperidine-1-carbonyl} cyclohexyl) methyl]- Preparation of 1-oxa-3,8-diazaspiro [4.5] decan-2-one (Compound No. 391) Instead of piperidine, N- [4- (trifluoromethyl) obtained in Reference Example 391-2 Phenyl] piperidin-4-amine dihydrochloride and triethylamine were used, and the reaction was carried out in substantially the same manner as in Example 16 to obtain the title compound (41 mg, yield 73%) as a white powder.

¹ H-NMR (CDCl ₃ ) δ: 1.05 (2H, q, J = 12.2 Hz), 1.36 (2H, q, J = 12.6 Hz), 1.46-1.90 (9H, m), 1.94 (2H, d, J = 13.2 Hz), 2.14 (2H, d, J = 12.9 Hz), 2.47 (1 H, t, J = 11.7 Hz), 2. 51-2.70 (4H, br m), 2.85 (1H, t, J = 11.6 Hz), 3.11 (2H, d, J = 7.6 Hz), 3.20 (1H, t, J = 12.9 Hz), 3.26 (2H, s), 3.51-3.68 (1H, br m), 3.57 (2H, s), 3.80-4.01 (2H, m) ), 4.52 (1H, d, J = 13.5 Hz), 6.60 (2H, d, J = 8.6 Hz), 7.40 (2H, d, J = 8.6 Hz), 7.44 (2H, d, J = 8.3 Hz), 7.57 (2H, d, J = 8.3 Hz).
LC / MS [Condition 1]: Retention time 3.68 minutes; m / z 680.9 [M + H] ⁺ (ESI positive ion mode), m / z 725.0 [M + HCOO] ⁻ (ESI negative ion mode)

参考例３９２−１
６−｛［８−（４−シアノ−２，６−ジフルオロベンジル）−２−オキソ−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル］メチル｝ニコチン酸エチルの製造
参考例１１１−３で得られた３−［｛５−（エトキシカルボニル）ピリジン−２−イル｝メチル］−２−オキソ−１−オキサ−３，８−ジアザスピロ［４．５］デカン−８−カルボン酸ｔ−ブチル（０．８４ｇ，２.０ｍｍｏｌ）に、４Ｍ塩化水素−ジオキサン溶液（１０ｍＬ）を加え、室温で１０分攪拌した。反応後、反応混合物を濃縮し、得られた残留物にジクロロメタンと飽和アンモニア水を加えた。有機層を分離し、無水硫酸ナトリウムで乾燥した後、減圧下濃縮乾固した。得られた白色固体と３，５−ジフルオロ−４−ホルミルベンゾニトリル（０．４０ｇ，２．４０ｍｍｏｌ）をジクロロメタン（６.０ｍＬ）に溶解し、トリアセトキシ水素化ホウ素ナトリウム（０．６４ｇ、３．０ｍｍｏｌ）を加えて、室温で１０分攪拌した。反応後、反応混合物に水と飽和炭酸水素ナトリウム水溶液を加え、ジクロロメタンで抽出し、得られた有機層を無水硫酸ナトリウムで乾燥し、減圧下濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー［昭光サイエンティフィック社製プリフパックＳＩ６０μｍ、展開溶媒：酢酸エチル］にて精製し、表題化合物（０．８０ｇ、収率８５％）を白色固体として得た。

^１Ｈ−ＮＭＲ（３００ＭＨｚ，ＣＤＣｌ_３）δ：１．４１（３Ｈ，ｔ，Ｊ＝７．２Ｈｚ），１．６８−１．８０（２Ｈ，ｍ），１．８９−２．００（２Ｈ，ｍ），２．６２（４Ｈ，ｂｒｓ），３．３１（２Ｈ，ｓ），３．７４（２Ｈ，ｓ），４．４１（２Ｈ，ｑ，Ｊ＝７．１Ｈｚ），４．５８（２Ｈ，ｓ），７．２２（２Ｈ，ｄ，Ｊ＝６．１Ｈｚ），７．３６（１Ｈ，ｄ，Ｊ＝８．０Ｈｚ），８．２８（１Ｈ，ｄｄ，Ｊ＝８．０，１．８Ｈｚ），９．１４（１Ｈ，ｄ，Ｊ＝１．８Ｈｚ）．

ＬＣ／ＭＳ［条件１］：保持時間１．９６分；ｍ／ｚ４７０．８［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）

Reference Example 392-1
Preparation of ethyl 6-{[8- (4-cyano-2,6-difluorobenzyl) -2-oxo-1-oxa-3,8-diazaspiro [4.5] decan-3-yl] methyl} nicotinate 3-[{5- (Ethoxycarbonyl) pyridin-2-yl} methyl] -2-oxo-1-oxa-3,8-diazaspiro [4.5] decane-8- obtained in Reference Example 111-3 A 4M hydrogen chloride-dioxane solution (10 mL) was added to t-butyl carboxylate (0.84 g, 2.0 mmol), and the mixture was stirred at room temperature for 10 minutes. After the reaction, the reaction mixture was concentrated, and dichloromethane and saturated aqueous ammonia were added to the obtained residue. The organic layer was separated, dried over anhydrous sodium sulfate, and concentrated to dryness under reduced pressure. The obtained white solid and 3,5-difluoro-4-formylbenzonitrile (0.40 g, 2.40 mmol) were dissolved in dichloromethane (6.0 mL), and sodium triacetoxyborohydride (0.64 g, 3. 0 mmol) was added and stirred at room temperature for 10 minutes. After the reaction, water and a saturated aqueous sodium hydrogen carbonate solution were added to the reaction mixture, and the mixture was extracted with dichloromethane. The obtained organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography [Prefpack SI 60 μm, manufactured by Shoko Scientific Co., Ltd., developing solvent: ethyl acetate] to obtain the title compound (0.80 g, yield 85%) as a white solid.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.41 (3H, t, J = 7.2 Hz), 1.68-1.80 (2H, m), 1.89-2.00 (2H, m), 2.62 (4H, brs), 3.31 (2H, s), 3.74 (2H, s), 4.41 (2H, q, J = 7.1 Hz), 4.58 (2H) , S), 7.22 (2H, d, J = 6.1 Hz), 7.36 (1H, d, J = 8.0 Hz), 8.28 (1H, dd, J = 8.0, 1.). 8 Hz), 9.14 (1H, d, J = 1.8 Hz).

LC / MS [Condition 1]: Retention time 1.96 minutes; m / z 470.8 [M + H] ⁺ (ESI positive ion mode)

参考例３９２−２
６−｛［８−（４−シアノ−２，６−ジフルオロベンジル）−２−オキソ−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル］メチル｝ニコチン酸の製造
参考例３９２−１で得られた６−｛［８−（４−シアノ−２，６−ジフルオロベンジル）−２−オキソ−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル］メチル｝ニコチン酸エチル（０．９７ｇ，２．０５ｍｍｏｌ）のテトラヒドロフラン溶液（２０ｍＬ）に、カリウムトリメチルシラノラート（０．５３ｇ，４．１ｍｍｏｌ）を加え、室温で３時間攪拌した。反応後、４Ｍ塩化水素−ジオキサン溶液（１．０ｍＬ）を加えた後、反応混合物を濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー［昭光サイエンティフィック社製プリフパックＳＩ６０μｍ、展開溶媒：クロロホルム／メタノール＝１０／１→２／１］にて精製し、表題化合物（０．５３ｇ、収率６０％）を白色固体として得た。

^１Ｈ−ＮＭＲ（３００ＭＨｚ，ＤＭＳＯ−ｄ_６）δ：１．６８−１．８６（４Ｈ，ｍ），２．２０−２．４５（４Ｈ，ｍ），３．２９（２Ｈ，ｓ），３．６３（２Ｈ，ｓ），４．４７（２Ｈ，ｓ），７．３４（１Ｈ，ｄ，Ｊ＝８．２Ｈｚ），７．７８（２Ｈ，ｄ，Ｊ＝６．３Ｈｚ），８．２０（１Ｈ，ｄ，Ｊ＝８．２Ｈｚ），８．９７（１Ｈ，ｓ）．

ＬＣ／ＭＳ［条件１］：保持時間０．５３分；ｍ／ｚ４４２．７［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ４４０．８［Ｍ−Ｈ］^―（ＥＳＩ負イオンモード）

Reference Example 392-2
6-{[8- (4-Cyano-2,6-difluorobenzyl) -2-oxo-1-oxa-3,8-diazaspiro [4.5] decan-3-yl] methyl} nicotinic acid 6-{[8- (4-Cyano-2,6-difluorobenzyl) -2-oxo-1-oxa-3,8-diazaspiro [4.5] decan-3-yl obtained in Example 392-1 ] To a tetrahydrofuran solution (20 mL) of methyl} ethyl nicotinate (0.97 g, 2.05 mmol) was added potassium trimethylsilanolate (0.53 g, 4.1 mmol), and the mixture was stirred at room temperature for 3 hours. After the reaction, 4M hydrogen chloride-dioxane solution (1.0 mL) was added, and then the reaction mixture was concentrated. The obtained residue was purified by silica gel column chromatography [Prefpack SI 60 μm, manufactured by Shoko Scientific Co., Ltd., developing solvent: chloroform / methanol = 10/1 → 2/1], and the title compound (0.53 g, yield 60%). ) Was obtained as a white solid.

¹ H-NMR (300 MHz, DMSO-d ₆ ) δ: 1.68-1.86 (4H, m), 2.20-2.45 (4H, m), 3.29 (2H, s), 3 .63 (2H, s), 4.47 (2H, s), 7.34 (1H, d, J = 8.2 Hz), 7.78 (2H, d, J = 6.3 Hz), 8.20 (1H, d, J = 8.2 Hz), 8.97 (1H, s).

LC / MS [Condition 1]: Retention time 0.53 minutes; m / z 442.7 [M + H] ⁺ (ESI positive ion mode), m / z 440.8 [M−H] ⁻ (ESI negative ion mode)

実施例３９２
３，５−ジフルオロ−４−｛［３−（｛５−［４−（４−フルオロベンゾイル）ピペリジン−１−カルボニル］ピリジン−２−イル｝メチル）−２−オキソ−１−オキサ−３，８−ジアザスピロ［４．５］デカン−８−イル］メチル｝ベンゾニトリル（化合物番号３９２）の製造
参考例３９２−２で得られた、６−｛［８−（４−シアノ−２，６−ジフルオロベンジル）−２−オキソ−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル］メチル｝ニコチン酸（２０ｍｇ、０．０４５ｍｍｏｌ）、１−ヒドロキシベンゾトリアゾール（２ｍｇ、０．０１ｍｍｏｌ）及び（４−フルオロフェニル）（ピペリジン−４−イル）メタノン塩酸塩（市販）（１３ｍｇ、０．０５４ｍｍｏｌ）のクロロホルム（１ｍＬ）懸濁液に、トリエチルアミン（２６μＬ，０．１９ｍｍｏｌ）及び１−エチル−３−（３−ジメチルアミノプロピル）カルボジイミド塩酸塩（１３ｍｇ、０．０６８ｍｍｏｌ）を加えて、反応混合物を室温で５日間攪拌した。クエン酸（２６ｍｇ）の水（１ｍＬ）溶液を加えたのち、有機層を分離し、減圧下濃縮乾固した。残留物に酢酸エチル（１ｍＬ）と、炭酸水素ナトリウム（３ｍｇ）の水（１ｍＬ）溶液を加えて、有機層を分離し、減圧下濃縮乾固して、表題化合物（２１ｍｇ、収率72％）を無色無定形物として得た。

^１Ｈ−ＮＭＲ（ＣＤＣｌ_３）δ：１．６６−２．０９（８Ｈ，ｍ），２．４５−２．８０（４Ｈ，ｍ），２．９７−３．３６（２Ｈ，ｍ），３．３１（２Ｈ，ｓ），３．４５−３．６１（１Ｈ，ｍ），３．６９−３．９７（１Ｈ，ｂｒ ｍ），３．７４（２Ｈ，ｓ），４．５５−４．７８（１Ｈ，ｂｒ ｍ），４．５６（２Ｈ，ｓ），７．１７（２Ｈ，ｔ，Ｊ＝８．６Ｈｚ），７．２２（２Ｈ，ｄ，Ｊ＝６．５Ｈｚ），７．３５（１Ｈ，ｄ，Ｊ＝８．２Ｈｚ），７．７６（１Ｈ，ｄｄ，Ｊ＝７．８，２．５Ｈｚ），７．９９（２Ｈ，ｄｄ，Ｊ＝８．６，５．７Ｈｚ），８．６１（１Ｈ，ｄ，Ｊ＝２．５Ｈｚ）．

ＬＣ／ＭＳ［条件１］：保持時間３．１２分；ｍ／ｚ６３１．９［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ６７５．９［Ｍ＋ＨＣＯＯ］⁻（ＥＳＩ負イオンモード）

Example 392
3,5-difluoro-4-{[3-({5- [4- (4-fluorobenzoyl) piperidin-1-carbonyl] pyridin-2-yl} methyl) -2-oxo-1-oxa-3, Preparation of 8-diazaspiro [4.5] decan-8-yl] methyl} benzonitrile (Compound No. 392) 6-{[8- (4-cyano-2,6- ) obtained in Reference Example 392-2 Difluorobenzyl) -2-oxo-1-oxa-3,8-diazaspiro [4.5] decan-3-yl] methyl} nicotinic acid (20 mg, 0.045 mmol), 1-hydroxybenzotriazole (2 mg, 0. 0). 01 mmol) and (4-fluorophenyl) (piperidin-4-yl) methanone hydrochloride (commercially available) (13 mg, 0.054 mmol) in chloroform (1 mL) Amine (26 [mu] L, 0.19 mmol) and 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (13 mg, 0.068 mmol) was added and the reaction mixture was stirred at room temperature for 5 days. After adding a solution of citric acid (26 mg) in water (1 mL), the organic layer was separated and concentrated to dryness under reduced pressure. To the residue was added ethyl acetate (1 mL) and a solution of sodium hydrogen carbonate (3 mg) in water (1 mL), the organic layer was separated and concentrated to dryness under reduced pressure to give the title compound (21 mg, yield 72%). Was obtained as a colorless amorphous product.

¹ H-NMR (CDCl ₃ ) δ: 1.66 to 2.09 (8H, m), 2.45-2.80 (4H, m), 2.97-3.36 (2H, m), 3 .31 (2H, s), 3.45-3.61 (1H, m), 3.69-3.97 (1H, br m), 3.74 (2H, s), 4.55-4. 78 (1H, br m), 4.56 (2H, s), 7.17 (2H, t, J = 8.6 Hz), 7.22 (2H, d, J = 6.5 Hz), 7.35 (1H, d, J = 8.2 Hz), 7.76 (1H, dd, J = 7.8, 2.5 Hz), 7.99 (2H, dd, J = 8.6, 5.7 Hz), 8.61 (1H, d, J = 2.5 Hz).

LC / MS [Condition 1]: Retention time 3.12 minutes; m / z 631.9 [M + H] ⁺ (ESI positive ion mode), m / z 675.9 [M + HCOO] ⁻ (ESI negative ion mode)

参考例３９３−１
４−（メチルスルホニルオキシ）ピペリジン−１−カルボン酸ｔ−ブチルの製造
１−（ｔ−ブトキシカルボニル）−４−ヒドロキシピペリジン（東京化成工業社より購入）（４．０ｇ、２０ｍｍｏｌ）をテトラヒドロフラン（２０ｍｌ）に溶解し、トリエチルアミン（２．４ｇ、２４ｍｍｏｌ）とメタンスルホニルクロリド（２．７ｇ、２４ｍｍｏｌ）を加えて、０℃にて３時間激しくかき混ぜた。反応終了後、酢酸エチルと１Ｍ塩酸を加えて振とうし、有機層を分離した。有機層を飽和炭酸水素ナトリウム水溶液と飽和塩化ナトリウム水溶液で洗浄した後、無水硫酸マグネシウムで乾燥し、減圧下濃縮乾固して４−（メチルスルホニルオキシ）ピペリジン−１−カルボン酸ｔ−ブチル（５．０ｇ、収率９０％）を無色固体として得た。

ＬＣ／ＭＳ［条件１］：保持時間３．７０分；ｍ／ｚ２８０．０［Ｍ＋Ｈ］^＋、２２３．９［Ｍ−ｉｓｏｂｕｔｅｎｅ＋Ｈ］^＋（ＥＳＩ正イオンモード）

Reference Example 393-1
Production of t-butyl 4- (methylsulfonyloxy) piperidine-1-carboxylate 1- (t-butoxycarbonyl) -4-hydroxypiperidine (purchased from Tokyo Chemical Industry Co., Ltd.) (4.0 g, 20 mmol) in tetrahydrofuran (20 ml) ), Triethylamine (2.4 g, 24 mmol) and methanesulfonyl chloride (2.7 g, 24 mmol) were added, and the mixture was vigorously stirred at 0 ° C. for 3 hours. After completion of the reaction, ethyl acetate and 1M hydrochloric acid were added and shaken to separate the organic layer. The organic layer was washed with a saturated aqueous sodium bicarbonate solution and a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, concentrated to dryness under reduced pressure, and t-butyl 4- (methylsulfonyloxy) piperidine-1-carboxylate (5 0.0 g, 90% yield) was obtained as a colorless solid.

LC / MS [Condition 1]: Retention time 3.70 minutes; m / z 280.0 [M + H] ⁺ , 223.9 [M-isobutene + H] ⁺ (ESI positive ion mode)

参考例３９３−２
４−［４−（トリフルオロメチル）フェニルチオ］ピペリジン−１−カルボン酸ｔ−ブチルの製造
参考例３９３−１で合成した４−（メチルスルホニルオキシ）ピペリジン−１−カルボン酸ｔ−ブチル（０．６０ｇ、２．２ｍｍｏｌ）をＮ，Ｎ−ジメチルホルムアミドに溶解し、４−（トリフルオロメチル）ベンゼンチオール（０．５０ｇ、２．８ｍｍｏｌ）と炭酸カリウム（０．３８ｇ、２．８ｍｍｏｌ）を加えて、７０℃で３時間激しく攪拌した。反応終了後、酢酸エチルと０．５Ｍ水酸化ナトリウム水溶液を加えて振とうした。有機層を分離し、飽和塩化ナトリウム水溶液で洗浄した後、無水硫酸マグネシウムで乾燥し、減圧下濃縮乾固した。得られた残留物をシリカゲルカラムクロマトグラフィー［充填剤：Ｍｅｒｃｋ ＧＭＢＨ製シリカゲル６０（０．０４０−０．０６３ｍｍ）、展開溶媒：酢酸エチル／ヘキサン＝１／１９］にて精製し、４−［４−（トリフルオロメチル）フェニルチオ］ピペリジン−１−カルボン酸ｔ−ブチル（０．５５ｇ、収率７０％）を無色液体として得た。

ＬＣ／ＭＳ［条件１］：保持時間５．１７分；ｍ／ｚ３０５．９［Ｍ−ｉｓｏｂｕｔｅｎｅ＋Ｈ］^＋（ＥＳＩ正イオンモード）

Reference Example 393-2
Production of t-butyl 4- [4- (trifluoromethyl) phenylthio] piperidine-1-carboxylate 4- (methylsulfonyloxy) piperidine-1-carboxylate t-butyl (0. 60 g, 2.2 mmol) is dissolved in N, N-dimethylformamide and 4- (trifluoromethyl) benzenethiol (0.50 g, 2.8 mmol) and potassium carbonate (0.38 g, 2.8 mmol) are added. The mixture was vigorously stirred at 70 ° C. for 3 hours. After completion of the reaction, ethyl acetate and 0.5M aqueous sodium hydroxide solution were added and shaken. The organic layer was separated, washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated to dryness under reduced pressure. The obtained residue was purified by silica gel column chromatography [filler: silica gel 60 (0.040-0.063 mm) manufactured by Merck GMBH, developing solvent: ethyl acetate / hexane = 1/19], and 4- [4 -(Trifluoromethyl) phenylthio] piperidine-1-carboxylate t-butyl (0.55 g, yield 70%) was obtained as a colorless liquid.

LC / MS [Condition 1]: Retention time 5.17 minutes; m / z 305.9 [M-isobutene + H] ⁺ (ESI positive ion mode)

参考例３９３−３
４−（３−フルオロフェニルチオ）ピペリジン−１−カルボン酸ｔ−ブチルの製造
４−（トリフルオロメチル）ベンゼンチオールの代わりに、３−フルオロベンゼンチオールを用いること以外は実質的に参考例３９３−２と同様に反応を行って、表題化合物（０．６２ｇ、収率９３％）を無色液体として得た。

ＬＣ／ＭＳ［条件１］：保持時間４．９４分；ｍ／ｚ２５５．９［Ｍ−ｉｓｏｂｕｔｅｎｅ＋Ｈ］^＋（ＥＳＩ正イオンモード）

Reference Example 393-3
Preparation of t-butyl 4- (3-fluorophenylthio) piperidine-1-carboxylate Substantially Reference Example 393 except that 3-fluorobenzenethiol was used instead of 4- (trifluoromethyl) benzenethiol The reaction was carried out in the same manner as 2 to give the title compound (0.62 g, yield 93%) as a colorless liquid.

LC / MS [Condition 1]: Retention time 4.94 minutes; m / z 255.9 [M-isobutene + H] ⁺ (ESI positive ion mode)

参考例３９３−４
４−（３−フルオロフェニルスルホニル）ピペリジン−１−カルボン酸ｔ−ブチルの製造
参考例３９３−３で合成した４−（３−フルオロフェニルチオ）ピペリジン−１−カルボン酸ｔ−ブチル（０．３１ｇ、０．９９ｍｍｏｌ）をメタノールに溶解し、３０％過酸化水素水（０．４５ｍｌ、４．０ｍｍｏｌ）とヘプタモリブデン酸ヘキサアンモニウム四水和物（０．１２ｇ、０．１０ｍｍｏｌ）を加えて、室温下、４日間激しく攪拌した。反応終了後、氷冷下、反応混合物にチオ硫酸ナトリウム（０．６３ｇ、４．０ｍｍｏｌ）、水とクロロホルムを加えて振とうし、有機層を分離した後、水層をクロロホルムで３回抽出した。合わせた有機層を無水硫酸マグネシウムで乾燥した後、減圧下濃縮乾固し、４−（３−フルオロフェニルスルホニル）ピペリジン−１−カルボン酸ｔ−ブチル（０．２９ｇ、収率８６％）を無色固体として得た。

ＬＣ／ＭＳ［条件１］：保持時間４．２６分；ｍ／ｚ３４３．９［Ｍ＋Ｈ］^＋、２８７．９［Ｍ−ｉｓｏｂｕｔｅｎｅ＋Ｈ］^＋（ＥＳＩ正イオンモード）

Reference Example 393-4
Production of t-butyl 4- (3-fluorophenylsulfonyl) piperidine-1-carboxylate t-butyl 4- (3-fluorophenylthio) piperidine-1-carboxylate synthesized in Reference Example 393-3 (0.31 g) , 0.99 mmol) is dissolved in methanol, 30% aqueous hydrogen peroxide (0.45 ml, 4.0 mmol) and hexaammonium heptamolybdate tetrahydrate (0.12 g, 0.10 mmol) are added at room temperature. Under vigorous stirring for 4 days. After completion of the reaction, sodium thiosulfate (0.63 g, 4.0 mmol), water and chloroform were added to the reaction mixture under ice cooling, and the mixture was shaken to separate the organic layer. The aqueous layer was extracted three times with chloroform. . The combined organic layers were dried over anhydrous magnesium sulfate and then concentrated to dryness under reduced pressure to give t-butyl 4- (3-fluorophenylsulfonyl) piperidine-1-carboxylate (0.29 g, yield 86%) as colorless. Obtained as a solid.

LC / MS [Condition 1]: Retention time 4.26 minutes; m / z 343.9 [M + H] ⁺ , 287.9 [M-isobutene + H] ⁺ (ESI positive ion mode)

参考例３９３−５
４−［４−（トリフルオロメチル）フェニルスルホニル］ピペリジン−１−カルボン酸ｔ−ブチルの製造
参考例３９３−２で合成した４−［４−（トリフルオロメチル）フェニルチオ］ピペリジン−１−カルボン酸ｔ−ブチル（０．３２ｇ、０．８８ｍｍｏｌ）をメタノールに溶解し、３０％過酸化水素水（０．４０ｍｌ、３．５ｍｍｏｌ）とヘプタモリブデン酸ヘキサアンモニウム四水和物（０．１１ｇ、０．１０ｍｍｏｌ）を加えて、室温下、終夜激しく攪拌した。反応終了後、氷冷下、反応混合物にチオ硫酸ナトリウム（０．５６ｇ、３．５２ｍｍｏｌ）と水を加え、攪拌した。析出した固体をろ取し、水で洗浄した後、減圧下乾燥した。固体をろ取した後のろ液をクロロホルムで３回抽出し、合わせた有機層を無水硫酸マグネシウムで乾燥した後、減圧下濃縮乾固した。先に得られた固体と合わせて、４−［４−（トリフルオロメチル）フェニルスルホニル］ピペリジン−１−カルボン酸ｔ−ブチル（０．３１ｇ、収率９０％）を無色固体として得た。

ＬＣ／ＭＳ［条件１］：保持時間４．５４分；ｍ／ｚ３３７．９［Ｍ−ｉｓｏｂｕｔｅｎｅ＋Ｈ］^＋（ＥＳＩ正イオンモード）

Reference Example 393-5
Production of t-butyl 4- [4- (trifluoromethyl) phenylsulfonyl] piperidine-1-carboxylate 4- [4- (trifluoromethyl) phenylthio] piperidine-1-carboxylic acid synthesized in Reference Example 393-2 t-Butyl (0.32 g, 0.88 mmol) was dissolved in methanol and 30% aqueous hydrogen peroxide (0.40 ml, 3.5 mmol) and hexaammonium heptamolybdate tetrahydrate (0.11 g, .0. 10 mmol) was added and stirred vigorously at room temperature overnight. After completion of the reaction, sodium thiosulfate (0.56 g, 3.52 mmol) and water were added to the reaction mixture under ice cooling and stirred. The precipitated solid was collected by filtration, washed with water, and dried under reduced pressure. The filtrate after the solid was collected by filtration was extracted three times with chloroform, and the combined organic layer was dried over anhydrous magnesium sulfate and then concentrated to dryness under reduced pressure. Combined with the previously obtained solid, 4- [4- (trifluoromethyl) phenylsulfonyl] piperidine-1-carboxylate t-butyl (0.31 g, yield 90%) was obtained as a colorless solid.

LC / MS [Condition 1]: Retention time 4.54 minutes; m / z 337.9 [M-isobutene + H] ⁺ (ESI positive ion mode)

参考例３９３−６
４−［４−（トリフルオロメチル）フェニルスルホニル］ピペリジン塩酸塩の製造
参考例３９３−５で合成した４−［４−（トリフルオロメチル）フェニルスルホニル］ピペリジン−１−カルボン酸ｔ−ブチル（０．１８ｇ、０．５０ｍｍｏｌ）を４Ｍ塩化水素−ジオキサン溶液に溶解し、１時間激しく攪拌した。反応終了後、析出した固体をろ取し、１，４−ジオキサンで洗浄した。得られた固体を減圧下乾燥し、４−［４−（トリフルオロメチル）フェニルスルホニル］ピペリジン塩酸塩（０．２０ｇ、収率１００％）を無色固体として得た。

ＬＣ／ＭＳ［条件１］：保持時間０．８１分；ｍ／ｚ２９３．９［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）

Reference Example 393-6
Preparation of 4- [4- (trifluoromethyl) phenylsulfonyl] piperidine hydrochloride 4- [4- (trifluoromethyl) phenylsulfonyl] piperidine-1-carboxylate t-butyl (0) synthesized in Reference Example 393-5 .18 g, 0.50 mmol) was dissolved in 4M hydrogen chloride-dioxane solution and stirred vigorously for 1 hour. After completion of the reaction, the precipitated solid was collected by filtration and washed with 1,4-dioxane. The obtained solid was dried under reduced pressure to obtain 4- [4- (trifluoromethyl) phenylsulfonyl] piperidine hydrochloride (0.20 g, yield 100%) as a colorless solid.

LC / MS [Condition 1]: Retention time 0.81 min; m / z 293.9 [M + H] ⁺ (ESI positive ion mode)

参考例３９３−７
４−（３−フルオロフェニルスルホニル）ピペリジン塩酸塩の製造
４−［４−（トリフルオロメチル）フェニルスルホニル］ピペリジン−１−カルボン酸ｔ−ブチルの代わりに、参考例３９３−４で合成した４−（３−フルオロフェニルスルホニル）ピペリジン−１−カルボン酸ｔ−ブチルを用いること以外は実質的に参考例３９３−６と同様に反応を行って、表題化合物（０．１１ｇ、収率８０％）を無色固体として得た。

ＬＣ／ＭＳ［条件１］：保持時間０．５４分；ｍ／ｚ２４３．９［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）

Reference Example 393-7
Preparation of 4- (3-fluorophenylsulfonyl) piperidine hydrochloride 4- [4- (trifluoromethyl) phenylsulfonyl] piperidine-1-carboxylate synthesized in Reference Example 393-4 instead of t-butyl 4- The reaction was carried out substantially in the same manner as in Reference Example 393-6, except that t-butyl (3-fluorophenylsulfonyl) piperidine-1-carboxylate was used, and the title compound (0.11 g, yield 80%) was obtained. Obtained as a colorless solid.

LC / MS [Condition 1]: Retention time 0.54 minutes; m / z 243.9 [M + H] ⁺ (ESI positive ion mode)

実施例３９３
３−（｛（１ｒ，４ｒ）−４−［４−（３−フルオロフェニルスルホニル）ピペリジン−１−カルボニル］シクロヘキシル｝メチル）−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−２−オン（化合物番号３９３）の製造
参考例６−３で得られた（１ｒ，４ｒ）−４−（｛２−オキソ−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）シクロヘキサンカルボン酸（４０ｍｇ、０．０９０ｍｍｏｌ）をＮ，Ｎ−ジメチルホルムアミドに溶解し、参考例３９３−７で得た４−（３−フルオロフェニルスルホニル）ピペリジン塩酸塩（２５ｍｇ、０．０８８ｍｍｏｌ）、ジイソプロピルエチルアミン（３０μｌ、０．１８ｍｍｏｌ）と２−（１Ｈ−７−アザベンゾトリアゾール−１−イル）−１，１，３，３−テトラメチルウロニウムヘキサフルオロホスフェートメタンアミニウム（４０ｍｇ、０．１１ｍｍｏｌ）を加え、室温で終夜激しく攪拌した。反応終了後、クエン酸（４２ｍｇ、０．２２ｍｍｏｌ）、水とクロロホルムを加えて振とうした。有機層を分離した後、飽和炭酸水素ナトリウム水溶液で洗浄し、減圧下濃縮乾固した。得られた残留物をシリカゲルカラムクロマトグラフィー［充填剤：Ｍｅｒｃｋ ＧＭＢＨ製シリカゲル６０（０．０４０−０．０６３ｍｍ）、展開溶媒：酢酸エチル／メタノール＝９／１］にて精製し、３−（｛（１ｒ，４ｒ）−４−［４−（３−フルオロフェニルスルホニル）ピペイジン−１−カルボニル］シクロヘキシル｝メチル）−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−２−オン（３．１ｍｇ、収率５．０％）を無色液体として得た。

^１Ｈ−ＮＭＲ（３００ＭＨｚ、ＣＤＣｌ_３）δ：１．０４（２Ｈ，ｑ，Ｊ＝１２．３Ｈｚ），１．４４−２．２０（１５Ｈ，ｍ），２．３４−２．５５（２Ｈ，ｍ），２．５８（４Ｈ，ｂｒ ｍ），２．９３−３．２１（４Ｈ，ｍ），３．２６（２Ｈ，ｓ），３．５９（２Ｈ，ｓ），４．０４（１Ｈ，ｄ，Ｊ＝１２．６Ｈｚ），４．７６（１Ｈ，ｄ，Ｊ＝１２．６Ｈｚ），７．３６−７．４８（３Ｈ，ｍ），７．５５−７．７０（５Ｈ，ｍ）．

ＬＣ／ＭＳ［条件１］：保持時間３．２９分；ｍ／ｚ６７９．９［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）

Example 393
3-({(1r, 4r) -4- [4- (3-fluorophenylsulfonyl) piperidine-1-carbonyl] cyclohexyl} methyl) -8- [4- (trifluoromethyl) benzyl] -1-oxa- Preparation of 3,8-diazaspiro [4.5] decan-2-one (Compound No. 393) (1r, 4r) -4-({2-oxo-8- [4- (Trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl) cyclohexanecarboxylic acid (40 mg, 0.090 mmol) was dissolved in N, N-dimethylformamide. 4- (3-fluorophenylsulfonyl) piperidine hydrochloride (25 mg, 0.088 mmol) obtained in Reference Example 393-7, diisopropylethylamine (30 μl, 0 18 mmol) and 2- (1H-7-azabenzotriazol-1-yl) -1,1,3,3-tetramethyluronium hexafluorophosphate methanaminium (40 mg, 0.11 mmol) were added overnight at room temperature. Stir vigorously. After completion of the reaction, citric acid (42 mg, 0.22 mmol), water and chloroform were added and shaken. The organic layer was separated, washed with a saturated aqueous sodium hydrogen carbonate solution, and concentrated to dryness under reduced pressure. The obtained residue was purified by silica gel column chromatography [filler: silica gel 60 (0.040-0.063 mm) manufactured by Merck GMBH, developing solvent: ethyl acetate / methanol = 9/1], and 3-({ (1r, 4r) -4- [4- (3-Fluorophenylsulfonyl) pipaidin-1-carbonyl] cyclohexyl} methyl) -8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8- Diazaspiro [4.5] decan-2-one (3.1 mg, 5.0% yield) was obtained as a colorless liquid.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.04 (2H, q, J = 12.3 Hz), 1.44-2.20 (15H, m), 2.34-2.55 (2H, m), 2.58 (4H, br m), 2.93-3.21 (4H, m), 3.26 (2H, s), 3.59 (2H, s), 4.04 (1H, d, J = 12.6 Hz), 4.76 (1H, d, J = 12.6 Hz), 7.36-7.48 (3H, m), 7.55-7.70 (5H, m).

LC / MS [Condition 1]: Retention time 3.29 minutes; m / z 679.9 [M + H] ⁺ (ESI positive ion mode)

実施例３９４
８−［４−（トリフルオロメチル）ベンジル］−３−[(（１ｒ，４ｒ）−４−{４−[４−(トリフルオロメチル)フェニルスルホニル]ピペリジン−１−カルボニル}シクロヘキシル)メチル]−１−オキサ−３，８−ジアザスピロ［４．５］デカン−２−オン（化合物番号３９４）の製造
４−（３−フルオロフェニルスルホニル）ピペリジン塩酸塩の代わりに、参考例３９３−６で得た４−［４−（トリフルオロメチル）フェニルスルホニル］ピペリジン塩酸塩を用いること以外は実質的に実施例３９３と同様に反応を行って、表題化合物（１５ｍｇ、収率２３％）を無色液体として得た。

^１Ｈ−ＮＭＲ（３００ＭＨｚ、ＣＤＣｌ_３）δ：１．０４（２Ｈ，ｑ，Ｊ＝１１．９Ｈｚ），１．４３−１．８８（１１Ｈ，ｍ），１．８９−２．１９（３Ｈ，ｍ），２．３４−２．６０（２Ｈ，ｍ），２．５６−２．５９（４Ｈ，ｂｒ ｍ），２．９５−３．２３（４Ｈ，ｍ），３．２６（２Ｈ，ｓ），３．５９（２Ｈ，ｓ），４．０５（１Ｈ，ｄ，Ｊ＝１４．０Ｈｚ），４．７７（１Ｈ，ｄ，Ｊ＝１３．６Ｈｚ），７．４５（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ），７．５８（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ），７．８８（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ），８．０３（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ）．

ＬＣ／ＭＳ［条件１］：保持時間３．４７分；ｍ／ｚ７２９．８［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）

Example 394
8- [4- (trifluoromethyl) benzyl] -3-[((1r, 4r) -4- {4- [4- (trifluoromethyl) phenylsulfonyl] piperidine-1-carbonyl} cyclohexyl) methyl]- Preparation of 1-oxa-3,8-diazaspiro [4.5] decan-2-one (Compound No. 394) Obtained in Reference Example 393-6 instead of 4- (3-fluorophenylsulfonyl) piperidine hydrochloride The reaction was carried out substantially in the same manner as in Example 393 except that 4- [4- (trifluoromethyl) phenylsulfonyl] piperidine hydrochloride was used to give the title compound (15 mg, yield 23%) as a colorless liquid. It was.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.04 (2H, q, J = 11.9 Hz), 1.43-1.88 (11H, m), 1.89-2.19 (3H, m), 2.34-2.60 (2H, m), 2.56 to 2.59 (4H, br m), 2.95-3.23 (4H, m), 3.26 (2H, s) ), 3.59 (2H, s), 4.05 (1H, d, J = 14.0 Hz), 4.77 (1H, d, J = 13.6 Hz), 7.45 (2H, d, J = 8.2 Hz), 7.58 (2H, d, J = 8.2 Hz), 7.88 (2H, d, J = 8.2 Hz), 8.03 (2H, d, J = 8.2 Hz) .

LC / MS [Condition 1]: Retention time 3.47 minutes; m / z 729.8 [M + H] ⁺ (ESI positive ion mode)

参考例３９５−１
５−（ブロモメチル）イソオキサゾールの製造
５−メチルイソオキサゾール（５．０ｇ、６０ｍｍｏｌ）とＮ−ブロモスクシンイミド（１２ｇ、６６ｍｍｏｌ）を１，２−ジクロロエタン（１５０ｍｌ）に溶解し、過酸化ベンゾイル（０．７３ｇ、３．０ｍｍｏｌ）を加え、８５℃で４時間激しく攪拌した。反応終了後、反応溶液を１Ｍ水酸化ナトリウム水溶液、チオ硫酸ナトリウム水溶液、塩化アンモニウム水溶液、飽和塩化ナトリウム水溶液で洗浄し、無水硫酸マグネシウムで乾燥した。得られた残留物をシリカゲルカラムクロマトグラフィー、展開溶媒：酢酸エチル／ヘキサン＝１／１９］にて精製した。減圧下濃縮し、５−（ブロモメチル）イソオキサゾール（５．２ｇ、収率５３％）を黄色液体として得た。

Reference Example 395-1
Preparation of 5- (bromomethyl) isoxazole 5-Methylisoxazole (5.0 g, 60 mmol) and N-bromosuccinimide (12 g, 66 mmol) were dissolved in 1,2-dichloroethane (150 ml) and benzoyl peroxide (0. 73 g, 3.0 mmol) was added and stirred vigorously at 85 ° C. for 4 hours. After completion of the reaction, the reaction solution was washed with 1M sodium hydroxide aqueous solution, sodium thiosulfate aqueous solution, ammonium chloride aqueous solution and saturated sodium chloride aqueous solution, and dried over anhydrous magnesium sulfate. The obtained residue was purified by silica gel column chromatography, developing solvent: ethyl acetate / hexane = 1/19]. Concentration under reduced pressure gave 5- (bromomethyl) isoxazole (5.2 g, 53% yield) as a yellow liquid.

参考例３９５−２
２−（イソオキサゾール−５−イルメチル）イソインドリン−１，３−ジオンの製造
参考例３９５−１で合成した５−（ブロモメチル）イソオキサゾール（３．２ｇ、２０ｍｍｏｌ）とフタルイミドカリウム（４．５ｇ、２４ｍｍｏｌ）をＮ，Ｎ−ジメチルホルムアミド（３２ｍｌ）に溶解し、９０℃で２時間激しく攪拌した。反応終了後、水（２００ｍｌ）を加え、析出した固体をろ取し、２−（イソオキサゾール−５−イルメチル）イソインドリン−１，３−ジオン（２．７ｇ、収率６０％）を褐色固体として得た。

^１Ｈ−ＮＭＲ（３００ＭＨｚ、ＣＤＣｌ_３）δ：５．０３（２Ｈ，ｓ），６．２５−６．２９（１Ｈ，ｍ），７．７２−７．８０（２Ｈ，ｍ），７．８６−７．９３（２Ｈ，ｍ），８．６７−８．６８（１Ｈ，ｍ）．

ＬＣ／ＭＳ［条件１］：保持時間３．２６分；ｍ／ｚ２２９．０［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）

Reference Example 395-2
Preparation of 2- (isoxazol-5-ylmethyl) isoindoline-1,3-dione 5- (Bromomethyl) isoxazole (3.2 g, 20 mmol) synthesized in Reference Example 395-1 and potassium phthalimide (4.5 g, 24 mmol) was dissolved in N, N-dimethylformamide (32 ml) and stirred vigorously at 90 ° C. for 2 hours. After completion of the reaction, water (200 ml) was added and the precipitated solid was collected by filtration to give 2- (isoxazol-5-ylmethyl) isoindoline-1,3-dione (2.7 g, yield 60%) as a brown solid. Got as.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 5.03 (2H, s), 6.25-6.29 (1H, m), 7.72-7.80 (2H, m), 7.86 -7.93 (2H, m), 8.67-8.68 (1H, m).

LC / MS [Condition 1]: Retention time 3.26 minutes; m / z 229.0 [M + H] ⁺ (ESI positive ion mode)

参考例３９５−３
イソオキサゾール−５−イルメタンアミンの製造
参考例３９５−２で合成した２−（イソオキサゾール−５−イルメチル）イソインドリン−１，３−ジオン（９１ｍｇ、０．４０ｍｍｏｌ）とヒドラジン１水和物（０．１０ｇ、２．０ｍｍｏｌ）をエタノール（４ｍｌ）に溶解し、３時間加熱還流した。反応終了後、エタノールでろ過し、ろ液を減圧下濃縮乾固した。得られた残留物をクロロホルムでろ過後、ろ液を減圧下濃縮し、イソオキサゾール−５−イルメタンアミン（６７ｍｇ、収率 ８５％）を無色液体として得た。

Reference Example 395-3
Production of isoxazol-5-ylmethanamine 2- (isoxazol-5-ylmethyl) isoindoline-1,3-dione (91 mg, 0.40 mmol) synthesized in Reference Example 395-2 and hydrazine monohydrate ( 0.10 g, 2.0 mmol) was dissolved in ethanol (4 ml) and heated to reflux for 3 hours. After completion of the reaction, the mixture was filtered with ethanol, and the filtrate was concentrated to dryness under reduced pressure. The obtained residue was filtered with chloroform, and the filtrate was concentrated under reduced pressure to obtain isoxazol-5-ylmethanamine (67 mg, yield 85%) as a colorless liquid.

参考例３９５−４
２−［（２−フルオロピリジン−４−イル）メチル］イソインドリン−１，３−ジオンの製造
ＷＯ２００９０５７８２７記載の方法に従い合成した。

ＬＣ／ＭＳ［条件１］：保持時間３．６２分；ｍ／ｚ２５６．９［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）

Reference Example 395-4
Preparation of 2-[(2-fluoropyridin-4-yl) methyl] isoindoline-1,3-dione Synthesized according to the method described in WO2009057827.

LC / MS [Condition 1]: retention time 3.62 minutes; m / z 256.9 [M + H] ⁺ (ESI positive ion mode)

参考例３９５−５
（２−フルオロピリジン−４−イル）メタンアミンの製造
２−（イソオキサゾール−５−イルメチル）イソインドリン−１，３−ジオンの代わりに、参考例３９５−４で得た２−［（２−フルオロピリジン−４−イル）メチル］イソインドリン−１，３−ジオンを用いること以外は実質的に参考例３９５−３と同様に反応を行って、表題化合物（５５ｍｇ、収率７３％）を無色固体として得た。

ＬＣ／ＭＳ［条件１］：保持時間０．４９分；ｍ／ｚ１２６．９［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）

Reference Example 395-5
Preparation of (2-fluoropyridin-4-yl) methanamine 2-[(2-fluoro) obtained in Reference Example 395-4 instead of 2- (isoxazol-5-ylmethyl) isoindoline-1,3-dione Pyridin-4-yl) methyl] isoindoline-1,3-dione was used in substantially the same manner as in Reference Example 395-3 to give the title compound (55 mg, yield 73%) as a colorless solid Got as.

LC / MS [Condition 1]: Retention time 0.49 min; m / z 126.9 [M + H] ⁺ (ESI positive ion mode)

実施例３９５
（１ｒ，４ｒ）−Ｎ−［（２−フルオロピリジン−４−イル）メチル］−４−（｛２−オキソ−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）シクロヘキサンカルボキサミド（化合物番号３９５）の製造
参考例３９５−５で得られた（２−フルオロピリジン−４−イル）メタンアミン（１１ｍｇ、０．０９０ｍｍｏｌ）と参考例６−３で得られた（１ｒ，４ｒ）−４−（｛２−オキソ−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）シクロヘキサンカルボン酸（４０ｍｇ、０．０９０ｍｍｏｌ）をクロロホルムに溶解し、ジイソプロピルエチルアミン（１５μｌ、０．０９０ｍｍｏｌ）と１−エチル−３−（３−ジメチルアミノプロピル）カルボジイミド塩酸塩（１７ｍｇ、０．０９０ｍｍｏｌ）を加えて室温で３時間激しく攪拌した。反応終了後、水を加え、振とうし、有機層を分離した後、水層をクロロホルムで３回抽出した。合わせた有機層を減圧下濃縮乾固した。得られた残留物をシリカゲルカラムクロマトグラフィー［充填剤：Ｍｅｒｃｋ ＧＭＢＨ製シリカゲル６０（０．０４０−０．０６３ｍｍ）、展開溶媒：酢酸エチル／メタノール＝９／１］にて精製し、（１ｒ，４ｒ）−Ｎ−［（２−フルオロピリジン−４−イル）メチル］−４−（｛２−オキソ−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）シクロヘキサンカルボキサミド（２４ｍｇ、収率４８％）を無色液体として得た。

^１Ｈ−ＮＭＲ（３００ＭＨｚ、ＣＤＣｌ_３）δ：１．０３（２Ｈ，ｄｑ，Ｊ＝３．３，１２．７Ｈｚ），１．４５−１．６８（３Ｈ，ｍ），１．７３−１．８７（４Ｈ，ｍ），１．８７−２．０２（４Ｈ，ｍ），２．１９（１Ｈ，ｔｔ，Ｊ＝１１．９，３．３Ｈｚ），２．５３−２．５６（４Ｈ，ｂｒ ｍ），３．１０（２Ｈ，ｄ，Ｊ＝７．０Ｈｚ），３．２８（２Ｈ，ｓ），３．５８（２Ｈ，ｓ），４．４７（２Ｈ，ｄ，Ｊ＝６．５Ｈｚ），６．７６（１Ｈ，ｔ，Ｊ＝６．１Ｈｚ），６．８２（１Ｈ，ｓ），７．０８（１Ｈ，ｄ，Ｊ＝４．９Ｈｚ），７．４５（２Ｈ，ｄ，Ｊ＝７．８Ｈｚ），７．５８（２Ｈ，ｄ，Ｊ＝７．８Ｈｚ），８．１４（１Ｈ，ｄ，Ｊ＝５．７Ｈｚ）．

ＬＣ／ＭＳ［条件１］：保持時間３．１１分；ｍ／ｚ５６３．１［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）

Example 395
(1r, 4r) -N-[(2-Fluoropyridin-4-yl) methyl] -4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8 -Diazaspiro [4.5] decan-3-yl} methyl) cyclohexanecarboxamide (Compound No. 395) (2-fluoropyridin-4-yl) methanamine (11 mg, 0.090 mmol) obtained in Reference Example 395-5 ) And (1r, 4r) -4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4. 5] Decan-3-yl} methyl) cyclohexanecarboxylic acid (40 mg, 0.090 mmol) was dissolved in chloroform and diisopropylethylamine (15 μl, 0.090 mmol) was dissolved. 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (17 mg, 0.090 mmol) was stirred vigorously at room temperature for 3 hours. After completion of the reaction, water was added and shaken to separate the organic layer, and then the aqueous layer was extracted three times with chloroform. The combined organic layers were concentrated to dryness under reduced pressure. The obtained residue was purified by silica gel column chromatography [filler: silica gel 60 (0.040-0.063 mm) manufactured by Merck GMBH, developing solvent: ethyl acetate / methanol = 9/1] (1r, 4r). ) -N-[(2-fluoropyridin-4-yl) methyl] -4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4 .5] decan-3-yl} methyl) cyclohexanecarboxamide (24 mg, 48% yield) was obtained as a colorless liquid.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.03 (2H, dq, J = 3.3, 12.7 Hz), 1.45-1.68 (3H, m), 1.73-1. 87 (4H, m), 1.87-2.02 (4H, m), 2.19 (1H, tt, J = 11.9, 3.3 Hz), 2.53-2.56 (4H, br m), 3.10 (2H, d, J = 7.0 Hz), 3.28 (2H, s), 3.58 (2H, s), 4.47 (2H, d, J = 6.5 Hz) , 6.76 (1H, t, J = 6.1 Hz), 6.82 (1H, s), 7.08 (1H, d, J = 4.9 Hz), 7.45 (2H, d, J = 7.8 Hz), 7.58 (2H, d, J = 7.8 Hz), 8.14 (1H, d, J = 5.7 Hz).

LC / MS [Condition 1]: Retention time 3.11 min; m / z 563.1 [M + H] ⁺ (ESI positive ion mode)

実施例３９６
（１ｒ，４ｒ）−Ｎ−（イソオキサゾール−５−イルメチル）−４−（｛２−オキソ−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）シクロヘキサンカルボキサミド（化合物番号３９６）の製造
（２−フルオロピリジン−４−イル）メタンアミンの代わりに、参考例３９５−３で得られたイソオキサゾール−５−イルメタンアミンを用いること以外は実質的に実施例３９５と同様に反応を行って、表題化合物（１９ｍｇ、収率４１％）を無色液体として得た。

^１Ｈ−ＮＭＲ（３００ＭＨｚ、ＣＤＣｌ_３）δ：１．０３（２Ｈ，ｄｑ，Ｊ＝２．５，１２．７Ｈｚ），１．４１−１．６６（３Ｈ，ｍ），１．７１−１．８６（４Ｈ，ｍ），１．８８−２．００（４Ｈ，ｍ），２．１２（１Ｈ，ｔｔ，Ｊ＝３．３，１１．９Ｈｚ），２．５４−２．５７（４Ｈ，ｂｒ ｍ），３．１０（２Ｈ，ｄ，Ｊ＝７．４Ｈｚ），３．２７（２Ｈ，ｓ），３．５８（２Ｈ，ｓ），３．９５（３Ｈ，ｓ），４．４４（２Ｈ，ｄ，Ｊ＝５．７Ｈｚ），５．８０（１Ｈ，ｓ），６．３０−６．４１（１Ｈ，ｂｒ ｍ），７．４５（２Ｈ，ｄ，Ｊ＝７．８Ｈｚ），７．５８（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ）．

ＬＣ／ＭＳ［条件１］：保持時間２．８１分；ｍ／ｚ５３４．８［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）

Example 396
(1r, 4r) -N- (isoxazol-5-ylmethyl) -4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4. 5] Preparation of decan-3-yl} methyl) cyclohexanecarboxamide (Compound No. 396) Instead of (2-fluoropyridin-4-yl) methanamine, isoxazol-5-ylmethane obtained in Reference Example 395-3 The reaction was carried out substantially in the same manner as in Example 395 except that amine was used, and the title compound (19 mg, yield 41%) was obtained as a colorless liquid.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.03 (2H, dq, J = 2.5, 12.7 Hz), 1.41-1.66 (3H, m), 1.71-1. 86 (4H, m), 1.88-2.00 (4H, m), 2.12 (1H, tt, J = 3.3, 11.9 Hz), 2.54-2.57 (4H, br m), 3.10 (2H, d, J = 7.4 Hz), 3.27 (2H, s), 3.58 (2H, s), 3.95 (3H, s), 4.44 (2H) , D, J = 5.7 Hz), 5.80 (1H, s), 6.30-6.41 (1H, br m), 7.45 (2H, d, J = 7.8 Hz), 7. 58 (2H, d, J = 8.2 Hz).

LC / MS [Condition 1]: Retention time 2.81 minutes; m / z 534.8 [M + H] ⁺ (ESI positive ion mode)

参考例３９７−１
メタンスルホン酸４−シアノフェネチルの製造
４−（２−ヒドロキシエチル）ベンゾニトリル（０．５０ｇ、３．４ｍｍｏｌ）とトリエチルアミン（０．６０ｍｌ、４．１ｍｍｏｌ）をテトラヒドロフランに溶解し、塩化メタンスルホニル（０．３０ｍｌ、４．１ｍｍｏｌ）を滴下して加え、氷冷下で２時間激しく攪拌した。反応終了後、酢酸エチルを加え、有機層を水、１Ｍ塩酸、飽和炭酸水素ナトリウム水溶液、飽和塩化ナトリウム水溶液で洗浄した。有機層を無水硫酸マグネシウムで乾燥した後、減圧下濃縮し、メタンスルホン酸４−シアノフェネチル（０．７０ｇ、収率９３％）を無色液体として得た。

ＬＣ／ＭＳ［条件１］：保持時間３．３２分；ｍ／ｚ２２５．８［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）

Reference Example 397-1
Preparation of 4 -cyanophenethyl methanesulfonate 4- (2-hydroxyethyl) benzonitrile (0.50 g, 3.4 mmol) and triethylamine (0.60 ml, 4.1 mmol) were dissolved in tetrahydrofuran, and methanesulfonyl chloride (0 .30 ml, 4.1 mmol) was added dropwise and stirred vigorously for 2 hours under ice cooling. After completion of the reaction, ethyl acetate was added, and the organic layer was washed with water, 1M hydrochloric acid, saturated aqueous sodium hydrogen carbonate solution and saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain 4-cyanophenethyl methanesulfonate (0.70 g, yield 93%) as a colorless liquid.

LC / MS [Condition 1]: Retention time 3.32 minutes; m / z 225.8 [M + H] ⁺ (ESI positive ion mode)

参考例３９７−２
４−［２−（１，３−ジオキソイソインドリン−２−イル）エチル］ベンゾニトリルの製造
５−（ブロモメチル）イソオキサゾールの代わりに、参考例３９７−１で得られたメタンスルホン酸４−シアノフェネチルを用いること以外は実質的に参考例３９５−２と同様に反応を行って、表題化合物（０．２０ｇ、収率５４％）を無色固体として得た。

ＬＣ／ＭＳ［条件１］：保持時間４．０４分；ｍ／ｚ２７６．９［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）

Reference Example 397-2
Preparation of 4- [2- (1,3-dioxoisoindoline-2-yl) ethyl] benzonitrile Instead of 5- (bromomethyl) isoxazole, methanesulfonic acid 4-methyl ester obtained in Reference Example 397-1 The reaction was carried out substantially in the same manner as in Reference Example 395-2 except that cyanophenethyl was used to give the title compound (0.20 g, yield 54%) as a colorless solid.

LC / MS [Condition 1]: Retention time 4.04 minutes; m / z 276.9 [M + H] ⁺ (ESI positive ion mode)

参考例３９７−３
４−（２−アミノエチル）ベンゾニトリルの製造
２−（イソオキサゾール−５−イルメチル）イソインドリン−１，３−ジオンの代わりに、参考例３９７−２で得られた４−［２−（１，３−ジオキソイソインドリン−２−イル）エチル］ベンゾニトリルを用いること以外は実質的に参考例３９５−３と同様に反応を行って、表題化合物（８０ｍｇ、収率７８％）を黄色固体として得た。

ＬＣ／ＭＳ［条件１］：保持時間０．５２分；ｍ／ｚ１４７．０［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）

Reference Example 397-3
Preparation of 4- (2-aminoethyl) benzonitrile 4- [2- (1) obtained in Reference Example 397-2 instead of 2- (isoxazol-5-ylmethyl) isoindoline-1,3-dione , 3-Dioxoisoindoline-2-yl) ethyl] benzonitrile was reacted in substantially the same manner as in Reference Example 395-3 to give the title compound (80 mg, yield 78%) as a yellow solid Got as.

LC / MS [Condition 1]: Retention time 0.52 minutes; m / z 147.0 [M + H] ⁺ (ESI positive ion mode)

実施例３９７
（１ｒ，４ｒ）−Ｎ−（４−シアノフェネチル）−４−（｛２−オキソ−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）シクロヘキサンカルボキサミド（化合物番号３９７）の製造
（２−フルオロピリジン−４−イル）メタンアミンの代わりに、参考例３９７−３で得られた４−（２−アミノエチル）ベンゾニトリルを用いること以外は実質的に実施例３９５と同様に反応を行って、表題化合物（２１ｍｇ、収率４２％）を無色固体として得た。

^１Ｈ−ＮＭＲ（３００ＭＨｚ、ＣＤＣｌ_３）δ：１．００（２Ｈ，ｑ，Ｊ＝１２．７Ｈｚ），１．４５（２Ｈ，ｄｑ，Ｊ＝３．３，１２．７Ｈｚ），１．５４−１．６７（１Ｈ，ｍ），１．７１−２．０５（９Ｈ，ｍ），２．５５−２．５８（４Ｈ，ｂｒ ｍ），２．９０（２Ｈ，ｔ，Ｊ＝７．０Ｈｚ），３．０９（２Ｈ，ｄ，Ｊ＝７．０Ｈｚ），３．２７（２Ｈ，ｓ），３．５２（２Ｈ，ｑ，Ｊ＝６．５Ｈｚ），３．５８（２Ｈ，ｓ），５．６９（１Ｈ，ｂｒｓ），７．３１（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ），７．４５（２Ｈ，ｄ，Ｊ＝８．６Ｈｚ），７．５４−７．６４（４Ｈ，ｍ）．

ＬＣ／ＭＳ［条件１］：保持時間３．２１分；ｍ／ｚ５８２．８［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ６２７．０［Ｍ＋ＨＣＯＯ］^―（ＥＳＩ負イオンモード）

Example 397
(1r, 4r) -N- (4-cyanophenethyl) -4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] Decan-3-yl} methyl) cyclohexanecarboxamide (Compound No. 397) 4- (2-aminoethyl) benzoate obtained in Reference Example 397-3 instead of (2-fluoropyridin-4-yl) methanamine The reaction was carried out in substantially the same manner as in Example 395 except that nitrile was used to give the title compound (21 mg, yield 42%) as a colorless solid.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.00 (2H, q, J = 12.7 Hz), 1.45 (2H, dq, J = 3.3, 12.7 Hz), 1.54- 1.67 (1H, m), 1.71-2.05 (9H, m), 2.55-2.58 (4H, br m), 2.90 (2H, t, J = 7.0 Hz) 3.09 (2H, d, J = 7.0 Hz), 3.27 (2H, s), 3.52 (2H, q, J = 6.5 Hz), 3.58 (2H, s), 5 .69 (1H, brs), 7.31 (2H, d, J = 8.2 Hz), 7.45 (2H, d, J = 8.6 Hz), 7.54-7.64 (4H, m) .

LC / MS [Condition 1]: retention time 3.21 minutes; m / z 582.8 [M + H] ⁺ (ESI positive ion mode), m / z 627.0 [M + HCOO] ⁻ (ESI negative ion mode)

参考例３９８−１
（１ｒ，４ｒ）−４−｛［８−（４−シアノ−２，６−ジフルオロベンジル）−２−オキソ−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル］メチル｝シクロヘキサンカルボン酸メチルの製造
３−［｛５−（エトキシカルボニル）ピリジン−２−イル｝メチル］−２−オキソ−１−オキサ−３，８−ジアザスピロ［４．５］デカン−８−カルボン酸ｔ−ブチルの代わりに、参考例２−２で得られた３−［｛（１ｒ，４ｒ）−４−（メトキシカルボニル）シクロヘキシル｝メチル］−２−オキソ−１−オキサ−３，８−ジアザスピロ［４．５］デカン−８−カルボン酸ｔ−ブチル（２．０５ｇ、５．０ｍｍｏｌ）を用いること以外は、実質的に参考例３９２−１と同様に反応を行って、表題化合物（２．１３ｇ、収率９２％）を白色固体として得た。

^１Ｈ−ＮＭＲ（３００ＭＨｚ，ＣＤＣｌ_３）δ：１．０１（２Ｈ，ｑｄ，Ｊ＝１３．０，３．３Ｈｚ），１．４０（２Ｈ，ｑｄ，Ｊ＝１３．０，３．３Ｈｚ），１．５１−１．６１（１Ｈ，ｍ），１．６９−１．８１（４Ｈ，ｍ），１．９０−２．０３（４Ｈ，ｍ），２．２４（１Ｈ，ｔｔ，Ｊ＝１２．３，３．６Ｈｚ），２．５４−２．６８（４Ｈ，ｍ），３．０７（２Ｈ，ｄ，Ｊ＝７．５Ｈｚ），３．２２（２Ｈ，ｓ），３．６６（３Ｈ，ｓ），３．７４（２Ｈ，ｓ），７．２１（２Ｈ，ｄ，Ｊ＝６．５Ｈｚ）．

ＬＣ／ＭＳ［条件１］：保持時間２．７６分；ｍ／ｚ４６１．８［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）

Reference Example 398-1
(1r, 4r) -4-{[8- (4-Cyano-2,6-difluorobenzyl) -2-oxo-1-oxa-3,8-diazaspiro [4.5] decan-3-yl] methyl } Production of methyl cyclohexanecarboxylate 3-[{5- (Ethoxycarbonyl) pyridin-2-yl} methyl] -2-oxo-1-oxa-3,8-diazaspiro [4.5] decane-8-carboxylic acid 3-[{(1r, 4r) -4- (methoxycarbonyl) cyclohexyl} methyl] -2-oxo-1-oxa-3,8-diazaspiro obtained in Reference Example 2-2 instead of t-butyl [4.5] The reaction was performed in substantially the same manner as in Reference Example 392-1 except that t-butyl decane-8-carboxylate (2.05 g, 5.0 mmol) was used, and the title compound (2. 13 g, yield 92%) It was obtained as a white solid.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.01 (2H, qd, J = 13.0, 3.3 Hz), 1.40 (2H, qd, J = 13.0, 3.3 Hz), 1.51-1.61 (1H, m), 1.69-1.81 (4H, m), 1.90-2.03 (4H, m), 2.24 (1H, tt, J = 12 .3, 3.6 Hz), 2.54-2.68 (4H, m), 3.07 (2H, d, J = 7.5 Hz), 3.22 (2H, s), 3.66 (3H) , S), 3.74 (2H, s), 7.21 (2H, d, J = 6.5 Hz).

LC / MS [Condition 1]: Retention time 2.76 minutes; m / z 461.8 [M + H] ⁺ (ESI positive ion mode)

参考例３９８−２
（１ｒ，４ｒ）−４−｛［８−（４−シアノ−２，６−ジフルオロベンジル）−２−オキソ−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル］メチル｝シクロヘキサンカルボン酸の製造
参考例３９８−１で得られた（１ｒ，４ｒ）−４−｛［８−（４−シアノ−２，６−ジフルオロベンジル）−２−オキソ−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル］メチル｝シクロヘキサンカルボン酸メチル（２．１３ｇ，４．６０ｍｍｏｌ）のテトラヒドロフラン溶液（２０ｍＬ）に、カリウムトリメチルシラノラート（１．７７ｇ，１３．８０ｍｍｏｌ）を加え、室温で３時間攪拌した。反応後、飽和塩化アンモニウム水溶液を加えた後、クロロホルムで抽出し、得られた有機層を無水硫酸ナトリウムで乾燥し、減圧下濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー［昭光サイエンティフィック社製プリフパックＳＩ６０μｍ、展開溶媒：クロロホルム／メタノール＝１０／１］にて精製し、表題化合物（１．３６ｇ、収率６６％）を白色固体として得た。

^１Ｈ−ＮＭＲ（３００ＭＨｚ，ＤＭＳＯ−ｄ_６）δ：０．９０（２Ｈ，ｑ，Ｊ＝９．９Ｈｚ），１．２６（２Ｈ，ｑ，Ｊ＝９．９Ｈｚ），１．４０−１．５５（１Ｈ，ｍ），１．６３（２Ｈ，ｄ，Ｊ＝１２．２Ｈｚ），１．７３−１．７４（４Ｈ，ｍ），１．８８（２Ｈ，ｄ，Ｊ＝１０．６Ｈｚ），２．１２（１Ｈ，ｔ，Ｊ＝１２．１Ｈｚ），２．４０−２．５０（４Ｈ，ｍ），２．９５（２Ｈ，ｄ，Ｊ＝７．３Ｈｚ），３．２６（２Ｈ，ｓ），３．６５（２Ｈ，ｓ），７．８１（２Ｈ，ｄｄ，Ｊ＝１２．４，５．４Ｈｚ），１２．０２（１Ｈ，ｂｒｓ）．

ＬＣ／ＭＳ［条件１］：保持時間０．７０分；ｍ／ｚ４４７．８［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）

Reference Example 398-2
(1r, 4r) -4-{[8- (4-Cyano-2,6-difluorobenzyl) -2-oxo-1-oxa-3,8-diazaspiro [4.5] decan-3-yl] methyl } Production of cyclohexanecarboxylic acid (1r, 4r) -4-{[8- (4-cyano-2,6-difluorobenzyl) -2-oxo-1-oxa-3, obtained in Reference Example 398-1 To a tetrahydrofuran solution (20 mL) of methyl 8-diazaspiro [4.5] decan-3-yl] methyl} cyclohexanecarboxylate (2.13 g, 4.60 mmol) was added potassium trimethylsilanolate (1.77 g, 13.80 mmol). And stirred at room temperature for 3 hours. After the reaction, a saturated aqueous ammonium chloride solution was added, followed by extraction with chloroform. The obtained organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography [Prefpack SI 60 μm, manufactured by Shoko Scientific Co., Ltd., developing solvent: chloroform / methanol = 10/1] to give the title compound (1.36 g, yield 66%) as a white solid Got as.

¹ H-NMR (300 MHz, DMSO-d ₆ ) δ: 0.90 (2H, q, J = 9.9 Hz), 1.26 (2H, q, J = 9.9 Hz), 1.40-1. 55 (1H, m), 1.63 (2H, d, J = 12.2 Hz), 1.73-1.74 (4H, m), 1.88 (2H, d, J = 10.6 Hz), 2.12 (1H, t, J = 12.1 Hz), 2.40-2.50 (4H, m), 2.95 (2H, d, J = 7.3 Hz), 3.26 (2H, s ), 3.65 (2H, s), 7.81 (2H, dd, J = 12.4, 5.4 Hz), 12.02 (1H, brs).

LC / MS [Condition 1]: Retention time 0.70 min; m / z 447.8 [M + H] ⁺ (ESI positive ion mode)

実施例３９８
（１ｒ，４ｒ）−４−｛［８−（４−シアノ−２，６−ジフルオロベンジル）−２−オキソ−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル］メチル｝−Ｎ−（４−シアノフェネチル）シクロヘキサンカルボキサミド（化合物番号３９８）の製造
（２−フルオロピリジン−４−イル）メタンアミンの代わりに、参考例３９７−３で得られた４−（２−アミノエチル）ベンゾニトリルを用いることと、（１ｒ，４ｒ）−４−（｛２−オキソ−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）シクロヘキサンカルボン酸の代わりに参考例３９８−２で得られた（１ｒ，４ｒ）−４−｛［８−（４−シアノ−２，６−ジフルオロベンジル）−２−オキソ−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル］メチル｝シクロヘキサンカルボン酸を用いること以外は実質的に実施例３９５と同様に反応を行って、表題化合物（２７ｍｇ、収率５３％）を無色固体として得た。

^１Ｈ−ＮＭＲ（３００ＭＨｚ、ＣＤＣｌ_３）δ：０．９９（２Ｈ，ｄｑ，Ｊ＝３．３，１３．１Ｈｚ），１．４４（２Ｈ，ｄｑ，Ｊ＝２．９，１３．１Ｈｚ），１．５２−１．６４（１Ｈ，ｍ），１．６５−２．０５（９Ｈ，ｍ），２．５４−２．７１（４Ｈ，ｍ），２．９０（２Ｈ，ｔ，Ｊ＝７．４Ｈｚ），３．０７（２Ｈ，ｄ，Ｊ＝７．８Ｈｚ），３．２３（２Ｈ，ｓ），３．５２（２Ｈ，ｑ，Ｊ＝６．５Ｈｚ），３．７５（２Ｈ，ｓ），５．５０−５．６９（１Ｈ，ｍ），７．２３（２Ｈ，ｄ，Ｊ＝６．１Ｈｚ），７．３１（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ），７．６０（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ）．

ＬＣ／ＭＳ［条件１］：保持時間３．０４分；ｍ／ｚ５７５．９［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ６２０．１［Ｍ＋ＨＣＯＯ］^―（ＥＳＩ負イオンモード）

Example 398
(1r, 4r) -4-{[8- (4-Cyano-2,6-difluorobenzyl) -2-oxo-1-oxa-3,8-diazaspiro [4.5] decan-3-yl] methyl } Preparation of —N- (4-cyanophenethyl) cyclohexanecarboxamide (Compound No. 398) 4- (2-aminoethyl) obtained in Reference Example 397-3 instead of (2-fluoropyridin-4-yl) methanamine ) Benzonitrile and (1r, 4r) -4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decane (1r, 4r) -4-{[8- (4-cyano-2,6-difluorobenzyl) -2-oxo obtained in Reference Example 398-2 instead of -3-yl} methyl) cyclohexanecarboxylic acid − -Oxa-3,8-diazaspiro [4.5] decan-3-yl] methyl} cyclohexanecarboxylic acid was used to carry out the reaction substantially in the same manner as in Example 395, and the title compound (27 mg, yield) 53%) was obtained as a colorless solid.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 0.99 (2H, dq, J = 3.3, 13.1 Hz), 1.44 (2H, dq, J = 2.9, 13.1 Hz), 1.52-1.64 (1H, m), 1.65-2.05 (9H, m), 2.54-2.71 (4H, m), 2.90 (2H, t, J = 7) .4 Hz), 3.07 (2H, d, J = 7.8 Hz), 3.23 (2H, s), 3.52 (2H, q, J = 6.5 Hz), 3.75 (2H, s) ), 5.50-5.69 (1H, m), 7.23 (2H, d, J = 6.1 Hz), 7.31 (2H, d, J = 8.2 Hz), 7.60 (2H) , D, J = 8.2 Hz).

LC / MS [Condition 1]: Retention time 3.04 minutes; m / z 575.9 [M + H] ⁺ (ESI positive ion mode), m / z 620.1 [M + HCOO] ⁻ (ESI negative ion mode)

参考例３９９
（２−クロロチアゾール−４−イル）メタンアミン塩酸塩の製造
ＷＯ２００９０５７８２７記載の方法に従い合成した。

^１Ｈ−ＮＭＲ（３００ＭＨｚ、ＤＭＳＯ−ｄ_６）δ：４．１０（２Ｈ，ｄｄ，Ｊ＝１１．９，５．７Ｈｚ），７．８１（１Ｈ，ｓ），８．５５（３Ｈ，ｂｒ ｓ）．

ＬＣ／ＭＳ［条件１］：保持時間０．５０分；ｍ／ｚ１４８．８［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）

Reference Example 399
Production of (2-chlorothiazol-4-yl) methanamine hydrochloride The compound was synthesized according to the method described in WO2009057827.

¹ H-NMR (300 MHz, DMSO-d ₆ ) δ: 4.10 (2H, dd, J = 11.9, 5.7 Hz), 7.81 (1H, s), 8.55 (3H, br s ).

LC / MS [Condition 1]: Retention time 0.50 min; m / z 148.8 [M + H] ⁺ (ESI positive ion mode)

実施例３９９
（１ｒ，４ｒ）−Ｎ−［（２−クロロチアゾール−４−イル）メチル］−４−（｛２−オキソ−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）シクロヘキサンカルボキサミド（化合物番号３９９）の製造
（２−フルオロピリジン−４−イル）メタンアミンの代わりに、参考例３９９で得られた（２−クロロチアゾール−４−イル）メタンアミン塩酸塩を用いること以外は実質的に実施例３９５と同様に反応を行って、表題化合物（２０ｍｇ、収率３８％）を無色固体として得た。

^１Ｈ−ＮＭＲ（３００ＭＨｚ、ＣＤＣｌ_３）δ：１．０４（２Ｈ，ｄｑ，Ｊ＝２．９，１２．７Ｈｚ），１．４１−１．６７（３Ｈ，ｍ），１．７０−１．８７（４Ｈ，ｍ），１．８９−２．０１（４Ｈ，ｍ），２．１０（１Ｈ，ｔｔ，Ｊ＝１１．９，３．３Ｈｚ），２．５５−２．５９（４Ｈ，ｂｒ ｍ），３．１１（２Ｈ，ｄ，Ｊ＝７．４Ｈｚ），３．２７（２Ｈ，ｓ），３．５９（２Ｈ，ｓ），４．４６（２Ｈ，ｄ，Ｊ＝５．７Ｈｚ），６．１７（１Ｈ，ｔ，Ｊ＝５．３Ｈｚ），７．０６（１Ｈ，ｓ），７．４５（２Ｈ，ｄ，Ｊ＝７．８Ｈｚ），７．５８（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ）．

ＬＣ／ＭＳ［条件１］：保持時間３．１１分；ｍ／ｚ５８４．６［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）

Example 399
(1r, 4r) -N-[(2-chlorothiazol-4-yl) methyl] -4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8 -Preparation of diazaspiro [4.5] decan-3-yl} methyl) cyclohexanecarboxamide (Compound No. 399) Instead of (2-fluoropyridin-4-yl) methanamine, (2-chloro The reaction was carried out substantially in the same manner as in Example 395 except that thiazol-4-yl) methanamine hydrochloride was used to obtain the title compound (20 mg, yield 38%) as a colorless solid.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.04 (2H, dq, J = 2.9, 12.7 Hz), 1.41-1.67 (3H, m), 1.70-1. 87 (4H, m), 1.89-2.01 (4H, m), 2.10 (1H, tt, J = 11.9, 3.3 Hz), 2.55 to 2.59 (4H, br m), 3.11 (2H, d, J = 7.4 Hz), 3.27 (2H, s), 3.59 (2H, s), 4.46 (2H, d, J = 5.7 Hz) 6.17 (1H, t, J = 5.3 Hz), 7.06 (1H, s), 7.45 (2H, d, J = 7.8 Hz), 7.58 (2H, d, J = 8.2 Hz).

LC / MS [Condition 1]: Retention time 3.11 min; m / z 584.6 [M + H] ⁺ (ESI positive ion mode)

参考例４００
（Ｓ）−２−（４−フルオロフェニル）ピロリジンの製造
Ｊ．Ｏｒｇ．Ｃｈｅｍ．，２０１０，７５，２２３６記載の合成方法に従い合成した。

ＬＣ／ＭＳ［条件１］：保持時間０．５６分；ｍ／ｚ１６６．１［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）

Reference Example 400
Preparation of (S) -2- (4-fluorophenyl) pyrrolidine Org. Chem. , 2010, 75, 2236.

LC / MS [Condition 1]: retention time 0.56 minutes; m / z 166.1 [M + H] ⁺ (ESI positive ion mode)

実施例４００
３−（｛（１ｒ，４ｒ）−４−［（Ｓ）−２−（４−フルオロフェニル）ピロリジン−１−カルボニル］シクロヘキシル｝メチル）−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−２−オン（化合物番号４００）の製造
４−（３−フルオロフェニルスルホニル）ピペリジン塩酸塩の代わりに、参考例４００で得られた（Ｓ）−２−（４−フルオロフェニル）ピロリジンを用いること以外は実質的に実施例３９３と同様に反応を行って、表題化合物（３２．８ｍｇ、収率６２％）を黄色固体として得た。

^１Ｈ−ＮＭＲ（３００ＭＨｚ、ＣＤＣｌ_３）δ：０．５７（０．６Ｈ，ｑ，Ｊ＝１２．３Ｈｚ），０．９０（０．６Ｈ，ｑ，Ｊ＝１２．３Ｈｚ），０．９９−１．１７（０．８Ｈ，ｍ），１．１６−１．２９（０．８Ｈ，ｍ），１．３６−２．１２（１４．２Ｈ，ｍ），２．１６−２．４５（１Ｈ，ｍ），２．４６−２．６５（４Ｈ，ｂｒ ｍ），２．８９−３．１７（２Ｈ，ｍ），３．２１（１．２Ｈ，ｓ），３．２６（０．８Ｈ，ｓ），３．５７（２Ｈ，ｂｒ ｓ），３．６１−３．８１（２Ｈ，ｍ），４．９６（０．６Ｈ，ｄ，Ｊ＝７．２Ｈｚ），５．１５（０．４Ｈ，ｄｄ，Ｊ＝２．７，７．８Ｈｚ），６．９１−７．１６（４Ｈ，ｍ），７．４４（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ），７．５７（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ）．

ＬＣ／ＭＳ［条件１］：保持時間３．４４分；ｍ／ｚ６０１．８［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）

Example 400
3-({(1r, 4r) -4-[(S) -2- (4-fluorophenyl) pyrrolidine-1-carbonyl] cyclohexyl} methyl) -8- [4- (trifluoromethyl) benzyl] -1 Preparation of Oxa-3,8-diazaspiro [4.5] decan-2-one (Compound No. 400) Instead of 4- (3-fluorophenylsulfonyl) piperidine hydrochloride, it was obtained in Reference Example 400 (S ) -2- (4-Fluorophenyl) pyrrolidine was used in substantially the same manner as in Example 393 to obtain the title compound (32.8 mg, 62% yield) as a yellow solid.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 0.57 (0.6 H, q, J = 12.3 Hz), 0.90 (0.6 H, q, J = 12.3 Hz), 0.99- 1.17 (0.8 H, m), 1.16-1.29 (0.8 H, m), 1.36-2.12 (14.2 H, m), 2.16-2.45 (1 H) M), 2.46-2.65 (4H, br m), 2.89-3.17 (2H, m), 3.21 (1.2H, s), 3.26 (0.8H, s), 3.57 (2H, br s), 3.61-3.81 (2H, m), 4.96 (0.6 H, d, J = 7.2 Hz), 5.15 (0.4 H) , Dd, J = 2.7, 7.8 Hz), 6.91-7.16 (4H, m), 7.44 (2H, d, J = 8.2 Hz), 7.57 (2H, d, J = 8.2 Hz).

LC / MS [Condition 1]: Retention time 3.44 minutes; m / z 601.8 [M + H] ⁺ (ESI positive ion mode)

参考例４０１−１
４−メチルベンゼンスルホン酸（３−メトキシイソオキサゾール−５−イル）メチルの製造
３−ヒドロキシイソオキサゾール−５−カルボン酸メチル（市販）（６．０ｇ、４２ｍｍｏｌ）のテトラヒドロフラン（６０ｍＬ）懸濁液に、室温にて、炭酸カリウム（６．４ｇ、４６ｍｍｏｌ）とジメチル硫酸（４．３ｇ、４６ｍｍｏｌ）を加えて７５℃で２１時間撹拌した。反応混合物に、飽和塩化アンモニウム水溶液を加えた後、酢酸エチルで２回抽出した。合わせた有機層を減圧下濃縮乾固し、得られた残留物をシリカゲルカラムクロマトグラフィーにて精製して３−メトキシイソオキサゾール−５−カルボン酸メチル（１．７ｇ、収率２６％）を固体として得た。
得られた３−メトキシイソオキサゾール−５−カルボン酸メチル（０．５０ｇ、３．２ｍｍｏｌ）のエタノール（１０ｍＬ）溶液に、室温にて、水素化ホウ素ナトリウム（０．１９ｇ、４．９ｍｍｏｌ）を加えた後、室温にて１．５時間攪拌した。反応混合物を減圧下濃縮乾固した。得られた残留物に飽和塩化アンモニウム水溶液を加えたのち、酢酸エチルで２回抽出し、合わせた有機層を減圧下濃縮乾固した。残留物（０．４７ｇ）をテトラヒドロフラン（５．０ｍＬ）に溶解し、トリエチルアミン（０．８０ｍＬ、５．８ｍｍｏｌ）と４−メチルベンゼンスルホン酸クロリド（０．８２ｇ、４．３ｍｍｏｌ）を加えて、室温にて１５時間攪拌した。反応混合物に飽和塩化アンモニウム水溶液と飽和塩化ナトリウム水溶液を加えた後、酢酸エチルで２回抽出し、有機層を減圧下濃縮乾固した。得られた残留物をシリカゲルカラムクロマトグラフィー［展開溶媒：ヘキサン／酢酸エチル＝３／１］にて精製し、４−メチルベンゼンスルホン酸（３−メトキシイソオキサゾール−５−イル）メチル（０．５１ｇ、収率５７％）を白色固体として得た。

Reference Example 401-1
Preparation of methyl 4-methylbenzenesulfonate (3-methoxyisoxazol-5-yl ) To a suspension of methyl 3-hydroxyisoxazole-5-carboxylate (commercially available) (6.0 g, 42 mmol) in tetrahydrofuran (60 mL) At room temperature, potassium carbonate (6.4 g, 46 mmol) and dimethyl sulfate (4.3 g, 46 mmol) were added and stirred at 75 ° C. for 21 hours. A saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted twice with ethyl acetate. The combined organic layers were concentrated to dryness under reduced pressure, and the resulting residue was purified by silica gel column chromatography to obtain methyl 3-methoxyisoxazole-5-carboxylate (1.7 g, yield 26%) as a solid. Got as.
Sodium borohydride (0.19 g, 4.9 mmol) was added to a solution of the obtained methyl 3-methoxyisoxazole-5-carboxylate (0.50 g, 3.2 mmol) in ethanol (10 mL) at room temperature. Then, the mixture was stirred at room temperature for 1.5 hours. The reaction mixture was concentrated to dryness under reduced pressure. A saturated aqueous ammonium chloride solution was added to the obtained residue, followed by extraction twice with ethyl acetate, and the combined organic layers were concentrated to dryness under reduced pressure. The residue (0.47 g) was dissolved in tetrahydrofuran (5.0 mL), triethylamine (0.80 mL, 5.8 mmol) and 4-methylbenzenesulfonic acid chloride (0.82 g, 4.3 mmol) were added, and room temperature was added. For 15 hours. A saturated aqueous ammonium chloride solution and a saturated aqueous sodium chloride solution were added to the reaction mixture, followed by extraction twice with ethyl acetate, and the organic layer was concentrated to dryness under reduced pressure. The obtained residue was purified by silica gel column chromatography [developing solvent: hexane / ethyl acetate = 3/1] to give 4-methylbenzenesulfonic acid (3-methoxyisoxazol-5-yl) methyl (0.51 g). Yield 57%) as a white solid.

参考例４０１−２
２−［（３−メトキシイソオキサゾール−５−イル）メチル］イソインドリン−１，３−ジオンの製造
参考例４０１−１で得られた、４−メチルベンゼンスルホン酸（３−メトキシイソオキサゾール−５−イル）メチル（０．５０ｇ、１．８ｍｍｏｌ）をＮ，Ｎ−ジメチルホルムアミド（５．０ｍＬ）に溶解し、フタルイミドカリウム（市販）（０．３９ｇ、２．１ｍｍｏｌ）を加えて、９０℃で１時間攪拌した。反応混合物を室温まで放冷したのち、水（２０ｍＬ）を加えた。析出した固体をろ取し、水で洗浄して、２−［（３−メトキシイソオキサゾール−５−イル）メチル］イソインドリン−１，３−ジオン（０．４３ｇ、収率９３％）を白色固体として得た。

Reference Example 401-2
Production of 2-[(3-methoxyisoxazol-5-yl) methyl] isoindoline-1,3-dione 4-methylbenzenesulfonic acid (3-methoxyisoxazole-5 obtained in Reference Example 401-1 -Yl) methyl (0.50 g, 1.8 mmol) was dissolved in N, N-dimethylformamide (5.0 mL), potassium phthalimido (commercially available) (0.39 g, 2.1 mmol) was added, and Stir for 1 hour. The reaction mixture was allowed to cool to room temperature, and water (20 mL) was added. The precipitated solid was collected by filtration, washed with water, and 2-[(3-methoxyisoxazol-5-yl) methyl] isoindoline-1,3-dione (0.43 g, yield 93%) was white. Obtained as a solid.

参考例４０１−３
（３−メトキシイソオキサゾール−５−イル）メタンアミンの製造
２−（イソオキサゾール−５−イルメチル）イソインドリン−１，３−ジオンの代わりに参考例４０１−２で得られた２−［（３−メトキシイソオキサゾール−５−イル）メチル］イソインドリン−１，３−ジオンを用いること以外は実質的に参考例３９５−３と同様に反応を行って、表題化合物（４６ｍｇ、収率９０％）を無色液体として得た。

^１Ｈ−ＮＭＲ（３００ＭＨｚ、ＣＤＣｌ_３）δ：３．８６（２Ｈ，ｓ），３．９６（３Ｈ，ｓ），５．７７（１Ｈ，ｓ）．

Reference Example 401-3
Preparation of (3-methoxyisoxazol-5-yl) methanamine 2-[(3-) obtained in Reference Example 401-2 instead of 2- (isoxazol-5-ylmethyl) isoindoline-1,3-dione Methoxyisoxazol-5-yl) methyl] isoindoline-1,3-dione was used in substantially the same manner as in Reference Example 395-3 to give the title compound (46 mg, yield 90%). Obtained as a colorless liquid.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 3.86 (2H, s), 3.96 (3H, s), 5.77 (1H, s).

実施例４０１
（１ｒ，４ｒ）−Ｎ−［（３−メトキシイソオキサゾール−５−イル）メチル］−４−（｛２−オキソ−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）シクロヘキサンカルボキサミド（化合物番号４０１）の製造
（２−フルオロピリジン−４−イル）メタンアミンの代わりに、参考例４０１−３で得られた（３−メトキシイソオキサゾール−５−イル）メタンアミンを用いること以外は実質的に実施例３９５と同様に反応を行って、表題化合物（１８ｍｇ、収率３７％）を無色固体として得た。

^１Ｈ−ＮＭＲ（３００ＭＨｚ、ＣＤＣｌ_３）δ：１．０３（２Ｈ，ｄｑ，Ｊ＝２．９，１２．３Ｈｚ），１．４１−１．６６（３Ｈ，ｍ），１．７２−１．８６（４Ｈ，ｍ），１．８８−２．００（４Ｈ，ｍ），２．１４（１Ｈ，ｔｔ，Ｊ＝１１．４，３．３Ｈｚ），２．５４−２．５７（４Ｈ，ｂｒ ｍ），３．１０（２Ｈ，ｄ，Ｊ＝７．０Ｈｚ），３．２８（２Ｈ，ｓ），３．５９（２Ｈ，ｓ），４．５８（２Ｈ，ｄ，Ｊ＝５．７Ｈｚ），６．１８（１Ｈ，ｄ，Ｊ＝１．２Ｈｚ），６．４５−６．５３（１Ｈ，ｂｒｍ），７．４５（２Ｈ，ｄ，Ｊ＝８．６Ｈｚ），７．５８（２Ｈ，ｄ，Ｊ＝７．８Ｈｚ），８．１８（１Ｈ，ｄ，Ｊ＝１．６Ｈｚ）．

ＬＣ／ＭＳ［条件１］：保持時間３．０１分；ｍ／ｚ５６４．９［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）

Example 401
(1r, 4r) -N-[(3-methoxyisoxazol-5-yl) methyl] -4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3, Preparation of 8-diazaspiro [4.5] decan-3-yl} methyl) cyclohexanecarboxamide (Compound No. 401) Obtained in Reference Example 401-3 instead of (2-fluoropyridin-4-yl) methanamine ( The reaction was carried out in substantially the same manner as in Example 395 except that 3-methoxyisoxazol-5-yl) methanamine was used to give the title compound (18 mg, yield 37%) as a colorless solid.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.03 (2H, dq, J = 2.9, 12.3 Hz), 1.41-1.66 (3H, m), 1.72-1. 86 (4H, m), 1.88-2.00 (4H, m), 2.14 (1H, tt, J = 11.4, 3.3 Hz), 2.54-2.57 (4H, br m), 3.10 (2H, d, J = 7.0 Hz), 3.28 (2H, s), 3.59 (2H, s), 4.58 (2H, d, J = 5.7 Hz) 6.18 (1H, d, J = 1.2 Hz), 6.45-6.53 (1H, brm), 7.45 (2H, d, J = 8.6 Hz), 7.58 (2H, d, J = 7.8 Hz), 8.18 (1H, d, J = 1.6 Hz).

LC / MS [Condition 1]: Retention time 3.01 minutes; m / z 564.9 [M + H] ⁺ (ESI positive ion mode)

実施例４０２
６−［１−（（１ｒ，４ｒ）−４−｛［８−（４−シアノ−２，６−ジフルオロベンジル）−２−オキソ−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル］メチル｝シクロヘキサンカルボニル）ピペリジン−４−イルオキシ］ニコチノニトリル（化合物番号４０２）の製造

４−（｛２−オキソ−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）安息香酸の代わりに参考例３９８−２で得られた（１ｒ，４ｒ）−４−｛［８−（４−シアノ−２，６−ジフルオロベンジル）−２−オキソ−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル］メチル｝シクロヘキサンカルボン酸を、４−（アミノメチル）ベンゾニトリル塩酸塩の代わりに参考例２９３−２で得られた６−（ピペリジン−４−イルオキシ）ニコチノニトリル塩酸塩を用いること以外は実質的に実施例１８０と同様に反応を行って、表題化合物（２８ｍｇ、収率６６％）を白色粉末として得た。

^１Ｈ−ＮＭＲ（３００ＭＨｚ、ＣＤＣｌ_３）δ：１．０４（２Ｈ，ｄｑ，Ｊ＝３．７，１１．９Ｈｚ），１．４６−１．６６（３Ｈ，ｂｒ ｍ），１．６９−１．８５（８Ｈ，ｂｒ ｍ），１．８６−２．１１（４Ｈ，ｂｒ ｍ），２．４７（１Ｈ，ｔｔ，Ｊ＝１１．９，２．９Ｈｚ），２．６３（４Ｈ，ｂｒ ｓ），３．０９（２Ｈ，ｄ，Ｊ＝７．４Ｈｚ），３．２２（２Ｈ，ｓ），３．３１−３．５３（２Ｈ，ｂｒ ｍ），３．６６−３．８０（１Ｈ，ｂｒ ｍ），３．７５（２Ｈ，ｓ），３．８８−４．０５（１Ｈ，ｂｒ ｍ），５．３５（１Ｈ，ｔｔ，Ｊ＝７．８，３．７Ｈｚ），６．７９（１Ｈ，ｄ，Ｊ＝８．６Ｈｚ），７．２２（２Ｈ，ｄ，Ｊ＝５．７Ｈｚ），７．７８（１Ｈ，ｄｄ，Ｊ＝８．６，２．０Ｈｚ），８．４５（１Ｈ，ｄ，Ｊ＝２．５Ｈｚ）．

ＬＣ／ＭＳ［条件１］：保持時間３．１８分；ｍ／ｚ６３２．８［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ６７６．９［Ｍ＋ＨＣＯＯ］^―（ＥＳＩ負イオンモード）

Example 402
6- [1-((1r, 4r) -4-{[8- (4-Cyano-2,6-difluorobenzyl) -2-oxo-1-oxa-3,8-diazaspiro [4.5] decane Preparation of -3-yl] methyl} cyclohexanecarbonyl) piperidin-4-yloxy] nicotinonitrile (Compound No. 402)

Reference example instead of 4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl) benzoic acid (1r, 4r) -4-{[8- (4-Cyano-2,6-difluorobenzyl) -2-oxo-1-oxa-3,8-diazaspiro [4.5] obtained in 398-2 Decan-3-yl] methyl} cyclohexanecarboxylic acid was substituted with 6- (piperidin-4-yloxy) nicotinonitrile hydrochloride obtained in Reference Example 293-2 instead of 4- (aminomethyl) benzonitrile hydrochloride. The reaction was carried out substantially in the same manner as in Example 180 except for using, and the title compound (28 mg, yield 66%) was obtained as a white powder.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.04 (2H, dq, J = 3.7, 11.9 Hz), 1.46 to 1.66 (3H, br m), 1.69-1 .85 (8H, br m), 1.86-2.11 (4H, br m), 2.47 (1H, tt, J = 11.9, 2.9 Hz), 2.63 (4H, br s) ), 3.09 (2H, d, J = 7.4 Hz), 3.22 (2H, s), 3.31-3.53 (2H, br m), 3.66-3.80 (1H, br m), 3.75 (2H, s), 3.88-4.05 (1H, br m), 5.35 (1 H, tt, J = 7.8, 3.7 Hz), 6.79 ( 1H, d, J = 8.6 Hz), 7.22 (2H, d, J = 5.7 Hz), 7.78 (1H, dd, J = 8.6, 2.0 Hz), 8.45 (1H , D, = 2.5Hz).

LC / MS [Condition 1]: Retention time 3.18 minutes; m / z 632.8 [M + H] ⁺ (ESI positive ion mode), m / z 676.9 [M + HCOO] ⁻ (ESI negative ion mode)

実施例４０３
（１ｒ，４ｒ）−４−｛［８−（４−シアノ−２，６−ジフルオロベンジル）−２−オキソ−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル］メチル｝−Ｎ−［（テトラヒドロフラン−２−イル）メチル］シクロヘキサンカルボキサミド（化合物番号４０３）の製造

６−（ピペリジン−４−イルオキシ）ニコチノニトリル塩酸塩の代わりに、テトラヒドロフルフリルアミン（市販）を用いること以外は実質的に実施例４０２と同様に反応を行って、表題化合物（２６ｍｇ、収率７２％）を白色粉末として得た。

^１Ｈ−ＮＭＲ（３００ＭＨｚ、ＣＤＣｌ_３）δ：１．００（２Ｈ，ｑ，Ｊ＝１２．３Ｈｚ），１．３６−１．６６（３Ｈ，ｍ），１．６７−１．８２（４Ｈ，ｂｒ ｍ），１．８２−２．１０（９Ｈ，ｍ），２．６３（４Ｈ，ｂｒ ｓ），３．０１−３．１８（１Ｈ，ｍ），３．０７（２Ｈ，ｄ，Ｊ＝７．８Ｈｚ），３．２２（２Ｈ，ｓ），３．５２−３．６３（１Ｈ，ｍ），３．６７−４．０１（３Ｈ，ｍ），３．７５（２Ｈ，ｓ），５．７９（１Ｈ，ｔ，Ｊ＝５．３Ｈｚ），７．２２（２Ｈ，ｄ，Ｊ＝５．７Ｈｚ）．

ＬＣ／ＭＳ［条件１］：保持時間１．３８分；ｍ／ｚ５３０．８［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ５７５．０［Ｍ＋ＨＣＯＯ］^―（ＥＳＩ負イオンモード）

Example 403
(1r, 4r) -4-{[8- (4-Cyano-2,6-difluorobenzyl) -2-oxo-1-oxa-3,8-diazaspiro [4.5] decan-3-yl] methyl } -N-[(Tetrahydrofuran-2-yl) methyl] cyclohexanecarboxamide (Compound No. 403)

The reaction was conducted in substantially the same manner as in Example 402 except that tetrahydrofurfurylamine (commercially available) was used instead of 6- (piperidin-4-yloxy) nicotinonitrile hydrochloride to give the title compound (26 mg, yield). 72%) was obtained as a white powder.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.00 (2H, q, J = 12.3 Hz), 1.36 to 1.66 (3H, m), 1.67 to 1.82 (4H, br m), 1.82-2.10 (9H, m), 2.63 (4H, br s), 3.01-3.18 (1H, m), 3.07 (2H, d, J = 7.8 Hz), 3.22 (2H, s), 3.52-3.63 (1H, m), 3.67-4.01 (3H, m), 3.75 (2H, s), 5 .79 (1H, t, J = 5.3 Hz), 7.22 (2H, d, J = 5.7 Hz).

LC / MS [Condition 1]: Retention time 1.38 minutes; m / z 530.8 [M + H] ⁺ (ESI positive ion mode), m / z 575.0 [M + HCOO] ⁻ (ESI negative ion mode)

実施例４０４
４−｛［３−（｛（１ｒ，４ｒ）−４−［４−（６−クロロピリミジン−４−イル）ピペラジン−１−カルボニル］シクロヘキシル｝メチル）−２−オキソ−１−オキサ−３，８−ジアザスピロ［４．５］デカン−８−イル］メチル｝−３，５−ジフルオロベンゾニトリル（化合物番号４０４）の製造
６−（ピペリジン−４−イルオキシ）ニコチノニトリル塩酸塩の代わりに参考例２８８で得られた４−クロロ−６−（ピペラジン−１−イル）ピリミジンニ塩酸塩を用いること以外は実質的に実施例４０２と同様に反応を行って、表題化合物（２６ｍｇ、収率７２％）を白色粉末として得た。

^１Ｈ−ＮＭＲ（３００ＭＨｚ、ＣＤＣｌ_３）δ：１．０５（２Ｈ，ｄｑ，Ｊ＝４．５，１１．４Ｈｚ），１．４７−１．６７（３Ｈ，ｂｒ ｍ），１．６８−１．８６（６Ｈ，ｂｒ ｍ），１．８６−１．９８（２Ｈ，ｂｒ ｍ），２．４６（１Ｈ，ｔｔ，Ｊ＝１１．７，２．５Ｈｚ），２．６３（４Ｈ，ｂｒ ｓ），３．１０（２Ｈ，ｄ，Ｊ＝７．４Ｈｚ），３．２３（２Ｈ，ｓ），３．６１（４Ｈ，ｂｒ ｓ），３．７５（６Ｈ，ｂｒ ｓ），６．５１（１Ｈ，ｓ），７．２２（２Ｈ，ｄ，Ｊ＝６．１Ｈｚ），８．４０（１Ｈ，ｓ）．

ＬＣ／ＭＳ［条件１］：保持時間２．９６分；ｍ／ｚ３１４．６［Ｍ＋２Ｈ］^２＋、６２７．８［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ６７１．９［Ｍ＋ＨＣＯＯ］^―（ＥＳＩ負イオンモード）

Example 404
4-{[3-({(1r, 4r) -4- [4- (6-chloropyrimidin-4-yl) piperazine-1-carbonyl] cyclohexyl} methyl) -2-oxo-1-oxa-3, Preparation of 8-diazaspiro [4.5] decan-8-yl] methyl} -3,5-difluorobenzonitrile (Compound No. 404) Reference example instead of 6- (piperidin-4-yloxy) nicotinonitrile hydrochloride The reaction was conducted in substantially the same manner as in Example 402 except that 4-chloro-6- (piperazin-1-yl) pyrimidine dihydrochloride obtained in 288 was used to give the title compound (26 mg, yield 72%) Was obtained as a white powder.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.05 (2H, dq, J = 4.5, 11.4 Hz), 1.47-1.67 (3H, br m), 1.68-1 .86 (6H, br m), 1.86-1.98 (2H, br m), 2.46 (1H, tt, J = 11.7, 2.5 Hz), 2.63 (4H, br s ), 3.10 (2H, d, J = 7.4 Hz), 3.23 (2H, s), 3.61 (4H, br s), 3.75 (6H, br s), 6.51 ( 1H, s), 7.22 (2H, d, J = 6.1 Hz), 8.40 (1H, s).

LC / MS [Condition 1]: Retention time 2.96 min; m / z 314.6 [M + 2H] ²⁺ , 627.8 [M + H] ⁺ (ESI positive ion mode), m / z 671.9 [M + HCOO] ⁻ (ESI Negative ion mode)

実施例４０５
３，５−ジフルオロ−４−｛［２−オキソ−３−（｛（１ｒ，４ｒ）−４−［４−（キノリン−４−イル）ピペラジン−１−カルボニル］シクロヘキシル｝メチル）−１−オキサ−３，８−ジアザスピロ［４．５］デカン−８−イル］メチル｝ベンゾニトリル（化合物番号４０５）の製造
６−（ピペリジン−４−イルオキシ）ニコチノニトリル塩酸塩の代わりに参考例２７８−２で得られた４−（ピペラジン−１−イル）キノリン二塩酸塩を用いること以外は実質的に実施例４０２と同様に反応を行って、表題化合物（３８ｍｇ、収率８７％）を無色無定形物として得た。

^１Ｈ−ＮＭＲ（３００ＭＨｚ、ＣＤＣｌ_３）δ：１．０６（２Ｈ，ｑ，Ｊ＝１３．１Ｈｚ），１．５５−１．７０（１Ｈ，ｍ），１．６０（２Ｈ，ｑ，Ｊ＝１２．７Ｈｚ），１．７０−１．９８（８Ｈ，ｂｒ ｍ），２．５１（１Ｈ，ｔｔ，Ｊ＝１２．３，３．３Ｈｚ），２．５７−２．７１（４Ｈ，ｂｒ ｍ），３．１０（２Ｈ，ｄ，Ｊ＝７．４Ｈｚ），３．１５−３．３２（４Ｈ，ｂｒ ｍ），３．２３（２Ｈ，ｓ），３．７５（２Ｈ，ｓ），３．７９（２Ｈ，ｂｒ ｓ），３．９１（２Ｈ，ｂｒ ｓ），６．８５（１Ｈ，ｄ，Ｊ＝４．９Ｈｚ），７．２２（２Ｈ，ｄ，Ｊ＝７．０Ｈｚ），７．５３（１Ｈ，ｔ，Ｊ＝７．８Ｈｚ），７．７０（１Ｈ，ｔ，Ｊ＝７．８Ｈｚ），８．０２（１Ｈ，ｄｄ，Ｊ＝８．２，１．２Ｈｚ），８．１１（１Ｈ，ｄ，Ｊ＝８．２Ｈｚ），８．７５（１Ｈ，ｄ，Ｊ＝４．９Ｈｚ）．

ＬＣ／ＭＳ［条件１］：保持時間０．８４分；ｍ／ｚ３２２．０［Ｍ＋２Ｈ］^２＋、６４２．８［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ６８６．９［Ｍ＋ＨＣＯＯ］^―（ＥＳＩ負イオンモード）

Example 405
3,5-difluoro-4-{[2-oxo-3-({(1r, 4r) -4- [4- (quinolin-4-yl) piperazine-1-carbonyl] cyclohexyl} methyl) -1-oxa Preparation of 3,8-diazaspiro [4.5] decan-8-yl] methyl} benzonitrile (Compound No. 405) Reference Example 278-2 instead of 6- (piperidin-4-yloxy) nicotinonitrile hydrochloride The title compound (38 mg, 87% yield) was obtained as a colorless amorphous substance by carrying out the reaction substantially in the same manner as in Example 402 except that 4- (piperazin-1-yl) quinoline dihydrochloride obtained in 1 above was used. Obtained as a thing.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.06 (2H, q, J = 13.1 Hz), 1.55-1.70 (1H, m), 1.60 (2H, q, J = 12.7 Hz), 1.70-1.98 (8 H, br m), 2.51 (1 H, tt, J = 12.3, 3.3 Hz), 2.57-2.71 (4 H, br m ), 3.10 (2H, d, J = 7.4 Hz), 3.15-3.32 (4H, br m), 3.23 (2H, s), 3.75 (2H, s), 3 .79 (2H, br s), 3.91 (2H, br s), 6.85 (1H, d, J = 4.9 Hz), 7.22 (2H, d, J = 7.0 Hz), 7 .53 (1H, t, J = 7.8 Hz), 7.70 (1H, t, J = 7.8 Hz), 8.02 (1H, dd, J = 8.2, 1.2 Hz), 8. 11 (1H , D, J = 8.2 Hz), 8.75 (1H, d, J = 4.9 Hz).

LC / MS [Condition 1]: Retention time 0.84 min; m / z 322.0 [M + 2H] ²⁺ , 642.8 [M + H] ⁺ (ESI positive ion mode), m / z 686.9 [M + HCOO] ⁻ (ESI Negative ion mode)

実施例４０６
３，５−ジフルオロ−４−｛［３−（｛（１ｒ，４ｒ）−４−［４−（６−フルオロベンゾ［ｄ］イソオキサゾール−３−イル）ピペリジン−１−カルボニル］シクロヘキシル｝メチル）−２−オキソ−１−オキサ−３，８−ジアザスピロ［４．５］デカン−８−イル］メチル｝ベンゾニトリル（化合物番号４０６）の製造
６−（ピペリジン−４−イルオキシ）ニコチノニトリル塩酸塩の代わりに６−フルオロ−３−（ピペリジン−４−イル）ベンゾ［ｄ］イソキサゾール（市販）を用いること以外は実質的に実施例４０２と同様に反応を行って、表題化合物（１９ｍｇ、収率４３％）を白色粉末として得た。

^１Ｈ−ＮＭＲ（３００ＭＨｚ、ＣＤＣｌ_３）δ：１．０５（２Ｈ，ｑ，Ｊ＝１２．３Ｈｚ），１．４６−１．６８（３Ｈ，ｂｒ ｍ），１．７０−２．０６（１０Ｈ，ｂｒ ｍ），２．０７−２．２５（２Ｈ，ｂｒ ｍ），２．４９（１Ｈ，ｔ，Ｊ＝１２．３Ｈｚ），２．６３（４Ｈ，ｂｒ ｓ），２．８７（１Ｈ，ｔ，Ｊ＝１１．４Ｈｚ），３．１０（２Ｈ，ｄ，Ｊ＝７．４Ｈｚ），３．１６−３．４１（２Ｈ，ｍ），３．２３（２Ｈ，ｓ），３．７５（２Ｈ，ｓ），４．０４（１Ｈ，ｄ，Ｊ＝１３．１Ｈｚ），４．６７（１Ｈ，ｄ，Ｊ＝１２．７Ｈｚ），７．０７（１Ｈ，ｔｄ，Ｊ＝８．９，２．２Ｈｚ），７．１６−７．２９（３Ｈ，ｍ），７．６１（１Ｈ，ｄｄ，Ｊ＝８．６，４．９Ｈｚ）．

ＬＣ／ＭＳ［条件１］：保持時間３．４０分；ｍ／ｚ６４９．９［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ６９４．０［Ｍ＋ＨＣＯＯ］^―（ＥＳＩ負イオンモード）

Example 406
3,5-difluoro-4-{[3-({(1r, 4r) -4- [4- (6-fluorobenzo [d] isoxazol-3-yl) piperidin-1-carbonyl] cyclohexyl} methyl) 2-Oxo-1-oxa-3,8-diazaspiro [4.5] decan-8-yl] methyl} benzonitrile (Compound No. 406) 6- (Piperidin-4-yloxy) nicotinonitrile hydrochloride The reaction was conducted in substantially the same manner as in Example 402 except that 6-fluoro-3- (piperidin-4-yl) benzo [d] isoxazole (commercially available) was used instead of 43%) as a white powder.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.05 (2H, q, J = 12.3 Hz), 1.46-1.68 (3H, br m), 1.70-2.06 (10H , Br m), 2.07-2.25 (2H, br m), 2.49 (1 H, t, J = 12.3 Hz), 2.63 (4 H, br s), 2.87 (1 H, t, J = 11.4 Hz), 3.10 (2H, d, J = 7.4 Hz), 3.16-3.41 (2H, m), 3.23 (2H, s), 3.75 ( 2H, s), 4.04 (1H, d, J = 13.1 Hz), 4.67 (1H, d, J = 12.7 Hz), 7.07 (1H, td, J = 8.9, 2) .2 Hz), 7.16-7.29 (3H, m), 7.61 (1H, dd, J = 8.6, 4.9 Hz).

LC / MS [Condition 1]: Retention time 3.40 minutes; m / z 649.9 [M + H] ⁺ (ESI positive ion mode), m / z 694.0 [M + HCOO] ⁻ (ESI negative ion mode)

実施例４０７
４−［（３−｛［（１ｒ，４ｒ）−４−（４−ベンジルピペリジン−１−カルボニル）シクロヘキシル］メチル｝−２−オキソ−１−オキサ−３，８−ジアザスピロ［４．５］デカン−８−イル）メチル］−３，５−ジフルオロベンゾニトリル（化合物番号４０７）の製造
６−（ピペリジン−４−イルオキシ）ニコチノニトリル塩酸塩の代わりに４−ベンジルピペリジン（市販）を用いること以外は実質的に実施例４０２と同様に反応を行って、表題化合物（３５ｍｇ、収率８６％）を白色粉末として得た。

^１Ｈ−ＮＭＲ（３００ＭＨｚ、ＣＤＣｌ_３）δ：０．８９−１．１１（２Ｈ，ｂｒ ｍ），１．１２（２Ｈ，ｄｑ，Ｊ＝３．３，１３．５Ｈｚ），１．４０−１．６４（３Ｈ，ｂｒ ｍ），１．６４−１．８４（９Ｈ，ｂｒ ｍ），１．８５−１．９９（２Ｈ，ｂｒ ｍ），２．３３−２．７２（８Ｈ，ｂｒ ｍ），２．９３（１Ｈ，ｔ，Ｊ＝１２．９Ｈｚ），３．０８（２Ｈ，ｄ，Ｊ＝７．４Ｈｚ），３．２１（２Ｈ，ｓ），３．７４（２Ｈ，ｓ），３．８４（１Ｈ，ｄ，Ｊ＝１２．７Ｈｚ），４．６０（１Ｈ，ｄ，Ｊ＝１４．３Ｈｚ），７．０８−７．１５（２Ｈ，ｍ），７．１５−７．３３（５Ｈ，ｍ）．

ＬＣ／ＭＳ［条件１］：保持時間３．５６分；ｍ／ｚ６０４．９［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ６４９．２［Ｍ＋ＨＣＯＯ］^―（ＥＳＩ負イオンモード）

Example 407
4-[(3-{[(1r, 4r) -4- (4-benzylpiperidine-1-carbonyl) cyclohexyl] methyl} -2-oxo-1-oxa-3,8-diazaspiro [4.5] decane -8-yl) methyl] -3,5-difluorobenzonitrile (Compound No. 407) Reacted substantially as in Example 402 to give the title compound (35 mg, 86% yield) as a white powder.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 0.89-1.11 (2H, br m), 1.12 (2H, dq, J = 3.3, 13.5 Hz), 1.40-1 .64 (3H, br m), 1.64-1.84 (9H, br m), 1.85-1.99 (2H, br m), 2.33-2.72 (8H, br m) 2.93 (1H, t, J = 12.9 Hz), 3.08 (2H, d, J = 7.4 Hz), 3.21 (2H, s), 3.74 (2H, s), 3 .84 (1H, d, J = 12.7 Hz), 4.60 (1 H, d, J = 14.3 Hz), 7.08-7.15 (2H, m), 7.15-7.33 ( 5H, m).

LC / MS [Condition 1]: Retention time 3.56 minutes; m / z 604.9 [M + H] ⁺ (ESI positive ion mode), m / z 649.2 [M + HCOO] ⁻ (ESI negative ion mode)

実施例４０８
４−（（１ｒ，４ｒ）−４−｛［８−（４−シアノ−２，６−ジフルオロベンジル）−２−オキソ−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル］メチル｝シクロヘキサンカルボキサミド）ピペリジン−１−カルボン酸エチル（化合物番号４０８）の製造
６−（ピペリジン−４−イルオキシ）ニコチノニトリル塩酸塩の代わりに４−アミノピペリジン−１−カルボン酸エチル（市販）を用いること以外は実質的に実施例４０２と同様に反応を行って、表題化合物（３３ｍｇ、収率８１％）を白色粉末として得た。

^１Ｈ−ＮＭＲ（３００ＭＨｚ、ＣＤＣｌ_３）δ：１．００（２Ｈ，ｄｑ，Ｊ＝２．９，１２．３Ｈｚ），１．２５（３Ｈ，ｔ，Ｊ＝７．０Ｈｚ），１．２７（２Ｈ，ｄｑ，Ｊ＝４．１，１１．０Ｈｚ），１．４６−１．６５（１Ｈ，ｂｒ ｍ），１．４７（２Ｈ，ｄｑ，Ｊ＝２．９，１１．９Ｈｚ），１．６５−１．８２（４Ｈ，ｂｒ ｍ），１．８２−２．０６（７Ｈ，ｂｒ ｍ），２．６３（４Ｈ，ｂｒ ｓ），２．８９（２Ｈ，ｔ，Ｊ＝１１．９Ｈｚ），３．０７（２Ｈ，ｄ，Ｊ＝７．０Ｈｚ），３．２２（２Ｈ，ｓ），３．７５（２Ｈ，ｓ），３．８２−３．９８（１Ｈ，ｍ），４．００−４．２１（２Ｈ，ｂｒ ｍ），４．１２（２Ｈ，ｑ，Ｊ＝７．２Ｈｚ），５．３４（１Ｈ，ｄ，Ｊ＝７．８Ｈｚ），７．２２（２Ｈ，ｄ，Ｊ＝５．７Ｈｚ）．

ＬＣ／ＭＳ［条件１］：保持時間２．９２分；ｍ／ｚ６０１．８［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ６４６．１［Ｍ＋ＨＣＯＯ］^―（ＥＳＩ負イオンモード）

Example 408
4-((1r, 4r) -4-{[8- (4-cyano-2,6-difluorobenzyl) -2-oxo-1-oxa-3,8-diazaspiro [4.5] decane-3- Yl] methyl} cyclohexanecarboxamide) Preparation of ethyl piperidine-1-carboxylate (Compound No. 408) Instead of 6- (piperidin-4-yloxy) nicotinonitrile hydrochloride, ethyl 4-aminopiperidine-1-carboxylate (commercially available) ) Was used substantially in the same manner as in Example 402 to obtain the title compound (33 mg, yield: 81%) as a white powder.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.00 (2H, dq, J = 2.9, 12.3 Hz), 1.25 (3H, t, J = 7.0 Hz), 1.27 ( 2H, dq, J = 4.1, 11.0 Hz), 1.46-1.65 (1H, br m), 1.47 (2H, dq, J = 2.9, 11.9 Hz), 1. 65-1.82 (4H, br m), 1.82-2.06 (7H, br m), 2.63 (4H, br s), 2.89 (2H, t, J = 11.9 Hz) 3.07 (2H, d, J = 7.0 Hz), 3.22 (2H, s), 3.75 (2H, s), 3.82-3.98 (1H, m), 4.00 -4.21 (2H, br m), 4.12 (2H, q, J = 7.2 Hz), 5.34 (1H, d, J = 7.8 Hz), 7.22 (2H, d, J = 5.7 Hz).

LC / MS [Condition 1]: Retention time 2.92 minutes; m / z 601.8 [M + H] ⁺ (ESI positive ion mode), m / z 646.1 [M + HCOO] ⁻ (ESI negative ion mode)

実施例４０９
１−（（１ｒ，４ｒ）−４−｛［８−（４−シアノ−２，６−ジフルオロベンジル）−２−オキソ−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル］メチル｝シクロヘキサンカルボニル）ピペリジン−４−カルボニトリル（化合物番号４０９）の製造
６−（ピペリジン−４−イルオキシ）ニコチノニトリル塩酸塩の代わりにピペリジン−４−カルボニトリル（市販）を用いること以外は実質的に実施例４０２と同様に反応を行って、表題化合物（３３ｍｇ、収率９１％）を白色粉末として得た。

^１Ｈ−ＮＭＲ（３００ＭＨｚ、ＣＤＣｌ_３）δ：０．９４−１．１４（２Ｈ，ｂｒ ｍ），１．４４−１．６８（３Ｈ，ｂｒ ｍ），１．６８−２．０２（１２Ｈ，ｂｒ ｍ），２．４２（１Ｈ，ｔ，Ｊ＝１０．２Ｈｚ），２．６４（４Ｈ，ｂｒ ｓ），２．８３−２．９７（１Ｈ，ｍ），３．０９（２Ｈ，ｄ，Ｊ＝７．４Ｈｚ），３．２２（２Ｈ，ｓ），３．３７−３．９１（４Ｈ，ｂｒ ｍ），３．７７（２Ｈ，ｓ），７．１６−７．３１（２Ｈ，ｍ）．

ＬＣ／ＭＳ［条件１］：保持時間１．４８分；ｍ／ｚ５３９．８［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ５８３．８［Ｍ＋ＨＣＯＯ］^―（ＥＳＩ負イオンモード）

Example 409
1-((1r, 4r) -4-{[8- (4-Cyano-2,6-difluorobenzyl) -2-oxo-1-oxa-3,8-diazaspiro [4.5] decane-3- Yl] methyl} cyclohexanecarbonyl) piperidine-4-carbonitrile (Compound No. 409) Reacted substantially as in Example 402 to give the title compound (33 mg, 91% yield) as a white powder.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 0.94-1.14 (2H, br m), 1.44-1.68 (3 H, br m), 1.68-2.02 (12 H, br m), 2.42 (1H, t, J = 10.2 Hz), 2.64 (4H, br s), 2.83-2.97 (1H, m), 3.09 (2H, d, J = 7.4 Hz), 3.22 (2H, s), 3.37-3.91 (4H, br m), 3.77 (2H, s), 7.16-7.31 (2H, m ).

LC / MS [Condition 1]: Retention time 1.48 minutes; m / z 539.8 [M + H] ⁺ (ESI positive ion mode), m / z 583.8 [M + HCOO] ⁻ (ESI negative ion mode)

実施例４１０
３，５−ジフルオロ−４−（｛３−［（（１ｒ，４ｒ）−４−｛［−（２−メトキシフェニルアミノ）ピペリジン−１−カルボニル］シクロヘキシル｝メチル）−２−オキソ−１−オキサ−３，８−ジアザスピロ［４．５］デカン−８−イル］メチル｝ベンゾニトリル（化合物番号４１０）の製造
６−（ピペリジン−４−イルオキシ）ニコチノニトリル塩酸塩の代わりに参考例２９２−２で得られたＮ−（２−メトキシフェニル）ピペリジン−４−アミン二塩酸塩を用いること以外は実質的に実施例４０２と同様に反応を行って、表題化合物（３２ｍｇ、収率７４％）を白色粉末として得た。

^１Ｈ−ＮＭＲ（３００ＭＨｚ、ＣＤＣｌ_３）δ：１．０３（２Ｈ，ｑ，Ｊ＝１３．１Ｈｚ），１．２７−１．４７（２Ｈ，ｂｒ ｍ），１．４７−１．６６（３Ｈ，ｂｒ ｍ），１．６７−１．８４（６Ｈ，ｂｒ ｍ），１．８６−１．９７（２Ｈ，ｂｒ ｍ），２．１１（２Ｈ，ｔ，Ｊ＝１３．５Ｈｚ），２．４６（１Ｈ，ｔｔ，Ｊ＝１１．９，２．９Ｈｚ），２．５３−２．７１（４Ｈ，ｂｒ ｍ），２．８９（１Ｈ，ｔ，Ｊ＝１１．４Ｈｚ），３．０８（２Ｈ，ｄ，Ｊ＝７．４Ｈｚ），３．１３−３．２６（１Ｈ，ｂｒ ｍ），３．２２（２Ｈ，ｓ），３．５１（１Ｈ，ｂｒ ｓ），３．７４（２Ｈ，ｓ），３．７９−３．９２（１Ｈ，ｂｒ ｍ），３．８４（３Ｈ，ｓ），４．１３（１Ｈ，ｂｒ ｓ），４．４６（１Ｈ，ｄ，Ｊ＝１４．３Ｈｚ），６．５９−６．７１（２Ｈ，ｍ），６．７８（１Ｈ，ｄｄ，Ｊ＝７．４，１．６Ｈｚ），６．８６（１Ｈ，ｔｄ，Ｊ＝７．０，１．６Ｈｚ），７．２２（２Ｈ，ｄ，Ｊ＝５．７Ｈｚ）．

ＬＣ／ＭＳ［条件１］：保持時間２．９８分；ｍ／ｚ３１８．５［Ｍ＋２Ｈ］^２＋、６３６．０［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ６８０．０［Ｍ＋ＨＣＯＯ］^―（ＥＳＩ負イオンモード）

Example 410
3,5-difluoro-4-({3-[((1r, 4r) -4-{[-(2-methoxyphenylamino) piperidine-1-carbonyl] cyclohexyl} methyl) -2-oxo-1-oxa Preparation of 3,8-diazaspiro [4.5] decan-8-yl] methyl} benzonitrile (Compound No. 410) Reference Example 292-2 instead of 6- (piperidin-4-yloxy) nicotinonitrile hydrochloride The reaction was carried out in substantially the same manner as in Example 402 except that N- (2-methoxyphenyl) piperidin-4-amine dihydrochloride obtained in the above was used to give the title compound (32 mg, yield 74%). Obtained as a white powder.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.03 (2H, q, J = 13.1 Hz), 1.27-1.47 (2H, br m), 1.47-1.66 (3H , Br m), 1.67-1.84 (6H, br m), 1.86-1.97 (2H, br m), 2.11 (2H, t, J = 13.5 Hz), 2. 46 (1H, tt, J = 11.9, 2.9 Hz), 2.53-2.71 (4H, br m), 2.89 (1H, t, J = 11.4 Hz), 3.08 ( 2H, d, J = 7.4 Hz), 3.13-3.26 (1 H, br m), 3.22 (2 H, s), 3.51 (1 H, br s), 3.74 (2 H, s), 3.79-3.92 (1H, br m), 3.84 (3H, s), 4.13 (1H, br s), 4.46 (1H, d, J = 14.3 Hz) 6.59-6.71 (2H, m), 6.78 (1H, dd, J = 7.4, 1.6 Hz), 6.86 (1H, td, J = 7.0, 1.6 Hz) ), 7.22 (2H, d, J = 5.7 Hz).

LC / MS [Condition 1]: Retention time 2.98 min; m / z 318.5 [M + 2H] ²⁺ , 636.0 [M + H] ⁺ (ESI positive ion mode), m / z 680.0 [M + HCOO] ⁻ (ESI Negative ion mode)

実施例４１１
４−（（１ｒ，４ｒ）−４−｛［８−（４−シアノ−２，６−ジフルオロベンジル）−２−オキソ−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル］メチル｝シクロヘキサンカルボニル）ピペラジン−１−カルボン酸メチル（化合物番号４１１）の製造
６−（ピペリジン−４−イルオキシ）ニコチノニトリル塩酸塩の代わりに参考例３３８−２で得られたピペラジン−１−カルボン酸メチル塩酸塩を用いること以外は実質的に実施例４０２と同様に反応を行って、表題化合物（２３ｍｇ、収率５９％）を白色粉末として得た。

^１Ｈ−ＮＭＲ（３００ＭＨｚ、ＣＤＣｌ_３）δ：１．０３（２Ｈ，ｑ，Ｊ＝１２．７Ｈｚ），１．４５−１．６５（３Ｈ，ｂｒ ｍ），１．６９−１．８３（６Ｈ，ｂｒ ｍ），１．８４−１．９７（２Ｈ，ｂｒ ｍ），２．４２（１Ｈ，ｔ，Ｊ＝１１．０Ｈｚ），２．６３（４Ｈ，ｂｒ ｓ），３．０９（２Ｈ，ｄ，Ｊ＝７．４Ｈｚ），３．２２（２Ｈ，ｓ），３．４６（６Ｈ，ｂｒ ｓ），３．５８（２Ｈ，ｂｒ ｓ），３．６７−３．７８（２Ｈ，ｂｒ ｍ），３．７２（３Ｈ，ｓ），７．２２（２Ｈ，ｄ，Ｊ＝５．７Ｈｚ）．

ＬＣ／ＭＳ［条件１］：保持時間２．４９分；ｍ／ｚ５７３．８［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ６１８．３［Ｍ＋ＨＣＯＯ］^―（ＥＳＩ負イオンモード）

Example 411
4-((1r, 4r) -4-{[8- (4-cyano-2,6-difluorobenzyl) -2-oxo-1-oxa-3,8-diazaspiro [4.5] decane-3- [Il] methyl} cyclohexanecarbonyl) piperazine-1-carboxylate (Compound No. 411) Preparation of Piperazine-1 obtained in Reference Example 338-2 instead of 6- (piperidin-4-yloxy) nicotinonitrile hydrochloride -The reaction was carried out in substantially the same manner as in Example 402 except that methyl carboxylate was used to obtain the title compound (23 mg, yield 59%) as a white powder.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.03 (2H, q, J = 12.7 Hz), 1.45 to 1.65 (3H, br m), 1.69-1.83 (6H , Br m), 1.84-1.97 (2H, br m), 2.42 (1H, t, J = 11.0 Hz), 2.63 (4H, br s), 3.09 (2H, d, J = 7.4 Hz), 3.22 (2H, s), 3.46 (6H, br s), 3.58 (2H, br s), 3.67-3.78 (2H, br m ), 3.72 (3H, s), 7.22 (2H, d, J = 5.7 Hz).

LC / MS [Condition 1]: Retention time 2.49 minutes; m / z 573.8 [M + H] ⁺ (ESI positive ion mode), m / z 618.3 [M + HCOO] ⁻ (ESI negative ion mode)

実施例４１２
３−｛［（１ｒ，４ｒ）−４−（４，４−ジフルオロピペリジン−１−カルボニル）シクロヘキシル］メチル｝−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−２−オン（化合物番号４１２）の製造
３，５−ジメチルピペリジンの代わりに４，４−ジフルオロピペリジン塩酸塩（市販）を用いること以外は実質的に実施例３４２と同様に反応を行って、表題化合物（２８ｍｇ、収率７６％）を白色粉末として得た。

^１Ｈ−ＮＭＲ（３００ＭＨｚ、ＣＤＣｌ_３）δ：１．０５（２Ｈ，ｑ，Ｊ＝１１．６Ｈｚ），１．４５−１．６８（３Ｈ，ｂｒ ｍ），１．７１−１．８５（６Ｈ，ｂｒ ｍ），１．８５−２．０８（６Ｈ，ｂｒ ｍ），２．４５（１Ｈ，ｔｔ，Ｊ＝１１．９，２．９Ｈｚ），２．５５（４Ｈ，ｂｒ ｓ），３．１１（２Ｈ，ｄ，Ｊ＝７．４Ｈｚ），３．２６（２Ｈ，ｓ），３．５９（４Ｈ，ｂｒ ｓ），３．７２（２Ｈ，ｂｒ ｓ），７．４３（２Ｈ，ｄ，Ｊ＝７．８Ｈｚ），７．５７（２Ｈ，ｄ，Ｊ＝７．８Ｈｚ）．

ＬＣ／ＭＳ［条件１］：保持時間３．１８分；ｍ／ｚ５５７．８［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ６０１．９［Ｍ＋ＨＣＯＯ］^―（ＥＳＩ負イオンモード）

Example 412
3-{[(1r, 4r) -4- (4,4-difluoropiperidine-1-carbonyl) cyclohexyl] methyl} -8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8- Preparation of diazaspiro [4.5] decan-2-one (Compound No. 412) Substantially Example 342 except that 4,4-difluoropiperidine hydrochloride (commercially available) was used instead of 3,5-dimethylpiperidine. The reaction was performed in the same manner to obtain the title compound (28 mg, yield 76%) as a white powder.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.05 (2H, q, J = 11.6 Hz), 1.45 to 1.68 (3H, br m), 1.71-1.85 (6H , Br m), 1.85-2.08 (6H, br m), 2.45 (1H, tt, J = 11.9, 2.9 Hz), 2.55 (4H, br s), 3. 11 (2H, d, J = 7.4 Hz), 3.26 (2H, s), 3.59 (4H, br s), 3.72 (2H, br s), 7.43 (2H, d, J = 7.8 Hz), 7.57 (2H, d, J = 7.8 Hz).

LC / MS [Condition 1]: Retention time 3.18 minutes; m / z 557.8 [M + H] ⁺ (ESI positive ion mode), m / z 601.9 [M + HCOO] ⁻ (ESI negative ion mode)

実施例４１３
３−｛［（１ｒ，４ｒ）−４−（４−ニコチノイルピペリジン−１−カルボニル）シクロヘキシル］メチル｝−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−２−オン（化合物番号４１３）の製造
３，５−ジメチルピペリジンの代わりにピペリジン−４−イル（ピリジン−３−イル）メタノン塩酸塩（市販）を用いること以外は実質的に実施例３４２と同様に反応を行って、表題化合物（３５ｍｇ、収率８６％）を白色粉末として得た。

^１Ｈ−ＮＭＲ（３００ＭＨｚ、ＣＤＣｌ_３）δ：１．０５（２Ｈ，ｑ，Ｊ＝１１．９Ｈｚ），１．４７−１．７０（４Ｈ，ｂｒ ｍ），１．７２−１．８７（７Ｈ，ｂｒ ｍ），１．８８−２．０２（２Ｈ，ｂｒ ｍ），２．４６（１Ｈ，ｔｔ，Ｊ＝１１．９，２．５Ｈｚ），２．５６（４Ｈ，ｂｒ ｓ），２．８３（１Ｈ，ｔ，Ｊ＝１２．１Ｈｚ），３．１１（２Ｈ，ｄ，Ｊ＝７．４Ｈｚ），３．２２（１Ｈ，ｔ，Ｊ＝１２．７Ｈｚ），３．２６（２Ｈ，ｓ），３．４８（１Ｈ，ｔｔ，Ｊ＝１０．６，３．７Ｈｚ），３．５７（２Ｈ，ｓ），３．９９（１Ｈ，ｄ，Ｊ＝１３．５Ｈｚ），４．６１（１Ｈ，ｄ，Ｊ＝１２．７Ｈｚ），７．３８−７．４９（３Ｈ，ｍ），７．５７（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ），８．２２（１Ｈ，ｄｔ，Ｊ＝７．８，２．０Ｈｚ），８．７５−８．８４（１Ｈ，ｍ），９．１６（１Ｈ，ｓ）．

ＬＣ／ＭＳ［条件１］：保持時間３．０６分；ｍ／ｚ３１３．９［Ｍ＋２Ｈ］^２＋、６２６．８［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ６７０．９［Ｍ＋ＨＣＯＯ］^―（ＥＳＩ負イオンモード）

Example 413
3-{[(1r, 4r) -4- (4-nicotinoylpiperidine-1-carbonyl) cyclohexyl] methyl} -8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] Preparation of decan-2-one (Compound No. 413) Substantially except that piperidin-4-yl (pyridin-3-yl) methanone hydrochloride (commercially available) is used instead of 3,5-dimethylpiperidine Specifically, the reaction was carried out in the same manner as in Example 342 to obtain the title compound (35 mg, yield 86%) as a white powder.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.05 (2H, q, J = 11.9 Hz), 1.47-1.70 (4H, br m), 1.72-1.87 (7H , Br m), 1.88-2.02 (2H, br m), 2.46 (1H, tt, J = 11.9, 2.5 Hz), 2.56 (4H, br s), 2. 83 (1H, t, J = 12.1 Hz), 3.11 (2H, d, J = 7.4 Hz), 3.22 (1H, t, J = 12.7 Hz), 3.26 (2H, s ), 3.48 (1H, tt, J = 10.6, 3.7 Hz), 3.57 (2H, s), 3.99 (1H, d, J = 13.5 Hz), 4.61 (1H , D, J = 12.7 Hz), 7.38-7.49 (3H, m), 7.57 (2H, d, J = 8.2 Hz), 8.22 (1H, dt, J = 7. 8 2.0Hz), 8.75-8.84 (1H, m), 9.16 (1H, s).

LC / MS [Condition 1]: Retention time 3.06 minutes; m / z 313.9 [M + 2H] ²⁺ , 626.8 [M + H] ⁺ (ESI positive ion mode), m / z 670.9 [M + HCOO] ⁻ (ESI Negative ion mode)

実施例４１４
４−｛［３−（｛（１ｒ，４ｒ）−４−［４−（２，４−ジフルオロベンゾイル）ピペリジン−１−カルボニル］シクロヘキシル｝メチル）−２−オキソ−１−オキサ−３，８−ジアザスピロ［４．５］デカン−８−イル］メチル｝−３，５−ジフルオロベンゾニトリル（化合物番号４１４）の製造
６−（ピペリジン−４−イルオキシ）ニコチノニトリル塩酸塩の代わりに（２，４−ジフルオロフェニル）（ピペリジン−４−イル）メタノン塩酸塩（市販）を用いること以外は実質的に実施例４０２と同様に反応を行って、表題化合物（２４ｍｇ、収率５１％）を黄色粉末として得た。

^１Ｈ−ＮＭＲ（３００ＭＨｚ、ＣＤＣｌ_３）δ：１．０３（２Ｈ，ｑ，Ｊ＝１２．３Ｈｚ），１．４４−１．６５（３Ｈ，ｂｒ ｍ），１．６５−１．８４（６Ｈ，ｂｒ ｍ），１．８５−２．０３（４Ｈ，ｂｒ ｍ），２．４５（１Ｈ，ｔ，Ｊ＝１１．７Ｈｚ），２．５１−２．６９（４Ｈ，ｂｒ ｍ），２．７７（１Ｈ，ｔ，Ｊ＝１１．９Ｈｚ），３．０６−３．２３（１Ｈ，ｂｒ ｍ），３．０８（２Ｈ，ｄ，Ｊ＝７．４Ｈｚ），３．２２（２Ｈ，ｓ），３．３３（１Ｈ，ｔｔ，Ｊ＝１０．４，３．３Ｈｚ），３．７４（２Ｈ，ｓ），３．９４（１Ｈ，ｄ，Ｊ＝１３．１Ｈｚ），４．５６（１Ｈ，ｄ，Ｊ＝１３．１Ｈｚ），６．８２−６．９３（１Ｈ，ｍ），６．９８（１Ｈ，ｔｄ，Ｊ＝８．２，２．５Ｈｚ），７．１６−７．２６（２Ｈ，ｍ），７．８６（１Ｈ，ｔｄ，Ｊ＝８．６，６．５Ｈｚ）．

ＬＣ／ＭＳ［条件１］：保持時間３．３６分；ｍ／ｚ６５４．８［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ６９８．９［Ｍ＋ＨＣＯＯ］^―（ＥＳＩ負イオンモード）

Example 414
4-{[3-({(1r, 4r) -4- [4- (2,4-difluorobenzoyl) piperidine-1-carbonyl] cyclohexyl} methyl) -2-oxo-1-oxa-3,8- Preparation of diazaspiro [4.5] decan-8-yl] methyl} -3,5-difluorobenzonitrile (Compound No. 414) instead of 6- (piperidin-4-yloxy) nicotinonitrile hydrochloride (2,4 -Difluorophenyl) (piperidin-4-yl) methanone hydrochloride (commercially available) was reacted in the same manner as in Example 402 to give the title compound (24 mg, yield 51%) as a yellow powder. Obtained.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.03 (2H, q, J = 12.3 Hz), 1.44 to 1.65 (3H, br m), 1.65 to 1.84 (6H) , Br m), 1.85-2.03 (4H, br m), 2.45 (1H, t, J = 11.7 Hz), 2.51-2.69 (4H, br m), 2. 77 (1H, t, J = 11.9 Hz), 3.06-3.23 (1H, br m), 3.08 (2H, d, J = 7.4 Hz), 3.22 (2H, s) 3.33 (1H, tt, J = 10.4, 3.3 Hz), 3.74 (2H, s), 3.94 (1H, d, J = 13.1 Hz), 4.56 (1H, d, J = 13.1 Hz), 6.82-6.93 (1H, m), 6.98 (1H, td, J = 8.2, 2.5 Hz), 7.16-7.26 (2H) , m), 7.86 (1H, td, J = 8.6, 6.5 Hz).

LC / MS [Condition 1]: Retention time 3.36 minutes; m / z 654.8 [M + H] ⁺ (ESI positive ion mode), m / z 698.9 [M + HCOO] ⁻ (ESI negative ion mode)

参考例４１５−１
４−［２−（ピリジン−２−イル）ヒドラジンカルボニル］ピペリジン−１−カルボン酸ｔ−ブチルの製造
２−ヒドラジノピペリジン（５２０ｍｇ、４．８ｍｍｏｌ、市販）、１−（ｔ−ブトキシカルボニル）ピペリジン−４−カルボン酸（１．０ｇ、４．４ｍｍｏｌ）と１−ヒドロキシベンゾトリアゾール（１８０ｍｇ、１．３ｍｍｏｌ）をクロロホルム（１０ｍＬ）に溶解した後、１−エチル−３−（３−ジメチルアミノプロピル）カルボジイミド塩酸塩（９２０ｍｇ、４．８ｍｍｏｌ）を加えて、室温で２７時間かき混ぜた。水を加えて有機層を分離し、水層をクロロホルムで抽出した。合わせた有機層を飽和炭酸水素ナトリウム水溶液、１．０Ｍ水酸化ナトリウム水溶液と飽和食塩水で洗浄した。有機層を無水硫酸ナトリウムで乾燥した後、減圧下濃縮乾固した。得られた黄色残留物をジエチルエーテル（５．０ｍＬ）に溶解した後、ヘキサンを加えた。その後、析出した白色固体を回収し、減圧下、３０度で１時間乾燥することで、表題化合物（９２０ｍｇ、収率６６％）を白色固体として得た。

^１Ｈ−ＮＭＲ（ＣＤＣｌ_３）δ：１．４６（９Ｈ，ｓ），１．５７−１．８２（２Ｈ，ｍ），１．８２−１．９５（２Ｈ，ｍ），２．３３−２．４６（１Ｈ，ｍ），２．６８−２．８６（２Ｈ，ｍ），４．０５−４．２６（２Ｈ，ｂｒｍ），６．６５（１Ｈ，ｄ，Ｊ＝８．５Ｈｚ），６．８０（１Ｈ，ｄｄ，Ｊ＝６．８，４．４Ｈｚ），７．５３（１Ｈ，ｄｄｄ，Ｊ＝８．５，６．８，２．０Ｈｚ），８．１６（１Ｈ，ｄｄ，Ｊ＝４．４，２．０Ｈｚ）．

ＬＣ／ＭＳ［条件１］：保持時間１．１２分；ｍ／ｚ３２０．９［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）

Reference Example 415-1
Preparation of 4- [2- (pyridin-2-yl) hydrazinecarbonyl] piperidine-1-carboxylate t-butyl 2-hydrazinopiperidine (520 mg, 4.8 mmol, commercially available), 1- (t-butoxycarbonyl) piperidine After dissolving 4-carboxylic acid (1.0 g, 4.4 mmol) and 1-hydroxybenzotriazole (180 mg, 1.3 mmol) in chloroform (10 mL), 1-ethyl-3- (3-dimethylaminopropyl) was dissolved. Carbodiimide hydrochloride (920 mg, 4.8 mmol) was added and stirred at room temperature for 27 hours. Water was added to separate the organic layer, and the aqueous layer was extracted with chloroform. The combined organic layers were washed with a saturated aqueous sodium hydrogen carbonate solution, a 1.0 M aqueous sodium hydroxide solution and saturated brine. The organic layer was dried over anhydrous sodium sulfate and then concentrated to dryness under reduced pressure. The obtained yellow residue was dissolved in diethyl ether (5.0 mL), and hexane was added. Thereafter, the precipitated white solid was collected and dried under reduced pressure at 30 ° C. for 1 hour to obtain the title compound (920 mg, yield 66%) as a white solid.

¹ H-NMR (CDCl ₃ ) δ: 1.46 (9H, s), 1.57-1.82 (2H, m), 1.82-1.95 (2H, m), 2.33-2 .46 (1H, m), 2.68-2.86 (2H, m), 4.05-4.26 (2H, brm), 6.65 (1H, d, J = 8.5 Hz), 6 .80 (1H, dd, J = 6.8, 4.4 Hz), 7.53 (1H, ddd, J = 8.5, 6.8, 2.0 Hz), 8.16 (1H, dd, J = 4.4, 2.0 Hz).

LC / MS [Condition 1]: Retention time 1.12 minutes; m / z 320.9 [M + H] ⁺ (ESI positive ion mode)

参考例４１５−２
４−（［１，２，４］トリアゾロ［４，３−ａ］ピリジン−３−イル）ピペリジン−１−カルボン酸ｔ−ブチルの製造
参考例４１５−１で得られた４−［２−（ピリジン−２−イル）ヒドラジンカルボニル］ピペリジン−１−カルボン酸ｔ−ブチル（７００ｍｇ、２．２ｍｍｏｌ）をテトラヒドロフラン（２０ｍＬ）に溶解した後、Ｂｕｒｇｅｓｓ試薬（詳細はＪ．Ａｍ．Ｃｈｅｍ．Ｓｏｃ．１２６，２００４，６２３４．を参照）（５７０ｍｇ、２．４ｍｍｏｌ）を加え、４時間加熱還流し、さらに室温で６０時間かき混ぜた。その後、反応混合物を減圧下濃縮した。得られた残留物を酢酸エチルに溶解した後、水を加えた。有機層を分離し、飽和食塩水で洗浄した後、無水硫酸ナトリウムで乾燥した。減圧下濃縮乾固した後、得られた残留物をシリカゲルカラムクロマトグラフィー［昭光サイエンティフィック社製プリフパックＳＩ６０μｍ、展開溶媒：クロロホルム−メタノール］にて精製し、表題化合物（４２０ｍｇ、収率６４％）を白色固体として得た。

^１Ｈ−ＮＭＲ（ＣＤＣｌ_３）δ：１．４９（９Ｈ，ｓ），１．９９−２．１４（４Ｈ，ｍ），２．９４−３．０９（２Ｈ，ｍ），３．１７−３．２９（１Ｈ，ｍ），４．１９−４．３２（２Ｈ，ｍ），６．８５（１Ｈ，ｄｄ，Ｊ＝６．６，７．２Ｈｚ），７．２４（１Ｈ，ｄｄ，Ｊ＝９．２，６．６Ｈｚ），７．７７（１Ｈ，ｄ，Ｊ＝９．２Ｈｚ），７．９４（１Ｈ，ｄ，Ｊ＝７．２Ｈｚ）．

ＬＣ／ＭＳ［条件１］：保持時間３．１１分；ｍ／ｚ３０２．９［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）

Reference Example 415-2
4-([1,2,4] Triazolo [4,3-a] pyridin-3-yl) piperidine-1-carboxylate 4- [2- (obtained in Reference Example 415-1 Pyrridin-2-yl) hydrazinecarbonyl] piperidine-1-carboxylate t-butyl (700 mg, 2.2 mmol) was dissolved in tetrahydrofuran (20 mL), and then Burgess reagent (for details, see J. Am. Chem. Soc. 126, 2004, 6234.) (570 mg, 2.4 mmol) was added and the mixture was heated to reflux for 4 hours and further stirred at room temperature for 60 hours. Thereafter, the reaction mixture was concentrated under reduced pressure. The obtained residue was dissolved in ethyl acetate, and water was added. The organic layer was separated, washed with saturated brine, and dried over anhydrous sodium sulfate. After concentrating to dryness under reduced pressure, the obtained residue was purified by silica gel column chromatography [Prefpack SI 60 μm manufactured by Shoko Scientific Co., Ltd., developing solvent: chloroform-methanol] to give the title compound (420 mg, yield 64%). Was obtained as a white solid.

¹ H-NMR (CDCl ₃ ) δ: 1.49 (9H, s), 1.99-2.14 (4H, m), 2.94-3.09 (2H, m), 3.17-3 .29 (1H, m), 4.19-4.32 (2H, m), 6.85 (1H, dd, J = 6.6, 7.2 Hz), 7.24 (1H, dd, J = 9.2, 6.6 Hz), 7.77 (1H, d, J = 9.2 Hz), 7.94 (1H, d, J = 7.2 Hz).

LC / MS [Condition 1]: Retention time 3.11 min; m / z 302.9 [M + H] ⁺ (ESI positive ion mode)

参考例４１５−３
３−（ピペリジン−４−イル）−［１，２，４］トリアゾロ［４，３−ａ］ピリジン二塩酸塩の製造
参考例４１５−２で得られた４−（［１，２，４］トリアゾロ［４，３−ａ］ピリジン−３−イル）ピペリジン−１−カルボン酸ｔ−ブチル（４２０ｍｇ、１．４ｍｍｏｌ）をメタノール（２．０ｍＬ）に溶解した後、４Ｍ塩化水素−ジオキサン溶液（６．０ｍＬ）を加え、室温で３時間かき混ぜた。析出した白色固体を回収し、減圧下、３０度で２時間乾燥することで、表題化合物（３２０ｍｇ、収率８４％）を得た。

^１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ_６）δ：２．０２−２．３２（４Ｈ，ｍ），３．００−３．２０（２Ｈ，ｍ），３．３４−３．４７（２Ｈ，ｍ），３．７４−３．９４（１Ｈ，ｍ），６．０７（１Ｈ，ｂｒ ｓ），７．４７（１Ｈ，ｄｄ，Ｊ＝６．７，６．９Ｈｚ），７．９４（１Ｈ，ｄｄ，Ｊ＝９．１，６．７Ｈｚ），８．０５（１Ｈ，ｄ，Ｊ＝９．１Ｈｚ），９．０３（１Ｈ，ｄ，Ｊ＝６．９Ｈｚ），９．２２−９．５３（２Ｈ，ｍ）．

ＬＣ／ＭＳ［条件１］：保持時間０．４７分；ｍ／ｚ２０３．０［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）

Reference Example 415-3
Production of 3- (piperidin-4-yl)-[1,2,4] triazolo [4,3-a] pyridine dihydrochloride 4-([1,2,4] obtained in Reference Example 415-2 After dissolving t-butyl triazolo [4,3-a] pyridin-3-yl) piperidine-1-carboxylate (420 mg, 1.4 mmol) in methanol (2.0 mL), 4M hydrogen chloride-dioxane solution (6 0.0 mL) and stirred at room temperature for 3 hours. The precipitated white solid was collected and dried under reduced pressure at 30 ° C. for 2 hours to obtain the title compound (320 mg, 84% yield).

¹ H-NMR (DMSO-d ₆ ) δ: 2.02-2.32 (4H, m), 3.00-3.20 (2H, m), 3.34-3.47 (2H, m) 3.74-3.94 (1H, m), 6.07 (1H, br s), 7.47 (1 H, dd, J = 6.7, 6.9 Hz), 7.94 (1 H, dd) , J = 9.1, 6.7 Hz), 8.05 (1H, d, J = 9.1 Hz), 9.03 (1H, d, J = 6.9 Hz), 9.22-9.53 ( 2H, m).

LC / MS [Condition 1]: Retention time 0.47 minutes; m / z 203.0 [M + H] ⁺ (ESI positive ion mode)

実施例４１５
３−（｛（１ｒ，４ｒ）−４−［４−（［１，２，４］トリアゾロ［４，３−ａ］ピリジン−３−イル）ピペリジン−１−カルボニル］シクロヘキシル｝メチル）−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−２−オン（化合物番号４１５）の製造
３，５−ジメチルピペリジンの代わりに参考例４１５−３で得られた３−（ピペリジン−４−イル）−［１，２，４］トリアゾロ［４，３−ａ］ピリジン二塩酸塩を用いること以外は実質的に実施例３４２と同様に反応を行って、表題化合物（１３ｍｇ、収率３４％）を白色粉末として得た。

^１Ｈ−ＮＭＲ（３００ＭＨｚ、ＣＤＣｌ_３）δ：１．０７（２Ｈ，ｑ，Ｊ＝１３．１Ｈｚ），１．４７−１．７１（３Ｈ，ｂｒ ｍ），１．７１−２．０１（９Ｈ，ｂｒ ｍ），２．０４−２．３０（３Ｈ，ｂｒ ｍ），２．５０（１Ｈ，ｔｔ，Ｊ＝１１．９，４．１Ｈｚ），２．５６（４Ｈ，ｂｒ ｓ），２．９９（１Ｈ，ｔ，Ｊ＝１１．９Ｈｚ），３．０７−３．１６（２Ｈ，ｍ），３．２４−３．４０（２Ｈ，ｍ），３．２６（２Ｈ，ｓ），３．５８（２Ｈ，ｓ），４．１２（１Ｈ，ｄ，Ｊ＝７．４Ｈｚ），４．５９（１Ｈ，ｄ，Ｊ＝１３．５Ｈｚ），６．８６（１Ｈ，ｔ，Ｊ＝６．５Ｈｚ），７．１９−７．３０（１Ｈ，ｍ），７．４４（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ），７．５７（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ），７．７８（１Ｈ，ｄ，Ｊ＝９．４Ｈｚ），７．９２（１Ｈ，ｄ，Ｊ＝７．０Ｈｚ）．

ＬＣ／ＭＳ［条件１］：保持時間２．８６分；ｍ／ｚ３２０．０［Ｍ＋２Ｈ］^２＋、６３８．９［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ６８２．９［Ｍ＋ＨＣＯＯ］^―（ＥＳＩ負イオンモード）

Example 415
3-({(1r, 4r) -4- [4-([1,2,4] triazolo [4,3-a] pyridin-3-yl) piperidine-1-carbonyl] cyclohexyl} methyl) -8- Preparation of [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-2-one (Compound No. 415)
Use 3- (piperidin-4-yl)-[1,2,4] triazolo [4,3-a] pyridine dihydrochloride obtained in Reference Example 415-3 instead of 3,5-dimethylpiperidine. Except for the above, the reaction was carried out in substantially the same manner as in Example 342 to give the title compound (13 mg, yield 34%) as a white powder.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.07 (2H, q, J = 13.1 Hz), 1.47-1.71 (3H, br m), 1.71-2.01 (9H , Br m), 2.04-2.30 (3H, br m), 2.50 (1H, tt, J = 11.9, 4.1 Hz), 2.56 (4H, br s), 2. 99 (1H, t, J = 11.9 Hz), 3.07-3.16 (2H, m), 3.24-3.40 (2H, m), 3.26 (2H, s), 3. 58 (2H, s), 4.12 (1H, d, J = 7.4 Hz), 4.59 (1H, d, J = 13.5 Hz), 6.86 (1H, t, J = 6.5 Hz) ), 7.19-7.30 (1H, m), 7.44 (2H, d, J = 8.2 Hz), 7.57 (2H, d, J = 8.2 Hz), 7.78 (1H) , D, J 9.4Hz), 7.92 (1H, d, J = 7.0Hz).

LC / MS [Condition 1]: Retention time 2.86 min; m / z 320.0 [M + 2H] ²⁺ , 638.9 [M + H] ⁺ (ESI positive ion mode), m / z 682.9 [M + HCOO] ⁻ (ESI Negative ion mode)

参考例４１６−１
イソプロピル［（テトラヒドロフラン−２−イル）メチル］カルバミン酸ｔ−ブチルの製造
参考例１８２−１で得られた（テトラヒドロフラン−２−イル）メチルカルバミン酸ｔ−ブチル（０．１０ｇ、０．５０ｍｍｏｌ）をＮ，Ｎ−ジメチルホルムアミド（１．０ｍＬ）に溶解し、０℃にて水素化ナトリウム（＞６３重量％、流動パラフィン分散）（３６ｍｇ、１．５ｍｍｏｌ）を加えた後、室温にて１時間かき混ぜた。その後、２−ヨードプロパン（０．２５ｍＬ、２．５ｍｍｏｌ）を加え、室温にて終夜かき混ぜた。水（２．０ｍＬ）と酢酸エチル（２．０ｍＬ）を加えた後、有機層を分離し、水（２．０ｍＬ）で洗浄した。有機層を無水硫酸マグネシウムで乾燥した後、減圧下濃縮乾固した。得られた残渣物をシリカゲルカラムクロマトグラフィー［モリテックス社製プリフパックＳＩ６０μｍ、展開溶媒：酢酸エチル／ヘキサン］にて精製し、表題化合物（３５ｍｇ、収率２９％）を無色油状物として得た。

ＬＣ／ＭＳ［条件１］：保持時間４．３１分；ｍ／ｚ１４３．９［Ｍ−ｉｓｏｂｕｔｅｎｅ−ＣＯ_２＋Ｈ］^＋（ＥＳＩ正イオンモード）

Reference Example 416-1
Preparation of t-butyl isopropyl [(tetrahydrofuran-2-yl) methyl] carbamate t-butyl (tetrahydrofuran-2-yl) methylcarbamate (0.10 g, 0.50 mmol) obtained in Reference Example 182-1 , N-dimethylformamide (1.0 mL), sodium hydride (> 63 wt%, liquid paraffin dispersion) (36 mg, 1.5 mmol) was added at 0 ° C., and the mixture was stirred at room temperature for 1 hour. . Thereafter, 2-iodopropane (0.25 mL, 2.5 mmol) was added and stirred overnight at room temperature. After adding water (2.0 mL) and ethyl acetate (2.0 mL), the organic layer was separated and washed with water (2.0 mL). The organic layer was dried over anhydrous magnesium sulfate and then concentrated to dryness under reduced pressure. The obtained residue was purified by silica gel column chromatography [Polipack SI 60 μm, developed by Mortex, developing solvent: ethyl acetate / hexane] to give the title compound (35 mg, yield 29%) as a colorless oil.

LC / MS [Condition 1]: Retention time 4.31 min; m / z 143.9 [M-isobutene-CO ₂ + H] ⁺ (ESI positive ion mode)

参考例４１６−２
Ｎ−［（テトラヒドロフラン−２−イル）メチル］プロパン−２−アミン塩酸塩の製造
参考例４１６−１で得られたイソプロピル［（テトラヒドロフラン−２−イル）メチル］カルバミン酸ｔ−ブチル（３５ｍｇ、０．１４ｍｍｏｌ）をメタノール（１．０ｍＬ）に溶解し、室温にて１０％塩化水素−メタノール（０．７ｍＬ）を加えて、５０℃にて３時間かき混ぜた。その後、反応溶液を減圧下濃縮乾固して、表題化合物（２５ｍｇ、定量的）を無色油状物として得た。

ＬＣ／ＭＳ［条件１］：保持時間０．４９分；ｍ／ｚ１４４．０［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）

Reference Example 416-2
Production of N-[(tetrahydrofuran-2-yl) methyl] propan-2-amine hydrochloride t-butyl isopropyl [(tetrahydrofuran-2-yl) methyl] carbamate obtained in Reference Example 416-1 (35 mg, 0 .14 mmol) was dissolved in methanol (1.0 mL), 10% hydrogen chloride-methanol (0.7 mL) was added at room temperature, and the mixture was stirred at 50 ° C. for 3 hr. The reaction solution was then concentrated to dryness under reduced pressure to give the title compound (25 mg, quantitative) as a colorless oil.

LC / MS [Condition 1]: Retention time 0.49 min; m / z 144.0 [M + H] ⁺ (ESI positive ion mode)

実施例４１６
（１ｒ，４ｒ）−Ｎ−イソプロピル−４−（｛２−オキソ−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）−Ｎ−［（テトラヒドロフラン−２−イル）メチル］シクロヘキサンカルボキサミド（化合物番号４１６）の製造
３，５−ジメチルピペリジンの代わりに参考例４１６−２で得られたＮ−［（テトラヒドロフラン−２−イル）メチル］プロパン−２−アミン塩酸塩を用いること以外は実質的に実施例３４２と同様に反応を行って、表題化合物（１１ｍｇ、収率２８％）を無色油状物として得た。

^１Ｈ−ＮＭＲ（３００ＭＨｚ、ＣＤＣｌ_３）δ：１．０５（２Ｈ，ｄｑ，Ｊ＝３．７，１３．１Ｈｚ），１．１１−１．２１（３．９Ｈ，ｍ），１．２６（２．１Ｈ，ｄ，Ｊ＝６．５Ｈｚ），１．４１−１．６７（３Ｈ，ｂｒ ｍ），１．６５−１．８６（７Ｈ，ｂｒ ｍ），１．８５−２．１０（５Ｈ，ｂｒ ｍ），２．４７（１Ｈ，ｔｔ，Ｊ＝１１．４，２．９Ｈｚ），２．５５（４Ｈ，ｂｒ ｓ），２．９７（０．６５Ｈ，ｄｄ，Ｊ＝１３．９，７．０Ｈｚ），３．１０（２Ｈ，ｄ，Ｊ＝７．４Ｈｚ），３．１１−３．３９（１Ｈ，ｍ），３．２５（２Ｈ，ｓ），３．４９−３．６２（０．６５Ｈ，ｍ），３．５７（２Ｈ，ｓ），３．６３−３．８８（２Ｈ，ｍ），３．８６−３．９８（０．３５Ｈ，ｍ），３．９８−４．１４（１Ｈ，ｍ），４．５１（０．３５Ｈ，ｔｔ，Ｊ＝７．４，７．４Ｈｚ），７．４３（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ），７．５６（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ）．

ＬＣ／ＭＳ［条件１］：保持時間３．２４分；ｍ／ｚ５７９．９［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ６２４．０［Ｍ＋ＨＣＯＯ］^―（ＥＳＩ負イオンモード）

Example 416
(1r, 4r) -N-isopropyl-4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl } Methyl) -N-[(tetrahydrofuran-2-yl) methyl] cyclohexanecarboxamide (Compound No. 416) N-[(tetrahydrofuran-2) obtained in Reference Example 416-2 instead of 3,5-dimethylpiperidine -Il) Methyl] The reaction was carried out in substantially the same manner as in Example 342, except that propan-2-amine hydrochloride was used, to give the title compound (11 mg, yield 28%) as a colorless oil.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.05 (2H, dq, J = 3.7, 13.1 Hz), 1.11-1.21 (3.9 H, m), 1.26 ( 2.1H, d, J = 6.5 Hz), 1.41-1.67 (3H, br m), 1.65-1.86 (7H, br m), 1.85-2.10 (5H) , Br m), 2.47 (1H, tt, J = 11.4, 2.9 Hz), 2.55 (4H, br s), 2.97 (0.65H, dd, J = 13.9, 7.0 Hz), 3.10 (2H, d, J = 7.4 Hz), 3.11-3.39 (1H, m), 3.25 (2H, s), 3.49-3.62 ( 0.65H, m), 3.57 (2H, s), 3.63-3.88 (2H, m), 3.86-3.98 (0.35H, m), 3.98-4. 14 (1H, m 4.51 (0.35H, tt, J = 7.4, 7.4 Hz), 7.43 (2H, d, J = 8.2 Hz), 7.56 (2H, d, J = 8.2 Hz) ).

LC / MS [Condition 1]: retention time 3.24 minutes; m / z 579.9 [M + H] ⁺ (ESI positive ion mode), m / z 624.0 [M + HCOO] ⁻ (ESI negative ion mode)

実施例４１７
（１ｒ，４ｒ）−４−｛［８−（４−シアノ−２，６−ジフルオロベンジル）−２−オキソ−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル］メチル｝−Ｎ−（フラン−２−イルメチル）シクロヘキサンカルボキサミド（化合物番号４１７）の製造
６−（ピペリジン−４−イルオキシ）ニコチノニトリル塩酸塩の代わりにフラン−２−イルメタンアミン（市販）を用いること以外は実質的に実施例４０２と同様に反応を行って、表題化合物（１９ｍｇ、収率５５％）を白色粉末として得た。

^１Ｈ−ＮＭＲ（３００ＭＨｚ、ＣＤＣｌ_３）δ：１．００（２Ｈ，ｄｑ，Ｊ＝３．３，１２．７Ｈｚ），１．４９（２Ｈ，ｄｑ，Ｊ＝２．９，１３．１Ｈｚ），１．５０−１．６４（１Ｈ，ｂｒ ｍ），１．６７−１．８４（４Ｈ，ｂｒ ｍ），１．８５−１．９８（４Ｈ，ｂｒ ｍ），２．０３（１Ｈ，ｔｔ，Ｊ＝１１．９，３．３Ｈｚ），２．６２（４Ｈ，ｂｒ ｓ），３．０７（２Ｈ，ｄ，Ｊ＝７．４Ｈｚ），３．２２（２Ｈ，ｓ），３．７５（２Ｈ，ｓ），４．４２（２Ｈ，ｄ，Ｊ＝５．３Ｈｚ），５．７１（１Ｈ，ｔ，Ｊ＝４．９Ｈｚ），６．２１（１Ｈ，ｄ，Ｊ＝２．５Ｈｚ），６．３１（１Ｈ，ｄｄ，Ｊ＝３．３，２．０Ｈｚ），７．２２（２Ｈ，ｄ，Ｊ＝５．７Ｈｚ），７．３４（１Ｈ，ｄｄ，Ｊ＝１．６，０．８Ｈｚ）．

ＬＣ／ＭＳ［条件１］：保持時間２．５５分；ｍ／ｚ５２７．０［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ５７１．１［Ｍ＋ＨＣＯＯ］^―（ＥＳＩ負イオンモード）

Example 417
(1r, 4r) -4-{[8- (4-Cyano-2,6-difluorobenzyl) -2-oxo-1-oxa-3,8-diazaspiro [4.5] decan-3-yl] methyl } Preparation of —N- (furan-2-ylmethyl) cyclohexanecarboxamide (Compound No. 417) Use of furan-2-ylmethanamine (commercially available) instead of 6- (piperidin-4-yloxy) nicotinonitrile hydrochloride The title compound (19 mg, yield 55%) was obtained as a white powder in substantially the same manner as in Example 402 except for the above.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.00 (2H, dq, J = 3.3, 12.7 Hz), 1.49 (2H, dq, J = 2.9, 13.1 Hz), 1.50-1.64 (1H, br m), 1.67-1.84 (4H, br m), 1.85-1.98 (4H, br m), 2.03 (1 H, tt, J = 11.9, 3.3 Hz), 2.62 (4H, brs), 3.07 (2H, d, J = 7.4 Hz), 3.22 (2H, s), 3.75 (2H) , S), 4.42 (2H, d, J = 5.3 Hz), 5.71 (1H, t, J = 4.9 Hz), 6.21 (1H, d, J = 2.5 Hz), 6 .31 (1H, dd, J = 3.3, 2.0 Hz), 7.22 (2H, d, J = 5.7 Hz), 7.34 (1H, dd, J = 1.6, 0.8 Hz) ).

LC / MS [Condition 1]: Retention time 2.55 minutes; m / z 527.0 [M + H] ⁺ (ESI positive ion mode), m / z 571.1 [M + HCOO] ⁻ (ESI negative ion mode)

実施例４１８
（１ｒ，４ｒ）−４−｛［８−（４−シアノ−２，６−ジフルオロベンジル）−２−オキソ−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル］メチル｝−Ｎ−（フラン−３−イルメチル）シクロヘキサンカルボキサミド（化合物番号４１８）の製造
６−（ピペリジン−４−イルオキシ）ニコチノニトリル塩酸塩の代わりにフラン−３−イルメタンアミン（市販）を用いること以外は実質的に実施例４０２と同様に反応を行って、表題化合物（１７ｍｇ、収率４８％）を白色粉末として得た。

^１Ｈ−ＮＭＲ（３００ＭＨｚ、ＣＤＣｌ_３）δ：１．００（２Ｈ，ｄｑ，Ｊ＝３．３，１３．１Ｈｚ），１．４９（２Ｈ，ｄｑ，Ｊ＝２．５，１２．３Ｈｚ），１．５１−１．６３（１Ｈ，ｂｒ ｍ），１．６８−１．８３（４Ｈ，ｂｒ ｍ），１．８５−１．９９（４Ｈ，ｂｒ ｍ），２．０２（１Ｈ，ｔｔ，Ｊ＝１１．９，３．３Ｈｚ），２．６２（４Ｈ，ｂｒ ｓ），３．０７（２Ｈ，ｄ，Ｊ＝７．４Ｈｚ），３．２２（１Ｈ，ｓ），３．７５（２Ｈ，ｓ），４．２７（２Ｈ，ｄ，Ｊ＝５．３Ｈｚ），５．５７（１Ｈ，ｔ，Ｊ＝４．９Ｈｚ），６．３３（１Ｈ，ｓ），７．２２（２Ｈ，ｄ，Ｊ＝５．７Ｈｚ），７．３３−７．３８（２Ｈ，ｍ）．

ＬＣ／ＭＳ［条件１］：保持時間２．２７分；ｍ／ｚ５２６．９［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ５７１．２［Ｍ＋ＨＣＯＯ］^―（ＥＳＩ負イオンモード）

Example 418
(1r, 4r) -4-{[8- (4-Cyano-2,6-difluorobenzyl) -2-oxo-1-oxa-3,8-diazaspiro [4.5] decan-3-yl] methyl } Preparation of —N- (furan-3-ylmethyl) cyclohexanecarboxamide (Compound No. 418) Using furan-3-ylmethanamine (commercially available) instead of 6- (piperidin-4-yloxy) nicotinonitrile hydrochloride Except for the above, the reaction was carried out in substantially the same manner as in Example 402 to give the title compound (17 mg, yield 48%) as a white powder.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.00 (2H, dq, J = 3.3, 13.1 Hz), 1.49 (2H, dq, J = 2.5, 12.3 Hz), 1.51-1.63 (1H, br m), 1.68-1.83 (4H, br m), 1.85-1.99 (4H, br m), 2.02 (1 H, tt, J = 11.9, 3.3 Hz), 2.62 (4H, brs), 3.07 (2H, d, J = 7.4 Hz), 3.22 (1 H, s), 3.75 (2H) , S), 4.27 (2H, d, J = 5.3 Hz), 5.57 (1H, t, J = 4.9 Hz), 6.33 (1H, s), 7.22 (2H, d) , J = 5.7 Hz), 7.33-7.38 (2H, m).

LC / MS [Condition 1]: Retention time 2.27 minutes; m / z 526.9 [M + H] ⁺ (ESI positive ion mode), m / z 571.2 [M + HCOO] ⁻ (ESI negative ion mode)

実施例４１９
（１ｒ，４ｒ）−４−｛［８−（４−シアノ−２，６−ジフルオロベンジル）−２−オキソ−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル］メチル｝−Ｎ−［（３−メトキシイソキサゾール−５−イル）メチル］シクロヘキサンカルボキサミド（化合物番号４１９）の製造
６−（ピペリジン−４−イルオキシ）ニコチノニトリル塩酸塩の代わりに参考例４０１−３で得られた（３−メトキシイソキサゾール−５−イル）メタンアミンを用いること以外は実質的に実施例４０２と同様に反応を行って、表題化合物（２６ｍｇ、収率７０％）を白色粉末として得た。

^１Ｈ−ＮＭＲ（３００ＭＨｚ、ＣＤＣｌ_３）δ：１．０１（２Ｈ，ｄｑ，Ｊ＝２．９，１３．１Ｈｚ），１．４８（２Ｈ，ｄｑ，Ｊ＝２．５，１３．１Ｈｚ），１．５０−１．６３（１Ｈ，ｂｒ ｍ），１．６７−１．８２（４Ｈ，ｂｒ ｍ），１．８４−１．９８（４Ｈ，ｂｒ ｍ），２．０７（１Ｈ，ｔｔ，Ｊ＝１１．９，３．３Ｈｚ），２．６３（４Ｈ，ｂｒ ｓ），３．０７（２Ｈ，ｄ，Ｊ＝７．４Ｈｚ），３．２２（２Ｈ，ｓ），３．７５（２Ｈ，ｓ），３．９４（３Ｈ，ｓ），４．４３（２Ｈ，ｄ，Ｊ＝５．７Ｈｚ），５．７８（１Ｈ，ｓ），５．９２（１Ｈ，ｔ，Ｊ＝５．７Ｈｚ），７．２２（２Ｈ，ｄ，Ｊ＝６．１Ｈｚ）．

ＬＣ／ＭＳ［条件１］：保持時間１．５０分；ｍ／ｚ５５８．０［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ５５６．１［Ｍ−Ｈ］^―、６０２．１［Ｍ＋ＨＣＯＯ］^―（ＥＳＩ負イオンモード）

Example 419
(1r, 4r) -4-{[8- (4-Cyano-2,6-difluorobenzyl) -2-oxo-1-oxa-3,8-diazaspiro [4.5] decan-3-yl] methyl } Preparation of —N-[(3-methoxyisoxazol-5-yl) methyl] cyclohexanecarboxamide (Compound No. 419) Reference Example 401-3 instead of 6- (piperidin-4-yloxy) nicotinonitrile hydrochloride The reaction was carried out in substantially the same manner as in Example 402 except that (3-methoxyisoxazol-5-yl) methanamine obtained in 1 was used to give the title compound (26 mg, yield 70%) as a white powder. Obtained.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.01 (2H, dq, J = 2.9, 13.1 Hz), 1.48 (2H, dq, J = 2.5, 13.1 Hz), 1.50-1.63 (1H, br m), 1.67-1.82 (4H, br m), 1.84-1.98 (4H, br m), 2.07 (1 H, tt, J = 11.9, 3.3 Hz), 2.63 (4H, brs), 3.07 (2H, d, J = 7.4 Hz), 3.22 (2H, s), 3.75 (2H) , S), 3.94 (3H, s), 4.43 (2H, d, J = 5.7 Hz), 5.78 (1H, s), 5.92 (1H, t, J = 5.7 Hz) ), 7.22 (2H, d, J = 6.1 Hz).

LC / MS [Condition 1]: Retention time 1.50 minutes; m / z 558.0 [M + H] ⁺ (ESI positive ion mode), m / z 556.1 [M−H] ⁻ , 602.1 [M + HCOO] ⁻ (ESI negative ion mode)

実施例４２０
（１ｒ，４ｒ）−４−｛［８−（４−シアノ−２，６−ジフルオロベンジル）−２−オキソ−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル］メチル｝−Ｎ−［（２−フルオロピリジン−４−イル）メチル］シクロヘキサンカルボキサミド（化合物番号４２０）の製造
６−（ピペリジン−４−イルオキシ）ニコチノニトリル塩酸塩の代わりに参考例３９５−５で得られた（２−フルオロピリジン−４−イル）メタンアミンを用いること以外は実質的に実施例４０２と同様に反応を行って、表題化合物（１８ｍｇ、収率４７％）を白色粉末として得た。
^１Ｈ−ＮＭＲ（３００ＭＨｚ、ＣＤＣｌ_３）δ：１．０３（２Ｈ，ｄｑ，Ｊ＝３．３，１２．７Ｈｚ），１．４２−１．６６（３Ｈ，ｂｒ ｍ），１．６８−１．８４（４Ｈ，ｂｒ ｍ），１．８５−２．０３（４Ｈ，ｂｒ ｍ），２．１２（１Ｈ，ｔｔ，Ｊ＝１１．０，４．１Ｈｚ），２．６２（４Ｈ，ｂｒ ｓ），３．０９（２Ｈ，ｄ，Ｊ＝７．４Ｈｚ），３．２３（２Ｈ，ｓ），３．７４（２Ｈ，ｓ），４．４７（２Ｈ，ｄ，Ｊ＝６．１Ｈｚ），５．９５（１Ｈ，ｔ，Ｊ＝６．１Ｈｚ），６．７９（１Ｈ，ｓ），７．０５（１Ｈ，ｄ，Ｊ＝４．９Ｈｚ），７．２２（２Ｈ，ｄ，Ｊ＝５．３Ｈｚ），８．１５（１Ｈ，ｄ，Ｊ＝４．９Ｈｚ）．

ＬＣ／ＭＳ［条件１］：保持時間１．４０分；ｍ／ｚ２７８．６［Ｍ＋２Ｈ］^２＋、５５５．９［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ５５４．２［Ｍ−Ｈ］^―、６００．０［Ｍ＋ＨＣＯＯ］^―（ＥＳＩ負イオンモード）

Example 420
(1r, 4r) -4-{[8- (4-Cyano-2,6-difluorobenzyl) -2-oxo-1-oxa-3,8-diazaspiro [4.5] decan-3-yl] methyl } Preparation of —N-[(2-fluoropyridin-4-yl) methyl] cyclohexanecarboxamide (Compound No. 420) Obtained in Reference Example 395-5 instead of 6- (piperidin-4-yloxy) nicotinonitrile hydrochloride The reaction was carried out substantially in the same manner as in Example 402 except that the obtained (2-fluoropyridin-4-yl) methanamine was used to obtain the title compound (18 mg, yield 47%) as a white powder.
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.03 (2H, dq, J = 3.3, 12.7 Hz), 1.42-1.66 (3H, br m), 1.68-1 .84 (4H, br m), 1.85-2.03 (4H, br m), 2.12 (1H, tt, J = 11.0, 4.1 Hz), 2.62 (4H, br s) ), 3.09 (2H, d, J = 7.4 Hz), 3.23 (2H, s), 3.74 (2H, s), 4.47 (2H, d, J = 6.1 Hz), 5.95 (1H, t, J = 6.1 Hz), 6.79 (1H, s), 7.05 (1H, d, J = 4.9 Hz), 7.22 (2H, d, J = 5) .3 Hz), 8.15 (1H, d, J = 4.9 Hz).

LC / MS [Condition 1]: Retention time 1.40 minutes; m / z 278.6 [M + 2H] ²⁺ , 555.9 [M + H] ⁺ (ESI positive ion mode), m / z 554.2 [M−H] ⁻ , 600.0 [M + HCOO] ^- (ESI negative ion mode)

実施例４２１
４−［（３−｛［（１ｒ，４ｒ）−４−（４，４−ジフルオロピペリジン−１−カルボニル）シクロヘキシル］メチル｝−２−オキソ−１−オキサ−３，８−ジアザスピロ［４．５］デカン−８−イル）メチル］−３，５−ジフルオロベンゾニトリル（化合物番号４２１）の製造
６−（ピペリジン−４−イルオキシ）ニコチノニトリル塩酸塩の代わりに４，４−ジフルオロピペリジン塩酸塩（市販）を用いること以外は実質的に実施例４０２と同様に反応を行って、表題化合物（４６ｍｇ、定量的）を白色粉末として得た。

^１Ｈ−ＮＭＲ（３００ＭＨｚ、ＣＤＣｌ_３）δ：１．０４（２Ｈ，ｑ，Ｊ＝１１．９Ｈｚ），１．４６−１．６７（３Ｈ，ｂｒ ｍ），１．６７−１．８５（６Ｈ，ｂｒ ｍ），１．８５−２．０７（６Ｈ，ｂｒ ｍ），２．４５（１Ｈ，ｔｔ，Ｊ＝１２．７，２．５Ｈｚ），２．５１−２．７４（４Ｈ，ｂｒ ｍ），３．０９（２Ｈ，ｄ，Ｊ＝７．４Ｈｚ），３．２２（２Ｈ，ｓ），３．５７（２Ｈ，ｂｒ ｓ），３．７１（２Ｈ，ｂｒ ｓ），３．７５（２Ｈ，ｓ），７．２２（２Ｈ，ｄ，Ｊ＝６．１Ｈｚ）．

ＬＣ／ＭＳ［条件１］：保持時間２．９２分；ｍ／ｚ５５１．０［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ５９５．２［Ｍ＋ＨＣＯＯ］^―（ＥＳＩ負イオンモード）

Example 421
4-[(3-{[(1r, 4r) -4- (4,4-difluoropiperidine-1-carbonyl) cyclohexyl] methyl} -2-oxo-1-oxa-3,8-diazaspiro [4.5 Preparation of decan-8-yl) methyl] -3,5-difluorobenzonitrile (Compound No. 421) 4,4-Difluoropiperidine hydrochloride (instead of 6- (piperidin-4-yloxy) nicotinonitrile hydrochloride) The title compound (46 mg, quantitative) was obtained as a white powder in substantially the same manner as in Example 402 except that a commercially available product was used.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.04 (2H, q, J = 11.9 Hz), 1.46-1.67 (3H, br m), 1.67-1.85 (6H , Br m), 1.85-2.07 (6H, br m), 2.45 (1H, tt, J = 12.7, 2.5 Hz), 2.51-2.74 (4H, br m ), 3.09 (2H, d, J = 7.4 Hz), 3.22 (2H, s), 3.57 (2H, br s), 3.71 (2H, br s), 3.75 ( 2H, s), 7.22 (2H, d, J = 6.1 Hz).

LC / MS [Condition 1]: Retention time 2.92 minutes; m / z 551.0 [M + H] ⁺ (ESI positive ion mode), m / z 595.2 [M + HCOO] ⁻ (ESI negative ion mode)

実施例４２２
３，５−ジフルオロ−４−｛［２−オキソ−３−（｛（１ｒ，４ｒ）−４−［４−（トリフルオロメチル）ピペリジン−１−カルボニル］シクロヘキシル｝メチル）−１−オキサ−３，８−ジアザスピロ［４．５］デカン−８−イル］メチル｝ベンゾニトリル（化合物番号４２２）の製造
６−（ピペリジン−４−イルオキシ）ニコチノニトリル塩酸塩の代わりに４−（トリフルオロメチル）ピペリジン塩酸塩（市販）を用いること以外は実質的に実施例４０２と同様に反応を行って、表題化合物（５３ｍｇ、定量的）を白色粉末として得た。

^１Ｈ−ＮＭＲ（３００ＭＨｚ、ＣＤＣｌ_３）δ：１．０３（２Ｈ，ｑ，Ｊ＝１３．１Ｈｚ），１．３６−１．６５（５Ｈ，ｂｒ ｍ），１．６７−１．８４（６Ｈ，ｂｒ ｍ），１．８５−２．０１（４Ｈ，ｂｒ ｍ），２．１６−２．３４（１Ｈ，ｍ），２．３５−２．５１（２Ｈ，ｍ），２．５２−２．７３（４Ｈ，ｂｒ ｍ），３．０１（１Ｈ，ｔ，Ｊ＝１２．７Ｈｚ），３．０９（２Ｈ，ｄ，Ｊ＝７．０Ｈｚ），３．２２（２Ｈ，ｓ），３．７５（２Ｈ，ｓ），３．９８（１Ｈ，ｄ，Ｊ＝１２．３Ｈｚ），４．７５（１Ｈ，ｄ，Ｊ＝１３．５Ｈｚ），７．２２（２Ｈ，ｄ，Ｊ＝６．１Ｈｚ）．

ＬＣ／ＭＳ［条件１］：保持時間３．１８分；ｍ／ｚ５８３．１［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ６２７．２［Ｍ＋ＨＣＯＯ］^―（ＥＳＩ負イオンモード）

Example 422
3,5-difluoro-4-{[2-oxo-3-({(1r, 4r) -4- [4- (trifluoromethyl) piperidine-1-carbonyl] cyclohexyl} methyl) -1-oxa-3 , 8-diazaspiro [4.5] decan-8-yl] methyl} benzonitrile (Compound No. 422) 4- (trifluoromethyl) instead of 6- (piperidin-4-yloxy) nicotinonitrile hydrochloride The reaction was carried out in substantially the same manner as in Example 402 except that piperidine hydrochloride (commercially available) was used, and the title compound (53 mg, quantitative) was obtained as a white powder.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.03 (2H, q, J = 13.1 Hz), 1.36 to 1.65 (5H, br m), 1.67 to 1.84 (6H) , Br m), 1.85-2.01 (4H, br m), 2.16-2.34 (1H, m), 2.35-2.51 (2H, m), 2.52-2 .73 (4H, br m), 3.01 (1H, t, J = 12.7 Hz), 3.09 (2H, d, J = 7.0 Hz), 3.22 (2H, s), 3. 75 (2H, s), 3.98 (1H, d, J = 12.3 Hz), 4.75 (1H, d, J = 13.5 Hz), 7.22 (2H, d, J = 6.1 Hz) ).

LC / MS [Condition 1]: Retention time 3.18 minutes; m / z 583.1 [M + H] ⁺ (ESI positive ion mode), m / z 627.2 [M + HCOO] ⁻ (ESI negative ion mode)

実施例４２３
４−（（１ｒ，４ｒ）−４−｛［８−（４−シアノ−２，６−ジフルオロベンジル）−２−オキソ−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル］メチル｝シクロヘキサンカルボニル）ピペラジン−１−カルボン酸エチル（化合物番号４２３）の製造
６−（ピペリジン−４−イルオキシ）ニコチノニトリル塩酸塩の代わりにピペラジン−１−カルボン酸エチル（市販）を用いること以外は実質的に実施例４０２と同様に反応を行って、表題化合物（４８ｍｇ、定量的）を白色粉末として得た。

^１Ｈ−ＮＭＲ（３００ＭＨｚ、ＣＤＣｌ_３）δ：１．０３（２Ｈ，ｑ，Ｊ＝１２．３Ｈｚ），１．２７（３Ｈ，ｔ，Ｊ＝７．４Ｈｚ），１．４４−１．６５（３Ｈ，ｂｒ ｍ），１．６８−１．８４（６Ｈ，ｂｒ ｍ），１．８４−１．９７（２Ｈ，ｂｒ ｍ），２．４２（１Ｈ，ｔ，Ｊ＝１１．９Ｈｚ），２．５０−２．７２（４Ｈ，ｂｒ ｍ），３．０９（２Ｈ，ｄ，Ｊ＝７．４Ｈｚ），３．２２（２Ｈ，ｓ），３．４７（６Ｈ，ｂｒ ｓ），３．５９（２Ｈ，ｂｒ ｓ），３．７５（２Ｈ，ｓ），４．１６（２Ｈ，ｑ，Ｊ＝６．５Ｈｚ），７．２２（２Ｈ，ｄ，Ｊ＝５．９Ｈｚ）．

ＬＣ／ＭＳ［条件１］：保持時間２．８８分；ｍ／ｚ５８８．１［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ６３２．２［Ｍ＋ＨＣＯＯ］^―（ＥＳＩ負イオンモード）

Example 423
4-((1r, 4r) -4-{[8- (4-cyano-2,6-difluorobenzyl) -2-oxo-1-oxa-3,8-diazaspiro [4.5] decane-3- [Ill] methyl} cyclohexanecarbonyl) Preparation of ethyl piperazine-1-carboxylate (Compound No. 423) Instead of 6- (piperidin-4-yloxy) nicotinonitrile hydrochloride, use is made of ethyl piperazine-1-carboxylate In substantially the same manner as in Example 402, the title compound (48 mg, quantitative) was obtained as a white powder.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.03 (2H, q, J = 12.3 Hz), 1.27 (3H, t, J = 7.4 Hz), 1.44 to 1.65 ( 3H, br m), 1.68-1.84 (6H, br m), 1.84-1.97 (2H, br m), 2.42 (1 H, t, J = 11.9 Hz), 2 50-2.72 (4H, br m), 3.09 (2H, d, J = 7.4 Hz), 3.22 (2H, s), 3.47 (6H, br s), 3.59 (2H, br s), 3.75 (2H, s), 4.16 (2H, q, J = 6.5 Hz), 7.22 (2H, d, J = 5.9 Hz).

LC / MS [Condition 1]: Retention time 2.88 minutes; m / z 588.1 [M + H] ⁺ (ESI positive ion mode), m / z 632.2 [M + HCOO] ⁻ (ESI negative ion mode)

実施例４２４
４−（（１ｒ，４ｒ）−４−｛［８−（４−シアノ−２，６−ジフルオロベンジル）−２−オキソ−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル］メチル｝シクロヘキサンカルボニル）−１，４−ジアゼパン−１−カルボン酸メチル（化合物番号４２４）の製造
６−（ピペリジン−４−イルオキシ）ニコチノニトリル塩酸塩の代わりに参考例３４９で得られた１，４−ジアゼパン−１−カルボン酸メチル塩酸塩を用いること以外は実質的に実施例４０２と同様に反応を行って、表題化合物（４２ｍｇ、定量的）を白色粉末として得た。

^１Ｈ−ＮＭＲ（３００ＭＨｚ、ＣＤＣｌ_３）δ：１．０３（２Ｈ，ｑ，Ｊ＝１１．６Ｈｚ），１．４２−１．６８（３Ｈ，ｂｒ ｍ），１．６７−１．９８（１０Ｈ，ｂｒ ｍ），２．４０（１Ｈ，ｔ，Ｊ＝１１．４Ｈｚ），２．５０−２．７３（４Ｈ，ｂｒ ｍ），３．０８（２Ｈ，ｄ，Ｊ＝７．４Ｈｚ），３．２２（２Ｈ，ｓ），３．３６−３．６１（８Ｈ，ｍ），３．６４−３．７９（５Ｈ，ｍ），７．１４−７．２８（２Ｈ，ｍ）．

ＬＣ／ＭＳ［条件１］：保持時間２．５５分；ｍ／ｚ５８８．１［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ６３２．２［Ｍ＋ＨＣＯＯ］^―（ＥＳＩ負イオンモード）

Example 424
4-((1r, 4r) -4-{[8- (4-cyano-2,6-difluorobenzyl) -2-oxo-1-oxa-3,8-diazaspiro [4.5] decane-3- Yl] methyl} cyclohexanecarbonyl) -1,4-diazepane-1-carboxylate methyl ester (Compound No. 424) obtained in Reference Example 349 instead of 6- (piperidin-4-yloxy) nicotinonitrile hydrochloride The reaction was carried out substantially in the same manner as in Example 402 except that 1,4-diazepane-1-carboxylic acid methyl hydrochloride was used to give the title compound (42 mg, quantitative) as a white powder.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.03 (2H, q, J = 11.6 Hz), 1.42-1.68 (3H, br m), 1.67-1.98 (10H , Br m), 2.40 (1H, t, J = 11.4 Hz), 2.50-2.73 (4H, br m), 3.08 (2H, d, J = 7.4 Hz), 3 .22 (2H, s), 3.36-3.61 (8H, m), 3.64-3.79 (5H, m), 7.14-7.28 (2H, m).

LC / MS [Condition 1]: Retention time 2.55 minutes; m / z 588.1 [M + H] ⁺ (ESI positive ion mode), m / z 632.2 [M + HCOO] ⁻ (ESI negative ion mode)

実施例４２５
２−（（１ｒ，４ｒ）−４−｛［８−（４−シアノ−２，６−ジフルオロベンジル）−２−オキソ−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル］メチル｝シクロヘキサンカルボニル）−１，２，５−オキサジアゼパン−５−カルボン酸メチル（化合物番号４２５）の製造
６−（ピペリジン−４−イルオキシ）ニコチノニトリル塩酸塩の代わりに参考例３０７で得られた１，２，５−オキサジアゼパン−５−カルボン酸メチル塩酸塩を用いること以外は実質的に実施例４０２と同様に反応を行って、表題化合物（１９ｍｇ、収率４８％）を白色粉末として得た。

^１Ｈ−ＮＭＲ（３００ＭＨｚ、ＣＤＣｌ_３）１Ｈ−ＮＭＲ（ＣＤＣｌ３）δ：１．０５（２Ｈ，ｑ，Ｊ＝１１．９Ｈｚ），１．３８−１．６６（４Ｈ，ｂｒ ｍ），１．６８−２．０４（８Ｈ，ｂｒ ｍ），２．６３（４Ｈ，ｂｒ ｓ），３．０９（２Ｈ，ｄ，Ｊ＝７．４Ｈｚ），３．２２（２Ｈ，ｓ），３．５６−３．８９（８Ｈ，ｍ），３．７２（３Ｈ，ｓ），３．９６−４．０８（２Ｈ，ｍ），７．１７−７．２６（２Ｈ，ｍ）．

ＬＣ／ＭＳ［条件１］：保持時間２．６９分；ｍ／ｚ５９０．０［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ６３４．２［Ｍ＋ＨＣＯＯ］^―（ＥＳＩ負イオンモード）

Example 425
2-((1r, 4r) -4-{[8- (4-Cyano-2,6-difluorobenzyl) -2-oxo-1-oxa-3,8-diazaspiro [4.5] decane-3- [Ill] methyl} cyclohexanecarbonyl) -1,2,5-oxadiazepan-5-methyl carboxylate (Compound No. 425) Obtained in Reference Example 307 instead of 6- (piperidin-4-yloxy) nicotinonitrile hydrochloride The reaction was conducted in substantially the same manner as in Example 402 except that the obtained 1,2,5-oxadiazepan-5-carboxylic acid methyl hydrochloride was used to give the title compound (19 mg, yield 48%) as a white powder. Obtained.

¹ H-NMR (300 MHz, CDCl ₃ ) ¹ H-NMR (CDCl ₃ ) δ: 1.05 (2H, q, J = 11.9 Hz), 1.38-1.66 (4H, br m), 1.68 -2.04 (8H, brm), 2.63 (4H, brs), 3.09 (2H, d, J = 7.4 Hz), 3.22 (2H, s), 3.56-3 .89 (8H, m), 3.72 (3H, s), 3.96-4.08 (2H, m), 7.17-7.26 (2H, m).

LC / MS [Condition 1]: Retention time 2.69 minutes; m / z 590.0 [M + H] ⁺ (ESI positive ion mode), m / z 634.2 [M + HCOO] ⁻ (ESI negative ion mode)

実施例４２６
３，５−ジフルオロ−４−［（３−｛［（１ｒ，４ｒ）−４−（４−ニコチノイルピペリジン−１−カルボニル）シクロヘキシル］メチル｝−２−オキソ−１−オキサ−３，８−ジアザスピロ［４．５］デカン−８−イル）メチル］ベンゾニトリル（化合物番号４２６）の製造
６−（ピペリジン−４−イルオキシ）ニコチノニトリル塩酸塩の代わりにピペリジン−４−イル（ピリジン−３−イル）メタノン塩酸塩（市販）を用いること以外は実質的に実施例４０２と同様に反応を行って、表題化合物（３６ｍｇ、収率８７％）を白色粉末として得た。

^１Ｈ−ＮＭＲ（３００ＭＨｚ、ＣＤＣｌ_３）δ：１．０４（２Ｈ，ｑ，Ｊ＝１１．６Ｈｚ），１．４５−１．６７（４Ｈ，ｂｒ ｍ），１．６８−１．８５（７Ｈ，ｂｒ ｍ），１．８６−２．０１（４Ｈ，ｂｒ ｍ），２．４６（１Ｈ，ｔ，Ｊ＝１１．９Ｈｚ），２．６３（４Ｈ，ｂｒ ｓ），２．８２（１Ｈ，ｔ，Ｊ＝１１．４Ｈｚ），３．０９（２Ｈ，ｄ，Ｊ＝７．４Ｈｚ），３．１３−３．２８（１Ｈ，ｂｒ ｍ），３．２２（２Ｈ，ｓ），３．４８（１Ｈ，ｔｔ，Ｊ＝１０．６，４．１Ｈｚ），３．７５（２Ｈ，ｓ），３．９９（１Ｈ，ｄ，Ｊ＝１３．９Ｈｚ），４．６１（１Ｈ，ｄ，Ｊ＝１４．３Ｈｚ），７．２２（２Ｈ，ｄ，Ｊ＝５．７Ｈｚ），７．４５（１Ｈ，ｄｄ，Ｊ＝８．２，４．５Ｈｚ），８．２２（１Ｈ，ｄｔ，Ｊ＝７．９，１．９Ｈｚ），８．８０（１Ｈ，ｄｄ，Ｊ＝４．９，１．６Ｈｚ），９．１５（１Ｈ，ｄ，Ｊ＝１．６Ｈｚ）．

ＬＣ／ＭＳ［条件１］：保持時間２．６５分；ｍ／ｚ３１０．６［Ｍ＋２Ｈ］^２＋、６１９．９［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ６６４．２［Ｍ＋ＨＣＯＯ］^―（ＥＳＩ負イオンモード）

Example 426
3,5-difluoro-4-[(3-{[(1r, 4r) -4- (4-nicotinoylpiperidine-1-carbonyl) cyclohexyl] methyl} -2-oxo-1-oxa-3,8- Preparation of diazaspiro [4.5] decan-8-yl) methyl] benzonitrile (Compound No. 426) Piperidin-4-yl (pyridine-3-yl) instead of 6- (piperidin-4-yloxy) nicotinonitrile hydrochloride Yl) The reaction was carried out in substantially the same manner as in Example 402 except that methanone hydrochloride (commercially available) was used to give the title compound (36 mg, yield 87%) as a white powder.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.04 (2H, q, J = 11.6 Hz), 1.45 to 1.67 (4H, br m), 1.68-1.85 (7H , Br m), 1.86-2.01 (4H, br m), 2.46 (1 H, t, J = 11.9 Hz), 2.63 (4 H, br s), 2.82 (1 H, t, J = 11.4 Hz), 3.09 (2H, d, J = 7.4 Hz), 3.13-3.28 (1H, br m), 3.22 (2H, s), 3.48. (1H, tt, J = 10.6, 4.1 Hz), 3.75 (2H, s), 3.99 (1H, d, J = 13.9 Hz), 4.61 (1H, d, J = 14.3 Hz), 7.22 (2H, d, J = 5.7 Hz), 7.45 (1H, dd, J = 8.2, 4.5 Hz), 8.22 (1H, dt, J = 7) . 9, 1.9 Hz), 8.80 (1 H, dd, J = 4.9, 1.6 Hz), 9.15 (1 H, d, J = 1.6 Hz).

LC / MS [Condition 1]: Retention time 2.65 minutes; m / z 310.6 [M + 2H] ²⁺ , 619.9 [M + H] ⁺ (ESI positive ion mode), m / z 664.2 [M + HCOO] ⁻ (ESI Negative ion mode)

実施例４２７
４−［６−（｛２−オキソ−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）ニコチノイル］ピペラジン−１−カルボン酸ｔ−ブチル（化合物番号４２７）の製造
テトラヒドロフルフリルアミンの代わりにピペラジン−１−カルボン酸ｔ−ブチル（市販）とトリエチルアミンを用いること以外は実質的に実施例１１１と同様に反応を行って、表題化合物（２０ｍｇ、収率８１％）を黄色無定形物として得た。

^１Ｈ−ＮＭＲ（３００ＭＨｚ、ＣＤＣｌ_３）δ：１．４７（９Ｈ，ｓ），１．６７−１．８７（２Ｈ，ｂｒ ｍ），１．９１−２．０５（２Ｈ，ｂｒ ｍ），２．５５（４Ｈ，ｂｒ ｓ），３．２９−３．６１（６Ｈ，ｂｒ ｍ），３．３５（２Ｈ，ｓ），３．５７（２Ｈ，ｓ），３．７４（２Ｈ，ｂｒ ｓ），４．５７（２Ｈ，ｓ），７．３７（１Ｈ，ｄ，Ｊ＝８．２Ｈｚ），７．４３（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ），７．５６（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ），７．７４（１Ｈ，ｄｄ，Ｊ＝８．０，２．２Ｈｚ），８．５９（１Ｈ，ｄ，Ｊ＝２．０Ｈｚ）．

ＬＣ／ＭＳ［条件１］：保持時間３．１６分；ｍ／ｚ５６１．９［Ｍ−ｉｓｏｂｕｔｅｎｅ＋Ｈ］^＋、６１８．０［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ６６２．２［Ｍ＋ＨＣＯＯ］^―（ＥＳＩ負イオンモード）

Example 427
4- [6-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl) nicotinoyl] piperazine- Preparation of t-butyl 1-carboxylate (Compound No. 427) The reaction was carried out in substantially the same manner as in Example 111 except that piperazine-1-carboxylate t-butyl (commercially available) and triethylamine were used instead of tetrahydrofurfurylamine. The title compound (20 mg, 81% yield) was obtained as a yellow amorphous product.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.47 (9H, s), 1.67-1.87 (2H, br m), 1.91-2.05 (2H, br m), 2 .55 (4H, br s), 3.29-3.61 (6H, br m), 3.35 (2H, s), 3.57 (2H, s), 3.74 (2H, br s) , 4.57 (2H, s), 7.37 (1H, d, J = 8.2 Hz), 7.43 (2H, d, J = 8.2 Hz), 7.56 (2H, d, J = 8.2 Hz), 7.74 (1H, dd, J = 8.0, 2.2 Hz), 8.59 (1H, d, J = 2.0 Hz).

LC / MS [Condition 1]: Retention time 3.16 minutes; m / z 561.9 [M-isobutene + H] ⁺ , 618.0 [M + H] ⁺ (ESI positive ion mode), m / z 662.2 [M + HCOO] ⁻ (ESI negative ion mode)

参考例４２８
３−｛［（１ｒ，４ｒ）−４−（１，２，５−オキサジアゼパン−５−カルボニル）シクロヘキシル］メチル｝−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−２−オン 二トリフルオロ酢酸塩の製造
実施例３０８で得られた５−［（１ｒ，４ｒ）−４−（｛２−オキソ−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）シクロヘキサンカルボニル］−１，２，５−オキサジアゼパン−２−カルボン酸ｔ−ブチル（４９ｍｇ、０．０７７ｍｍｏｌ）をトリフルオロ酢酸（１．０ｍＬ）に溶解し、室温にて１時間かき混ぜた。反応混合物を減圧下濃縮乾固して、表題化合物（５９ｍｇ、定量的）を黄色油状物として得た。

ＬＣ／ＭＳ［条件１］：保持時間２．２１分；ｍ／ｚ５３８．９［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ５８２．９［Ｍ＋ＨＣＯＯ］^―（ＥＳＩ負イオンモード）

Reference Example 428
3-{[(1r, 4r) -4- (1,2,5-oxadiazepan-5-carbonyl) cyclohexyl] methyl} -8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8 Preparation of diazaspiro [4.5] decan-2-one ditrifluoroacetate 5-[(1r, 4r) -4-({2-oxo-8- [4- (tri Fluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl) cyclohexanecarbonyl] -1,2,5-oxadiazepane-2-carboxylate (49 mg, 0.077 mmol) was dissolved in trifluoroacetic acid (1.0 mL) and stirred at room temperature for 1 hour. The reaction mixture was concentrated to dryness under reduced pressure to give the title compound (59 mg, quantitative) as a yellow oil.

LC / MS [Condition 1]: Retention time 2.21 minutes; m / z 538.9 [M + H] ⁺ (ESI positive ion mode), m / z 582.9 [M + HCOO] ⁻ (ESI negative ion mode)

実施例４２８
５−［（１ｒ，４ｒ）−４−（｛２−オキソ−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）シクロヘキサンカルボニル］−１，２，５−オキサジアゼパン−２−カルボン酸メチルトリフルオロ酢酸塩（化合物番号４２８）の製造
参考例４２８で得られた３−｛［（１ｒ，４ｒ）−４−（１，２，５−オキサジアゼパン−５−カルボニル）シクロヘキシル］メチル｝−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−２−オン 二トリフルオロ酢酸塩（５９ｍｇ、０．０７７ｍｍｏｌ）をクロロホルム（３．０ｍＬ）に溶解し、０℃にてトリエチルアミン（０．０５４ｍＬ、０．３９ｍｍｏｌ）とクロロギ酸メチル（０．０１２ｍＬ、０．０１２ｍＬ）を加え、室温にて１時間かき混ぜた。得られた反応混合物に、クロロホルム（２．０ｍＬ）と１．０Ｍクエン酸水溶液（０．３８ｍＬ）と水（２．０ｍＬ）を加え、有機層を分離した。得られた有機層を飽和炭酸水素ナトリウム水溶液で洗浄した後、無水硫酸ナトリウムで乾燥し、減圧下濃縮乾固して、表題化合物（３９ｍｇ、収率８４％）を無色無定形物として得た。

^１Ｈ−ＮＭＲ（３００ＭＨｚ、ＣＤＣｌ_３）δ：０．９０−１．１３（２Ｈ，ｂｒ ｍ），１．４６−１．６８（３Ｈ，ｂｒ ｍ），１．６９−１．８８（４Ｈ，ｂｒ ｍ），１．９６−２．１１（２Ｈ，ｂｒ ｍ），２．２６−２．５０（３Ｈ，ｂｒ ｍ），２．９８−３．１６（２Ｈ，ｂｒ ｍ），３．１０（２Ｈ，ｄ，Ｊ＝７．４Ｈｚ），３．３６（２Ｈ，ｓ），３．４２（２Ｈ，ｂｒ ｓ），３．６７（２Ｈ，ｑ，Ｊ＝４．５Ｈｚ），３．７０−３．８５（７Ｈ，ｍ），３．９６−４．０７（２Ｈ，ｂｒ ｍ），４．１８（２Ｈ，ｂｒ ｓ），７．５７（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ），７．７１（２Ｈ，ｄ，Ｊ＝７．８Ｈｚ）．１３．８７(１Ｈ，ｂｒ ｓ)．

ＬＣ／ＭＳ［条件１］：保持時間２．８８分；ｍ／ｚ５９７．０［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ６４１．１［Ｍ＋ＨＣＯＯ］^―（ＥＳＩ負イオンモード）

Example 428
5-[(1r, 4r) -4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} Preparation of methyl) cyclohexanecarbonyl] -1,2,5-oxadiazepane-2-carboxylic acid methyl trifluoroacetate (Compound No. 428) 3-{[(1r, 4r) -4- ( 1,2,5-oxadiazepan-5-carbonyl) cyclohexyl] methyl} -8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-2-one Trifluoroacetate (59 mg, 0.077 mmol) was dissolved in chloroform (3.0 mL), and triethylamine (0.054 mL, 0.39 mmol) and chloroformate were dissolved at 0 ° C. Chill (0.012 mL, 0.012 mL) was added and stirred at room temperature for 1 hour. To the obtained reaction mixture, chloroform (2.0 mL), 1.0 M aqueous citric acid solution (0.38 mL) and water (2.0 mL) were added, and the organic layer was separated. The obtained organic layer was washed with saturated aqueous sodium hydrogen carbonate solution, dried over anhydrous sodium sulfate, and concentrated to dryness under reduced pressure to give the title compound (39 mg, yield 84%) as a colorless amorphous product.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 0.90 to 1.13 (2H, br m), 1.46 to 1.68 (3H, br m), 1.69 to 1.88 (4H, br m), 1.96-2.11 (2H, br m), 2.26-2.50 (3H, br m), 2.98-3.16 (2H, br m), 3.10 ( 2H, d, J = 7.4 Hz), 3.36 (2H, s), 3.42 (2H, br s), 3.67 (2H, q, J = 4.5 Hz), 3.70-3 .85 (7H, m), 3.96-4.07 (2H, br m), 4.18 (2H, br s), 7.57 (2H, d, J = 8.2 Hz), 7.71 (2H, d, J = 7.8 Hz). 13.87 (1H, br s).

LC / MS [Condition 1]: Retention time 2.88 minutes; m / z 597.0 [M + H] ⁺ (ESI positive ion mode), m / z 641.1 [M + HCOO] ⁻ (ESI negative ion mode)

実施例４２９
（１ｒ，４ｒ）−４−｛［８−（４−シアノ−２，６−ジフルオロベンジル）−２−オキソ−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル］メチル｝−Ｎ−（３−シアノベンジル）シクロヘキサンカルボキサミド（化合物番号４２９）の製造
６−（ピペリジン−４−イルオキシ）ニコチノニトリル塩酸塩の代わりに、３−（アミノメチル）ベンゾニトリル塩酸塩（ＷＯ２００７／００２３１３記載の方法により製造）を用いること以外は実質的に実施例４０２と同様に反応を行なって、表題化合物（１３ｍｇ、収率５０％）を白色固体として得た。

^１Ｈ−ＮＭＲ（３００ＭＨｚ，ＣＤＣｌ_３）δ：１．０２（２Ｈ，ｑｄ，Ｊ＝１２．３，２．９Ｈｚ），１．５２（２Ｈ，ｑｄ，Ｊ＝１３．１，３．３Ｈｚ），１．５９−１．６４（１Ｈ，ｍ），１．６９−１．８４（４Ｈ，ｍ），１．８６−１．９９（４Ｈ，ｍ），２．０９（１Ｈ，ｔｔ，Ｊ＝１２．３，３．７Ｈｚ），２．５４−２．６７（４Ｈ，ｍ），３．０９（２Ｈ，ｄ，Ｊ＝７．４Ｈｚ），３．２２（２Ｈ，ｓ），３．７５（２Ｈ，ｓ），４．４７（２Ｈ，ｄ，Ｊ＝６．１Ｈｚ），５．８７（１Ｈ，ｔ，Ｊ＝５．７Ｈｚ），７．２２（２Ｈ，ｄ，Ｊ＝５．９Ｈｚ），７．３９−７．６０（４Ｈ，ｍ）．

ＬＣ／ＭＳ［条件１］：保持時間２．８６分；ｍ／ｚ５６１．８［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ５６０．０［Ｍ−Ｈ］^―（ＥＳＩ負イオンモード）

Example 429
(1r, 4r) -4-{[8- (4-Cyano-2,6-difluorobenzyl) -2-oxo-1-oxa-3,8-diazaspiro [4.5] decan-3-yl] methyl } Preparation of —N- (3-cyanobenzyl) cyclohexanecarboxamide (Compound No. 429) Instead of 6- (piperidin-4-yloxy) nicotinonitrile hydrochloride, 3- (aminomethyl) benzonitrile hydrochloride (WO2007 / The title compound (13 mg, 50% yield) was obtained as a white solid in substantially the same manner as in Example 402 except that the above compound was used.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.02 (2H, qd, J = 12.3, 2.9 Hz), 1.52 (2H, qd, J = 13.1, 3.3 Hz), 1.59-1.64 (1H, m), 1.69-1.84 (4H, m), 1.86-1.99 (4H, m), 2.09 (1H, tt, J = 12) .3, 3.7 Hz), 2.54-2.67 (4 H, m), 3.09 (2 H, d, J = 7.4 Hz), 3.22 (2 H, s), 3.75 (2 H , S), 4.47 (2H, d, J = 6.1 Hz), 5.87 (1H, t, J = 5.7 Hz), 7.22 (2H, d, J = 5.9 Hz), 7 .39-7.60 (4H, m).

LC / MS [Condition 1]: Retention time 2.86 minutes; m / z 561.8 [M + H] ⁺ (ESI positive ion mode), m / z 560.0 [M−H] ⁻ (ESI negative ion mode)

実施例４３０
３，５−ジフルオロ−４−（｛３−［（（１ｒ，４ｒ）−４−｛４−［４−（メチルスルホニル）ベンゾイル］ピペリジン−１−カルボニル｝シクロヘキシル）メチル］−２−オキソ−１−オキサ−３，８−ジアザスピロ［４．５］デカン−８−イル｝メチル）ベンゾニトリル（化合物番号４３０）の製造
６−（ピペリジン−４−イルオキシ）ニコチノニトリル塩酸塩の代わりに、参考例３６７−２で得られた４−［４−（メチルスルホニル）ベンゾイル］ピペリジン塩酸塩を用いること以外は実質的に実施例４０２と同様に反応を行なって、表題化合物（２０ｍｇ、収率９５％）を白色固体として得た。

^１Ｈ−ＮＭＲ（３００ＭＨｚ，ＣＤＣｌ_３）δ：１．０４（２Ｈ，ｑ，Ｊ＝１１．９Ｈｚ），１．４７−１．７０（４Ｈ，ｍ），１．７０−１．８７（７Ｈ，ｍ），１．８８−１．９９（４Ｈ，ｍ），２．４６（１Ｈ，ｔｔ，Ｊ＝１０．０，３．３Ｈｚ），２．５４−２．７１（４Ｈ，ｍ），２．８３（１Ｈ，ｔ，Ｊ＝１１．９Ｈｚ），３．０９（２Ｈ，ｄ，Ｊ＝４．６Ｈｚ），３．１０（３Ｈ，ｓ），３．２２（１Ｈ，ｔ，Ｊ＝１２．２Ｈｚ），３．２３（２Ｈ，ｓ），３．５１（１Ｈ，ｔｔ，Ｊ＝１１．１，３．６Ｈｚ），３．７５（２Ｈ，ｓ），３．９９（１Ｈ，ｄ，Ｊ＝１４．５Ｈｚ），４．６０（１Ｈ，ｄ，Ｊ＝１３．５Ｈｚ），７．２３（２Ｈ，ｄ，Ｊ＝６．３Ｈｚ），８．０７（２Ｈ，ｄ，Ｊ＝８．９Ｈｚ），８．１１（２Ｈ，ｄ，Ｊ＝８．９Ｈｚ）．

ＬＣ／ＭＳ［条件１］：保持時間３．０８分；ｍ／ｚ６９６．８［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ７４０．９［Ｍ＋ＨＣＯＯ］^―（ＥＳＩ負イオンモード）

Example 430
3,5-difluoro-4-({3-[((1r, 4r) -4- {4- [4- (methylsulfonyl) benzoyl] piperidine-1-carbonyl} cyclohexyl) methyl] -2-oxo-1 -Preparation of Oxa-3,8-diazaspiro [4.5] decan-8-yl} methyl) benzonitrile (Compound No. 430) Reference example instead of 6- (piperidin-4-yloxy) nicotinonitrile hydrochloride The reaction was carried out in substantially the same manner as in Example 402 except that 4- [4- (methylsulfonyl) benzoyl] piperidine hydrochloride obtained in 367-2 was used, and the title compound (20 mg, yield 95%) Was obtained as a white solid.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.04 (2H, q, J = 11.9 Hz), 1.47-1.70 (4H, m), 1.70-1.87 (7H, m), 1.88-1.99 (4H, m), 2.46 (1H, tt, J = 10.0, 3.3 Hz), 2.54-2.71 (4H, m), 2. 83 (1H, t, J = 11.9 Hz), 3.09 (2H, d, J = 4.6 Hz), 3.10 (3H, s), 3.22 (1H, t, J = 12.2 Hz) ), 3.23 (2H, s), 3.51 (1H, tt, J = 11.1, 3.6 Hz), 3.75 (2H, s), 3.99 (1H, d, J = 14) .5Hz), 4.60 (1H, d, J = 13.5 Hz), 7.23 (2H, d, J = 6.3 Hz), 8.07 (2H, d, J = 8.9 Hz), 8 .11 (2 , D, J = 8.9Hz).

LC / MS [Condition 1]: Retention time 3.08 minutes; m / z 696.8 [M + H] ⁺ (ESI positive ion mode), m / z 740.9 [M + HCOO] ⁻ (ESI negative ion mode)

参考例４３１−１
６−［（１，３−ジオキソイソインドリン−２−イル）メチル］ニコチン酸エチルの製造
参考例１１１−２で得られた６−（ヒドロキシメチル）ニコチン酸エチル（３．６２ｇ，２０ｍｍｏｌ）、トリフェニルホスフィン（６．３０ｇ，２４ｍｍｏｌ）及びフタルイミド（３．５３ｇ，２４ｍｍｏｌ）のテトラヒドロフラン溶液（１００ｍＬ）に０℃でアゾジカルボン酸ジイソプロピルのトルエン溶液（１．９Ｍ，１２．７０ｍＬ，２４ｍｍｏｌ）を滴下して、室温で３０分撹拌した。反応終了後、反応溶液に水を加え、酢酸エチルで抽出した。有機層を飽和塩化アンモニウム水溶液と飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥した後、減圧留去した。得られた残渣をシリカゲルカラムクロマトグラフィー［展開溶媒：ヘキサン／酢酸エチル＝２／１］にて精製し、得られた固体をエタノールにて再結晶することで、表題化合物（４．８２ｇ、収率７８％）を白色固体として得た。

^１Ｈ−ＮＭＲ（３００ＭＨｚ，ＣＤＣｌ_３）δ：１．３８（３Ｈ，ｔ，Ｊ＝７．２Ｈｚ），４．３８（２Ｈ，ｑ，Ｊ＝７．１Ｈｚ），５．０７（２Ｈ，ｓ），７．３５（１Ｈ，ｄ，Ｊ＝８．３Ｈｚ），７．７３−７．７９（２Ｈ，ｍ），７．８７−７．９２（２Ｈ，ｍ），８．２５（１Ｈ，ｄｄ，Ｊ＝８．３，２．２Ｈｚ），９．１２（１Ｈ，ｄ，Ｊ＝１．４Ｈｚ）．

ＬＣ／ＭＳ［条件１］：保持時間３．９７分；ｍ／ｚ３１０．９［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）

Reference Example 431-1
Preparation of ethyl 6-[(1,3-dioxoisoindoline-2-yl) methyl] nicotinate Ethyl 6- (hydroxymethyl) nicotinate (3.62 g, 20 mmol) obtained in Reference Example 111-2, Toluene solution (1.9 M, 12.70 mL, 24 mmol) of diisopropyl azodicarboxylate was added dropwise to a tetrahydrofuran solution (100 mL) of triphenylphosphine (6.30 g, 24 mmol) and phthalimide (3.53 g, 24 mmol) at 0 ° C. And stirred at room temperature for 30 minutes. After completion of the reaction, water was added to the reaction solution and extracted with ethyl acetate. The organic layer was washed with saturated aqueous ammonium chloride solution and saturated brine, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography [developing solvent: hexane / ethyl acetate = 2/1], and the obtained solid was recrystallized from ethanol to give the title compound (4.82 g, yield). 78%) was obtained as a white solid.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.38 (3H, t, J = 7.2 Hz), 4.38 (2H, q, J = 7.1 Hz), 5.07 (2H, s) , 7.35 (1H, d, J = 8.3 Hz), 7.73-7.79 (2H, m), 7.87-7.92 (2H, m), 8.25 (1H, dd, J = 8.3, 2.2 Hz), 9.12 (1H, d, J = 1.4 Hz).

LC / MS [Condition 1]: Retention time 3.97 minutes; m / z 310.9 [M + H] ⁺ (ESI positive ion mode)

参考例４３１−２
６−［（ｔ−ブトキシカルボニルアミノ）メチル］ニコチン酸エチルの製造
上記で得られた６−［（１，３−ジオキソイソインドリン−２−イル）メチル］ニコチン酸エチル（２．５８ｇ，８．３２ｍｍｏｌ）のエタノール溶液（３０ｍＬ）にヒドラジン一水和物（８０７．５０μＬ，１６．６５ｍｍｏＬ）を加え、１時間還流した。放冷後、反応溶液にジクロロメタンを加え、不溶物をろ別し、ろ液を減圧留去した。得られた残渣にジクロロメタンを加え、不溶物を再度ろ別し、ろ液を減圧留去することで白色固体を得た。得られた白色固体のジクロロメタン溶液（１０ｍＬ）に二炭酸ジ−ｔ−ブチル（２．１８ｇ，９．９９ｍｍｏｌ）を加え、室温で１０分撹拌した。反応終了後、溶媒を減圧留去し、得られた残渣をシリカゲルカラムクロマトグラフィー［展開溶媒：ヘキサン／酢酸エチル＝２／１］にて精製することで、表題化合物（２．２０ｇ、収率９４％）を白色固体として得た。

ＬＣ／ＭＳ［条件１］：保持時間３．８７分；ｍ／ｚ２８０．９［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）

Reference Example 431-2
Preparation of ethyl 6-[(t-butoxycarbonylamino) methyl] nicotinate Ethyl 6-[(1,3-dioxoisoindoline-2-yl) methyl] nicotinate obtained above (2.58 g, 8 Hydrazine monohydrate (807.50 μL, 16.65 mmol) was added to an ethanol solution (30 mL) of .32 mmol), and the mixture was refluxed for 1 hour. After allowing to cool, dichloromethane was added to the reaction solution, insolubles were filtered off, and the filtrate was distilled off under reduced pressure. Dichloromethane was added to the resulting residue, the insoluble material was filtered off again, and the filtrate was distilled off under reduced pressure to obtain a white solid. Di-t-butyl dicarbonate (2.18 g, 9.99 mmol) was added to a dichloromethane solution (10 mL) of the obtained white solid, and the mixture was stirred at room temperature for 10 minutes. After completion of the reaction, the solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography [developing solvent: hexane / ethyl acetate = 2/1] to give the title compound (2.20 g, yield 94). %) As a white solid.

LC / MS [Condition 1]: Retention time 3.87 minutes; m / z 280.9 [M + H] ⁺ (ESI positive ion mode)

参考例４３１−３
［５−（ヒドロキシメチル）ピリジン−２−イル］メチルカルバミン酸ｔ−ブチルの製造
上記で得られた６−［（ｔ−ブトキシカルボニルアミノ）メチル］ニコチン酸エチル（０．２８ｇ，１．０ｍｍｏｌ）のエタノール溶液（４．０ｍＬ）に水素化ホウ素ナトリウム（０．１９ｇ，４．０ｍｍｏＬ）を加え、３０分間還流した。反応終了後、水と１Ｍ塩酸を加え、酸性にした。飽和炭酸水素ナトリウム水溶液で中和した後、酢酸エチルで抽出した。得られた有機層を無水硫酸マグネシウムで乾燥した後、減圧留去した。得られた残渣をシリカゲルカラムクロマトグラフィー［展開溶媒：酢酸エチル｝にて精製することで、表題化合物（０．１７ｇ、収率７３％）を無色液体として得た。

^１Ｈ−ＮＭＲ（３００ＭＨｚ，ＣＤＣｌ_３）δ：１．４５（９Ｈ，ｓ），４．３６（２Ｈ，ｂｒｓ），４．６７（２Ｈ，ｂｒｓ），５．６９（１Ｈ，ｂｒｓ），７．２４（１Ｈ，ｄ，Ｊ＝８．０Ｈｚ），７．６７（１Ｈ，ｄ，Ｊ＝６．６Ｈｚ），８．３８（１Ｈ，ｓ）．

ＬＣ／ＭＳ［条件１］：保持時間０．６１分；ｍ／ｚ２３９．０［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）

Reference Example 431-3
Preparation of t-butyl [5- (hydroxymethyl) pyridin-2-yl] methylcarbamate of ethyl 6-[(t-butoxycarbonylamino) methyl] nicotinate (0.28 g, 1.0 mmol) obtained above. Sodium borohydride (0.19 g, 4.0 mmol) was added to an ethanol solution (4.0 mL), and the mixture was refluxed for 30 minutes. After completion of the reaction, water and 1M hydrochloric acid were added to make it acidic. The mixture was neutralized with saturated aqueous sodium hydrogen carbonate solution and extracted with ethyl acetate. The obtained organic layer was dried over anhydrous magnesium sulfate and then distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [developing solvent: ethyl acetate} to give the title compound (0.17 g, yield 73%) as a colorless liquid.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.45 (9H, s), 4.36 (2H, brs), 4.67 (2H, brs), 5.69 (1H, brs), 7. 24 (1H, d, J = 8.0 Hz), 7.67 (1H, d, J = 6.6 Hz), 8.38 (1H, s).

LC / MS [Condition 1]: Retention time 0.61 min; m / z 239.0 [M + H] ⁺ (ESI positive ion mode)

参考例４３１−４
（５−シアノピリジン−２−イル）メチルカルバミン酸ｔ−ブチルの製造
上記で得られた［５−（ヒドロキシメチル）ピリジン−２−イル］メチルカルバミン酸ｔ−ブチル（９４．７０ｍｇ，０．４０ｍｍｏｌ）のクロロホルム溶液（２．０ｍＬ）に二酸化マンガン（０．１７ｇ，２．０ｍｍｏＬ）を加え、３０分間還流した。反応終了後、セライトろ過し、ろ液を濃縮した。得られた液体のエタノール溶液（３．０ｍＬ）に、ヒドロキシルアミン塩酸塩（１３８．９８ｍｇ，２．０ｍｍｏｌ）とピリジン（３２１．９０μＬ，４．０ｍｍｏｌ）を加え、１０分間還流した。放冷後、溶媒を留去し、水と酢酸エチルを加え、有機層を分離した。有機層を無水硫酸ナトリウムで乾燥した後、減圧留去することで、白色固体を得た。得られた白色固体とトリエチルアミン（１１６．２０μＬ，１．２ｍｍｏｌ）のジクロロメタン溶液（３．０ｍＬ）に、塩化メタンスルホニル（６１．９０μＬ，０．８０ｍｍｏｌ）を０℃でゆっくり加えた後、２時間還流した。反応後、反応混合物を減圧下濃縮し、得られた残渣をシリカゲルカラムクロマトグラフィー［展開溶媒：ヘキサン／酢酸エチル＝１／１］にて精製することで、表題化合物（７１．３０ｍｇ、収率７６％）を無色液体として得た。

^１Ｈ−ＮＭＲ（３００ＭＨｚ，ＣＤＣｌ_３）δ：１．４６（９Ｈ，ｓ），４．５１（２Ｈ，ｄ，Ｊ＝５．８Ｈｚ），５．４７（１Ｈ，ｓ），７．４３（１Ｈ，ｄｄ，Ｊ＝８．２，０．７Ｈｚ），７．９３（１Ｈ，ｄｄ，Ｊ＝８．２，２．１Ｈｚ），８．８２（１Ｈ，ｄ，Ｊ＝０．７Ｈｚ）．

ＬＣ／ＭＳ［条件１］：保持時間３．４４分；ｍ／ｚ２３４．０［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）

Reference Example 431-4
Preparation of (5-cyanopyridin-2-yl) methylcarbamate t-butyl [5- (hydroxymethyl) pyridin-2-yl] methylcarbamate t-butyl (94.70 mg, 0.40 mmol) obtained above Manganese dioxide (0.17 g, 2.0 mmol) was added to the chloroform solution (2.0 mL), and the mixture was refluxed for 30 minutes. After completion of the reaction, the mixture was filtered through Celite, and the filtrate was concentrated. Hydroxylamine hydrochloride (138.98 mg, 2.0 mmol) and pyridine (321.90 μL, 4.0 mmol) were added to the obtained liquid ethanol solution (3.0 mL), and the mixture was refluxed for 10 minutes. After allowing to cool, the solvent was distilled off, water and ethyl acetate were added, and the organic layer was separated. The organic layer was dried over anhydrous sodium sulfate and then evaporated under reduced pressure to obtain a white solid. Methanesulfonyl chloride (61.90 μL, 0.80 mmol) was slowly added to a dichloromethane solution (3.0 mL) of the obtained white solid and triethylamine (116.20 μL, 1.2 mmol) at 0 ° C. and then refluxed for 2 hours. did. After the reaction, the reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography [developing solvent: hexane / ethyl acetate = 1/1] to give the title compound (71.30 mg, yield 76). %) As a colorless liquid.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.46 (9H, s), 4.51 (2H, d, J = 5.8 Hz), 5.47 (1H, s), 7.43 (1H , Dd, J = 8.2, 0.7 Hz), 7.93 (1H, dd, J = 8.2, 2.1 Hz), 8.82 (1H, d, J = 0.7 Hz).

LC / MS [Condition 1]: Retention time 3.44 minutes; m / z 234.0 [M + H] ⁺ (ESI positive ion mode)

参考例４３１−５
６−（アミノメチル）ニコチノニトリル・二塩酸塩の製造
上記で得られた（５−シアノピリジン−２−イル）メチルカルバミン酸ｔ−ブチル（７１．３０ｍｇ，０．３０ｍｍｏｌ）の１，４−ジオキサン溶液（１．０ｍＬ）に、４Ｍ塩化水素−ジオキサン溶液（１．０ｍＬ）を加え、室温で１時間攪拌した。反応後、析出した固体をろ取することで、表題化合物（３７．５０ｍｇ、収率５９％）を白色固体として得た。

ＬＣ／ＭＳ［条件１］：保持時間０．４７分；ｍ／ｚ１３４．０［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）

Reference Example 431-5
Preparation of 6- (aminomethyl) nicotinonitrile dihydrochloride t-butyl (5-cyanopyridin-2-yl) methylcarbamate (71.30 mg, 0.30 mmol) obtained above, 1,4-dioxane To the solution (1.0 mL) was added 4M hydrogen chloride-dioxane solution (1.0 mL), and the mixture was stirred at room temperature for 1 hour. After the reaction, the precipitated solid was collected by filtration to give the title compound (37.50 mg, yield 59%) as a white solid.

LC / MS [Condition 1]: retention time 0.47 minutes; m / z 134.0 [M + H] ⁺ (ESI positive ion mode)

実施例４３１
（１ｒ，４ｒ）−Ｎ−［（５−シアノピリジン−２−イル）メチル］−４−（｛２−オキソ−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）シクロヘキサンカルボキサミド（化合物番号４３１）の製造
（２−フルオロピリジン−４−イル）メタンアミンの代わりに、参考例４３１−５で得られた６−（アミノメチル）ニコチノニトリル・二塩酸塩を用いること以外は実質的に実施例３９５と同様に反応を行って、表題化合物（２３ｍｇ、収率４７％）を無色液体として得た。

^１Ｈ−ＮＭＲ（３００ＭＨｚ、ＣＤＣｌ_３）δ：１．０５（２Ｈ，ｄｑ，Ｊ＝２．９，１２．７Ｈｚ），１．４３−１．６８（３Ｈ，ｍ），１．７２−１．８６（４Ｈ，ｍ），１．８８−２．０３（４Ｈ，ｍ），２．１８（１Ｈ，ｔｔ，Ｊ＝１２．３，３．３Ｈｚ），２．５３−２．５６（４Ｈ，ｂｒ ｍ），３．１０（２Ｈ，ｄ，Ｊ＝７．４Ｈｚ），３．２６（２Ｈ，ｓ），３．５８（２Ｈ，ｓ），４．６１（２Ｈ，ｄ，Ｊ＝５．３Ｈｚ），６．７１（１Ｈ，ｔ，Ｊ＝５．３Ｈｚ），７．３９（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ），７．４４（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ），７．５７（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ），７．９２（１Ｈ，ｄｄ，Ｊ＝８．２，２．０Ｈｚ），８．８０（１Ｈ，ｄ，Ｊ＝２．０Ｈｚ）．

ＬＣ／ＭＳ［条件１］：保持時間２．９２分；ｍ／ｚ５６９．７［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）

Example 431
(1r, 4r) -N-[(5-Cyanopyridin-2-yl) methyl] -4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8 -Preparation of diazaspiro [4.5] decan-3-yl} methyl) cyclohexanecarboxamide (Compound No. 431) Instead of (2-fluoropyridin-4-yl) methanamine, obtained in Reference Example 431-5 The reaction was carried out substantially in the same manner as in Example 395 except that (aminomethyl) nicotinonitrile dihydrochloride was used to give the title compound (23 mg, yield 47%) as a colorless liquid.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.05 (2H, dq, J = 2.9, 12.7 Hz), 1.43-1.68 (3H, m), 1.72-1. 86 (4H, m), 1.88-2.03 (4H, m), 2.18 (1H, tt, J = 12.3, 3.3 Hz), 2.53-2.56 (4H, br m), 3.10 (2H, d, J = 7.4 Hz), 3.26 (2H, s), 3.58 (2H, s), 4.61 (2H, d, J = 5.3 Hz) 6.71 (1H, t, J = 5.3 Hz), 7.39 (2H, d, J = 8.2 Hz), 7.44 (2H, d, J = 8.2 Hz), 7.57 ( 2H, d, J = 8.2 Hz), 7.92 (1H, dd, J = 8.2, 2.0 Hz), 8.80 (1H, d, J = 2.0 Hz).

LC / MS [Condition 1]: Retention time 2.92 minutes; m / z 569.7 [M + H] ⁺ (ESI positive ion mode)

参考例４３２−１
４−［１−（１，３−ジオキソイソインドリン−２−イル）エチル］ベンゾニトリルの製造
６−（ヒドロキシメチル）ニコチン酸エチルの代わりに、４−（１−ヒドロキシエチル）ベンゾニトリル（７３５．９０ｍｇ，５．０ｍｍｏｌ，ＷＯ２００６０６０４６１に記載の方法により合成した）を用いること以外は、実質的に参考例４３１−１と同様に反応を行って、表題化合物（９７７．７０ｍｇ，収率７１％）を白色固体として得た。

^１Ｈ−ＮＭＲ（３００ＭＨｚ，ＣＤＣｌ_３）δ：１．９３（３Ｈ，ｄ，Ｊ＝７．４Ｈｚ），５．５９（１Ｈ，ｑ，Ｊ＝７．４Ｈｚ），７．６０（２Ｈ，ｄ，Ｊ＝８．６Ｈｚ），７．６４（２Ｈ，ｄ，Ｊ＝８．６Ｈｚ），７．７２−７．７３（２Ｈ，ｍ），７．８２−７．８４（２Ｈ，ｍ）．

ＬＣ／ＭＳ［条件１］：保持時間３．８９分；ｍ／ｚ２７６．９［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）

Reference Example 432-1
Preparation of 4- [1- (1,3-dioxoisoindoline-2-yl) ethyl] benzonitrile 4- (1-hydroxyethyl) benzonitrile (735) instead of ethyl 6- (hydroxymethyl) nicotinate The compound was reacted in substantially the same manner as in Reference Example 431-1 except that 90 mg, 5.0 mmol, synthesized by the method described in WO2006060461), and the title compound (977.70 mg, 71% yield) was obtained. Was obtained as a white solid.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.93 (3H, d, J = 7.4 Hz), 5.59 (1H, q, J = 7.4 Hz), 7.60 (2H, d, J = 8.6 Hz), 7.64 (2H, d, J = 8.6 Hz), 7.72-7.73 (2H, m), 7.82-7.84 (2H, m).

LC / MS [Condition 1]: Retention time 3.89 minutes; m / z 276.9 [M + H] ⁺ (ESI positive ion mode)

参考例４３２−２
４−（１−アミノエチル）ベンゾニトリルの製造
上記で得られた４−［１−（１，３−ジオキソイソインドリン−２−イル）エチル］ベンゾニトリル（２７６．３０ｍｇ，１．０ｍｍｏｌ）のエタノール溶液（５．０ｍＬ）に、ヒドラジン一水和物（４８．５０μＬ，１．０ｍｍｏＬ）を加え、１時間還流した。放冷後、反応溶液にクロロホルムを加え、不溶物をろ別し、ろ液を減圧下濃縮した。残留物に１Ｍ塩酸（５．０ｍＬ）を加え、ジエチルエーテル（５．０ｍＬ）で水層を２回洗浄した。水層に飽和アンモニア水を加えて溶液を塩基性（ｐＨ＞９）にした後、クロロホルムで２回抽出した。合わせた有機層を、飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥した後、減圧下濃縮することで、表題化合物（８１．９０ｍｇ、収率５９％）を無色液体として得た。

^１Ｈ−ＮＭＲ（３００ＭＨｚ，ＣＤＣｌ_３）δ：１．３８（３Ｈ，ｄｄ，Ｊ＝６．６，１．２Ｈｚ），４．１９（１Ｈ，ｑ，Ｊ＝６．６Ｈｚ），７．４７（２Ｈ，ｄ，Ｊ＝７．８Ｈｚ），７．６２（２Ｈ，ｄ，Ｊ＝７．８Ｈｚ）．

ＬＣ／ＭＳ［条件１］：保持時間０．５０分；ｍ／ｚ１４６．９［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）

Reference Example 432-2
Preparation of 4- (1-aminoethyl) benzonitrile of 4- [1- (1,3-dioxoisoindoline-2-yl) ethyl] benzonitrile (276.30 mg, 1.0 mmol) obtained above. Hydrazine monohydrate (48.50 μL, 1.0 mmol) was added to an ethanol solution (5.0 mL) and refluxed for 1 hour. After allowing to cool, chloroform was added to the reaction solution, insoluble matters were filtered off, and the filtrate was concentrated under reduced pressure. 1M hydrochloric acid (5.0 mL) was added to the residue, and the aqueous layer was washed twice with diethyl ether (5.0 mL). Saturated aqueous ammonia was added to the aqueous layer to make the solution basic (pH> 9), and then extracted twice with chloroform. The combined organic layers were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the title compound (81.90 mg, yield 59%) as a colorless liquid.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.38 (3H, dd, J = 6.6, 1.2 Hz), 4.19 (1H, q, J = 6.6 Hz), 7.47 ( 2H, d, J = 7.8 Hz), 7.62 (2H, d, J = 7.8 Hz).

LC / MS [Condition 1]: Retention time 0.50 min; m / z 146.9 [M + H] ⁺ (ESI positive ion mode)

実施例４３２
（１ｒ，４ｒ）−Ｎ−［１−（４−シアノフェニル）エチル］−４−（｛２−オキソ−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）シクロヘキサンカルボキサミド（化合物番号４３２）の製造
（２−フルオロピリジン−４−イル）メタンアミンの代わりに、参考例４３２−２で得られた４−（１−アミノエチル）ベンゾニトリルを用いること以外は実質的に実施例３９５と同様に反応を行って、表題化合物（１１ｍｇ、収率２１％）を無色固体として得た。

^１Ｈ−ＮＭＲ（３００ＭＨｚ、ＣＤＣｌ_３）δ：１．０２（２Ｈ，ｄｄ，Ｊ＝２４．１，１２．３Ｈｚ），１．３５−１．６４（３Ｈ，ｍ），１．４７（３Ｈ，ｄ，Ｊ＝７．０Ｈｚ），１．６６−２．００（８Ｈ，ｍ），２．１０（１Ｈ，ｔｔ，Ｊ＝１１．９，３．３Ｈｚ），２．５４−２．５７（４Ｈ，ｂｒ ｍ），３．１０（２Ｈ，ｄ，Ｊ＝７．４Ｈｚ），３．２７（２Ｈ，ｓ），３．５８（２Ｈ，ｓ），５．０３−５．１７（１Ｈ，ｑｕｉｎ，Ｊ＝７．０Ｈｚ），６．１４（１Ｈ，ｄ，Ｊ＝７．４Ｈｚ），７．３７−７．４８（４Ｈ，ｍ），７．５３−７．６５（４Ｈ，ｍ）．

ＬＣ／ＭＳ［条件１］：保持時間３．２２分；ｍ／ｚ５８２．８［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ６２７．０［Ｍ＋ＨＣＯＯ］^―（ＥＳＩ負イオンモード）

Example 432
(1r, 4r) -N- [1- (4-Cyanophenyl) ethyl] -4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro Preparation of [4.5] decan-3-yl} methyl) cyclohexanecarboxamide (Compound No. 432) 4- (1) obtained in Reference Example 432-2 instead of (2-fluoropyridin-4-yl) methanamine Reaction was carried out in substantially the same manner as in Example 395 except that -aminoethyl) benzonitrile was used to obtain the title compound (11 mg, yield 21%) as a colorless solid.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.02 (2H, dd, J = 24.1, 12.3 Hz), 1.35 to 1.64 (3H, m), 1.47 (3H, d, J = 7.0 Hz), 1.66-2.00 (8H, m), 2.10 (1H, tt, J = 11.9, 3.3 Hz), 2.54-2.57 (4H) , Br m), 3.10 (2H, d, J = 7.4 Hz), 3.27 (2H, s), 3.58 (2H, s), 5.03-5.17 (1H, quin, J = 7.0 Hz), 6.14 (1H, d, J = 7.4 Hz), 7.37-7.48 (4H, m), 7.53-7.65 (4H, m).

LC / MS [Condition 1]: Retention time 3.22 minutes; m / z 582.8 [M + H] ⁺ (ESI positive ion mode), m / z 627.0 [M + HCOO] ⁻ (ESI negative ion mode)

参考例４３３−１
５−［（１，３−ジオキソイソインドリン−２−イル）メチル］ピラジン−２−カルボン酸エチルの製造
５−（ブロモメチル）ピラジン−２−カルボン酸エチル（２．４５ｇ，１０ｍｍｏｌ，ＷＯ２００５０１８５５７に記載の方法により合成した）とフタルイミドカリウム（１．８５ｇ，１０ｍｍｏｌ）のＮ，Ｎ−ジメチルホルムアミド溶液（１５ｍｌ）を、８０℃で２０分間加熱攪拌した。反応終了後、反応混合物を減圧下濃縮し、酢酸エチルと水を加え、有機層を分離した。有機層を無水硫酸ナトリウムで乾燥した後、減圧留去した。得られた残渣にエタノール（５０ｍＬ）を加え、６０℃に加温した後、０℃まで冷却し、析出した固体をろ取することで、表題化合物（２．４０ｇ、収率７７％）を白色固体として得た。

^１Ｈ−ＮＭＲ（３００ＭＨｚ，ＣＤＣｌ_３）δ：１．４３（４Ｈ，ｔ，Ｊ＝７．２Ｈｚ），４．４９（２Ｈ，ｑ，Ｊ＝７．２Ｈｚ），５．１３（２Ｈ，ｓ），７．７６−７．７８（２Ｈ，ｍ），７．９０−７．９２（２Ｈ，ｍ），８．７６（１Ｈ，ｓ），９．１７（１Ｈ，ｓ）．

ＬＣ／ＭＳ［条件１］：保持時間３．６４分；ｍ／ｚ３１１．８［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）

Reference Example 433-1
Preparation of ethyl 5-[(1,3-dioxoisoindoline-2-yl) methyl] pyrazine-2-carboxylate ethyl 5- (bromomethyl) pyrazine-2-carboxylate (2.45 g, 10 mmol, described in WO2005018557 And a solution of potassium phthalimide (1.85 g, 10 mmol) in N, N-dimethylformamide (15 ml) was stirred with heating at 80 ° C. for 20 minutes. After completion of the reaction, the reaction mixture was concentrated under reduced pressure, ethyl acetate and water were added, and the organic layer was separated. The organic layer was dried over anhydrous sodium sulfate and evaporated under reduced pressure. Ethanol (50 mL) was added to the obtained residue, and the mixture was heated to 60 ° C., cooled to 0 ° C., and the precipitated solid was collected by filtration to give the title compound (2.40 g, yield 77%) as white. Obtained as a solid.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.43 (4H, t, J = 7.2 Hz), 4.49 (2H, q, J = 7.2 Hz), 5.13 (2H, s) , 7.76-7.78 (2H, m), 7.90-7.92 (2H, m), 8.76 (1H, s), 9.17 (1H, s).

LC / MS [Condition 1]: Retention time 3.64 minutes; m / z 311.8 [M + H] ⁺ (ESI positive ion mode)

参考例４３３−２
５−（アミノメチル）ピラジン−２−カルボン酸エチルの製造
上記で得られた５−［（１，３−ジオキソイソインドリン−２−イル）メチル］ピラジン−２−カルボン酸エチル（１．５６ｇ，５．０ｍｍｏｌ）のエタノール溶液（２０ｍＬ）に、ヒドラジン一水和物（４８５μＬ，１０．０ｍｍｏｌ）を加え、１時間還流した。放冷後、反応溶液にジクロロメタンを加え、不溶物をろ別し、ろ液を減圧留去した。残渣にジクロロメタンを加え、不溶物を再度ろ別し、ろ液を減圧留去することで、表題化合物（７１６．７０ｍｇ、収率８０％）を褐色液体として得た。

^１Ｈ−ＮＭＲ（ＣＤＣｌ_３）δ：１．４６（３Ｈ，ｔ，Ｊ＝７．１Ｈｚ），４．１４（２Ｈ，ｓ），４．５１（２Ｈ，ｑ，Ｊ＝７．１Ｈｚ），８．７３（１Ｈ，ｄ，Ｊ＝１．４Ｈｚ），９．２４（１Ｈ，ｄ，Ｊ＝１．４Ｈｚ）．

Reference Example 433-2
Preparation of ethyl 5- (aminomethyl) pyrazine-2-carboxylate ethyl 5-[(1,3-dioxoisoindoline-2-yl) methyl] pyrazine-2-carboxylate obtained above (1.56 g , 5.0 mmol) in ethanol solution (20 mL) was added hydrazine monohydrate (485 μL, 10.0 mmol) and refluxed for 1 hour. After allowing to cool, dichloromethane was added to the reaction solution, insolubles were filtered off, and the filtrate was distilled off under reduced pressure. Dichloromethane was added to the residue, the insoluble material was filtered off again, and the filtrate was evaporated under reduced pressure to give the title compound (716.70 mg, yield 80%) as a brown liquid.

¹ H-NMR (CDCl ₃ ) δ: 1.46 (3H, t, J = 7.1 Hz), 4.14 (2H, s), 4.51 (2H, q, J = 7.1 Hz), 8 .73 (1H, d, J = 1.4 Hz), 9.24 (1H, d, J = 1.4 Hz).

実施例４３３
５−｛［（１ｒ，４ｒ）−４−（｛２−オキソ−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）シクロヘキサンカルボキサミド］メチル｝ピラジン−２−カルボン酸エチル（化合物番号４３３）の製造
（２−フルオロピリジン−４−イル）メタンアミンの代わりに、参考例４３３−２で得られた５−（アミノメチル）ピラジン−２−カルボン酸エチルを用いること以外は実質的に実施例３９５と同様に反応を行って、表題化合物（１１ｍｇ、収率２１％）を無色液体として得た。

^１Ｈ−ＮＭＲ（３００ＭＨｚ、ＣＤＣｌ_３）δ：１．０６（２Ｈ，ｄｑ，Ｊ＝３．７，１２．３Ｈｚ），１．４７（３Ｈ，ｔ，Ｊ＝７．４Ｈｚ），１．５１−１．７２（３Ｈ，ｍ），１．７３−１．８７（４Ｈ，ｍ），１．９０−２．０４（４Ｈ，ｍ），２．１９（１Ｈ，ｔｔ，Ｊ＝１１．９，３．７Ｈｚ），２．５８（４Ｈ，ｂｒ ｍ），３．１２（２Ｈ，ｄ，Ｊ＝６．５Ｈｚ），３．２８（２Ｈ，ｓ），３．５９（２Ｈ，ｓ），４．５２（２Ｈ，ｑ，Ｊ＝７．８Ｈｚ），４．７０（２Ｈ，ｄ，Ｊ＝５．３Ｈｚ），６．５８（１Ｈ，ｂｒｓ），７．４５（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ），７．５８（２Ｈ，ｄ，Ｊ＝７．８Ｈｚ），８．７０（１Ｈ，ｓ），９．２３（１Ｈ，ｓ）．

ＬＣ／ＭＳ［条件１］：保持時間３．０４分；ｍ／ｚ６１７．７［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）

Example 433
5-{[(1r, 4r) -4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl } Methyl) cyclohexanecarboxamide] Production of methyl} pyrazine-2-carboxylate (Compound No. 433) Instead of (2-fluoropyridin-4-yl) methanamine 5- (amino) obtained in Reference Example 433-2 The reaction was carried out substantially in the same manner as in Example 395 except that ethyl methyl) pyrazine-2-carboxylate was used to give the title compound (11 mg, yield 21%) as a colorless liquid.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.06 (2H, dq, J = 3.7, 12.3 Hz), 1.47 (3H, t, J = 7.4 Hz), 1.51- 1.72 (3H, m), 1.73-1.87 (4H, m), 1.90-2.04 (4H, m), 2.19 (1H, tt, J = 11.9, 3 .7 Hz), 2.58 (4 H, br m), 3.12 (2 H, d, J = 6.5 Hz), 3.28 (2 H, s), 3.59 (2 H, s), 4.52 (2H, q, J = 7.8 Hz), 4.70 (2H, d, J = 5.3 Hz), 6.58 (1H, brs), 7.45 (2H, d, J = 8.2 Hz) 7.58 (2H, d, J = 7.8 Hz), 8.70 (1H, s), 9.23 (1H, s).

LC / MS [Condition 1]: Retention time 3.04 minutes; m / z 617.7 [M + H] ⁺ (ESI positive ion mode)

参考例４３４−１
１，１，１−トリフルオロ−２−（４−フルオロフェニル）−３−ニトロプロパン−２−オールの製造
１−ブロモ−４−フルオロベンゼン（５．２５ｇ，３０ｍｍｏｌ）のテトラヒドロフラン溶液（５０ｍＬ）に、−７８℃でｎ−ブチルリチウムのヘキサン溶液（２．６６Ｍ，１２．４ｍＬ，３３ｍｍｏｌ）をゆっくり滴下した。−７８℃で３０分間攪拌した後、トリフルオロ酢酸エチル（４．６４ｍＬ，４５ｍｍｏｌ）を−７８℃で加え、室温まで昇温した。室温で反応混合物にニトロメタン（３．２５ｍＬ，６０ｍｍｏｌ）を加えた後、３０分間攪拌した。反応溶液を１Ｍ塩酸（７５ｍＬ）に注いだ後、酢酸エチルで抽出した。得られた有機層を無水硫酸ナトリウムで乾燥し、減圧下濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー［展開溶媒：ヘキサン／酢酸エチル＝５／１］にて精製し、表題化合物（６．０７ｇ、収率８０％）を無色液体として得た。

^１Ｈ−ＮＭＲ（３００ＭＨｚ，ＣＤＣｌ_３）δ：４．６６（１Ｈ，ｂｒｓ），５．０４（２Ｈ，ｄｄ，Ｊ＝２３．１，１３．８Ｈｚ），７．１５（２Ｈ，ｄｄ，Ｊ＝８．９，８．５Ｈｚ），７．５９（２Ｈ，ｄｄ，Ｊ＝８．５，５．１Ｈｚ）．

Reference Example 434-1
Preparation of 1,1,1-trifluoro-2- (4-fluorophenyl) -3-nitropropan-2-ol To a tetrahydrofuran solution (50 mL) of 1-bromo-4-fluorobenzene (5.25 g, 30 mmol) A hexane solution of n-butyllithium (2.66 M, 12.4 mL, 33 mmol) was slowly added dropwise at −78 ° C. After stirring at −78 ° C. for 30 minutes, ethyl trifluoroacetate (4.64 mL, 45 mmol) was added at −78 ° C., and the temperature was raised to room temperature. Nitromethane (3.25 mL, 60 mmol) was added to the reaction mixture at room temperature, and then stirred for 30 minutes. The reaction solution was poured into 1M hydrochloric acid (75 mL) and extracted with ethyl acetate. The obtained organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography [developing solvent: hexane / ethyl acetate = 5/1] to give the title compound (6.07 g, yield 80%) as a colorless liquid.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 4.66 (1H, brs), 5.04 (2H, dd, J = 23.1, 13.8 Hz), 7.15 (2H, dd, J = 8.9, 8.5 Hz), 7.59 (2H, dd, J = 8.5, 5.1 Hz).

参考例４３４−２
３−アミノ−１，１，１−トリフルオロ−２−（４−フルオロフェニル）プロパン−２−オールの製造
上記で得られた１，１，１−トリフルオロ−２−（４−フルオロフェニル）−３−ニトロプロパン−２−オール（６．０７ｇ，２４ｍｍｏｌ）のエタノール溶液（２５ｍＬ）に、１０重量％パラジウム−カーボン（１．０ｇ）を加え、水素雰囲気下、室温で１６時間撹拌した。反応終了後、反応溶液をセライトろ過し、ろ液を減圧下濃縮乾固することで、表題化合物（４．５２ｇ、収率８４％）を白色固体として得た。

^１Ｈ−ＮＭＲ（３００ＭＨｚ，ＣＤＣｌ_３）δ：２．９７（１Ｈ，ｄ，Ｊ＝１３．０Ｈｚ），３．５７（１Ｈ，ｄ，Ｊ＝１３．０Ｈｚ），７．０８（２Ｈ，ｄｄ，Ｊ＝８．９，８．５Ｈｚ），７．５５（２Ｈ，ｄｄ，Ｊ＝８．５，５．２Ｈｚ）．

ＬＣ／ＭＳ［条件１］：保持時間０．５４分；ｍ／ｚ２２４．０［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）

Reference Example 434-2
Preparation of 3-amino-1,1,1-trifluoro-2- (4-fluorophenyl) propan-2-ol 1,1,1-trifluoro-2- (4-fluorophenyl) obtained above To an ethanol solution (25 mL) of -3-nitropropan-2-ol (6.07 g, 24 mmol) was added 10 wt% palladium-carbon (1.0 g), and the mixture was stirred at room temperature for 16 hours in a hydrogen atmosphere. After completion of the reaction, the reaction solution was filtered through Celite, and the filtrate was concentrated to dryness under reduced pressure to obtain the title compound (4.52 g, yield 84%) as a white solid.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 2.97 (1H, d, J = 13.0 Hz), 3.57 (1H, d, J = 13.0 Hz), 7.08 (2H, dd, J = 8.9, 8.5 Hz), 7.55 (2H, dd, J = 8.5, 5.2 Hz).

LC / MS [Condition 1]: Retention time 0.54 minutes; m / z 224.0 [M + H] ⁺ (ESI positive ion mode)

実施例４３４
（１ｒ，４ｒ）−４−｛［８−（４−シアノ−２，６−ジフルオロベンジル）−２−オキソ−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル］メチル｝−Ｎ−［３，３，３−トリフルオロ−２−（４−フルオロフェニル）−２−ヒドロキシプロピル］シクロヘキサンカルボキサミド（化合物番号４３４）の製造
（２−フルオロピリジン−４−イル）メタンアミンの代わりに、参考例４３４−２で得られた３−アミノ−１，１，１−トリフルオロ−２−（４−フルオロフェニル）プロパン−２−オールを用いることと、（１ｒ，４ｒ）−４−（｛２−オキソ−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）シクロヘキサンカルボン酸の代わりに参考例３９８−２で得られた（１ｒ，４ｒ）−４−｛［８−（４−シアノ−２，６−ジフルオロベンジル）−２−オキソ−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル］メチル｝シクロヘキサンカルボン酸を用いること以外は実質的に実施例３９５と同様に反応を行って、表題化合物（３２ｍｇ、収率５４％）を無色固体として得た。

^１Ｈ−ＮＭＲ（３００ＭＨｚ、ＣＤＣｌ_３）δ：０．８１−１．０２（２Ｈ，ｍ），１．２４−２．０７（１２Ｈ，ｍ），２．５３−２．７１（４Ｈ，ｂｒ ｍ），３．０３（２Ｈ，ｄ，Ｊ＝６．１Ｈｚ），３．２３（２Ｈ，ｓ），３．７５（２Ｈ，ｓ），３．７８（１Ｈ，ｄｄ，Ｊ＝１３．５，５．７Ｈｚ），４．００（１Ｈ，ｄｔ，Ｊ＝１３．５，４．１Ｈｚ），６．１３−６．６６（２Ｈ，ｂｒｍ），７．０６（２Ｈ，ｔ，Ｊ＝８．６Ｈｚ），７．２３（２Ｈ，ｄ，Ｊ＝６．１Ｈｚ），７．５７（２Ｈ，ｄｄ，Ｊ＝９．０，４．９Ｈｚ）．

ＬＣ／ＭＳ［条件１］：保持時間３．３９分；ｍ／ｚ６５２．９［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ６５０．９［Ｍ−Ｈ］^―（ＥＳＩ負イオンモード）

Example 434
(1r, 4r) -4-{[8- (4-Cyano-2,6-difluorobenzyl) -2-oxo-1-oxa-3,8-diazaspiro [4.5] decan-3-yl] methyl } Preparation of -N- [3,3,3-trifluoro-2- (4-fluorophenyl) -2-hydroxypropyl] cyclohexanecarboxamide (Compound No. 434) instead of (2-fluoropyridin-4-yl) methanamine And 3-amino-1,1,1-trifluoro-2- (4-fluorophenyl) propan-2-ol obtained in Reference Example 434-2, and (1r, 4r) -4- ({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl) Reference instead of cyclohexanecarboxylic acid (1r, 4r) -4-{[8- (4-Cyano-2,6-difluorobenzyl) -2-oxo-1-oxa-3,8-diazaspiro [4.5] obtained in 398-2 The reaction was carried out in substantially the same manner as in Example 395 except that decan-3-yl] methyl} cyclohexanecarboxylic acid was used to give the title compound (32 mg, yield 54%) as a colorless solid.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 0.81-1.02 (2H, m), 1.24-2.07 (12H, m), 2.53-2.71 (4H, br m ), 3.03 (2H, d, J = 6.1 Hz), 3.23 (2H, s), 3.75 (2H, s), 3.78 (1H, dd, J = 13.5, 5) .7 Hz), 4.00 (1 H, dt, J = 13.5, 4.1 Hz), 6.13-6.66 (2 H, brm), 7.06 (2 H, t, J = 8.6 Hz) , 7.23 (2H, d, J = 6.1 Hz), 7.57 (2H, dd, J = 9.0, 4.9 Hz).

LC / MS [Condition 1]: Retention time 3.39 minutes; m / z 652.9 [M + H] ⁺ (ESI positive ion mode), m / z 650.9 [M−H] ⁻ (ESI negative ion mode)

実施例４３５
４−｛［３−（｛（１ｒ，４ｒ）−４−［３−（４−シアノフェノキシ）アゼチジン−１−カルボニル］シクロヘキシル｝メチル）−２−オキソ−１−オキサ−３，８−ジアザスピロ［４．５］デカン−８−イル］メチル｝−３，５−ジフルオロベンゾニトリル（化合物番号４３５）の製造
（２−フルオロピリジン−４−イル）メタンアミンの代わりに、参考例３８３−２で得られた４−（アゼチジン−３−イルオキシ）ベンゾニトリルを用いることと、（１ｒ，４ｒ）−４−（｛２−オキソ−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）シクロヘキサンカルボン酸の代わりに参考例３９８−２で得られた（１ｒ，４ｒ）−４−｛［８−（４−シアノ−２，６−ジフルオロベンジル）−２−オキソ−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル］メチル｝シクロヘキサンカルボン酸を用いること以外は実質的に実施例３９５と同様に反応を行って、表題化合物（１．２ｍｇ、収率３．０％）を無色液体として得た。

^１Ｈ−ＮＭＲ（３００ＭＨｚ、ＣＤＣｌ_３）δ：１．０２（２Ｈ，ｑ，Ｊ＝１２．７Ｈｚ），１．４３−１．６６（３Ｈ，ｍ），１．７０−１．８７（６Ｈ，ｍ），１．８７−１．９８（２Ｈ，ｍ），２．１４（１Ｈ，ｔｔ，Ｊ＝１１．４，２．９Ｈｚ），２．６１−２．６４（４Ｈ，ｂｒ ｍ），３．０９（２Ｈ，ｄ，Ｊ＝６．５Ｈｚ），３．２２（２Ｈ，ｓ），３．７６（２Ｈ，ｓ），４．０６（１Ｈ，ｄｄ，Ｊ＝４．１，１１．０Ｈｚ），４．２１（１Ｈ，ｄｄ，Ｊ＝９．０，３．３Ｈｚ），４．４１（１Ｈ，ｄｄ，Ｊ＝１１．４，６．１Ｈｚ），４．５５（１Ｈ，ｄｄ，Ｊ＝９．０，６．５Ｈｚ），４．９４−５．０５（１Ｈ，ｍ），６．８２（２Ｈ，ｄ，Ｊ＝９．４Ｈｚ），７．２３（２Ｈ，ｄ，Ｊ＝６．５Ｈｚ），７．６２（２Ｈ，ｄ，Ｊ＝８．６Ｈｚ）．

ＬＣ／ＭＳ［条件１］：保持時間３．１６分；ｍ／ｚ６０３．９［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ６４８．０［Ｍ＋ＨＣＯＯ］^―（ＥＳＩ負イオンモード）

Example 435
4-{[3-({(1r, 4r) -4- [3- (4-cyanophenoxy) azetidine-1-carbonyl] cyclohexyl} methyl) -2-oxo-1-oxa-3,8-diazaspiro [ 4.5] Preparation of decan-8-yl] methyl} -3,5-difluorobenzonitrile (Compound No. 435) Obtained instead of (2-fluoropyridin-4-yl) methanamine in Reference Example 383-2. 4- (azetidin-3-yloxy) benzonitrile and (1r, 4r) -4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3, (1r, 4r) -4-{[8- (4-cyano-2,8) obtained in Reference Example 398-2 instead of 8-diazaspiro [4.5] decan-3-yl} methyl) cyclohexanecarboxylic acid 6- Fluorobenzyl) -2-oxo-1-oxa-3,8-diazaspiro [4.5] decan-3-yl] methyl} cyclohexanecarboxylic acid was used for the reaction substantially the same as in Example 395. The title compound (1.2 mg, yield 3.0%) was obtained as a colorless liquid.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.02 (2H, q, J = 12.7 Hz), 1.43-1.66 (3H, m), 1.70-1.87 (6H, m), 1.87-1.98 (2H, m), 2.14 (1H, tt, J = 11.4, 2.9 Hz), 2.61-2.64 (4H, br m), 3 .09 (2H, d, J = 6.5 Hz), 3.22 (2H, s), 3.76 (2H, s), 4.06 (1H, dd, J = 4.1, 11.0 Hz) 4.21 (1H, dd, J = 9.0, 3.3 Hz), 4.41 (1H, dd, J = 11.4, 6.1 Hz), 4.55 (1H, dd, J = 9) 0.0, 6.5 Hz), 4.94-5.05 (1 H, m), 6.82 (2 H, d, J = 9.4 Hz), 7.23 (2 H, d, J = 6.5 Hz) , 7.62 (2 , D, J = 8.6Hz).

LC / MS [Condition 1]: Retention time 3.16 minutes; m / z 603.9 [M + H] ⁺ (ESI positive ion mode), m / z 648.0 [M + HCOO] ⁻ (ESI negative ion mode)

実施例４３６
４−｛［３−（｛（１ｒ，４ｒ）−４−［３−（３−シアノフェノキシ）アゼチジン−１−カルボニル］シクロヘキシル｝メチル）−２−オキソ−１−オキサ−３，８−ジアザスピロ［４．５］デカン−８−イル］メチル｝−３，５−ジフルオロベンゾニトリル（化合物番号４３６）の製造
（２−フルオロピリジン−４−イル）メタンアミンの代わりに、参考例３９０−２で得られた３−（アゼチジン−３−イルオキシ）ベンゾニトリル塩酸塩を用いることと、（１ｒ，４ｒ）−４−（｛２−オキソ−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）シクロヘキサンカルボン酸の代わりに参考例３９８−２で得られた（１ｒ，４ｒ）−４−｛［８−（４−シアノ−２，６−ジフルオロベンジル）−２−オキソ−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル］メチル｝シクロヘキサンカルボン酸を用いること以外は実質的に実施例３９５と同様に反応を行って、表題化合物（３１ｍｇ、収率７２％）を無色固体として得た。

^１Ｈ−ＮＭＲ（３００ＭＨｚ、ＣＤＣｌ_３）δ：１．０２（２Ｈ，ｑ，Ｊ＝１１．９Ｈｚ），１．４３−１．６６（３Ｈ，ｍ），１．７０−１．８７（６Ｈ，ｍ），１．８７−１．９９（２Ｈ，ｍ），２．０７−３．１９（４Ｈ，ｂｒ ｍ），２．１５（１Ｈ，ｔｔ，Ｊ＝１１．９，３．３Ｈｚ），３．１０（２Ｈ，ｄ，Ｊ＝７．４Ｈｚ），３．２３（２Ｈ，ｓ），３．７６（２Ｈ，ｓ），４．０５（１Ｈ，ｄｄ，Ｊ＝３．７，１１．０Ｈｚ），４．２０（１Ｈ，ｄｄ，Ｊ＝８．６，３．３Ｈｚ），４．４１（１Ｈ，ｄｄ，Ｊ＝１０．６，６．１Ｈｚ），４．５７（１Ｈ，ｄｄ，Ｊ＝９．０，６．１Ｈｚ），４．９１−５．０３（１Ｈ，ｍ），６．９８−７．０５（２Ｈ，ｍ），７．２４（２Ｈ，ｄ，Ｊ＝６．１Ｈｚ），７．３３（１Ｈ，ｄ，Ｊ＝７．４Ｈｚ），７．４３（１Ｈ，ｔ，Ｊ＝７．８Ｈｚ）．

ＬＣ／ＭＳ［条件１］：保持時間３．２１分；ｍ／ｚ６０３．９［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ６４８．１［Ｍ＋ＨＣＯＯ］^―（ＥＳＩ負イオンモード）

Example 436
4-{[3-({(1r, 4r) -4- [3- (3-cyanophenoxy) azetidine-1-carbonyl] cyclohexyl} methyl) -2-oxo-1-oxa-3,8-diazaspiro [ 4.5] Preparation of decan-8-yl] methyl} -3,5-difluorobenzonitrile (Compound No. 436) Obtained in Reference Example 390-2 instead of (2-fluoropyridin-4-yl) methanamine 3- (azetidin-3-yloxy) benzonitrile hydrochloride and (1r, 4r) -4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa- (1r, 4r) -4-{[8- (4-cyano-) obtained in Reference Example 398-2 instead of 3,8-diazaspiro [4.5] decan-3-yl} methyl) cyclohexanecarboxylic acid 2 6-Difluorobenzyl) -2-oxo-1-oxa-3,8-diazaspiro [4.5] decan-3-yl] methyl} cyclohexanecarboxylic acid, but substantially in the same manner as in Example 395 To give the title compound (31 mg, 72% yield) as a colorless solid.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.02 (2H, q, J = 11.9 Hz), 1.43-1.66 (3H, m), 1.70-1.87 (6H, m), 1.87-1.99 (2H, m), 2.07-3.19 (4H, br m), 2.15 (1H, tt, J = 11.9, 3.3 Hz), 3 .10 (2H, d, J = 7.4 Hz), 3.23 (2H, s), 3.76 (2H, s), 4.05 (1H, dd, J = 3.7, 11.0 Hz) , 4.20 (1H, dd, J = 8.6, 3.3 Hz), 4.41 (1H, dd, J = 10.6, 6.1 Hz), 4.57 (1H, dd, J = 9) 0.0, 6.1 Hz), 4.91-5.03 (1H, m), 6.98-7.05 (2H, m), 7.24 (2H, d, J = 6.1 Hz), 7 .33 (1H, d J = 7.4Hz), 7.43 (1H, t, J = 7.8Hz).

LC / MS [Condition 1]: Retention time 3.21 minutes; m / z 603.9 [M + H] ⁺ (ESI positive ion mode), m / z 648.1 [M + HCOO] ⁻ (ESI negative ion mode)

参考例４３７−１
１，１，１−トリフルオロ−２−（６−メトキシピリジン−３−イル）−３−ニトロプロパン−２−オールの製造
１−ブロモ−４−フルオロベンゼンの代わりに、５−ブロモ−２−メトキシピリジンを用いること以外は、実質的に参考例４３４−１と同様に反応を行って、表題化合物（２．０３ｇ、収率９１％）を無色液体として得た。

^１Ｈ−ＮＭＲ（３００ＭＨｚ，ＣＤＣｌ_３）δ：３．９６（３Ｈ，ｓ），５．０４（２Ｈ，ｄｄ，Ｊ＝２１．３，１３．２Ｈｚ），６．８２（１Ｈ，ｄ，Ｊ＝９．０Ｈｚ），７．７８（１Ｈ，ｄｄ，Ｊ＝９．０，３．０Ｈｚ），８．３８（１Ｈ，ｄ，Ｊ＝３．０Ｈｚ）．

Reference Example 437-1
Preparation of 1,1,1-trifluoro-2- (6-methoxypyridin-3-yl) -3-nitropropan-2-ol Instead of 1-bromo-4-fluorobenzene, 5-bromo-2- The reaction was carried out substantially in the same manner as in Reference Example 434-1 except that methoxypyridine was used to give the title compound (2.03 g, yield 91%) as a colorless liquid.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 3.96 (3H, s), 5.04 (2H, dd, J = 21.3, 13.2 Hz), 6.82 (1H, d, J = 9.0 Hz), 7.78 (1H, dd, J = 9.0, 3.0 Hz), 8.38 (1H, d, J = 3.0 Hz).

参考例４３７−２
３−アミノ−１，１，１−トリフルオロ−２−（６−メトキシピリジン−３−イル）プロパン−２−オールの製造
１，１，１−トリフルオロ−２−（４−フルオロフェニル）−３−ニトロプロパン−２−オールの代わりに、上記で得られた１，１，１−トリフルオロ−２−（６−メトキシピリジン−３−イル）−３−ニトロプロパン−２−オールを用いること以外は、実質的に参考例４３４−２と同様に反応を行って、表題化合物（１．５２ｇ、収率８４％）を無色液体として得た。

ＬＣ／ＭＳ［条件１］：保持時間０．５４分；ｍ／ｚ２３７．０［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）

Reference Example 437-2
Preparation of 3-amino-1,1,1-trifluoro-2- (6-methoxypyridin-3-yl) propan-2-ol 1,1,1-trifluoro-2- (4-fluorophenyl)- Instead of 3-nitropropan-2-ol, use 1,1,1-trifluoro-2- (6-methoxypyridin-3-yl) -3-nitropropan-2-ol obtained above. Except for the above, the reaction was carried out in substantially the same manner as in Reference Example 434-2 to obtain the title compound (1.52 g, yield 84%) as a colorless liquid.

LC / MS [Condition 1]: Retention time 0.54 minutes; m / z 237.0 [M + H] ⁺ (ESI positive ion mode)

実施例４３７
（１ｒ，４ｒ）−４−（｛２−オキソ−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）−Ｎ−［３，３，３−トリフルオロ−２−ヒドロキシ−２−（６−メトキシピリジン−３−イル）プロピル］シクロヘキサンカルボキサミド（化合物番号４３７）の製造
４−（３−フルオロフェニルスルホニル）ピペリジン塩酸塩の代わりに、参考例４３７−２で得られた３−アミノ−１，１，１−トリフルオロ−２−（６−メトキシピリジン−３−イル）プロパン−２−オールを用いること以外は実質的に実施例３９３と同様に反応を行って、表題化合物（５．１ｍｇ、収率９．０％）を無色固体として得た。

^１Ｈ−ＮＭＲ（３００ＭＨｚ、ＣＤＣｌ_３）δ：０．８１−１．００（２Ｈ，ｍ），１．２３−１．８８（９Ｈ，ｍ），１．９０−２．１１（３Ｈ，ｍ），２．４７−２．６６（４Ｈ，ｍ），３．０３（２Ｈ，ｄ，Ｊ＝７．２Ｈｚ），３．２８（２Ｈ，ｓ），３．５８（２Ｈ，ｓ），３．８０（１Ｈ，ｄｄ，Ｊ＝１４．６，６．５Ｈｚ），３．９３（３Ｈ，ｓ），４．００（１Ｈ，ｄｄ，Ｊ＝１４．６，５．４Ｈｚ），６．７４（１Ｈ，ｄ，Ｊ＝８．５Ｈｚ），７．０３（１Ｈ，ｔ，Ｊ＝６．１Ｈｚ），７．４４（２Ｈ，ｄ，Ｊ＝７．８Ｈｚ），７．５８（２Ｈ，ｄ，Ｊ＝７．８Ｈｚ），７．８１（１Ｈ，ｄｄ，Ｊ＝８．５，２．７Ｈｚ），８．３４（１Ｈ，ｄ，Ｊ＝２．７Ｈｚ）．

ＬＣ／ＭＳ［条件１］：保持時間３．３２分；ｍ／ｚ６７２．８［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）

Example 437
(1r, 4r) -4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl)- Preparation of N- [3,3,3-trifluoro-2-hydroxy-2- (6-methoxypyridin-3-yl) propyl] cyclohexanecarboxamide (Compound No. 437) 4- (3-Fluorophenylsulfonyl) piperidine hydrochloride Substantially other than using 3-amino-1,1,1-trifluoro-2- (6-methoxypyridin-3-yl) propan-2-ol obtained in Reference Example 437-2 instead of the salt Specifically, the reaction was carried out in the same manner as in Example 393 to obtain the title compound (5.1 mg, yield 9.0%) as a colorless solid.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 0.81-1.00 (2H, m), 1.23-1.88 (9H, m), 1.90-2.11 (3H, m) 2.47-2.66 (4H, m), 3.03 (2H, d, J = 7.2 Hz), 3.28 (2H, s), 3.58 (2H, s), 3.80. (1H, dd, J = 14.6, 6.5 Hz), 3.93 (3H, s), 4.00 (1H, dd, J = 14.6, 5.4 Hz), 6.74 (1H, d, J = 8.5 Hz), 7.03 (1H, t, J = 6.1 Hz), 7.44 (2H, d, J = 7.8 Hz), 7.58 (2H, d, J = 7) .8 Hz), 7.81 (1H, dd, J = 8.5, 2.7 Hz), 8.34 (1H, d, J = 2.7 Hz).

LC / MS [Condition 1]: Retention time 3.32 minutes; m / z 672.8 [M + H] ⁺ (ESI positive ion mode)

実施例４３８
（１ｒ，４ｒ）−４−（｛２−オキソ−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）−Ｎ−［３，３，３−トリフルオロ−２−（４−フルオロフェニル）−２−ヒドロキシプロピル］シクロヘキサンカルボキサミド（化合物番号４３８）の製造
４−（３−フルオロフェニルスルホニル）ピペリジン塩酸塩の代わりに、参考例４３４−２で得られた３−アミノ−１，１，１−トリフルオロ−２−（４−フルオロフェニル）プロパン−２−オールを用いること以外は実質的に実施例３９３と同様に反応を行って、表題化合物（２８ｍｇ、収率４８％）を黄色液体として得た。

^１Ｈ−ＮＭＲ（３００ＭＨｚ、ＣＤＣｌ_３）δ：０．８０−１．０１（２Ｈ，ｍ），１．２４−１．４６（２Ｈ，ｍ），１．４６−１．８７（７Ｈ，ｍ），１．８７−２．０７（３Ｈ，ｍ），２．５４−２．５７（４Ｈ，ｂｒ ｍ），３．０３（２Ｈ，ｄ，Ｊ＝７．５Ｈｚ），３．２５（２Ｈ，ｓ），３．５６（２Ｈ，ｓ），３．７８（１Ｈ，ｄｄ，Ｊ＝６．５，１４．７Ｈｚ），４．００（１Ｈ，ｄｄ，Ｊ＝５．８，１４．７Ｈｚ），６．２７（１Ｈ，ｂｒ ｓ），６．５９（１Ｈ，ｂｒ ｓ），７．０６（２Ｈ，ｔ，Ｊ＝８．５Ｈｚ），７．４４（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ），７．５１−７．６２（４Ｈ，ｍ）．

ＬＣ／ＭＳ［条件１］：保持時間３．５１分；ｍ／ｚ６５９．８［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）

Example 438
(1r, 4r) -4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl)- Preparation of N- [3,3,3-trifluoro-2- (4-fluorophenyl) -2-hydroxypropyl] cyclohexanecarboxamide (Compound No. 438) Instead of 4- (3-fluorophenylsulfonyl) piperidine hydrochloride Substantially the same as Example 393 except that 3-amino-1,1,1-trifluoro-2- (4-fluorophenyl) propan-2-ol obtained in Reference Example 434-2 was used. Reaction was performed to obtain the title compound (28 mg, yield 48%) as a yellow liquid.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 0.80 to 1.01 (2H, m), 1.24 to 1.46 (2H, m), 1.46 to 1.87 (7H, m) , 1.87-2.07 (3H, m), 2.54-2.57 (4H, br m), 3.03 (2H, d, J = 7.5 Hz), 3.25 (2H, s ), 3.56 (2H, s), 3.78 (1H, dd, J = 6.5, 14.7 Hz), 4.00 (1H, dd, J = 5.8, 14.7 Hz), 6 .27 (1H, br s), 6.59 (1H, br s), 7.06 (2H, t, J = 8.5 Hz), 7.44 (2H, d, J = 8.2 Hz), 7 51-7.62 (4H, m).

LC / MS [Condition 1]: Retention time 3.51 minutes; m / z 659.8 [M + H] ⁺ (ESI positive ion mode)

参考例４３９−１
２−（６−クロロピリジン−３−イル）−１，１，１−トリフルオロ−３−ニトロプロパン−２−オールの製造
１−ブロモ−４−フルオロベンゼンの代わりに、５−ブロモ−２−クロロピリジン（５．２ｇ，２７ｍｍｏｌ）を用いること以外は、実質的に参考例４３４−１と同様に反応を行って、表題化合物（４．９３ｇ、収率６７％）を黄色液体として得た。

^１Ｈ−ＮＭＲ（３００ＭＨｚ，ＣＤＣｌ_３）δ：４．９６（１Ｈ，ｂｒｓ），５．０６（２Ｈ，ｓ），７．４５（１Ｈ，ｄ，Ｊ＝８．４Ｈｚ），７．９２（１Ｈ，ｄｄ，Ｊ＝８．４，２．８Ｈｚ），８．６２（１Ｈ，ｄ，Ｊ＝２．８Ｈｚ）．

ＬＣ／ＭＳ［条件１］：保持時間３．６０分；ｍ／ｚ２７０．９，２７２．８［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）

Reference Example 439-1
Preparation of 2- (6-chloropyridin-3-yl) -1,1,1-trifluoro-3-nitropropan-2-ol Instead of 1-bromo-4-fluorobenzene, 5-bromo-2- The reaction was carried out substantially in the same manner as in Reference Example 434-1 except that chloropyridine (5.2 g, 27 mmol) was used, and the title compound (4.93 g, yield 67%) was obtained as a yellow liquid.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 4.96 (1H, brs), 5.06 (2H, s), 7.45 (1H, d, J = 8.4 Hz), 7.92 (1H , Dd, J = 8.4, 2.8 Hz), 8.62 (1H, d, J = 2.8 Hz).

LC / MS [Condition 1]: Retention time 3.60 minutes; m / z 270.9, 272.8 [M + H] ⁺ (ESI positive ion mode)

参考例４３９−２
３−アミノ−１，１，１−トリフルオロ−２−（ピリジン−３−イル）プロパン−２−オールの製造
上記で得られた２−（６−クロロピリジン−３−イル）−１，１，１−トリフルオロ−３−ニトロプロパン−２−オール（２．５３ｇ，９．３９ｍｍｏｌ）のテトラヒドロフラン溶液（２０ｍＬ）に、トリエチルアミン（２．６０ｍＬ，１８．８ｍｍｏｌ）と１０重量％パラジウム−カーボン（０．６０ｇ）を加え、水素雰囲気下、室温で２４時間撹拌した。反応終了後、反応溶液をセライトろ過し、ろ液を減圧下濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー［昭光サイエンティフィック社製プリフパックＳＩ６０μｍ、展開溶媒：酢酸エチル／メタノール／トリエチルアミン＝９／１／１］にて精製し、表題化合物（０．９１ｇ、収率４７％）を白色無定形物として得た。

^１Ｈ−ＮＭＲ（３００ＭＨｚ，ＣＤＣｌ_３）δ：３．０１（１Ｈ，ｄ，Ｊ＝１３．５Ｈｚ），３．６２（１Ｈ，ｄ，Ｊ＝１３．５Ｈｚ），５．８４（１Ｈ，ｂｒｓ），７．３４（１Ｈ，ｄｄ，Ｊ＝８．１，４．８Ｈｚ），７．９５（１Ｈ，ｄ，Ｊ＝８．１Ｈｚ），８．６１（１Ｈ，ｄ，Ｊ＝４．８Ｈｚ），８．７９（１Ｈ，ｓ）．

Reference Example 439-2
Preparation of 3-amino-1,1,1-trifluoro-2- (pyridin-3-yl) propan-2-ol 2- (6-chloropyridin-3-yl) -1,1 obtained above , 1-trifluoro-3-nitropropan-2-ol (2.53 g, 9.39 mmol) in tetrahydrofuran (20 mL) was added triethylamine (2.60 mL, 18.8 mmol) and 10 wt% palladium-carbon (0 .60 g) was added, and the mixture was stirred at room temperature for 24 hours under a hydrogen atmosphere. After completion of the reaction, the reaction solution was filtered through Celite, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography [Prefpack SI 60 μm, manufactured by Shoko Scientific Co., Ltd., developing solvent: ethyl acetate / methanol / triethylamine = 9/1/1], and the title compound (0.91 g, yield 47) was obtained. %) As a white amorphous product.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 3.01 (1H, d, J = 13.5 Hz), 3.62 (1H, d, J = 13.5 Hz), 5.84 (1H, brs) , 7.34 (1H, dd, J = 8.1, 4.8 Hz), 7.95 (1H, d, J = 8.1 Hz), 8.61 (1H, d, J = 4.8 Hz), 8.79 (1H, s).

実施例４３９
（１ｒ，４ｒ）−４−（｛２−オキソ−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）−Ｎ−［３，３，３−トリフルオロ−２−ヒドロキシ−２−（ピリジン−３−イル）プロピル］シクロヘキサンカルボキサミド（化合物番号４３９）の製造
４−（３−フルオロフェニルスルホニル）ピペリジン塩酸塩の代わりに、参考例４３９−２で得られた３−アミノ−１，１，１−トリフルオロ−２−（ピリジン−３−イル）プロパン−２−オールを用いること以外は実質的に実施例３９３と同様に反応を行って、表題化合物（２２ｍｇ、収率３８％）を無色固体として得た。

^１Ｈ−ＮＭＲ（３００ＭＨｚ、ＣＤＣｌ_３）δ：０．７９−１．００（２Ｈ，ｍ），１．２２−１．４２（２Ｈ，ｍ），１．４５−１．６１（１Ｈ，ｍ），１．６１−１．８７（６Ｈ，ｍ），１．８９−２．０８（３Ｈ，ｍ），２．５４−２．５７（４Ｈ，ｂｒ ｍ），３．０２（２Ｈ，ｄ，Ｊ＝７．２Ｈｚ），３．２６（２Ｈ，ｓ），３．５８（２Ｈ，ｓ），３．８４（１Ｈ，ｄｄ，Ｊ＝１５．０，６．５Ｈｚ），４．０８（１Ｈ，ｄｄ，Ｊ＝１５．７，５．８Ｈｚ），６．６６−６．９０（１Ｈ，ｍ），７．３６（１Ｈ，ｄｄ，Ｊ＝４．８，７．５Ｈｚ），７．４４（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ），７．５８（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ），８．０４（１Ｈ，ｄ，Ｊ＝７．５Ｈｚ），８．５４−８．６０（１Ｈ，ｍ），８．７１（１Ｈ，ｓ）．

ＬＣ／ＭＳ［条件１］：保持時間２．９７分；ｍ／ｚ６４２．７［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）

Example 439
(1r, 4r) -4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl)- Preparation of N- [3,3,3-trifluoro-2-hydroxy-2- (pyridin-3-yl) propyl] cyclohexanecarboxamide (Compound No. 439) Instead of 4- (3-fluorophenylsulfonyl) piperidine hydrochloride In Example 393, except that 3-amino-1,1,1-trifluoro-2- (pyridin-3-yl) propan-2-ol obtained in Reference Example 439-2 was used. The reaction was performed in the same manner to obtain the title compound (22 mg, yield 38%) as a colorless solid.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 0.79-1.00 (2H, m), 1.22-1.42 (2H, m), 1.45-1.61 (1H, m) , 1.61-1.87 (6H, m), 1.89-2.08 (3H, m), 2.54-2.57 (4H, br m), 3.02 (2H, d, J = 7.2 Hz), 3.26 (2H, s), 3.58 (2H, s), 3.84 (1H, dd, J = 15.0, 6.5 Hz), 4.08 (1H, dd) , J = 15.7, 5.8 Hz), 6.66-6.90 (1H, m), 7.36 (1H, dd, J = 4.8, 7.5 Hz), 7.44 (2H, d, J = 8.2 Hz), 7.58 (2H, d, J = 8.2 Hz), 8.04 (1H, d, J = 7.5 Hz), 8.54-8.60 (1H, m ), 8.71 (1H, ).

LC / MS [Condition 1]: Retention time 2.97 minutes; m / z 642.7 [M + H] ⁺ (ESI positive ion mode)

参考例４４０−１
５−［（１，３−ジオキソイソインドリン−２−イル）メチル］ピコリノニトリルの製造
５−（ブロモエチル）ピラジン−２−カルボン酸エチルの代わりに、参考例３８７で得られた、５−（ブロモメチル）ピコリノニトリルを用いること以外は実質的に参考例４３３−１と同様に反応を行なって、表題化合物（０．１７ｇ、収率６３％）を白色粉末として得た。

^１Ｈ−ＮＭＲ（ＣＤＣｌ_３）δ：４．９２（２Ｈ，ｓ），７．６６（１Ｈ，ｄ，Ｊ＝８．６Ｈｚ），７．７６（２Ｈ，ｄｄ，Ｊ＝５．３，２．９Ｈｚ），７．８８（２Ｈ，ｄｄ，Ｊ＝５．３，２．９Ｈｚ），７．９１（１Ｈ，ｄｄ，Ｊ＝８．６，２．０Ｈｚ），８．８１（１Ｈ，ｄ，Ｊ＝２．０Ｈｚ）．

ＬＣ／ＭＳ［条件１］：保持時間３．５８分；ｍ／ｚ２６３．９［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）

Reference Example 440-1
Preparation of 5-[(1,3-dioxoisoindoline-2-yl) methyl] picolinonitrile 5-ethyl bromoethyl) pyrazine-2-carboxylate was obtained in Reference Example 387 instead of 5- The reaction was carried out substantially in the same manner as in Reference Example 433-1 except that (bromomethyl) picolinonitrile was used to give the title compound (0.17 g, yield 63%) as a white powder.

¹ H-NMR (CDCl ₃ ) δ: 4.92 (2H, s), 7.66 (1H, d, J = 8.6 Hz), 7.76 (2H, dd, J = 5.3, 2. 9 Hz), 7.88 (2H, dd, J = 5.3, 2.9 Hz), 7.91 (1H, dd, J = 8.6, 2.0 Hz), 8.81 (1H, d, J = 2.0 Hz).

LC / MS [Condition 1]: retention time 3.58 minutes; m / z 263.9 [M + H] ⁺ (ESI positive ion mode)

参考例４４０−２
５−（アミノメチル）ピコリノニトリルの製造
５−［（１，３−ジオキソイソインドリン−２−イル）メチル］ピラジン−２−カルボン酸エチルの代わりに、参考例４４０−１で得られた、５−［（１，３−ジオキソイソインドリン−２−イル）メチル］ピコリノニトリルを用いること以外は実質的に参考例４３３−２と同様に反応を行なって、表題化合物（１０ｍｇ、収率１２％）を淡黄色油状物として得た。

^１Ｈ−ＮＭＲ（ＣＤＣｌ_３）δ：４．０２（２Ｈ，ｓ），７．６８（１Ｈ，ｄ，Ｊ＝８．０Ｈｚ），７．８６（１Ｈ，ｄｄ，Ｊ＝８．０，２．０Ｈｚ），８．６８（１Ｈ，ｄ，Ｊ＝２．０Ｈｚ）．

ＬＣ／ＭＳ［条件１］：保持時間０．４９分；ｍ／ｚ１３３．８［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）

Reference Example 440-2
Preparation of 5- (aminomethyl) picolinonitrile Obtained in Reference Example 440-1 instead of ethyl 5-[(1,3-dioxoisoindoline-2-yl) methyl] pyrazine-2-carboxylate , 5-[(1,3-dioxoisoindoline-2-yl) methyl] picolinonitrile was reacted in substantially the same manner as in Reference Example 433-2 to give the title compound (10 mg, yield). 12%) as a pale yellow oil.

¹ H-NMR (CDCl ₃ ) δ: 4.02 (2H, s), 7.68 (1H, d, J = 8.0 Hz), 7.86 (1H, dd, J = 8.0, 2. 0 Hz), 8.68 (1H, d, J = 2.0 Hz).

LC / MS [Condition 1]: Retention time 0.49 min; m / z 133.8 [M + H] ⁺ (ESI positive ion mode)

実施例４４０
（１ｒ，４ｒ）−Ｎ−［（６−シアノピリジン−３−イル）メチル］−４−（｛２−オキソ−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）シクロヘキサンカルボキサミド（化合物番号４４０）の製造
ピペリジンの代わりに、参考例４４０−２で得られた５−（アミノメチル）ピコリノニトリルを用いること以外は実質的に実施例１６と同様に反応を行なって、表題化合物（１１ｍｇ、収率２６％）を白色粉末として得た。

^１Ｈ−ＮＭＲ（ＣＤＣｌ_３）δ：１．０１（２Ｈ，ｄｑ，Ｊ＝３．０，１３．０Ｈｚ），１．５１（２Ｈ，ｄｑ，Ｊ＝３．０，１２．５Ｈｚ），１．５９−１．８７（５Ｈ，ｍ），１．９３（４Ｈ，ｄ，Ｊ＝１３．０Ｈｚ），２．１２（１Ｈ，ｔｔ，Ｊ＝１２．２，３．３Ｈｚ），２．４４−２．６４（４Ｈ，ｂｒ ｍ），３．０９（２Ｈ，ｄ，Ｊ＝７．３Ｈｚ），３．２６（２Ｈ，ｓ），３．５８（２Ｈ，ｓ），４．５０（２Ｈ，ｄ，Ｊ＝５．９Ｈｚ），６．３７（１Ｈ，ｔ，Ｊ＝５．９Ｈｚ），７．４４（２Ｈ，ｄ，Ｊ＝８．３Ｈｚ），７．５７（２Ｈ，ｄ，Ｊ＝８．３Ｈｚ），７．６５（１Ｈ，ｄ，Ｊ＝７．９Ｈｚ），７．７６（１Ｈ，ｄｄ，Ｊ＝７．９，２．１Ｈｚ），８．６２（１Ｈ，ｄ，Ｊ＝２．１Ｈｚ）．

ＬＣ／ＭＳ［条件１］：保持時間３．００分；ｍ／ｚ５６９．７［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ６０４．０［Ｍ＋Ｃｌ］⁻、６１３．９［Ｍ＋ＨＣＯＯ］⁻（ＥＳＩ負イオンモード）

Example 440
(1r, 4r) -N-[(6-Cyanopyridin-3-yl) methyl] -4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8 -Preparation of diazaspiro [4.5] decan-3-yl} methyl) cyclohexanecarboxamide (Compound No. 440) Using 5- (aminomethyl) picolinonitrile obtained in Reference Example 440-2 instead of piperidine The title compound (11 mg, yield 26%) was obtained as a white powder in substantially the same manner as in Example 16 except for the above.

¹ H-NMR (CDCl ₃ ) δ: 1.01 (2H, dq, J = 3.0, 13.0 Hz), 1.51 (2H, dq, J = 3.0, 12.5 Hz), 1. 59-1.87 (5H, m), 1.93 (4H, d, J = 13.0 Hz), 2.12 (1H, tt, J = 12.2, 3.3 Hz), 2.44-2 .64 (4H, br m), 3.09 (2H, d, J = 7.3 Hz), 3.26 (2H, s), 3.58 (2H, s), 4.50 (2H, d, J = 5.9 Hz), 6.37 (1H, t, J = 5.9 Hz), 7.44 (2H, d, J = 8.3 Hz), 7.57 (2H, d, J = 8.3 Hz) ), 7.65 (1H, d, J = 7.9 Hz), 7.76 (1H, dd, J = 7.9, 2.1 Hz), 8.62 (1H, d, J = 2.1 Hz) .

LC / MS [Condition 1]: Retention time 3.00 min; m / z 569.7 [M + H] ⁺ (ESI positive ion mode), m / z 604.0 [M + Cl] ⁻ , 613.9 [M + HCOO] ⁻ (ESI Negative ion mode)

参考例４４１−１
４−（４−シアノフェニルアミノ）ピペリジン−１−カルボン酸ｔ−ブチルの製造
４−（トリフルオロメチル）アニリンの代わりに、４−アミノベンゾニトリルを用いること以外は実質的に参考例３９１−１と同様に反応を行なって、表題化合物（０．８４ｇ、収率５６％）を白色粉末として得た。

^１Ｈ−ＮＭＲ（ＣＤＣｌ_３）δ：１．３７（２Ｈ，ｑ，Ｊ＝１１．５Ｈｚ），１．４７（９Ｈ，ｓ），２．０２（２Ｈ，ｄ，Ｊ＝１１．９Ｈｚ），２．９３（２Ｈ，ｔ，Ｊ＝１１．５Ｈｚ），３．３９−３．５５（１Ｈ，ｍ），３．９６−４．２２（０Ｈ，ｍ），６．５５（２Ｈ，ｄ，Ｊ＝８．６Ｈｚ），７．４２（２Ｈ，ｄ，Ｊ＝８．６Ｈｚ）．

ＬＣ／ＭＳ［条件１］：保持時間４．２９分；ｍ／ｚ２４６．０［Ｍ−ｉｓｏｂｕｔｅｎｅ＋Ｈ］^＋（ＥＳＩ正イオンモード）

Reference Example 441-1
Preparation of t-butyl 4- (4-cyanophenylamino) piperidine-1-carboxylate Substantially Reference Example 391-1 except that 4-aminobenzonitrile was used instead of 4- (trifluoromethyl) aniline The title compound (0.84 g, yield 56%) was obtained as a white powder.

¹ H-NMR (CDCl ₃ ) δ: 1.37 (2H, q, J = 11.5 Hz), 1.47 (9H, s), 2.02 (2H, d, J = 11.9 Hz), 2 .93 (2H, t, J = 11.5 Hz), 3.39-3.55 (1H, m), 3.96-4.22 (0H, m), 6.55 (2H, d, J = 8.6 Hz), 7.42 (2H, d, J = 8.6 Hz).

LC / MS [Condition 1]: Retention time 4.29 minutes; m / z 246.0 [M-isobutene + H] ⁺ (ESI positive ion mode)

参考例４４１−２
４−（ピペリジン−４−イルアミノ）ベンゾニトリル二塩酸塩の製造
４−［４−（トリフルオロメチル）フェニルアミノ］ピペリジン−１−カルボン酸ｔ−ブチルの代わりに、参考例４４１−１で得られた、４−（４−シアノフェニルアミノ）ピペリジン−１−カルボン酸ｔ−ブチルを用いること以外は実質的に参考例３９１−２と同様に反応を行なって、表題化合物（０．７３ｇ、収率９６％）を白色粉末として得た。

^１Ｈ−ＮＭＲ（ＣＤＣｌ_３）δ：１．５６（２Ｈ，ｄｔ，Ｊ＝２７．０，１２．５Ｈｚ），１．９３（２Ｈ，ｄ，Ｊ＝１１．２Ｈｚ），２．８９（２Ｈ，ｑ，Ｊ＝９．６Ｈｚ），３．２０（２Ｈ，ｄ，Ｊ＝１１．２Ｈｚ），３．５５（１Ｈ，ｔｔ，Ｊ＝１０．２，３．６Ｈｚ），６．６３（２Ｈ，ｄ，Ｊ＝８．３Ｈｚ），７．３８（２Ｈ，ｄ，Ｊ＝８．３Ｈｚ），８．９２−９．１６（２Ｈ，ｂｒ ｍ）．

ＬＣ／ＭＳ［条件１］：保持時間０．５２分；ｍ／ｚ２０２．１［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）

Reference Example 441-2
Preparation of 4- (piperidin-4-ylamino) benzonitrile dihydrochloride obtained in Reference Example 441-1 instead of t-butyl 4- [4- (trifluoromethyl) phenylamino] piperidine-1-carboxylate The reaction was conducted in substantially the same manner as in Reference Example 391-2 except that t-butyl 4- (4-cyanophenylamino) piperidine-1-carboxylate was used, and the title compound (0.73 g, yield) was obtained. 96%) was obtained as a white powder.

¹ H-NMR (CDCl ₃ ) δ: 1.56 (2H, dt, J = 27.0, 12.5 Hz), 1.93 (2H, d, J = 111.2 Hz), 2.89 (2H, q, J = 9.6 Hz), 3.20 (2H, d, J = 11.2 Hz), 3.55 (1H, tt, J = 10.2, 3.6 Hz), 6.63 (2H, d) , J = 8.3 Hz), 7.38 (2H, d, J = 8.3 Hz), 8.92-9.16 (2H, br m).

LC / MS [Condition 1]: Retention time 0.52 minutes; m / z 202.1 [M + H] ⁺ (ESI positive ion mode)

実施例４４１
４−｛１−［（１ｒ，４ｒ）−４−（｛２−オキソ−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）シクロヘキサンカルボニル］ピペリジン−４−イルアミノ｝ベンゾニトリル（化合物番号４４１）の製造

ピペリジンの代わりに、参考例４４１−２で得られた４−（ピペリジン−４−イルアミノ）ベンゾニトリル二塩酸塩を用いること以外は実質的に実施例１６と同様に反応を行なって、表題化合物（２６ｍｇ、収率５１％）を白色粉末として得た。

^１Ｈ−ＮＭＲ（ＣＤＣｌ_３）δ：１．０５（２Ｈ，ｑ，Ｊ＝１１．５Ｈｚ），１．３７（２Ｈ，ｑ，Ｊ＝１１．３Ｈｚ），１．４６−１．６９（３Ｈ，ｍ），１．７１−１．８６（６Ｈ，ｍ），１．９４（２Ｈ，ｄ，Ｊ＝１３．１Ｈｚ），２．１３（２Ｈ，ｄ，Ｊ＝１３．９Ｈｚ），２．４６（１Ｈ，ｔｔ，Ｊ＝１１．９，３．３Ｈｚ），２．５２−２．６４（４Ｈ，ｂｒ ｍ），２．８３（１Ｈ，ｔ，Ｊ＝１１．９Ｈｚ），３．１１（２Ｈ，ｄ，Ｊ＝７．４Ｈｚ），３．１９（１Ｈ，ｔ，Ｊ＝１２．７Ｈｚ），３．２６（２Ｈ，ｓ），３．４８−３．６５（１Ｈ，ｍ），３．５７（２Ｈ，ｓ），３．９０（１Ｈ，ｄ，Ｊ＝１３．９Ｈｚ），４．１２（１Ｈ，ｄ，Ｊ＝７．０Ｈｚ），４．５３（１Ｈ，ｄ，Ｊ＝１３．１Ｈｚ），６．５６（２Ｈ，ｄ，Ｊ＝９．０Ｈｚ），７．４３（２Ｈ，ｄ，Ｊ＝９．０Ｈｚ），７．４４（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ），７．５７（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ）．

ＬＣ／ＭＳ［条件１］：保持時間３．３６分；ｍ／ｚ６３７．８［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ６７２．２［Ｍ＋Ｃｌ］⁻、６８２．０［Ｍ＋ＨＣＯＯ］⁻（ＥＳＩ負イオンモード）

Example 441
4- {1-[(1r, 4r) -4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decane-3 -Il} methyl) cyclohexanecarbonyl] piperidin-4-ylamino} benzonitrile (Compound No. 441)

The reaction was conducted in substantially the same manner as in Example 16 except that 4- (piperidin-4-ylamino) benzonitrile dihydrochloride obtained in Reference Example 441-2 was used instead of piperidine to give the title compound ( 26 mg, yield 51%) was obtained as a white powder.

¹ H-NMR (CDCl ₃ ) δ: 1.05 (2H, q, J = 11.5 Hz), 1.37 (2H, q, J = 11.3 Hz), 1.46-1.69 (3H, m), 1.71-1.86 (6H, m), 1.94 (2H, d, J = 13.1 Hz), 2.13 (2H, d, J = 13.9 Hz), 2.46 ( 1H, tt, J = 11.9, 3.3 Hz), 2.52-2.64 (4H, br m), 2.83 (1H, t, J = 11.9 Hz), 3.11 (2H, d, J = 7.4 Hz), 3.19 (1H, t, J = 12.7 Hz), 3.26 (2H, s), 3.48-3.65 (1H, m), 3.57 ( 2H, s), 3.90 (1H, d, J = 13.9 Hz), 4.12 (1H, d, J = 7.0 Hz), 4.53 (1H, d, J = 13.1 Hz), 6.56 (2 , D, J = 9.0 Hz), 7.43 (2H, d, J = 9.0 Hz), 7.44 (2H, d, J = 8.2 Hz), 7.57 (2H, d, J = 8.2 Hz).

LC / MS [Condition 1]: Retention time 3.36 minutes; m / z 637.8 [M + H] ⁺ (ESI positive ion mode), m / z 672.2 [M + Cl] ⁻ , 682.0 [M + HCOO] ⁻ (ESI Negative ion mode)

参考例４４２−１
４−（３−シアノ−４−フルオロフェニルアミノ）ピペリジン−１−カルボン酸ｔ−ブチルの製造
４−（トリフルオロメチル）アニリンの代わりに、５−アミノ−２−フルオロベンゾニトリルを用いること以外は実質的に参考例３９１−１と同様に反応を行なって、表題化合物（０．７３ｇ、収率９６％）を白色粉末として得た。

^１Ｈ−ＮＭＲ（ＣＤＣｌ_３）δ：１．２２−１．４２（２Ｈ，ｍ），１．４７（９Ｈ，ｓ），２．０１（２Ｈ，ｄｄ，Ｊ＝１２．６，３．７Ｈｚ），２．９３（２Ｈ，ｔ，Ｊ＝１１．７Ｈｚ），３．２６−３．４３（１Ｈ，ｂｒ ｍ），３．７６−３．９２（１Ｈ，ｂｒ ｍ），４．０６（２Ｈ，ｄ，Ｊ＝１２．３Ｈｚ），６．７１（１Ｈ，ｄｄ，Ｊ＝４．９，３．３Ｈｚ），６．７７（１Ｈ，ｄｄｄ，Ｊ＝９．０，４．５，３．３Ｈｚ），７．００（１Ｈ，ｔ，Ｊ＝８．６Ｈｚ）．

ＬＣ／ＭＳ［条件１］：保持時間４．４３分；ｍ／ｚ３１９．９［Ｍ＋Ｈ］^＋、２６３．９［Ｍ−ｉｓｏｂｕｔｅｎｅ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ３６３．９［Ｍ＋ＨＣＯＯ］⁻（ＥＳＩ負イオンモード）

Reference Example 442-1
Preparation of t-butyl 4- (3-cyano-4-fluorophenylamino) piperidine-1-carboxylate Other than using 5-amino-2-fluorobenzonitrile instead of 4- (trifluoromethyl) aniline The reaction was carried out substantially in the same manner as in Reference Example 391-1 to give the title compound (0.73 g, yield 96%) as a white powder.

¹ H-NMR (CDCl ₃ ) δ: 1.22-1.42 (2H, m), 1.47 (9H, s), 2.01 (2H, dd, J = 12.6, 3.7 Hz) 2.93 (2H, t, J = 11.7 Hz), 3.26-3.43 (1H, br m), 3.76-3.92 (1H, br m), 4.06 (2H, d, J = 12.3 Hz), 6.71 (1H, dd, J = 4.9, 3.3 Hz), 6.77 (1H, ddd, J = 9.0, 4.5, 3.3 Hz) , 7.00 (1H, t, J = 8.6 Hz).

LC / MS [Condition 1]: retention time 4.43 minutes; m / z 319.9 [M + H] ⁺ , 263.9 [M-isobutene + H] ⁺ (ESI positive ion mode), m / z 363.9 [M + HCOO] ⁻ (ESI negative ion mode)

参考例４４２−２
２−フルオロ−５−（ピペリジン−４−イルアミノ）ベンゾニトリル二塩酸塩の製造
４−［４−（トリフルオロメチル）フェニルアミノ］ピペリジン−１−カルボン酸ｔ−ブチルの代わりに、参考例４４２−１で得られた、４−（３−シアノ−４−フルオロフェニルアミノ）ピペリジン−１−カルボン酸ｔ−ブチルを用いること以外は実質的に参考例３９１−２と同様に反応を行なって、表題化合物（０．６３ｇ、収率５０％）を白色粉末として得た。

^１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ_６）δ：１．５４（２Ｈ，ｄｑ，Ｊ＝４．１，１１．９Ｈｚ），２．０２（２Ｈ，ｂｒ ｄ，Ｊ＝１３．９Ｈｚ），２．９６（２Ｈ，ｑ，Ｊ＝１１．１Ｈｚ），３．２８（２Ｈ，ｂｒ ｄ，Ｊ＝１２．３Ｈｚ），３．４１−３．６６（２Ｈ，ｂｒ ｍ），６．９２−７．００（２Ｈ，ｍ），７．２３（１Ｈ，ｔ，Ｊ＝９．８Ｈｚ），８．７９（２Ｈ，ｂｒ ｓ）．

ＬＣ／ＭＳ［条件１］：保持時間０．６７分；ｍ／ｚ２２０．０［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）

Reference Example 442-2
Preparation of 2-fluoro-5- (piperidin-4-ylamino) benzonitrile dihydrochloride Reference example 442 instead of t-butyl 4- [4- (trifluoromethyl) phenylamino] piperidine-1-carboxylate The reaction was conducted in substantially the same manner as in Reference Example 391-2 except that t-butyl 4- (3-cyano-4-fluorophenylamino) piperidine-1-carboxylate obtained in 1 was used to give the title The compound (0.63 g, yield 50%) was obtained as a white powder.

¹ H-NMR (DMSO-d ₆ ) δ: 1.54 (2H, dq, J = 4.1, 11.9 Hz), 2.02 (2H, br d, J = 13.9 Hz), 2.96 (2H, q, J = 11.1 Hz), 3.28 (2H, br d, J = 12.3 Hz), 3.41-3.66 (2H, br m), 6.92-7.00 ( 2H, m), 7.23 (1H, t, J = 9.8 Hz), 8.79 (2H, br s).

LC / MS [Condition 1]: Retention time 0.67 minutes; m / z 220.0 [M + H] ⁺ (ESI positive ion mode)

実施例４４２
２−フルオロ−５−｛１−［（１ｒ，４ｒ）−４−（｛２−オキソ−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）シクロヘキサンカルボニル］ピペリジン−４−イルアミノ｝ベンゾニトリル（化合物番号４４２）の製造
ピペリジンの代わりに、参考例４４２−２で得られた２−フルオロ−５−（ピペリジン−４−イルアミノ）ベンゾニトリル二塩酸塩とトリエチルアミンを用いること以外は実質的に実施例１６と同様に反応を行なって、表題化合物（３６ｍｇ、収率６９％）を白色粉末として得た。

^１Ｈ−ＮＭＲ（ＣＤＣｌ_３）δ：１．０５（２Ｈ，ｑ，Ｊ＝１１．５Ｈｚ），１．３３（２Ｈ，ｑ，Ｊ＝１１．１Ｈｚ），１．４５−１．８８（９Ｈ，ｍ），１．９４（２Ｈ，ｄ，Ｊ＝１３．１Ｈｚ），２．１１（２Ｈ，ｄ，Ｊ＝１６．０Ｈｚ），２．４６（１Ｈ，ｔｔ，Ｊ＝１１．５，２．９Ｈｚ），２．５２−２．６３（４Ｈ，ｂｒ ｍ），２．８３（１Ｈ，ｔ，Ｊ＝１１．５Ｈｚ），３．１１（２Ｈ，ｄ，Ｊ＝７．４Ｈｚ），３．１９（１Ｈ，ｔ，Ｊ＝１２．７Ｈｚ），３．２６（２Ｈ，ｓ），３．３６−３．５２（１Ｈ，ｍ），３．５８（２Ｈ，ｓ），３．７２（１Ｈ，ｄ，Ｊ＝７．８Ｈｚ），３．９０（１Ｈ，ｄ，Ｊ＝１３．５Ｈｚ），４．５２（１Ｈ，ｄ，Ｊ＝１３．１Ｈｚ），６．７２（１Ｈ，ｄｄ，Ｊ＝４．９，２．９Ｈｚ），６．７６（１Ｈ，ｄｄｄ，Ｊ＝８．８，４．１，２．９Ｈｚ），７．０１（１Ｈ，ｔ，Ｊ＝８．８Ｈｚ），７．４４（２Ｈ，ｄ，Ｊ＝７．８Ｈｚ），７．５７（２Ｈ，ｄ，Ｊ＝７．８Ｈｚ）．

ＬＣ／ＭＳ［条件１］：保持時間３．４４分；ｍ／ｚ６５５．８［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ６９０．２［Ｍ＋Ｃｌ］⁻、７００．０［Ｍ＋ＨＣＯＯ］⁻（ＥＳＩ負イオンモード）

Example 442
2-Fluoro-5- {1-[(1r, 4r) -4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5 Preparation of Decan-3-yl} methyl) cyclohexanecarbonyl] piperidin-4-ylamino} benzonitrile (Compound No. 442) Instead of piperidine, 2-fluoro-5- (piperidine-) obtained in Reference Example 442-2 The reaction was carried out in substantially the same manner as in Example 16 except that 4-ylamino) benzonitrile dihydrochloride and triethylamine were used to obtain the title compound (36 mg, yield 69%) as a white powder.

¹ H-NMR (CDCl ₃ ) δ: 1.05 (2H, q, J = 11.5 Hz), 1.33 (2H, q, J = 11.1 Hz), 1.45-1.88 (9H, m), 1.94 (2H, d, J = 13.1 Hz), 2.11 (2H, d, J = 16.0 Hz), 2.46 (1 H, tt, J = 11.5, 2.9 Hz) ), 2.52-2.63 (4H, br m), 2.83 (1H, t, J = 11.5 Hz), 3.11 (2H, d, J = 7.4 Hz), 3.19 ( 1H, t, J = 12.7 Hz), 3.26 (2H, s), 3.36-3.52 (1H, m), 3.58 (2H, s), 3.72 (1H, d, J = 7.8 Hz), 3.90 (1 H, d, J = 13.5 Hz), 4.52 (1 H, d, J = 13.1 Hz), 6.72 (1 H, dd, J = 4.9). 2.9Hz 6.76 (1H, ddd, J = 8.8, 4.1, 2.9 Hz), 7.01 (1H, t, J = 8.8 Hz), 7.44 (2H, d, J = 7) .8 Hz), 7.57 (2H, d, J = 7.8 Hz).

LC / MS [Condition 1]: retention time 3.44 minutes; m / z 655.8 [M + H] ⁺ (ESI positive ion mode), m / z 690.2 [M + Cl] ⁻ , 700.0 [M + HCOO] ⁻ (ESI Negative ion mode)

参考例４４３−１
（６−フルオロピリジン−３−イル）メタノ−ルの製造
６−［（ｔ−ブトキシカルボニルアミノ）メチル］ニコチン酸エチルの代わりに、６−フルオロニコチンアルデヒドを用いること以外は実質的に参考例４３１−３と同様に反応を行なって、表題化合物（０．２６ｇ、収率５０％）を無色油状物として得た。

^１Ｈ−ＮＭＲ（ＣＤＣｌ_３）δ：４．７１（２Ｈ，ｓ），６．９３（１Ｈ，ｄｄ，Ｊ＝８．２，２．５Ｈｚ），７．８３（１Ｈ，ｔｄ，Ｊ＝８．２，２．５Ｈｚ），８．１５（１Ｈ，ｂｒ ｓ）．

ＬＣ／ＭＳ［条件１］：保持時間０．７４分；ｍ／ｚ１２７．８［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）

Reference Example 443-1
Production of (6-fluoropyridin-3-yl) methanol Substantially Reference Example 431 except that 6-fluoronicotinaldehyde is used in place of ethyl 6-[(t-butoxycarbonylamino) methyl] nicotinate The reaction was conducted in the same manner as for -3 to give the title compound (0.26 g, yield 50%) as a colorless oil.

¹ H-NMR (CDCl ₃ ) δ: 4.71 (2H, s), 6.93 (1H, dd, J = 8.2, 2.5 Hz), 7.83 (1H, td, J = 8. 2, 2.5 Hz), 8.15 (1 H, br s).

LC / MS [Condition 1]: retention time 0.74 minutes; m / z 127.8 [M + H] ⁺ (ESI positive ion mode)

参考例４４３−２
２−［（６−フルオロピリジン−３−イル）メチル］イソインドリン−１，３−ジオンの製造
６−（ヒドロキシメチル）ニコチン酸エチルの代わりに、参考例４４３−１で得られた、（６−フルオロピリジン−３−イル）メタノ−ルを用いること以外は実質的に参考例４３１−１と同様に反応を行なって、表題化合物（０．３６ｇ、収率６９％）を白色粉末として得た。

^１Ｈ−ＮＭＲ（ＣＤＣｌ_３）δ：４．８４（２Ｈ，ｓ），６．８９（１Ｈ，ｄｄ，Ｊ＝８．６，２．９Ｈｚ），７．７１−７．７８（２Ｈ，ｍ），７．８３−７．９０（３Ｈ，ｍ），８．３３（１Ｈ，ｄ，Ｊ＝２．５Ｈｚ）．

ＬＣ／ＭＳ［条件１］：保持時間３．６４分；ｍ／ｚ２５６．９［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）

Reference Example 443-2
Preparation of 2-[(6-fluoropyridin-3-yl) methyl] isoindoline-1,3-dione Instead of ethyl 6- (hydroxymethyl) nicotinate, it was obtained in Reference Example 443-1 (6 The reaction was carried out in substantially the same manner as in Reference Example 431-1 except that -fluoropyridin-3-yl) methanol was used to obtain the title compound (0.36 g, yield 69%) as a white powder. .

¹ H-NMR (CDCl ₃ ) δ: 4.84 (2H, s), 6.89 (1H, dd, J = 8.6, 2.9 Hz), 7.71-7.78 (2H, m) 7.83-7.90 (3H, m), 8.33 (1H, d, J = 2.5 Hz).

LC / MS [Condition 1]: Retention time 3.64 minutes; m / z 256.9 [M + H] ⁺ (ESI positive ion mode)

参考例４４３−３
（６−フルオロピリジン−３−イル）メタンアミンの製造
５−［（１，３−ジオキソイソインドリン−２−イル）メチル］ピラジン−２−カルボン酸エチルの代わりに、参考例４４３−２で得られた、２−［（６−フルオロピリジン−３−イル）メチル］イソインドリン−１，３−ジオンを用いること以外は実質的に参考例４３３−２と同様に反応を行なって、表題化合物（２４ｍｇ、収率２４％）を無色油状物として得た。

^１Ｈ−ＮＭＲ（ＣＤＣｌ_３）δ：３．８９（２Ｈ，ｓ），６．９０（１Ｈ，ｄｄ，Ｊ＝８．２，２．９Ｈｚ），７．７９（１Ｈ，ｔｄ，Ｊ＝８．２，２．９Ｈｚ），８．１３（１Ｈ，ｂｒ ｓ）．

ＬＣ／ＭＳ［条件１］：保持時間０．４９分；ｍ／ｚ１２６．９［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）

Reference Example 443-3
Preparation of (6-fluoropyridin-3-yl) methanamine Obtained in Reference Example 443-2 instead of ethyl 5-[(1,3-dioxoisoindoline-2-yl) methyl] pyrazine-2-carboxylate The reaction was conducted in substantially the same manner as in Reference Example 433-2 except that 2-[(6-fluoropyridin-3-yl) methyl] isoindoline-1,3-dione was used to give the title compound ( 24 mg, 24% yield) was obtained as a colorless oil.

¹ H-NMR (CDCl ₃ ) δ: 3.89 (2H, s), 6.90 (1H, dd, J = 8.2, 2.9 Hz), 7.79 (1H, td, J = 8. 2, 2.9 Hz), 8.13 (1H, br s).

LC / MS [Condition 1]: Retention time 0.49 min; m / z 126.9 [M + H] ⁺ (ESI positive ion mode)

実施例４４３
（１ｒ，４ｒ）−Ｎ−［（６−フルオロピリジン−３−イル）メチル］−４−（｛２−オキソ−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）シクロヘキサンカルボキサミド（化合物番号４４３）の製造
ピペリジンの代わりに、参考例４４３−３で得られた（６−フルオロピリジン−３−イル）メタンアミンを用いること以外は実質的に実施例１６と同様に反応を行なって、表題化合物（２４ｍｇ、収率５３％）を白色粉末として得た。

^１Ｈ−ＮＭＲ（ＣＤＣｌ_３）δ：１．０１（２Ｈ，ｄｑ，Ｊ＝３．３，１３．０Ｈｚ），１．５０（２Ｈ，ｄｑ，Ｊ＝３．３，１２．３Ｈｚ），１．５８−１．６６（１Ｈ，ｍ），１．７０−１．８４（４Ｈ，ｍ），１．８７−１．９８（４Ｈ，ｍ），２．０８（１Ｈ，ｔｔ，Ｊ＝１２．１，３．３Ｈｚ），２．４７−２．６２（４Ｈ，ｂｒ ｍ），３．０８（２Ｈ，ｄ，Ｊ＝７．４Ｈｚ），３．２５（２Ｈ，ｓ），３．５７（２Ｈ，ｓ），４．４３（２Ｈ，ｄ，Ｊ＝６．１Ｈｚ），６．０９（１Ｈ，ｔ，Ｊ＝６．１Ｈｚ），６．８９（１Ｈ，ｄｄ，Ｊ＝８．６，２．９Ｈｚ），７．４４（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ），７．５７（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ），７．７４（１Ｈ，ｔｄ，Ｊ＝８．６，２．５Ｈｚ），８．１１（１Ｈ，ｄ，Ｊ＝２．５Ｈｚ）．

ＬＣ／ＭＳ［条件１］：保持時間３．００分；ｍ／ｚ５６２．７［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ５６０．８［Ｍ−Ｈ］⁻、６０６．９［Ｍ＋ＨＣＯＯ］⁻（ＥＳＩ負イオンモード）

Example 443
(1r, 4r) -N-[(6-Fluoropyridin-3-yl) methyl] -4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8 -Preparation of diazaspiro [4.5] decan-3-yl} methyl) cyclohexanecarboxamide (Compound No. 443) Instead of piperidine, (6-fluoropyridin-3-yl) methanamine obtained in Reference Example 443-3 was used. The reaction was carried out substantially in the same manner as in Example 16 except for using, to give the title compound (24 mg, yield 53%) as a white powder.

¹ H-NMR (CDCl ₃ ) δ: 1.01 (2H, dq, J = 3.3, 13.0 Hz), 1.50 (2H, dq, J = 3.3, 12.3 Hz), 1. 58-1.66 (1H, m), 1.70-1.84 (4H, m), 1.87-1.98 (4H, m), 2.08 (1H, tt, J = 12.1) , 3.3 Hz), 2.47-2.62 (4H, br m), 3.08 (2H, d, J = 7.4 Hz), 3.25 (2H, s), 3.57 (2H, s), 4.43 (2H, d, J = 6.1 Hz), 6.09 (1H, t, J = 6.1 Hz), 6.89 (1H, dd, J = 8.6, 2.9 Hz) ), 7.44 (2H, d, J = 8.2 Hz), 7.57 (2H, d, J = 8.2 Hz), 7.74 (1H, td, J = 8.6, 2.5 Hz) , 8.11 (1H, d, J 2.5Hz).

LC / MS [Condition 1]: Retention time 3.00 minutes; m / z 562.7 [M + H] ⁺ (ESI positive ion mode), m / z 560.8 [M−H] ⁻ , 606.9 [M + HCOO] ⁻ (ESI negative ion mode)

参考例４４４−１
３−｛［５−（エトキシカルボニル）ピラジン−２−イル］メチル｝−２−オキソ−１−オキサ−３，８−ジアザスピロ［４．５］デカン−８−カルボン酸ｔ−ブチルの製造
参考例１１１−１で得られた２−オキソ−１−オキサ−３，８−ジアザスピロ［４．５］デカン−８−カルボン酸ｔ−ブチル（２５６．３０ｍｇ，１．０ｍｍｏｌ）のテトラヒドロフラン溶液（４．０ｍＬ）に、０℃で水素化ナトリウム（＞５５重量％、流動パラフィン分散、関東化学株式会社より購入）（４３．６０ｍｇ，１．０ｍｍｏｌ）を加えた後、５−（ブロモメチル）ピラジン−２−カルボン酸エチル（２４５．０７ｍｇ，１．０ｍｍｏｌ，ＷＯ２００５０１８５５７に記載の方法により合成した）を加え、１時間加熱還流した。反応終了後、飽和塩化アンモニウム水溶液と水を加え、酢酸エチルで抽出し、有機層を無水硫酸ナトリウムで乾燥した後、減圧下濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー［昭光サイエンティフィック社製プリフパックＮＨ６０μｍ、展開溶媒：ヘキサン／酢酸エチル＝１：３］にて精製し、表題化合物（２００．９６ｍｇ、収率４８％）を白色固体として得た。

^１Ｈ−ＮＭＲ（３００ＭＨｚ，ＣＤＣｌ_３）δ：１．４４−１．５４（４Ｈ，ｍ），１．４６（３Ｈ，ｔ，Ｊ＝７．１Ｈｚ），１．４６（９Ｈ，ｓ），１．６２−１．７２（３Ｈ，ｍ），１．９１−１．９６（２Ｈ，ｍ），３．２８−３．３２（２Ｈ，ｍ），３．４０（２Ｈ，ｓ），３．８２−３．８６（２Ｈ，ｍ），４．５２（２Ｈ，ｑ，Ｊ＝７．１Ｈｚ），４．６９（２Ｈ，ｓ），８．７２（１Ｈ，ｓ），９．２６（１Ｈ，ｓ）．

ＬＣ／ＭＳ［条件１］：保持時間３．８９分；ｍ／ｚ４４２．８［Ｍ＋Ｎａ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ４１８．８［Ｍ−Ｈ］^―（ＥＳＩ負イオンモード）

Reference Example 444-1
Reference example for production of t-butyl 3-{[5- (ethoxycarbonyl) pyrazin-2-yl] methyl} -2-oxo-1-oxa-3,8-diazaspiro [4.5] decane-8-carboxylate Tetrahydrofuran solution (4.0 mL) of 2-oxo-1-oxa-3,8-diazaspiro [4.5] decane-8-carboxylate t-butyl (256.30 mg, 1.0 mmol) obtained in 111-1. ), Sodium hydride (> 55% by weight, liquid paraffin dispersion, purchased from Kanto Chemical Co., Inc.) (43.60 mg, 1.0 mmol) was added at 0 ° C. Ethyl acid (245.07 mg, 1.0 mmol, synthesized by the method described in WO2005018557) was added, and the mixture was heated to reflux for 1 hour. After completion of the reaction, a saturated aqueous ammonium chloride solution and water were added, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography [Prefpack NH 60 μm, manufactured by Shoko Scientific Co., Ltd., developing solvent: hexane / ethyl acetate = 1: 3], and the title compound (20.96 mg, yield 48%) was white. Obtained as a solid.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.44 to 1.54 (4H, m), 1.46 (3H, t, J = 7.1 Hz), 1.46 (9H, s), 1 .62-1.72 (3H, m), 1.91-1.96 (2H, m), 3.28-3.32 (2H, m), 3.40 (2H, s), 3.82 −3.86 (2H, m), 4.52 (2H, q, J = 7.1 Hz), 4.69 (2H, s), 8.72 (1H, s), 9.26 (1H, s) ).

LC / MS [Condition 1]: Retention time 3.89 minutes; m / z 442.8 [M + Na] ⁺ (ESI positive ion mode), m / z 418.8 [M−H] ⁻ (ESI negative ion mode)

参考例４４４−２
５−｛［８−（ｔ−ブトキシカルボニル）−２−オキソ−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル］メチル｝ピラジン−２−カルボン酸の製造
３−｛［（１ｒ，４ｒ）−４−（メトキシカルボニル）シクロヘキシル］メチル｝−２−オキソ−１−オキサ−３，８−ジアザスピロ［４．５］デカン−８−カルボン酸ｔ−ブチルの代わりに、参考例４４４−１で得られた、３−｛［５−（エトキシカルボニル）ピラジン−２−イル］メチル｝−２−オキソ−１−オキサ−３，８−ジアザスピロ［４．５］デカン−８−カルボン酸ｔ−ブチルを用いること以外は実質的に参考例２−３と同様に反応を行なって、表題化合物（０．２４ｇ、収率７９％）を白色粉末として得た。

^１Ｈ−ＮＭＲ（ＣＤＣｌ_３）δ：１．４７（９Ｈ，ｓ），１．７０（２Ｈ，ｄｄｄ，Ｊ＝１３．６，１１．５，４．５Ｈｚ），１．９５（２Ｈ，ｄ，Ｊ＝１３．６Ｈｚ），３．３０（２Ｈ，ｔ，Ｊ＝１１．３Ｈｚ），３．４５（２Ｈ，ｓ），３．７８−３．９４（２Ｈ，ｍ），４．７２（２Ｈ，ｓ），６．１１（１Ｈ，ｂｒ ｓ），８．７２（１Ｈ，ｓ），９．３４（１Ｈ，ｓ）．

ＬＣ／ＭＳ［条件１］：保持時間３．５２分；ｍ／ｚ３９２．９［Ｍ＋Ｈ］^＋、３３６．８［Ｍ−ｉｓｏｂｕｔｅｎｅ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ３９０．９［Ｍ−Ｈ］⁻（ＥＳＩ負イオンモード）

Reference Example 444-2
Preparation of 5-{[8- (t-butoxycarbonyl) -2-oxo-1-oxa-3,8-diazaspiro [4.5] decan-3-yl] methyl} pyrazine-2-carboxylic acid 3- { Instead of [(1r, 4r) -4- (methoxycarbonyl) cyclohexyl] methyl} -2-oxo-1-oxa-3,8-diazaspiro [4.5] decane-8-carboxylate instead of t-butyl 3-{[5- (Ethoxycarbonyl) pyrazin-2-yl] methyl} -2-oxo-1-oxa-3,8-diazaspiro [4.5] decan-8-obtained in Example 444-1 The reaction was conducted in substantially the same manner as in Reference Example 2-3 except that t-butyl carboxylate was used to give the title compound (0.24 g, yield 79%) as a white powder.

¹ H-NMR (CDCl ₃ ) δ: 1.47 (9H, s), 1.70 (2H, ddd, J = 13.6, 11.5, 4.5 Hz), 1.95 (2H, d, J = 13.6 Hz), 3.30 (2H, t, J = 11.3 Hz), 3.45 (2H, s), 3.78-3.94 (2H, m), 4.72 (2H, s), 6.11 (1H, br s), 8.72 (1H, s), 9.34 (1H, s).

LC / MS [Condition 1]: retention time 3.52 minutes; m / z 392.9 [M + H] ⁺ , 336.8 [M-isobutene + H] ⁺ (ESI positive ion mode), m / z 390.9 [M-H ] ^- (ESI negative ion mode)

参考例４４４−３
３−（｛５−［４−（４−フルオロベンゾイル）ピペリジン−１−カルボニル］ピラジン−２−イル］メチル｝−２−オキソ−１−オキサ−３，８−ジアザスピロ［４．５］デカン−８−カルボン酸ｔ−ブチルの製造
（１ｒ，４ｒ）−４−｛［８−（ｔ−ブトキシカルボニル）−２−オキソ−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル］メチル｝シクロヘキサンカルボン酸の代わりに、参考例４４４−２で得られた、５−｛［８−（ｔ−ブトキシカルボニル）−２−オキソ−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル］メチル｝ピラジン−２−カルボン酸を用いることと、テトラヒドロフルフリルアミンの代わりに、（４−フルオロフェニル）（ピペリジン−４−イル）メタノン塩酸塩（市販）用いること以外は実質的に実施例２と同様に反応を行なって、表題化合物（５４ｍｇ、収率６２％）を無色油状物として得た。

^１Ｈ−ＮＭＲ（ＣＤＣｌ_３）δ：１．４６（９Ｈ，ｓ），１．６１−１．７４（２Ｈ，ｍ），１．７６−１．９８（６Ｈ，ｍ），３．１４（１Ｈ，ｄｔ，Ｊ＝２．４，１２．３Ｈｚ），３．２２−３．３８（３Ｈ，ｍ），３．４２（２Ｈ，ｓ），３．４７−３．６１（１Ｈ，ｍ），３．７１−３．９２（２Ｈ，ｂｒ ｍ），４．０４−４．１４（２Ｈ，ｍ），４．６３（２Ｈ，ｓ），４．６９（１Ｈ，ｄ，Ｊ＝１３．５Ｈｚ），７．１７（２Ｈ，ｔ，Ｊ＝８．６Ｈｚ），７．９９（２Ｈ，ｄｄ，Ｊ＝８．６，５．３Ｈｚ），８．５５（１Ｈ，ｄ，Ｊ＝１．５Ｈｚ），８．８９（１Ｈ，ｄ，Ｊ＝１．５Ｈｚ）．

ＬＣ／ＭＳ［条件１］：保持時間４．１７分；ｍ／ｚ５８０．１［Ｍ−Ｈ］⁻、６２６．０［Ｍ＋ＨＣＯＯ］⁻（ＥＳＩ負イオンモード）

Reference Example 444-3
3-({5- [4- (4-Fluorobenzoyl) piperidin-1-carbonyl] pyrazin-2-yl] methyl} -2-oxo-1-oxa-3,8-diazaspiro [4.5] decane- Preparation of t-butyl 8-carboxylate (1r, 4r) -4-{[8- (t-butoxycarbonyl) -2-oxo-1-oxa-3,8-diazaspiro [4.5] decane-3- Yl] methyl} cyclohexanecarboxylic acid instead of 5-{[8- (t-butoxycarbonyl) -2-oxo-1-oxa-3,8-diazaspiro [4. 5] Use of decan-3-yl] methyl} pyrazine-2-carboxylic acid and (4-fluorophenyl) (piperidin-4-yl) methanone hydrochloride (commercially available) instead of tetrahydrofurfurylamine Except isosamples performing the reaction as a substantially Example 2 to give the title compound (54 mg, 62% yield) as a colorless oil.

¹ H-NMR (CDCl ₃ ) δ: 1.46 (9H, s), 1.61-1.74 (2H, m), 1.76-1.98 (6H, m), 3.14 (1H , Dt, J = 2.4, 12.3 Hz), 3.22-3.38 (3H, m), 3.42 (2H, s), 3.47-3.61 (1H, m), 3 71-3.92 (2H, br m), 4.04-4.14 (2H, m), 4.63 (2H, s), 4.69 (1H, d, J = 13.5 Hz), 7.17 (2H, t, J = 8.6 Hz), 7.99 (2H, dd, J = 8.6, 5.3 Hz), 8.55 (1H, d, J = 1.5 Hz), 8 .89 (1H, d, J = 1.5 Hz).

LC / MS [Condition 1]: Retention time 4.17 minutes; m / z 580.1 [M−H] ⁻ , 626.0 [M + HCOO] ⁻ (ESI negative ion mode)

参考例４４４−４
３−（｛５−［４−（４−フルオロベンゾイル）ピペリジン−１−カルボニル］ピラジン−２−イル｝メチル）−１−オキサ−３，８−ジアザスピロ［４．５］デカン−２−オンの製造
参考例４４４−３で得られた、３−（｛５−［４−（４−フルオロベンゾイル）ピペリジン−１−カルボニル］ピラジン−２−イル］メチル｝−２−オキソ−１−オキサ−３，８−ジアザスピロ［４．５］デカン−８−カルボン酸ｔ−ブチル（５４ｍｇ、０．０９３ｍｍｏｌ）をメタノール（２ｍＬ）に溶解し、室温にて１０質量％塩化水素メタノール溶液（０．２３ｍＬ）を加えて、４０℃にて１時間かき混ぜた。反応終了後、反応混合物を減圧下濃縮乾固して、残留物にクロロホルム（２０ｍＬ）と飽和炭酸水素ナトリウム水溶液（１０ｍＬ）を加えた。有機層を減圧下濃縮乾固して、表題化合物（４６ｍｇ、収率定量的）を無色無定形物として得た。

^１Ｈ−ＮＭＲ（ＣＤＣｌ_３）δ：１．７２（２Ｈ，ｄｄｄ，Ｊ＝１３．２，９．２，４．０Ｈｚ），１．７９−２．１３（６Ｈ，ｍ），２．８４（２Ｈ，ｄｔ，Ｊ＝１２．９，５．０Ｈｚ），３．０７（２Ｈ，ｄｄｄ，Ｊ＝１２．６，９．６，３．３Ｈｚ），３．０８−３．２０（１Ｈ，ｍ），３．３２（１Ｈ，ｄｄｄ，Ｊ＝１４．５，９．９，５．０Ｈｚ），３．４２（２Ｈ，ｓ），３．５６（１Ｈ，ｔｔ，Ｊ＝９．９，４．６Ｈｚ），４．０６−４．１４（１Ｈ，ｍ），４．６３（２Ｈ，ｓ），４．６６−４．７４（１Ｈ，ｍ），７．１７（２Ｈ，ｔ，Ｊ＝８．６Ｈｚ），７．９９（２Ｈ，ｄｄ，Ｊ＝８．９，５．６Ｈｚ），８．５６（１Ｈ，ｄ，Ｊ＝１．３Ｈｚ），８．８９（１Ｈ，ｄ，Ｊ＝１．３Ｈｚ）．

ＬＣ／ＭＳ［条件１］：保持時間１．５６分；ｍ／ｚ４８１．７［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ４７９．９［Ｍ−Ｈ］⁻、５２５．９［Ｍ＋ＨＣＯＯ］⁻（ＥＳＩ負イオンモード）

Reference Example 444-4
3-({5- [4- (4-Fluorobenzoyl) piperidin-1-carbonyl] pyrazin-2-yl} methyl) -1-oxa-3,8-diazaspiro [4.5] decan-2-one 3-({5- [4- (4-Fluorobenzoyl) piperidin-1-carbonyl] pyrazin-2-yl] methyl} -2-oxo-1-oxa-3 obtained in Production Reference Example 444-3 , 8-diazaspiro [4.5] decane-8-carboxylate t-butyl (54 mg, 0.093 mmol) was dissolved in methanol (2 mL), and a 10 mass% hydrogen chloride methanol solution (0.23 mL) was added at room temperature. In addition, the mixture was stirred for 1 hour at 40 ° C. After completion of the reaction, the reaction mixture was concentrated to dryness under reduced pressure, and chloroform (20 mL) and saturated aqueous sodium hydrogen carbonate solution (10 mL) were added to the residue. The organic layer concentrated to dryness under reduced pressure to give the title compound (46 mg, yield quantitative) as a colorless amorphous substance.

¹ H-NMR (CDCl ₃ ) δ: 1.72 (2H, ddd, J = 13.2, 9.2, 4.0 Hz), 1.79-2.13 (6H, m), 2.84 ( 2H, dt, J = 12.9, 5.0 Hz), 3.07 (2H, ddd, J = 12.6, 9.6, 3.3 Hz), 3.08-3.20 (1H, m) 3.32 (1H, ddd, J = 14.5, 9.9, 5.0 Hz), 3.42 (2H, s), 3.56 (1H, tt, J = 9.9, 4.6 Hz) ), 4.06-4.14 (1H, m), 4.63 (2H, s), 4.66-4.74 (1H, m), 7.17 (2H, t, J = 8.6 Hz) ), 7.9 (2H, dd, J = 8.9, 5.6 Hz), 8.56 (1H, d, J = 1.3 Hz), 8.89 (1H, d, J = 1.3 Hz) .

LC / MS [Condition 1]: Retention time 1.56 minutes; m / z 481.7 [M + H] ⁺ (ESI positive ion mode), m / z 479.9 [M−H] ⁻ , 525.9 [M + HCOO] ⁻ (ESI negative ion mode)

実施例４４４
３−（｛５−［４−（４−フルオロベンゾイル）ピペリジン−１−カルボニル］ピラジン−２−イル｝メチル）−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−２−オン（化合物番号４４４）の製造

（１ｒ，４ｒ）−４−［（２−オキソ−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル）メチル］−Ｎ−［（テトラヒドロフラン−２−イル）メチル］シクロヘキサンカルボキサミド塩酸塩の代わりに、参考例４４４−４で得られた３−（｛５−［４−（４−フルオロベンゾイル）ピペリジン−１−カルボニル］ピラジン−２−イル｝メチル）−１−オキサ−３，８−ジアザスピロ［４．５］デカン−２−オンを用いることと、３−（ブロモメチル）ピリジン臭化水素酸塩の代わりに、１−（ブロモメチル）−４−（トリフルオロメチル）ベンゼン（市販）を用いること以外は実質的に実施例４と同様に反応を行なって、表題化合物（７．６ｍｇ、収率２４％）を淡赤色粉末として得た。

^１Ｈ−ＮＭＲ（ＣＤＣｌ_３）δ：１．７３−２．１１（８Ｈ，ｍ），２．４１−２．６８（４Ｈ，ｂｒ ｍ），３．１４（１Ｈ，ｄｔ，Ｊ＝３．０，１２．８Ｈｚ），３．３２（１Ｈ，ｔｔ，Ｊ＝４．９，８．９Ｈｚ），３．４１（２Ｈ，ｓ），３．４８−３．６４（１Ｈ，ｍ），３．５７（２Ｈ，ｓ），４．０９（１Ｈ，ｄ，Ｊ＝１２．８Ｈｚ），４．６３（２Ｈ，ｓ），４．６９（１Ｈ，ｄ，Ｊ＝１３．９Ｈｚ），７．１７（２Ｈ，ｔ，Ｊ＝８．８Ｈｚ），７．４４（２Ｈ，ｄ，Ｊ＝７．９Ｈｚ），７．５７（２Ｈ，ｄ，Ｊ＝７．９Ｈｚ），７．９９（２Ｈ，ｄｄ，Ｊ＝８．８，５．４Ｈｚ），８．５５（１Ｈ，ｄ，Ｊ＝１．０Ｈｚ），８．８８（１Ｈ，ｄ，Ｊ＝１．０Ｈｚ）．

ＬＣ／ＭＳ［条件１］：保持時間３．３２分；ｍ／ｚ６３９．８［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ６３７．９［Ｍ−Ｈ］⁻、６８３．９［Ｍ＋ＨＣＯＯ］⁻（ＥＳＩ負イオンモード）

Example 444
3-({5- [4- (4-Fluorobenzoyl) piperidin-1-carbonyl] pyrazin-2-yl} methyl) -8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8 -Preparation of diazaspiro [4.5] decan-2-one (Compound No. 444)

(1r, 4r) -4-[(2-oxo-1-oxa-3,8-diazaspiro [4.5] decan-3-yl) methyl] -N-[(tetrahydrofuran-2-yl) methyl] cyclohexane Instead of carboxamide hydrochloride, 3-({5- [4- (4-fluorobenzoyl) piperidin-1-carbonyl] pyrazin-2-yl} methyl) -1-oxa- obtained in Reference Example 444-4 Using 3,8-diazaspiro [4.5] decan-2-one and instead of 3- (bromomethyl) pyridine hydrobromide, 1- (bromomethyl) -4- (trifluoromethyl) benzene ( The reaction was carried out in substantially the same manner as in Example 4 except that (commercially available) was used to give the title compound (7.6 mg, yield 24%) as a pale red powder.

¹ H-NMR (CDCl ₃ ) δ: 1.73-1.11 (8H, m), 2.41-2.68 (4H, br m), 3.14 (1H, dt, J = 3.0 , 12.8 Hz), 3.32 (1 H, tt, J = 4.9, 8.9 Hz), 3.41 (2 H, s), 3.48-3.64 (1 H, m), 3.57 (2H, s), 4.09 (1H, d, J = 12.8 Hz), 4.63 (2H, s), 4.69 (1H, d, J = 13.9 Hz), 7.17 (2H , T, J = 8.8 Hz), 7.44 (2H, d, J = 7.9 Hz), 7.57 (2H, d, J = 7.9 Hz), 7.9 (2H, dd, J = 8.8, 5.4 Hz), 8.55 (1H, d, J = 1.0 Hz), 8.88 (1H, d, J = 1.0 Hz).

LC / MS [Condition 1]: Retention time 3.32 minutes; m / z 639.8 [M + H] ⁺ (ESI positive ion mode), m / z 637.9 [M−H] ⁻ , 683.9 [M + HCOO] ⁻ (ESI negative ion mode)

実施例４４５
３，５−ジフルオロ−４−｛［３−（｛５−［４−（４−フルオロベンゾイル）ピペリジン−１−カルボニル］ピラジン−２−イル｝メチル）−２−オキソ−１−オキサ−３，８−ジアザスピロ［４．５］デカン−８−イル］メチル｝ベンゾニトリル（化合物番号４４５）の製造
３−｛［（１ｒ，４ｒ）−４−（４−ベンゾイルピペリジン−１−カルボニル）シクロヘキシル］メチル｝−１−オキサ−３，８−ジアザスピロ［４．５］デカン−２−オン塩酸塩の代わりに、参考例４４４−４で得られた３−（｛５−［４−（４−フルオロベンゾイル）ピペリジン−１−カルボニル］ピラジン−２−イル｝メチル）−１−オキサ−３，８−ジアザスピロ［４．５］デカン−２−オンを用いることと、６−（トリフルオロメチル）ニコチンアルデヒドの代わりに、３，５−ジフルオロ−４−ホルミルベンゾニトリル（市販）を用いること以外は実質的に実施例３８４と同様に反応を行なって、表題化合物（１４ｍｇ、収率５６％）を白色粉末として得た。

^１Ｈ−ＮＭＲ（ＣＤＣｌ_３）δ：１．７０−２．１１（８Ｈ，ｍ），２．５３−２．７１（４Ｈ，ｂｒ ｍ），３．１３（１Ｈ，ｔｄ，Ｊ＝１２．３，３．３Ｈｚ），３．２４−３．３５（１Ｈ，ｍ），３．３７（２Ｈ，ｓ），３．５５（１Ｈ，ｔｔ，Ｊ＝９．２，４．６Ｈｚ），３．７４（２Ｈ，ｓ），４．０９（１Ｈ，ｄ，Ｊ＝１４．５Ｈｚ），４．６１（２Ｈ，ｓ），４．６９（１Ｈ，ｄ，Ｊ＝１３．５Ｈｚ），７．１７（２Ｈ，ｔ，Ｊ＝８．８Ｈｚ），７．２２（２Ｈ，ｄ，Ｊ＝５．９Ｈｚ），７．９９（２Ｈ，ｄｄ，Ｊ＝８．８，５．４Ｈｚ），８．５４（１Ｈ，ｄ，Ｊ＝１．３Ｈｚ），８．８８（１Ｈ，ｄ，Ｊ＝１．３Ｈｚ）．

ＬＣ／ＭＳ［条件１］：保持時間３．１０分；ｍ／ｚ６３２．８［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ６３０．９［Ｍ−Ｈ］⁻、６７６．９［Ｍ＋ＨＣＯＯ］⁻（ＥＳＩ負イオンモード）

Example 445
3,5-difluoro-4-{[3-({5- [4- (4-fluorobenzoyl) piperidin-1-carbonyl] pyrazin-2-yl} methyl) -2-oxo-1-oxa-3, Preparation of 8-diazaspiro [4.5] decan-8-yl] methyl} benzonitrile (Compound No. 445) 3-{[(1r, 4r) -4- (4-benzoylpiperidine-1-carbonyl) cyclohexyl] methyl } In place of 1-oxa-3,8-diazaspiro [4.5] decan-2-one hydrochloride, 3-({5- [4- (4-fluorobenzoyl) obtained in Reference Example 444-4 was used. ) Piperidin-1-carbonyl] pyrazin-2-yl} methyl) -1-oxa-3,8-diazaspiro [4.5] decan-2-one and 6- (trifluoromethyl) nicotine alde The reaction was conducted in substantially the same manner as in Example 384, except that 3,5-difluoro-4-formylbenzonitrile (commercially available) was used instead of 3, and the title compound (14 mg, yield 56%) was white. Obtained as a powder.

¹ H-NMR (CDCl ₃ ) δ: 1.70-2.11 (8H, m), 2.53-2.71 (4H, br m), 3.13 (1H, td, J = 12.3) , 3.3 Hz), 3.24-3.35 (1H, m), 3.37 (2H, s), 3.55 (1H, tt, J = 9.2, 4.6 Hz), 3.74. (2H, s), 4.09 (1H, d, J = 14.5 Hz), 4.61 (2H, s), 4.69 (1H, d, J = 13.5 Hz), 7.17 (2H , T, J = 8.8 Hz), 7.22 (2H, d, J = 5.9 Hz), 7.99 (2H, dd, J = 8.8, 5.4 Hz), 8.54 (1H, d, J = 1.3 Hz), 8.88 (1H, d, J = 1.3 Hz).

LC / MS [Condition 1]: Retention time 3.10 minutes; m / z 632.8 [M + H] ⁺ (ESI positive ion mode), m / z 630.9 [M−H] ⁻ , 676.9 [M + HCOO] ⁻ (ESI negative ion mode)

実施例４４６
３−（｛５−［４−（４−シアノフェニルアミノ）ピペリジン−１−カルボニル］ピラジン−２−イル｝メチル）−２−オキソ−１−オキサ−３，８−ジアザスピロ［４．５］デカン−８−カルボン酸ｔ−ブチル（化合物番号４４６）の製造

（４−フルオロフェニル）（ピペリジン−４−イル）メタノン塩酸塩の代わりに、参考例４４１−２で得られた４−（ピペリジン−４−イルアミノ）ベンゾニトリル２塩酸塩とトリエチルアミンを用いること以外は実質的に参考例４４４−３と同様に反応を行なって、表題化合物（７６ｍｇ、収率４４％）を無色無定形物として得た。また、副生成物として、３−［（５−カルバモイルピラジン−２−イル）メチル］−２−オキソ−１−オキサ−３，８−ジアザスピロ［４．５］デカン−８−カルボン酸ｔ−ブチル（４３ｍｇ、収率３７％）を白色粉末として得た。

３−（｛５−［４−（４−シアノフェニルアミノ）ピペリジン−１−カルボニル］ピラジン−２−イル｝メチル）−２−オキソ−１−オキサ−３，８−ジアザスピロ［４．５］デカン−８−カルボン酸ｔ−ブチル（化合物番号４４６）のデータ

^１Ｈ−ＮＭＲ（ＣＤＣｌ_３）δ：１．４６（９Ｈ，ｓ），１．５７（２Ｈ，ｄｑ，Ｊ＝４．０，１３．５Ｈｚ），１．６１−１．７６（４Ｈ，ｍ），１．９３（２Ｈ，ｄ，Ｊ＝１３．５Ｈｚ），２．１０（１Ｈ，ｄ，Ｊ＝１３．９Ｈｚ），２．２１（１Ｈ，ｄ，Ｊ＝１１．１Ｈｚ），３．１２（１Ｈ，ｄｔ，Ｊ＝２．５，１２．６Ｈｚ），３．２９（３Ｈ，ｔ，Ｊ＝１１．３Ｈｚ），３．４３（２Ｈ，ｓ），３．５６−３．７２（２Ｈ，ｍ），３．８３（２Ｈ，ｄ，Ｊ＝１２．７Ｈｚ），４．０５（１Ｈ，ｄ，Ｊ＝１３．１Ｈｚ），４．２６（１Ｈ，ｄ，Ｊ＝７．８Ｈｚ），４．６３（２Ｈ，ｓ），４．６５（１Ｈ，ｄ，Ｊ＝１１．１Ｈｚ），６．５８（２Ｈ，ｄ，Ｊ＝８．６Ｈｚ），７．４３（２Ｈ，ｄ，Ｊ＝８．６Ｈｚ），８．５５（１Ｈ，ｄ，Ｊ＝１．６Ｈｚ），８．８９（１Ｈ，ｄ，Ｊ＝１．６Ｈｚ）．

ＬＣ／ＭＳ［条件１］：保持時間４．０５分；ｍ／ｚ５７５．９［Ｍ＋Ｈ］^＋、４７５．７［Ｍ−ｉｓｏｂｕｔｅｎｅ＋Ｈ］^＋、４３１．９［Ｍ−ｉｓｏｂｕｔｅｎｅ−ＣＯ２＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ５７３．９［Ｍ−Ｈ］⁻、６１９．９［Ｍ＋ＨＣＯＯ］⁻（ＥＳＩ負イオンモード）

３−［（５−カルバモイルピラジン−２−イル）メチル］−２−オキソ−１−オキサ−３，８−ジアザスピロ［４．５］デカン−８−カルボン酸ｔ−ブチル（副生成物）のデータ

^１Ｈ−ＮＭＲ（ＣＤＣｌ_３）δ：１．４６（９Ｈ，ｓ），１．６２−１．７４（２Ｈ，ｍ），１．９２（２Ｈ，ｄ，Ｊ＝１２．３Ｈｚ），３．３０（２Ｈ，ｔ，Ｊ＝１１．５Ｈｚ），３．４２（２Ｈ，ｂｒ ｓ），３．８３（２Ｈ，ｄ，Ｊ＝１３．１Ｈｚ），４．６７（２Ｈ，ｓ），５．７２（１Ｈ，ｂｒ ｓ），７．６０（１Ｈ，ｂｒ ｓ），８．５８（１Ｈ，ｓ），９．３４（１Ｈ，ｓ）．

ＬＣ／ＭＳ［条件１］：保持時間３．４１分；ｍ／ｚ３３５．９［Ｍ−ｉｓｏｂｕｔｅｎｅ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ３９０．１［Ｍ−Ｈ］⁻（ＥＳＩ負イオンモード）

Example 446
3-({5- [4- (4-Cyanophenylamino) piperidin-1-carbonyl] pyrazin-2-yl} methyl) -2-oxo-1-oxa-3,8-diazaspiro [4.5] decane Production of t-butyl 8-carboxylate (Compound No. 446)

Other than using 4- (piperidin-4-ylamino) benzonitrile dihydrochloride obtained in Reference Example 441-2 and triethylamine instead of (4-fluorophenyl) (piperidin-4-yl) methanone hydrochloride The reaction was carried out substantially in the same manner as in Reference Example 444-3 to give the title compound (76 mg, yield 44%) as a colorless amorphous product. In addition, as a by-product, t-butyl 3-[(5-carbamoylpyrazin-2-yl) methyl] -2-oxo-1-oxa-3,8-diazaspiro [4.5] decane-8-carboxylate (43 mg, 37% yield) was obtained as a white powder.

3-({5- [4- (4-Cyanophenylamino) piperidin-1-carbonyl] pyrazin-2-yl} methyl) -2-oxo-1-oxa-3,8-diazaspiro [4.5] decane Data of t-butyl-8-carboxylate (Compound No. 446)

¹ H-NMR (CDCl ₃ ) δ: 1.46 (9H, s), 1.57 (2H, dq, J = 4.0, 13.5 Hz), 1.61-1.76 (4H, m) 1.93 (2H, d, J = 13.5 Hz), 2.10 (1 H, d, J = 13.9 Hz), 2.21 (1 H, d, J = 11.1 Hz), 3.12 ( 1H, dt, J = 2.5, 12.6 Hz), 3.29 (3H, t, J = 11.3 Hz), 3.43 (2H, s), 3.56-3.72 (2H, m ), 3.83 (2H, d, J = 12.7 Hz), 4.05 (1H, d, J = 13.1 Hz), 4.26 (1H, d, J = 7.8 Hz), 4.63 (2H, s), 4.65 (1H, d, J = 11.1 Hz), 6.58 (2H, d, J = 8.6 Hz), 7.43 (2H, d, J = 8.6 Hz) , 8.55 ( H, d, J = 1.6Hz), 8.89 (1H, d, J = 1.6Hz).

LC / MS [Condition 1]: Retention time 4.05 min; m / z 575.9 [M + H] ⁺ , 475.7 [M-isobutene + H] ⁺ , 431.9 [M-isobutene-CO2 + H] ⁺ (ESI positive ion Mode), m / z 573.9 [M−H] ⁻ , 619.9 [M + HCOO] ⁻ (ESI negative ion mode)

Data for t-butyl 3-[(5-carbamoylpyrazin-2-yl) methyl] -2-oxo-1-oxa-3,8-diazaspiro [4.5] decane-8-carboxylate (byproduct)

¹ H-NMR (CDCl ₃ ) δ: 1.46 (9H, s), 1.62-1.74 (2H, m), 1.92 (2H, d, J = 12.3 Hz), 3.30 (2H, t, J = 11.5 Hz), 3.42 (2H, br s), 3.83 (2H, d, J = 13.1 Hz), 4.67 (2H, s), 5.72 ( 1H, br s), 7.60 (1H, br s), 8.58 (1H, s), 9.34 (1H, s).

LC / MS [Condition 1]: Retention time 3.41 minutes; m / z 335.9 [M-isobutene + H] ⁺ (ESI positive ion mode), m / z 390.1 [M−H] ⁻ (ESI negative ion mode)

参考例４４７
４−（１−｛５−［（２−オキソ−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル）メチル］ピラジン−２−カルボニル｝ピペリジン−４−イルアミノ）ベンゾニトリルの製造
実施例４４６で得られた、３−（｛５−［４−（４−シアノフェニルアミノ）ピペリジン−１−カルボニル］ピラジン−２−イル｝メチル）−２−オキソ−１−オキサ−３，８−ジアザスピロ［４．５］デカン−８−カルボン酸ｔ−ブチル（７５ｍｇ、０．１３ｍｍｏｌ）をメタノール（２ｍＬ）に溶解し、室温にて１０質量％塩化水素メタノール溶液（０．３２ｍＬ）を加えて、４０℃にて１時間かき混ぜた。反応終了後、反応混合物を減圧下濃縮乾固して、残留物にクロロホルム（２０ｍＬ）と飽和炭酸水素ナトリウム水溶液（１０ｍＬ）を加えた。有機層を減圧下濃縮乾固して、表題化合物（６０ｍｇ、収率９８％）を無色無定形物として得た。

^１Ｈ−ＮＭＲ（ＣＤＣｌ_３）δ：１．４８−１．７９（４Ｈ，ｍ），１．９２（２Ｈ，ｄｔ，Ｊ＝１３．５，３．６Ｈｚ），２．１０（１Ｈ，ｄ，Ｊ＝１３．９Ｈｚ），２．２１（１Ｈ，ｄ，Ｊ＝１３．１Ｈｚ），２．８４（２Ｈ，ｄｔ，Ｊ＝１３．１，４．５Ｈｚ），２．９９−３．１９（３Ｈ，ｍ），３．２９（１Ｈ，ｄｔ，Ｊ＝２．９，１２．９Ｈｚ），３．４２（２Ｈ，ｓ），３．５６−３．７２（１Ｈ，ｍ），４．０５（１Ｈ，ｄ，Ｊ＝１２．３Ｈｚ），４．１９（１Ｈ，ｄ，Ｊ＝７．８Ｈｚ），４．６３−４．７２（１Ｈ，ｍ），４．６３（２Ｈ，ｓ），６．５８（２Ｈ，ｄ，Ｊ＝９．０Ｈｚ），７．４３（２Ｈ，ｄ，Ｊ＝９．０Ｈｚ），８．５５（１Ｈ，ｄ，Ｊ＝１．６Ｈｚ），８．８９（１Ｈ，ｄ，Ｊ＝１．６Ｈｚ）．

ＬＣ／ＭＳ［条件１］：保持時間１．０４分；ｍ／ｚ４７５．８［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ４７３．９［Ｍ−Ｈ］⁻、５２０．０［Ｍ＋ＨＣＯＯ］⁻（ＥＳＩ負イオンモード）

Reference Example 447
4- (1- {5-[(2-oxo-1-oxa-3,8-diazaspiro [4.5] decan-3-yl) methyl] pyrazin-2-carbonyl} piperidin-4-ylamino) benzonitrile obtained in example 446, 3 - ({5- [4- (4-cyanophenyl) piperidine-1-carbonyl] pyrazin-2-yl} methyl) -2-oxo-1-oxa -3 , 8-diazaspiro [4.5] decane-8-carboxylate t-butyl (75 mg, 0.13 mmol) was dissolved in methanol (2 mL), and a 10 mass% hydrogen chloride methanol solution (0.32 mL) was added at room temperature. In addition, the mixture was stirred at 40 ° C. for 1 hour. After completion of the reaction, the reaction mixture was concentrated to dryness under reduced pressure, and chloroform (20 mL) and saturated aqueous sodium hydrogen carbonate solution (10 mL) were added to the residue. The organic layer was concentrated to dryness under reduced pressure to give the title compound (60 mg, 98% yield) as a colorless amorphous product.

¹ H-NMR (CDCl ₃ ) δ: 1.48-1.79 (4H, m), 1.92 (2H, dt, J = 13.5, 3.6 Hz), 2.10 (1H, d, J = 13.9 Hz), 2.21 (1H, d, J = 13.1 Hz), 2.84 (2H, dt, J = 13.1, 4.5 Hz), 2.99-3.19 (3H M), 3.29 (1H, dt, J = 2.9, 12.9 Hz), 3.42 (2H, s), 3.56-3.72 (1H, m), 4.05 (1H , D, J = 12.3 Hz), 4.19 (1H, d, J = 7.8 Hz), 4.63-4.72 (1H, m), 4.63 (2H, s), 6.58. (2H, d, J = 9.0 Hz), 7.43 (2H, d, J = 9.0 Hz), 8.55 (1H, d, J = 1.6 Hz), 8.89 (1H, d, J = 1.6 Hz).

LC / MS [Condition 1]: Retention time 1.04 minutes; m / z 475.8 [M + H] ⁺ (ESI positive ion mode), m / z 473.9 [M−H] ⁻ , 520.0 [M + HCOO] ⁻ (ESI negative ion mode)

実施例４４７
４−｛［３−（｛５−［４−（４−シアノフェニルアミノ）ピペリジン−１−カルボニル］ピラジン−２−イル｝メチル）−２−オキソ−１−オキサ−３，８−ジアザスピロ［４．５］デカン−８−イル］メチル｝−３，５−ジフルオロ−ベンゾニトリル（化合物番号４４７）の製造
３−（｛５−［４−（４−フルオロベンゾイル）ピペリジン−１−カルボニル］ピラジン−２−イル｝メチル）−１−オキサ−３，８−ジアザスピロ［４．５］デカン−２−オンの代わりに、参考例４４７で得られた４−（１−｛５−［（２−オキソ−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル）メチル］ピラジン−２−カルボニル｝ピペリジン−４−イルアミノ）ベンゾニトリルを用いること以外は実質的に実施例４４５と同様に反応を行なって、表題化合物（１４ｍｇ、収率４５％）を無色無定形物として得た。

^１Ｈ−ＮＭＲ（ＣＤＣｌ_３）δ：１．５６（２Ｈ，ｄｑ，Ｊ＝４．１，１２．１Ｈｚ），１．７０−１．８５（２Ｈ，ｍ），１．９６（２Ｈ，ｄ，Ｊ＝１３．１Ｈｚ），２．０５−２．１５（１Ｈ，ｍ），２．２２（１Ｈ，ｄ，Ｊ＝１１．５Ｈｚ），２．５１−２．７２（４Ｈ，ｂｒ ｍ），３．１２（１Ｈ，ｔｄ，Ｊ＝１２．５，２．９Ｈｚ），３．２９（１Ｈ，ｔｄ，Ｊ＝１２．９，２．９Ｈｚ），３．３７（２Ｈ，ｓ），３．５６−３．７１（１Ｈ，ｍ），３．７４（２Ｈ，ｓ），４．０４（１Ｈ，ｄ，Ｊ＝１３．５Ｈｚ），４．１９（１Ｈ，ｄ，Ｊ＝７．４Ｈｚ），４．６１（２Ｈ，ｓ），４．６５（１Ｈ，ｄ，Ｊ＝１２．３Ｈｚ），６．５８（２Ｈ，ｄ，Ｊ＝９．０Ｈｚ），７．２３（２Ｈ，ｄ，Ｊ＝６．１Ｈｚ），７．４３（２Ｈ，ｄ，Ｊ＝９．０Ｈｚ），８．５３（１Ｈ，ｄ，Ｊ＝１．５Ｈｚ），８．８８（１Ｈ，ｄ，Ｊ＝１．５Ｈｚ）．


ＬＣ／ＭＳ［条件１］：保持時間３．００分；ｍ／ｚ６２６．９［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ６２４．７［Ｍ−Ｈ］⁻、６７１．０［Ｍ＋ＨＣＯＯ］⁻（ＥＳＩ負イオンモード）

Example 447
4-{[3-({5- [4- (4-Cyanophenylamino) piperidin-1-carbonyl] pyrazin-2-yl} methyl) -2-oxo-1-oxa-3,8-diazaspiro [4 .5] Preparation of decan-8-yl] methyl} -3,5-difluoro-benzonitrile (Compound No. 447) 3-({5- [4- (4-Fluorobenzoyl) piperidine-1-carbonyl] pyrazine- 4- (1- {5-[(2-oxo) obtained in Reference Example 447 instead of 2-yl} methyl) -1-oxa-3,8-diazaspiro [4.5] decan-2-one -1-oxa-3,8-diazaspiro [4.5] decan-3-yl) methyl] pyrazin-2-carbonyl} piperidin-4-ylamino) benzonitrile, substantially the same as Example 445, but using benzonitrile. React to We conducted to give the title compound (14 mg, 45% yield) as a colorless amorphous substance.

¹ H-NMR (CDCl ₃ ) δ: 1.56 (2H, dq, J = 4.1, 12.1 Hz), 1.70-1.85 (2H, m), 1.96 (2H, d, J = 13.1 Hz), 2.05-2.15 (1 H, m), 2.22 (1 H, d, J = 11.5 Hz), 2.51-2.72 (4 H, br m), 3 .12 (1H, td, J = 12.5, 2.9 Hz), 3.29 (1H, td, J = 12.9, 2.9 Hz), 3.37 (2H, s), 3.56- 3.71 (1H, m), 3.74 (2H, s), 4.04 (1H, d, J = 13.5 Hz), 4.19 (1H, d, J = 7.4 Hz), 4. 61 (2H, s), 4.65 (1H, d, J = 12.3 Hz), 6.58 (2H, d, J = 9.0 Hz), 7.23 (2H, d, J = 6.1 Hz) ), 7.43 (2 , D, J = 9.0Hz), 8.53 (1H, d, J = 1.5Hz), 8.88 (1H, d, J = 1.5Hz).


LC / MS [Condition 1]: Retention time 3.00 minutes; m / z 626.9 [M + H] ⁺ (ESI positive ion mode), m / z 624.7 [M−H] ⁻ , 671.0 [M + HCOO] ⁻ (ESI negative ion mode)

実施例４４８
４−｛［３−（｛（１ｒ，４ｒ）−４−［４−（４−シアノフェニルアミノ）ピペリジン−１−カルボニル］シクロヘキシル｝メチル）−２−オキソ−１−オキサ−３，８−ジアザスピロ［４．５］デカン−８−イル］メチル｝−３，５−ジフルオロベンゾニトリル（化合物番号４４８）の製造

６−（ピペリジン−４−イルオキシ）ニコチノニトリル塩酸塩の代わりに参考例４４１−２で得られた４−（ピペリジン−４−イルアミノ）ベンゾニトリル二塩酸塩を用いること以外は実質的に実施例４０２と同様に反応を行って、表題化合物（３３ｍｇ、収率７８％）を白色粉末として得た。

^１Ｈ−ＮＭＲ（３００ＭＨｚ、ＣＤＣｌ_３）δ：１．０３（２Ｈ，ｑ，Ｊ＝１３．１Ｈｚ），１．２４−１．６７（５Ｈ，ｂｒ ｍ），１．６６−１．８４（６Ｈ，ｂｒ ｍ），１．８３−２．０１（２Ｈ，ｂｒ ｍ），２．０１−２．２３（２Ｈ，ｂｒ ｍ），２．４５（１Ｈ，ｔ，Ｊ＝１１．９Ｈｚ），２．５２−２．７３（４Ｈ，ｂｒ ｍ），２．８３（１Ｈ，ｔ，Ｊ＝１１．７Ｈｚ），３．０５−３．２５（１Ｈ，ｂｒ ｍ），３．０８（２Ｈ，ｄ，Ｊ＝６．５Ｈｚ），３．２２（２Ｈ，ｓ），３．４７−３．６３（１Ｈ，ｂｒ ｍ），３．７５（２Ｈ，ｓ），３．８３−３．９７（１Ｈ，ｂｒ ｍ），４．０７（１Ｈ，ｄ，Ｊ＝７．４Ｈｚ），４．４６−４．６０（１Ｈ，ｂｒ ｍ），６．５５（２Ｈ，ｄ，Ｊ＝８．６Ｈｚ），７．２２（２Ｈ，ｄ，Ｊ＝６．１Ｈｚ），７．４２（２Ｈ，ｄ，Ｊ＝９．０Ｈｚ）．

ＬＣ／ＭＳ［条件１］：保持時間３．２０分；ｍ／ｚ６３１．１［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ６２９．２［Ｍ−Ｈ］^―、６７５．２［Ｍ＋ＨＣＯＯ］^―（ＥＳＩ負イオンモード）

Example 448
4-{[3-({(1r, 4r) -4- [4- (4-cyanophenylamino) piperidine-1-carbonyl] cyclohexyl} methyl) -2-oxo-1-oxa-3,8-diazaspiro Production of [4.5] decan-8-yl] methyl} -3,5-difluorobenzonitrile (Compound No. 448)

Examples substantially except that 4- (piperidin-4-ylamino) benzonitrile dihydrochloride obtained in Reference Example 441-2 was used instead of 6- (piperidin-4-yloxy) nicotinonitrile hydrochloride. The reaction was conducted in the same manner as in 402 to give the title compound (33 mg, yield 78%) as a white powder.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.03 (2H, q, J = 13.1 Hz), 1.24 to 1.67 (5H, br m), 1.66 to 1.84 (6H) , Br m), 1.83 to 2.01 (2H, br m), 2.01-2.23 (2H, br m), 2.45 (1 H, t, J = 11.9 Hz), 2. 52-2.73 (4H, br m), 2.83 (1H, t, J = 11.7 Hz), 3.05-3.25 (1H, br m), 3.08 (2H, d, J = 6.5 Hz), 3.22 (2H, s), 3.47-3.63 (1H, br m), 3.75 (2H, s), 3.83-3.97 (1 H, br m ), 4.07 (1H, d, J = 7.4 Hz), 4.46-4.60 (1H, br m), 6.55 (2H, d, J = 8.6 Hz), 7.22 ( 2 , D, J = 6.1Hz), 7.42 (2H, d, J = 9.0Hz).

LC / MS [Condition 1]: Retention time 3.20 minutes; m / z 631.1 [M + H] ⁺ (ESI positive ion mode), m / z 629.2 [M−H] ⁻ , 675.2 [M + HCOO] ⁻ (ESI negative ion mode)

実施例４４９
４−［２−（３−｛［（１ｒ，４ｒ）−４−（４−ベンゾイルピペリジン−１−カルボニル）シクロヘキシル］メチル｝−２−オキソ−１−オキサ−３，８−ジアザスピロ［４．５］デカン−８−イル）エチル］ベンゾニトリル（化合物番号４４９）の製造

１−（ブロモメチル）−２，４−ビス（トリフルオロメチル）ベンゼンの代わりに、参考例３９７−１で得られた、メタンスルホン酸４−シアノフェネチルを用いること以外は実質的に実施例２５５と同様に反応を行なって、表題化合物（３．５ｍｇ、収率７．０％）を無色無定形物として得た。

^１Ｈ−ＮＭＲ（ＣＤＣｌ_３）δ：１．０６（２Ｈ，ｑ，Ｊ＝１３．１Ｈｚ），１．４９−１．７１（４Ｈ，ｍ），１．７１−１．８７（７Ｈ，ｍ），１．８７−２．０２（４Ｈ，ｍ），２．４７（１Ｈ，ｔｔ，Ｊ＝１１．９，３．３Ｈｚ），２．５３−２．７３（６Ｈ，ｍ），２．７４−２．９０（３Ｈ，ｍ），３．１１（２Ｈ，ｄ，Ｊ＝７．４Ｈｚ），３．２１（１Ｈ，ｂｒ ｔ，Ｊ＝１２．３Ｈｚ），３．２６（２Ｈ，ｓ），３．５２（１Ｈ，ｔｔ，Ｊ＝１０．６，３．７Ｈｚ），３．９８（１Ｈ，ｂｒ ｄ，Ｊ＝１３．５Ｈｚ），４．６０（１Ｈ，ｂｒ ｄ，Ｊ＝１３．５Ｈｚ），７．３１（２Ｈ，ｄ，Ｊ＝７．８Ｈｚ），７．４９（２Ｈ，ｔ，Ｊ＝７．４Ｈｚ），７．５７（２Ｈ，ｄ，Ｊ＝７．８Ｈｚ），７．５９（１Ｈ，ｔ，Ｊ＝７．４Ｈｚ），７．９４（２Ｈ，ｄ，Ｊ＝７．４Ｈｚ）．

ＬＣ／ＭＳ［条件１］：保持時間３．１８分；ｍ／ｚ５９７．０［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ６４１．２［Ｍ＋ＨＣＯＯ］⁻（ＥＳＩ負イオンモード）

Example 449
4- [2- (3-{[(1r, 4r) -4- (4-benzoylpiperidine-1-carbonyl) cyclohexyl] methyl} -2-oxo-1-oxa-3,8-diazaspiro [4.5 Production of decane-8-yl) ethyl] benzonitrile (Compound No. 449)

Example 255 is substantially the same as Example 255 except that 4-cyanophenethyl methanesulfonate, obtained in Reference Example 397-1, is used instead of 1- (bromomethyl) -2,4-bis (trifluoromethyl) benzene. The reaction was conducted in the same manner to obtain the title compound (3.5 mg, yield 7.0%) as a colorless amorphous product.

¹ H-NMR (CDCl ₃ ) δ: 1.06 (2H, q, J = 13.1 Hz), 1.49-1.71 (4H, m), 1.71-1.87 (7H, m) 1.87-2.02 (4H, m), 2.47 (1 H, tt, J = 11.9, 3.3 Hz), 2.53-2.73 (6H, m), 2.74- 2.90 (3H, m), 3.11 (2H, d, J = 7.4 Hz), 3.21 (1H, br t, J = 12.3 Hz), 3.26 (2H, s), 3 .52 (1H, tt, J = 10.6, 3.7 Hz), 3.98 (1H, br d, J = 13.5 Hz), 4.60 (1 H, br d, J = 13.5 Hz), 7.31 (2H, d, J = 7.8 Hz), 7.49 (2H, t, J = 7.4 Hz), 7.57 (2H, d, J = 7.8 Hz), 7.59 (1H , T, J = 7 4Hz), 7.94 (2H, d, J = 7.4Hz).

LC / MS [Condition 1]: Retention time 3.18 minutes; m / z 597.0 [M + H] ⁺ (ESI positive ion mode), m / z 641.2 [M + HCOO] ⁻ (ESI negative ion mode)

参考例４５０−１
１Ｈ−イミダゾール−１−カルボン酸（１，１，１−トリフルオロ−２−メチルプロパン−２−イル）の製造
１，１，１−トリフルオロ−２−メチルプロパン−２−オール（市販）（１．３ｇ、１０ｍｍｏｌ）をクロロホルム（１０ｍＬ）に溶解し、室温にて１，１’−カルボニルジイミダゾ−ル（３．２ｇ、２０ｍｍｏｌ）を加えた後、室温にて１日間かき混ぜた。反応終了後、水（１０ｍＬ）とクロロホルム（２０ｍＬ）を加えて、有機層を分離した。得られた有機層を無水硫酸ナトリウムで乾燥、減圧下濃縮乾固した後、表題化合物（２．７ｇ、収率定量的）を白色粉末として得た。

^１Ｈ−ＮＭＲ（ＣＤＣｌ_３）δ：１．８４（６Ｈ，ｓ），７．０８（１Ｈ，ｂｒ ｓ），７．３７（１Ｈ，ｂｒ ｓ），８．０９（１Ｈ，ｂｒ ｓ）．

ＬＣ／ＭＳ［条件１］：保持時間３．４６分；ｍ／ｚ２２２．９［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）

Reference Example 450-1
Preparation of 1H-imidazole-1-carboxylic acid (1,1,1-trifluoro-2-methylpropan-2-yl) 1,1,1-trifluoro-2-methylpropan-2-ol (commercially available) ( 1.3 g, 10 mmol) was dissolved in chloroform (10 mL), 1,1′-carbonyldiimidazole (3.2 g, 20 mmol) was added at room temperature, and the mixture was stirred at room temperature for 1 day. After completion of the reaction, water (10 mL) and chloroform (20 mL) were added, and the organic layer was separated. The obtained organic layer was dried over anhydrous sodium sulfate and concentrated to dryness under reduced pressure to obtain the title compound (2.7 g, quantitative yield) as a white powder.

¹ H-NMR (CDCl ₃ ) δ: 1.84 (6H, s), 7.08 (1H, br s), 7.37 (1H, br s), 8.09 (1H, br s).

LC / MS [Condition 1]: Retention time 3.46 minutes; m / z 222.9 [M + H] ⁺ (ESI positive ion mode)

参考例４５０−２
３−メチル−１−［（１，１，１−トリフルオロ−２−メチルプロパン−２−イルオキシ）カルボニル］−1Ｈ−イミダゾール−３−イウムヨージドの製造
参考例４５０−１で得られた、１Ｈ−イミダゾール−１−カルボン酸（１，１，１−トリフルオロ−２−メチルプロパン−２−イル）（１．１ｇ、４．８ｍｍｏｌ）をアセトニトリル（１０ｍＬ）に溶解し、室温にてヨ−ドメタン（１．２ｍＬ、１９ｍｍｏｌ）を加えた後、室温にて３日間かき混ぜた。反応終了後、減圧下濃縮乾固し、表題化合物（１．２ｇ、収率定量的）を黄色油状物として得た。

Reference Example 450-2
Production of 3-methyl-1-[(1,1,1-trifluoro-2-methylpropan-2-yloxy) carbonyl] -1H-imidazole-3-ium iodide 1H- obtained in Reference Example 450-1 Imidazole-1-carboxylic acid (1,1,1-trifluoro-2-methylpropan-2-yl) (1.1 g, 4.8 mmol) was dissolved in acetonitrile (10 mL), and iodine methane ( 1.2 mL, 19 mmol) was added, and the mixture was stirred at room temperature for 3 days. After completion of the reaction, the mixture was concentrated to dryness under reduced pressure to give the title compound (1.2 g, quantitative yield) as a yellow oil.

実施例４５０
３−｛［（１ｒ，４ｒ）−４−（４−ベンゾイルピペリジン−１−カルボニル）シクロヘキシル］メチル｝−２−オキソ−１−オキサ−３，８−ジアザスピロ［４．５］デカン−８−カルボン酸１，１，１−トリフルオロ−２−メチルプロパン−２−イル（化合物番号４５０）の製造

１−（ブロモメチル）−２，４−ビス（トリフルオロメチル）ベンゼンの代わりに、参考例４５０−２で得られた、３−メチル−１−［（１，１，１−トリフルオロ−２−メチルプロパン−２−イルオキシ）カルボニル］−１Ｈ−イミダゾール−３−イウムヨージドを用いること以外は実質的に実施例２５５と同様に反応を行なって、表題化合物（３２ｍｇ、定量的）を白色粉末として得た。

^１Ｈ−ＮＭＲ（ＣＤＣｌ_３）δ：１．０６（２Ｈ，ｑ，Ｊ＝１１．９Ｈｚ），１．４７−１．８７（１１Ｈ，ｍ），１．９３（４Ｈ，ｂｒ ｄ，Ｊ＝１３．９Ｈｚ），２．４８（１Ｈ，ｔｔ，Ｊ＝１１．９，３．３Ｈｚ），２．８２（１Ｈ，ｂｒ ｔ，Ｊ＝１２．３Ｈｚ），３．１２（２Ｈ，ｄ，Ｊ＝７．４Ｈｚ），３．１３−３．４３（３Ｈ，ｂｒ ｍ），３．２８（２Ｈ，ｓ），３．５２（１Ｈ，ｔｔ，Ｊ＝１０．６，３．３Ｈｚ），３．７５−４．０５（３Ｈ，ｂｒ ｍ），４．６０（１Ｈ，ｂｒ ｄ，Ｊ＝１３．９Ｈｚ），７．４９（２Ｈ，ｔ，Ｊ＝７．８Ｈｚ），７．５９（１Ｈ，ｔ，Ｊ＝７．４Ｈｚ），７．９５（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ）．

ＬＣ／ＭＳ［条件１］：保持時間４．４３分；ｍ／ｚ６２１．９［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ６６６．１［Ｍ＋ＨＣＯＯ］⁻（ＥＳＩ負イオンモード）

Example 450
3-{[(1r, 4r) -4- (4-Benzoylpiperidine-1-carbonyl) cyclohexyl] methyl} -2-oxo-1-oxa-3,8-diazaspiro [4.5] decane-8-carvone Preparation of acid 1,1,1-trifluoro-2-methylpropan-2-yl (compound no. 450)

Instead of 1- (bromomethyl) -2,4-bis (trifluoromethyl) benzene, 3-methyl-1-[(1,1,1-trifluoro-2-ethyl) obtained in Reference Example 450-2 was used. Methylpropan-2-yloxy) carbonyl] -1H-imidazole-3-ium iodide was used for a reaction substantially in the same manner as in Example 255 to obtain the title compound (32 mg, quantitative) as a white powder. .

¹ H-NMR (CDCl ₃ ) δ: 1.06 (2H, q, J = 11.9 Hz), 1.47-1.87 (11H, m), 1.93 (4H, br d, J = 13) .9 Hz), 2.48 (1H, tt, J = 11.9, 3.3 Hz), 2.82 (1H, br t, J = 12.3 Hz), 3.12 (2H, d, J = 7) .4Hz), 3.13-3.43 (3H, br m), 3.28 (2H, s), 3.52 (1H, tt, J = 10.6, 3.3 Hz), 3.75- 4.05 (3H, br m), 4.60 (1H, br d, J = 13.9 Hz), 7.49 (2H, t, J = 7.8 Hz), 7.59 (1H, t, J = 7.4 Hz), 7.95 (2H, d, J = 8.2 Hz).

LC / MS [Condition 1]: Retention time 4.43 minutes; m / z 621.9 [M + H] ⁺ (ESI positive ion mode), m / z 666.1 [M + HCOO] ⁻ (ESI negative ion mode)

実施例４５１
４−［（１ｒ，４ｒ）−４−（｛２−オキソ−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）シクロヘキサンカルボニル］ピペラジン−１−カルボン酸１，１，１−トリフルオロ−２−メチルプロパン−２−イル（化合物番号４５１）の製造

クロロギ酸メチルの代わりに、参考例４５０−２で得られた、３−メチル−１−［（１，１，１−トリフルオロ−２−メチルプロパン−２−イルオキシ）カルボニル］−１Ｈ−イミダゾール−３−イウムヨージドを用いること以外は実質的に実施例１４９と同様に反応を行なって、表題化合物（２８ｍｇ、収率５２％）を白色粉末として得た。

^１Ｈ−ＮＭＲ（ＣＤＣｌ_３）δ：１．０４（２Ｈ，ｑ，Ｊ＝１１．５Ｈｚ），１．５０−１．６９（３Ｈ，ｍ），１．７０（６Ｈ，ｓ），１．７２−１．８５（６Ｈ，ｍ），１．９４（２Ｈ，ｄ，Ｊ＝１３．１Ｈｚ），２．４１（１Ｈ，ｔ，Ｊ＝１１．５Ｈｚ），２．４９−２．６５（４Ｈ，ｂｒ ｍ），３．１１（２Ｈ，ｄ，Ｊ＝７．４Ｈｚ），３．２５（２Ｈ，ｓ），３．３６−３．５３（６Ｈ，ｂｒ ｍ），３．５４−３．６５（２Ｈ，ｍ），３．５７（２Ｈ，ｓ），７．４４（２Ｈ，ｄ，Ｊ＝７．８Ｈｚ），７．５７（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ）．

ＬＣ／ＭＳ［条件１］：保持時間３．３８分；ｍ／ｚ６７７．１［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ７２１．０［Ｍ＋ＨＣＯＯ］⁻（ＥＳＩ負イオンモード）

Example 451
4-[(1r, 4r) -4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} Methyl) cyclohexanecarbonyl] piperazine-1-carboxylic acid 1,1,1-trifluoro-2-methylpropan-2-yl (Compound No. 451)

3-methyl-1-[(1,1,1-trifluoro-2-methylpropan-2-yloxy) carbonyl] -1H-imidazole- obtained in Reference Example 450-2 instead of methyl chloroformate The reaction was carried out substantially in the same manner as in Example 149 except that 3-ium iodide was used to give the title compound (28 mg, yield 52%) as a white powder.

¹ H-NMR (CDCl ₃ ) δ: 1.04 (2H, q, J = 11.5 Hz), 1.50-1.69 (3H, m), 1.70 (6H, s), 1.72 -1.85 (6H, m), 1.94 (2H, d, J = 13.1 Hz), 2.41 (1 H, t, J = 11.5 Hz), 2.49-2.65 (4H, br m), 3.11 (2H, d, J = 7.4 Hz), 3.25 (2H, s), 3.36-3.53 (6H, br m), 3.54-3.65 ( 2H, m), 3.57 (2H, s), 7.44 (2H, d, J = 7.8 Hz), 7.57 (2H, d, J = 8.2 Hz).

LC / MS [Condition 1]: Retention time 3.38 minutes; m / z 677.1 [M + H] ⁺ (ESI positive ion mode), m / z 721.0 [M + HCOO] ⁻ (ESI negative ion mode)

参考例４５２−１
１Ｈ−イミダゾ−ル−１−カルボン酸（２−シアノプロパン−２−イル）の製造
１，１，１−トリフルオロ−２−メチルプロパン−２−オールの代わりに、２−ヒドロキシ−２−メチルプロパンニトリル（市販）を用いること以外は実質的に参考例４５０−１と同様に反応を行なって、表題化合物（２．０ｇ、定量的）を白色粉末として得た。

^１Ｈ−ＮＭＲ（ＣＤＣｌ_３）δ：１．９６（６Ｈ，ｓ），７．０８（１Ｈ，ｂｒ ｓ），７．４１（１Ｈ，ｂｒ ｓ），８．１２（１Ｈ，ｂｒ ｓ）．

ＬＣ／ＭＳ［条件１］：保持時間１．１８分；ｍ／ｚ１７９．９［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）

Reference Example 452-1
Preparation of 1H-imidazol-1-carboxylic acid (2-cyanopropan-2-yl) Instead of 1,1,1-trifluoro-2-methylpropan-2-ol, 2-hydroxy-2-methyl The reaction was carried out substantially in the same manner as in Reference Example 450-1, except that propanenitrile (commercially available) was used, to give the title compound (2.0 g, quantitative) as a white powder.

¹ H-NMR (CDCl ₃ ) δ: 1.96 (6H, s), 7.08 (1H, br s), 7.41 (1H, br s), 8.12 (1H, br s).

LC / MS [Condition 1]: Retention time 1.18 minutes; m / z 179.9 [M + H] ⁺ (ESI positive ion mode)

参考例４５２−２
１−［（２−シアノプロパン−２−イルオキシ）カルボニル］−３−メチル−１Ｈ−イミダゾール−３−イウムヨージドの製造
１Ｈ−イミダゾール−１−カルボン酸（１，１，１−トリフルオロ−２−メチルプロパン−２−イル）の代わりに、参考例４５２−１で得られた、１Ｈ−イミダゾ−ル−１−カルボン酸（２−シアノプロパン−２−イル）を用いること以外は実質的に参考例４５０−２と同様に反応を行なって、表題化合物（２．１ｇ、定量的）を黄色油状物として得た。

ＬＣ／ＭＳ［条件１］：保持時間０．５１分；ｍ／ｚ１９４．１ Ｍ^＋（ＥＳＩ正イオンモード）

Reference Example 452-2
Preparation of 1-[(2-cyanopropan-2-yloxy) carbonyl] -3-methyl-1H-imidazole-3-ium iodide 1H-imidazole- 1-carboxylic acid (1,1,1-trifluoro-2-methyl) Reference example substantially except that 1H-imidazol-1-carboxylic acid (2-cyanopropan-2-yl) obtained in Reference Example 452-1 was used instead of propan-2-yl) The reaction was conducted in the same manner as in 450-2 to give the title compound (2.1 g, quantitative) as a yellow oil.

LC / MS [Condition 1]: retention time 0.51 min; m / z 194.1 M ⁺ (ESI positive ion mode)

実施例４５２
３−｛［（１ｒ，４ｒ）−４−（４−ベンゾイルピペリジン−１−カルボニル）シクロヘキシル］メチル｝−２−オキソ−１−オキサ−３，８−ジアザスピロ［４．５］デカン−８−カルボン酸２−シアノプロパン−２−イル（化合物番号４５２）の製造
１−（ブロモメチル）−２，４−ビス（トリフルオロメチル）ベンゼンの代わりに、参考例４５２−２で得られた、１−［（２−シアノプロパン−２−イルオキシ）カルボニル］−３−メチル−１Ｈ−イミダゾール−３−イウムヨージドを用いること以外は実質的に実施例２５５と同様に反応を行なって、表題化合物（２８ｍｇ、収率６０％）を白色粉末として得た。

^１Ｈ−ＮＭＲ（ＣＤＣｌ_３）δ：１．０６（２Ｈ，ｑ，Ｊ＝１１．９Ｈｚ），１．４７−２．００（１３Ｈ，ｍ），１．７８（６Ｈ，ｓ），２．４８（１Ｈ，ｔｔ，Ｊ＝１１．９，３．３Ｈｚ），２．８２（１Ｈ，ｔ，Ｊ＝１１．７Ｈｚ），３．１３（２Ｈ，ｄ，Ｊ＝７．４Ｈｚ），３．２６−３．３０（４Ｈ，ｍ），３．２８（２Ｈ，ｓ），３．５２（１Ｈ，ｔｔ，Ｊ＝１０．６，３．７Ｈｚ），３．８３（１Ｈ，ｄ，Ｊ＝１０．６Ｈｚ），３．９２−４．１０（２Ｈ，ｍ），４．６０（１Ｈ，ｄ，Ｊ＝１３．１Ｈｚ），７．４９（２Ｈ，ｔ，Ｊ＝７．０Ｈｚ），７．５９（１Ｈ，ｔ，Ｊ＝７．０Ｈｚ），７．９４（２Ｈ，ｄ，Ｊ＝７．０Ｈｚ）．

ＬＣ／ＭＳ［条件１］：保持時間４．１３分；ｍ／ｚ５７９．０［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ６１２．９［Ｍ＋Ｃｌ］⁻、６２３．１［Ｍ＋ＨＣＯＯ］⁻（ＥＳＩ負イオンモード）

Example 452
3-{[(1r, 4r) -4- (4-Benzoylpiperidine-1-carbonyl) cyclohexyl] methyl} -2-oxo-1-oxa-3,8-diazaspiro [4.5] decane-8-carvone Preparation of 2-cyanopropan-2-yl acid (Compound No. 452) Instead of 1- (bromomethyl) -2,4-bis (trifluoromethyl) benzene, 1- [ The reaction was carried out in substantially the same manner as in Example 255 except that (2-cyanopropan-2-yloxy) carbonyl] -3-methyl-1H-imidazol-3-ium iodide was used, and the title compound (28 mg, yield) was obtained. 60%) was obtained as a white powder.

¹ H-NMR (CDCl ₃ ) δ: 1.06 (2H, q, J = 11.9 Hz), 1.47-2.00 (13H, m), 1.78 (6H, s), 2.48 (1H, tt, J = 11.9, 3.3 Hz), 2.82 (1H, t, J = 11.7 Hz), 3.13 (2H, d, J = 7.4 Hz), 3.26− 3.30 (4H, m), 3.28 (2H, s), 3.52 (1H, tt, J = 10.6, 3.7 Hz), 3.83 (1H, d, J = 10.6 Hz) ), 3.92-4.10 (2H, m), 4.60 (1H, d, J = 13.1 Hz), 7.49 (2H, t, J = 7.0 Hz), 7.59 (1H , T, J = 7.0 Hz), 7.94 (2H, d, J = 7.0 Hz).

LC / MS [Condition 1]: Retention time 4.13 minutes; m / z 579.0 [M + H] ⁺ (ESI positive ion mode), m / z 612.9 [M + Cl] ⁻ , 623.1 [M + HCOO] ⁻ (ESI Negative ion mode)

実施例４５３
４−［（１ｒ，４ｒ）−４−（｛２−オキソ−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）シクロヘキサンカルボニル］ピペラジン−１−カルボン酸２−シアノプロパン−２−イル（化合物番号４５３）の製造
クロロギ酸メチルの代わりに、参考例４５２−２で得られた、１−［（２−シアノプロパン−２−イルオキシ）カルボニル］−３−メチル−１Ｈ−イミダゾール−３−イウムヨージドを用いること以外は実質的に実施例１４９と同様に反応を行なって、表題化合物（１９ｍｇ、収率３９％）を白色粉末として得た。

^１Ｈ−ＮＭＲ（ＣＤＣｌ_３）δ：１．０５（２Ｈ，ｑ，Ｊ＝１１．６Ｈｚ），１．４２−１．８７（９Ｈ，ｍ），１．７９（６Ｈ，ｓ），１．９４（２Ｈ，ｄ，Ｊ＝１３．１Ｈｚ），２．４３（１Ｈ，ｔ，Ｊ＝１１．５Ｈｚ），２．４９−２．６１（４Ｈ，ｂｒ ｍ），３．１１（２Ｈ，ｄ，Ｊ＝７．４Ｈｚ），３．２６（２Ｈ，ｓ），３．３５−３．６６（８Ｈ，ｍ），３．５７（２Ｈ，ｓ），７．４４（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ），７．５７（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ）．

ＬＣ／ＭＳ［条件１］：保持時間３．１８分；ｍ／ｚ６３４．０［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ６６８．２［Ｍ＋Ｃｌ］⁻、６７８．０［Ｍ＋ＨＣＯＯ］⁻（ＥＳＩ負イオンモード）

Example 453
4-[(1r, 4r) -4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} Preparation of methyl) cyclohexanecarbonyl] piperazine-1-carboxylate 2- cyanopropan -2-yl (Compound No. 453) 1-[(2-cyano) obtained in Reference Example 452-2 instead of methyl chloroformate Propan-2-yloxy) carbonyl] -3-methyl-1H-imidazol-3-ium iodide was used to carry out the reaction in substantially the same manner as in Example 149 to give the title compound (19 mg, yield 39%). Obtained as a white powder.

¹ H-NMR (CDCl ₃ ) δ: 1.05 (2H, q, J = 11.6 Hz), 1.42-1.87 (9H, m), 1.79 (6H, s), 1.94 (2H, d, J = 13.1 Hz), 2.43 (1H, t, J = 11.5 Hz), 2.49-2.61 (4H, br m), 3.11 (2H, d, J = 7.4 Hz), 3.26 (2H, s), 3.35-3.66 (8 H, m), 3.57 (2H, s), 7.44 (2H, d, J = 8.2 Hz) ), 7.57 (2H, d, J = 8.2 Hz).

LC / MS [Condition 1]: Retention time 3.18 minutes; m / z 634.0 [M + H] ⁺ (ESI positive ion mode), m / z 668.2 [M + Cl] ⁻ , 678.0 [M + HCOO] ⁻ (ESI Negative ion mode)

参考例４５４−１
１Ｈ−イミダゾ−ル−１−カルボン酸（２，２，２−トリフルオロエチル）の製造
１，１，１−トリフルオロ−２−メチルプロパン−２−オールの代わりに、２，２，２−トリフルオロエタノ−ル（市販）を用いること以外は実質的に参考例４５０−１と同様に反応を行なって、表題化合物（２．２ｇ、定量的）を無色油状物として得た。

^１Ｈ−ＮＭＲ（ＣＤＣｌ_３）δ：４．７９（２Ｈ，ｑ，Ｊ＝７．９Ｈｚ），７．０９−７．１４（１Ｈ，ｍ），７．４４−７．４７（１Ｈ，ｍ），８．１８（１Ｈ，ｂｒ ｓ）．

ＬＣ／ＭＳ［条件１］：保持時間１．６７分；ｍ／ｚ１９４．８［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）

Reference Example 454-1
Preparation of 1H-imidazol-1-carboxylic acid (2,2,2-trifluoroethyl) In place of 1,1,1-trifluoro-2-methylpropan-2-ol, 2,2,2- The reaction was carried out in substantially the same manner as in Reference Example 450-1 except that trifluoroethanol (commercially available) was used to give the title compound (2.2 g, quantitative) as a colorless oil.

¹ H-NMR (CDCl ₃ ) δ: 4.79 (2H, q, J = 7.9 Hz), 7.09-7.14 (1H, m), 7.44-7.47 (1H, m) , 8.18 (1H, br s).

LC / MS [Condition 1]: Retention time 1.67 minutes; m / z 194.8 [M + H] ⁺ (ESI positive ion mode)

参考例４５４−２
３−メチル−１−［（２，２，２−トリフルオロエトキシ）カルボニル］−１Ｈ−イミダゾール−３−イウムヨージドの製造
１Ｈ−イミダゾール−１−カルボン酸（１，１，１−トリフルオロ−２−メチルプロパン−２−イル）の代わりに、参考例４５４−１で得られた、１Ｈ−イミダゾ−ル−１−カルボン酸（２，２，２−トリフルオロエチル）を用いること以外は実質的に参考例４５０−２と同様に反応を行なって、表題化合物（２．２ｇ、定量的）を黄色油状物として得た。

^１Ｈ−ＮＭＲ（ＣＤ_３ＯＤ）δ：４．００（３Ｈ，ｓ），４．６４（１Ｈ，ｑ，Ｊ＝７．４Ｈｚ），４．８０−５．０２（１Ｈ，ｍ），７．５６−７．５９（１Ｈ，ｍ），７．６１−７．６４（１Ｈ，ｍ），８．９６（１Ｈ，ｓ）．

ＬＣ／ＭＳ［条件１］：保持時間０．５１分；ｍ／ｚ２０８．９ Ｍ^＋（ＥＳＩ正イオンモード）

Reference Example 454-2
Preparation of 3-methyl-1-[(2,2,2-trifluoroethoxy) carbonyl] -1H-imidazole-3-ium iodide 1H-imidazole-1-carboxylic acid (1,1,1-trifluoro-2- Substantially, except that 1H-imidazole-1-carboxylic acid (2,2,2-trifluoroethyl) obtained in Reference Example 454-1 was used instead of methylpropan-2-yl). The reaction was carried out in the same manner as in Reference Example 450-2 to obtain the title compound (2.2 g, quantitative) as a yellow oil.

¹ H-NMR (CD ₃ OD) δ: 4.00 (3H, s), 4.64 (1H, q, J = 7.4 Hz), 4.80-5.02 (1H, m), 7. 56-7.59 (1H, m), 7.61-7.64 (1H, m), 8.96 (1H, s).

LC / MS [Condition 1]: Retention time 0.51 min; m / z 208.9 M ⁺ (ESI positive ion mode)

実施例４５４
４−［（１ｒ，４ｒ）−４−（｛２−オキソ−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）シクロヘキサンカルボニル］ピペラジン−１−カルボン酸２，２，２−トリフルオロエチル（化合物番号４５４）の製造
クロロギ酸メチルの代わりに、参考例４５４−２で得られた、３−メチル−１−［（２，２，２−トリフルオロエトキシ）カルボニル］−１Ｈ−イミダゾール−３−イウムヨージドを用いること以外は実質的に実施例１４９と同様に反応を行なって、表題化合物（２７ｍｇ、収率８４％）を淡黄色粉末として得た。

^１Ｈ−ＮＭＲ（ＣＤＣｌ_３）δ：１．０５（２Ｈ，ｑ，Ｊ＝１１．７Ｈｚ），１．４４−１．８７（９Ｈ，ｍ），１．８８−１．９９（２Ｈ，ｍ），２．４３（１Ｈ，ｔ，Ｊ＝１１．７Ｈｚ），２．５０−２．６５（４Ｈ，ｂｒ ｍ），３．１１（２Ｈ，ｄ，Ｊ＝７．３Ｈｚ），３．２６（２Ｈ，ｓ），３．４５−３．６９（８Ｈ，ｍ），３．５８（２Ｈ，ｓ），４．５１（２Ｈ，ｑ，Ｊ＝８．３Ｈｚ），７．４４（２Ｈ，ｄ，Ｊ＝８．３Ｈｚ），７．５７（２Ｈ，ｄ，Ｊ＝８．３Ｈｚ）．

ＬＣ／ＭＳ［条件１］：保持時間３．２４分；ｍ／ｚ６４９．０［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ６８３．１［Ｍ＋Ｃｌ］⁻、６９３．１［Ｍ＋ＨＣＯＯ］⁻（ＥＳＩ負イオンモード）

Example 454
4-[(1r, 4r) -4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} Preparation of 2,2,2-trifluoroethyl (methyl) cyclohexanecarbonyl] piperazine-1-carboxylate (Compound No. 454) 3-Methyl-1- obtained in Reference Example 454-2 instead of methyl chloroformate The reaction was carried out in substantially the same manner as in Example 149 except that [(2,2,2-trifluoroethoxy) carbonyl] -1H-imidazol-3-ium iodide was used, and the title compound (27 mg, yield 84%) was obtained. ) Was obtained as a pale yellow powder.

¹ H-NMR (CDCl ₃ ) δ: 1.05 (2H, q, J = 11.7 Hz), 1.4-1.87 (9H, m), 1.88-1.99 (2H, m) , 2.43 (1H, t, J = 11.7 Hz), 2.50-2.65 (4H, br m), 3.11 (2H, d, J = 7.3 Hz), 3.26 (2H , S), 3.45-3.69 (8H, m), 3.58 (2H, s), 4.51 (2H, q, J = 8.3 Hz), 7.44 (2H, d, J = 8.3 Hz), 7.57 (2H, d, J = 8.3 Hz).

LC / MS [Condition 1]: retention time 3.24 minutes; m / z 649.0 [M + H] ⁺ (ESI positive ion mode), m / z 683.1 [M + Cl] ⁻ , 693.1 [M + HCOO] ⁻ (ESI Negative ion mode)

実施例４５５
３−｛［（１ｒ，４ｒ）−４−（４−ベンゾイルピペリジン−１−カルボニル）シクロヘキシル］メチル｝−２−オキソ−１−オキサ−３，８−ジアザスピロ［４．５］デカン−８−カルボン酸２，２，２−トリフルオロエチル（化合物番号４５５）の製造

１−（ブロモメチル）−２，４−ビス（トリフルオロメチル）ベンゼンの代わりに、参考例４５４−２で得られた、３−メチル−１−［（２，２，２−トリフルオロエトキシ）カルボニル］−１Ｈ−イミダゾール−３−イウムヨージドを用いること以外は実質的に実施例２５５と同様に反応を行なって、表題化合物（２５ｍｇ、収率５３％）を白色粉末として得た。

^１Ｈ−ＮＭＲ（ＣＤＣｌ_３）δ：１．０６（２Ｈ，ｑ，Ｊ＝１２．３Ｈｚ），１．４７−２．００（４Ｈ，ｍ），２．４８（１Ｈ，ｔｔ，Ｊ＝１１．７，３．１Ｈｚ），２．８２（１Ｈ，ｔ，Ｊ＝１１．７Ｈｚ），３．１２（２Ｈ，ｄ，Ｊ＝７．２Ｈｚ），３．２１（１Ｈ，ｔ，Ｊ＝１３．５Ｈｚ），３．２８（２Ｈ，ｓ），３．３５（２Ｈ，ｑ，Ｊ＝１１．９Ｈｚ），３．５２（１Ｈ，ｔｔ，Ｊ＝１０．８，３．９Ｈｚ），３．８６−４．０９（３Ｈ，ｍ），４．３４−４．６６（３Ｈ，ｍ），７．４９（２Ｈ，ｔ，Ｊ＝７．４Ｈｚ），７．５９（１Ｈ，ｔ，Ｊ＝７．４Ｈｚ），７．９４（２Ｈ，ｄ，Ｊ＝７．４Ｈｚ）．

ＬＣ／ＭＳ［条件１］：保持時間４．２３分；ｍ／ｚ５９３．８［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ６２８．０［Ｍ＋Ｃｌ］⁻、６３７．９［Ｍ＋ＨＣＯＯ］⁻（ＥＳＩ負イオンモード）

Example 455
3-{[(1r, 4r) -4- (4-Benzoylpiperidine-1-carbonyl) cyclohexyl] methyl} -2-oxo-1-oxa-3,8-diazaspiro [4.5] decane-8-carvone Preparation of acid 2,2,2-trifluoroethyl (Compound No. 455)

3-methyl-1-[(2,2,2-trifluoroethoxy) carbonyl obtained in Reference Example 454-2 instead of 1- (bromomethyl) -2,4-bis (trifluoromethyl) benzene The reaction was carried out in substantially the same manner as in Example 255 except that 1H-imidazole-3-ium iodide was used to obtain the title compound (25 mg, yield 53%) as a white powder.

¹ H-NMR (CDCl ₃ ) δ: 1.06 (2H, q, J = 12.3 Hz), 1.47-2.00 (4H, m), 2.48 (1H, tt, J = 11.1. 7, 3.1 Hz), 2.82 (1H, t, J = 11.7 Hz), 3.12 (2H, d, J = 7.2 Hz), 3.21 (1H, t, J = 13.5 Hz) ), 3.28 (2H, s), 3.35 (2H, q, J = 11.9 Hz), 3.52 (1H, tt, J = 10.8, 3.9 Hz), 3.86-4 .09 (3H, m), 4.34-4.66 (3H, m), 7.49 (2H, t, J = 7.4 Hz), 7.59 (1H, t, J = 7.4 Hz) , 7.94 (2H, d, J = 7.4 Hz).

LC / MS [Condition 1]: Retention time 4.23 minutes; m / z 593.8 [M + H] ⁺ (ESI positive ion mode), m / z 628.0 [M + Cl] ⁻ , 637.9 [M + HCOO] ⁻ (ESI Negative ion mode)

実施例４５６
６−［１−（（１ｒ，４ｒ）−４−｛［８−（４−シアノ−２，６−ジフルオロベンジル）−２−オキソ−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル］メチル｝シクロヘキサンカルボニル）アゼチジン−３−イルオキシ］ニコチノニトリル（化合物番号４５６）の製造
６−（ピペリジン−４−イルオキシ）ニコチノニトリル塩酸塩の代わりに参考例３８１−２で得られた、６−（アゼチジン−３−イルオキシ）ニコチノニトリルを用いること以外は実質的に実施例４０２と同様に反応を行って、表題化合物（１６ｍｇ、収率３３％）を白色粉末として得た。

^１Ｈ−ＮＭＲ（ＣＤＣｌ_３）δ：０．９１−１．１０（２Ｈ，ｍ），１．４１−１．８５（９Ｈ，ｍ），１．９１（２Ｈ，ｂｒ ｄ，Ｊ＝１２．７Ｈｚ），２．１２（１Ｈ，ｔｔ，Ｊ＝１１．９，３．３Ｈｚ），２．５２−２．７１（４Ｈ，ｍ），３．０７（２Ｈ，ｄ，Ｊ＝７．８Ｈｚ），３．２１（２Ｈ，ｓ），３．７５（２Ｈ，ｓ），４．０５（１Ｈ，ｄｄ，Ｊ＝１１．１，４．１Ｈｚ），４．１４（１Ｈ，ｄｄ，Ｊ＝９．８，４．１Ｈｚ），４．４０（１Ｈ，ｄｄ，Ｊ＝１１．１，７．０Ｈｚ），４．５６（１Ｈ，ｄｄ，Ｊ＝９．８，７．０Ｈｚ），５．４２（１Ｈ，ｔｔ，Ｊ＝７．０，４．１Ｈｚ），６．９０（１Ｈ，ｄ，Ｊ＝８．６Ｈｚ），７．２２（２Ｈ，ｄ，Ｊ＝６．１Ｈｚ），７．８５（１Ｈ，ｄｄ，Ｊ＝８．６，２．５Ｈｚ），８．４５（１Ｈ，ｄ，Ｊ＝２．５Ｈｚ）．

ＬＣ／ＭＳ［条件１］：保持時間２．９８分；ｍ／ｚ６０４．９［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ６４９．１［Ｍ＋ＨＣＯＯ］⁻（ＥＳＩ負イオンモード）

Example 456
6- [1-((1r, 4r) -4-{[8- (4-Cyano-2,6-difluorobenzyl) -2-oxo-1-oxa-3,8-diazaspiro [4.5] decane Preparation of -3-yl] methyl} cyclohexanecarbonyl) azetidin-3-yloxy] nicotinonitrile (Compound No. 456) Obtained in Reference Example 381-2 instead of 6- (piperidin-4-yloxy) nicotinonitrile hydrochloride The reaction was conducted in substantially the same manner as in Example 402 except that 6- (azetidin-3-yloxy) nicotinonitrile was used to give the title compound (16 mg, yield 33%) as a white powder. .

¹ H-NMR (CDCl ₃ ) δ: 0.91-1.10 (2H, m), 1.41-1.85 (9H, m), 1.91 (2H, br d, J = 12.7 Hz) ), 2.12 (1H, tt, J = 11.9, 3.3 Hz), 2.52-2.71 (4H, m), 3.07 (2H, d, J = 7.8 Hz), 3 .21 (2H, s), 3.75 (2H, s), 4.05 (1H, dd, J = 11.1, 4.1 Hz), 4.14 (1H, dd, J = 9.8, 4.1 Hz), 4.40 (1 H, dd, J = 11.1, 7.0 Hz), 4.56 (1 H, dd, J = 9.8, 7.0 Hz), 5.42 (1 H, tt) , J = 7.0, 4.1 Hz), 6.90 (1H, d, J = 8.6 Hz), 7.22 (2H, d, J = 6.1 Hz), 7.85 (1H, dd, J = 8.6, 2.5H ), 8.45 (1H, d, J = 2.5Hz).

LC / MS [Condition 1]: Retention time 2.98 minutes; m / z 604.9 [M + H] ⁺ (ESI positive ion mode), m / z 649.1 [M + HCOO] ⁻ (ESI negative ion mode)

参考例４５７−１
５−［（トリフルオロメチル）ピリジン−２−イル］メタノ−ルの製造
参考例３８９で得られた、５−（トリフルオロメチル）ピコリンアルデヒド（０．２４ｇ、１．４ｍｍｏｌ）をクロロホルム（６．０ｍＬ）に溶解し、室温にてナトリウムトリアセトキシボロヒドリド（０．５１ｇ、２．４ｍｍｏｌ）を加え、室温にて７０分間かき混ぜた。反応終了後、水（１０ｍＬ）と飽和炭酸水素ナトリウム水溶液（２０ｍＬ）とクロロホルム（６０ｍＬ）を加えて、有機層を分離した。得られた有機層を無水硫酸ナトリウムで乾燥、減圧下濃縮乾固した後、シリカゲルカラムクロマトグラフィ−［充填剤：株式会社山善製ＨＩ−ＦＬＡＳＨ（登録商標）ＣＯＬＵＭＮｓｉｌｉｃａｇｅｌ４０μｍ、展開溶媒：ヘキサン／酢酸エチル＝９／１→０／１］にて精製し、表題化合物（０．２４ｇ、収率１００％）を無色油状物として得た。

^１Ｈ−ＮＭＲ（ＣＤＣｌ_３）δ：３．４８（１Ｈ，ｂｒ ｓ），４．８６（２Ｈ，ｓ），７．４４（１Ｈ，ｄ，Ｊ＝８．３Ｈｚ），７．９４（１Ｈ，ｄ，Ｊ＝８．３Ｈｚ），８．８５（１Ｈ，ｓ）．

ＬＣ／ＭＳ［条件１］：保持時間２．０３分；ｍ／ｚ１７７．９［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）

Reference Example 457-1
Production of 5-[(trifluoromethyl) pyridin-2-yl] methanol 5- (trifluoromethyl) picolinaldehyde (0.24 g, 1.4 mmol) obtained in Reference Example 389 was added to chloroform (6. 0 mL), sodium triacetoxyborohydride (0.51 g, 2.4 mmol) was added at room temperature, and the mixture was stirred at room temperature for 70 minutes. After completion of the reaction, water (10 mL), saturated aqueous sodium hydrogen carbonate solution (20 mL) and chloroform (60 mL) were added, and the organic layer was separated. The obtained organic layer was dried over anhydrous sodium sulfate and concentrated to dryness under reduced pressure, followed by silica gel column chromatography [filler: HI-FLASH (registered trademark) COLUMNsilica gel 40 μm manufactured by Yamazen Co., Ltd., developing solvent: hexane / ethyl acetate = 9. / 1 → 0/1] to give the title compound (0.24 g, yield 100%) as a colorless oil.

¹ H-NMR (CDCl ₃ ) δ: 3.48 (1H, brs), 4.86 (2H, s), 7.44 (1H, d, J = 8.3 Hz), 7.94 (1H, d, J = 8.3 Hz), 8.85 (1H, s).

LC / MS [Condition 1]: Retention time 2.03 minutes; m / z 177.9 [M + H] ⁺ (ESI positive ion mode)

参考例４５７−２
２−｛［５−（トリフルオロメチル）ピリジン−２−イル］メチル｝イソインドリン−１，３−ジオンの製造
６−（ヒドロキシメチル）ニコチン酸エチルの代わりに、参考例４５７−１で得られた、５−［（トリフルオロメチル）ピリジン−２−イル］メタノ−ルを用いること以外は実質的に参考例４３１−１と同様に反応を行なって、表題化合物（０．３１ｇ、収率７３％）を白色粉末として得た。

^１Ｈ−ＮＭＲ（ＣＤＣｌ_３）δ：５．０８（２Ｈ，ｓ），７．４２（１Ｈ，ｄ，Ｊ＝８．２Ｈｚ），７．６７−８．００（５Ｈ，ｍ），８．７７（１Ｈ，ｓ）．

ＬＣ／ＭＳ［条件１］：保持時間４．１３分；ｍ／ｚ３０６．８［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）

Reference Example 457-2
Preparation of 2-{[5- (trifluoromethyl) pyridin-2-yl] methyl} isoindoline-1,3-dione Obtained in Reference Example 457-1 instead of ethyl 6- (hydroxymethyl) nicotinate The reaction was conducted in substantially the same manner as in Reference Example 431-1 except that 5-[(trifluoromethyl) pyridin-2-yl] methanol was used, and the title compound (0.31 g, yield 73) was obtained. %) As a white powder.

¹ H-NMR (CDCl ₃ ) δ: 5.08 (2H, s), 7.42 (1H, d, J = 8.2 Hz), 7.67-8.00 (5H, m), 8.77 (1H, s).

LC / MS [Condition 1]: Retention time 4.13 minutes; m / z 306.8 [M + H] ⁺ (ESI positive ion mode)

参考例４５７−３
［５−（トリフルオロメチル）ピリジン−２−イル］メタンアミンの製造
５−［（１，３−ジオキソイソインドリン−２−イル）メチル］ピラジン−２−カルボン酸エチルの代わりに、参考例４５７−２で得られた、２−｛［５−（トリフルオロメチル）ピリジン−２−イル］メチル｝イソインドリン−１，３−ジオンを用いること以外は実質的に参考例４３３−２と同様に反応を行なって、表題化合物（０．１０ｇ、収率５７％）を淡黄色油状物として得た。

^１Ｈ−ＮＭＲ（ＣＤＣｌ_３）δ：４．０７（２Ｈ，ｓ），７．４５（１Ｈ，ｄ，Ｊ＝８．２Ｈｚ），７．８９（１Ｈ，ｄｄ，Ｊ＝８．２，１．８Ｈｚ），８．８３（１Ｈ，ｂｒ ｓ）．

ＬＣ／ＭＳ［条件１］：保持時間０．５１分；ｍ／ｚ１７７．０［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）

Reference Example 457-3
Preparation of [5- (trifluoromethyl) pyridin-2-yl] methanamine Reference Example 457 instead of ethyl 5-[(1,3-dioxoisoindoline-2-yl) methyl] pyrazine-2-carboxylate -2, substantially the same as Reference Example 433-2, except that 2-{[5- (trifluoromethyl) pyridin-2-yl] methyl} isoindoline-1,3-dione was used. The reaction was performed to give the title compound (0.10 g, yield 57%) as a pale yellow oil.

¹ H-NMR (CDCl ₃ ) δ: 4.07 (2H, s), 7.45 (1H, d, J = 8.2 Hz), 7.89 (1H, dd, J = 8.2, 1. 8 Hz), 8.83 (1 H, br s).

LC / MS [Condition 1]: Retention time 0.51 min; m / z 177.0 [M + H] ⁺ (ESI positive ion mode)

実施例４５７
（１ｒ，４ｒ）−４−｛［８−（４−シアノ−２，６−ジフルオロベンジル）−２−オキソ−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル］メチル｝−Ｎ−｛［５−（トリフルオロメチル）ピリジン−２−イル］メチル｝シクロヘキサンカルボキサミド（化合物番号４５７）の製造
６−（ピペリジン−４−イルオキシ）ニコチノニトリル塩酸塩の代わりに参考例４５７−３で得られた、［５−（トリフルオロメチル）ピリジン−２−イル］メタンアミンを用いること以外は実質的に実施例４０２と同様に反応を行って、表題化合物（１１ｍｇ、収率２３％）を白色粉末として得た。

^１Ｈ−ＮＭＲ（ＣＤＣｌ_３）δ：１．０４（２Ｈ，ｄｑ，Ｊ＝２．９，１３．１Ｈｚ），１．４１−１．８５（７Ｈ，ｍ），１．８６−２．０４（４Ｈ，ｍ），２．１７（１Ｈ，ｔｔ，Ｊ＝１１．９，３．７Ｈｚ），２．５２−２．７４（４Ｈ，ｍ），３．０９（２Ｈ，ｄ，Ｊ＝７．４Ｈｚ），３．２２（２Ｈ，ｓ），３．７５（２Ｈ，ｓ），４．６２（２Ｈ，ｄ，Ｊ＝５．７Ｈｚ），６．７０（１Ｈ，ｂｒ ｔ，Ｊ＝４．９Ｈｚ），７．２２（２Ｈ，ｄ，Ｊ＝６．１Ｈｚ），７．３９（１Ｈ，ｄ，Ｊ＝８．２Ｈｚ），７．９０（１Ｈ，ｄ，Ｊ＝８．２Ｈｚ），８．８１（１Ｈ，ｓ）．

ＬＣ／ＭＳ［条件１］：保持時間３．０２分；ｍ／ｚ６０５．６［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ６５０．２［Ｍ＋ＨＣＯＯ］⁻（ＥＳＩ負イオンモード）

Example 457
(1r, 4r) -4-{[8- (4-Cyano-2,6-difluorobenzyl) -2-oxo-1-oxa-3,8-diazaspiro [4.5] decan-3-yl] methyl } -N-{[5- (Trifluoromethyl) pyridin-2-yl] methyl} cyclohexanecarboxamide (Compound No. 457) Reference Example 457 instead of 6- (piperidin-4-yloxy) nicotinonitrile hydrochloride The reaction was conducted in substantially the same manner as in Example 402 except that [5- (trifluoromethyl) pyridin-2-yl] methanamine obtained in -3 was used, and the title compound (11 mg, yield 23%) was obtained. ) Was obtained as a white powder.

¹ H-NMR (CDCl ₃ ) δ: 1.04 (2H, dq, J = 2.9, 13.1 Hz), 1.41-1.85 (7H, m), 1.86-2.04 ( 4H, m), 2.17 (1H, tt, J = 11.9, 3.7 Hz), 2.52-2.74 (4H, m), 3.09 (2H, d, J = 7.4 Hz) ), 3.22 (2H, s), 3.75 (2H, s), 4.62 (2H, d, J = 5.7 Hz), 6.70 (1H, br t, J = 4.9 Hz) , 7.22 (2H, d, J = 6.1 Hz), 7.39 (1H, d, J = 8.2 Hz), 7.90 (1H, d, J = 8.2 Hz), 8.81 ( 1H, s).

LC / MS [Condition 1]: Retention time 3.02 minutes; m / z 605.6 [M + H] ⁺ (ESI positive ion mode), m / z 650.2 [M + HCOO] ⁻ (ESI negative ion mode)

実施例４５８
（１ｒ，４ｒ）−４−｛［８−（４−シアノ−２，６−ジフルオロベンジル）−２−オキソ−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル］メチル｝−Ｎ−［（６−フルオロピリジン−３−イル）メチル］シクロヘキサンカルボキサミド）（化合物番号４５８）の製造

６−（ピペリジン−４−イルオキシ）ニコチノニトリル塩酸塩の代わりに参考例４４３−３で得られた、（６−フルオロピリジン−３−イル）メタンアミンを用いること以外は実質的に実施例４０２と同様に反応を行って、表題化合物（１５ｍｇ、収率３４％）を白色粉末として得た。

^１Ｈ−ＮＭＲ（ＣＤＣｌ_３）δ：０．９９（２Ｈ，ｄｑ，Ｊ＝３．３，１２．６Ｈｚ），１．４０−１．６３（３Ｈ，ｍ），１．６４−１．８３（４Ｈ，ｍ），１．９１（４Ｈ，ｄ，Ｊ＝１２．７Ｈｚ），２．０７（１Ｈ，ｔｔ，Ｊ＝１２．１，３．５Ｈｚ），２．５０−２．６９（４Ｈ，ｍ），３．０６（２Ｈ，ｄ，Ｊ＝７．４Ｈｚ），３．２２（２Ｈ，ｓ），３．７４（２Ｈ，ｓ），４．４１（２Ｈ，ｄ，Ｊ＝５．７Ｈｚ），６．１４（１Ｈ，ｔ，Ｊ＝５．９Ｈｚ），６．８８（１Ｈ，ｄｄ，Ｊ＝８．２，２．９Ｈｚ），７．２２（２Ｈ，ｄ，Ｊ＝６．１Ｈｚ），７．７３（１Ｈ，ｔｄ，Ｊ＝８．１，２．６Ｈｚ），８．０９（１Ｈ，ｓ）．

ＬＣ／ＭＳ［条件１］：保持時間２．４５分；ｍ／ｚ５５５．９［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ５５４．１［Ｍ−Ｈ］⁻、ｍ／ｚ６００．１［Ｍ＋ＨＣＯＯ］⁻（ＥＳＩ負イオンモード）

Example 458
(1r, 4r) -4-{[8- (4-Cyano-2,6-difluorobenzyl) -2-oxo-1-oxa-3,8-diazaspiro [4.5] decan-3-yl] methyl } -N-[(6-Fluoropyridin-3-yl) methyl] cyclohexanecarboxamide) (Compound No. 458)

Example 402 substantially except that (6-fluoropyridin-3-yl) methanamine obtained in Reference Example 443-3 was used instead of 6- (piperidin-4-yloxy) nicotinonitrile hydrochloride. The reaction was performed in the same manner to obtain the title compound (15 mg, yield 34%) as a white powder.

¹ H-NMR (CDCl ₃ ) δ: 0.99 (2H, dq, J = 3.3, 12.6 Hz), 1.40-1.63 (3H, m), 1.64-1.83 ( 4H, m), 1.91 (4H, d, J = 12.7 Hz), 2.07 (1H, tt, J = 12.1, 3.5 Hz), 2.50-2.69 (4H, m ), 3.06 (2H, d, J = 7.4 Hz), 3.22 (2H, s), 3.74 (2H, s), 4.41 (2H, d, J = 5.7 Hz), 6.14 (1H, t, J = 5.9 Hz), 6.88 (1H, dd, J = 8.2, 2.9 Hz), 7.22 (2H, d, J = 6.1 Hz), 7 .73 (1H, td, J = 8.1, 2.6 Hz), 8.09 (1H, s).

LC / MS [Condition 1]: Retention time 2.45 minutes; m / z 555.9 [M + H] ⁺ (ESI positive ion mode), m / z 554.1 [M−H] ⁻ , m / z 600.1 [M + HCOO] ] ^- (ESI negative ion mode)

実施例４５９
４−［６−（｛２−オキソ−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジザスピロ［４．５］デカン−３−イル｝メチル）ニコチノイル］ピペラジン−１−カルボン酸エチル（化合物番号４５９）の製造
テトラヒドロフルフリルアミンの代わりにピペラジン−１−カルボン酸エチル（市販）を用いること以外は実質的に実施例１１１と同様に反応を行って、表題化合物（１８ｍｇ、収率７８％）を淡橙色無定形物として得た。

^１Ｈ−ＮＭＲ（ＣＤＣｌ_３）δ：１．２７（３Ｈ，ｔ，Ｊ＝６．７Ｈｚ），１．７１−１．８９（２Ｈ，ｍ），１．９７（２Ｈ，ｄ，Ｊ＝１３．５Ｈｚ），２．４６−２．６２（４Ｈ，ｂｒ ｍ），３．３５（２Ｈ，ｓ），３．３８−３．６１（６Ｈ，ｂｒ ｍ），３．５７（２Ｈ，ｓ），３．６２−３．８８（２Ｈ，ｂｒ ｍ），４．１７（２Ｈ，ｑ，Ｊ＝７．２Ｈｚ），４．５７（２Ｈ，ｓ），７．３８（１Ｈ，ｄ，Ｊ＝７．８Ｈｚ），７．４４（２Ｈ，ｄ，Ｊ＝７．８Ｈｚ），７．５７（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ），７．７６（１Ｈ，ｄｄ，Ｊ＝７．８，２．０Ｈｚ），８．６１（１Ｈ，ｄ，Ｊ＝２．０Ｈｚ）．

ＬＣ／ＭＳ［条件１］：保持時間２．８８分；ｍ／ｚ５９０．０［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ６３４．２［Ｍ＋ＨＣＯＯ］⁻（ＥＳＩ負イオンモード）

Example 459
4- [6-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-dizaspiro [4.5] decan-3-yl} methyl) nicotinoyl] piperazine- Preparation of ethyl 1-carboxylate (Compound No. 459) The reaction was conducted in substantially the same manner as in Example 111 except that piperazine-1-carboxylate ethyl (commercially available) was used instead of tetrahydrofurfurylamine to give the title compound 18 mg, 78% yield) was obtained as a pale orange amorphous product.

¹ H-NMR (CDCl ₃ ) δ: 1.27 (3H, t, J = 6.7 Hz), 1.71-1.89 (2H, m), 1.97 (2H, d, J = 13. 5Hz), 2.46-2.62 (4H, br m), 3.35 (2H, s), 3.38-3.61 (6H, br m), 3.57 (2H, s), 3 .62-3.88 (2H, br m), 4.17 (2H, q, J = 7.2 Hz), 4.57 (2H, s), 7.38 (1H, d, J = 7.8 Hz) ), 7.44 (2H, d, J = 7.8 Hz), 7.57 (2H, d, J = 8.2 Hz), 7.76 (1H, dd, J = 7.8, 2.0 Hz) , 8.61 (1H, d, J = 2.0 Hz).

LC / MS [Condition 1]: Retention time 2.88 min; m / z 590.0 [M + H] ⁺ (ESI positive ion mode), m / z 634.2 [M + HCOO] ⁻ (ESI negative ion mode)

実施例４６０
１−［６−（｛２−オキソ−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジザスピロ［４．５］デカン−３−イル｝メチル）ニコチノイル］ピペリジン−４−カルボニトリル（化合物番号４６０）の製造
テトラヒドロフルフリルアミンの代わりにピペリジン−４−カルボニトリル（市販）を用いること以外は実質的に実施例１１１と同様に反応を行って、表題化合物（２５ｍｇ、定量的）を淡橙色無定形物として得た。

^１Ｈ−ＮＭＲ（ＣＤＣｌ_３）δ：１．６４−２．０３（８Ｈ，ｍ），２．４５−２．６３（４Ｈ，ｂｒ ｍ），２．９２−３．０２（１Ｈ，ｍ），３．３６（２Ｈ，ｓ），３．３９−４．０２（４Ｈ，ｍ），３．５７（３Ｈ，ｓ），４．５８（２Ｈ，ｓ），７．３７（１Ｈ，ｄ，Ｊ＝８．２Ｈｚ），７．４４（２Ｈ，ｄ，Ｊ＝７．８Ｈｚ），７．５７（２Ｈ，ｄ，Ｊ＝７．８Ｈｚ），７．７４（１Ｈ，ｄｄ，Ｊ＝８．２，２．０Ｈｚ），８．５９（１Ｈ，ｄ，Ｊ＝１．６Ｈｚ）．

ＬＣ／ＭＳ［条件１］：保持時間１．９０分；ｍ／ｚ５４１．９［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ５４０．０［Ｍ−Ｈ］⁻、５８６．１［Ｍ＋ＨＣＯＯ］⁻（ＥＳＩ負イオンモード）

Example 460
1- [6-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-dizaspiro [4.5] decan-3-yl} methyl) nicotinoyl] piperidine- Preparation of 4-carbonitrile (Compound No. 460) The reaction was conducted in substantially the same manner as in Example 111 except that piperidine-4-carbonitrile (commercially available) was used instead of tetrahydrofurfurylamine to give the title compound (25 mg, Quantitative) was obtained as a pale orange amorphous.

¹ H-NMR (CDCl ₃ ) δ: 1.64-2.03 (8H, m), 2.45-2.63 (4H, br m), 2.92-3.02 (1H, m), 3.36 (2H, s), 3.39-4.02 (4H, m), 3.57 (3H, s), 4.58 (2H, s), 7.37 (1H, d, J = 8.2 Hz), 7.44 (2H, d, J = 7.8 Hz), 7.57 (2H, d, J = 7.8 Hz), 7.74 (1H, dd, J = 8.2, 2) .0Hz), 8.59 (1H, d, J = 1.6 Hz).

LC / MS [Condition 1]: Retention time 1.90 minutes; m / z 541.9 [M + H] ⁺ (ESI positive ion mode), m / z 540.0 [M−H] ⁻ , 586.1 [M + HCOO] ⁻ (ESI negative ion mode)

実施例４６１
４−［６−（｛２−オキソ−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジザスピロ［４．５］デカン−３−イル｝メチル）ニコチンアミド］ピペリジン−１−カルボン酸エチル（化合物番号４６１）の製造
テトラヒドロフルフリルアミンの代わりに４−アミノピペリジン−１−カルボン酸エチル（市販）を用いること以外は実質的に実施例１１１と同様に反応を行って、表題化合物（２６ｍｇ、定量的）を白色粉末として得た。

^１Ｈ−ＮＭＲ（ＣＤＣｌ_３）δ：１．２６（３Ｈ，ｔ，Ｊ＝７．０Ｈｚ），１．４５（２Ｈ，ｄｑ，Ｊ＝４．０，１２．７Ｈｚ），１．７０−１．８４（２Ｈ，ｍ），１．８８−２．１０（４Ｈ，ｍ），２．４０−２．６４（０Ｈ，ｂｒ ｍ），２．９５（２Ｈ，ｔ，Ｊ＝１１．９Ｈｚ），３．３３（２Ｈ，ｓ），３．５６（２Ｈ，ｓ），３．９９−４．２４（５Ｈ，ｍ），４．５８（２Ｈ，ｓ），６．２９（１Ｈ，ｄ，Ｊ＝７．８Ｈｚ），７．３６（１Ｈ，ｄ，Ｊ＝７．８Ｈｚ），７．４３（２Ｈ，ｄ，Ｊ＝７．８Ｈｚ），７．５７（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ），８．０９（１Ｈ，ｄｄ，Ｊ＝８．２，２．０Ｈｚ），８．９１（１Ｈ，ｄ，Ｊ＝２．０Ｈｚ）．

ＬＣ／ＭＳ［条件１］：保持時間２．９６分；ｍ／ｚ６０４．０［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ６０２．１［Ｍ−Ｈ］⁻、６４８．１［Ｍ＋ＨＣＯＯ］⁻（ＥＳＩ負イオンモード）

Example 461
4- [6-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-dizaspiro [4.5] decan-3-yl} methyl) nicotinamide] piperidine Preparation of ethyl-1-carboxylate (Compound No. 461) The reaction was carried out in substantially the same manner as in Example 111 except that ethyl 4-aminopiperidine-1-carboxylate (commercially available) was used instead of tetrahydrofurfurylamine. The title compound (26 mg, quantitative) was obtained as a white powder.

¹ H-NMR (CDCl ₃ ) δ: 1.26 (3H, t, J = 7.0 Hz), 1.45 (2H, dq, J = 4.0, 12.7 Hz), 1.70-1. 84 (2H, m), 1.88-2.10 (4H, m), 2.40-2.64 (0H, br m), 2.95 (2H, t, J = 11.9 Hz), 3 .33 (2H, s), 3.56 (2H, s), 3.99-4.24 (5H, m), 4.58 (2H, s), 6.29 (1H, d, J = 7) .8 Hz), 7.36 (1 H, d, J = 7.8 Hz), 7.43 (2 H, d, J = 7.8 Hz), 7.57 (2 H, d, J = 8.2 Hz), 8 .09 (1H, dd, J = 8.2, 2.0 Hz), 8.91 (1H, d, J = 2.0 Hz).

LC / MS [Condition 1]: Retention time 2.96 minutes; m / z 604.0 [M + H] ⁺ (ESI positive ion mode), m / z 602.1 [M−H] ⁻ , 648.1 [M + HCOO] ⁻ (ESI negative ion mode)

実施例４６２
Ｎ−（フラン−２−イルメチル）−６−（｛２−オキソ−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジザスピロ［４．５］デカン−３−イル｝メチル）ニコチンアミド（化合物番号４６２）の製造
テトラヒドロフルフリルアミンの代わりにフラン−２−イルメタンアミン（市販）を用いること以外は実質的に実施例１１１と同様に反応を行って、表題化合物（２３ｍｇ、定量的）を白色粉末として得た。

^１Ｈ−ＮＭＲ（ＣＤＣｌ_３）δ：１．７６（２Ｈ，ｄｔ，Ｊ＝１２．７，７．０Ｈｚ），１．９６（２Ｈ，ｄ，Ｊ＝１２．７Ｈｚ），２．４０−２．６２（４Ｈ，ｂｒ ｍ），３．３２（２Ｈ，ｓ），３．５６（２Ｈ，ｓ），４．５８（２Ｈ，ｓ），４．６６（２Ｈ，ｄ，Ｊ＝５．３Ｈｚ），６．３２（１Ｈ，ｄ，Ｊ＝３．３Ｈｚ），６．３６（１Ｈ，ｄｄ，Ｊ＝３．３，２．０Ｈｚ），６．４２−６．５３（１Ｈ，ｍ），７．３７（１Ｈ，ｄ，Ｊ＝８．２Ｈｚ），７．３９（１Ｈ，ｄｄ，Ｊ＝１．６，０．８Ｈｚ），７．４３（２Ｈ，ｄ，Ｊ＝７．８Ｈｚ），７．５７（２Ｈ，ｄ，Ｊ＝７．８Ｈｚ），８．０９（１Ｈ，ｄｄ，Ｊ＝８．２，２．０Ｈｚ），８．９３（１Ｈ，ｄ，Ｊ＝２．０Ｈｚ）．

ＬＣ／ＭＳ［条件１］：保持時間２．８２分；ｍ／ｚ５２８．９［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ５２７．０［Ｍ−Ｈ］⁻（ＥＳＩ負イオンモード）

Example 462
N- (furan-2-ylmethyl) -6-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-dizaspiro [4.5] decan-3-yl } Preparation of methyl) nicotinamide (Compound No. 462) The reaction was conducted in substantially the same manner as in Example 111 except that furan-2-ylmethanamine (commercially available) was used instead of tetrahydrofurfurylamine. 23 mg, quantitative) was obtained as a white powder.

¹ H-NMR (CDCl ₃ ) δ: 1.76 (2H, dt, J = 12.7, 7.0 Hz), 1.96 (2H, d, J = 12.7 Hz), 2.40-2. 62 (4H, br m), 3.32 (2H, s), 3.56 (2H, s), 4.58 (2H, s), 4.66 (2H, d, J = 5.3 Hz), 6.32 (1H, d, J = 3.3 Hz), 6.36 (1H, dd, J = 3.3, 2.0 Hz), 6.42-6.53 (1H, m), 7.37 (1H, d, J = 8.2 Hz), 7.39 (1H, dd, J = 1.6, 0.8 Hz), 7.43 (2H, d, J = 7.8 Hz), 7.57 ( 2H, d, J = 7.8 Hz), 8.09 (1H, dd, J = 8.2, 2.0 Hz), 8.93 (1H, d, J = 2.0 Hz).

LC / MS [Condition 1]: Retention time 2.82 minutes; m / z 528.9 [M + H] ⁺ (ESI positive ion mode), m / z 527.0 [M−H] ⁻ (ESI negative ion mode)

実施例４６３
３−｛［５−（４，４−ジフルオロピペリジン−１−カルボニル）ピリジン−２−イル］メチル｝−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジザスピロ［４．５］デカン−２−オン（化合物番号４６３）の製造
テトラヒドロフルフリルアミンの代わりに４，４−ジフルオロピペリジン塩酸塩（市販）とトリエチルアミンを用いること以外は実質的に実施例１１１と同様に反応を行って、表題化合物（２６ｍｇ、定量的）を淡黄色無定形物として得た。

^１Ｈ−ＮＭＲ（ＣＤＣｌ_３）δ：１．８０（２Ｈ，ｔｄ，Ｊ＝１３．８，６．７Ｈｚ），１．８４−２．２３（４Ｈ，ｂｒ ｍ），１．９８（２Ｈ，ｄ，Ｊ＝１３．８Ｈｚ），２．４４−２．６４（４Ｈ，ｍ），３．３６（２Ｈ，ｓ），３．４３−３．９８（４Ｈ，ｍ），３．５７（２Ｈ，ｓ），４．５８（２Ｈ，ｓ），７．３８（１Ｈ，ｄ，Ｊ＝８．２Ｈｚ），７．４４（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ），７．５７（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ），７．７６（１Ｈ，ｄｄ，Ｊ＝８．２，２．０Ｈｚ），８．６１（１Ｈ，ｄ，Ｊ＝２．０Ｈｚ）．

ＬＣ／ＭＳ［条件１］：保持時間２．９２分；ｍ／ｚ５５２．９［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ５５１．１［Ｍ−Ｈ］⁻、５９７．０［Ｍ＋ＨＣＯＯ］⁻（ＥＳＩ負イオンモード）

Example 463
3-{[5- (4,4-Difluoropiperidin-1-carbonyl) pyridin-2-yl] methyl} -8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-dizaspiro [ 4.5] Preparation of decan-2-one (Compound No. 463) Reaction substantially in the same manner as in Example 111 except that 4,4-difluoropiperidine hydrochloride (commercially available) and triethylamine were used instead of tetrahydrofurfurylamine. To give the title compound (26 mg, quantitative) as a pale yellow amorphous.

¹ H-NMR (CDCl ₃ ) δ: 1.80 (2H, td, J = 13.8, 6.7 Hz), 1.84-2.23 (4H, br m), 1.98 (2H, d , J = 13.8 Hz), 2.44-2.64 (4H, m), 3.36 (2H, s), 3.43-3.98 (4H, m), 3.57 (2H, s) ), 4.58 (2H, s), 7.38 (1H, d, J = 8.2 Hz), 7.44 (2H, d, J = 8.2 Hz), 7.57 (2H, d, J = 8.2 Hz), 7.76 (1H, dd, J = 8.2, 2.0 Hz), 8.61 (1H, d, J = 2.0 Hz).

LC / MS [Condition 1]: Retention time 2.92 minutes; m / z 552.9 [M + H] ⁺ (ESI positive ion mode), m / z 551.1 [M−H] ⁻ , 597.0 [M + HCOO] ⁻ (ESI negative ion mode)

実施例４６４
６−｛１−［６−（｛２−オキソ−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジザスピロ［４．５］デカン−３−イル｝メチル）ニコチノイル］アゼチジン−３−イルオキシ｝ニコチノニトリル（化合物番号４６４）の製造
テトラヒドロフルフリルアミンの代わりに、参考例３８１−２で得られた、６−（アゼチジン−３−イルオキシ）ニコチノニトリルを用いること以外は実質的に実施例１１１と同様に反応を行って、表題化合物（１７ｍｇ、６９％）を淡橙色無定形物として得た。

^１Ｈ−ＮＭＲ（ＣＤＣｌ_３）δ：１．７７（２Ｈ，ｄｔ，Ｊ＝１３．５，６．５Ｈｚ），１．９７（２Ｈ，ｄ，Ｊ＝１３．５Ｈｚ），２．４１−２．６７（４Ｈ，ｂｒ ｍ），３．３４（２Ｈ，ｓ），３．５６（２Ｈ，ｓ），４．２３−４．３９（２Ｈ，ｂｒ ｍ），４．５８（２Ｈ，ｓ），４．６１−４．７９（２Ｈ，ｂｒ ｍ），５．４９（１Ｈ，ｔｔ，Ｊ＝７．０，２．５Ｈｚ），６．９２（１Ｈ，ｄ，Ｊ＝９．０Ｈｚ），７．３７（１Ｈ，ｄ，Ｊ＝８．２Ｈｚ），７．４３（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ），７．５７（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ），７．８６（１Ｈ，ｄｄ，Ｊ＝９．０，２．５Ｈｚ），７．９８（１Ｈ，ｄｄ，Ｊ＝８．２，２．０Ｈｚ），８．４４（１Ｈ，ｄ，Ｊ＝２．５Ｈｚ），８．８０（１Ｈ，ｄ，Ｊ＝２．０Ｈｚ）．

ＬＣ／ＭＳ［条件１］：保持時間３．０４分；ｍ／ｚ６０７．０［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ６５１．２［Ｍ＋ＨＣＯＯ］⁻（ＥＳＩ負イオンモード）

Example 464
6- {1- [6-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-dizaspiro [4.5] decan-3-yl} methyl) nicotinoyl Preparation of azetidin-3-yloxy} nicotinonitrile (Compound No. 464) Instead of using tetrahydrofurfurylamine, 6- (azetidin-3-yloxy) nicotinonitrile obtained in Reference Example 381-2 was used. Reacted substantially as in Example 111 to give the title compound (17 mg, 69%) as a pale orange amorphous.

¹ H-NMR (CDCl ₃ ) δ: 1.77 (2H, dt, J = 13.5, 6.5 Hz), 1.97 (2H, d, J = 13.5 Hz), 2.41-2. 67 (4H, br m), 3.34 (2H, s), 3.56 (2H, s), 4.23-4.39 (2H, br m), 4.58 (2H, s), 4 .61-4.79 (2H, br m), 5.49 (1H, tt, J = 7.0, 2.5 Hz), 6.92 (1H, d, J = 9.0 Hz), 7.37 (1H, d, J = 8.2 Hz), 7.43 (2H, d, J = 8.2 Hz), 7.57 (2H, d, J = 8.2 Hz), 7.86 (1H, dd, J = 9.0, 2.5 Hz), 7.98 (1H, dd, J = 8.2, 2.0 Hz), 8.44 (1H, d, J = 2.5 Hz), 8.80 (1H , D, J = 2.0 Hz .

LC / MS [Condition 1]: Retention time 3.04 minutes; m / z 607.0 [M + H] ⁺ (ESI positive ion mode), m / z 651.2 [M + HCOO] ⁻ (ESI negative ion mode)

実施例４６５
５−（｛２−オキソ−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝｝メチル）ピラジン−２−カルボキサミド（化合物番号４６５）の製造
実施例４４６で得られた、３−［（５−カルバモイルピラジン−２−イル）メチル］−２−オキソ−１−オキサ−３，８−ジアザスピロ［４．５］デカン−８−カルボン酸ｔ−ブチル（４３ｍｇ、０．１１ｍｍｏｌ）をメタノール（２．０ｍＬ）に溶解し、室温にて１０％塩化水素−メタノ−ル溶液（０．２８ｍＬ）を加え、室温にて１日間かき混ぜた。反応終了後、反応混合物を減圧下濃縮乾固した。得られた白色固体をＮ，Ｎ−ジメチルホルムアミド（１．０ｍＬ）に溶解し、室温にてトリエチルアミン（０．０３７ｍＬ、０．２６ｍｍｏｌ）と４−（トリフルオロメチル）ベンジルブロミド（２９ｍｇ、０．１１ｍｍｏｌ）を加えて、室温で１日間かき混ぜた。反応終了後、酢酸エチルと水を加えて、有機層を無水硫酸ナトリウムで乾燥、減圧下濃縮乾固した。得られた反応残渣をシリカゲルカラムクロマトグラフィー［充填剤：富士シリシア製ＦＬ１００Ｄ、展開溶媒：クロロホルム／メタノール＝３０／１］にて精製し、表題化合物（２．９ｍｇ、収率６．０％）を白色粉末として得た。

^１Ｈ−ＮＭＲ（ＣＤＣｌ_３）δ：１．７９（３Ｈ，ｄｄｄ，Ｊ＝１３．９，１２．７，６．５Ｈｚ），１．９７（２Ｈ，ｄ，Ｊ＝１２．７Ｈｚ），２．４２−２．６８（４Ｈ，ｂｒ ｍ），３．４１（２Ｈ，ｓ），３．５７（２Ｈ，ｓ），４．６６（２Ｈ，ｓ），５．６４（１Ｈ，ｂｒ ｓ），７．４３（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ），７．５２−７．６４（１Ｈ，ｂｒ ｍ），７．５７（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ），８．５８（１Ｈ，ｄ，Ｊ＝１．３Ｈｚ），９．３４（１Ｈ，ｄ，Ｊ＝１．３Ｈｚ）．

ＬＣ／ＭＳ［条件１］：保持時間０．８０分；ｍ／ｚ４４９．９［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ４４８．０［Ｍ−Ｈ］⁻、４９３．７［Ｍ＋ＨＣＯＯ］⁻（ＥＳＩ負イオンモード）

Example 465
5-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl}} methyl) pyrazine-2-carboxamide ( Preparation of Compound No. 465) 3-[(5-carbamoylpyrazin-2-yl) methyl] -2-oxo-1-oxa-3,8-diazaspiro [4.5] decane- obtained in Example 446 T-butyl 8-carboxylate (43 mg, 0.11 mmol) was dissolved in methanol (2.0 mL), 10% hydrogen chloride-methanol solution (0.28 mL) was added at room temperature, and 1 day at room temperature. Stir. After completion of the reaction, the reaction mixture was concentrated to dryness under reduced pressure. The resulting white solid was dissolved in N, N-dimethylformamide (1.0 mL) and triethylamine (0.037 mL, 0.26 mmol) and 4- (trifluoromethyl) benzyl bromide (29 mg, 0.11 mmol) at room temperature. ) And stirred at room temperature for 1 day. After completion of the reaction, ethyl acetate and water were added, and the organic layer was dried over anhydrous sodium sulfate and concentrated to dryness under reduced pressure. The obtained reaction residue was purified by silica gel column chromatography [filler: FL100D manufactured by Fuji Silysia, developing solvent: chloroform / methanol = 30/1] to give the title compound (2.9 mg, yield 6.0%). Obtained as a white powder.

¹ H-NMR (CDCl ₃ ) δ: 1.79 (3H, ddd, J = 13.9, 12.7, 6.5 Hz), 1.97 (2H, d, J = 12.7 Hz), 2. 42-2.68 (4H, br m), 3.41 (2H, s), 3.57 (2H, s), 4.66 (2H, s), 5.64 (1H, br s), 7 .43 (2H, d, J = 8.2 Hz), 7.52-7.64 (1H, br m), 7.57 (2H, d, J = 8.2 Hz), 8.58 (1H, d , J = 1.3 Hz), 9.34 (1H, d, J = 1.3 Hz).

LC / MS [Condition 1]: Retention time 0.80 min; m / z 449.9 [M + H] ⁺ (ESI positive ion mode), m / z 448.0 [M−H] ⁻ , 493.7 [M + HCOO] ⁻ (ESI negative ion mode)

参考例４６６
３−［４−（４−ベンゾイルピペリジン−１−カルボニル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−２−オン塩酸塩の製造
２−オキソ−３−［（（１ｒ，４ｒ）−４−｛［（テトラヒドロフラン−２−イル）メチル］カルバモイル｝シクロヘキシル）メチル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−８−カルボン酸ｔ−ブチルの代わりに、実施例１５８で得られた３−［４−（４−ベンゾイルピペリジン−１−カルボニル）ベンジル］−２−オキソ−１−オキサ−３，８−ジアザスピロ［４．５］デカン−８−カルボン酸ｔ−ブチルを用いること以外は実質的に実施例３と同様に反応を行って表題化合物（１．１ｇ、定量的）を無色無定形物として得た。

^１Ｈ−ＮＭＲ（３００ＭＨｚ、ＣＤＣｌ_３）δ：１．７０−２．１４（６Ｈ，ｍ），２．２５（２Ｈ，ｔ，Ｊ＝９．８Ｈｚ），２．９２−４．０２（１０Ｈ，ｍ），４．４４（２Ｈ，ｓ），４．６７（１Ｈ，ｂｒ ｓ），７．３０（２Ｈ，ｄ，Ｊ＝７．４Ｈｚ），７．３６−７．５４（４Ｈ，ｍ），７．５９（１Ｈ，ｔ，Ｊ＝７．４Ｈｚ），７．９４（２Ｈ，ｄ，Ｊ＝７．０Ｈｚ），９．７０（１Ｈ，ｓ）．
ＬＣ／ＭＳ［条件１］：保持時間３．１６分；ｍ／ｚ４６１．９［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）

Reference Example 466
Preparation of 3- [4- (4-benzoylpiperidine-1-carbonyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-2-one hydrochloride 2-oxo-3-[(( 1r, 4r) -4-{[(Tetrahydrofuran-2-yl) methyl] carbamoyl} cyclohexyl) methyl] -1-oxa-3,8-diazaspiro [4.5] decan-8-carboxyl instead of t-butyl 3- [4- (4-benzoylpiperidine-1-carbonyl) benzyl] -2-oxo-1-oxa-3,8-diazaspiro [4.5] decane-8-carvone obtained in Example 158 The reaction was carried out substantially in the same manner as in Example 3 except for using t-butyl acid to obtain the title compound (1.1 g, quantitative) as a colorless amorphous product.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.70-2.14 (6H, m), 2.25 (2H, t, J = 9.8 Hz), 2.92-4.02 (10H, m), 4.44 (2H, s), 4.67 (1H, br s), 7.30 (2H, d, J = 7.4 Hz), 7.36-7.54 (4H, m), 7.59 (1H, t, J = 7.4 Hz), 7.94 (2H, d, J = 7.0 Hz), 9.70 (1H, s).
LC / MS [Condition 1]: Retention time 3.16 minutes; m / z 461.9 [M + H] ⁺ (ESI positive ion mode)

実施例４６６
４−（｛３−［４−（４−ベンゾイルピペリジン−１−カルボニル）ベンジル］−２−オキソ−１−オキサ−３，８−ジアザ−スピロ［４．５］デカン−８−イル｝メチル）−３，５−ジフルオロベンゾニトリル（化合物番号４６６）の製造
（１ｒ，４ｒ）−４−［（２−オキソ−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル）メチル］−Ｎ−［（テトラヒドロフラン−２−イル）メチル］シクロヘキサンカルボキサミド塩酸塩の代わりに、参考例４６６で得られた、３−［４−（４−ベンゾイルピペリジン−１−カルボニル）ベンジル］−１−オキサ−３，８−ジアザ−スピロ［４．５］デカン−２−オン塩酸塩を用いることと、３，５‐ビス（トリフルオロメチル）ベンズアルデヒドの代わりに、３，５−ジフルオロ−４−ホルミルベンゾニトリル（市販）を用いること以外は実質的に実施例２３５と同様に反応を行なって、表題化合物（２１．４ｍｇ、収率７０％）を白色粉末として得た。

^１Ｈ−ＮＭＲ（ＣＤＣｌ_３）δ：１．５４−２．０３（８Ｈ，ｍ），２．４４−２．７０（４Ｈ，ｂｒ ｍ），３．０３−３．２６（２Ｈ，ｍ），３．１０（２Ｈ，ｓ），３．４９−３．６１（１Ｈ，ｍ），３．７３（２Ｈ，ｓ），３．７６−３．９７（１Ｈ，ｂｒ ｍ），４．４３（２Ｈ，ｓ），４．５０−４．８２（１Ｈ，ｂｒ ｍ），７．２１（２Ｈ，ｄ，Ｊ＝５．７Ｈｚ），７．２９（２Ｈ，ｄ，Ｊ＝７．８Ｈｚ），７．４１（２Ｈ，ｄ，Ｊ＝７．８Ｈｚ），７．４９（２Ｈ，ｔ，Ｊ＝７．４Ｈｚ），７．５９（１Ｈ，ｔ，Ｊ＝７．４Ｈｚ），７．９５（２Ｈ，ｄ，Ｊ＝７．４Ｈｚ）．

ＬＣ／ＭＳ［条件１］：保持時間３．３０分；ｍ／ｚ６１３．０［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ６４７．０［Ｍ＋Ｃｌ］⁻、６５７．１［Ｍ＋ＨＣＯＯ］⁻（ＥＳＩ負イオンモード）

Example 466
4-({3- [4- (4-Benzoylpiperidine-1-carbonyl) benzyl] -2-oxo-1-oxa-3,8-diaza-spiro [4.5] decan-8-yl} methyl) Preparation of 3,5-difluorobenzonitrile (Compound No. 466) (1r, 4r) -4-[(2-oxo-1-oxa-3,8-diazaspiro [4.5] decan-3-yl) methyl ] -N-[(tetrahydrofuran-2-yl) methyl] cyclohexanecarboxamide hydrochloride instead of 3- [4- (4-benzoylpiperidine-1-carbonyl) benzyl] -1- obtained in Reference Example 466 Using oxa-3,8-diaza-spiro [4.5] decan-2-one hydrochloride and 3,5-difluoro instead of 3,5-bis (trifluoromethyl) benzaldehyde Except using 4-formyl-benzonitrile (commercially available) is carried out the same reaction as substantially Example 235 to give the title compound (21.4 mg, 70% yield) as a white powder.

¹ H-NMR (CDCl ₃ ) δ: 1.54-2.03 (8H, m), 2.44-2.70 (4H, br m), 3.03-3.26 (2H, m), 3.10 (2H, s), 3.49-3.61 (1H, m), 3.73 (2H, s), 3.76-3.97 (1H, br m), 4.43 (2H , S), 4.50-4.82 (1H, br m), 7.21 (2H, d, J = 5.7 Hz), 7.29 (2H, d, J = 7.8 Hz), 7. 41 (2H, d, J = 7.8 Hz), 7.49 (2H, t, J = 7.4 Hz), 7.59 (1H, t, J = 7.4 Hz), 7.95 (2H, d , J = 7.4 Hz).

LC / MS [Condition 1]: Retention time 3.30 minutes; m / z 613.0 [M + H] ⁺ (ESI positive ion mode), m / z 647.0 [M + Cl] ⁻ , 657.1 [M + HCOO] ⁻ (ESI Negative ion mode)

参考例４６７−１
（１ｒ，４ｒ）−４−（｛８−［２−メトキシ−４−（トリフルオロメチル）ベンジル］−２−オキソ−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル］｝メチル）シクロヘキサンカルボン酸メチルの製造
３，５−ジフルオロ−４−ホルミルベンゾニトリルの代わりに、２−メトキシ−４−（トリフルオロメチル）ベンズアルデヒド（市販）を用いること以外は実質的に参考例３９８−１と同様に反応を行なって、表題化合物（０．６８ｇ、収率８４％）を白色粉末として得た。

^１Ｈ−ＮＭＲ（ＣＤＣｌ_３）δ：１．０２（２Ｈ，ｄｑ，Ｊ＝３．３，１２．７Ｈｚ），１．４１（２Ｈ，ｄｑ，Ｊ＝３．３，１３．１Ｈｚ），１．５０−２．０９（９Ｈ，ｍ），２．２５（１Ｈ，ｔｔ，Ｊ＝１２．３，３．３Ｈｚ），２．４８−２．７６（４Ｈ，ｂｒ ｍ），３．０９（２Ｈ，ｄ，Ｊ＝７．４Ｈｚ），３．２６（２Ｈ，ｓ），３．６０（２Ｈ，ｓ），３．６６（３Ｈ，ｓ），３．８６（３Ｈ，ｓ），７．０５（１Ｈ，ｂｒ ｓ），７．２０（１Ｈ，ｄ，Ｊ＝７．８Ｈｚ），７．４６（１Ｈ，ｄ，Ｊ＝７．８Ｈｚ）．

ＬＣ／ＭＳ［条件１］：保持時間３．１４分；ｍ／ｚ４９９．０［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）

Reference Example 467-1
(1r, 4r) -4-({8- [2-methoxy-4- (trifluoromethyl) benzyl] -2-oxo-1-oxa-3,8-diazaspiro [4.5] decan-3-yl ]} Production of methyl) cyclohexanecarboxylate Substantially Reference Example except that 2-methoxy-4- (trifluoromethyl) benzaldehyde (commercially available) is used instead of 3,5-difluoro-4-formylbenzonitrile The reaction was carried out in the same manner as 398-1 to give the title compound (0.68 g, yield 84%) as a white powder.

¹ H-NMR (CDCl ₃ ) δ: 1.02 (2H, dq, J = 3.3, 12.7 Hz), 1.41 (2H, dq, J = 3.3, 13.1 Hz), 1. 50-2.09 (9H, m), 2.25 (1H, tt, J = 12.3, 3.3 Hz), 2.48-2.76 (4H, br m), 3.09 (2H, d, J = 7.4 Hz), 3.26 (2H, s), 3.60 (2H, s), 3.66 (3H, s), 3.86 (3H, s), 7.05 (1H) , Br s), 7.20 (1H, d, J = 7.8 Hz), 7.46 (1H, d, J = 7.8 Hz).

LC / MS [Condition 1]: Retention time 3.14 minutes; m / z 499.0 [M + H] ⁺ (ESI positive ion mode)

参考例４６７−２
（１ｒ，４ｒ）−４−（｛８−［２−メトキシ−４−（トリフルオロメチル）ベンジル］−２−オキソ−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）シクロヘキサンカルボン酸の製造
参考例４６７−１で得られた（１ｒ，４ｒ）−４−（{８−[２−メトキシ−４−（トリフルオロメチル）ベンジル]−２−オキソ−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル}メチル）シクロヘキサンカルボン酸メチル（０．６５ｇ、１．３ｍｍｏｌ）を１，４−ジオキサンに溶解し、１．０Ｍ水酸化ナトリウム水溶液（１．９ｍＬ）を加えて、室温にて終夜かき混ぜた。反応混合物を減圧下濃縮して１，４−ジオキサンを留去し、水（２．０ｍＬ）を加えた。１．０Ｍ塩酸をｐＨ６になるまで加え、析出した固体をろ取し、表題化合物（０．５９ｇ、収率９４％）を白色粉末として得た。

ＬＣ／ＭＳ［条件１］：保持時間２．８２分；ｍ／ｚ４８４．８［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ４８３．０［Ｍ−Ｈ］^―（ＥＳＩ負イオンモード）

Reference Example 467-2
(1r, 4r) -4-({8- [2-methoxy-4- (trifluoromethyl) benzyl] -2-oxo-1-oxa-3,8-diazaspiro [4.5] decan-3-yl } Production of methyl) cyclohexanecarboxylic acid (1r, 4r) -4-({8- [2-methoxy-4- (trifluoromethyl) benzyl] -2-oxo-1-) obtained in Reference Example 467-1 Oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl) cyclohexanecarboxylate methyl (0.65 g, 1.3 mmol) is dissolved in 1,4-dioxane and 1.0 M aqueous sodium hydroxide solution is dissolved. (1.9 mL) was added and stirred overnight at room temperature. The reaction mixture was concentrated under reduced pressure to distill off 1,4-dioxane, and water (2.0 mL) was added. 1.0 M hydrochloric acid was added until the pH reached 6, and the precipitated solid was collected by filtration to give the title compound (0.59 g, yield 94%) as a white powder.

LC / MS [Condition 1]: Retention time 2.82 minutes; m / z 484.8 [M + H] ⁺ (ESI positive ion mode), m / z 483.0 [M−H] ⁻ (ESI negative ion mode)

実施例４６７
４−｛１−［（１ｒ，４ｒ）−４−（｛８−［２−メトキシ−４−（トリフルオロメチル）ベンジル］−２−オキソ−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）シクロヘキサンカルボニル］アゼチジン−３−イルオキシ｝ベンゾニトリル（化合物番号４６７）の製造
（１ｒ，４ｒ）−４−（｛２−オキソ−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）シクロヘキサンカルボン酸の代わりに、参考例４６７−２で得られた（１ｒ，４ｒ）−４−（｛８−［２−メトキシ−４−（トリフルオロメチル）ベンジル］−２−オキソ−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）シクロヘキサンカルボン酸を、テトラヒドロフルフリルアミンの代わりに参考例３８３−２で得られた４−（アゼチジン−３−イルオキシ）ベンゾニトリル塩酸塩を用いること以外は実質的に実施例１０と同様に反応を行なって、表題化合物（３３ｍｇ、収率８４％）を白色固体として得た。

^１Ｈ−ＮＭＲ（３００ＭＨｚ，ＣＤＣｌ_３）δ：１．０１（２Ｈ，ｑ，Ｊ＝１１．９Ｈｚ），１．５３（２Ｈ，ｑ，Ｊ＝１３．５Ｈｚ），１．６２−１．８７（７Ｈ，ｍ），１．９４（２Ｈ，ｄ，Ｊ＝１２．９Ｈｚ），２．１３（１Ｈ，ｔｔ，Ｊ＝１２．２，３．３Ｈｚ），２．５２−２．６８（４Ｈ，ｍ），３．１０（２Ｈ，ｄ，Ｊ＝７．３Ｈｚ），３．２５（２Ｈ，ｓ），３．６０（２Ｈ，ｓ），３．８６（３Ｈ，ｓ），４．０５（１Ｈ，ｄｄ，Ｊ＝１０．９，４．３Ｈｚ），４．２０（１Ｈ，ｄｄ，Ｊ＝９．２，３．３Ｈｚ），４．３９（１Ｈ，ｄｄ，Ｊ＝１０．９，６．６Ｈｚ），４．５５（１Ｈ，ｄｄ，Ｊ＝９．６，６．９Ｈｚ），４．９９（１Ｈ，ｔｔ，Ｊ＝６．３，３．３Ｈｚ），６．８１（２Ｈ，ｄ，Ｊ＝８．６Ｈｚ），７．０６（１Ｈ，ｓ），７．２０（１Ｈ，ｄ，Ｊ＝７．９Ｈｚ），７．４７（１Ｈ，ｄ，Ｊ＝７．９Ｈｚ），７．６２（２Ｈ，ｄ，Ｊ＝８．３Ｈｚ）．

ＬＣ／ＭＳ［条件１］：保持時間３．２６分；ｍ／ｚ６４１．１［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ６８５．２［Ｍ＋ＨＣＯＯ］^―（ＥＳＩ負イオンモード）

Example 467
4- {1-[(1r, 4r) -4-({8- [2-methoxy-4- (trifluoromethyl) benzyl] -2-oxo-1-oxa-3,8-diazaspiro [4.5 ] Decan-3-yl} methyl) cyclohexanecarbonyl] azetidin-3-yloxy} benzonitrile (Compound No. 467) (1r, 4r) -4-({2-oxo-8- [4- (trifluoromethyl) )] Benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl) (1r, 4r) -4- obtained in Reference Example 467-2 instead of cyclohexanecarboxylic acid ({8- [2-methoxy-4- (trifluoromethyl) benzyl] -2-oxo-1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl) cyclohexanecarboxylic acid The reaction was conducted in substantially the same manner as in Example 10 except that 4- (azetidin-3-yloxy) benzonitrile hydrochloride obtained in Reference Example 383-2 was used instead of tetrahydrofurfurylamine to give the title compound ( 33 mg, 84% yield) was obtained as a white solid.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.01 (2H, q, J = 11.9 Hz), 1.53 (2H, q, J = 13.5 Hz), 1.62-1.87 ( 7H, m), 1.94 (2H, d, J = 12.9 Hz), 2.13 (1H, tt, J = 12.2, 3.3 Hz), 2.52-2.68 (4H, m ), 3.10 (2H, d, J = 7.3 Hz), 3.25 (2H, s), 3.60 (2H, s), 3.86 (3H, s), 4.05 (1H, dd, J = 10.9, 4.3 Hz), 4.20 (1H, dd, J = 9.2, 3.3 Hz), 4.39 (1H, dd, J = 10.9, 6.6 Hz) , 4.55 (1H, dd, J = 9.6, 6.9 Hz), 4.99 (1H, tt, J = 6.3, 3.3 Hz), 6.81 (2H, d, J = 8) .6Hz), .06 (1H, s), 7.20 (1H, d, J = 7.9 Hz), 7.47 (1H, d, J = 7.9 Hz), 7.62 (2H, d, J = 8. 3 Hz).

LC / MS [condition 1]: retention time 3.26 minutes; m / z 641.1 [M + H] ⁺ (ESI positive ion mode), m / z 685.2 [M + HCOO] ⁻ (ESI negative ion mode)

実施例４６８
（１ｒ，４ｒ）−４−（｛８−［２−メトキシ−４−（トリフルオロメチル）ベンジル］−２−オキソ−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）−Ｎ−［（テトラヒドロフラン−２−イル）メチル］シクロヘキサンカルボキサミド（化合物番号４６８）の製造
（１ｒ，４ｒ）−４−（｛２−オキソ−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）シクロヘキサンカルボン酸の代わりに、参考例４６７−２で得られた（１ｒ，４ｒ）−４−（｛８−［２−メトキシ−４−（トリフルオロメチル）ベンジル］−２−オキソ−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）シクロヘキサンカルボン酸を用いること以外は実質的に実施例１０と同様に反応を行なって、表題化合物（３１ｍｇ、収率８９％）を淡黄色固体として得た。

^１Ｈ−ＮＭＲ（３００ＭＨｚ，ＣＤＣｌ_３）δ：１．０２（２Ｈ，ｑｄ，Ｊ＝１１．５，２．９Ｈｚ），１．４８（２Ｈ，ｑｄ，Ｊ＝１３．５，３．３Ｈｚ），１．５８−１．６７（１Ｈ，ｍ），１．７２−２．０３（１２Ｈ，ｍ），２．０４（１Ｈ，ｔｔ，Ｊ＝１１．５，４．１Ｈｚ），２．５４−２．６７（４Ｈ，ｍ），３．０９（２Ｈ，ｄ，Ｊ＝７．４Ｈｚ），３．１１（１Ｈ，ｄｄｄ，Ｊ＝１３．９，７．０，４．５Ｈｚ），３．２５（２Ｈ，ｓ），３．５８（１Ｈ，ｄｄｄ，Ｊ＝１３．５，６．５，３．３Ｈｚ），３．６０（２Ｈ，ｓ），３．７５（１Ｈ，ｄｔ，Ｊ＝８．２，７．０Ｈｚ），３．８５（１Ｈ，ｄｔ，Ｊ＝８．２，６．１Ｈｚ），３．８７（３Ｈ，ｓ），３．９４（１Ｈ，ｑｄ，Ｊ＝７．０，２．９Ｈｚ），５．７９（１Ｈ，ｔ，Ｊ＝５．７Ｈｚ），７．０６（１Ｈ，ｓ），７．２０（１Ｈ，ｄ，Ｊ＝８．２Ｈｚ），７．４７（１Ｈ，ｄ，Ｊ＝７．４Ｈｚ）．

ＬＣ／ＭＳ［条件１］：保持時間２．９０分；ｍ／ｚ５６７．９［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ６１２．２［Ｍ＋ＨＣＯＯ］^―（ＥＳＩ負イオンモード）

Example 468
(1r, 4r) -4-({8- [2-methoxy-4- (trifluoromethyl) benzyl] -2-oxo-1-oxa-3,8-diazaspiro [4.5] decan-3-yl } Methyl) -N-[(tetrahydrofuran-2-yl) methyl] cyclohexanecarboxamide (Compound No. 468) (1r, 4r) -4-({2-oxo-8- [4- (trifluoromethyl) benzyl ] -L-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl) (1r, 4r) -4-({ 8- [2-methoxy-4- (trifluoromethyl) benzyl] -2-oxo-1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl) cyclohexanecarboxylic acid It except by performing the same reaction as substantially Example 10 to give the title compound (31 mg, 89% yield) as a pale yellow solid.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.02 (2H, qd, J = 11.5, 2.9 Hz), 1.48 (2H, qd, J = 13.5, 3.3 Hz), 1.58-1.67 (1H, m), 1.72-2.03 (12H, m), 2.04 (1H, tt, J = 11.5, 4.1 Hz), 2.54-2 .67 (4H, m), 3.09 (2H, d, J = 7.4 Hz), 3.11 (1H, ddd, J = 13.9, 7.0, 4.5 Hz), 3.25 ( 2H, s), 3.58 (1H, ddd, J = 13.5, 6.5, 3.3 Hz), 3.60 (2H, s), 3.75 (1H, dt, J = 8.2) 7.0 Hz), 3.85 (1H, dt, J = 8.2, 6.1 Hz), 3.87 (3H, s), 3.94 (1H, qd, J = 7.0, 2. 9 Hz), 5. 9 (1H, t, J = 5.7 Hz), 7.06 (1H, s), 7.20 (1H, d, J = 8.2 Hz), 7.47 (1H, d, J = 7.4 Hz) ).

LC / MS [Condition 1]: Retention time 2.90 minutes; m / z 567.9 [M + H] ⁺ (ESI positive ion mode), m / z 612.2 [M + HCOO] ⁻ (ESI negative ion mode)

実施例４６９
８−［２−メトキシ−４−（トリフルオロメチル）ベンジル］−３−（｛（１ｒ，４ｒ）−４−［４−（キノリン−４−イル）ピペラジン−１−カルボニル］シクロヘキシル｝メチル）−１−オキサ−３，８−ジアザスピロ［４．５］デカン−２−オン（化合物番号４６９）の製造
（１ｒ，４ｒ）−４−（｛２−オキソ−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）シクロヘキサンカルボン酸の代わりに、参考例４６７−２で得られた（１ｒ，４ｒ）−４−（｛８−［２−メトキシ−４−（トリフルオロメチル）ベンジル］−２−オキソ−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）シクロヘキサンカルボン酸を、テトラヒドロフルフリルアミンの代わりに参考例２７８−２で得られた４−（ピペラジン−１−イル）キノリン二塩酸塩を用いること以外は実質的に実施例１０と同様に反応を行なって、表題化合物（２２ｍｇ、収率５１％）を淡黄色固体として得た。

^１Ｈ−ＮＭＲ（３００ＭＨｚ，ＣＤＣｌ_３）δ：１．０８（２Ｈ，ｑ，Ｊ＝１１．５Ｈｚ），１．６１（２Ｈ，ｑ，Ｊ＝１３．５Ｈｚ），１．６１−１．７０（１Ｈ，ｍ），１．７４−１．９０（６Ｈ，ｍ），１．９１−２．０１（２Ｈ，ｍ），２．５２（１Ｈ，ｔｔ，Ｊ＝１２．３，３．７Ｈｚ），２．５４−２．６７（４Ｈ，ｍ），３．１２（２Ｈ，ｄ，Ｊ＝７．４Ｈｚ），３．１６−３．２７（４Ｈ，ｍ），３．２７（２Ｈ，ｓ），３．６０（２Ｈ，ｓ），３．７３−３．９５（４Ｈ，ｍ），３．８６（３Ｈ，ｓ），６．８５（１Ｈ，ｄ，Ｊ＝４．９Ｈｚ），７．０６（１Ｈ，ｓ），７．２０（１Ｈ，ｄ，Ｊ＝７．４Ｈｚ），７．４７（１Ｈ，ｄ，Ｊ＝７．８Ｈｚ），７．５２（１Ｈ，ｄｄｄ，Ｊ＝８．２，７．０，１．２Ｈｚ），７．６９（１Ｈ，ｄｄｄ，Ｊ＝８．２，６．５，１．６Ｈｚ），８．０３（１Ｈ，ｄ，Ｊ＝８．６Ｈｚ），８．０８（１Ｈ，ｄ，Ｊ＝８．２Ｈｚ），８．７７（１Ｈ，ｄ，Ｊ＝４．９Ｈｚ）．

ＬＣ／ＭＳ［条件１］：保持時間２．０７分；ｍ／ｚ６７９．９［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ７２４．３［Ｍ＋ＨＣＯＯ］^―（ＥＳＩ負イオンモード）

Example 469
8- [2-methoxy-4- (trifluoromethyl) benzyl] -3-({(1r, 4r) -4- [4- (quinolin-4-yl) piperazin-1-carbonyl] cyclohexyl} methyl)- Preparation of 1-oxa-3,8-diazaspiro [4.5] decan-2-one (Compound No. 469) (1r, 4r) -4-({2-oxo-8- [4- (trifluoromethyl) (1r, 4r) -4- () obtained in Reference Example 467-2 instead of [benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl) cyclohexanecarboxylic acid {8- [2-methoxy-4- (trifluoromethyl) benzyl] -2-oxo-1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl) cyclohexanecarboxylic acid is converted to tetrahydro F The reaction was conducted in substantially the same manner as in Example 10 except that 4- (piperazin-1-yl) quinoline dihydrochloride obtained in Reference Example 278-2 was used instead of furylamine to give the title compound (22 mg Yield 51%) as a pale yellow solid.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.08 (2H, q, J = 11.5 Hz), 1.61 (2H, q, J = 13.5 Hz), 1.61-1.70 ( 1H, m), 1.74-1.90 (6H, m), 1.91-2.01 (2H, m), 2.52 (1H, tt, J = 12.3, 3.7 Hz), 2.54-2.67 (4H, m), 3.12 (2H, d, J = 7.4 Hz), 3.16-3.27 (4H, m), 3.27 (2H, s), 3.60 (2H, s), 3.73-3.95 (4H, m), 3.86 (3H, s), 6.85 (1H, d, J = 4.9 Hz), 7.06 ( 1H, s), 7.20 (1H, d, J = 7.4 Hz), 7.47 (1H, d, J = 7.8 Hz), 7.52 (1H, ddd, J = 8.2, 7) .0, 1.2 Hz), .69 (1H, ddd, J = 8.2, 6.5, 1.6 Hz), 8.03 (1H, d, J = 8.6 Hz), 8.08 (1H, d, J = 8.2 Hz) ), 8.77 (1H, d, J = 4.9 Hz).

LC / MS [Condition 1]: Retention time 2.07 minutes; m / z 679.9 [M + H] ⁺ (ESI positive ion mode), m / z 724.3 [M + HCOO] ⁻ (ESI negative ion mode)

参考例４７０−１
（１ｒ，４ｒ）−４−[（２−オキソ−８−｛［６−（トリフルオロメチル）ピリジン−３−イル］メチル｝−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル）メチル］シクロヘキサンカルボン酸メチルの製造
３，５−ジフルオロ−４−ホルミルベンゾニトリルの代わりに、６−（トリフルオロメチル）ニコチンアルデヒド（市販）を用いること以外は実質的に参考例３９８−１と同様に反応を行なって、表題化合物（１．１ｇ、収率８７％）を白色粉末として得た。

^１Ｈ−ＮＭＲ（ＣＤＣｌ_３）δ：１．０２（２Ｈ，ｄｑ，Ｊ＝３．３，１２．９Ｈｚ），１．４１（２Ｈ，ｄｑ，Ｊ＝３．３，１３．１Ｈｚ），１．５１−１．６６（１Ｈ，ｍ），１．６８−１．８６（４Ｈ，ｍ），１．８８−２．０８（４Ｈ，ｍ），２．２５（１Ｈ，ｔｔ，Ｊ＝１２．３，３．６Ｈｚ），２．４９−２．６５（４Ｈ，ｂｒ ｍ），３．０９（２Ｈ，ｄ，Ｊ＝７．４Ｈｚ），３．２６（２Ｈ，ｓ），３．６１（２Ｈ，ｓ），３．６６（３Ｈ，ｓ），７．６５（１Ｈ，ｄ，Ｊ＝７．８Ｈｚ），７．８３（１Ｈ，ｄ，Ｊ＝７．８Ｈｚ），８．６８（１Ｈ，ｂｒ ｓ）．

ＬＣ／ＭＳ［条件１］：保持時間２．７５分；ｍ／ｚ４６９．７［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ４６７．８［Ｍ−Ｈ］⁻、ｍ／ｚ５０３．７［Ｍ＋Ｃｌ］⁻、５１３．８［Ｍ＋ＨＣＯＯ］⁻（ＥＳＩ負イオンモード）

Reference Example 470-1
(1r, 4r) -4-[(2-oxo-8-{[6- (trifluoromethyl) pyridin-3-yl] methyl} -1-oxa-3,8-diazaspiro [4.5] decane- Preparation of methyl 3-yl) methyl] cyclohexanecarboxylate Essentially Reference Example 398 except that 6- (trifluoromethyl) nicotinaldehyde (commercially available) was used instead of 3,5-difluoro-4-formylbenzonitrile. The reaction was conducted in the same manner as for -1 to give the title compound (1.1 g, yield 87%) as a white powder.

¹ H-NMR (CDCl ₃ ) δ: 1.02 (2H, dq, J = 3.3, 12.9 Hz), 1.41 (2H, dq, J = 3.3, 13.1 Hz), 1. 51-1.66 (1H, m), 1.68-1.86 (4H, m), 1.88-2.08 (4H, m), 2.25 (1H, tt, J = 12.3) , 3.6 Hz), 2.49-2.65 (4H, br m), 3.09 (2H, d, J = 7.4 Hz), 3.26 (2H, s), 3.61 (2H, s), 3.66 (3H, s), 7.65 (1H, d, J = 7.8 Hz), 7.83 (1H, d, J = 7.8 Hz), 8.68 (1H, br s) ).

LC / MS [Condition 1]: Retention time 2.75 minutes; m / z 469.7 [M + H] ⁺ (ESI positive ion mode), m / z 467.8 [M−H] ⁻ , m / z 503.7 [M + Cl ] ^- , 513.8 [M + HCOO] ^- (ESI negative ion mode)

参考例４７０−２
（１ｒ，４ｒ）−４−［（２−オキソ−８−｛［６−（トリフルオロメチル）ピリジン−３−イル］メチル｝−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル）メチル］シクロヘキサンカルボン酸の製造
３−｛［（１ｒ，４ｒ）−４−（メトキシカルボニル）シクロヘキシル］メチル｝−２−オキソ−１−オキサ−３，８−ジアザスピロ［４．５］デカン−８−カルボン酸ｔ−ブチルの代わりに、参考例４７０−１で得られた、（１ｒ，４ｒ）−４−［（２−オキソ−８−｛［６−（トリフルオロメチル）ピリジン−３−イル］メチル｝−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル）メチル］シクロヘキサンカルボン酸メチルを用いること以外は実質的に参考例２−３と同様に反応を行なって、表題化合物（０．５１ｇ、収率１００％）を白色粉末として得た。

^１Ｈ−ＮＭＲ（ＣＤＣｌ_３）δ：１．０４（２Ｈ，ｄｑ，Ｊ＝３．７，１２．３Ｈｚ），１．４２（２Ｈ，ｄｑ，Ｊ＝３．３，１３．０Ｈｚ），１．５１−１．６７（１Ｈ，ｍ），１．８０（４Ｈ，ｄｄ，Ｊ＝１３．９，９．０Ｈｚ），１．９４（２Ｈ，ｄ，Ｊ＝１３．０Ｈｚ），２．０６（２Ｈ，ｄ，Ｊ＝１３．０Ｈｚ），２．２８（１Ｈ，ｔｔ，Ｊ＝１２．３，３．７Ｈｚ），２．５０−２．６７（４Ｈ，ｂｒ ｍ），３．１０（２Ｈ，ｄ，Ｊ＝７．４Ｈｚ），３．２７（２Ｈ，ｓ），３．６２（２Ｈ，ｓ），７．６４（１Ｈ，ｄ，Ｊ＝８．２Ｈｚ），７．８３（１Ｈ，ｄ，Ｊ＝８．２Ｈｚ），８．６７（１Ｈ，ｓ）．

ＬＣ／ＭＳ［条件１］：保持時間０．９４分；ｍ／ｚ４５６．０［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ４５４．１［Ｍ−Ｈ］⁻（ＥＳＩ負イオンモード）

Reference Example 470-2
(1r, 4r) -4-[(2-oxo-8-{[6- (trifluoromethyl) pyridin-3-yl] methyl} -1-oxa-3,8-diazaspiro [4.5] decane- Preparation of 3 -yl) methyl] cyclohexanecarboxylic acid 3-{[(1r, 4r) -4- (methoxycarbonyl) cyclohexyl] methyl} -2-oxo-1-oxa-3,8-diazaspiro [4.5] (1r, 4r) -4-[(2-oxo-8-{[6- (trifluoromethyl) pyridine-] obtained in Reference Example 470-1 instead of t-butyl decane-8-carboxylate [3-yl] methyl} -1-oxa-3,8-diazaspiro [4.5] decan-3-yl) methyl] reacts in substantially the same manner as in Reference Example 2-3 except that methyl cyclohexanecarboxylate is used. And title it Things a (0.51 g, 100% yield) as a white powder.

¹ H-NMR (CDCl ₃ ) δ: 1.04 (2H, dq, J = 3.7, 12.3 Hz), 1.42 (2H, dq, J = 3.3, 13.0 Hz), 1. 51-1.67 (1H, m), 1.80 (4H, dd, J = 13.9, 9.0 Hz), 1.94 (2H, d, J = 13.0 Hz), 2.06 (2H , D, J = 13.0 Hz), 2.28 (1H, tt, J = 12.3, 3.7 Hz), 2.50-2.67 (4H, br m), 3.10 (2H, d , J = 7.4 Hz), 3.27 (2H, s), 3.62 (2H, s), 7.64 (1H, d, J = 8.2 Hz), 7.83 (1H, d, J = 8.2 Hz), 8.67 (1H, s).

LC / MS [Condition 1]: Retention time 0.94 minutes; m / z 456.0 [M + H] ⁺ (ESI positive ion mode), m / z 454.1 [M−H] ⁻ (ESI negative ion mode)

実施例４７０
３−｛［（１ｒ，４ｒ）−４−（４，４−ジフルオロピペリジン−１−カルボニル）シクロヘキシル］メチル｝−８−｛［６−（トリフルオロメチル）ピリジン−３−イル］メチル｝−１−オキサ−３，８−ジアザスピロ［４．５］デカン−２−オン（化合物番号４７０）の製造
（１ｒ，４ｒ）−４−（｛２−オキソ−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）シクロヘキサンカルボン酸の代わりに、参考例４７０−２で得られた（１ｒ，４ｒ）−４−［（２−オキソ−８−｛［６−（トリフルオロメチル）ピリジン−３−イル］メチル｝−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル）メチル］シクロヘキサンカルボン酸を、テトラヒドロフルフリルアミンの代わりに４、４−ジフルオロピペリジン塩酸塩とトリエチルアミンを用いること以外は実質的に実施例１０と同様に反応を行なって、表題化合物（３３ｍｇ、収率９０％）を白色固体として得た。

^１Ｈ−ＮＭＲ（３００ＭＨｚ，ＣＤＣｌ_３）δ：１．０６（２Ｈ，ｑ，Ｊ＝１１．４Ｈｚ），１．５６（２Ｈ，ｑ，Ｊ＝１２．９Ｈｚ），１．６０−１．６７（１Ｈ，ｍ），１．７９（６Ｈ，ｄ，Ｊ＝１２．２Ｈｚ），１．９５（６Ｈ，ｄ，Ｊ＝１２．９Ｈｚ），２．４６（１Ｈ，ｔｔ，Ｊ＝１１．９，３．３Ｈｚ），２．４８−２．６７（４Ｈ，ｍ），３．１１（２Ｈ，ｄ，Ｊ＝７．３Ｈｚ），３．２７（２Ｈ，ｓ），３．５９（２Ｈ，ｂｒｔ，Ｊ＝７．３Ｈｚ），３．６１（２Ｈ，ｓ），３．７２（２Ｈ，ｂｒｔ，Ｊ＝５．６Ｈｚ），７．６５（１Ｈ，ｄ，Ｊ＝７．９Ｈｚ），７．８４（１Ｈ，ｄ，Ｊ＝６．９Ｈｚ），８．６８（１Ｈ，ｓ）．

ＬＣ／ＭＳ［条件１］：保持時間２．９４分；ｍ／ｚ５５８．９［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ６０３．１［Ｍ＋ＨＣＯＯ］^―（ＥＳＩ負イオンモード）

Example 470
3-{[(1r, 4r) -4- (4,4-difluoropiperidine-1-carbonyl) cyclohexyl] methyl} -8-{[6- (trifluoromethyl) pyridin-3-yl] methyl} -1 Preparation of Oxa-3,8-diazaspiro [4.5] decan-2-one (Compound No. 470) (1r, 4r) -4-({2-oxo-8- [4- (trifluoromethyl) benzyl ) -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl) cyclohexanecarboxylic acid (1r, 4r) -4-[( 2-Oxo-8-{[6- (trifluoromethyl) pyridin-3-yl] methyl} -1-oxa-3,8-diazaspiro [4.5] decan-3-yl) methyl] cyclohexanecarboxylic acid. Tetrahydr The reaction was carried out substantially in the same manner as in Example 10 except that 4,4-difluoropiperidine hydrochloride and triethylamine were used instead of furfurylamine to obtain the title compound (33 mg, yield 90%) as a white solid. .

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.06 (2H, q, J = 11.4 Hz), 1.56 (2H, q, J = 12.9 Hz), 1.60-1.67 ( 1H, m), 1.79 (6H, d, J = 12.2 Hz), 1.95 (6H, d, J = 12.9 Hz), 2.46 (1H, tt, J = 11.9, 3) .3 Hz), 2.48-2.67 (4 H, m), 3.11 (2 H, d, J = 7.3 Hz), 3.27 (2 H, s), 3.59 (2 H, brt, J = 7.3 Hz), 3.61 (2H, s), 3.72 (2H, brt, J = 5.6 Hz), 7.65 (1H, d, J = 7.9 Hz), 7.84 (1H) , D, J = 6.9 Hz), 8.68 (1H, s).

LC / MS [Condition 1]: Retention time 2.94 minutes; m / z 558.9 [M + H] ⁺ (ESI positive ion mode), m / z 603.1 [M + HCOO] ⁻ (ESI negative ion mode)

実施例４７１
３−（｛（１ｒ，４ｒ）−４−［４−（トリフルオロメチル）ピペリジン−１−カルボニル］シクロヘキシル｝メチル）−８−｛［６−（トリフルオロメチル）ピリジン−３−イル］メチル｝−１−オキサ−３，８−ジアザスピロ［４．５］デカン−２−オン（化合物番号４７１）の製造
（１ｒ，４ｒ）−４−（｛２−オキソ−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）シクロヘキサンカルボン酸の代わりに、参考例４７０−２で得られた（１ｒ，４ｒ）−４−［（２−オキソ−８−｛［６−（トリフルオロメチル）ピリジン−３−イル］メチル｝−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル）メチル］シクロヘキサンカルボン酸を、テトラヒドロフルフリルアミンの代わりに４−（トリフルオロメチル）ピペリジン塩酸塩とトリエチルアミンを用いること以外は実質的に実施例１０と同様に反応を行なって、表題化合物（３６ｍｇ、収率９４％）を白色固体として得た。

^１Ｈ−ＮＭＲ（３００ＭＨｚ，ＣＤＣｌ_３）δ：１．０５（２Ｈ，ｑ，Ｊ＝１２．２Ｈｚ），１．３７−１．６７（５Ｈ，ｍ），１．７２−１．８６（６Ｈ，ｍ），１．８７−２．０２（４Ｈ，ｍ），２．１５−２．３５（１Ｈ，ｍ），２．３８−２．５３（２Ｈ，ｍ），２．５４−２．６４（４Ｈ，ｍ），３．０２（１Ｈ，ｔ，Ｊ＝１３．２Ｈｚ），３．１１（２Ｈ，ｄ，Ｊ＝７．３Ｈｚ），３．２７（２Ｈ，ｓ），３．６２（２Ｈ，ｓ），３．９９（１Ｈ，ｄ，Ｊ＝１１．６Ｈｚ），４．７６（１Ｈ，ｄ，Ｊ＝１２．６Ｈｚ），７．６５（１Ｈ，ｄ，Ｊ＝７．９Ｈｚ），７．８４（１Ｈ，ｄ，Ｊ＝７．６Ｈｚ），８．６８（１Ｈ，ｓ）．

ＬＣ／ＭＳ［条件１］：保持時間３．１６分；ｍ／ｚ５９０．９［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ６３５．２［Ｍ＋ＨＣＯＯ］^―（ＥＳＩ負イオンモード）

Example 471
3-({(1r, 4r) -4- [4- (trifluoromethyl) piperidine-1-carbonyl] cyclohexyl} methyl) -8-{[6- (trifluoromethyl) pyridin-3-yl] methyl} Preparation of -1-oxa-3,8-diazaspiro [4.5] decan-2-one (Compound No. 471) (1r, 4r) -4-({2-oxo-8- [4- (trifluoromethyl ) Benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl) (1r, 4r) -4- obtained in Reference Example 470-2 instead of cyclohexanecarboxylic acid [(2-Oxo-8-{[6- (trifluoromethyl) pyridin-3-yl] methyl} -1-oxa-3,8-diazaspiro [4.5] decan-3-yl) methyl] cyclohexanecarboxylic Acid The reaction was carried out in substantially the same manner as in Example 10 except that 4- (trifluoromethyl) piperidine hydrochloride and triethylamine were used instead of lahydrofurfurylamine to give the title compound (36 mg, 94% yield) in white Obtained as a solid.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.05 (2H, q, J = 12.2 Hz), 1.37-1.67 (5H, m), 1.72-1.86 (6H, m), 1.87-2.02 (4H, m), 2.15-2.35 (1H, m), 2.38-2.53 (2H, m), 2.54-2.64 ( 4H, m), 3.02 (1H, t, J = 13.2 Hz), 3.11 (2H, d, J = 7.3 Hz), 3.27 (2H, s), 3.62 (2H, s), 3.99 (1H, d, J = 11.6 Hz), 4.76 (1H, d, J = 12.6 Hz), 7.65 (1H, d, J = 7.9 Hz), 7. 84 (1H, d, J = 7.6 Hz), 8.68 (1H, s).

LC / MS [Condition 1]: retention time 3.16 minutes; m / z 590.9 [M + H] ⁺ (ESI positive ion mode), m / z 635.2 [M + HCOO] ⁻ (ESI negative ion mode)

実施例４７２
４−（１−｛（１ｒ，４ｒ）−４−［（２−オキソ−８−｛［６−（トリフルオロメチル）ピリジン−３−イル］メチル｝−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル）メチル］シクロヘキサンカルボニル｝ピペリジン−４−イルアミノ）ベンゾニトリル（化合物番号４７２）の製造
（１ｒ，４ｒ）−４−（｛２−オキソ−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）シクロヘキサンカルボン酸の代わりに、参考例４７０−２で得られた（１ｒ，４ｒ）−４−［（２−オキソ−８−｛［６−（トリフルオロメチル）ピリジン−３−イル］メチル｝−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル）メチル］シクロヘキサンカルボン酸を、テトラヒドロフルフリルアミンの代わりに参考例４４１−２で得られた４−（ピペリジン−４−イルアミノ）ベンゾニトリル二塩酸塩とトリエチルアミンを用いること以外は実質的に実施例１０と同様に反応を行なって、表題化合物（３０ｍｇ、収率７１％）を白色固体として得た。

^１Ｈ−ＮＭＲ（３００ＭＨｚ，ＣＤＣｌ_３）δ：１．０５（２Ｈ，ｑ，Ｊ＝１１．３Ｈｚ），１．３７（２Ｈ，ｑ，Ｊ＝１１．９Ｈｚ），１．４７−１．６７（３Ｈ，ｍ），１．７１−１．８６（６Ｈ，ｍ），１．９４（２Ｈ，ｄ，Ｊ＝１３．１Ｈｚ），２．１０（２Ｈ，ｂｒｔ，Ｊ＝１３．１Ｈｚ），２．４６（１Ｈ，ｔｔ，Ｊ＝１１．９，３．３Ｈｚ），２．５２−２．６５（４Ｈ，ｍ），２．８３（１Ｈ，ｔ，Ｊ＝１１．５Ｈｚ），３．１１（２Ｈ，ｄ，Ｊ＝７．４Ｈｚ），３．１９（１Ｈ，ｔ，Ｊ＝１１．９Ｈｚ），３．２７（２Ｈ，ｓ），３．５０−３．６４（１Ｈ，ｍ），３．６１（２Ｈ，ｓ），３．９０（１Ｈ，ｄ，Ｊ＝１４．３Ｈｚ），４．０９（１Ｈ，ｄ，Ｊ＝７．４Ｈｚ），４．５４（１Ｈ，ｄ，Ｊ＝１３．５Ｈｚ），６．５６（２Ｈ，ｄ，Ｊ＝８．６Ｈｚ），７．４３（２Ｈ，ｄ，Ｊ＝８．６Ｈｚ），７．６５（１Ｈ，ｄ，Ｊ＝７．８Ｈｚ），７．８４（１Ｈ，ｄ，Ｊ＝８．２Ｈｚ），８．６８（１Ｈ，ｓ）．

ＬＣ／ＭＳ［条件１］：保持時間３．１４分；ｍ／ｚ６３９．０［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ６８３．２［Ｍ＋ＨＣＯＯ］^―（ＥＳＩ負イオンモード）

Example 472
4- (1-{(1r, 4r) -4-[(2-oxo-8-{[6- (trifluoromethyl) pyridin-3-yl] methyl} -1-oxa-3,8-diazaspiro [ 4.5] Preparation of decan-3-yl) methyl] cyclohexanecarbonyl} piperidin-4-ylamino) benzonitrile (Compound No. 472) (1r, 4r) -4-({2-oxo-8- [4- ( (Trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl) cyclohexanecarboxylic acid, instead of (1r, 4r) obtained in Reference Example 470-2 -4-[(2-oxo-8-{[6- (trifluoromethyl) pyridin-3-yl] methyl} -1-oxa-3,8-diazaspiro [4.5] decan-3-yl) methyl ] Cyclohexane The rubonic acid was reacted in the same manner as in Example 10 except that 4- (piperidin-4-ylamino) benzonitrile dihydrochloride obtained in Reference Example 441-2 and triethylamine were used instead of tetrahydrofurfurylamine. To give the title compound (30 mg, 71% yield) as a white solid.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.05 (2H, q, J = 11.3 Hz), 1.37 (2H, q, J = 11.9 Hz), 1.47-1.67 ( 3H, m), 1.71-1.86 (6H, m), 1.94 (2H, d, J = 13.1 Hz), 2.10 (2H, brt, J = 13.1 Hz), 2. 46 (1H, tt, J = 11.9, 3.3 Hz), 2.52-2.65 (4H, m), 2.83 (1H, t, J = 11.5 Hz), 3.11 (2H , D, J = 7.4 Hz), 3.19 (1H, t, J = 11.9 Hz), 3.27 (2H, s), 3.50-3.64 (1H, m), 3.61 (2H, s), 3.90 (1H, d, J = 14.3 Hz), 4.09 (1H, d, J = 7.4 Hz), 4.54 (1H, d, J = 13.5 Hz) 6.56 (2H, d, J = 8.6 Hz), 7.43 (2H, d, J = 8.6 Hz), 7.65 (1H, d, J = 7.8 Hz), 7.84 (1H , D, J = 8.2 Hz), 8.68 (1H, s).

LC / MS [Condition 1]: Retention time 3.14 minutes; m / z 639.0 [M + H] ⁺ (ESI positive ion mode), m / z 683.2 [M + HCOO] ⁻ (ESI negative ion mode)

実施例４７３
１−｛（１ｒ，４ｒ）−４−［（２−オキソ−８−｛［６−（トリフルオロメチル）ピリジン−３−イル］メチル｝−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル）メチル］シクロヘキサンカルボニル｝ピペリジン−４−カルボニトリル（化合物番号４７３）の製造
（１ｒ，４ｒ）−４−（｛２−オキソ−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）シクロヘキサンカルボン酸の代わりに、参考例４７０−２で得られた（１ｒ，４ｒ）−４−［（２−オキソ−８−｛［６−（トリフルオロメチル）ピリジン−３−イル］メチル｝−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル）メチル］シクロヘキサンカルボン酸を、テトラヒドロフルフリルアミンの代わりに４−シアノピペリジンを用いること以外は実質的に実施例１０と同様に反応を行なって、表題化合物（３５ｍｇ、収率９６％）を淡黄色固体として得た。

^１Ｈ−ＮＭＲ（３００ＭＨｚ，ＣＤＣｌ_３）δ：１．０５（２Ｈ，ｑ，Ｊ＝１１．５Ｈｚ），１．５５（２Ｈ，ｑ，Ｊ＝１１．９Ｈｚ），１．５７−１．６７（１Ｈ，ｍ），１．７０−２．００（１２Ｈ，ｍ），２．４３（１Ｈ，ｔｔ，Ｊ＝１１．９，３．３Ｈｚ），２．４９−２．６６（４Ｈ，ｍ），２．９０（１Ｈ，ｄｔｔ，Ｊ＝７．４，４．１，４．１Ｈｚ），３．１１（２Ｈ，ｄ，Ｊ＝７．４Ｈｚ），３．２７（２Ｈ，ｓ），３．３８−３．８７（４Ｈ，ｍ），３．６２（２Ｈ，ｓ），７．６５（１Ｈ，ｄ，Ｊ＝７．８Ｈｚ），７．８４（１Ｈ，ｄ，Ｊ＝７．４Ｈｚ），８．６８（１Ｈ，ｓ）．

ＬＣ／ＭＳ［条件１］：保持時間２．１２分；ｍ／ｚ５４７．８［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ５９２．１［Ｍ＋ＨＣＯＯ］^―（ＥＳＩ負イオンモード）

Example 473
1-{(1r, 4r) -4-[(2-oxo-8-{[6- (trifluoromethyl) pyridin-3-yl] methyl} -1-oxa-3,8-diazaspiro [4.5 ] Decan-3-yl) methyl] cyclohexanecarbonyl} piperidine-4-carbonitrile (Compound No. 473) (1r, 4r) -4-({2-oxo-8- [4- (trifluoromethyl) benzyl] ) -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl) cyclohexanecarboxylic acid (1r, 4r) -4-[( 2-Oxo-8-{[6- (trifluoromethyl) pyridin-3-yl] methyl} -1-oxa-3,8-diazaspiro [4.5] decan-3-yl) methyl] cyclohexanecarboxylic acid. , Tet Except using 4-cyano-piperidine instead of tetrahydrofurfuryl amine is carried out the same reaction as substantially Example 10 to give the title compound (35 mg, 96% yield) as a pale yellow solid.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.05 (2H, q, J = 11.5 Hz), 1.55 (2H, q, J = 11.9 Hz), 1.57-1.67 ( 1H, m), 1.70-2.00 (12H, m), 2.43 (1H, tt, J = 11.9, 3.3 Hz), 2.49-2.66 (4H, m), 2.90 (1H, dtt, J = 7.4, 4.1, 4.1 Hz), 3.11 (2H, d, J = 7.4 Hz), 3.27 (2H, s), 3.38 -3.87 (4H, m), 3.62 (2H, s), 7.65 (1H, d, J = 7.8 Hz), 7.84 (1H, d, J = 7.4 Hz), 8 .68 (1H, s).

LC / MS [Condition 1]: Retention time 2.12 minutes; m / z 547.8 [M + H] ⁺ (ESI positive ion mode), m / z 592.1 [M + HCOO] ⁻ (ESI negative ion mode)

参考例４７４−１
４−[（２−オキソ−１−オキサ−３，９−ジアザスピロ[５.５]ウンデカン−３−イル）メチル]安息香酸メチルの製造
参考例２１７−３で得られた３−[４−(メトキシカルボニル)ベンジル]−２−オキソ−１−オキサ−３，９−ジアザスピロ[５.５]ウンデカン−９−カルボン酸ｔ−ブチル（０．３５ｇ、０．８４ｍｍｏｌ）のメタノール溶液（０．５ｍＬ）に４Ｍ塩化水素−ジオキサン溶液（５．０ｍＬ）を加えて１時間かき混ぜた。反応混合物を減圧下濃縮乾固した。得られた黄色油状物にクロロホルム（１０ｍＬ）と飽和炭酸水素ナトリウム水溶液（５．０ｍＬ）を加えて振とうし、有機層を分離した後、水層をクロロホルム（１０ｍＬ）で３回抽出した。合わせた有機層を無水硫酸マグネシウムで乾燥し、減圧下濃縮乾固して、表題化合物を黄色油状物（０．３０ｇ)として得た。得られた油状物は、未精製のまま次の反応に使用した。

Reference Example 474-1
Preparation of methyl 4-[(2-oxo-1-oxa-3,9-diazaspiro [5.5] undecan-3-yl) methyl] benzoate 3- [4- ( Methoxycarbonyl) benzyl] -2-oxo-1-oxa-3,9-diazaspiro [5.5] t-butyl-9-carboxylate (0.35 g, 0.84 mmol) in methanol (0.5 mL) 4M hydrogen chloride-dioxane solution (5.0 mL) was added and stirred for 1 hour. The reaction mixture was concentrated to dryness under reduced pressure. Chloroform (10 mL) and saturated aqueous sodium hydrogen carbonate solution (5.0 mL) were added to the obtained yellow oil and shaken to separate the organic layer. The aqueous layer was extracted three times with chloroform (10 mL). The combined organic layers were dried over anhydrous magnesium sulfate and concentrated to dryness under reduced pressure to give the title compound as a yellow oil (0.30 g). The obtained oil was used in the next reaction without purification.

参考例４７４−２
４−{[９−（４−シアノ−２，６−ジフルオロベンジル）−２−オキソ−１−オキサ−３，９−ジアザスピロ[５.５]ウンデカン−３−イル]メチル}安息香酸メチルの製造
参考例４７４−１で得られた４−[（２−オキソ−１−オキサ−３，９−ジアザスピロ[５.５]ウンデカン−３−イル）メチル]安息香酸メチル（０．３０ｇ）のジクロロメタン溶液（２．０ｍＬ）に３，５−ジフルオロ−４−ホルミルベンゾニトリル（アルドリッチ（株）より購入）（０．１５ｇ、０．９２ｍｍｏｌ）とトリアセトキシ水素化ホウ素ナトリウム（アルドリッチ社より購入）（０．２７ｇ、１．３ｍｍｏｌ）を加えて２時間かき混ぜた。反応混合物に炭酸水素ナトリウム水溶液（５．０ｍＬ）と酢酸エチル（５．０ｍＬ）を加えて振とうし、有機層を分離した後、水層を酢酸エチル（１０ｍＬ）で２回抽出した。合わせた有機層を飽和塩化ナトリウム水溶液（１０ｍＬ）で洗浄したのち、無水硫酸マグネシウムで乾燥し、減圧下濃縮乾固した。得られた黄色油状物にジエチルエーテルを加えた後、析出した固体をろ取して、表題化合物を黄色固体（０．２８ｇ、収率７１％）として得た。

^１Ｈ−ＮＭＲ（３００ＭＨｚ，ＣＤＣｌ_３）δ：１．５８−１．７１（２Ｈ，ｍ），１．７６−１．９０（２Ｈ，ｍ），１．８２（２Ｈ，ｔ，Ｊ＝６．１Ｈｚ），２．５８−２．７０（４Ｈ，ｍ），３．１８（２Ｈ，ｔ，Ｊ＝６．３Ｈｚ），３．７３（２Ｈ，ｓ），３．９２（３Ｈ，ｓ），４．６１（２Ｈ，ｓ），７．２２（２Ｈ，ｄ，Ｊ＝６．１Ｈｚ），７．３５（２Ｈ，ｄ，Ｊ＝７．８Ｈｚ），８．０１（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ）．

ＬＣ／ＭＳ［条件１］：保持時間１．７１分；ｍ／ｚ４６９．８［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）

Reference Example 474-2
4-{[9- (4-Cyano-2,6-difluorobenzyl) -2-oxo-1-oxa-3,9-diazaspiro [5.5] undecan-3-yl] methyl} Preparation of methylbenzoate A solution of methyl 4-[(2-oxo-1-oxa-3,9-diazaspiro [5.5] undecan-3-yl) methyl] benzoate (0.30 g) obtained in Reference Example 474-1 (2.0 mL) 3,5-difluoro-4-formylbenzonitrile (purchased from Aldrich Co.) (0.15 g, 0.92 mmol) and sodium triacetoxyborohydride (purchased from Aldrich) (0. 27 g, 1.3 mmol) was added and stirred for 2 hours. To the reaction mixture, an aqueous sodium hydrogen carbonate solution (5.0 mL) and ethyl acetate (5.0 mL) were added and shaken to separate the organic layer, and then the aqueous layer was extracted twice with ethyl acetate (10 mL). The combined organic layers were washed with a saturated aqueous sodium chloride solution (10 mL), dried over anhydrous magnesium sulfate, and concentrated to dryness under reduced pressure. Diethyl ether was added to the obtained yellow oil, and the precipitated solid was collected by filtration to give the title compound as a yellow solid (0.28 g, yield 71%).

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.58-1.71 (2H, m), 1.76-1.90 (2H, m), 1.82 (2H, t, J = 6. 1 Hz), 2.58-2.70 (4H, m), 3.18 (2H, t, J = 6.3 Hz), 3.73 (2H, s), 3.92 (3H, s), 4 .61 (2H, s), 7.22 (2H, d, J = 6.1 Hz), 7.35 (2H, d, J = 7.8 Hz), 8.01 (2H, d, J = 8. 2 Hz).

LC / MS [Condition 1]: Retention time 1.71 minutes; m / z 469.8 [M + H] ⁺ (ESI positive ion mode)

参考例４７４−３
４−{[９−（４−シアノ−２，６−ジフルオロベンジル）−２−オキソ−１−オキサ−３，９−ジアザスピロ[５.５]ウンデカン−３−イル]メチル}安息香酸の製造
参考例４７４−２で得られた４−{[９−（４−シアノ−２，６−ジフルオロベンジル）−２−オキソ−１−オキサ−３，９−ジアザスピロ[５.５]ウンデカン−３−イル]メチル}安息香酸メチル（８２ｍｇ、０．１７ｍｍｏｌ）のテトラヒドロフラン溶液（１．０ｍＬ）にカリウムトリメチルシラノラート（アルドリッチ社より購入）（３７ｍｇ、０．２６ｍｍｏｌ）を加えて４時間かき混ぜた。反応混合物に４Ｍ塩化水素−ジオキサン溶液（０．１３ｍＬ）を加えた後、酢酸エチル（５．０ｍＬ）と飽和炭酸水素ナトリウム水溶液（５．０ｍＬ）を加えて振とうし、水層を分離した。得られた水層に１Ｍ塩酸（５．０ｍＬ）と酢酸エチルを加えて振とうし、有機層を分離した後、水層を酢酸エチル（１０ｍＬ）で２回抽出した。合わせた有機層を飽和塩化ナトリウム水溶液（１０ｍＬ）で洗浄したのち、無水硫酸マグネシウムで乾燥し、減圧下濃縮乾固して、表題化合物を黄色固体（３２ｍｇ、収率４１％）として得た。

^１Ｈ−ＮＭＲ（３００ＭＨｚ，ＣＤＣｌ_３）δ：１．７４−１．９４（６Ｈ，ｍ），２．６８−２．９０（４Ｈ，ｂｒ ｍ），３．２１（２Ｈ，ｔ，Ｊ＝６．５Ｈｚ），３．８５（２Ｈ，ｓ），４．６２（２Ｈ，ｓ），７．２２（２Ｈ，ｄ，Ｊ＝６．５Ｈｚ），７．３６（２Ｈ，ｄ，Ｊ＝８．６Ｈｚ），８．０３（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ）．

ＬＣ／ＭＳ［条件１］：保持時間０．７０分；ｍ／ｚ４５５．８［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ４５３．９［Ｍ−Ｈ］^―（ＥＳＩ負イオンモード）

Reference Example 474-3
Preparation of 4-{[9- (4-cyano-2,6-difluorobenzyl) -2-oxo-1-oxa-3,9-diazaspiro [5.5] undecan-3-yl] methyl} benzoic acid 4-{[9- (4-Cyano-2,6-difluorobenzyl) -2-oxo-1-oxa-3,9-diazaspiro [5.5] undecan-3-yl obtained in Example 474-2 ] To a tetrahydrofuran solution (1.0 mL) of methyl} methyl benzoate (82 mg, 0.17 mmol), potassium trimethylsilanolate (purchased from Aldrich) (37 mg, 0.26 mmol) was added and stirred for 4 hours. A 4M hydrogen chloride-dioxane solution (0.13 mL) was added to the reaction mixture, and then ethyl acetate (5.0 mL) and saturated aqueous sodium hydrogen carbonate solution (5.0 mL) were added and shaken to separate the aqueous layer. To the obtained aqueous layer, 1 M hydrochloric acid (5.0 mL) and ethyl acetate were added and shaken to separate the organic layer, and then the aqueous layer was extracted twice with ethyl acetate (10 mL). The combined organic layers were washed with saturated aqueous sodium chloride solution (10 mL), dried over anhydrous magnesium sulfate, and concentrated to dryness under reduced pressure to give the title compound as a yellow solid (32 mg, 41% yield).

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.74-1.94 (6H, m), 2.68-2.90 (4H, br m), 3.21 (2H, t, J = 6) .5Hz), 3.85 (2H, s), 4.62 (2H, s), 7.22 (2H, d, J = 6.5 Hz), 7.36 (2H, d, J = 8.6 Hz) ), 8.03 (2H, d, J = 8.2 Hz).

LC / MS [Condition 1]: retention time 0.70 min; m / z 455.8 [M + H] ⁺ (ESI positive ion mode), m / z 453.9 [M−H] ⁻ (ESI negative ion mode)

実施例４７４
４−{[９−（４−シアノ−２，６−ジフルオロベンジル）−２−オキソ−１−オキサ−３，９−ジアザスピロ[５.５]ウンデカン−３−イル]メチル}−Ｎ−[(テトラヒドロフラン−２−イル)メチル]ベンズアミド（化合物番号４７４）の製造
４−({２−オキソ−９−[４−（トリフルオロメチル）ベンジル]−１−オキサ−３，９−ジアザスピロ[５.５]ウンデカン−３−イル}メチル)安息香酸の代わりに参考例４７４−３で得られた４−{[９−（４−シアノ−２，６−ジフルオロベンジル）−２−オキソ−１−オキサ−３，９−ジアザスピロ[５.５]ウンデカン−３−イル]メチル}安息香酸を用いること以外は実質的に実施例２１８と同様に反応を行なって、表題化合物を黄色油状物(１４ｍｇ、収率４７％)として得た。

^１Ｈ−ＮＭＲ（３００ＭＨｚ，ＣＤＣｌ_３）δ：１．５４−１．７５（３Ｈ，ｍ），１．７７−２．１０（７Ｈ，ｍ），２．６０−２．７８（４Ｈ，ｍ），３．１７（２Ｈ，ｔ，Ｊ＝６．１Ｈｚ），３．３２（１Ｈ，ｄｄｄ，Ｊ＝１３．９，７．４，４．５Ｈｚ），３．７２−３．９４（３Ｈ，ｍ），３．７５（２Ｈ，ｓ），４．０７（１Ｈ，ｄｑ，Ｊ＝３．３，７．４Ｈｚ），４．５９（２Ｈ，ｓ），６．５４（１Ｈ，ｔ，Ｊ＝４．９Ｈｚ），７．２０（２Ｈ，ｄ，Ｊ＝６．１Ｈｚ），７．３４（２Ｈ，ｄ，Ｊ＝８．６Ｈｚ），７．７５（２Ｈ，ｄ，Ｊ＝７．８Ｈｚ）．

ＬＣ／ＭＳ［条件１］：保持時間０．９４分；ｍ／ｚ５３８．９［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ５３６．９［Ｍ−Ｈ］^―（ＥＳＩ負イオンモード）

Example 474
4-{[9- (4-Cyano-2,6-difluorobenzyl) -2-oxo-1-oxa-3,9-diazaspiro [5.5] undecan-3-yl] methyl} -N-[( Preparation of Tetrahydrofuran-2-yl) methyl] benzamide (Compound No. 474) 4-({2-Oxo-9- [4- (trifluoromethyl) benzyl] -1-oxa-3,9-diazaspiro [5.5 ] 4-decano [3- (4-cyano-2,6-difluorobenzyl) -2-oxo-1-oxa-] obtained in Reference Example 474-3 instead of undecan-3-yl} methyl) benzoic acid The reaction was carried out in substantially the same manner as in Example 218 except that 3,9-diazaspiro [5.5] undecan-3-yl] methyl} benzoic acid was used to give the title compound as a yellow oil (14 mg, yield). 47%).

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.54-1.75 (3H, m), 1.77-2.10 (7H, m), 2.60-2.78 (4H, m) 3.17 (2H, t, J = 6.1 Hz), 3.32 (1H, ddd, J = 13.9, 7.4, 4.5 Hz), 3.72-3.94 (3H, m ), 3.75 (2H, s), 4.07 (1H, dq, J = 3.3, 7.4 Hz), 4.59 (2H, s), 6.54 (1H, t, J = 4) .9 Hz), 7.20 (2H, d, J = 6.1 Hz), 7.34 (2H, d, J = 8.6 Hz), 7.75 (2H, d, J = 7.8 Hz).

LC / MS [Condition 1]: Retention time 0.94 minutes; m / z 538.9 [M + H] ⁺ (ESI positive ion mode), m / z 536.9 [M−H] ⁻ (ESI negative ion mode)

実施例４７５
６−[１−（４−{[９−（４−シアノ−２，６−ジフルオロベンジル）−２−オキソ−１−オキサ−３，９−ジアザスピロ[５.５]ウンデカン−３−イル]メチル}ベンゾイル）アゼチジン−３−イルオキシ]ニコチノニトリル（化合物番号４７５）の製造
テトラヒドロフルフリルアミンの代わりに、参考例３８１−２で合成した６−（アゼチジン−３−イルオキシ）ニコチノニトリルを用いること以外は実質的に実施例４７４と同様に反応を行なって、表題化合物を無色油状物(１４ｍｇ、収率７０％)として得た。

^１Ｈ−ＮＭＲ（３００ＭＨｚ，ＣＤＣｌ_３）δ：１．５８−１．７３（２Ｈ，ｍ），１．７７−１．９２（２Ｈ，ｍ），１．８２（２Ｈ，ｔ，Ｊ＝６．２Ｈｚ），２．５６−２．７２（４Ｈ，ｍ），３．１９（２Ｈ，ｔ，Ｊ＝６．５Ｈｚ），３．７４（２Ｈ，ｓ），４．２２−４．３３（２Ｈ，ｍ），４．５１−４．７３（２Ｈ，ｂｒ ｍ），４．５８（２Ｈ，ｓ），５．４２−５．５２（１Ｈ，ｍ），６．９１（１Ｈ，ｄ，Ｊ＝８．６Ｈｚ），７．２２（２Ｈ，ｄ，Ｊ＝６．５Ｈｚ），７．３３（２Ｈ，ｄ，Ｊ＝７．８Ｈｚ），７．６２（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ），７．８５（１Ｈ，ｄｄ，Ｊ＝８．６，２．５Ｈｚ），８．４４（１Ｈ，ｄ，Ｊ＝２．５Ｈｚ）．

ＬＣ／ＭＳ［条件１］：保持時間２．８６分；ｍ／ｚ６１２．９［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ６５７．０［Ｍ＋ＨＣＯＯ］^―（ＥＳＩ負イオンモード）

Example 475
6- [1- (4-{[9- (4-Cyano-2,6-difluorobenzyl) -2-oxo-1-oxa-3,9-diazaspiro [5.5] undecan-3-yl] methyl } Preparation of Benzoyl) azetidin-3-yloxy] nicotinonitrile (Compound No. 475) Other than using 6- (azetidin-3-yloxy) nicotinonitrile synthesized in Reference Example 381-2 instead of tetrahydrofurfurylamine Was carried out in substantially the same manner as in Example 474 to give the title compound as a colorless oil (14 mg, yield 70%).

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.58-1.73 (2H, m), 1.77-1.92 (2H, m), 1.82 (2H, t, J = 6. 2Hz), 2.56-2.72 (4H, m), 3.19 (2H, t, J = 6.5 Hz), 3.74 (2H, s), 4.22-4.33 (2H, m), 4.51-4.73 (2H, br m), 4.58 (2H, s), 5.42-5.52 (1H, m), 6.91 (1H, d, J = 8) .6 Hz), 7.22 (2H, d, J = 6.5 Hz), 7.33 (2H, d, J = 7.8 Hz), 7.62 (2H, d, J = 8.2 Hz), 7 .85 (1H, dd, J = 8.6, 2.5 Hz), 8.44 (1H, d, J = 2.5 Hz).

LC / MS [Condition 1]: Retention time 2.86 minutes; m / z 612.9 [M + H] ⁺ (ESI positive ion mode), m / z 657.0 [M + HCOO] ⁻ (ESI negative ion mode)

実施例４７６
４−[（３−{４−[４−（３−シアノフェノキシ）ピペリジン−１−カルボニル]ベンジル}−２−オキソ−１−オキサ−３，９−ジアザスピロ[５.５]ウンデカン−９−イル）メチル]−３，５−ジフルオロベンゾニトリル（化合物番号４７６）の製造
テトラヒドロフルフリルアミンの代わりに、参考例２８１−２で合成した３−（ピペリジン−４−イルオキシ）ベンゾニトリル塩酸塩とトリエチルアミンを用いること以外は実質的に実施例４７４と同様に反応を行なって、表題化合物を無色油状物(１８ｍｇ、収率８６％)として得た。

^１Ｈ−ＮＭＲ（３００ＭＨｚ，ＣＤＣｌ_３）δ：１．５９−１．７３（２Ｈ，ｍ），１．７５−２．１３（８Ｈ，ｍ），２．６０−２．７０（４Ｈ，ｍ），３．１９（２Ｈ，ｔ，Ｊ＝６．２Ｈｚ），３．３１−３．５１（１Ｈ，ｂｒ ｍ），３．５５−４．０２（３Ｈ，ｂｒ ｍ），３．７４（２Ｈ，ｓ），４．５２−４．６７（１Ｈ，ｍ），４．５８（２Ｈ，ｓ），７．１２−７．１８（２Ｈ，ｍ），７．２２（２Ｈ，ｄ，Ｊ＝５．６Ｈｚ），７．２６（１Ｈ，ｄ，Ｊ＝７．４Ｈｚ），７．３３（２Ｈ，ｄ，Ｊ＝８．０Ｈｚ），７．３９（１Ｈ，ｔ，Ｊ＝７．４Ｈｚ），７．３９（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ）．

ＬＣ／ＭＳ［条件１］：保持時間３．１８分；ｍ／ｚ６４０．０［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ６８４．０［Ｍ＋ＨＣＯＯ］^―（ＥＳＩ負イオンモード）

Example 476
4-[(3- {4- [4- (3-Cyanophenoxy) piperidine-1-carbonyl] benzyl} -2-oxo-1-oxa-3,9-diazaspiro [5.5] undecan-9-yl ) Preparation of methyl] -3,5-difluorobenzonitrile (Compound No. 476) Instead of tetrahydrofurfurylamine, 3- (piperidin-4-yloxy) benzonitrile hydrochloride and triethylamine synthesized in Reference Example 281-2 were used. In substantially the same manner as in Example 474, the title compound was obtained as a colorless oil (18 mg, yield 86%).

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.59-1.73 (2H, m), 1.75-2.13 (8H, m), 2.60-2.70 (4H, m) , 3.19 (2H, t, J = 6.2 Hz), 3.31-3.51 (1H, br m), 3.55-4.02 (3H, br m), 3.74 (2H, s), 4.52-4.67 (1H, m), 4.58 (2H, s), 7.12-7.18 (2H, m), 7.22 (2H, d, J = 5. 6 Hz), 7.26 (1 H, d, J = 7.4 Hz), 7.33 (2 H, d, J = 8.0 Hz), 7.39 (1 H, t, J = 7.4 Hz), 7. 39 (2H, d, J = 8.2 Hz).

LC / MS [Condition 1]: Retention time 3.18 minutes; m / z 640.0 [M + H] ⁺ (ESI positive ion mode), m / z 684.0 [M + HCOO] ⁻ (ESI negative ion mode)

実施例４７７
４−{[９−（４−シアノ−２，６−ジフルオロベンジル）−２−オキソ−１−オキサ−３，９−ジアザスピロ[５.５]ウンデカン−３−イル]メチル}−Ｎ−（フラン−２−イルメチル）ベンズアミド（化合物番号４７７）の製造
テトラヒドロフルフリルアミンの代わりに、フルフリルアミン（東京化成工業社より購入）を用いること以外は実質的に実施例４７４と同様に反応を行なって、表題化合物を無色油状物(２２ｍｇ、収率９２％)として得た。

^１Ｈ−ＮＭＲ（３００ＭＨｚ，ＣＤＣｌ_３）δ：１．５７−１．８７（６Ｈ，ｍ），２．５６−２．６８（４Ｈ，ｍ），３．１６（２Ｈ，ｔ，Ｊ＝６．５Ｈｚ），３．７３（２Ｈ，ｓ），４．５８（２Ｈ，ｓ），４．６３（２Ｈ，ｄ，Ｊ＝５．７Ｈｚ），６．３０（１Ｈ，ｄ，Ｊ＝３．０Ｈｚ），６．３２−６．３６（１Ｈ，ｍ），６．５７（１Ｈ，ｔ，Ｊ＝５．３Ｈｚ），７．２１（２Ｈ，ｄ，Ｊ＝６．１Ｈｚ），７．３３（２Ｈ，ｄ，Ｊ＝８．６Ｈｚ），７．３８（１Ｈ，ｄ，Ｊ＝１．２Ｈｚ），７．７６（２Ｈ，ｄ，Ｊ＝８．６Ｈｚ）．

ＬＣ／ＭＳ［条件１］：保持時間１．６９分；ｍ／ｚ５３４．９［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ５３３．０［Ｍ−Ｈ］^―（ＥＳＩ負イオンモード）

Example 477
4-{[9- (4-Cyano-2,6-difluorobenzyl) -2-oxo-1-oxa-3,9-diazaspiro [5.5] undecan-3-yl] methyl} -N- (furan Preparation of 2-ylmethyl) benzamide (Compound No. 477) The reaction was conducted in substantially the same manner as in Example 474 except that furfurylamine (purchased from Tokyo Chemical Industry Co., Ltd.) was used instead of tetrahydrofurfurylamine. The compound was obtained as a colorless oil (22 mg, 92% yield).

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.57-1.87 (6H, m), 2.56-2.68 (4H, m), 3.16 (2H, t, J = 6. 5Hz), 3.73 (2H, s), 4.58 (2H, s), 4.63 (2H, d, J = 5.7 Hz), 6.30 (1H, d, J = 3.0 Hz) , 6.32-6.36 (1H, m), 6.57 (1H, t, J = 5.3 Hz), 7.21 (2H, d, J = 6.1 Hz), 7.33 (2H, d, J = 8.6 Hz), 7.38 (1H, d, J = 1.2 Hz), 7.76 (2H, d, J = 8.6 Hz).

LC / MS [Condition 1]: Retention time 1.69 minutes; m / z 534.9 [M + H] ⁺ (ESI positive ion mode), m / z 533.0 [M−H] ⁻ (ESI negative ion mode)

参考例４７８−１
３−（｛５−［４−（４−シアノフェノキシ）ピペリジン−１−カルボニル］ピラジン−２−イル｝メチル）−２−オキソ−１−オキサ−３，８−ジアザスピロ［４．５］デカン−８−カルボン酸ｔ−ブチルの製造

（４−フルオロフェニル）（ピペリジン−４−イル）メタノン塩酸塩の代わりに、参考例２６４−２で得られた４−（ピペリジン−４−イルオキシ）ベンゾニトリル塩酸塩を用いること以外は、実質的に参考例４４４−３と同様に反応を行って、表題化合物（４６ｍｇ、収率５３％）を黄色粉末として得た。

ＬＣ／ＭＳ［条件１］：保持時間４．１３分；ｍ／ｚ５２０．７［Ｍ−ｉｓｏｂｕｔｅｎｅ＋Ｈ］^＋、４７６．８［Ｍ−ｉｓｏｂｕｔｅｎｅ−ＣＯ_２＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ５７５．０［Ｍ−Ｈ］^―、６２１．０［Ｍ＋ＨＣＯＯ］^―（ＥＳＩ負イオンモード）

Reference Example 478-1
3-({5- [4- (4-Cyanophenoxy) piperidin-1-carbonyl] pyrazin-2-yl} methyl) -2-oxo-1-oxa-3,8-diazaspiro [4.5] decane- Production of t-butyl 8-carboxylate

Substantially except that 4- (piperidin-4-yloxy) benzonitrile hydrochloride obtained in Reference Example 264-2 is used instead of (4-fluorophenyl) (piperidin-4-yl) methanone hydrochloride. The reaction was carried out in the same manner as in Reference Example 444-3 to give the title compound (46 mg, yield 53%) as a yellow powder.

LC / MS [Condition 1]: Retention time 4.13 minutes; m / z 520.7 [M-isobutene + H] ⁺ , 476.8 [M-isobutene-CO ₂ + H] ⁺ (ESI positive ion mode), m / z 575 0.0 [M−H] ⁻ , 621.0 [M + HCOO] ⁻ (ESI negative ion mode)

参考例４７８−２
４−（１−｛５−［（２−オキソ−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル）メチル］ピラジン−２−カルボニル｝ピペリジン−４−イルオキシ）ベンゾニトリル塩酸塩の製造

３−（｛５−［４−（４−フルオロベンゾイル）ピペリジン−１−カルボニル］ピラジン−２−イル｝メチル）−２−オキソ−１−オキサ−３，８−ジアザスピロ［４．５］デカン−８−カルボン酸ｔ−ブチルの代わりに、参考例４７８−１で得られた３−（｛５−［４−（４−シアノフェノキシ）ピペリジン−１−カルボニル］ピラジン−２−イル｝メチル）−２−オキソ−１−オキサ−３，８−ジアザスピロ［４．５］デカン−８−カルボン酸ｔ−ブチルを用いること以外は、実質的に参考例４４４−４と同様に反応を行って、表題化合物（４５ｍｇ、定量的）を黄色油状物として得た。

ＬＣ／ＭＳ［条件１］：保持時間１．５４分；ｍ／ｚ４７６．８［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ４７４．９［Ｍ−Ｈ］^―（ＥＳＩ負イオンモード）

Reference Example 478-1
4- (1- {5-[(2-oxo-1-oxa-3,8-diazaspiro [4.5] decan-3-yl) methyl] pyrazin-2-carbonyl} piperidin-4-yloxy) benzonitrile Production of hydrochloride

3-({5- [4- (4-Fluorobenzoyl) piperidin-1-carbonyl] pyrazin-2-yl} methyl) -2-oxo-1-oxa-3,8-diazaspiro [4.5] decane- 3-({5- [4- (4-Cyanophenoxy) piperidin-1-carbonyl] pyrazin-2-yl} methyl) obtained in Reference Example 478-1 instead of t-butyl 8-carboxylate The reaction was conducted in substantially the same manner as in Reference Example 444-4, except that t-butyl 2-oxo-1-oxa-3,8-diazaspiro [4.5] decane-8-carboxylate was used. The compound (45 mg, quantitative) was obtained as a yellow oil.

LC / MS [Condition 1]: Retention time 1.54 minutes; m / z 476.8 [M + H] ⁺ (ESI positive ion mode), m / z 474.9 [M−H] ⁻ (ESI negative ion mode)

実施例４７８
４−｛１−［５−（｛２−オキソ−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）ピラジン−２−カルボニル］ピペリジン−４−イルオキシ｝ベンゾニトリル（化合物番号４７８）の製造
参考例４７８−２で得られた４−（１−｛５−［（２−オキソ−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル）メチル］ピラジン−２−カルボニル｝ピペリジン−４−イルオキシ）ベンゾニトリル塩酸塩（２０ｍｇ、０．０４０ｍｍｏｌ）と１−（ブロモメチル）−４−（トリフルオロメチル）ベンゼン（市販）（１０．２０ｍｇ、０．０４０ｍｍｏｌ）をＮ，Ｎ−ジメチルホルムアミドに溶解し、トリエチルアミン（１３μｌ、０．０９０ｍｍｏｌ）を加えて室温で３時間激しく攪拌した。反応終了後、反応混合物に水を加えた後、クロロホルムで３回抽出した。合わせた有機層を無水硫酸マグネシウムで乾燥した後、減圧下濃縮乾固した。得られた残留物をシリカゲルカラムクロマトグラフィー［充填剤：Ｍｅｒｃｋ ＧＭＢＨ製シリカゲル６０（０．０４０−０．０６３ｍｍ）、展開溶媒：酢酸エチル／メタノール＝９／１］にて精製し、４−｛１−［５−（｛２−オキソ−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）ピラジン−２−カルボニル］ピペリジン−４−イルオキシ｝ベンゾニトリル（６．６ｍｇ、収率２６％）を無色液体として得た。

^１Ｈ−ＮＭＲ（３００ＭＨｚ、ＣＤＣｌ_３）δ：１．８３−２．１６（６Ｈ，ｍ），２．１９−２．４８（２Ｈ，ｂｒｍ），２．７８−３．００（２Ｈ，ｍ），３．０１−３．２５（２Ｈ，ｂｒ ｍ），３．４８（２Ｈ，ｓ），３．６３（１Ｈ，ｄｄｄ，Ｊ＝１３．５，６．５，４．９Ｈｚ），３．７４−４．０９（５Ｈ，ｍ），４．６３（２Ｈ，ｓ），４．７３（１Ｈ，ｔｔ，Ｊ＝５．３，２．９Ｈｚ），６．９８（２Ｈ，ｄ，Ｊ＝８．６Ｈｚ），７．５６−７．７１（６Ｈ，ｍ），８．５３（１Ｈ，ｄ，Ｊ＝１．６Ｈｚ），８．８８（１Ｈ，ｄ，Ｊ＝１．６Ｈｚ）．

ＬＣ／ＭＳ［条件１］：保持時間３．３２分；ｍ／ｚ６３４．８［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ６３２．９［Ｍ−Ｈ］^―（ＥＳＩ負イオンモード）

Example 478
4- {1- [5-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl) pyrazine 2-Carbonyl] piperidin-4-yloxy} benzonitrile (Compound No. 478) 4- (1- {5-[(2-oxo-1-oxa-3,8 ) obtained in Reference Example 478-2 -Diazaspiro [4.5] decan-3-yl) methyl] pyrazin-2-carbonyl} piperidin-4-yloxy) benzonitrile hydrochloride (20 mg, 0.040 mmol) and 1- (bromomethyl) -4- (trifluoro Methyl) benzene (commercially available) (10.20 mg, 0.040 mmol) was dissolved in N, N-dimethylformamide and triethylamine (13 μl, 0.090 mmol) was added. It was vigorously stirred for 3 hours at room temperature Te. After completion of the reaction, water was added to the reaction mixture, followed by extraction three times with chloroform. The combined organic layers were dried over anhydrous magnesium sulfate and then concentrated to dryness under reduced pressure. The obtained residue was purified by silica gel column chromatography [filler: silica gel 60 (0.040-0.063 mm) manufactured by Merck GMBH, developing solvent: ethyl acetate / methanol = 9/1], and 4- {1 -[5-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl) pyrazine-2-carbonyl Piperidin-4-yloxy} benzonitrile (6.6 mg, 26% yield) was obtained as a colorless liquid.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.83-2.16 (6H, m), 2.19-2.48 (2H, brm), 2.78-3.00 (2H, m) 3.01-3.25 (2H, br m), 3.48 (2H, s), 3.63 (1H, ddd, J = 13.5, 6.5, 4.9 Hz), 3.74. -4.09 (5H, m), 4.63 (2H, s), 4.73 (1H, tt, J = 5.3, 2.9 Hz), 6.98 (2H, d, J = 8. 6 Hz), 7.56-7.71 (6 H, m), 8.53 (1 H, d, J = 1.6 Hz), 8.88 (1 H, d, J = 1.6 Hz).

LC / MS [Condition 1]: Retention time 3.32 minutes; m / z 634.8 [M + H] ⁺ (ESI positive ion mode), m / z 632.9 [M−H] ⁻ (ESI negative ion mode)

実施例４７９
４−｛［３−（｛５−［４−（４−シアノフェノキシ）ピペリジン−１−カルボニル］ピラジン−２−イル｝メチル）−２−オキソ−１−オキサ−３，８−ジアザスピロ［４．５］デカン−８−イル］メチル｝−３，５−ジフルオロベンゾニトリル（化合物番号４７９）の製造
参考例４７８−２で得られた４−（１−｛５−［（２−オキソ−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル）メチル］ピラジン−２−カルボニル｝ピペリジン−４−イルオキシ）ベンゾニトリル塩酸塩（１５ｍｇ、０．０３０ｍｍｏｌ）に炭酸水素ナトリウム水溶液を加えた後、クロロホルムで３回抽出した。合わせた有機層を減圧下濃縮した後、得られた残留物に３，５−ジフルオロ−４−ホルミルベンゾニトリル（５．８ｍｇ、０．０４０ｍｍｏｌ）を加え、次いでジクロロメタンに溶解した。反応混合物にトリアセトキシ水素化ホウ素ナトリウム（９．５ｍｇ、０．０５０ｍｍｏｌ）を加えて室温で１０分間激しく攪拌した。反応終了後、水を加え、クロロホルムで２回抽出した。合わせた有機層を減圧下濃縮した。得られた残留物をシリカゲルカラムクロマトグラフィー［充填剤：Ｍｅｒｃｋ ＧＭＢＨ製シリカゲル６０（０．０４０−０．０６３ｍｍ）、展開溶媒：酢酸エチル／メタノール＝９／１］にて精製した。減圧下濃縮後、残留物にヘキサンを加え、減圧下濃縮乾固し、４−｛［３−（｛５−［４−（４−シアノフェノキシ）ピペリジン−１−カルボニル］ピラジン−２−イル｝メチル）−２−オキソ−１−オキサ−３，８−ジアザスピロ［４．５］デカン−８−イル］メチル｝−３，５−ジフルオロベンゾニトリル（１４ｍｇ、収率７５％）を無色液体として得た。

^１Ｈ−ＮＭＲ（３００ＭＨｚ、ＣＤＣｌ_３）δ：１．７９（２Ｈ，ｄｔ，Ｊ＝１３．５，６．５Ｈｚ），１．８７−２．１７（６Ｈ，ｍ），２．６４（４Ｈ，ｂｒ ｍ），３．３９（３Ｈ，ｓ），３．６３（１Ｈ，ｄｄｄ，Ｊ＝１３．１，５．７，４．５Ｈｚ），３．７６（２Ｈ，ｓ），３．８２（１Ｈ，ｄｄｄ，Ｊ＝１３．１，８．２，３．７Ｈｚ），３．８８（１Ｈ，ｄｄｄ，Ｊ＝１３．１，８．２，３．７Ｈｚ），３．９９（１Ｈ，ｄｄｄ，Ｊ＝１３．１，６．５，４．９Ｈｚ），４．６２（２Ｈ，ｓ），４．７３（１Ｈ，ｔｔ，Ｊ＝５．７，２．９Ｈｚ），６．９８（２Ｈ，ｄ，Ｊ＝９．０Ｈｚ），７．２３（２Ｈ，ｄ，Ｊ＝５．７Ｈｚ），７．６１（２Ｈ，ｄ，Ｊ＝８．６Ｈｚ），８．５５（１Ｈ，ｄ，Ｊ＝１．６Ｈｚ），８．９０（１Ｈ，ｄ，Ｊ＝１．６Ｈｚ）．

ＬＣ／ＭＳ［条件１］：保持時間３．１１分；ｍ／ｚ６２７．８［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ６２５．９［Ｍ−Ｈ］^―（ＥＳＩ負イオンモード）

Example 479
4-{[3-({5- [4- (4-Cyanophenoxy) piperidin-1-carbonyl] pyrazin-2-yl} methyl) -2-oxo-1-oxa-3,8-diazaspiro [4. 5] Production of decan-8-yl] methyl} -3,5-difluorobenzonitrile (Compound No. 479) 4- (1- {5-[(2-oxo-1- ) obtained in Reference Example 478-2 To the oxa-3,8-diazaspiro [4.5] decan-3-yl) methyl] pyrazin-2-carbonyl} piperidin-4-yloxy) benzonitrile hydrochloride (15 mg, 0.030 mmol) was added aqueous sodium bicarbonate solution. And extracted three times with chloroform. After the combined organic layers were concentrated under reduced pressure, 3,5-difluoro-4-formylbenzonitrile (5.8 mg, 0.040 mmol) was added to the obtained residue, and then dissolved in dichloromethane. Sodium triacetoxyborohydride (9.5 mg, 0.050 mmol) was added to the reaction mixture, and the mixture was vigorously stirred at room temperature for 10 minutes. After completion of the reaction, water was added and extracted twice with chloroform. The combined organic layers were concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography [filler: silica gel 60 (0.040-0.063 mm) manufactured by Merck GMBH, developing solvent: ethyl acetate / methanol = 9/1]. After concentration under reduced pressure, hexane was added to the residue, concentrated to dryness under reduced pressure, and 4-{[3-({5- [4- (4-cyanophenoxy) piperidin-1-carbonyl] pyrazin-2-yl}. Methyl) -2-oxo-1-oxa-3,8-diazaspiro [4.5] decan-8-yl] methyl} -3,5-difluorobenzonitrile (14 mg, 75% yield) was obtained as a colorless liquid. It was.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.79 (2H, dt, J = 13.5, 6.5 Hz), 1.87-2.17 (6H, m), 2.64 (4H, br m), 3.39 (3H, s), 3.63 (1H, ddd, J = 13.1, 5.7, 4.5 Hz), 3.76 (2H, s), 3.82 (1H) , Ddd, J = 13.1, 8.2, 3.7 Hz), 3.88 (1H, ddd, J = 13.1, 8.2, 3.7 Hz), 3.99 (1H, ddd, J = 13.1, 6.5, 4.9 Hz), 4.62 (2H, s), 4.73 (1H, tt, J = 5.7, 2.9 Hz), 6.98 (2H, d, J = 9.0 Hz), 7.23 (2H, d, J = 5.7 Hz), 7.61 (2H, d, J = 8.6 Hz), 8.55 (1H, d, J = 1.6 Hz) ), 8.9 (1H, d, J = 1.6Hz).

LC / MS [Condition 1]: Retention time 3.11 min; m / z 627.8 [M + H] ⁺ (ESI positive ion mode), m / z 625.9 [M−H] ⁻ (ESI negative ion mode)

実施例４８０
３，５−ジフルオロ−４−｛［３−（｛５−［４−（６−フルオロベンゾ［ｄ］イソキサゾル−３−イル）ピペリジン−１−カルボニル］ピリジン−２−イル｝メチル）−２−オキソ−１−オキサ−３，８−ジアザスピロ［４．５］デカン−８−イル］メチル｝ベンゾニトリル（化合物番号４８０）の製造
（４−フルオロフェニル）（ピペリジン−４−イル）メタノン塩酸塩の代わりに、６−フルオロ−３−（ピペリジン−４−イル）ベンゾ［ｄ］イソキサゾール（市販）を用いること以外は実質的に実施例３９２と同様に反応を行なって、表題化合物（２４ｍｇ、収率８３％）を無色無定形物として得た。

^１Ｈ−ＮＭＲ（ＣＤＣｌ_３）δ：１．７６（２Ｈ，ｄｔ，Ｊ＝１３．５，７．４Ｈｚ），１．９６（２Ｈ，ｂｒ ｄ，Ｊ＝１３．１Ｈｚ），１．９７−２．３７（４Ｈ，ｂｒ ｍ），２．４８−２．７５（４Ｈ，ｂｒ ｍ），３．０３−３．４３（２Ｈ，ｂｒ ｍ），３．３２（２Ｈ，ｓ），３．４０（１Ｈ，ｔｔ，Ｊ＝１１．１，３．７Ｈｚ），３．７４（２Ｈ，ｓ），３．７５−４．０３（１Ｈ，ｂｒ ｍ），４．５６−４．８６（１Ｈ，ｂｒ ｍ），４．５７（２Ｈ，ｓ），７．１０（１Ｈ，ｄｔ，Ｊ＝２．５，８．８Ｈｚ），７．２２（２Ｈ，ｄ，Ｊ＝５．７Ｈｚ），７．２８（１Ｈ，ｄｄ，Ｊ＝８．８，２．５Ｈｚ），７．３６（１Ｈ，ｄ，Ｊ＝８．２Ｈｚ），７．６３（１Ｈ，ｄｄ，Ｊ＝８．６，４．９Ｈｚ），７．７８（１Ｈ，ｄｄ，Ｊ＝８．２，２．０Ｈｚ），８．６４（１Ｈ，ｄ，Ｊ＝２．０Ｈｚ）．

ＬＣ／ＭＳ［条件１］：保持時間３．２０分；ｍ／ｚ６４４．８［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ６８８．９［Ｍ＋ＨＣＯＯ］⁻（ＥＳＩ負イオンモード）

Example 480
3,5-difluoro-4-{[3-({5- [4- (6-fluorobenzo [d] isoxazol-3-yl) piperidin-1-carbonyl] pyridin-2-yl} methyl) -2- Preparation of Oxo-1-oxa-3,8-diazaspiro [4.5] decan-8-yl] methyl} benzonitrile (Compound No. 480) (4-Fluorophenyl) (piperidin-4-yl) methanone hydrochloride Instead, the reaction was carried out in substantially the same manner as in Example 392 except that 6-fluoro-3- (piperidin-4-yl) benzo [d] isoxazole (commercially available) was used to give the title compound (24 mg, yield). 83%) was obtained as a colorless amorphous product.

¹ H-NMR (CDCl ₃ ) δ: 1.76 (2H, dt, J = 13.5, 7.4 Hz), 1.96 (2H, br d, J = 13.1 Hz), 1.97-2 .37 (4H, br m), 2.48-2.75 (4H, br m), 3.03-3.43 (2H, br m), 3.32 (2H, s), 3.40 ( 1H, tt, J = 11.1, 3.7 Hz), 3.74 (2H, s), 3.75-4.03 (1H, br m), 4.56-4.86 (1 H, br m ), 4.57 (2H, s), 7.10 (1H, dt, J = 2.5, 8.8 Hz), 7.22 (2H, d, J = 5.7 Hz), 7.28 (1H , Dd, J = 8.8, 2.5 Hz), 7.36 (1H, d, J = 8.2 Hz), 7.63 (1H, dd, J = 8.6, 4.9 Hz), 7. 78 (1H, dd J = 8.2,2.0Hz), 8.64 (1H, d, J = 2.0Hz).

LC / MS [Condition 1]: Retention time 3.20 minutes; m / z 644.8 [M + H] ⁺ (ESI positive ion mode), m / z 688.9 [M + HCOO] ⁻ (ESI negative ion mode)

実施例４８１
Ｎ−（ベンゾ［ｄ］［１，３］ジオキソル−５−イルメチル）−６−｛［８−（４−シアノ−２，６−ジフルオロベンジル）−２−オキソ−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル］メチル｝ニコチンアミド（化合物番号４８１）の製造

（４−フルオロフェニル）（ピペリジン−４−イル）メタノン塩酸塩の代わりに、ベンゾ［ｄ］［１，３］ジオキソール−５−イルメタンアミン（市販）を用いること以外は実質的に実施例３９２と同様に反応を行なって、表題化合物（２０ｍｇ、収率７７％）を白色固体として得た。

^１Ｈ−ＮＭＲ（ＣＤＣｌ_３）δ：１．７４（２Ｈ，ｄｔ，Ｊ＝１３．５，７．４Ｈｚ），１．９４（２Ｈ，ｂｒ ｄ，Ｊ＝１３．１Ｈｚ，），２．５０−２．７０（４Ｈ，ｂｒ ｍ），３．２９（２Ｈ，ｓ），３．７３（２Ｈ，ｓ），４．５５（２Ｈ，ｄ，Ｊ＝５．３Ｈｚ），４．５５（２Ｈ，ｓ），５．９６（２Ｈ，ｓ），６．４６（１Ｈ，ｂｒ ｔ，Ｊ＝５．０Ｈｚ），６．７８（３Ｈ，ｄ，Ｊ＝７．８Ｈｚ），６．８２（１Ｈ，ｄｄ，Ｊ＝７．８，１．６Ｈｚ），６．８５（１Ｈ，ｄ，Ｊ＝１．６Ｈｚ），７．２２（２Ｈ，ｄ，Ｊ＝６．１Ｈｚ），７．３４（１Ｈ，ｄ，Ｊ＝８．２Ｈｚ），８．０８（１Ｈ，ｄｄ，Ｊ＝８．２，２．０Ｈｚ），８．９１（１Ｈ，ｄ，Ｊ＝２．０Ｈｚ）．

ＬＣ／ＭＳ［条件１］：保持時間２．７１分；ｍ／ｚ５７５．８［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ５７３．８［Ｍ−Ｈ］⁻（ＥＳＩ負イオンモード）

Example 481
N- (benzo [d] [1,3] dioxol-5-ylmethyl) -6-{[8- (4-cyano-2,6-difluorobenzyl) -2-oxo-1-oxa-3,8- Preparation of diazaspiro [4.5] decan-3-yl] methyl} nicotinamide (Compound No. 481)

Example 392 substantially except that benzo [d] [1,3] dioxol-5-ylmethanamine (commercially available) was used instead of (4-fluorophenyl) (piperidin-4-yl) methanone hydrochloride. The title compound (20 mg, yield 77%) was obtained as a white solid.

¹ H-NMR (CDCl ₃ ) δ: 1.74 (2H, dt, J = 13.5, 7.4 Hz), 1.94 (2H, br d, J = 13.1 Hz,), 2.50 − 2.70 (4H, br m), 3.29 (2H, s), 3.73 (2H, s), 4.55 (2H, d, J = 5.3 Hz), 4.55 (2H, s) ), 5.96 (2H, s), 6.46 (1H, br t, J = 5.0 Hz), 6.78 (3H, d, J = 7.8 Hz), 6.82 (1H, dd, J = 7.8, 1.6 Hz), 6.85 (1H, d, J = 1.6 Hz), 7.22 (2H, d, J = 6.1 Hz), 7.34 (1H, d, J = 8.2 Hz), 8.08 (1H, dd, J = 8.2, 2.0 Hz), 8.91 (1H, d, J = 2.0 Hz).

LC / MS [Condition 1]: Retention time 2.71 minutes; m / z 575.8 [M + H] ⁺ (ESI positive ion mode), m / z 573.8 [MH] ⁻ (ESI negative ion mode)

実施例４８２
４−｛［３−（｛５−［４−（４−シアノフェノキシ）ピペリジン−１−カルボニル］ピリジン−２−イル｝メチル）−２−オキソ−１−オキサ−３，８−ジアザスピロ［４．５］デカン−８−イル］メチル｝−３，５−ジフルオロベンゾニトリル（化合物番号４８２）の製造
（４−フルオロフェニル）（ピペリジン−４−イル）メタノン塩酸塩の代わりに、参考例２６４−２で得られた４−（ピペリジン−４−イルオキシ）ベンゾニトリル塩酸塩を用いること以外は実質的に実施例３９２と同様に反応を行なって、表題化合物（２５ｍｇ、収率８９％）を白色固体として得た。

^１Ｈ−ＮＭＲ（ＣＤＣｌ_３）δ：１．７４−２．１４（４Ｈ，ｂｒ ｍ），１．７６（２Ｈ，ｄｔ，Ｊ＝１２．７，７．８Ｈｚ），１．９６（２Ｈ，ｂｒ ｄ，Ｊ＝１２．７Ｈｚ），２．５１−２．７２（４Ｈ，ｍ），３．２９−４．０３（４Ｈ，ｂｒ ｍ），３．３１（２Ｈ，ｓ），３．７４（２Ｈ，ｓ），４．５６（２Ｈ，ｓ），４．６５−４．７５（１Ｈ，ｍ），６．９７（２Ｈ，ｄ，Ｊ＝８．６Ｈｚ），７．２２（２Ｈ，ｄ，Ｊ＝５．７Ｈｚ），７．３６（１Ｈ，ｄ，Ｊ＝７．８Ｈｚ），７．６０（２Ｈ，ｄ，Ｊ＝８．６Ｈｚ），７．７６（１Ｈ，ｄｄ，Ｊ＝８．２，２．０Ｈｚ），８．６１（１Ｈ，ｄ，Ｊ＝２．０Ｈｚ）．

ＬＣ／ＭＳ［条件１］：保持時間３．０８分；ｍ／ｚ６２６．８［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ６７０．９［Ｍ＋ＨＣＯＯ］⁻（ＥＳＩ負イオンモード）

Example 482
4-{[3-({5- [4- (4-Cyanophenoxy) piperidin-1-carbonyl] pyridin-2-yl} methyl) -2-oxo-1-oxa-3,8-diazaspiro [4. 5] Preparation of decan-8-yl] methyl} -3,5-difluorobenzonitrile (Compound No. 482) Instead of (4-fluorophenyl) (piperidin-4-yl) methanone hydrochloride, Reference Example 264-2 The reaction was conducted in substantially the same manner as in Example 392 except that 4- (piperidin-4-yloxy) benzonitrile hydrochloride obtained in 1 above was used to give the title compound (25 mg, yield 89%) as a white solid Obtained.

¹ H-NMR (CDCl ₃ ) δ: 1.74-2.14 (4H, br m), 1.76 (2H, dt, J = 12.7, 7.8 Hz), 1.96 (2H, br d, J = 12.7 Hz), 2.51-2.72 (4H, m), 3.29-4.03 (4H, br m), 3.31 (2H, s), 3.74 (2H) , S), 4.56 (2H, s), 4.65-4.75 (1H, m), 6.97 (2H, d, J = 8.6 Hz), 7.22 (2H, d, J = 5.7 Hz), 7.36 (1H, d, J = 7.8 Hz), 7.60 (2H, d, J = 8.6 Hz), 7.76 (1H, dd, J = 8.2) 2.0 Hz), 8.61 (1H, d, J = 2.0 Hz).

LC / MS [Condition 1]: Retention time 3.08 minutes; m / z 626.8 [M + H] ⁺ (ESI positive ion mode), m / z 670.9 [M + HCOO] ⁻ (ESI negative ion mode)

実施例４８３
６−［１−（６−｛［８−（４−シアノ−２，６−ジフルオロベンジル）−２−オキソ−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル］メチル｝ニコチノイル）ピペリジン−４−イルオキシ］ニコチノニトリル（化合物番号４８３）の製造
（４−フルオロフェニル）（ピペリジン−４−イル）メタノン塩酸塩の代わりに、参考例２９３−２で得られた６−（ピペリジン−４−イルオキシ）ニコチノニトリル塩酸塩を用いること以外は実質的に実施例３９２と同様に反応を行なって、表題化合物（２４ｍｇ、収率８６％）を白色固体として得た。

^１Ｈ−ＮＭＲ（ＣＤＣｌ_３）δ：１．７１−２．２２（４Ｈ，ｂｒ ｍ），１．７６（２Ｈ，ｄｔ，Ｊ＝１３．９，６．５Ｈｚ），１．９５（２Ｈ，ｄ，Ｊ＝１３．５Ｈｚ），２．４９−２．７２（４Ｈ，ｂｒ ｍ），３．３０−３．５２（１Ｈ，ｂｒ ｍ），３．３１（２Ｈ，ｓ），３．５５−３．８４（２Ｈ，ｂｒ ｍ），３．７４（２Ｈ，ｓ），３．９５−４．１８（１Ｈ，ｂｒ ｍ），４．５６（２Ｈ，ｓ），５．４３（１Ｈ，ｔｔ，Ｊ＝７．４，３．７Ｈｚ），６．８２（１Ｈ，ｄ，Ｊ＝９．０Ｈｚ），７．２２（２Ｈ，ｄ，Ｊ＝６．１Ｈｚ），７．３６（１Ｈ，ｄ，Ｊ＝８．２Ｈｚ），７．７６（２Ｈ，ｄｄ，Ｊ＝８．２，２．５Ｈｚ），７．８１（２Ｈ，ｄｄ，Ｊ＝８．６，２．５Ｈｚ），８．４６（１Ｈ，ｄ，Ｊ＝２．５Ｈｚ），８．６２（１Ｈ，ｄ，Ｊ＝２．５Ｈｚ）．

ＬＣ／ＭＳ［条件１］：保持時間２．９６分；ｍ／ｚ６２７．８［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ６７１．９［Ｍ＋ＨＣＯＯ］⁻（ＥＳＩ負イオンモード）

Example 483
6- [1- (6-{[8- (4-Cyano-2,6-difluorobenzyl) -2-oxo-1-oxa-3,8-diazaspiro [4.5] decan-3-yl] methyl } Preparation of Nicotinoyl) piperidin-4-yloxy] nicotinonitrile (Compound No. 483) Instead of (4-fluorophenyl) (piperidin-4-yl) methanone hydrochloride, the 6- 6 obtained in Reference Example 293-2 The reaction was carried out substantially in the same manner as in Example 392 except that (piperidin-4-yloxy) nicotinonitrile hydrochloride was used to obtain the title compound (24 mg, yield 86%) as a white solid.

¹ H-NMR (CDCl ₃ ) δ: 1.71-2.22 (4H, br m), 1.76 (2H, dt, J = 13.9, 6.5 Hz), 1.95 (2H, d , J = 13.5 Hz), 2.49-2.72 (4H, br m), 3.30-3.52 (1H, br m), 3.31 (2H, s), 3.55-3 .84 (2H, br m), 3.74 (2H, s), 3.95-4.18 (1H, br m), 4.56 (2H, s), 5.43 (1H, tt, J = 7.4, 3.7 Hz), 6.82 (1H, d, J = 9.0 Hz), 7.22 (2H, d, J = 6.1 Hz), 7.36 (1H, d, J = 8.2 Hz), 7.76 (2H, dd, J = 8.2, 2.5 Hz), 7.81 (2H, dd, J = 8.6, 2.5 Hz), 8.46 (1H, d , J = 2.5 Hz), 8.62 (1H, d, J = 2.5 Hz).

LC / MS [Condition 1]: Retention time 2.96 minutes; m / z 627.8 [M + H] ⁺ (ESI positive ion mode), m / z 671.9 [M + HCOO] ⁻ (ESI negative ion mode)

実施例４８４
６−｛［８−（４−シアノ−２，６−ジフルオロベンジル）−２−オキソ−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル］メチル｝−Ｎ−（４−シアノベンジル）ニコチンアミド（化合物番号４８４）の製造
（４−フルオロフェニル）（ピペリジン−４−イル）メタノン塩酸塩の代わりに、４−（アミノメチル）ベンゾニトリル塩酸塩（市販）を用いること以外は実質的に実施例３９２と同様に反応を行なって、表題化合物（２３ｍｇ、収率９２％）を白色固体として得た。

^１Ｈ−ＮＭＲ（ＣＤＣｌ_３）δ：１．７４（２Ｈ，ｄｔ，Ｊ＝１３．９，７．４Ｈｚ），１．９３（２Ｈ，ｂｒ ｄ，Ｊ＝１３．１Ｈｚ），２．４９−２．６９（４Ｈ，ｂｒ ｍ），３．３１（２Ｈ，ｓ），３．７３（２Ｈ，ｓ），４．５５（２Ｈ，ｓ），４．７１（２Ｈ，ｄ，Ｊ＝５．７Ｈｚ），６．８６（１Ｈ，ｂｒ ｔ，Ｊ＝５．７Ｈｚ），７．２２（２Ｈ，ｄ，Ｊ＝５．７Ｈｚ），７．３５（１Ｈ，ｄ，Ｊ＝８．２Ｈｚ），７．４７（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ），７．６５（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ），８．１２（１Ｈ，ｄｄ，Ｊ＝８．２，２．０Ｈｚ），８．９５（１Ｈ，ｄ，Ｊ＝２．０Ｈｚ）．

ＬＣ／ＭＳ［条件１］：保持時間２．５３分；ｍ／ｚ５５６．７［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ５５４．８［Ｍ−Ｈ］⁻（ＥＳＩ負イオンモード）

Example 484
6-{[8- (4-Cyano-2,6-difluorobenzyl) -2-oxo-1-oxa-3,8-diazaspiro [4.5] decan-3-yl] methyl} -N- (4 -Cyanobenzyl) Preparation of Nicotinamide (Compound No. 484) Other than using 4- (aminomethyl) benzonitrile hydrochloride (commercially available) instead of (4-fluorophenyl) (piperidin-4-yl) methanone hydrochloride Was carried out in substantially the same manner as in Example 392 to give the title compound (23 mg, yield 92%) as a white solid.

¹ H-NMR (CDCl ₃ ) δ: 1.74 (2H, dt, J = 13.9, 7.4 Hz), 1.93 (2H, br d, J = 13.1 Hz), 2.49-2 .69 (4H, br m), 3.31 (2H, s), 3.73 (2H, s), 4.55 (2H, s), 4.71 (2H, d, J = 5.7 Hz) 6.86 (1H, br t, J = 5.7 Hz), 7.22 (2H, d, J = 5.7 Hz), 7.35 (1H, d, J = 8.2 Hz), 7.47 (2H, d, J = 8.2 Hz), 7.65 (2H, d, J = 8.2 Hz), 8.12 (1H, dd, J = 8.2, 2.0 Hz), 8.95 ( 1H, d, J = 2.0 Hz).

LC / MS [Condition 1]: Retention time 2.53 minutes; m / z 556.7 [M + H] ⁺ (ESI positive ion mode), m / z 554.8 [MH] ⁻ (ESI negative ion mode)

実施例４８５
３，５−ジフルオロ−４−｛［２−オキソ−３−（｛５−［４−（キノリン−４−イル）ピペラジン−１−カルボニル］ピリジン−２−イル｝メチル）−１−オキサ−３，８−ジアザスピロ［４．５］デカン−８−イル］メチル｝ベンゾニトリル（化合物番号４８５）の製造
（４−フルオロフェニル）（ピペリジン−４−イル）メタノン塩酸塩の代わりに、参考例２７８−２で得られた４−（ピペラジン−１−イル）キノリン二塩酸塩を用いること以外は実質的に実施例３９２と同様に反応を行なって、表題化合物（２５ｍｇ、収率８８％）をクリーム色固体として得た。

^１Ｈ−ＮＭＲ（ＣＤＣｌ_３）δ：１．７７（２Ｈ，ｄｔ，Ｊ＝１３．１，７．０Ｈｚ），１．９６（２Ｈ，ｂｒ ｄ，Ｊ＝１３．５Ｈｚ），２．５１−２．７３（４Ｈ，ｂｒ ｍ），３．１０−３．４５（４Ｈ，ｂｒ ｍ），３．３２（２Ｈ，ｓ），３．５７−３．８９（２Ｈ，ｂｒ ｍ），３．７５（２Ｈ，ｓ），３．９１−４．２７（２Ｈ，ｂｒ ｍ），４．５８（２Ｈ，ｓ），６．８７（１Ｈ，ｄ，Ｊ＝４．９Ｈｚ），７．２２（２Ｈ，ｄ，Ｊ＝６．１Ｈｚ），７．３９（１Ｈ，ｄ，Ｊ＝８．２Ｈｚ），７．５３（１Ｈ，ｔ，Ｊ＝７．８Ｈｚ），７．７０（１Ｈ，ｔ，Ｊ＝７．４Ｈｚ），７．８２（１Ｈ，ｄｄ，Ｊ＝７．８，２．０Ｈｚ），８．０２（１Ｈ，ｄ，Ｊ＝８．２Ｈｚ），８．０９（１Ｈ，ｄ，Ｊ＝８．６Ｈｚ），８．６７（１Ｈ，ｄ，Ｊ＝２．０Ｈｚ），８．７８（１Ｈ，ｄ，Ｊ＝４．９Ｈｚ）．

ＬＣ／ＭＳ［条件１］：保持時間０．５３分；ｍ／ｚ６３８．０［Ｍ＋Ｈ］^＋、３１９．５［Ｍ＋２Ｈ］^２＋（ＥＳＩ正イオンモード）、ｍ／ｚ６８１．８［Ｍ＋ＨＣＯＯ］⁻（ＥＳＩ負イオンモード）

Example 485
3,5-difluoro-4-{[2-oxo-3-({5- [4- (quinolin-4-yl) piperazin-1-carbonyl] pyridin-2-yl} methyl) -1-oxa-3 , 8-Diazaspiro [4.5] decan-8-yl] methyl} benzonitrile (Compound No. 485) instead of (4-fluorophenyl) (piperidin-4-yl) methanone hydrochloride Reference Example 278- The reaction was carried out in substantially the same manner as in Example 392 except that 4- (piperazin-1-yl) quinoline dihydrochloride obtained in 2 was used, and the title compound (25 mg, yield 88%) was cream colored Obtained as a solid.

¹ H-NMR (CDCl ₃ ) δ: 1.77 (2H, dt, J = 13.1, 7.0 Hz), 1.96 (2H, br d, J = 13.5 Hz), 2.51-2 .73 (4H, br m), 3.10-3.45 (4H, br m), 3.32 (2H, s), 3.57-3.89 (2H, br m), 3.75 ( 2H, s), 3.91-4.27 (2H, br m), 4.58 (2H, s), 6.87 (1H, d, J = 4.9 Hz), 7.22 (2H, d , J = 6.1 Hz), 7.39 (1H, d, J = 8.2 Hz), 7.53 (1H, t, J = 7.8 Hz), 7.70 (1H, t, J = 7. 4 Hz), 7.82 (1 H, dd, J = 7.8, 2.0 Hz), 8.02 (1 H, d, J = 8.2 Hz), 8.09 (1 H, d, J = 8.6 Hz) ), 8.67 (1H , D, J = 2.0 Hz), 8.78 (1H, d, J = 4.9 Hz).

LC / MS [Condition 1]: retention time 0.53 min; m / z 638.0 [M + H] ⁺ , 319.5 [M + 2H] ²⁺ (ESI positive ion mode), m / z 681.8 [M + HCOO] ⁻ (ESI Negative ion mode)

実施例４８６
４−｛［３−（｛５−［４−（２−クロロフェニルアミノ）ピペリジン−１−カルボニル］ピリジン−２−イル｝メチル）−２−オキソ−１−オキサ−３，８−ジアザスピロ［４．５］デカン−８−イル］メチル｝−３，５−ジフルオロベンゾニトリル（化合物番号４８６）の製造
（４−フルオロフェニル）（ピペリジン−４−イル）メタノン塩酸塩の代わりに、参考例２８６−２で得られたＮ−（２−クロロフェニル）ピペリジン−４−アミン二塩酸塩を用いること以外は実質的に実施例３９２と同様に反応を行なって、表題化合物（２９ｍｇ、収率定量的）を無色無定形物として得た。

^１Ｈ−ＮＭＲ（ＣＤＣｌ_３）δ：１．３８−１．７２（２Ｈ，ｂｒ ｍ），１．７８（２Ｈ，ｄｔ，Ｊ＝１３．９，７．４Ｈｚ），１．９８（２Ｈ，ｂｒ ｄ，Ｊ＝１３．９Ｈｚ），２．０３−２．３６（２Ｈ，ｂｒ ｍ），２．５０−２．７８（４Ｈ，ｂｒ ｍ），３．１１−３．３４（２Ｈ，ｂｒ ｍ），３．３３（２Ｈ，ｓ），３．５５−３．７７（２Ｈ，ｂｒ ｍ），３．７６（２Ｈ，ｓ），４．２７（１Ｈ，ｄ，Ｊ＝７．８Ｈｚ），４．４７−４．６７（１Ｈ，ｂｒ ｍ），４．５８（２Ｈ，ｓ），６．６８（１Ｈ，ｔ，Ｊ＝７．４Ｈｚ），６．７０（１Ｈ，ｄ，Ｊ＝７．８Ｈｚ），７．１６（１Ｈ，ｔ，Ｊ＝７．８Ｈｚ），７．２４（２Ｈ，ｄ，Ｊ＝５．７Ｈｚ），７．２９（１Ｈ，ｄ，Ｊ＝７．４Ｈｚ），７．３７（１Ｈ，ｂｒ ｄ，Ｊ＝８．６Ｈｚ），７．７８（１Ｈ，ｄ，Ｊ＝７．９Ｈｚ），８．６３（１Ｈ，ｂｒ ｓ）．

ＬＣ／ＭＳ［条件１］：保持時間３．３２分；ｍ／ｚ６３４．８［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ６７９．０［Ｍ＋ＨＣＯＯ］⁻（ＥＳＩ負イオンモード）

Example 486
4-{[3-({5- [4- (2-chlorophenylamino) piperidin-1-carbonyl] pyridin-2-yl} methyl) -2-oxo-1-oxa-3,8-diazaspiro [4. 5] Preparation of decan-8-yl] methyl} -3,5-difluorobenzonitrile (Compound No. 486) Instead of (4-fluorophenyl) (piperidin-4-yl) methanone hydrochloride, Reference Example 286-2 The reaction was conducted in substantially the same manner as in Example 392 except that N- (2-chlorophenyl) piperidin-4-amine dihydrochloride obtained in 1 above was used to give the title compound (29 mg, yield quantitative) as a colorless product. Obtained as an amorphous material.

¹ H-NMR (CDCl ₃ ) δ: 1.38-1.72 (2H, br m), 1.78 (2H, dt, J = 13.9, 7.4 Hz), 1.98 (2H, br d, J = 13.9 Hz), 2.03-2.36 (2H, br m), 2.50-2.78 (4H, br m), 3.11-3.34 (2H, br m) 3.33 (2H, s), 3.55-3.77 (2H, br m), 3.76 (2H, s), 4.27 (1 H, d, J = 7.8 Hz), 4. 47-4.67 (1H, br m), 4.58 (2H, s), 6.68 (1H, t, J = 7.4 Hz), 6.70 (1H, d, J = 7.8 Hz) 7.16 (1H, t, J = 7.8 Hz), 7.24 (2H, d, J = 5.7 Hz), 7.29 (1H, d, J = 7.4 Hz), 7.37 ( 1H, br d, J = 8.6 Hz), 7.78 (1 H, d, J = 7.9 Hz), 8.63 (1 H, br s).

LC / MS [Condition 1]: Retention time 3.32 minutes; m / z 634.8 [M + H] ⁺ (ESI positive ion mode), m / z 679.0 [M + HCOO] ⁻ (ESI negative ion mode)

実施例４８７
４−｛［３−（｛５−［４−（２，４−ジフルオロベンゾイル）ピペリジン−１−カルボニル］ピリジン−２−イル｝メチル）−２−オキソ−１−オキサ−３，８−ジアザスピロ［４．５］デカン−８−イル］メチル｝−３，５−ジフルオロベンゾニトリル（化合物番号４８７）の製造
（４−フルオロフェニル）（ピペリジン−４−イル）メタノン塩酸塩の代わりに、（２，４−ジフルオロフェニル）（ピペリジン−４−イル）メタノン塩酸塩（市販）を用いること以外は実質的に実施例３９２と同様に反応を行なって、表題化合物（２７ｍｇ、収率９２％）をクリーム色無定形物として得た。

^１Ｈ−ＮＭＲ（ＣＤＣｌ_３）δ：１．６４−１．８３（４Ｈ，ｍ），１．８３−２．１３（２Ｈ，ｍ），１．９５（２Ｈ，ｂｒ ｄ，Ｊ＝１３．１Ｈｚ），２．４２−２．７７（４Ｈ，ｂｒ ｍ），２．９５−３．３０（２Ｈ，ｂｒ ｍ），３．３１（２Ｈ，ｓ），３．３４−３．５０（１Ｈ，ｍ），３．５７−３．９４（１Ｈ，ｂｒ ｍ），３．７４（２Ｈ，ｓ），４．４２−４．８０（１Ｈ，ｂｒ ｍ），４．５６（２Ｈ，ｓ），６．９０（１Ｈ，ｄｔ，Ｊ＝２．５，１０．０Ｈｚ），７．００（１Ｈ，ｔ，Ｊ＝９．０Ｈｚ），７．２２（２Ｈ，ｄ，Ｊ＝６．１Ｈｚ），７．３４（１Ｈ，ｄ，Ｊ＝８．６Ｈｚ），７．７４（１Ｈ，ｄ，Ｊ＝８．６Ｈｚ），７．８９（１Ｈ，ｑ，Ｊ＝８．２Ｈｚ），８．５９（１Ｈ，ｂｒ ｓ）．

ＬＣ／ＭＳ［条件１］：保持時間３．１６分；ｍ／ｚ６４９．８［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ６９３．９［Ｍ＋ＨＣＯＯ］⁻（ＥＳＩ負イオンモード）

Example 487
4-{[3-({5- [4- (2,4-difluorobenzoyl) piperidin-1-carbonyl] pyridin-2-yl} methyl) -2-oxo-1-oxa-3,8-diazaspiro [ 4.5] Preparation of decan-8-yl] methyl} -3,5-difluorobenzonitrile (Compound No. 487) Instead of (4-fluorophenyl) (piperidin-4-yl) methanone hydrochloride, (2, The reaction was carried out in substantially the same manner as in Example 392 except that 4-difluorophenyl) (piperidin-4-yl) methanone hydrochloride (commercially available) was used, and the title compound (27 mg, yield 92%) was cream colored Obtained as an amorphous material.

¹ H-NMR (CDCl ₃ ) δ: 1.64-1.83 (4H, m), 1.83-2.13 (2H, m), 1.95 (2H, br d, J = 13.1 Hz) ), 2.42-2.77 (4H, br m), 2.95-3.30 (2H, br m), 3.31 (2H, s), 3.34-3.50 (1H, m ), 3.57-3.94 (1H, brm), 3.74 (2H, s), 4.42-4.80 (1H, brm), 4.56 (2H, s), 6. 90 (1H, dt, J = 2.5, 10.0 Hz), 7.00 (1H, t, J = 9.0 Hz), 7.22 (2H, d, J = 6.1 Hz), 7.34 (1H, d, J = 8.6 Hz), 7.74 (1H, d, J = 8.6 Hz), 7.89 (1H, q, J = 8.2 Hz), 8.59 (1H, br s ).

LC / MS [Condition 1]: Retention time 3.16 min; m / z 649.8 [M + H] ⁺ (ESI positive ion mode), m / z 693.9 [M + HCOO] ⁻ (ESI negative ion mode)

実施例４８８
４−｛［３−（｛５−［４−（３−シアノフェノキシ）ピペリジン−１−カルボニル］ピリジン−２−イル｝メチル）−２−オキソ−１−オキサ−３，８−ジアザスピロ［４．５］デカン−８−イル］メチル｝−３，５−ジフルオロベンゾニトリル（化合物番号４８８）の製造
（４−フルオロフェニル）（ピペリジン−４−イル）メタノン塩酸塩の代わりに、参考例２８１−２で得られた３−（ピペリジン−４−イルオキシ）ベンゾニトリル塩酸塩を用いること以外は実質的に実施例３９２と同様に反応を行なって、表題化合物（２９ｍｇ、収率定量的）を無色無定形物として得た。

^１Ｈ−ＮＭＲ（ＣＤＣｌ_３）δ：１．６８−２．１３（４Ｈ，ｂｒ ｍ），１．７６（２Ｈ，ｄｔ，Ｊ＝１３．１，７．４Ｈｚ），１．９５（２Ｈ，ｂｒ ｄ，Ｊ＝１３．５Ｈｚ），２．５０−２．７２（４Ｈ，ｂｒ ｍ），３．３１（２Ｈ，ｓ），３．３３−３．５６（１Ｈ，ｂｒ ｍ），３．５７−３．７８（１Ｈ，ｂｒ ｍ），３．７４（２Ｈ，ｓ），３．７８−３．９９（２Ｈ，ｂｒ ｍ），４．５６（２Ｈ，ｓ），４．５９−４．６９（１Ｈ，ｍ），７．１５（１Ｈ，ｄ，Ｊ＝７．８Ｈｚ），７．１７（１Ｈ，ｂｒ ｓ），７．２２（２Ｈ，ｄ，Ｊ＝６．５Ｈｚ），７．２７（１Ｈ，ｄ，Ｊ＝７．８Ｈｚ），７．３６（１Ｈ，ｄ，Ｊ＝８．２Ｈｚ），７．４０（１Ｈ，ｔ，Ｊ＝７．８Ｈｚ），７．７６（１Ｈ，ｄｄ，Ｊ＝８．２，２．０Ｈｚ），８．６１（１Ｈ，ｄ，Ｊ＝２．０Ｈｚ）．

ＬＣ／ＭＳ［条件１］：保持時間３．１４分；ｍ／ｚ６２６．８［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ６７０．９［Ｍ＋ＨＣＯＯ］⁻（ＥＳＩ負イオンモード）

Example 488
4-{[3-({5- [4- (3-Cyanophenoxy) piperidin-1-carbonyl] pyridin-2-yl} methyl) -2-oxo-1-oxa-3,8-diazaspiro [4. 5] Preparation of decan-8-yl] methyl} -3,5-difluorobenzonitrile (Compound No. 488) Instead of (4-fluorophenyl) (piperidin-4-yl) methanone hydrochloride, Reference Example 281-2 The title compound (29 mg, quantitative yield) was obtained as a colorless amorphous substance by carrying out the reaction in substantially the same manner as in Example 392 except that 3- (piperidin-4-yloxy) benzonitrile hydrochloride obtained in 1 above was used. Obtained as a thing.

¹ H-NMR (CDCl ₃ ) δ: 1.68-2.13 (4H, br m), 1.76 (2H, dt, J = 13.1, 7.4 Hz), 1.95 (2H, br d, J = 13.5 Hz), 2.50-2.72 (4H, br m), 3.31 (2H, s), 3.33-3.56 (1H, br m), 3.57- 3.78 (1H, br m), 3.74 (2H, s), 3.78-3.99 (2H, br m), 4.56 (2H, s), 4.59-4.69 ( 1H, m), 7.15 (1H, d, J = 7.8 Hz), 7.17 (1H, brs), 7.22 (2H, d, J = 6.5 Hz), 7.27 (1H , D, J = 7.8 Hz), 7.36 (1H, d, J = 8.2 Hz), 7.40 (1H, t, J = 7.8 Hz), 7.76 (1H, dd, J = 8.2, 2.0H ), 8.61 (1H, d, J = 2.0Hz).

LC / MS [Condition 1]: Retention time 3.14 min; m / z 626.8 [M + H] ⁺ (ESI positive ion mode), m / z 670.9 [M + HCOO] ⁻ (ESI negative ion mode)

実施例４８９
４−｛［３−（｛５−［４−（４−クロロベンゾイル）ピペリジン−１−カルボニル］ピリジン−２−イル｝メチル）−２−オキソ−１−オキサ−３，８−ジアザスピロ［４．５］デカン−８−イル］メチル｝−３，５−ジフルオロベンゾニトリル（化合物番号４８９）の製造
（４−フルオロフェニル）（ピペリジン−４−イル）メタノン塩酸塩の代わりに、（４−クロロフェニル）（ピペリジン−４−イル）メタノン塩酸塩（市販）を用いること以外は実質的に実施例３９２と同様に反応を行なって、表題化合物（２７ｍｇ、収率９２％）を無色無定形物として得た。

^１Ｈ−ＮＭＲ（ＣＤＣｌ_３）δ：１．７２−２．００（４Ｈ，ｍ），１．７６（２Ｈ，ｄｔ，Ｊ＝１２．７，８．２Ｈｚ），１．９６（２Ｈ，ｂｒ ｄ，Ｊ＝１３．９Ｈｚ），２．５１−２．７２（４Ｈ，ｂｒ ｍ），３．００−３．３６（２Ｈ，ｂｒ ｍ），３．３１（２Ｈ，ｓ），３．４５−３．５９（１Ｈ，ｍ），３．６７−３．９４（１Ｈ，ｂｒ ｍ），３．７４（２Ｈ，ｓ），４．５２−４．７７（１Ｈ，ｂｒ ｍ），４．５６（２Ｈ，ｓ），７．２２（２Ｈ，ｄ，Ｊ＝５．７Ｈｚ），７．３５（１Ｈ，ｄ，Ｊ＝８．２Ｈｚ），７．４７（２Ｈ，ｄ，Ｊ＝９．０Ｈｚ），７．７６（１Ｈ，ｄｄ，Ｊ＝８．２，２．５Ｈｚ），７．９０（２Ｈ，ｄ，Ｊ＝９．０Ｈｚ），８．６１（１Ｈ，ｄ，Ｊ＝２．０Ｈｚ）．

ＬＣ／ＭＳ［条件１］：保持時間３．２４分；ｍ／ｚ６４７．８［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ６９１．８［Ｍ＋ＨＣＯＯ］⁻（ＥＳＩ負イオンモード）

Example 489
4-{[3-({5- [4- (4-Chlorobenzoyl) piperidin-1-carbonyl] pyridin-2-yl} methyl) -2-oxo-1-oxa-3,8-diazaspiro [4. 5] Preparation of decan-8-yl] methyl} -3,5-difluorobenzonitrile (Compound No. 489) instead of (4-fluorophenyl) (piperidin-4-yl) methanone hydrochloride (4-chlorophenyl) The reaction was carried out substantially in the same manner as in Example 392 except that (piperidin-4-yl) methanone hydrochloride (commercially available) was used to give the title compound (27 mg, yield 92%) as a colorless amorphous product. .

¹ H-NMR (CDCl ₃ ) δ: 1.72-2.00 (4H, m), 1.76 (2H, dt, J = 12.7, 8.2 Hz), 1.96 (2H, br d , J = 13.9 Hz), 2.51-2.72 (4H, br m), 3.00-3.36 (2H, br m), 3.31 (2H, s), 3.45-3-3. .59 (1H, m), 3.67-3.94 (1H, brm), 3.74 (2H, s), 4.52-4.77 (1H, brm), 4.56 (2H) , S), 7.22 (2H, d, J = 5.7 Hz), 7.35 (1H, d, J = 8.2 Hz), 7.47 (2H, d, J = 9.0 Hz), 7 .76 (1H, dd, J = 8.2, 2.5 Hz), 7.90 (2H, d, J = 9.0 Hz), 8.61 (1H, d, J = 2.0 Hz).

LC / MS [condition 1]: retention time 3.24 minutes; m / z 647.8 [M + H] ⁺ (ESI positive ion mode), m / z 691.8 [M + HCOO] ⁻ (ESI negative ion mode)

実施例４９０
６−｛［８−（４−シアノ−２，６−ジフルオロベンジル）−２−オキソ−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル］メチル｝−Ｎ−（フラン−２−イルメチル）ニコチンアミド（化合物番号４９０）の製造
（４−フルオロフェニル）（ピペリジン−４−イル）メタノン塩酸塩の代わりに、フラン−２−イルメタンアミン（市販）を用いること以外は実質的に実施例３９２と同様に反応を行なって、表題化合物（１８ｍｇ、収率７６％）を白色固体として得た。

^１Ｈ−ＮＭＲ（ＣＤＣｌ_３）δ：１．７４（２Ｈ，ｄｔ，Ｊ＝１３．５，７．４Ｈｚ），１．９４（２Ｈ，ｂｒ ｄ，Ｊ＝１３．１Ｈｚ），２．５１−２．７２（４Ｈ，ｂｒ ｍ），３．２９（２Ｈ，ｓ），３．７３（２Ｈ，ｓ），４．５６（２Ｈ，ｓ），４．６６（２Ｈ，ｄ，Ｊ＝５．７Ｈｚ），６．２９−６．３９（２Ｈ，ｍ），６．３９−６．５１（１Ｈ，ｂｒ ｍ），７．２２（２Ｈ，ｄ，Ｊ＝５．７Ｈｚ），７．３６（１Ｈ，ｄ，Ｊ＝８．２Ｈｚ），７．３９（１Ｈ，ｂｒ ｓ），８．０９（１Ｈ，ｄｄ，Ｊ＝８．２，２．０Ｈｚ），８．９２（１Ｈ，ｄ，Ｊ＝２．０Ｈｚ）．

ＬＣ／ＭＳ［条件１］：保持時間１．３０分；ｍ／ｚ５２１．７［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ５１９．９［Ｍ−Ｈ］⁻（ＥＳＩ負イオンモード）

Example 490
6-{[8- (4-Cyano-2,6-difluorobenzyl) -2-oxo-1-oxa-3,8-diazaspiro [4.5] decan-3-yl] methyl} -N- (furan Preparation of 2-ylmethyl) nicotinamide (Compound No. 490) Substantially except that furan-2-ylmethanamine (commercially available) is used instead of (4-fluorophenyl) (piperidin-4-yl) methanone hydrochloride The reaction was carried out in the same manner as in Example 392 to give the title compound (18 mg, yield 76%) as a white solid.

¹ H-NMR (CDCl ₃ ) δ: 1.74 (2H, dt, J = 13.5, 7.4 Hz), 1.94 (2H, br d, J = 13.1 Hz), 2.51-2 .72 (4H, br m), 3.29 (2H, s), 3.73 (2H, s), 4.56 (2H, s), 4.66 (2H, d, J = 5.7 Hz) , 6.29-6.39 (2H, m), 6.39-6.51 (1H, br m), 7.22 (2H, d, J = 5.7 Hz), 7.36 (1H, d , J = 8.2 Hz), 7.39 (1 H, br s), 8.09 (1 H, dd, J = 8.2, 2.0 Hz), 8.92 (1 H, d, J = 2.0 Hz) ).

LC / MS [Condition 1]: Retention time 1.30 minutes; m / z 521.7 [M + H] ⁺ (ESI positive ion mode), m / z 519.9 [M−H] ⁻ (ESI negative ion mode)

実施例４９１
４−｛［３−（｛５−［３−（３−シアノフェノキシ）アゼチジン−１−カルボニル］ピリジン−２−イル｝メチル）−２−オキソ−１−オキサ−３，８−ジアザスピロ［４．５］デカン−８−イル］メチル｝−３，５−ジフルオロベンゾニトリル（化合物番号４９１）の製造
（４−フルオロフェニル）（ピペリジン−４−イル）メタノン塩酸塩の代わりに、参考例３９０−２で得られた３−（アゼチジン−３−イルオキシ）ベンゾニトリル塩酸塩を用いること以外は実質的に実施例３９２と同様に反応を行なって、表題化合物（１６ｍｇ、収率５９％）を白色固体として得た。

^１Ｈ−ＮＭＲ（ＣＤＣｌ_３）δ：１．７５（２Ｈ，ｄｔ，Ｊ＝１３．５，７．０Ｈｚ），１．９５（２Ｈ，ｂｒ ｄ，Ｊ＝１３．１Ｈｚ），２．５１−２．７３（４Ｈ，ｂｒ ｍ），３．３１（２Ｈ，ｓ），３．７４（２Ｈ，ｓ），４．２２−４．４４（２Ｈ，ｂｒ ｍ），４．５６（２Ｈ，ｓ），４．５９−４．７７（２Ｈ，ｂｒ ｍ），５．０５（１Ｈ，ｔｔ，Ｊ＝６．１，３．７Ｈｚ），６．９６−７．０５（２Ｈ，ｍ），７．２２（２Ｈ，ｄ，Ｊ＝６．０Ｈｚ），７．３３（１Ｈ，ｄｔ，Ｊ＝７．８，１．２Ｈｚ），７．３７（１Ｈ，ｄ，Ｊ＝８．２Ｈｚ），７．４２（１Ｈ，ｔ，Ｊ＝７．８Ｈｚ），７．９８（１Ｈ，ｄｄ，Ｊ＝８．２，２．０Ｈｚ），８．７２−８．８４（１Ｈ，ｍ）．

ＬＣ／ＭＳ［条件１］：保持時間３．００分；ｍ／ｚ５９８．８［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ６４２．９［Ｍ＋ＨＣＯＯ］⁻（ＥＳＩ負イオンモード）

Example 491
4-{[3-({5- [3- (3-Cyanophenoxy) azetidin-1-carbonyl] pyridin-2-yl} methyl) -2-oxo-1-oxa-3,8-diazaspiro [4. 5] Preparation of decan-8-yl] methyl} -3,5-difluorobenzonitrile (Compound No. 491) Instead of (4-fluorophenyl) (piperidin-4-yl) methanone hydrochloride, Reference Example 390-2 The reaction was conducted in substantially the same manner as in Example 392 except that 3- (azetidin-3-yloxy) benzonitrile hydrochloride obtained in 1 above was used to give the title compound (16 mg, yield 59%) as a white solid Obtained.

¹ H-NMR (CDCl ₃ ) δ: 1.75 (2H, dt, J = 13.5, 7.0 Hz), 1.95 (2H, br d, J = 13.1 Hz), 2.51-2 .73 (4H, br m), 3.31 (2H, s), 3.74 (2H, s), 4.22-4.44 (2H, br m), 4.56 (2H, s), 4.59-4.77 (2H, br m), 5.05 (1H, tt, J = 6.1, 3.7 Hz), 6.96-7.05 (2H, m), 7.22 ( 2H, d, J = 6.0 Hz), 7.33 (1H, dt, J = 7.8, 1.2 Hz), 7.37 (1H, d, J = 8.2 Hz), 7.42 (1H , T, J = 7.8 Hz), 7.98 (1H, dd, J = 8.2, 2.0 Hz), 8.72-8.84 (1H, m).

LC / MS [Condition 1]: Retention time 3.00 minutes; m / z 598.8 [M + H] ⁺ (ESI positive ion mode), m / z 642.9 [M + HCOO] ⁻ (ESI negative ion mode)

実施例４９２
３，５−ジフルオロ−４−（｛２−オキソ−３−［（５−｛４−［４−（トリフルオロメチル）フェニルアミノ］ピペリジン−１−カルボニル｝ピリジン−２−イル）メチル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−８−イル｝メチル）ベンゾニトリル（化合物番号４９２）の製造
（４−フルオロフェニル）（ピペリジン−４−イル）メタノン塩酸塩の代わりに、参考例３９１−２で得られたＮ−［４−（トリフルオロメチル）フェニル］ピペリジン−４−アミン二塩酸塩を用いること以外は実質的に実施例３９２と同様に反応を行なって、表題化合物（２５ｍｇ、収率８５％）を無色無定形物として得た。

^１Ｈ−ＮＭＲ（ＣＤＣｌ_３）δ：１．２９−１．６９（２Ｈ，ｂｒ ｍ），１．７５（２Ｈ，ｄｔ，Ｊ＝１３．５，７．０Ｈｚ），１．９５（２Ｈ，ｄ，Ｊ＝１３．５Ｈｚ），１．９９−２．３５（２Ｈ，ｂｒ ｍ），２．４８−２．７４（４Ｈ，ｍ），３．００−３．３６（２Ｈ，ｂｒ ｍ），３．３０（２Ｈ，ｓ），３．５３−３．６９（１Ｈ，ｍ），３．６５−３．８８（１Ｈ，ｂｒ ｍ），３．７４（２Ｈ，ｓ），３．９１（１Ｈ，ｄ，Ｊ＝７．８Ｈｚ），４．４４−４．７７（３Ｈ，ｍ），４．５４−４．５７（３Ｈ，ｍ），６．６１（２Ｈ，ｄ，Ｊ＝８．６Ｈｚ），７．２２（２Ｈ，ｄ，Ｊ＝５．７Ｈｚ），７．３５（１Ｈ，ｄ，Ｊ＝８．２Ｈｚ），７．４１（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ），７．７５（１Ｈ，ｄｄ，Ｊ＝７．８，２．０Ｈｚ），８．６０（１Ｈ，ｂｒ ｓ）．

ＬＣ／ＭＳ［条件１］：保持時間３．５０分；ｍ／ｚ６６９．０［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ７１２．９［Ｍ＋ＨＣＯＯ］⁻（ＥＳＩ負イオンモード）

Example 492
3,5-difluoro-4-({2-oxo-3-[(5- {4- [4- (trifluoromethyl) phenylamino] piperidin-1-carbonyl} pyridin-2-yl) methyl] -1 -Preparation of Oxa-3,8-diazaspiro [4.5] decan-8-yl} methyl) benzonitrile (Compound No. 492) Instead of (4-fluorophenyl) (piperidin-4-yl) methanone hydrochloride, The title compound was reacted in substantially the same manner as in Example 392 except that N- [4- (trifluoromethyl) phenyl] piperidin-4-amine dihydrochloride obtained in Reference Example 391-2 was used. (25 mg, 85% yield) was obtained as a colorless amorphous product.

¹ H-NMR (CDCl ₃ ) δ: 1.29-1.69 (2H, br m), 1.75 (2H, dt, J = 13.5, 7.0 Hz), 1.95 (2H, d , J = 13.5 Hz), 1.99-2.35 (2H, br m), 2.48-2.74 (4H, m), 3.00-3.36 (2H, br m), 3 .30 (2H, s), 3.53-3.69 (1H, m), 3.65-3.88 (1H, br m), 3.74 (2H, s), 3.91 (1H, d, J = 7.8 Hz), 4.44-4.77 (3H, m), 4.54-4.57 (3H, m), 6.61 (2H, d, J = 8.6 Hz), 7.22 (2H, d, J = 5.7 Hz), 7.35 (1H, d, J = 8.2 Hz), 7.41 (2H, d, J = 8.2 Hz), 7.75 (1H , Dd, J = 7.8, 2 0Hz), 8.60 (1H, br s).

LC / MS [Condition 1]: Retention time 3.50 min; m / z 669.0 [M + H] ⁺ (ESI positive ion mode), m / z 712.9 [M + HCOO] ⁻ (ESI negative ion mode)

実施例４９３
４−｛［３−（｛５−［４−（３−シアノ−４−フルオロフェニルアミノ）ピペリジン−１−カルボニル］ピリジン−２−イル｝メチル）−２−オキソ−１−オキサ−３，８−ジアザスピロ［４．５］デカン−８−イル］メチル｝−３，５−ジフルオロベンゾニトリル（化合物番号４９３）の製造
（４−フルオロフェニル）（ピペリジン−４−イル）メタノン塩酸塩の代わりに、参考例４４２−２で得られた２−フルオロ−５−（ピペリジン−４−イルアミノ）ベンゾニトリル二塩酸塩を用いること以外は実質的に実施例３９２と同様に反応を行なって、表題化合物（２５ｍｇ、収率８６％）をクリーム色無定形物として得た。

^１Ｈ−ＮＭＲ（ＣＤＣｌ_３）δ：１．２７−１．５９（２Ｈ，ｂｒ ｍ），１．７６（２Ｈ，ｄｔ，Ｊ＝１３．９，７．４Ｈｚ），１．９６（２Ｈ，ｄ，Ｊ＝１３．５Ｈｚ），２．００−２．３１（２Ｈ，ｂｒ ｍ），２．４５−２．７８（４Ｈ，ｂｒ ｍ），２．９６−３．３２（２Ｈ，ｂｒ ｍ），３．３１（２Ｈ，ｓ），３．４１−３．５７（１Ｈ，ｍ），３．５８−３．９２（１Ｈ，ｂｒ ｍ），３．６９（１Ｈ，ｄ，Ｊ＝８．２Ｈｚ），３．７４（２Ｈ，ｓ），４．４２−４．８１（１Ｈ，ｂｒ ｍ），４．４７−４．７５（３Ｈ，ｍ），４．５５（２Ｈ，ｓ），６．６７−６．８４（２Ｈ，ｍ），７．０２（１Ｈ，ｔ，Ｊ＝９．０Ｈｚ），７．２２（２Ｈ，ｄ，Ｊ＝６．１Ｈｚ），７．３５（１Ｈ，ｄ，Ｊ＝８．２Ｈｚ），７．７５（１Ｈ，ｄｄ，Ｊ＝８．２，２．０Ｈｚ），８．６０（１Ｈ，ｄ，Ｊ＝１．６Ｈｚ）．

ＬＣ／ＭＳ［条件１］：保持時間３．１６分；ｍ／ｚ６４３．８［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ６８８．０［Ｍ＋ＨＣＯＯ］⁻（ＥＳＩ負イオンモード）

Example 493
4-{[3-({5- [4- (3-Cyano-4-fluorophenylamino) piperidin-1-carbonyl] pyridin-2-yl} methyl) -2-oxo-1-oxa-3,8 -Preparation of diazaspiro [4.5] decan-8-yl] methyl} -3,5-difluorobenzonitrile (Compound No. 493) Instead of (4-fluorophenyl) (piperidin-4-yl) methanone hydrochloride, The reaction was conducted in substantially the same manner as in Example 392 except that 2-fluoro-5- (piperidin-4-ylamino) benzonitrile dihydrochloride obtained in Reference Example 442-2 was used, and the title compound (25 mg Yield 86%) as a cream-colored amorphous product.

¹ H-NMR (CDCl ₃ ) δ: 1.27-1.59 (2H, br m), 1.76 (2H, dt, J = 13.9, 7.4 Hz), 1.96 (2H, d , J = 13.5 Hz), 2.00-2.31 (2H, br m), 2.45-2.78 (4H, br m), 2.96-3.32 (2H, br m), 3.31 (2H, s), 3.41-3.57 (1H, m), 3.58-3.92 (1H, br m), 3.69 (1H, d, J = 8.2 Hz) 3.74 (2H, s), 4.42-4.81 (1H, br m), 4.47-4.75 (3H, m), 4.55 (2H, s), 6.67-. 6.84 (2H, m), 7.02 (1H, t, J = 9.0 Hz), 7.22 (2H, d, J = 6.1 Hz), 7.35 (1H, d, J = 8) .2 Hz), 7.75 ( H, dd, J = 8.2,2.0Hz), 8.60 (1H, d, J = 1.6Hz).

LC / MS [Condition 1]: Retention time 3.16 minutes; m / z 643.8 [M + H] ⁺ (ESI positive ion mode), m / z 688.0 [M + HCOO] ⁻ (ESI negative ion mode)

実施例４９４
３，５−ジフルオロ−４−（｛２−オキソ−３−［（５−｛４−［４−（トリフルオロメチル）フェニルスルホニル］ピペリジン−１−カルボニル｝ピリジン−２−イル）メチル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−８−イル｝メチル）ベンゾニトリル（化合物番号４９４）の製造
（４−フルオロフェニル）（ピペリジン−４−イル）メタノン塩酸塩の代わりに、参考例３９３−６で得られた４−［４−（トリフルオロメチル）フェニルスルホニル］ピペリジン塩酸塩を用いること以外は実質的に実施例３９２と同様に反応を行なって、表題化合物（２７ｍｇ、収率８４％）を無色無定形物として得た。

^１Ｈ−ＮＭＲ（ＣＤＣｌ_３）δ：１．６６−１．８８（４Ｈ，ｍ），１．９６（２Ｈ，ｄ，Ｊ＝１３．１Ｈｚ），２．０１−２．１７（２Ｈ，ｍ），２．４４−２．７２（４Ｈ，ｂｒ ｍ），２．７０−３．１６（２Ｈ，ｂｒ ｍ），３．１２−３．２７（１Ｈ，ｍ），３．３１（２Ｈ，ｓ），３．７１−４．０９（１Ｈ，ｂｒ ｍ），３．７４（２Ｈ，ｓ），４．５５（２Ｈ，ｂｒ ｓ），４．５８−５．００（１Ｈ，ｂｒ ｍ），７．２２（２Ｈ，ｄ，Ｊ＝５．７Ｈｚ），７．３４（１Ｈ，ｄ，Ｊ＝７．８Ｈｚ），７．７１（１Ｈ，ｄｄ，Ｊ＝７．８，１．６Ｈｚ），７．８８（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ），８．０３（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ），８．５５（１Ｈ，ｓ）．

ＬＣ／ＭＳ［条件１］：保持時間３．２６分；ｍ／ｚ７１７．９［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ７６１．９［Ｍ＋ＨＣＯＯ］⁻（ＥＳＩ負イオンモード）

Example 494
3,5-difluoro-4-({2-oxo-3-[(5- {4- [4- (trifluoromethyl) phenylsulfonyl] piperidin-1-carbonyl} pyridin-2-yl) methyl] -1 -Preparation of Oxa-3,8-diazaspiro [4.5] decan-8-yl} methyl) benzonitrile (Compound No. 494) Instead of (4-fluorophenyl) (piperidin-4-yl) methanone hydrochloride, The reaction was conducted in substantially the same manner as in Example 392 except that 4- [4- (trifluoromethyl) phenylsulfonyl] piperidine hydrochloride obtained in Reference Example 393-6 was used, and the title compound (27 mg, yield) 84%) was obtained as a colorless amorphous product.

¹ H-NMR (CDCl ₃ ) δ: 1.66-1.88 (4H, m), 1.96 (2H, d, J = 13.1 Hz), 2.01-2.17 (2H, m) , 2.44-2.72 (4H, br m), 2.70-3.16 (2H, br m), 3.12-3.27 (1H, m), 3.31 (2H, s) 3.71-4.09 (1H, br m), 3.74 (2H, s), 4.55 (2H, br s), 4.58-5.00 (1H, br m), 7. 22 (2H, d, J = 5.7 Hz), 7.34 (1H, d, J = 7.8 Hz), 7.71 (1H, dd, J = 7.8, 1.6 Hz), 7.88 (2H, d, J = 8.2 Hz), 8.03 (2H, d, J = 8.2 Hz), 8.55 (1H, s).

LC / MS [Condition 1]: Retention time 3.26 minutes; m / z 717.9 [M + H] ⁺ (ESI positive ion mode), m / z 761.9 [M + HCOO] ⁻ (ESI negative ion mode)

実施例４９５
６−｛［８−（４−シアノ−２，６−ジフルオロベンジル）−２−オキソ−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル］メチル｝−Ｎ−［３，３，３−トリフルオロ−２−（４−フルオロフェニル）−２−ヒドロキシプロピル］ニコチンアミド（化合物番号４９５）の製造
（４−フルオロフェニル）（ピペリジン−４−イル）メタノン塩酸塩の代わりに、参考例４３４−２で得られた３−アミノ−１，１，１−トリフルオロ−２−（４−フルオロフェニル）プロパン−２−オールを用いること以外は実質的に実施例３９２と同様に反応を行なって、表題化合物（２０ｍｇ、収率６８％）を無色無定形物として得た。

^１Ｈ−ＮＭＲ（ＣＤＣｌ_３）δ：１．６７−１．８３（２Ｈ，ｍ），１．９３（２Ｈ，ｂｒ ｄ，Ｊ＝１３．５Ｈｚ），２．４３−２．７１（４Ｈ，ｂｒ ｍ），３．３０（２Ｈ，ｓ），３．７２（２Ｈ，ｓ），４．０５（１Ｈ，ｄｄ，Ｊ＝１５．１，７．０Ｈｚ），４．２１（１Ｈ，ｄｄ，Ｊ＝１５．１，６．１Ｈｚ），４．４５（２Ｈ，ｓ），５．８８（１Ｈ，ｓ），７．０７（１Ｈ，ｔ，Ｊ＝８．６Ｈｚ），７．１４−７．２５（３Ｈ，ｍ），７．３６（１Ｈ，ｔ，Ｊ＝５．３Ｈｚ），７．６３（２Ｈ，ｄｄ，Ｊ＝８．２，５．７Ｈｚ），７．９８（１Ｈ，ｄｄ，Ｊ＝８．２，２．０Ｈｚ），８．８０（１Ｈ，ｄ，Ｊ＝２．０Ｈｚ）．

ＬＣ／ＭＳ［条件１］：保持時間３．２４分；ｍ／ｚ６４７．８［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ６４５．９［Ｍ−Ｈ］⁻（ＥＳＩ負イオンモード）

Example 495
6-{[8- (4-Cyano-2,6-difluorobenzyl) -2-oxo-1-oxa-3,8-diazaspiro [4.5] decan-3-yl] methyl} -N- [3 , 3,3-trifluoro-2- (4-fluorophenyl) -2-hydroxypropyl] nicotinamide (Compound No. 495) instead of (4-fluorophenyl) (piperidin-4-yl) methanone hydrochloride Substantially the same as Example 392 except that 3-amino-1,1,1-trifluoro-2- (4-fluorophenyl) propan-2-ol obtained in Reference Example 434-2 was used. The reaction was performed to give the title compound (20 mg, yield 68%) as a colorless amorphous product.

¹ H-NMR (CDCl ₃ ) δ: 1.67-1.83 (2H, m), 1.93 (2H, br d, J = 13.5 Hz), 2.43-2.71 (4H, br m), 3.30 (2H, s), 3.72 (2H, s), 4.05 (1H, dd, J = 15.1, 7.0 Hz), 4.21 (1H, dd, J = 15.1, 6.1 Hz), 4.45 (2H, s), 5.88 (1 H, s), 7.07 (1 H, t, J = 8.6 Hz), 7.14-7.25 ( 3H, m), 7.36 (1H, t, J = 5.3 Hz), 7.63 (2H, dd, J = 8.2, 5.7 Hz), 7.98 (1H, dd, J = 8) .2, 2.0 Hz), 8.80 (1H, d, J = 2.0 Hz).

LC / MS [Condition 1]: retention time 3.24 minutes; m / z 647.8 [M + H] ⁺ (ESI positive ion mode), m / z 645.9 [M−H] ⁻ (ESI negative ion mode)

参考例４９６−１
４−［２−（トリフルオロメチル）キノリン−４−イル］ピペラジン−１−カルボン酸ｔ−ブチルの製造
４−クロロ−２−（トリフルオロメチル）キノリン（０．２０ｇ、０．８６ｍｍｏｌ）、ピペラジン−１−カルボン酸ｔ−ブチル（０．２４ｇ、１．３ｍｍｏｌ）のＮ−メチル−２−ピロリドン（２ｍＬ）溶液にＮ，Ｎ−ジイソプロピルエチルアミン（０．３０ｍＬ，１．７ｍｍｏｌ）を加え、反応混合物を１２０℃で５時間静置したのち、酢酸エチル（８ｍＬ）と水（４ｍＬ）を加えた。有機層を水（４ｍＬ×２）で洗浄し、減圧下濃縮乾固したのち、残留物を再結晶（ｎ−ヘキサン−酢酸エチル）により精製して、表題化合物（０．１９ｇ、収率５７％）をこはく色固体として得た。

ＬＣ／ＭＳ［条件２］：保持時間３．７７分；ｍ／ｚ３８２．０［Ｍ＋Ｈ］^＋、３２６．０［Ｍ−ｉｓｏｂｕｔｅｎｅ＋Ｈ］^＋（ＥＳＩ正イオンモード）

Reference Example 496-1
Preparation of 4- [2- (trifluoromethyl) quinolin-4-yl] piperazine-1-carboxylate t-butyl 4-chloro-2- (trifluoromethyl) quinoline (0.20 g, 0.86 mmol), piperazine N, N-Diisopropylethylamine (0.30 mL, 1.7 mmol) was added to a solution of t-butyl-1-carboxylate (0.24 g, 1.3 mmol) in N-methyl-2-pyrrolidone (2 mL), and the reaction mixture was added. Was allowed to stand at 120 ° C. for 5 hours, and then ethyl acetate (8 mL) and water (4 mL) were added. The organic layer was washed with water (4 mL × 2) and concentrated to dryness under reduced pressure. The residue was purified by recrystallization (n-hexane-ethyl acetate) to give the title compound (0.19 g, yield 57%). ) Was obtained as an amber solid.

LC / MS [Condition 2]: Retention time 3.77 minutes; m / z 382.0 [M + H] ⁺ , 326.0 [M-isobutene + H] ⁺ (ESI positive ion mode)

参考例４９６−２
４−（ピペラジン−１−イル）−２−（トリフルオロメチル）キノリン二塩酸塩の製造
４−（キノリン−４−イル）ピペラジン−１−カルボン酸ｔ−ブチルの代わりに、参考例４９６−１で得られた４−［２−（トリフルオロメチル）キノリン−４−イル］ピペラジン−１−カルボン酸ｔ−ブチルを用いること以外は実質的に参考例２７８−２と同様に反応を行なって、表題化合物（０．３０ｇ、収率定量的）をクリーム色固体として得た。

^１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ_６）δ：３．３６−３．４８（４Ｈ，ｍ），３．４８−３．６０（４Ｈ，ｍ），７．３７（１Ｈ，ｓ），７．７３（１Ｈ，ｄｄｄ，Ｊ＝８．２，７．０，１．２Ｈｚ），７．８８（１Ｈ，ｄｄｄ，Ｊ＝８．６，７．０，１．２Ｈｚ），８．１２（１Ｈ，ｄ，Ｊ＝８．６Ｈｚ），８．１７（１Ｈ，ｄ，Ｊ＝８．２Ｈｚ），９．３９（２Ｈ，ｂｒ ｓ）．

Reference Example 496-2
Preparation of 4- (piperazin-1-yl) -2- (trifluoromethyl) quinoline dihydrochloride Reference Example 496-1 instead of t-butyl 4- (quinolin-4-yl) piperazine-1-carboxylate The reaction was carried out in substantially the same manner as in Reference Example 278-2, except that t-butyl 4- [2- (trifluoromethyl) quinolin-4-yl] piperazine-1-carboxylate obtained in The title compound (0.30 g, quantitative yield) was obtained as a cream solid.

¹ H-NMR (DMSO-d ₆ ) δ: 3.36-3.48 (4H, m), 3.48-3.60 (4H, m), 7.37 (1H, s), 7.73 (1H, ddd, J = 8.2, 7.0, 1.2 Hz), 7.88 (1H, ddd, J = 8.6, 7.0, 1.2 Hz), 8.12 (1H, d , J = 8.6 Hz), 8.17 (1H, d, J = 8.2 Hz), 9.39 (2H, br s).

実施例４９６
３，５−ジフルオロ−４−（｛２−オキソ−３−［（５−｛４−［２−（トリフルオロメチル）キノリン−４−イル］ピペラジン−１−カルボニル｝ピリジン−２−イル）メチル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−８−イル｝メチル）ベンゾニトリル（化合物番号４９６）の製造
（４−フルオロフェニル）（ピペリジン−４−イル）メタノン塩酸塩の代わりに、参考例４９６−２で得られた４−（ピペラジン−１−イル）−２−（トリフルオロメチル）キノリン二塩酸塩を用いること以外は実質的に実施例３９２と同様に反応を行なって、表題化合物（２７ｍｇ、収率８４％）を無色無定形物として得た。

^１Ｈ−ＮＭＲ（ＣＤＣｌ_３）δ：１．７９（２Ｈ，ｄｔ，Ｊ＝１３．５，７．０Ｈｚ），１．９７（２Ｈ，ｄ，Ｊ＝１３．１Ｈｚ），２．５１−２．７６（４Ｈ，ｂｒ ｍ），３．１２−３．５７（２Ｈ，ｂｒ ｍ），３．３３（２Ｈ，ｓ），３．６３−４．２５（４Ｈ，ｂｒ ｍ），３．７６（２Ｈ，ｓ），４．５８（２Ｈ，ｓ），７．１７（１Ｈ，ｓ），７．２３（２Ｈ，ｄ，Ｊ＝６．１Ｈｚ），７．３９（１Ｈ，ｄ，Ｊ＝８．２Ｈｚ），７．６４（１Ｈ，ｔ，Ｊ＝７．４Ｈｚ），７．７９（１Ｈ，ｔ，Ｊ＝７．８Ｈｚ），７．８２（１Ｈ，ｄｄ，Ｊ＝７．８，１．６Ｈｚ），８．０５（１Ｈ，ｄ，Ｊ＝８．６Ｈｚ），８．２０（１Ｈ，ｄ，Ｊ＝８．６Ｈｚ），８．６７（１Ｈ，ｄ，Ｊ＝１．６Ｈｚ）．

ＬＣ／ＭＳ［条件１］：保持時間３．３６分；ｍ／ｚ７０５．９［Ｍ＋Ｈ］^＋、３５３．５［Ｍ＋２Ｈ］^２＋（ＥＳＩ正イオンモード）、ｍ／ｚ７４９．９［Ｍ＋ＨＣＯＯ］⁻（ＥＳＩ負イオンモード）

Example 496
3,5-difluoro-4-({2-oxo-3-[(5- {4- [2- (trifluoromethyl) quinolin-4-yl] piperazin-1-carbonyl} pyridin-2-yl) methyl ] -1-Oxa-3,8-diazaspiro [4.5] decan-8-yl} methyl) benzonitrile (Compound No. 496) Preparation of (4-Fluorophenyl) (piperidin-4-yl) methanone hydrochloride Instead, the reaction was carried out in substantially the same manner as in Example 392 except that 4- (piperazin-1-yl) -2- (trifluoromethyl) quinoline dihydrochloride obtained in Reference Example 496-2 was used. The title compound (27 mg, 84% yield) was obtained as a colorless amorphous product.

¹ H-NMR (CDCl ₃ ) δ: 1.79 (2H, dt, J = 13.5, 7.0 Hz), 1.97 (2H, d, J = 13.1 Hz), 2.51-2. 76 (4H, br m), 3.12-3.57 (2H, br m), 3.33 (2H, s), 3.63-4.25 (4H, br m), 3.76 (2H , S), 4.58 (2H, s), 7.17 (1H, s), 7.23 (2H, d, J = 6.1 Hz), 7.39 (1H, d, J = 8.2 Hz) ), 7.64 (1H, t, J = 7.4 Hz), 7.79 (1H, t, J = 7.8 Hz), 7.82 (1H, dd, J = 7.8, 1.6 Hz) , 8.05 (1H, d, J = 8.6 Hz), 8.20 (1H, d, J = 8.6 Hz), 8.67 (1H, d, J = 1.6 Hz).

LC / MS [Condition 1]: Retention time 3.36 minutes; m / z 705.9 [M + H] ⁺ , 353.5 [M + 2H] ²⁺ (ESI positive ion mode), m / z 749.9 [M + HCOO] ⁻ (ESI Negative ion mode)

実施例４９７
６−｛［８−（４−シアノ−２，６−ジフルオロベンジル）−２−オキソ−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル］メチル｝−Ｎ−［３，３，３−トリフルオロ−２−ヒドロキシ−２−（６−メトキシピリジン−３−イル）プロピル］ニコチンアミド（化合物番号４９７）の製造
（４−フルオロフェニル）（ピペリジン−４−イル）メタノン塩酸塩の代わりに、参考例４３７−２で得られた３−アミノ−１，１，１−トリフルオロ−２−（６−メトキシピリジン−３−イル）プロパン−２−オールを用いること以外は実質的に実施例３９２と同様に反応を行なって、表題化合物（１７ｍｇ、収率５７％）を無色無定形物として得た。

^１Ｈ−ＮＭＲ（ＣＤＣｌ_３）δ：１．７５（２Ｈ，ｄｔ，Ｊ＝１２．３，７．４Ｈｚ），１．９４（２Ｈ，ｂｒ ｄ，Ｊ＝１３．９Ｈｚ），２．４１−２．７３（４Ｈ，ｂｒ ｍ），３．３１（２Ｈ，ｓ），３．７２（２Ｈ，ｓ），３．９２（２Ｈ，ｓ），４．０５（１Ｈ，ｄｄ，Ｊ＝１５．１，７．０Ｈｚ），４．２１（１Ｈ，ｄｄ，Ｊ＝１５．１，５．７Ｈｚ），４．４６（２Ｈ，ｓ），６．０３（１Ｈ，ｓ），６．７４（１Ｈ，ｄ，Ｊ＝９．０Ｈｚ），７．１４−７．２５（３Ｈ，ｍ），７．５６（１Ｈ，ｂｒ ｔ，Ｊ＝４．９Ｈｚ），７．８６（１Ｈ，ｄｄ，Ｊ＝８．６，２．５Ｈｚ），８．００（１Ｈ，ｄｄ，Ｊ＝８．２，２．０Ｈｚ），８．３７（１Ｈ，ｓ），８．８３（１Ｈ，ｓ）．

ＬＣ／ＭＳ［条件１］：保持時間３．０４分；ｍ／ｚ６６０．７［Ｍ＋Ｈ］^＋、３３０．９［Ｍ＋２Ｈ］^２＋（ＥＳＩ正イオンモード）、ｍ／ｚ６５８．９［Ｍ−Ｈ］⁻（ＥＳＩ負イオンモード）

Example 497
6-{[8- (4-Cyano-2,6-difluorobenzyl) -2-oxo-1-oxa-3,8-diazaspiro [4.5] decan-3-yl] methyl} -N- [3 , 3,3-Trifluoro-2-hydroxy-2- (6-methoxypyridin-3-yl) propyl] nicotinamide (Compound No. 497) (4-Fluorophenyl) (piperidin-4-yl) methanone hydrochloride Substantially other than using 3-amino-1,1,1-trifluoro-2- (6-methoxypyridin-3-yl) propan-2-ol obtained in Reference Example 437-2 instead of the salt The reaction was carried out in the same manner as in Example 392 to obtain the title compound (17 mg, yield 57%) as a colorless amorphous product.

¹ H-NMR (CDCl ₃ ) δ: 1.75 (2H, dt, J = 12.3, 7.4 Hz), 1.94 (2H, br d, J = 13.9 Hz), 2.41-2 .73 (4H, br m), 3.31 (2H, s), 3.72 (2H, s), 3.92 (2H, s), 4.05 (1H, dd, J = 15.1, 7.0 Hz), 4.21 (1H, dd, J = 15.1, 5.7 Hz), 4.46 (2H, s), 6.03 (1H, s), 6.74 (1H, d, J = 9.0 Hz), 7.14-7.25 (3H, m), 7.56 (1H, br t, J = 4.9 Hz), 7.86 (1H, dd, J = 8.6) 2.5 Hz), 8.00 (1H, dd, J = 8.2, 2.0 Hz), 8.37 (1H, s), 8.83 (1H, s).

LC / MS [Condition 1]: Retention time 3.04 minutes; m / z 660.7 [M + H] ⁺ , 330.9 [M + 2H] ²⁺ (ESI positive ion mode), m / z 658.9 [M−H] ⁻ (ESI negative ion mode)

実施例４９８
４−｛［３−（｛５−［４−（４−ｔ−ブチルベンゾイル）ピペリジン−１−カルボニル］ピリジン−２−イル｝メチル）−２−オキソ−１−オキサ−３，８−ジアザスピロ［４．５］デカン−８−イル］メチル｝−３，５−ジフルオロベンゾニトリル（化合物番号４９８）の製造
（４−フルオロフェニル）（ピペリジン−４−イル）メタノン塩酸塩の代わりに、参考例３３３−２で得られた（４−ｔ−ブチルフェニル）（ピペリジン−４−イル）メタノン塩酸塩を用いること以外は実質的に実施例３９２と同様に反応を行なって、表題化合物（３０ｍｇ、収率定量的）を無色無定形物として得た。

^１Ｈ−ＮＭＲ（ＣＤＣｌ_３）δ：１．３５（９Ｈ，ｓ），１．７３−２．１５（４Ｈ，ｂｒ ｍ），１．７６（２Ｈ，ｄｔ，Ｊ＝１３．５，７．４Ｈｚ），１．９６（２Ｈ，ｂｒ ｄ，Ｊ＝１３．５Ｈｚ），２．４９−２．７２（４Ｈ，ｂｒ ｍ），３．００−３．３６（２Ｈ，ｂｒ ｍ），３．３０（２Ｈ，ｓ），３．４８−３．６５（１Ｈ，ｍ），３．６８−３．９２（１Ｈ，ｂｒ ｍ），３．７４（２Ｈ，ｓ），４．５３−４．７５（１Ｈ，ｂｒ ｍ），４．５６（２Ｈ，ｓ），７．２２（２Ｈ，ｄ，Ｊ＝６．１Ｈｚ），７．３４（１Ｈ，ｄ，Ｊ＝７．８Ｈｚ），７．５０（２Ｈ，ｄ，Ｊ＝８．４Ｈｚ），７．７６（１Ｈ，ｄｄ，Ｊ＝８．２，２．０Ｈｚ），７．８９（２Ｈ，ｄ，Ｊ＝８．４Ｈｚ），８．６１（１Ｈ，ｄ，Ｊ＝２．０Ｈｚ）

ＬＣ／ＭＳ［条件１］：保持時間３．６０分；ｍ／ｚ６６９．９［Ｍ＋Ｈ］^＋、３３５．５［Ｍ＋２Ｈ］^２＋（ＥＳＩ正イオンモード）、ｍ／ｚ７１４．１［Ｍ＋ＨＣＯＯ］⁻（ＥＳＩ負イオンモード）

Example 498
4-{[3-({5- [4- (4-t-butylbenzoyl) piperidin-1-carbonyl] pyridin-2-yl} methyl) -2-oxo-1-oxa-3,8-diazaspiro [ 4.5] Preparation of decan-8-yl] methyl} -3,5-difluorobenzonitrile (Compound No. 498) Reference Example 333 instead of (4-fluorophenyl) (piperidin-4-yl) methanone hydrochloride The reaction was carried out in substantially the same manner as in Example 392 except that (4-t-butylphenyl) (piperidin-4-yl) methanone hydrochloride obtained in -2 was used, and the title compound (30 mg, yield) was obtained. Quantitative) was obtained as a colorless amorphous.

¹ H-NMR (CDCl ₃ ) δ: 1.35 (9H, s), 1.73-2.15 (4H, br m), 1.76 (2H, dt, J = 13.5, 7.4 Hz) ), 1.96 (2H, br d, J = 13.5 Hz), 2.49-2.72 (4H, br m), 3.00-3.36 (2H, br m), 3.30 ( 2H, s), 3.48-3.65 (1H, m), 3.68-3.92 (1H, br m), 3.74 (2H, s), 4.53-4.75 (1H , Br m), 4.56 (2H, s), 7.22 (2H, d, J = 6.1 Hz), 7.34 (1H, d, J = 7.8 Hz), 7.50 (2H, d, J = 8.4 Hz), 7.76 (1H, dd, J = 8.2, 2.0 Hz), 7.89 (2H, d, J = 8.4 Hz), 8.61 (1H, d , J = 2.0Hz)

LC / MS [Condition 1]: retention time 3.60 minutes; m / z 669.9 [M + H] ⁺ , 335.5 [M + 2H] ²⁺ (ESI positive ion mode), m / z 714.1 [M + HCOO] ⁻ (ESI Negative ion mode)

実施例４９９
３，５−ジフルオロ−４−｛［３−（｛５−［４−（２−メトキシフェニルアミノ）ピペリジン−１−カルボニル］ピリジン−２−イル｝メチル）−２−オキソ−１−オキサ−３，８−ジアザスピロ［４．５］デカン−８−イル］メチル｝ベンゾニトリル（化合物番号４９９）の製造
（４−フルオロフェニル）（ピペリジン−４−イル）メタノン塩酸塩の代わりに、参考例２９２−２で得られたＮ−（２−メトキシフェニル）ピペリジン−４−アミン二塩酸塩を用いること以外は実質的に実施例３９２と同様に反応を行なって、表題化合物（２３ｍｇ、収率８１％）を無色無定形物として得た。

^１Ｈ−ＮＭＲ（ＣＤＣｌ_３）δ：１．３７−１．６４（２Ｈ，ｂｒ ｍ），１．７５（２Ｈ，ｄｔ，Ｊ＝１３．５，６．９Ｈｚ），１．９５（２Ｈ，ｂｒ ｄ，Ｊ＝１３．５Ｈｚ），２．０１−２．２８（２Ｈ，ｂｒ ｍ），２．５４−２．７０（４Ｈ，ｂｒ ｍ），３．０７−３．３２（２Ｈ，ｂｒ ｍ），３．３０（２Ｈ，ｓ），３．５１−３．６５（１Ｈ，ｂｒ ｍ），３．６５−３．８０（１Ｈ，ｂｒ ｍ），３．７４（２Ｈ，ｓ），３．８５（３Ｈ，ｓ），４．１２−４．２５（１Ｈ，ｂｒ ｍ），４．４９−４．６４（１Ｈ，ｂｒ ｍ），４．５６（２Ｈ，ｓ），６．６３（１Ｈ，ｄｄ，Ｊ＝１．７，７．６Ｈｚ），６．６９（１Ｈ，ｄｔ，Ｊ＝１．７，７．９Ｈｚ），６．７９（１Ｈ，ｄｄ，Ｊ＝１．７，７．９Ｈｚ），６．８６（１Ｈ，ｄｔ，Ｊ＝１．７，７．６Ｈｚ），７．２２（２Ｈ，ｄ，Ｊ＝６．３Ｈｚ），７．３５（１Ｈ，ｄ，Ｊ＝７．９Ｈｚ），７．７５（１Ｈ，ｄｄ，Ｊ＝７．９，２．３Ｈｚ），８．６０（１Ｈ，ｄ，Ｊ＝２．０Ｈｚ）．

ＬＣ／ＭＳ［条件１］：保持時間２．７１分；ｍ／ｚ６３０．８［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ６７５．１［Ｍ＋ＨＣＯＯ］⁻（ＥＳＩ負イオンモード）

Example 499
3,5-difluoro-4-{[3-({5- [4- (2-methoxyphenylamino) piperidin-1-carbonyl] pyridin-2-yl} methyl) -2-oxo-1-oxa-3 , 8-Diazaspiro [4.5] decan-8-yl] methyl} benzonitrile (Compound No. 499) instead of (4-fluorophenyl) (piperidin-4-yl) methanone hydrochloride Reference Example 292 The reaction was conducted in substantially the same manner as in Example 392 except that N- (2-methoxyphenyl) piperidin-4-amine dihydrochloride obtained in 2 was used, and the title compound (23 mg, yield 81%) Was obtained as a colorless amorphous product.

¹ H-NMR (CDCl ₃ ) δ: 1.37-1.64 (2H, br m), 1.75 (2H, dt, J = 13.5, 6.9 Hz), 1.95 (2H, br d, J = 13.5 Hz), 2.01-2.28 (2H, br m), 2.54-2.70 (4H, br m), 3.07-3.32 (2H, br m) 3.30 (2H, s), 3.51-3.65 (1H, br m), 3.65-3.80 (1 H, br m), 3.74 (2H, s), 3.85. (3H, s), 4.12-4.25 (1H, br m), 4.49-4.64 (1H, br m), 4.56 (2H, s), 6.63 (1H, dd) , J = 1.7, 7.6 Hz), 6.69 (1H, dt, J = 1.7, 7.9 Hz), 6.79 (1H, dd, J = 1.7, 7.9 Hz), 6.86 (1H dt, J = 1.7, 7.6 Hz), 7.22 (2H, d, J = 6.3 Hz), 7.35 (1H, d, J = 7.9 Hz), 7.75 (1H, dd) , J = 7.9, 2.3 Hz), 8.60 (1H, d, J = 2.0 Hz).

LC / MS [Condition 1]: Retention time 2.71 minutes; m / z 630.8 [M + H] ⁺ (ESI positive ion mode), m / z 675.1 [M + HCOO] ⁻ (ESI negative ion mode)

実施例５００
４−［（３−｛［５−（４−ベンジルピペリジン−１−カルボニル）ピリジン−２−イル］メチル｝−２−オキソ−１−オキサ−３，８−ジアザスピロ［４．５］デカン−８−イル）メチル］−３，５−ジフルオロベンゾニトリル（化合物番号５００）の製造
（４−フルオロフェニル）（ピペリジン−４−イル）メタノン塩酸塩の代わりに、４−ベンジルピペリジン（市販）を用いること以外は実質的に実施例３９２と同様に反応を行なって、表題化合物（２２ｍｇ、収率８２％）をクリーム色無定形物として得た。

^１Ｈ−ＮＭＲ（ＣＤＣｌ_３）δ：１．０７−１．４２（２Ｈ，ｂｒ ｍ），１．６６−１．８８（４Ｈ，ｍ），１．９４（２Ｈ，ｂｒ ｄ，Ｊ＝１３．１Ｈｚ），２．４３−２．７０（６Ｈ，ｂｒ ｍ），２．６５−２．８５（１Ｈ，ｂｒ ｍ），２．８７−３．１１（１Ｈ，ｂｒ ｍ），３．２８（２Ｈ，ｓ），３．５６−３．７６（１Ｈ，ｂｒ ｍ），３．７４（２Ｈ，ｓ），４．５４（２Ｈ，ｓ），４．５８−４．７８（１Ｈ，ｂｒ ｍ），７．１４（２Ｈ，ｄ，Ｊ＝７．８Ｈｚ），７．１７−７．２５（１Ｈ，ｍ），７．２２（２Ｈ，ｄ，Ｊ＝７．０Ｈｚ），７．２７−７．３７（３Ｈ，ｍ），７．７２（１Ｈ，ｄｄ，Ｊ＝７．８，２．０Ｈｚ），８．５７（１Ｈ，ｄ，Ｊ＝２．０Ｈｚ）．

ＬＣ／ＭＳ［条件１］：保持時間３．３８分；ｍ／ｚ５９９．９［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ６４４．１［Ｍ＋ＨＣＯＯ］⁻（ＥＳＩ負イオンモード）

Example 500
4-[(3-{[5- (4-Benzylpiperidin-1-carbonyl) pyridin-2-yl] methyl} -2-oxo-1-oxa-3,8-diazaspiro [4.5] decane-8 -Il) methyl] -3,5-difluorobenzonitrile (Compound No. 500) Preparation (4-Fluorophenyl) (piperidin-4-yl) methanone hydrochloride instead of 4-benzylpiperidine (commercially available) The title compound (22 mg, yield 82%) was obtained as a cream amorphous product in substantially the same manner as in Example 392 except for the above.

¹ H-NMR (CDCl ₃ ) δ: 1.07-1.42 (2H, br m), 1.6-1.88 (4H, m), 1.94 (2H, br d, J = 13. 1 Hz), 2.43-2.70 (6H, br m), 2.65-2.85 (1 H, br m), 2.87-3.11 (1 H, br m), 3.28 (2H) , S), 3.56-3.76 (1H, br m), 3.74 (2H, s), 4.54 (2H, s), 4.58-4.78 (1H, br m), 7.14 (2H, d, J = 7.8 Hz), 7.17-7.25 (1 H, m), 7.22 (2H, d, J = 7.0 Hz), 7.27-7.37 (3H, m), 7.72 (1H, dd, J = 7.8, 2.0 Hz), 8.57 (1H, d, J = 2.0 Hz).

LC / MS [Condition 1]: Retention time 3.38 minutes; m / z 599.9 [M + H] ⁺ (ESI positive ion mode), m / z 644.1 [M + HCOO] ⁻ (ESI negative ion mode)

実施例５０１
４−｛［３−（｛（１ｒ，４ｒ）−４−［４−（３−シアノフェノキシ）ピペリジン−１−カルボニル］シクロヘキシル｝メチル）−２−オキソ−１−オキサ−３，８−ジアザスピロ［４．５］デカン−８−イル］メチル｝−３，５−ジフルオロベンゾニトリル（化合物番号５０１）の製造
参考例３９８−２で得られた、（１ｒ，４ｒ）−４−｛［８−（４−シアノ−２，６−ジフルオロベンジル）−２−オキソ−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル］メチル｝シクロヘキサンカルボン酸（２０ｍｇ、０．０４５ｍｍｏｌ）、１−ヒドロキシベンゾトリアゾール（２ｍｇ、０．０１ｍｍｏｌ）及び参考例２８１−２で得られた、３−（ピペリジン−４−イルオキシ）ベンゾニトリル塩酸塩（１２ｍｇ、０．０４９ｍｍｏｌ）のクロロホルム（１ｍＬ）溶液に、トリエチルアミン（２５μＬ，０．１８ｍｍｏｌ）及び１−エチル−３−（３−ジメチルアミノプロピル）カルボジイミド塩酸塩（１３ｍｇ、０．０６７ｍｍｏｌ）を加えて、反応混合物を室温で５日間静置した。クエン酸（２６ｍｇ）の水（１ｍＬ）溶液を加えたのち、有機層を分離し、炭酸水素ナトリウム（３ｍｇ）の水（１ｍＬ）溶液で洗浄し、減圧下濃縮乾固して、表題化合物（２７ｍｇ、収率９６％）を無色無定形物として得た。

^１Ｈ−ＮＭＲ（ＣＤＣｌ_３）δ：１．０４（２Ｈ，ｑ，Ｊ＝１２．７Ｈｚ），１．４６−１．６７（３Ｈ，ｍ），１．６８−２．０３（１２Ｈ，ｍ），２．３９−２．５２（１Ｈ，ｍ），２．５２−２．７３（４Ｈ，ｂｒ ｍ），３．０９（２Ｈ，ｄ，Ｊ＝７．４Ｈｚ），３．２２（２Ｈ，ｓ），３．３７−３．５３（１Ｈ，ｍ），３．５４−３．８８（３Ｈ，ｍ），３．７５（２Ｈ，ｓ），４．５１−４．６２（１Ｈ，ｍ），７．１０−７．１８（２Ｈ，ｍ），７．１９−７．２９（３Ｈ，ｍ），７．３９（１Ｈ，ｔ，Ｊ＝７．８Ｈｚ）．

ＬＣ／ＭＳ［条件１］：保持時間３．３６分；ｍ／ｚ６３１．８［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ６７５．９［Ｍ＋ＨＣＯＯ］⁻（ＥＳＩ負イオンモード）

Example 501
4-{[3-({(1r, 4r) -4- [4- (3-cyanophenoxy) piperidine-1-carbonyl] cyclohexyl} methyl) -2-oxo-1-oxa-3,8-diazaspiro [ 4.5] Decan-8-yl] methyl} -3,5-difluorobenzonitrile (Compound No. 501) , (1r, 4r) -4-{[8- ( 4-cyano-2,6-difluorobenzyl) -2-oxo-1-oxa-3,8-diazaspiro [4.5] decan-3-yl] methyl} cyclohexanecarboxylic acid (20 mg, 0.045 mmol), 1 3-Hydroxybenzotriazole (2 mg, 0.01 mmol) and 3- (piperidin-4-yloxy) benzonitrile hydrochloride (12 mg, 0.049) obtained in Reference Example 281-2. mol) in chloroform (1 mL) was added triethylamine (25 μL, 0.18 mmol) and 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (13 mg, 0.067 mmol) and the reaction mixture was allowed to cool to room temperature. And left for 5 days. After adding a solution of citric acid (26 mg) in water (1 mL), the organic layer was separated, washed with a solution of sodium bicarbonate (3 mg) in water (1 mL), concentrated to dryness under reduced pressure, and the title compound (27 mg , Yield 96%) was obtained as a colorless amorphous product.

¹ H-NMR (CDCl ₃ ) δ: 1.04 (2H, q, J = 12.7 Hz), 1.46 to 1.67 (3H, m), 1.68 to 2.03 (12H, m) 2.39-2.52 (1H, m), 2.52-2.73 (4H, br m), 3.09 (2H, d, J = 7.4 Hz), 3.22 (2H, s) ), 3.37-3.53 (1H, m), 3.54-3.88 (3H, m), 3.75 (2H, s), 4.51-4.62 (1H, m), 7.10-7.18 (2H, m), 7.19-7.29 (3H, m), 7.39 (1 H, t, J = 7.8 Hz).

LC / MS [Condition 1]: Retention time 3.36 minutes; m / z 631.8 [M + H] ⁺ (ESI positive ion mode), m / z 675.9 [M + HCOO] ⁻ (ESI negative ion mode)

実施例５０２
４−｛［３−（｛（１ｒ，４ｒ）−４−［４−（３−シアノ−４−フルオロフェニルアミノ）ピペリジン−１−カルボニル］シクロヘキシル｝メチル）−２−オキソ−１−オキサ−３，８−ジアザスピロ［４．５］デカン−８−イル］メチル｝−３，５−ジフルオロベンゾニトリル（化合物番号５０２）の製造
３−（ピペリジン−４−イルオキシ）ベンゾニトリル塩酸塩の代わりに、参考例４４２−２で得られた２−フルオロ−５−（ピペリジン−４−イルアミノ）ベンゾニトリル二塩酸塩を用いること以外は実質的に実施例５０１と同様に反応を行なって、表題化合物(２９ｍｇ、収率定量的)をクリーム色固体として得た。

^１Ｈ−ＮＭＲ（ＣＤＣｌ_３）δ：１．０４（２Ｈ，ｑ，Ｊ＝１１．９Ｈｚ），１．３２（２Ｈ，ｑ，Ｊ＝１１．９Ｈｚ），１．４７−１．６７（３Ｈ，ｍ），１．６９−１．８６（４Ｈ，ｍ），１．９２（２Ｈ，ｂｒ ｄ，Ｊ＝１３．５Ｈｚ），２．００−２．１８（３Ｈ，ｍ），２．４６（１Ｈ，ｔｔ，Ｊ＝１１．６，２．６Ｈｚ），２．５３−２．７２（４Ｈ，ｍ），２．８２（１Ｈ，ｔ，Ｊ＝１１．６Ｈｚ），３．０９（２Ｈ，ｄ，Ｊ＝７．６Ｈｚ），３．１８（１Ｈ，ｔ，Ｊ＝１２．９Ｈｚ），３．２２（２Ｈ，ｓ），３．３６−３．５１（１Ｈ，ｍ），３．６３（１Ｈ，ｄ，Ｊ＝８．３Ｈｚ），３．７５（２Ｈ，ｓ），３．８９（１Ｈ，ｂｒ ｄ，Ｊ＝１３．９Ｈｚ），４．５３（１Ｈ，ｂｒ ｄ，Ｊ＝１３．２Ｈｚ），６．６８−６．８０（２Ｈ，ｍ），７．０１（１Ｈ，ｔ，Ｊ＝８．６Ｈｚ），７．２２（２Ｈ，ｄ，Ｊ＝５．９Ｈｚ）．

ＬＣ／ＭＳ［条件１］：保持時間３．３４分；ｍ／ｚ６４８．８［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ６９２．９［Ｍ＋ＨＣＯＯ］⁻（ＥＳＩ負イオンモード）

Example 502
4-{[3-({(1r, 4r) -4- [4- (3-cyano-4-fluorophenylamino) piperidine-1-carbonyl] cyclohexyl} methyl) -2-oxo-1-oxa-3 , 8-Diazaspiro [4.5] decan-8-yl] methyl} -3,5-difluorobenzonitrile (Compound No. 502) Reference instead of 3- (piperidin-4-yloxy) benzonitrile hydrochloride The reaction was carried out in substantially the same manner as in Example 501, except that 2-fluoro-5- (piperidin-4-ylamino) benzonitrile dihydrochloride obtained in Example 442-2 was used, and the title compound (29 mg, Yield quantitative) was obtained as a cream colored solid.

¹ H-NMR (CDCl ₃ ) δ: 1.04 (2H, q, J = 11.9 Hz), 1.32 (2H, q, J = 11.9 Hz), 1.47-1.67 (3H, m), 1.69-1.86 (4H, m), 1.92 (2H, br d, J = 13.5 Hz), 2.00-2.18 (3H, m), 2.46 (1H) , Tt, J = 11.6, 2.6 Hz), 2.53-2.72 (4H, m), 2.82 (1H, t, J = 11.6 Hz), 3.09 (2H, d, J = 7.6 Hz), 3.18 (1H, t, J = 12.9 Hz), 3.22 (2H, s), 3.36-3.51 (1H, m), 3.63 (1H, d, J = 8.3 Hz), 3.75 (2H, s), 3.89 (1H, br d, J = 13.9 Hz), 4.53 (1 H, br d, J = 13.2 Hz), 6.68- .80 (2H, m), 7.01 (1H, t, J = 8.6Hz), 7.22 (2H, d, J = 5.9Hz).

LC / MS [Condition 1]: Retention time 3.34 minutes; m / z 648.8 [M + H] ⁺ (ESI positive ion mode), m / z 692.9 [M + HCOO] ⁻ (ESI negative ion mode)

参考例５０３−１
（１ｒ，４ｒ）−４−（｛２−オキソ−８−［２，３，５，６−テトラフルオロ−４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）シクロヘキサンカルボン酸メチルの製造
４−（トリフルオロメチル）ベンジルブロミドの代わりに、１−（ブロモメチル）−２，３，５，６−テトラフルオロ−４−（トリフルオロメチル）ベンゼンを用いること以外は実質的に参考例６−２と同様に反応を行なって、表題化合物（０．１８ｇ、収率５２％）を白色粉末として得た。

^１Ｈ−ＮＭＲ（ＣＤＣｌ_３）δ：１．０１（２Ｈ，ｄｑ，Ｊ＝３．７，１３．１Ｈｚ），１．４１（２Ｈ，ｄｑ，Ｊ＝３．７，１３．１Ｈｚ），１．５０−１．６４（４Ｈ，ｍ），１．６６−１．８４（４Ｈ，ｍ），１．９８（４Ｈ，ｄｔ，Ｊ＝２２．２，９．３Ｈｚ），２．２５（１Ｈ，ｔｔ，Ｊ＝１２．１，３．５Ｈｚ），２．５１−２．７５（４Ｈ，ｂｒ ｍ），３．０８（２Ｈ，ｄ，Ｊ＝７．４Ｈｚ），３．２３（２Ｈ，ｓ），３．６６（３Ｈ，ｓ），３．８３（２Ｈ，ｓ）．

ＬＣ／ＭＳ［条件１］：保持時間３．８７分；ｍ／ｚ５４０．６［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ５３９．０［Ｍ−Ｈ］⁻、５８４．９［Ｍ＋ＨＣＯＯ］⁻（ＥＳＩ負イオンモード）

Reference Example 503-1
(1r, 4r) -4-({2-oxo-8- [2,3,5,6-tetrafluoro-4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4. 5] Preparation of methyl decan-3-yl} methyl) cyclohexanecarboxylate Instead of 4- (trifluoromethyl) benzyl bromide, 1- (bromomethyl) -2,3,5,6-tetrafluoro-4- (tri The reaction was carried out substantially in the same manner as in Reference Example 6-2, except that fluoromethyl) benzene was used, to give the title compound (0.18 g, yield 52%) as a white powder.

¹ H-NMR (CDCl ₃ ) δ: 1.01 (2H, dq, J = 3.7, 13.1 Hz), 1.41 (2H, dq, J = 3.7, 13.1 Hz), 1. 50-1.64 (4H, m), 1.66-1.84 (4H, m), 1.98 (4H, dt, J = 22.2, 9.3 Hz), 2.25 (1H, tt , J = 12.1, 3.5 Hz), 2.51-2.75 (4H, br m), 3.08 (2H, d, J = 7.4 Hz), 3.23 (2H, s), 3.66 (3H, s), 3.83 (2H, s).

LC / MS [Condition 1]: Retention time 3.87 minutes; m / z 540.6 [M + H] ⁺ (ESI positive ion mode), m / z 539.0 [M−H] ⁻ , 584.9 [M + HCOO] ⁻ (ESI negative ion mode)

参考例５０３−２
（１ｒ，４ｒ）−４−（｛２−オキソ−８−［２，３，５，６−テトラフルオロ−４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）シクロヘキサンカルボン酸の製造
参考例５０３−１で得られた、（１ｒ，４ｒ）−４−（｛２−オキソ−８−［２，３，５，６−テトラフルオロ−４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）シクロヘキサンカルボン酸メチル（０．１６ｇ、０．３０ｍｍｏｌ）の１，４−ジオキサン（４ｍＬ）懸濁液に水（０．３０ｍＬ）と１Ｍ水酸化ナトリウム水溶液（０．３３ｍＬ）を加えて、室温で１日間攪拌した。その後、水（１．０ｍＬ）を加えてさらに５日間攪拌した。減圧下濃縮して、反応混合物から１，４−ジオキサンを留去したのち、残留物に１Ｍ塩酸（０．３３ｍＬ）とクロロホルム（５ｍＬ）を加えて有機層を分離した。その有機層を減圧下濃縮乾固して、表題化合物（０．１４ｇ、収率８７％）を無色無定形物として得た。

^１Ｈ−ＮＭＲ（ＣＤＣｌ_３）δ：１．０３（２Ｈ，ｑ，Ｊ＝１２．６Ｈｚ），１．４２（２Ｈ，ｑ，Ｊ＝１３．０Ｈｚ），１．５１−１．６５（１Ｈ，ｍ），１．７０−１．８６（４Ｈ，ｍ），１．９４（２Ｈ，ｂｒ ｄ，Ｊ＝１３．９Ｈｚ），２．０７（２Ｈ，ｂｒ ｄ，Ｊ＝１２．９Ｈｚ），２．２８（１Ｈ，ｔｔ，Ｊ＝１２．２，３．０Ｈｚ），２．５３−２．７６（４Ｈ，ｂｒ ｍ），３．０９（２Ｈ，ｄ，Ｊ＝７．９Ｈｚ），３．２４（２Ｈ，ｓ），３．８４（２Ｈ，ｓ）．

ＬＣ／ＭＳ［条件１］：保持時間３．４６分；ｍ／ｚ５２６．６［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ５２４．８［Ｍ−Ｈ］⁻（ＥＳＩ負イオンモード）

Reference Example 503-2
(1r, 4r) -4-({2-oxo-8- [2,3,5,6-tetrafluoro-4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4. 5] Production of decan-3-yl} methyl) cyclohexanecarboxylic acid (1r, 4r) -4-({2-oxo-8- [2,3,5,6-) obtained in Reference Example 503-1 1 of methyl tetrafluoro-4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl) cyclohexanecarboxylate (0.16 g, 0.30 mmol) Water (0.30 mL) and 1M aqueous sodium hydroxide solution (0.33 mL) were added to a suspension of 1,4-dioxane (4 mL), and the mixture was stirred at room temperature for 1 day. Thereafter, water (1.0 mL) was added and the mixture was further stirred for 5 days. After concentration under reduced pressure and 1,4-dioxane was distilled off from the reaction mixture, 1M hydrochloric acid (0.33 mL) and chloroform (5 mL) were added to the residue to separate the organic layer. The organic layer was concentrated to dryness under reduced pressure to give the title compound (0.14 g, yield 87%) as a colorless amorphous product.

¹ H-NMR (CDCl ₃ ) δ: 1.03 (2H, q, J = 12.6 Hz), 1.42 (2H, q, J = 13.0 Hz), 1.51-1.65 (1H, m), 1.70-1.86 (4H, m), 1.94 (2H, br d, J = 13.9 Hz), 2.07 (2H, br d, J = 12.9 Hz), 2. 28 (1H, tt, J = 12.2, 3.0 Hz), 2.53-2.76 (4H, br m), 3.09 (2H, d, J = 7.9 Hz), 3.24 ( 2H, s), 3.84 (2H, s).

LC / MS [Condition 1]: retention time 3.46 minutes; m / z 526.6 [M + H] ⁺ (ESI positive ion mode), m / z 524.8 [M−H] ⁻ (ESI negative ion mode)

実施例５０３
３−（｛（１ｒ，４ｒ）−４−［４−（ピリミジン−４−イル）ピペラジン−１−カルボニル］シクロヘキシル｝メチル）−８−［２，３，５，６−テトラフルオロ−４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−２−オン（化合物番号５０３）の製造
参考例５０３−２で得られた、（１ｒ，４ｒ）−４−（｛２−オキソ−８−［２，３，５，６−テトラフルオロ−４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）シクロヘキサンカルボン酸（２０ｍｇ、０．０３８ｍｍｏｌ）、参考例２８７−３で得られた、４−（ピペラジン−１−イル）ピリミジン二塩酸塩（１０ｍｇ、０．０４２ｍｍｏｌ）及び１−ヒドロキシベンゾトリアゾール（２ｍｇ、０．０１ｍｍｏｌ）のクロロホルム（１ｍＬ）溶液に、トリエチルアミン（２６μＬ，０．１９ｍｍｏｌ）及び１−エチル−３−（３−ジメチルアミノプロピル）カルボジイミド塩酸塩（１１ｍｇ、０．０５７ｍｍｏｌ）を加えて、室温で２日間静置したのち、クエン酸（２２ｍｇ）の水（１ｍＬ）溶液を加えた。有機層を分離し、炭酸水素ナトリウム（３ｍｇ）の水（１ｍＬ）溶液で洗浄したのち、減圧下濃縮乾固して、表題化合物（２０ｍｇ、収率７７％）を白色固体として得た。

^１Ｈ−ＮＭＲ（ＣＤＣｌ_３）δ：１．０６（２Ｈ，ｑ，Ｊ＝１２．３Ｈｚ），１．４９−１．６９（３Ｈ，ｍ），１．７０−１．８７（６Ｈ，ｍ），１．９３（２Ｈ，ｂｒ ｄ，Ｊ＝１３．５Ｈｚ），２．４７（１Ｈ，ｂｒ ｔ，Ｊ＝１１．５Ｈｚ），２．５３−２．７６（４Ｈ，ｍ），３．１１（２Ｈ，ｄ，Ｊ＝７．４Ｈｚ），３．２４（２Ｈ，ｓ），３．５５−３．６８（４Ｈ，ｂｒ ｍ），３．６６−３．８０（４Ｈ，ｂｒ ｍ），３．８３（２Ｈ，ｓ），６．５２（１Ｈ，ｄ，Ｊ＝６．１Ｈｚ），８．２６（１Ｈ，ｄ，Ｊ＝６．１Ｈｚ），８．６３（１Ｈ，ｓ）．

ＬＣ／ＭＳ［条件１］：保持時間２．６５分；ｍ／ｚ６７３．２［Ｍ＋Ｈ］^＋、３３７．０［Ｍ＋２Ｈ］^２＋（ＥＳＩ正イオンモード）、ｍ／ｚ７１７．２［Ｍ＋ＨＣＯＯ］⁻（ＥＳＩ負イオンモード）

Example 503
3-({(1r, 4r) -4- [4- (pyrimidin-4-yl) piperazine-1-carbonyl] cyclohexyl} methyl) -8- [2,3,5,6-tetrafluoro-4- ( (Trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-2-one (Compound No. 503) (1r, 4r) -4 obtained in Reference Example 503-2 -({2-oxo-8- [2,3,5,6-tetrafluoro-4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl } Methyl) cyclohexanecarboxylic acid (20 mg, 0.038 mmol), 4- (piperazin-1-yl) pyrimidine dihydrochloride (10 mg, 0.042 mmol) and 1-hydroxybenen obtained in Reference Example 287-3 To a solution of triazole (2 mg, 0.01 mmol) in chloroform (1 mL) was added triethylamine (26 μL, 0.19 mmol) and 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (11 mg, 0.057 mmol). After standing at room temperature for 2 days, a solution of citric acid (22 mg) in water (1 mL) was added. The organic layer was separated, washed with a solution of sodium hydrogen carbonate (3 mg) in water (1 mL) and concentrated to dryness under reduced pressure to give the title compound (20 mg, 77% yield) as a white solid.

¹ H-NMR (CDCl ₃ ) δ: 1.06 (2H, q, J = 12.3 Hz), 1.49-1.69 (3H, m), 1.70-1.87 (6H, m) , 1.93 (2H, br d, J = 13.5 Hz), 2.47 (1 H, br t, J = 11.5 Hz), 2.53-2.76 (4H, m), 3.11 ( 2H, d, J = 7.4 Hz), 3.24 (2H, s), 3.55-3.68 (4H, br m), 3.66-3.80 (4H, br m), 3. 83 (2H, s), 6.52 (1H, d, J = 6.1 Hz), 8.26 (1H, d, J = 6.1 Hz), 8.63 (1H, s).

LC / MS [Condition 1]: Retention time 2.65 minutes; m / z 673.2 [M + H] ⁺ , 337.0 [M + 2H] ²⁺ (ESI positive ion mode), m / z 717.2 [M + HCOO] ⁻ (ESI Negative ion mode)

実施例５０４
４−｛［３−（｛５−［３−（４−シアノフェノキシ）アゼチジン−１−カルボニル］ピリジン−２−イル｝メチル）−２−オキソ−１−オキサ−３，８−ジアザスピロ［４．５］デカン−８−イル］メチル｝−３，５−ジフルオロベンゾニトリル（化合物番号５０４）の製造
（４−フルオロフェニル）（ピペリジン−４−イル）メタノン塩酸塩の代わりに、参考例３８３−２で得られた４−（アゼチジン−３−イルオキシ）ベンゾニトリルを用いること以外は実質的に実施例３９２と同様に反応を行なって、表題化合物（２７ｍｇ、収率定量的）をクリーム色無定形物として得た。

^１Ｈ−ＮＭＲ（ＣＤＣｌ_３）δ：１．７５（２Ｈ，ｄｔ，Ｊ＝１３．１，７．８Ｈｚ），１．９５（２Ｈ，ｂｒ ｄ，Ｊ＝１３．１Ｈｚ），２．５０−２．７２（４Ｈ，ｂｒ ｍ），３．３１（２Ｈ，ｓ），３．７４（２Ｈ，ｓ），４．２０−４．４７（２Ｈ，ｂｒ ｍ），４．５６（２Ｈ，ｓ），４．５９−４．７６（２Ｈ，ｂｒ ｍ），５．０８（１Ｈ，ｔｔ，Ｊ＝６．５，４．１Ｈｚ），６．８２（２Ｈ，ｄ，Ｊ＝８．６Ｈｚ），７．２２（２Ｈ，ｄ，Ｊ＝５．７Ｈｚ），７．３６（１Ｈ，ｄ，Ｊ＝８．２Ｈｚ），７．６２（２Ｈ，ｄ，Ｊ＝８．６Ｈｚ），７．９８（１Ｈ，ｄｄ，Ｊ＝８．２，２．５Ｈｚ），８．７９（１Ｈ，ｄ，Ｊ＝２．５Ｈｚ）．

ＬＣ／ＭＳ［条件１］：保持時間２．９４分；ｍ／ｚ５９８．９［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ６４３．１［Ｍ＋ＨＣＯＯ］⁻（ＥＳＩ負イオンモード）

Example 504
4-{[3-({5- [3- (4-Cyanophenoxy) azetidin-1-carbonyl] pyridin-2-yl} methyl) -2-oxo-1-oxa-3,8-diazaspiro [4. 5] Preparation of decan-8-yl] methyl} -3,5-difluorobenzonitrile (Compound No. 504) Instead of (4-fluorophenyl) (piperidin-4-yl) methanone hydrochloride, Reference Example 383-2 The title compound (27 mg, quantitative yield) was cream-colored amorphous in substantially the same manner as in Example 392 except that 4- (azetidin-3-yloxy) benzonitrile obtained in 1 was used. Got as.

¹ H-NMR (CDCl ₃ ) δ: 1.75 (2H, dt, J = 13.1, 7.8 Hz), 1.95 (2H, br d, J = 13.1 Hz), 2.50-2 .72 (4H, br m), 3.31 (2H, s), 3.74 (2H, s), 4.20-4.47 (2H, br m), 4.56 (2H, s), 4.59-4.76 (2H, br m), 5.08 (1H, tt, J = 6.5, 4.1 Hz), 6.82 (2H, d, J = 8.6 Hz), 7. 22 (2H, d, J = 5.7 Hz), 7.36 (1 H, d, J = 8.2 Hz), 7.62 (2H, d, J = 8.6 Hz), 7.98 (1H, dd) , J = 8.2, 2.5 Hz), 8.79 (1H, d, J = 2.5 Hz).

LC / MS [Condition 1]: Retention time 2.94 minutes; m / z 598.9 [M + H] ⁺ (ESI positive ion mode), m / z 643.1 [M + HCOO] ⁻ (ESI negative ion mode)

実施例５０５
６−［１−（６−｛［８−（４−シアノ−２，６−ジフルオロベンジル）−２−オキソ−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル］メチル｝ニコチノイル）アゼチジン−３−イルオキシ］ニコチノニトリル（化合物番号５０５）の製造
（４−フルオロフェニル）（ピペリジン−４−イル）メタノン塩酸塩の代わりに、参考例３８１−２で得られた６−（アゼチジン−３−イルオキシ）ニコチノニトリルを用いること以外は実質的に実施例３９２と同様に反応を行なって、表題化合物（９ｍｇ、収率３３％）を無色無定形物として得た。

^１Ｈ−ＮＭＲ（ＣＤＣｌ_３）δ：１．７５（２Ｈ，ｄｔ，Ｊ＝１３．５，７．４Ｈｚ），１．９５（２Ｈ，ｂｒ ｄ，Ｊ＝１３．５Ｈｚ），２．４７−２．７８（４Ｈ，ｂｒ ｍ），３．３１（２Ｈ，ｓ），３．７４（２Ｈ，ｓ），４．２５−４．４５（２Ｈ，ｂｒ ｍ），４．５６（２Ｈ，ｓ），４．５６−４．８６（２Ｈ，ｂｒ ｍ），５．４３−５．５８（１Ｈ，ｍ），６．９２（１Ｈ，ｄ，Ｊ＝８．２Ｈｚ），７．２２（２Ｈ，ｄ，Ｊ＝６．１Ｈｚ），７．３６（１Ｈ，ｄ，Ｊ＝８．２Ｈｚ），７．８６（１Ｈ，ｄｄ，Ｊ＝８．２，２．０Ｈｚ），７．９８（１Ｈ，ｄｄ，Ｊ＝８．２，２．０Ｈｚ），８．４４（１Ｈ，ｄ，Ｊ＝２．０Ｈｚ），８．８０（１Ｈ，ｄ，Ｊ＝２．０Ｈｚ）．

ＬＣ／ＭＳ［条件１］：保持時間２．７３分；ｍ／ｚ６００．０［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ６４４．１［Ｍ＋ＨＣＯＯ］⁻（ＥＳＩ負イオンモード）

Example 505
6- [1- (6-{[8- (4-Cyano-2,6-difluorobenzyl) -2-oxo-1-oxa-3,8-diazaspiro [4.5] decan-3-yl] methyl } Preparation of Nicotinoyl) azetidin-3-yloxy] nicotinonitrile (Compound No. 505) Instead of (4-fluorophenyl) (piperidin-4-yl) methanone hydrochloride, 6- 6 obtained in Reference Example 381-2 The reaction was carried out substantially in the same manner as in Example 392 except that (azetidin-3-yloxy) nicotinonitrile was used to give the title compound (9 mg, yield 33%) as a colorless amorphous product.

¹ H-NMR (CDCl ₃ ) δ: 1.75 (2H, dt, J = 13.5, 7.4 Hz), 1.95 (2H, br d, J = 13.5 Hz), 2.47-2 .78 (4H, br m), 3.31 (2H, s), 3.74 (2H, s), 4.25-4.45 (2H, br m), 4.56 (2H, s), 4.56-4.86 (2H, br m), 5.43-5.58 (1H, m), 6.92 (1H, d, J = 8.2 Hz), 7.22 (2H, d, J = 6.1 Hz), 7.36 (1H, d, J = 8.2 Hz), 7.86 (1H, dd, J = 8.2, 2.0 Hz), 7.98 (1H, dd, J = 8.2, 2.0 Hz), 8.44 (1H, d, J = 2.0 Hz), 8.80 (1H, d, J = 2.0 Hz).

LC / MS [Condition 1]: Retention time 2.73 minutes; m / z 600.0 [M + H] ⁺ (ESI positive ion mode), m / z 644.1 [M + HCOO] ⁻ (ESI negative ion mode)

実施例５０６
４−｛［３−（｛５−［４−（４−シアノフェニルアミノ）ピペリジン−１−カルボニル］ピリジン−２−イル｝メチル）−２−オキソ−１−オキサ−３，８−ジアザスピロ［４．５］デカン−８−イル］メチル｝−３，５−ジフルオロベンゾニトリル（化合物番号５０６）の製造
（４−フルオロフェニル）（ピペリジン−４−イル）メタノン塩酸塩の代わりに、参考例４４１−２で得られた４−（ピペリジン−４−イルアミノ）ベンゾニトリル二塩酸塩を用いること以外は実質的に実施例３９２と同様に反応を行なって、表題化合物（２５ｍｇ、収率８９％）を白色固体として得た。

^１Ｈ−ＮＭＲ（ＣＤＣｌ_３）δ：１．３２−１．６２（２Ｈ，ｂｒ ｍ），１．７６（２Ｈ，ｄｔ，Ｊ＝１３．１，７．４Ｈｚ），１．９５（２Ｈ，ｂｒ ｄ，Ｊ＝１３．１Ｈｚ），２．０１−２．３２（２Ｈ，ｂｒ ｍ），２．４９−２．７２（４Ｈ，ｂｒ ｍ），２．９９−３．３９（２Ｈ，ｂｒ ｍ），３．３０（２Ｈ，ｓ），３．５４−３．６９（１Ｈ，ｍ），３．６２−３．９４（１Ｈ，ｂｒ ｍ），３．７４（２Ｈ，ｓ），４．０１−４．１６（１Ｈ，ｂｒ ｍ），４．５０−４．７８（１Ｈ，ｂｒ ｍ），４．５５（２Ｈ，ｓ），６．５７（２Ｈ，ｄ，Ｊ＝８．６Ｈｚ），７．２２（２Ｈ，ｄ，Ｊ＝６．１Ｈｚ），７．３５（１Ｈ，ｄ，Ｊ＝７．８Ｈｚ），７．４４（２Ｈ，ｄ，Ｊ＝８．６Ｈｚ），７．７５（１Ｈ，ｄｄ，Ｊ＝７．８，２．０Ｈｚ），８．６０（１Ｈ，ｄ，Ｊ＝２．０Ｈｚ）．

ＬＣ／ＭＳ［条件１］：保持時間３．００分；ｍ／ｚ６２６．０［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ６７０．１［Ｍ＋ＨＣＯＯ］⁻（ＥＳＩ負イオンモード）

Example 506
4-{[3-({5- [4- (4-Cyanophenylamino) piperidin-1-carbonyl] pyridin-2-yl} methyl) -2-oxo-1-oxa-3,8-diazaspiro [4 .5] Preparation of decan-8-yl] methyl} -3,5-difluorobenzonitrile (Compound No. 506) Instead of (4-fluorophenyl) (piperidin-4-yl) methanone hydrochloride, Reference Example 441 The reaction was conducted in substantially the same manner as in Example 392 except that 4- (piperidin-4-ylamino) benzonitrile dihydrochloride obtained in 2 was used to give the title compound (25 mg, 89% yield) in white Obtained as a solid.

¹ H-NMR (CDCl ₃ ) δ: 1.32-1.62 (2H, br m), 1.76 (2H, dt, J = 13.1, 7.4 Hz), 1.95 (2H, br d, J = 13.1 Hz), 2.01-2.32 (2H, br m), 2.49-2.72 (4H, br m), 2.99-3.39 (2H, br m). , 3.30 (2H, s), 3.54-3.69 (1H, m), 3.62-3.94 (1H, br m), 3.74 (2H, s), 4.01- 4.16 (1H, br m), 4.50-4.78 (1 H, br m), 4.55 (2H, s), 6.57 (2H, d, J = 8.6 Hz), 7. 22 (2H, d, J = 6.1 Hz), 7.35 (1H, d, J = 7.8 Hz), 7.44 (2H, d, J = 8.6 Hz), 7.75 (1H, dd) , J = 7.8, 2.0 Hz), 8.60 (1H, d, J = 2.0 Hz).

LC / MS [Condition 1]: Retention time 3.00 minutes; m / z 626.0 [M + H] ⁺ (ESI positive ion mode), m / z 670.1 [M + HCOO] ⁻ (ESI negative ion mode)

実施例５０７
４−［（３−｛［５−（４，４−ジフルオロピペリジン−１−カルボニル）ピリジン−２−イル］メチル｝−２−オキソ−１−オキサ−３，８−ジアザスピロ［４．５］デカン−８−イル）メチル］−３，５−ジフルオロベンゾニトリル（化合物番号５０７）の製造
（４−フルオロフェニル）（ピペリジン−４−イル）メタノン塩酸塩の代わりに、４，４−ジフルオロピペリジン塩酸塩（市販）を用いること以外は実質的に実施例３９２と同様に反応を行なって、表題化合物（２３ｍｇ、収率９２％）をクリーム色無定形物として得た。

^１Ｈ−ＮＭＲ（ＣＤＣｌ_３）δ：１．７６（２Ｈ，ｄｔ，Ｊ＝１３．１，７．８Ｈｚ），１．９５−２．２２（４Ｈ，ｂｒ ｍ），１．９６（２Ｈ，ｄ，Ｊ＝１３．１Ｈｚ），２．５１−２．７４（４Ｈ，ｂｒ ｍ），３．３１（２Ｈ，ｓ），３．４４−４．０４（４Ｈ，ｂｒ ｍ），３．７４（２Ｈ，ｓ），４．５６（２Ｈ，ｓ），７．２２（２Ｈ，ｄ，Ｊ＝５．７Ｈｚ），７．３６（１Ｈ，ｄ，Ｊ＝８．２Ｈｚ），７．７５（１Ｈ，ｄｄ，Ｊ＝７．８，２．０Ｈｚ），８．６１（１Ｈ，ｄ，Ｊ＝２．０Ｈｚ）．

ＬＣ／ＭＳ［条件１］：保持時間１．５２分；ｍ／ｚ５４５．９［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ５９０．０［Ｍ＋ＨＣＯＯ］⁻（ＥＳＩ負イオンモード）

Example 507
4-[(3-{[5- (4,4-Difluoropiperidin-1-carbonyl) pyridin-2-yl] methyl} -2-oxo-1-oxa-3,8-diazaspiro [4.5] decane Preparation of -8-yl) methyl] -3,5-difluorobenzonitrile (Compound No. 507) 4,4-Difluoropiperidine hydrochloride instead of (4-fluorophenyl) (piperidin-4-yl) methanone hydrochloride The reaction was carried out substantially in the same manner as in Example 392 except that (commercially available) was used, and the title compound (23 mg, yield 92%) was obtained as a cream-colored amorphous product.

¹ H-NMR (CDCl ₃ ) δ: 1.76 (2H, dt, J = 13.1, 7.8 Hz), 1.95-2.22 (4H, br m), 1.96 (2H, d , J = 13.1 Hz), 2.51-2.74 (4H, br m), 3.31 (2H, s), 3.44-4.04 (4H, br m), 3.74 (2H) , S), 4.56 (2H, s), 7.22 (2H, d, J = 5.7 Hz), 7.36 (1H, d, J = 8.2 Hz), 7.75 (1H, dd) , J = 7.8, 2.0 Hz), 8.61 (1H, d, J = 2.0 Hz).

LC / MS [Condition 1]: Retention time 1.52 minutes; m / z 545.9 [M + H] ⁺ (ESI positive ion mode), m / z 590.0 [M + HCOO] ⁻ (ESI negative ion mode)

実施例５０８
４−｛［９−（４−シアノ−２，６−ジフルオロベンジル）−２−オキソ−１−オキサ−３，９−ジアザスピロ［５．５］ウンデカン−３−イル］メチル｝−Ｎ−［（３−メトキシイソキサゾル−５−イル）メチル］ベンズアミド（化合物番号５０８）の製造
６−｛［８−（４−シアノ−２，６−ジフルオロベンジル）−２−オキソ−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル］メチル｝ニコチン酸の代わりに、
参考例４７４−３で得られた、４−｛［９−（４−シアノ−２，６−ジフルオロベンジル）−２−オキソ−１−オキサ−３，９−ジアザスピロ［５．５］ウンデカン−３−イル］メチル｝安息香酸を用いることと、（４−フルオロフェニル）（ピペリジン−４−イル）メタノン塩酸塩の代わりに参考例４０１−３で得られた、（３−メトキシイソオキサゾール−５−イル）メタンアミンを用いること以外は実質的に実施例３９２と同様に反応を行なって、表題化合物(１１ｍｇ、収率７６％)を無色無定形物として得た。

^１Ｈ−ＮＭＲ（ＣＤＣｌ_３）δ：１．６０−１．７１（２Ｈ，ｍ），１．７３−１．９２（４Ｈ，ｍ），２．５０−２．７３（４Ｈ，ｂｒ ｍ），３．１８（２Ｈ，ｔ，Ｊ＝６．５Ｈｚ），３．７２（２Ｈ，ｓ），３．９６（３Ｈ，ｓ），４．５９（２Ｈ，ｓ），４．６４（２Ｈ，ｄ，Ｊ＝５．７Ｈｚ），５．８９（１Ｈ，ｓ），６．７０（１Ｈ，ｔ，Ｊ＝６．１Ｈｚ），７．２１（２Ｈ，ｄ，Ｊ＝６．１Ｈｚ），７．３６（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ），７．７６（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ）．

ＬＣ／ＭＳ［条件１］：保持時間１．４２分；ｍ／ｚ５６５．８［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ５６４．０［Ｍ−Ｈ］⁻（ＥＳＩ負イオンモード）

Example 508
4-{[9- (4-Cyano-2,6-difluorobenzyl) -2-oxo-1-oxa-3,9-diazaspiro [5.5] undecan-3-yl] methyl} -N-[( Preparation of 3-methoxyisoxazol-5-yl) methyl] benzamide (Compound No. 508) 6-{[8- (4-Cyano-2,6-difluorobenzyl) -2-oxo-1-oxa-3, Instead of 8-diazaspiro [4.5] decan-3-yl] methyl} nicotinic acid,
4-{[9- (4-Cyano-2,6-difluorobenzyl) -2-oxo-1-oxa-3,9-diazaspiro [5.5] undecane-3 obtained in Reference Example 474-3 -Il] methyl} benzoic acid and (3-methoxyisoxazole-5- 5) obtained in Reference Example 401-3 instead of (4-fluorophenyl) (piperidin-4-yl) methanone hydrochloride Yl) The reaction was carried out in substantially the same manner as in Example 392 except that methanamine was used to give the title compound (11 mg, yield 76%) as a colorless amorphous product.

¹ H-NMR (CDCl ₃ ) δ: 1.60-1.71 (2H, m), 1.73-1.92 (4H, m), 2.50-2.73 (4H, br m), 3.18 (2H, t, J = 6.5 Hz), 3.72 (2H, s), 3.96 (3H, s), 4.59 (2H, s), 4.64 (2H, d, J = 5.7 Hz), 5.89 (1 H, s), 6.70 (1 H, t, J = 6.1 Hz), 7.21 (2 H, d, J = 6.1 Hz), 7.36 ( 2H, d, J = 8.2 Hz), 7.76 (2H, d, J = 8.2 Hz).

LC / MS [Condition 1]: Retention time 1.42 minutes; m / z 565.8 [M + H] ⁺ (ESI positive ion mode), m / z 564.0 [M−H] ⁻ (ESI negative ion mode)

実施例５０９
６−｛［８−（４−シアノ−２，６−ジフルオロベンジル）−２−オキソ−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル］メチル｝−Ｎ−｛［５−（トリフルオロメチル）ピリジン−２−イル］メチル｝ニコチンアミド）（化合物番号５０９）の製造
（４−フルオロフェニル）（ピペリジン−４−イル）メタノン塩酸塩の代わりに参考例４５７−３で得られた、［５−（トリフルオロメチル）ピリジン−２−イル］メタンアミンを用いること以外は実質的に実施例３９２と同様に反応を行って、表題化合物（４．９ｍｇ、収率１８％）を白色粉末として得た。

^１Ｈ−ＮＭＲ（ＣＤＣｌ_３）δ：１．７５（２Ｈ，ｄｔ，Ｊ＝１２．７，６．１Ｈｚ），１．９５（２Ｈ，ｄ，Ｊ＝１２．７Ｈｚ），２．５４−２．６５（４Ｈ，ｂｒ ｍ），３．３１（２Ｈ，ｓ），３．７４（２Ｈ，ｓ），４．５９（２Ｈ，ｓ），４．８５（２Ｈ，ｄ，Ｊ＝４．９Ｈｚ），７．２２（２Ｈ，ｄ，Ｊ＝６．１Ｈｚ），７．４０（１Ｈ，ｄ，Ｊ＝８．２Ｈｚ），７．４８（１Ｈ，ｄ，Ｊ＝８．２Ｈｚ），７．５９（１Ｈ，ｔ，Ｊ＝４．９Ｈｚ），７．９６（１Ｈ，ｄｄ，Ｊ＝８．２，２．０Ｈｚ），８．１７（１Ｈ，ｄｄ，Ｊ＝８．２，２．０Ｈｚ），８．８４（１Ｈ，ｓ），９．０２（１Ｈ，ｄ，Ｊ＝２．５Ｈｚ）．

ＬＣ／ＭＳ［条件１］：保持時間２．８８分；ｍ／ｚ６００．９［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ５９９．０［Ｍ−Ｈ］⁻（ＥＳＩ負イオンモード）

Example 509
6-{[8- (4-Cyano-2,6-difluorobenzyl) -2-oxo-1-oxa-3,8-diazaspiro [4.5] decan-3-yl] methyl} -N-{[ Preparation of 5- (trifluoromethyl) pyridin-2-yl] methyl} nicotinamide) (Compound No. 509) Reference Example 457-3 instead of (4-fluorophenyl) (piperidin-4-yl) methanone hydrochloride The reaction was carried out in substantially the same manner as in Example 392 except that [5- (trifluoromethyl) pyridin-2-yl] methanamine was obtained, and the title compound (4.9 mg, yield 18%) Was obtained as a white powder.

¹ H-NMR (CDCl ₃ ) δ: 1.75 (2H, dt, J = 12.7, 6.1 Hz), 1.95 (2H, d, J = 12.7 Hz), 2.54-2. 65 (4H, br m), 3.31 (2H, s), 3.74 (2H, s), 4.59 (2H, s), 4.85 (2H, d, J = 4.9 Hz), 7.22 (2H, d, J = 6.1 Hz), 7.40 (1H, d, J = 8.2 Hz), 7.48 (1H, d, J = 8.2 Hz), 7.59 (1H , T, J = 4.9 Hz), 7.96 (1H, dd, J = 8.2, 2.0 Hz), 8.17 (1H, dd, J = 8.2, 2.0 Hz), 8. 84 (1H, s), 9.02 (1H, d, J = 2.5 Hz).

LC / MS [Condition 1]: Retention time 2.88 minutes; m / z 600.9 [M + H] ⁺ (ESI positive ion mode), m / z 599.0 [M−H] ⁻ (ESI negative ion mode)

実施例５１０
（１ｒ，４ｒ）−４−（｛２−オキソ−８−［２，３，５，６−テトラフルオロ−４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）−Ｎ−［（テトラヒドロフラン−２−イル）メチル］シクロヘキサンカルボキサミド（化合物番号５１０）の製造
（１ｒ，４ｒ）−４−（｛２−オキソ−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）シクロヘキサンカルボン酸の代わりに、参考例５０３−２で得られた（１ｒ，４ｒ）−４−（｛２−オキソ−８−［２、３、５、６−テトラフルオロ−４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）シクロヘキサンカルボン酸を用いること以外は実質的に実施例１０と同様に反応を行なって、表題化合物（２７ｍｇ、収率７８％）を白色固体として得た。

^１Ｈ−ＮＭＲ（３００ＭＨｚ，ＣＤＣｌ_３）δ：１．０１（２Ｈ，ｑｄ，Ｊ＝１２．９，３．３Ｈｚ），１．３９−１．６４（４Ｈ，ｍ），１．６９−１．８３（４Ｈ，ｍ），１．８４−２．００（７Ｈ，ｍ），２．０３（１Ｈ，ｔｔ，Ｊ＝１１．９，３．６Ｈｚ），２．５２−２．７４（４Ｈ，ｍ），３．０８（２Ｈ，ｄ，Ｊ＝７．３Ｈｚ），３．１１（３Ｈ，ｄｄｄ，Ｊ＝１０．０，７．６，４．３Ｈｚ），３．２３（２Ｈ，ｓ），３．５８（１Ｈ，ｄｄｄ，Ｊ＝１３．５，６．３，３．０Ｈｚ），３．７５（１Ｈ，ｄｔ，Ｊ＝７．６，６．９Ｈｚ），３．７９−３．８９（１Ｈ，ｍ），３．８３（２Ｈ，ｓ），３．９４（１Ｈ，ｑｄ，Ｊ＝７．３，３．０Ｈｚ），５．８０（１Ｈ，ｔ，Ｊ＝５．３Ｈｚ）．

ＬＣ／ＭＳ［条件１］：保持時間３．４６分；ｍ／ｚ６１０．０［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ６５４．１［Ｍ＋ＨＣＯＯ］^―（ＥＳＩ負イオンモード）

Example 510
(1r, 4r) -4-({2-oxo-8- [2,3,5,6-tetrafluoro-4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4. 5] Preparation of decan-3-yl} methyl) -N-[(tetrahydrofuran-2-yl) methyl] cyclohexanecarboxamide (Compound No. 510) (1r, 4r) -4-({2-oxo-8- [4 Instead of-(trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl) cyclohexanecarboxylic acid, it was obtained in Reference Example 503-2 (1r, 4r) -4-({2-oxo-8- [2,3,5,6-tetrafluoro-4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decane -3-Ile} But using Le) cyclohexanecarboxylic acid by performing the same reaction as substantially Example 10 to give the title compound (27 mg, 78% yield) as a white solid.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.01 (2H, qd, J = 12.9, 3.3 Hz), 1.39-1.64 (4H, m), 1.69-1. 83 (4H, m), 1.84 to 2.00 (7H, m), 2.03 (1H, tt, J = 11.9, 3.6 Hz), 2.52-2.74 (4H, m ), 3.08 (2H, d, J = 7.3 Hz), 3.11 (3H, ddd, J = 10.0, 7.6, 4.3 Hz), 3.23 (2H, s), 3 .58 (1H, ddd, J = 13.5, 6.3, 3.0 Hz), 3.75 (1H, dt, J = 7.6, 6.9 Hz), 3.79-3.89 (1H M), 3.83 (2H, s), 3.94 (1H, qd, J = 7.3, 3.0 Hz), 5.80 (1H, t, J = 5.3 Hz).

LC / MS [condition 1]: retention time 3.46 minutes; m / z 610.0 [M + H] ⁺ (ESI positive ion mode), m / z 654.1 [M + HCOO] ⁻ (ESI negative ion mode)

実施例５１１
４−｛１−［（１ｒ，４ｒ）−４−（｛２−オキソ−８−［２，３，５，６−テトラフルオロ−４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）シクロヘキサンカルボニル］アゼチジン−３−イルオキシ｝ベンゾニトリル（化合物番号５１１）の製造

（１ｒ，４ｒ）−４−（｛２−オキソ−８−［４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）シクロヘキサンカルボン酸の代わりに、参考例５０３−２で得られた（１ｒ，４ｒ）−４−（｛２−オキソ−８−［２，３，５，６−テトラフルオロ−４−（トリフルオロメチル）ベンジル］−１−オキサ−３，８−ジアザスピロ［４．５］デカン−３−イル｝メチル）シクロヘキサンカルボン酸を、テトラヒドロフルフリルアミンの代わりに参考例３８３−２で得られた４−（アゼチジン−３−イルオキシ）ベンゾニトリルを用いること以外は実質的に実施例１０と同様に反応を行なって、表題化合物（３１ｍｇ、収率８１％）を白色固体として得た。

^１Ｈ−ＮＭＲ（３００ＭＨｚ，ＣＤＣｌ_３）δ：１．００（２Ｈ，ｑ，Ｊ＝１２．６Ｈｚ），１．５２（２Ｈ，ｑ，Ｊ＝１２．３Ｈｚ），１．５９−１．６８（１Ｈ，ｍ），１．６９−１．８６（６Ｈ，ｍ），１．９３（２Ｈ，ｄ，Ｊ＝１４．２Ｈｚ），２．１２（１Ｈ，ｔｔ，Ｊ＝１２．２，３．６Ｈｚ），２．５３−２．７５（４Ｈ，ｍ），３．０８（２Ｈ，ｄ，Ｊ＝７．３Ｈｚ），３．２２（２Ｈ，ｓ），３．８３（２Ｈ，ｓ），４．０５（１Ｈ，ｄｄ，Ｊ＝１０．６，４．０Ｈｚ），４．２０（１Ｈ，ｄｄ，Ｊ＝９．４，３．８Ｈｚ），４．３９（１Ｈ，ｄｄ，Ｊ＝１０．７，６．８Ｈｚ），４．５５（１Ｈ，ｄｄ，Ｊ＝８．３，７．３Ｈｚ），４．９９（１Ｈ，ｔｔ，Ｊ＝６．３，３．６Ｈｚ），６．８１（２Ｈ，ｄ，Ｊ＝８．９Ｈｚ），７．６２（２Ｈ，ｄ，Ｊ＝８．３Ｈｚ）．

ＬＣ／ＭＳ［条件１］：保持時間３．８７分；ｍ／ｚ６８３．０［Ｍ＋Ｈ］^＋（ＥＳＩ正イオンモード）、ｍ／ｚ７２７．２［Ｍ＋ＨＣＯＯ］^―（ＥＳＩ負イオンモード）

Example 511
4- {1-[(1r, 4r) -4-({2-oxo-8- [2,3,5,6-tetrafluoro-4- (trifluoromethyl) benzyl] -1-oxa-3, 8-Diazaspiro [4.5] decan-3-yl} methyl) cyclohexanecarbonyl] azetidin-3-yloxy} benzonitrile (Compound No. 511)

(1r, 4r) -4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl) cyclohexane (1r, 4r) -4-({2-oxo-8- [2,3,5,6-tetrafluoro-4- (trifluoromethyl) obtained in Reference Example 503-2 instead of carboxylic acid] [Benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl) cyclohexanecarboxylic acid instead of tetrahydrofurfurylamine 4- (azetidine-) obtained in Reference Example 383-2 The reaction was carried out in substantially the same manner as in Example 10 except that 3-yloxy) benzonitrile was used to give the title compound (31 mg, yield 81%) as a white solid.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.00 (2H, q, J = 12.6 Hz), 1.52 (2H, q, J = 12.3 Hz), 1.59-1.68 ( 1H, m), 1.69-1.86 (6H, m), 1.93 (2H, d, J = 14.2 Hz), 2.12 (1H, tt, J = 12.2, 3.6 Hz) ), 2.53-2.75 (4H, m), 3.08 (2H, d, J = 7.3 Hz), 3.22 (2H, s), 3.83 (2H, s), 4. 05 (1H, dd, J = 10.6, 4.0 Hz), 4.20 (1H, dd, J = 9.4, 3.8 Hz), 4.39 (1H, dd, J = 10.7, 6.8 Hz), 4.55 (1H, dd, J = 8.3, 7.3 Hz), 4.99 (1H, tt, J = 6.3, 3.6 Hz), 6.81 (2H, d , J = 8. Hz), 7.62 (2H, d, J = 8.3Hz).

LC / MS [Condition 1]: Retention time 3.87 minutes; m / z 683.0 [M + H] ⁺ (ESI positive ion mode), m / z 727.2 [M + HCOO] ⁻ (ESI negative ion mode)

  In the present invention, in order to evaluate and select the target compound, it is desirable that the direct action on the adiponectin receptor can be verified. Examples of such an evaluation system include an evaluation system using cells in which adiponectin receptor is stably expressed, and an evaluation system using genetically modified animals (so-called knockout mice, etc.). Moreover, an invention compound can be evaluated efficiently by using these evaluation systems appropriately.

Test Example: Measurement of ACC Phosphorylation in Human AdipoR1 Stable Expression CHO Cell Line The ACC phosphorylation ability of the compound of the present invention, which is a compound of the present invention, was measured by constructing a human AdipoR1 stable expression CHO cell line (CHOR1). In the description of activity, a Rigel compound (WO2008 / 083124 Compound 94) reported as a low molecular weight compound exhibiting an adiponectin receptor agonist-like action was used as an index.

(1) Cells and culture The human AdipoR1 stable expression CHO cell line (CHOR1) stably expresses human AdipoR1. In addition, the CHO cell which is the parent strain is less responsive to the Rigel compound (Compound 94) than CHOR1. The above two types of cells were subcultured in a F-12 medium containing 10% bovine serum using a CO ₂ incubator (5% CO ₂ , 37 ° C.).
(2) Measurement of ACC phosphorylation ability The subcultured cells were suspended in F-12 medium containing 10% bovine serum, and this suspension was transferred to a 96-well plate for tissue culture. This cell suspension was cultured in a CO ₂ incubator for 1 day.
A Rigel compound (Compound 94) or a compound synthesized in a separate example dissolved in dimethyl sulfoxide was diluted with a medium without serum, added after removing the culture supernatant from a 96-well plate, and then added in a CO ₂ incubator. Incubated for 30 minutes.
ACC phosphorylation was measured according to the following procedure using a time fluorescence decomposition method (PerkinElmer DELFIA assay). Specifically, cells were immobilized on a 96-well plate using 4% paraformaldehyde, washed, blocked with an albumin-containing buffer (purchased from Sigma), and primary antibody (ACC phosphorylated antibody) (Cell signaling) And purchased at 4 ° C. for 12 to 15 hours. After washing, a europium-labeled secondary antibody (purchased from PerkinElmer) was added and incubated at room temperature for 1 hour. After washing with PBST (a mixture of phosphate buffer (pH 7.4) containing 0.1% by weight of Tween 20), enhancer (registered trademark) (purchased from PerkinElmer) was added, and time-resolved fluorescence Measurement was performed with a detector (ARVO-HTS manufactured by PerkinElmer).
The compound concentration (ECR50) that gives a 50% phosphorylation rate when the ACC phosphorylation rate of human AdipoR1 stably expressing CHO cells in the Rigel compound (Compound 94) is defined as 100% as the active concentration of the synthesis example compound is Rigel. It was expressed as a specific activity value divided by the compound concentration (EC ₅₀ ) giving a 50% phosphorylation rate of the company compound (Compound 94). The results are shown below.
―――――――――――――――
Compound number Specific activity value ――――――――――――――――
1 0.57
2> 5
3> 5
4> 5
5> 5
6 0.21
7> 4
8 0.88
9 1.36
10 0.61
11 0.64
12 0.86
13 2.45
14> 4.5
16 0.16
17 0.44
18 3.44
19> 5
20 2.29
21 0.47
22 0.55
23 0.60
24 5.56
25 2.12
26 0.64
27 0.48
28 0.52
29 3.29
30 0.35
31 2.68
32 0.10
33 0.78
34 0.21
35 0.29
36 0.24
37 0.29
38 0.41
39 0.45
40 0.30
41 4.51
42 0.79
43 1.30
44 0.68
45 1.37
46 0.70
47 0.28
48 0.48
49 1.16
50 4.77
51 0.24
52 0.70
53 0.65
54> 5
55 0.41
56 0.44
57 1.16
58 1.43
59 0.31
60 0.85
61 1.85
62 0.45
63 2.06
64 0.42
65> 5
66 0.99
67 2.29
68 2.04
69 0.30
70 0.57
71 0.34
72 0.39
73 1.51
74 0.71
75 0.12
76 1.40
77 0.73
78 0.54
79 0.32
80 0.46
81 0.50
82 0.30
83 0.68
84 1.20
85 0.72
86 0.80
87 1.54
88 0.71
89 0.96
90 1.02
91 1.62
92 0.28
93 0.27
94 0.74
95 0.23
96 1.07
97 0.24
98 1.18
99 0.88
100 0.48
101> 5
102 1.13
103 1.05
104> 5
105> 5
106 0.48
107 5.77
108 0.46
109 1.28
110 1.25
111 1.58
112 1.72
113 0.53
114 0.71
115 0.80
116 0.39
117 0.71
118 0.61
119 0.85
120 0.22
121 1.37
122 0.43
123 1.12
124 0.19
125 0.42
126 0.08
127 0.47
128 8.76
129 4.50
130 3.54
131 0.10
132 3.82
133 1.40
134 0.82
135 1.73
136 0.43
137 0.72
138 8.10
139 0.60
140 0.69
141 0.27
142 0.66
143 1.03
144 0.85
145 0.46
146 0.24
147 1.99
149 0.32
150 1.46
151 2.76
152 0.29
153 0.89
154 0.16
155 1.13
156 1.15
157 0.84
158 2.19
159 2.87
160 0.51
161 0.15
162 0.32
163 1.70
164 2.43
165 0.75
166 1.44
167 0.62
169 0.55
170 5.84
171 0.48
172 3.36
173 8.64
174 5.32
175 1.00
176 0.88
177 1.64
178 2.52
179 2.00
180 0.18
181 0.37
182 0.13
183 0.56
184 0.87
185 4.61
186 0.52
187 0.38
188> 5
189 0.27
190 0.92
191 0.20
192 0.09
193 0.13
194 1.03
195 0.11
197 0.54
198 0.27
199 0.89
200 2.12
201 0.56
202 0.54
203 0.52
204 0.88
205 1.08
206 0.48
207 0.88
208 0.48
209 0.36
210 1.24
211 0.34
212 0.33
213 1.28
214 0.22
215 1.21
216 0.73
217 0.36
218 2.98
219 1.29
220 0.89
221 0.32
222 0.64
223 0.60
224> 5
225 5.77
226> 5
227 3.34
228> 5
229 7.11
230 0.50
231 0.42
232 6.29
233 10.02
234 1.36
235 8.84
236 5.38
237 0.61
238 0.57
239 0.74
240 0.98
241 1.52
242 1.48
243 9.88
244 6.64
245> 5
246 7.68
247 0.84
248 0.44
249 1.24
250 6.84
251 0.62
252 1.05
253 0.44
254 0.28
255 0.46
256 0.23
257 0.36
258 0.56
259 1.08
260 0.96
261 0.92
262 0.04
263 0.61
264 0.20
265 0.04
266 0.12
267 0.34
268 0.50
269 2.62
270 0.17
271 0.65
272 0.44
273 3.76
274 0.20
275 0.39
276 0.06
277 0.25
278 0.31
279 0.26
280 0.10
281 0.27
282 0.07
283 0.54
284 2.62
285 0.30
286 0.18
287 0.41
288 0.21
289 0.92
290 0.58
291 0.05
292 0.20
293 0.04
294 0.17
295 0.21
296 0.10
297 0.56
298 0.40
299 0.64
300 0.24
301 0.72
302 0.15
303 0.12
304 1.68
305 0.52
306 0.37
307 0.25
308 0.20
309 0.68
310 2.30
311 5.26
312 0.16
313 1.90
314 0.35
315 0.44
316 0.57
317 0.35
318 3.40
319 0.71
320 0.96
321 0.84
322 1.15
323 0.73
324> 5
325 0.99
326 0.23
327 0.83
328 2.00
329 7.70
330 1.88
331 4.77
332 1.00
333 0.19
334 0.79
335 0.13
336 0.31
337 0.47
338 2.41
339 3.12
340 1.53
341 1.69
342 0.22
343 0.23
344 0.09
345 0.22
346 0.68
347 0.16
348 0.20
349 0.42
350 0.61
351 0.17
352 3.50
353> 5
354 1.56
355 0.24
356 0.25
357 0.64
358 0.29
359 0.14
360 0.41
361 0.10
362 0.23
363 2.01
364 1.84
365 1.64
366 0.14
367 0.42
368 2.09
369 0.76
370 0.52
371 2.10
372 0.75
373 0.58
374 2.93
375 0.38
376 0.20
377 4.51
378 0.73
379 0.27
380 0.86
381 0.40
382 0.26
383 0.08
384 0.28
385 0.08
386 1.18
387 1.03
388 0.73
389 0.29
390 0.13
391 0.09
392 0.65
393 0.48
394 0.36
395 0.25
396 1.19
397 0.09
398 1.36
399 0.40
400 0.76
401 0.38
402 0.18
403 0.09
404 2.25
405 0.68
406 0.26
407 0.16
408 2.94
409 4.36
410 0.71
411 1.93
412 0.20
413 0.31
414 0.27
415 2.70
416 0.66
417 5.44
418 5.90
419> 5
420 9.07
421 1.29
422 1.59
423 6.28
424> 5
425 6.37
426 3.09
427 1.45
428 1.02
429 2.67
430 2.96
431 0.54
432 0.18
433 0.48
434 0.59
435 0.55
436 1.07
437 0.45
438 0.22
439 1.00
440 0.31
441 0.09
442 0.15
443 0.29
444 0.48
445 1.42
446 3.11
447 3.26
448 0.44
449 0.33
450 0.90
451 0.14
452 2.85
453 0.76
454 0.10
455 0.99
456 0.87
457 2.42
458> 5
459 3.97
460 7.83
461 1.20
462 3.07
463 2.72
464 1.21
465 7.94
466 1.30
467 0.94
468 5.38
469 0.40
470 1.46
471 0.89
472 0.59
473 7.49
474> 5
475 2.75
476 0.56
477 13.68
478 0.21
479 0.58
480 1.12
481 8.92
482 0.85
483 2.11.
484 6.39
485 2.46
486 1.15
487 0.25
488 7.73
489 0.75
490 0.56
491 5.40
492 0.32
493 5.95
494 7.57
495 3.99
496 4.77
497 8.49
498 0.10
499 2.56
500 0.90
501 0.36
502 0.52
503 0.73
504 3.41
505 5.37
506 6.75
507> 5
508> 5
509 9.95
510 1.29
511 0.26

Formulation Example 1
A granule containing the following ingredients is produced.
Component Compound represented by formula (I) 10 mg
Lactose 700mg
Corn starch 274mg
HPC-L 16mg
---------------------------
1000mg total
The compound of formula (I) and lactose are passed through a 60 mesh sieve. Pass corn starch through a 120 mesh sieve. These are mixed in a V-type mixer. A low-viscosity hydroxypropylcellulose (HPC-L) aqueous solution is added to the mixed powder, kneaded and granulated (extruded granulation, pore diameter: 0.5 to 1 mm), and then dried. The obtained dried granules are sieved with a vibrating sieve (12/60 mesh) to obtain granules.

Formulation Example 2
A powder for capsule filling containing the following components is produced.
Component Compound represented by formula (I) 10 mg
Lactose 79mg
Corn starch 10mg
Magnesium stearate 1mg
---------------------------
100mg total
The compound of formula (I) and lactose are passed through a 60 mesh sieve. Pass corn starch through a 120 mesh sieve. These and magnesium stearate are mixed in a V-type mixer. 100 mg of 10 times powder is filled into a No. 5 hard gelatin capsule.

Formulation Example 3
A capsule filling granule containing the following ingredients is produced.
Component Compound represented by formula (I) 15 mg
Lactose 90mg
Corn starch 42mg
HPC-L 3mg
---------------------------
150mg total
The compound of formula (I) and lactose are passed through a 60 mesh sieve. Pass corn starch through a 120 mesh sieve. These are mixed in a V-type mixer. A low-viscosity hydroxypropylcellulose (HPC-L) aqueous solution is added to the mixed powder, kneaded and granulated, and then dried. The obtained dried granule is sieved with a vibrating sieve (12/60 mesh) and sized, and 150 mg thereof is filled into a No. 4 hard gelatin capsule.

Formulation Example 4
A tablet containing the following ingredients is produced.
Component Compound represented by formula (I) 10 mg
Lactose 90mg
Microcrystalline cellulose 30mg
Magnesium stearate 5mg
CMC-Na 15mg
---------------------------
150mg total
The compound represented by the formula (I), lactose, microcrystalline cellulose, and CMC-Na (carboxymethylcellulose sodium salt) are passed through a 60 mesh sieve and mixed. Magnesium stearate is added to the mixed powder to obtain a mixed powder for preparation. The mixed powder is directly hit to obtain a 150 mg tablet.

Formulation Example 5
The intravenous formulation is produced as follows.
Compound represented by formula (I) 100 mg
Saturated fatty acid glyceride 1000mL
The solution of the above components is usually administered intravenously to the patient at a rate of 1 mL per minute.

Since the compound of the present invention has an affinity and / or agonist action for adiponectin receptor, it is a prophylactic / therapeutic / ameliorating agent for diseases in which adiponectin receptor activation action is effective, particularly metabolic syndrome, particularly metabolic syndrome associated with obesity and diabetes It can be used for the prevention or treatment of syndrome and arteriosclerosis and is useful as a pharmaceutical.
The entire contents of the specification, claims, and abstract of Japanese Patent Application No. 2010-108491 filed on May 10, 2010 are incorporated herein as the disclosure of the specification of the present invention. Is.

Claims (35)

Formula (I)

[In the formula (I),
E means an oxygen atom or a sulfur atom;
L 1 is a single bond, a C 1-3 alkylene group, a C 2-3 alkenylene group or a C 2-3 alkynylene group (the C 1-3 alkylene group, C 2-3 alkenylene group and C 2-3 alkynylene group are , Unsubstituted or substituted by a cyclopropyl group)
L 2 is a single bond, a C 1-3 alkylene group, a C 2-3 alkenylene group or a C 2-3 alkynylene group (the C 1-3 alkylene group, C 2-3 alkenylene group and C 2-3 alkynylene group are , Unsubstituted or substituted by a cyclopropyl group)
X is a C 3-11 cycloalkylene group, a C 3-11 cycloalkenylene group (the C 3-11 cycloalkylene group and the C 3-11 cycloalkenylene group are unsubstituted or a C 1-3 alkyl group Substituted with one or more substituents independently selected from the group consisting of C 2-3 alkenyl group, —OR 16 and cyano group.), C 6-10 arylene group or 5-10 membered heteroarylene. Group (the C 6-10 arylene group and the 5- to 10-membered heteroarylene group are unsubstituted or a halogen atom, a nitro group, a cyano group, a C 1-3 alkyl group (the C 1-3 alkyl group is or an unsubstituted, substituted by one or more substituents independently selected from the group consisting of a halogen atom and -OR 16.), C 2-3 alkenyl, C 2-3 Rukiniru group, -OR 16, -O (C 2-3 alkenyl group), - O (C 3-4 cycloalkyl group), - N (R 16) C (= O) OR 17, -N (R 16) C (═O) R 17 , —N (R 16 ) C (═O) H, —N (R 16 ) R 17 , —NH 2 , —N (R 16 ) S (═O) 2 R 17 , — C (= O) NR 16 R 17, -C (= O) NH 2, -C (= O) R 16, -S (= O) 2 R 17, -S (= O) 2 NR 16 R 17, -S (= O) substituted by one or more substituents independently selected from the group consisting of 2 NH 2.) I mean,
Z 1 represents the formulas (II-1) to (II-8)

(Where
J ¹ each independently represents an oxygen atom or a sulfur atom;
G ¹ means a single bond, an oxygen atom or a sulfur atom,
R ¹ and R ³ are
R ¹ is a hydrogen atom, OR ¹¹ , NR ¹¹ R ¹² , C _1-9 alkyl group (the C _1-9 alkyl group is unsubstituted or one independently selected from substituent group A ₃ Substituted with the above substituents), a C _3-11 cycloalkyl group or a 4-11 membered heterocycloalkyl group (the C _3-11 cycloalkyl group and 4-11 membered heterocycloalkyl group are C _{6 -10} aryl or 5-10 membered heteroaryl (wherein the C _6-10 aryl and 5-10 membered heteroaryl are unsubstituted or independently of the group consisting of substituent groups A ₂ and C _4-6 alkyl groups) The C _3-11 cycloalkyl group and the 4-11 membered heterocycloalkyl group may be unsubstituted or substituted with one or more selected substituents). Substituent Which is substituted by one or more substituents independently selected from the group consisting of A ₁ and C _4-6 alkyl groups.) Means, R ³ means a hydrogen atom or a C _1-3 alkyl group Or
Or R ¹ and R ³ , together with the nitrogen atom to which they are attached, are a 4-11 membered heterocycloalkyl group (the 4-11 membered heterocycloalkyl group is unsubstituted or substituted) Substituted with one or more substituents independently selected from the group consisting of group A ₁ and a C _4-6 alkyl group.
R ² represents a C _1-9 alkyl group (the C _1-9 alkyl group is unsubstituted or substituted with one or more substituents independently selected from Substituent Group A ₃ ). , A C _3-11 cycloalkyl group or a 4-11 membered heterocycloalkyl group (the C _3-11 cycloalkyl group and 4-11 membered heterocycloalkyl group are C _6-10 aryl or 5-10 membered heteroaryl ( The C _6-10 aryl and 5-10 membered heteroaryl are unsubstituted or substituted by one or more substituents independently selected from the group consisting of the substituent groups A ₂ and C _4-6 alkyl groups. And the C _3-11 cycloalkyl group and the 4-11 membered heterocycloalkyl group may be unsubstituted or substituted with the substituent groups A ₁ and C _4-6 alkyl. A group of groups Substituted by one or more substituents independently selected),
R ⁴ and R ⁵ each independently represent a hydrogen atom or a C _1-3 alkyl group. )
Means either
m means an integer of 1 or 2,
R ⁶ independently represents a hydrogen atom, a C _1-3 alkyl group or a cyclopropyl group, or two R ⁶ existing on the same carbon atom are bonded to the carbon atom to which they are bonded. Together with C to form a C _3-6 cycloalkane,
n means an integer of 0 to 4,
R ⁷ each independently represents a C _1-3 alkyl group;
T represents formulas (VI-1) to (VI-3)

(Where
L ⁴ means a C _1-3 alkylene group,
L ⁵ represents a single bond, an oxygen atom, a sulfur atom, S (═O), S (═O) ₂ , C═O or C═NOR ¹² ;
R ⁸ represents a C _6-10 aryl group or a 5- to 10-membered heteroaryl group (the C _6-10 aryl group and the 5- to 10-membered heteroaryl group are unsubstituted or substituted by the substituent groups A ₂ and C _4. Substituted with one or more substituents independently selected from the group consisting of _-6 alkyl groups).
J ² means an oxygen atom or a sulfur atom,
G ² means an oxygen atom, a sulfur atom or NR ¹¹ ,
R ⁹ represents a C _1-9 alkyl group (the C _1-9 alkyl group is unsubstituted or substituted with one or more substituents independently selected from substituent group A ₄ ). , A C _6-10 aryl group (wherein the C _6-10 aryl group is unsubstituted or one or more substituents independently selected from the group consisting of the substituent group A ₂ and the C _4-6 alkyl group) A C _3-11 cycloalkyl group (wherein the C _3-11 cycloalkyl group is a C _6-10 aryl or 5-10 membered heteroaryl (the C _6-10 aryl and 5-10 membered). Heteroaryl is unsubstituted or substituted by one or more substituents independently selected from the group consisting of substituent groups A ₂ and C _4-6 alkyl groups. well, and the _{C 3-11} cycloalkyl Group is substituted by one or more substituents selected as or independently from Substituent group A ₂ unsubstituted.), Or, a C _1-3 alkyl group (the C _1-3 alkyl group Is a C _6-10 aryl group or a C _3-11 cycloalkyl group (the C _6-10 aryl group and the C _3-11 cycloalkyl group are unsubstituted or substituted with the substituent groups A ₂ and C _4-6. Substituted with one or more substituents independently selected from the group consisting of alkyl groups).
R ¹⁰ represents a C _1-9 alkyl group (the C _1-9 alkyl group is unsubstituted or substituted with one or more substituents independently selected from substituent group A ₄ ). A C _6-10 aryl group, a 5-10 membered heteroaryl group (the C _6-10 aryl group and the 5-10 membered heteroaryl group are unsubstituted or substituted with a substituent group A ₂ and a C _4-6 alkyl). Substituted with one or more substituents independently selected from the group consisting of groups), a C _3-11 cycloalkyl group (wherein the C _3-11 cycloalkyl group is C _6-10 aryl or 5- 10-membered heteroaryl (wherein the C _6-10 aryl and the 5-10 membered heteroaryl are unsubstituted or selected from the group consisting of the substituent groups A ₂ and C _4-6 alkyl group independently) Substituted by substituents It is.) And may be a condensed ring, and the C _3-11 cycloalkyl group, optionally substituted by one or more substituents selected as or independently from Substituent group A ₂ unsubstituted Or a C _1-3 alkyl group (the C _1-3 alkyl group is a C _3-11 cycloalkyl group (the C _3-11 cycloalkyl group is unsubstituted or from substituent group A ₂₎ . Substituted with one or more independently selected substituents)). )
Means either
Substituent group A ₁ is a C _1-3 alkyl group (the C _1-3 alkyl group is unsubstituted or substituted by one or more substituents independently selected from substituent group A ₃ ). .) and means a substituent group consisting of substituent group a _3,
Substituent group A ₃ is
A C _3-11 cycloalkyl group, a 4-11 membered heterocycloalkyl group (the C _3-11 cycloalkyl group and 4-11 membered heterocycloalkyl group are C _6-10 aryl or 5-10 membered heteroaryl (the C _6-10 aryl and 5-10 membered heteroaryl are unsubstituted or substituted by one or more substituents independently selected from the group consisting of substituent groups A ₂ and C _4-6 alkyl groups. The C _3-11 cycloalkyl group and the 4- to 11-membered heterocycloalkyl group may be unsubstituted or substituted with a substituent group A ₂ and a C _4-6 alkyl group. which is substituted by one or more substituents independently selected from the group consisting _{of.), C 6-10} aryl group, 5-10-membered heteroaryl group (the _{C 6-10} aryl and 5 to 1 Membered heteroaryl group, 4-11-membered heterocycloalkyl alkane (said 4-11 membered heterocycloalkyl cycloalkane is substituted by one or more substituents selected as or independently from Substituent group A ₂ unsubstituted And the C _6-10 aryl group and the 5- to 10-membered heteroaryl group are unsubstituted or a group consisting of the substituent group A ₂ and the C _4-6 alkyl group. Substituted with one or more substituents selected more independently.), —C (═O) OR ¹³ , —C (═O) NR ¹² R ¹³ , —C (═O) R ¹³ , — _{^{C (= NOR 12) R 13}} , -S (= O) R 13, -S (= O) 2 R 13, -OR 13, -SR 13, -N (R 12) C (= O) OR 13, ^{-N (R 12) C (=} O) R 13, -N (R 12) R 13, C Gen atom, a cyano group, a nitro group, means a formyl ^{group, -C (= NOR 12) H} , -N (R 12) C (= O) H, or a substituent group consisting of a hydroxyl group,
Substituent group A ₂ is
Means a substituent group composed of a C _1-3 alkyl group (the C _1-3 alkyl group is unsubstituted or substituted by one or more halogen atoms) and a substituent group A ₄ ,
Substituent group A ₄ is
A halogen atom, a nitro group, a cyano group, —OR ¹⁴ , —SR ¹⁴ , —C (═O) OR ¹⁴ , —C (═O) NR ¹⁴ R ¹⁵ , —C (═O) R ¹⁵ , —C (= ^{NOR 15) R 14, -C (} = NOR 15) H, -S (= O) R 14, -S (= O) 2 R 14, -N (R 15) C (= O) OR 14, -N Means a group of substituents composed of (R ¹⁵ ) C (═O) R ¹⁴ or —N (R ¹⁵ ) C (═O) H;
Each of R ¹¹ independently represents a hydrogen atom or a C _1-6 alkyl group;
R ¹² each independently represents a hydrogen atom or a C _1-3 alkyl group;
Each R ¹³ is independently
A C _1-6 alkyl group (the C _1-6 alkyl group is unsubstituted or substituted by one or more substituents independently selected from Substituent Group A ₄ );
A C _3-11 cycloalkyl group, a 4-11 membered heterocycloalkyl group, a C _6-10 aryl group, or a 5-10 membered heteroaryl group (the C _3-11 cycloalkyl group, 4-11 membered heterocycloalkyl group; , The C _6-10 aryl group and the 5-10 membered heteroaryl group are one or more substituents which are unsubstituted or independently selected from the group consisting of the substituent groups A ₂ and C _4-6 alkyl groups Is replaced by
R ¹⁴ represents a C _1-3 alkyl group (the C _1-3 alkyl group is unsubstituted or substituted by one or more halogen atoms);
R ¹⁵ represents a hydrogen atom or a C _1-3 alkyl group (the C _1-3 alkyl group is unsubstituted or substituted by one or more halogen atoms);
R ¹⁶ represents a hydrogen atom or a C _1-3 alkyl group,
R ¹⁷ means a C _1-3 alkyl group. ]
Or a tautomer of the compound, or a pharmaceutically acceptable salt thereof. Formula (I)

[In the formula (I),
E means an oxygen atom or a sulfur atom;
L 1 is a single bond, a C 1-3 alkylene group, a C 2-3 alkenylene group or a C 2-3 alkynylene group (the C 1-3 alkylene group, C 2-3 alkenylene group and C 2-3 alkynylene group are , Unsubstituted or substituted by a cyclopropyl group)
L 2 is a single bond, a C 1-3 alkylene group, a C 2-3 alkenylene group or a C 2-3 alkynylene group (the C 1-3 alkylene group, C 2-3 alkenylene group and C 2-3 alkynylene group are , Unsubstituted or substituted by a cyclopropyl group)
X is a C 3-11 cycloalkylene group, a C 3-11 cycloalkenylene group (the C 3-11 cycloalkylene group and the C 3-11 cycloalkenylene group are unsubstituted or a C 1-3 alkyl group Substituted with one or more substituents independently selected from the group consisting of C 2-3 alkenyl group, —OR 16 and cyano group.), C 6-10 arylene group or 5-10 membered heteroarylene. Group (the C 6-10 arylene group and the 5- to 10-membered heteroarylene group are unsubstituted or a halogen atom, a nitro group, a cyano group, a C 1-3 alkyl group (the C 1-3 alkyl group is or an unsubstituted, substituted by one or more substituents independently selected from the group consisting of a halogen atom and -OR 16.), C 2-3 alkenyl, C 2-3 Rukiniru group, -OR 16, -O (C 2-3 alkenyl group), - O (C 3-4 cycloalkyl group), - N (R 16) C (= O) OR 17, -N (R 16) C (═O) R 17 , —N (R 16 ) C (═O) H, —N (R 16 ) R 17 , —NH 2 , —N (R 16 ) S (═O) 2 R 17 , — C (= O) NR 16 R 17, -C (= O) NH 2, -C (= O) R 16, -S (= O) 2 R 17, -S (= O) 2 NR 16 R 17, -S (= O) substituted by one or more substituents independently selected from the group consisting of 2 NH 2.) I mean,
Z 1 represents the formulas (II-1) to (II-8)

(Where
J ¹ each independently represents an oxygen atom or a sulfur atom;
G ¹ means a single bond, an oxygen atom or a sulfur atom,
R ¹ and R ³ are
R ¹ is a hydrogen atom, OR ¹¹ , NR ¹¹ R ¹² , C _1-9 alkyl group (the C _1-9 alkyl group is unsubstituted or one independently selected from substituent group A ₃ Substituted with the above substituents), a C _3-11 cycloalkyl group or a 4-11 membered heterocycloalkyl group (the C _3-11 cycloalkyl group and 4-11 membered heterocycloalkyl group are C _{6 -10} aryl or 5-10 membered heteroaryl (wherein the C _6-10 aryl and 5-10 membered heteroaryl are unsubstituted or substituted by one or more substituents independently selected from substituent group A ₂₎ It is.) and may be a condensed ring, and the C _3-11 cycloalkyl group and 4-11 membered heterocycloalkyl group chosen as or independently from substituent group a ₁ unsubstituted One or more Which is substituted by substituents.) I mean, or R ³ means a hydrogen atom or a C _1-3 alkyl group,
Or R ¹ and R ³ , together with the nitrogen atom to which they are attached, are a 4-11 membered heterocycloalkyl group (the 4-11 membered heterocycloalkyl group is unsubstituted or substituted) which is substituted by one or more substituents independently selected from the group a _1.) means,
R ² represents a C _1-9 alkyl group (the C _1-9 alkyl group is unsubstituted or substituted with one or more substituents independently selected from Substituent Group A ₃ ). , A C _3-11 cycloalkyl group or a 4-11 membered heterocycloalkyl group (the C _3-11 cycloalkyl group and 4-11 membered heterocycloalkyl group are C _6-10 aryl or 5-10 membered heteroaryl ( The C _6-10 aryl and the 5-10 membered heteroaryl are unsubstituted or substituted with one or more substituents independently selected from substituent group A ₂ ). And the C _3-11 cycloalkyl group and the 4- to 11-membered heterocycloalkyl group are unsubstituted or substituted with one or more substituents independently selected from Substituent Group A ₁ ) And,
R ⁴ and R ⁵ each independently represent a hydrogen atom or a C _1-3 alkyl group. )
Means either
m means an integer of 1 or 2,
R ⁶ independently represents a hydrogen atom, a C _1-3 alkyl group or a cyclopropyl group, or two R ⁶ existing on the same carbon atom are bonded to the carbon atom to which they are bonded. Together with C to form a C _3-6 cycloalkane,
n means an integer of 0 to 4,
R ⁷ each independently represents a C _1-3 alkyl group;
T represents formulas (VI-1) to (VI-3)

(Where
L ⁴ means a C _1-3 alkylene group,
L ⁵ represents a single bond, an oxygen atom, a sulfur atom, S (═O), S (═O) ₂ , C═O or C═NOR ¹² ;
R ⁸ represents a C _6-10 aryl group or a 5-10 membered heteroaryl group (the C _6-10 aryl group and the 5-10 membered heteroaryl group are unsubstituted or independent of substituent group A _2). Substituted with one or more substituents selected from
J ² means an oxygen atom or a sulfur atom,
G ² means an oxygen atom, a sulfur atom or NR ¹¹ ,
R ⁹ represents a C _1-9 alkyl group (the C _1-9 alkyl group is unsubstituted or substituted with one or more substituents independently selected from substituent group A ₄ ). , C _6-10 aryl group (the C _6-10 aryl group is unsubstituted or substituted by one or more substituents independently selected from substituent group A ₂ ), C _{3. -11} cycloalkyl group (wherein the C _3-11 cycloalkyl group is C _6-10 aryl or 5-10 membered heteroaryl (the C _6-10 aryl and 5-10 membered heteroaryl are unsubstituted or substituted) Substituted with one or more substituents independently selected from group A ₂ ), and the C _3-11 cycloalkyl group may be unsubstituted or substituted. one or more independently selected from the group & A ₂ Which is substituted by a substituent.), _{Or, a C 1-3} alkyl group (the _{C 1-3} alkyl _{group, C 6-10} aryl group or _{C 3-11} cycloalkyl group (the _{C 6-10} aryl Group and C _3-11 cycloalkyl group are unsubstituted or substituted by one or more substituents independently selected from substituent group A ₂ ). And
R ¹⁰ represents a C _1-9 alkyl group (the C _1-9 alkyl group is unsubstituted or substituted with one or more substituents independently selected from substituent group A ₄ ). , C _6-10 aryl group, 5-10 membered heteroaryl group (the C _6-10 aryl group and 5-10 membered heteroaryl group are unsubstituted or independently selected from substituent group A ₂ Substituted with one or more substituents), a C _3-11 cycloalkyl group (wherein the C _3-11 cycloalkyl group is C _6-10 aryl or 5-10 membered heteroaryl (the C _6-10 aryl and 5-10 membered heteroaryl is substituted by one or more substituents selected as or independently from substituent group a ₂ unsubstituted.) and may be a condensed ring, and the The C _3-11 cycloalkyl group is , Unsubstituted or substituted by one or more substituents independently selected from substituent group A ₂ ), or a C _1-3 alkyl group (the C _1-3 alkyl group is C _3). Substituted with an _-11 cycloalkyl group (the C _3-11 cycloalkyl group is unsubstituted or substituted by one or more substituents independently selected from substituent group A ₂ ). Means). )
Means either
Substituent group A ₁ is a C _1-3 alkyl group (the C _1-3 alkyl group is unsubstituted or substituted by one or more substituents independently selected from substituent group A ₃ ). .) and means a substituent group consisting of substituent group a _3,
Substituent group A ₃ is
A C _3-11 cycloalkyl group, a 4-11 membered heterocycloalkyl group (the C _3-11 cycloalkyl group and 4-11 membered heterocycloalkyl group are C _6-10 aryl or 5-10 membered heteroaryl (the C _6-10 aryl and 5-10 membered heteroaryl may be unsubstituted or substituted with one or more substituents independently selected from substituent group A ₂ ). well, and the C _3-11 cycloalkyl group and 4-11 membered heterocycloalkyl group is substituted by one or more substituents selected as or independently from substituent group a ₂ unsubstituted _{.), C 6-10} aryl group, 5-10-membered heteroaryl group (the _{C 6-10} aryl and 5-10 membered heteroaryl groups, 4-11 membered heterocycloalkyl alkane (said 4-11 Heterocycloalkane may be condensed with unsubstituted or substituted with or independently from the substituent group A ₂ is substituted by one or more substituents selected.), And the C _6-10 aryl groups and 5-10 membered heteroaryl group is substituted by one or more substituents selected as or independently from substituent group a ₂ unsubstituted), -. C (= O ) oR 13, ^{-C (= O) NR 12 R} 13, -C (= O) R 13, -C (= NOR 12) R 13, -S (= O) R 13, -S (= O) 2 R 13, - OR ¹³ , —SR ¹³ , —N (R ¹² ) C (═O) OR ¹³ , —N (R ¹² ) C (═O) R ¹³ , —N (R ¹² ) R ¹³ , halogen atom, cyano group, nitro group, formyl ^{group, -C (= NOR 12) H} , -N (R 12) C (= O) H, Or a group of substituents composed of hydroxyl groups,
Substituent group A ₂ is
Means a substituent group composed of a C _1-3 alkyl group (the C _1-3 alkyl group is unsubstituted or substituted by one or more halogen atoms) and a substituent group A ₄ ,
Substituent group A ₄ is
A halogen atom, a nitro group, a cyano group, —OR ¹⁴ , —SR ¹⁴ , —C (═O) OR ¹⁴ , —C (═O) NR ¹⁴ R ¹⁵ , —C (═O) R ¹⁵ , —C (= ^{NOR 15) R 14, -C (} = NOR 15) H, -S (= O) R 14, -S (= O) 2 R 14, -N (R 15) C (= O) OR 14, -N Means a group of substituents composed of (R ¹⁵ ) C (═O) R ¹⁴ or —N (R ¹⁵ ) C (═O) H;
Each of R ¹¹ independently represents a hydrogen atom or a C _1-6 alkyl group;
R ¹² each independently represents a hydrogen atom or a C _1-3 alkyl group;
Each R ¹³ is independently
A C _1-6 alkyl group (the C _1-6 alkyl group is unsubstituted or substituted by one or more substituents independently selected from Substituent Group A ₄ );
A C _3-11 cycloalkyl group, a 4-11 membered heterocycloalkyl group, a C _6-10 aryl group, or a 5-10 membered heteroaryl group (the C _3-11 cycloalkyl group, 4-11 membered heterocycloalkyl group; , C _6-10 aryl and 5-10 membered heteroaryl group is substituted by one or more substituents selected as or independently from substituent group a ₂ unsubstituted.) means ,
R ¹⁴ represents a C _1-3 alkyl group (the C _1-3 alkyl group is unsubstituted or substituted by one or more halogen atoms);
R ¹⁵ represents a hydrogen atom or a C _1-3 alkyl group (the C _1-3 alkyl group is unsubstituted or substituted by one or more halogen atoms);
R ¹⁶ represents a hydrogen atom or a C _1-3 alkyl group,
R ¹⁷ means a C _1-3 alkyl group. ]
The spiro compound of Claim 1 represented by this, the tautomer of this compound, or its pharmaceutically acceptable salt. X is a C _3-11 cycloalkylene group or a C _3-11 cycloalkenylene group (the C _3-11 cycloalkylene group and the C _3-11 cycloalkenylene group are unsubstituted or a C _1-3 alkyl group) Substituted with one or more substituents independently selected from the group consisting of C _{2 -3} alkenyl groups, —OR ¹⁶ and cyano groups.)
The spiro compound according to claim 2, a tautomer of the compound, or a pharmaceutically acceptable salt thereof. X is a C _6-10 arylene group or a 5- to 10-membered heteroarylene group (the C _6-10 arylene group and the 5- to 10-membered heteroarylene group are unsubstituted, a halogen atom, a nitro group, or a cyano group A C _1-3 alkyl group (the C _1-3 alkyl group is unsubstituted or substituted by one or more substituents independently selected from the group consisting of a halogen atom and —OR ¹⁶ ). ), C _2-3 alkenyl group, C _2-3 alkynyl group, —OR ¹⁶ , —O (C _2-3 alkenyl group), —O (C _3-4 cycloalkyl group), —N (R ¹⁶ ) C (═O) OR ¹⁷ , —N (R ¹⁶ ) C (═O) R ¹⁷ , —N (R ¹⁶ ) C (═O) H, —N (R ¹⁶ ) R ¹⁷ , —NH ₂ , —N ( _{^{R 16) S (= O)}} 2 R 17, -C (= O) NR 16 R 1 _{^{, -C (= O) NH 2}} , -C (= O) R 16, -S (= O) 2 R 17, -S (= O) 2 NR 16 R 17, -S (= O) 2 NH 2 Substituted with one or more substituents independently selected from the group consisting of
The spiro compound according to claim 2, a tautomer of the compound, or a pharmaceutically acceptable salt thereof. L ¹ is a C _1-3 alkylene group, a C _2-3 alkenylene group or a C _2-3 alkynylene group (the C _1-3 alkylene group, C _2-3 alkenylene group and C _2-3 alkynylene group are unsubstituted) Or is substituted by a cyclopropyl group.)
The spiro compound according to claim 4, a tautomer of the compound, or a pharmaceutically acceptable salt thereof. Z ¹ is represented by formulas (II-1) to (II-8).

(Where
J ¹ each independently represents an oxygen atom or a sulfur atom;
G ¹ means a single bond, an oxygen atom or a sulfur atom,
R ¹ and R ³ are
R ¹ is a hydrogen atom, OR ¹¹ , NR ¹¹ R ¹² , C _1-5 alkyl group (the C _1-5 alkyl group is unsubstituted or one selected independently from substituent group A ₃ Substituted by the above substituents, provided that when m is 1 and both R ⁶ are hydrogen atoms, the C _1-5 alkyl group is independently selected from the substituent group A ₃ A C _6-9 alkyl group (the C _6-9 alkyl group is unsubstituted or independently selected from Substituent Group A ₃ ). Substituted with the above substituents), a C _3-11 cycloalkyl group or a 4-11 membered heterocycloalkyl group (the C _3-11 cycloalkyl group and 4-11 membered heterocycloalkyl group are C _{6 -10} aryl or 5-10 membered hetero ants (The C _6-10 aryl and 5-10 membered heteroaryl are unsubstituted or substituted by one or more substituents independently selected from substituent group A ₂ ) and fused rings. And the C _3-11 cycloalkyl group and the 4-11 membered heterocycloalkyl group may be unsubstituted or substituted by one or more substituents independently selected from the substituent group A ₁ Substituted, and R ³ represents a hydrogen atom or a C _1-3 alkyl group,
Or R ¹ and R ³ , together with the nitrogen atom to which they are attached, are a 4-11 membered heterocycloalkyl group (the 4-11 membered heterocycloalkyl group is unsubstituted or substituted) which is substituted by one or more substituents independently selected from the group a _1.) means,
R ² represents a C _1-5 alkyl group (the C _1-5 alkyl group is unsubstituted or substituted with one or more substituents independently selected from Substituent Group A ₃ . , M represents 1 and two R ⁶ both represent a hydrogen atom, the C _1-5 alkyl group is substituted with one or more substituents independently selected from substituent group A ₃ C _6-9 alkyl group (the C _6-9 alkyl group is unsubstituted or substituted by one or more substituents independently selected from substituent group A ₃ ). , A C _3-11 cycloalkyl group or a 4-11 membered heterocycloalkyl group (the C _3-11 cycloalkyl group and 4-11 membered heterocycloalkyl group are C _6-10 aryl or 5-10 membered heteroaryl ( the _{C 6-10} aryl and 5-10 Heteroaryl may be condensed one or more are replaced by a substituent.) And selected as or independently from Substituent group A ₂ unsubstituted, and the C _3-11 cycloalkyl groups and 4-11 membered heterocycloalkyl group is substituted by one or more substituents selected as or independently from substituent group a ₁ unsubstituted.) I mean,
R ⁴ and R ⁵ each independently represents a hydrogen atom or a C _1-3 alkyl group. )
The spiro compound according to claim 5, a tautomer of the compound, or a pharmaceutically acceptable salt thereof. L ¹ is a C _1-3 alkylene group,
L ² is a single bond,
Z ¹ is represented by formula (II-1), (II-4) or (II-7)

The spiro according to claim 2 or 3, wherein R ¹ , R ² , R ³ , R ⁴ , J ¹ and G ¹ have the same meaning as defined in claim 2. A compound, a tautomer of the compound, or a pharmaceutically acceptable salt thereof. L ¹ is a C _1-3 alkylene group,
L ² is a single bond,
Z ¹ is represented by formula (II-1), (II-4) or (II-7)

(Wherein R ¹ , R ² , R ³ , R ⁴ , J ¹ and G ¹ have the same meaning as defined in claim 6), the spiro compound according to claim 6, A tautomer of the compound, or a pharmaceutically acceptable salt thereof.   E is an oxygen atom, m is 1, and n is 0. The spiro compound according to any one of claims 2 to 8, a tautomer of the compound, or a pharmaceutically acceptable salt thereof. salt.   E is an oxygen atom, m is 2, and n is 0. The spiro compound according to any one of claims 2 to 8, a tautomer of the compound, or a pharmaceutically acceptable salt thereof. salt. T is the formula (VI-1) or (VI-2)

(Wherein L ⁴ represents a C _1-3 alkylene group, L ⁵ represents a single bond, and R ⁸ and R ¹⁰ have the same meaning as defined in claim 2). The spiro compound according to any one of claims 2 to 10, a tautomer of the compound, or a pharmaceutically acceptable salt thereof. Z ¹ is
Formula (II-1), (II-4) or (II-7)

(Wherein R ¹ and R ³ are
R ¹ is substituted with a C _1-6 alkyl group (the C _1-6 alkyl group is a 4- to 7-membered oxygen-containing heterocycloalkyl group or —NHC (═O) O (C _1-6 alkyl)). Or R ³ represents a hydrogen atom,
R ¹ is a C _1-6 alkyl group (the C _1-6 alkyl group is a C _6-10 aryl group or a 5-10 membered heteroaryl group (the C _6-10 aryl group and a 5-10 membered heteroaryl group). is 4-11 membered heterocycloalkyl alkane (said 4-11 membered heterocycloalkyl alkanes are substituted by one or more substituents selected as or independently from substituent group a ₂ unsubstituted.) and The C _6-10 aryl group and the 5- to 10-membered heteroaryl group may be condensed or substituted with one or more substituents independently selected from substituent group A ₂ And the C _1-6 alkyl group is substituted with one or more substituents independently selected from the group consisting of a hydroxyl group, a halogen atom and a cyano group. means may be.), ^{R 3} Means a hydrogen atom,
R ¹ is a 4- to 11-membered nitrogen-containing heterocycloalkyl group (the 4- to 11-membered nitrogen-containing heterocycloalkyl group is a C _1-3 alkyl group (the C _1-3 alkyl group is a phenyl group (the phenyl group is Is unsubstituted or independently of the group consisting of —C (═O) OCH ₃ , cyano group, nitro group, —SCH ₃ , —OCF ₃ , —OCH ₃ , chlorine atom, —CF ₃ and —CH _3. Substituted with one or more selected substituents)) or substituted with either a cyano group) or substituted with either —C (═O) O (C _1-6 alkyl). R ³ represents a hydrogen atom, or
R ¹ and R ³ , together with the nitrogen atom to which they are bonded, form a 4- to 11-membered nitrogen-containing heterocycloalkyl group (the 4- to 11-membered nitrogen-containing heterocycloalkyl group is represented by substituent group A ₁ Substituted by one or more independently selected substituents),
R ² is substituted with a C _1-6 alkyl group (the C _1-6 alkyl group is a 4- to 7-membered oxygen-containing heterocycloalkyl group or —NHC (═O) O (C _1-6 alkyl)). .)
R ⁴ represents a hydrogen atom,
J ¹ means an oxygen atom,
G ¹ means a single bond or an oxygen atom. )
The spiro compound according to any one of claims 2 to 11, a tautomer of the compound, or a pharmaceutically acceptable salt thereof. Z ¹ is
Formula (II-1), (II-4) or (II-7)

(Wherein R ¹ and R ³ are
R ¹ is substituted with a C _1-6 alkyl group (the C _1-6 alkyl group is a 4- to 7-membered oxygen-containing heterocycloalkyl group or —NHC (═O) O (C _1-6 alkyl)). Or R ³ represents a hydrogen atom,
R ¹ is a 5- to 7-membered nitrogen-containing heterocycloalkyl group (the 5- to 7-membered nitrogen-containing heterocycloalkyl group is a C _1-3 alkyl group (the C _1-3 alkyl group is a phenyl group (the phenyl group is Is unsubstituted or independently of the group consisting of —C (═O) OCH ₃ , cyano group, nitro group, —SCH ₃ , —OCF ₃ , —OCH ₃ , chlorine atom, —CF ₃ and —CH _3. Substituted with one or more selected substituents)), substituted with), and R ³ represents a hydrogen atom, or R ¹ and R ³ are , 1 they are attached a 5- to 7-membered nitrogen-containing heterocycloalkyl group together with the nitrogen atom to which (the 5- to 7-membered nitrogen-containing heterocycloalkyl group is independently selected from substituent group a ₁ Substituted with one or more substituents.
R ² is substituted with a C _1-6 alkyl group (the C _1-6 alkyl group is a 4- to 7-membered oxygen-containing heterocycloalkyl group or —NHC (═O) O (C _1-6 alkyl)). .)
R ⁴ represents a hydrogen atom,
J ¹ means an oxygen atom,
G ¹ means a single bond or an oxygen atom. )
The spiro compound according to any one of claims 2 to 12, a tautomer of the compound, or a pharmaceutically acceptable salt thereof. Z ¹ is
Formula (II-1) or (II-4)

(Wherein R ¹ and R ³ are
R ¹ is a C _1-6 alkyl group (the C _1-6 alkyl group is a C _6-10 aryl group or a 5-10 membered heteroaryl group (the C _6-10 aryl group and a 5-10 membered heteroaryl group). Is a 4- to 7-membered oxygen-containing heterocycloalkane (the 4- to 7-membered oxygen-containing heterocycloalkane is unsubstituted or substituted by one or more substituents independently selected from Substituent Group A ₂₎ And the C _6-10 aryl group and the 5- to 10-membered heteroaryl group are unsubstituted or independently selected from Substituent Group A ₂ The C _1-6 alkyl group is substituted with one or more substituents independently selected from the group consisting of a hydroxyl group, a halogen atom and a cyano group. Meaning R) ³ means a hydrogen atom,
R ¹ represents a 4-11 membered nitrogen-containing heterocycloalkyl group (the 4-11 membered nitrogen-containing heterocycloalkyl group is substituted by —C (═O) O (C _1-6 alkyl)). R ³ represents a hydrogen atom, or R ¹ and R ³ together with the nitrogen atom to which they are bonded are an azetidinyl group (the azetidinyl group is independently of the substituent group A ₁ Substituted with one or more selected substituents),
R ⁴ represents a hydrogen atom,
J ¹ is, means an oxygen atom. )
The spiro compound according to any one of claims 2 to 12, a tautomer of the compound, or a pharmaceutically acceptable salt thereof. T is the formula (VI-1) or (VI-2)

(In the formula, L ⁴ represents a C _1-3 alkylene group, L ⁵ represents a single bond, and R ⁸ and R ¹⁰ each independently represents a C _6-10 aryl group or a 5-10 membered nitrogen-containing group. A heteroaryl group (a C _6-10 aryl group and a 5-10 membered nitrogen-containing heteroaryl group are unsubstituted or a fluorine atom, a C _1-3 alkyl group (the C _1-3 alkyl group is one or more Or a substituent selected from the group consisting of a cyano group and one or more substituents independently selected from the group consisting of a cyano group. The spiro compound according to any one of 1 to 14, a tautomer of the compound, or a pharmaceutically acceptable salt thereof. T is the formula (VI-1) or (VI-2)

(In the formula, L ⁴ represents a C _1-3 alkylene group, L ⁵ represents a single bond, R ⁸ and R ¹⁰ are each independently a phenyl group or a pyridyl group (the phenyl group and the pyridyl group are , Unsubstituted or independently selected from the group consisting of a fluorine atom, a C _1-3 alkyl group (wherein the C _1-3 alkyl group is substituted by one or more fluorine atoms) and a cyano group. 16. A spiro compound according to any one of claims 2 to 15, a tautomer of the compound, or a pharmaceutical thereof. Acceptable salt. T is the formula (VI-1) or (VI-2)

(In the formula, L ⁴ represents a C _1-3 alkylene group, L ⁵ represents a single bond, R ⁸ and R ¹⁰ are each independently a phenyl group (the phenyl group represents one or two Or a C _1-3 alkyl group (the C _1-3 alkyl group is substituted with one or more fluorine atoms) or a cyano group). The spiro compound according to any one of claims 2 to 16, a tautomer of the compound, or a pharmaceutically acceptable salt thereof. T is the formula (VI-1) or (VI-2)

(Wherein L ⁴ represents a C _1-3 alkylene group, L ⁵ represents a single bond, R ⁸ and R ¹⁰ are each independently a phenyl group (the phenyl group is one or more fluorine atoms) Substituted by an atom and the phenyl group is substituted by either a C _1-3 alkyl group (the C _1-3 alkyl group is substituted by one or more fluorine atoms) or a cyano group The spiro compound according to any one of claims 2 to 16, a tautomer of the compound, or a pharmaceutically acceptable salt thereof. Z ¹ is
Formula (II-1) or (II-4)

(Wherein R ¹ and R ³ are
R ¹ and R ³ are combined with the nitrogen atom to which they are bonded to form a 5- to 7-membered nitrogen-containing heterocycloalkyl group (the 5- to 7-membered nitrogen-containing heterocycloalkyl group is a phenyl group, 5-10 A member heteroaryl group (the phenyl group and the 5-10 membered heteroaryl group are unsubstituted or a C _1-3 alkyl group (the C _1-3 alkyl group is unsubstituted or one or more Substituted with one or more substituents independently selected from the group consisting of halogen atoms and cyano groups.), -C (= O) OR ¹³ , -C ( = O) R ¹³ , —OR ¹³ , —NR ¹² R ¹³ , substituted with one or more substituents independently selected from the group consisting of halogen atoms and cyano groups.
R ¹² represents a hydrogen atom,
R ¹³ is a C _1-6 alkyl group (the C _1-6 alkyl group is unsubstituted or substituted by one or more fluorine atoms), a C _6-10 aryl group, or 5 to 10 members. A heteroaryl group (the C _6-10 aryl group and the 5-10 membered heteroaryl group are unsubstituted or a C _1-3 alkyl group (the C _1-3 alkyl group is unsubstituted or Substituted with one or more substituents independently selected from the group consisting of a halogen atom, a cyano group, and —OR ¹⁴ ).
R ¹⁴ represents a C _1-3 alkyl group (the C _1-3 alkyl group is unsubstituted or substituted by one or more halogen atoms);
R ⁴ represents a hydrogen atom,
J ¹ is, means an oxygen atom. )
The spiro compound according to any one of claims 2 to 13 or any one of claims 15 to 18, a tautomer of the compound, or a pharmaceutically acceptable salt thereof. Z ¹ is
Formula (II-1) or (II-4)

(Wherein R ¹ and R ³ are
R ¹ is a C _1-3 alkyl group (the C _1-3 alkyl group is a phenyl group, a pyridyl group, a furyl group or an isoxazolyl group (the phenyl group, pyridyl group, furyl group and isoxazolyl group are 4 to 7 members It may be condensed with an oxygen-containing heterocycloalkane, and the phenyl group, pyridyl group, furyl group and isoxazolyl group may be unsubstituted, halogen atoms, cyano groups, C _1-3 alkyl groups (the C _1-3 alkyl groups are substituted by one or more fluorine atoms.) And one or more substituents independently selected from the group consisting of —O (C _1-3 alkyl). And R ³ is a hydrogen atom, or R ¹ is a C _1-3 alkyl group (the C _1-3 alkyl group is a phenyl group). , Pyridyl group or furyl group (the phenyl group, pyridyl group and furyl group may be condensed with a 4- to 7-membered oxygen-containing heterocycloalkane, and the phenyl group, pyridyl group and furyl group are unsubstituted. Or one or more independently selected from the group consisting of a halogen atom, a cyano group and a C _1-3 alkyl group (wherein the C _1-3 alkyl group is substituted by one or more fluorine atoms). And the C _1-3 alkyl group is one or more independently selected from the group consisting of a hydroxyl group, a halogen atom, and a cyano group. Substituted with a substituent group), R ³ represents a hydrogen atom,
R ⁴ represents a hydrogen atom,
J ¹ is, means an oxygen atom. )
The spiro compound according to any one of claims 2 to 12 or any one of claims 14 to 18, a tautomer of the compound, or a pharmaceutically acceptable salt thereof. Z ¹ is
Formula (II-1) or (II-4)

(Wherein R ¹ and R ³ are
R ¹ and R ³ together with the nitrogen atom to which they are attached are piperidyl, piperazinyl, homopiperidyl or homopiperazinyl (the piperidyl, piperazinyl, homopiperidyl and homopiperazinyl groups are -C (═O) OR ¹³ , —C (═O) R ¹³ , —OR ¹³ , —NR ¹² R ¹³ , substituted by one or more substituents independently selected from the group consisting of a halogen atom and a cyano group Means)
R ¹² represents a hydrogen atom,
R ¹³ is a C _1-6 alkyl group (the C _1-6 alkyl group is unsubstituted or substituted by one or more fluorine atoms), a phenyl group or a pyridyl group (the phenyl group and pyridyl group). The group may be unsubstituted or a C _1-3 alkyl group (the C _1-3 alkyl group is unsubstituted or substituted by one or more fluorine atoms), a halogen atom, a cyano group, and Substituted with one or more substituents independently selected from the group consisting of —O (C _1-3 alkyl).
R ⁴ represents a hydrogen atom,
J ¹ is, means an oxygen atom. )
The spiro compound according to claim 19, a tautomer of the compound, or a pharmaceutically acceptable salt thereof.
Z ¹ is
Formula (II-1) or (II-4)

(Wherein R ¹ and R ³ are
R ¹ and R ³ together with the nitrogen atom to which they are bonded are piperidyl, piperazinyl, homopiperidyl or homopiperazinyl (the piperidyl, piperazinyl, homopiperidyl and homopiperazinyl groups are phenyl groups , Pyridyl group, oxadiazolyl group, benzimidazolyl group, benzisoxazolyl group or quinolyl group (the phenyl group, pyridyl group, oxadiazolyl group, benzimidazolyl group, benzisoxazolyl group and quinolyl group are unsubstituted) Or a C _1-3 alkyl group (the C _1-3 alkyl group is unsubstituted or substituted by one or more fluorine atoms), a halogen atom and a cyano group independently. Substituted by one or more substituents)). Taste,
R ⁴ represents a hydrogen atom,
J ¹ is, means an oxygen atom. )
The spiro compound according to claim 19, a tautomer of the compound, or a pharmaceutically acceptable salt thereof. Z ¹ is
Formula (II-1) or (II-4)

(Wherein R ¹ and R ³ are
R ¹ and R ³ together with the nitrogen atom to which they are attached are azetidinyl groups (the azetidinyl group is unsubstituted or —C (═O) OR ¹³ , —C (═O) R ¹³ , —OR ¹³ , —NR ¹² R ¹³ , substituted with one or more substituents independently selected from the group consisting of a halogen atom and a cyano group.
R ¹² represents a hydrogen atom,
R ¹³ represents a C _1-6 alkyl group, a phenyl group or a pyridyl group (the phenyl group and the pyridyl group are unsubstituted or a C _1-3 alkyl group (the C _1-3 alkyl group is unsubstituted). Or substituted by one or more fluorine atoms.), Substituted by one or more substituents independently selected from the group consisting of halogen atoms, cyano groups and —O (C _1-3 alkyl). Means either)
R ⁴ represents a hydrogen atom,
J ¹ is, means an oxygen atom. )
The spiro compound according to any one of claims 2 to 12 and 14, a tautomer of the compound, or a pharmaceutically acceptable salt thereof. L ¹ is a C _1-3 alkylene group,
L ² is a single bond,
E is an oxygen atom,
m is an integer of 1 or 2,
R ⁶ is a hydrogen atom,
n is 0,
T is the formula (VI-1) or (VI-2)

(Wherein L ⁴ represents a C _1-3 alkylene group, L ⁵ represents a single bond, and R ⁸ and R ¹⁰ have the same meaning as defined in claim 1). The spiro compound according to claim 1, a tautomer of the compound, or a pharmaceutically acceptable salt thereof. Z ¹ is
Formula (II-1) or (II-4)

(Wherein R ¹ and R ³ are
R ¹ is either a C _1-3 alkyl group (the C _1-3 alkyl group is a phenyl group or a pyridyl group (the phenyl group and the pyridyl group are substituted by a C _4-6 alkyl group)). Or R ³ represents a hydrogen atom, or
R ¹ represents a piperidyl group (the piperidyl group is substituted by a C _4-6 alkyl group), and R ³ represents a hydrogen atom, or R ¹ and R ³ are bonded to each other. A piperidyl group together with the nitrogen atom in which the piperidyl group is independently selected from the group consisting of —C (═O) R ¹³ , —OR ¹³ and —NR ¹² R ¹³ Substituted by a group)
R ¹² represents a hydrogen atom,
R ¹³ represents either a phenyl group or a pyridyl group (the phenyl group and the pyridyl group are unsubstituted or substituted by a C _4-6 alkyl group);
R ⁴ represents a hydrogen atom,
J ¹ is, means an oxygen atom. )
The spiro compound according to claim 1 or 24, a tautomer of the compound, or a pharmaceutically acceptable salt thereof. Z ¹ is
Formula (II-1) or (II-4)

(Wherein R ¹ and R ³ are
R ¹ is substituted with a C _1-6 alkyl group (the C _1-6 alkyl group is a 4- to 7-membered oxygen-containing heterocycloalkyl group or —NHC (═O) O (C _1-6 alkyl)). Or R ³ represents a hydrogen atom,
R ¹ is a C _1-6 alkyl group (the C _1-6 alkyl group is a C _6-10 aryl group or a 5-10 membered heteroaryl group (the C _6-10 aryl group and a 5-10 membered heteroaryl group). May be condensed with a 4- to 7-membered oxygen-containing heterocycloalkane, and the C _6-10 aryl group and the 5- to 10-membered heteroaryl group are unsubstituted or a halogen atom, a cyano group, C _1-3 alkyl groups (the C _1-3 alkyl groups are unsubstituted or substituted by one or more fluorine atoms), —O (C _1-3 alkyl) and C _4-6 alkyl groups And the C _1-6 alkyl group is substituted with a hydroxyl group, a halogen atom and a cyano group, each of which is substituted with one or more substituents independently selected from the group consisting of Chosen independently from the group May be substituted with one or more substituents.) Means, or R ³ means a hydrogen atom,
R ¹ represents a 4-11 membered nitrogen-containing heterocycloalkyl group (the 4-11 membered nitrogen-containing heterocycloalkyl group is substituted by —C (═O) O (C _1-6 alkyl)). R ³ represents a hydrogen atom, or R ¹ and R ³ together with the nitrogen atom to which they are bonded are an azetidinyl group or a 5- to 7-membered nitrogen-containing heterocycloalkyl group (the azetidinyl group). And a 5- to 7-membered nitrogen-containing heterocycloalkyl group is a phenyl group, a 5-10-membered heteroaryl group (the phenyl group and the 5-10-membered heteroaryl group are unsubstituted, or a C _1-3 alkyl group (The C _1-3 alkyl group is unsubstituted or substituted by one or more fluorine atoms), by one or more substituents independently selected from the group consisting of halogen atoms and cyano groups Replaced One or more independently selected from the group consisting of —C (═O) OR ¹³ , —C (═O) R ¹³ , —OR ¹³ , —NR ¹² R ¹³ , a halogen atom and a cyano group. Substituted with a substituent of
R ¹² represents a hydrogen atom,
R ¹³ is a C _1-6 alkyl group (the C _1-6 alkyl group is unsubstituted or substituted by one or more fluorine atoms), a phenyl group or a pyridyl group (the phenyl group and pyridyl group). The group may be unsubstituted or a C _1-3 alkyl group (the C _1-3 alkyl group is unsubstituted or substituted by one or more fluorine atoms), a halogen atom, a cyano group, and Substituted with one or more substituents independently selected from the group consisting of —O (C _1-3 alkyl).
R ⁴ represents a hydrogen atom,
J ¹ is, means an oxygen atom. The spiro compound according to claim 1 or 24, a tautomer of the compound, or a pharmaceutically acceptable salt thereof. T is the formula (VI-1) or (VI-2)

(In the formula, L ⁴ represents a C _1-3 alkylene group, L ⁵ represents a single bond, R ⁸ and R ¹⁰ are each independently a phenyl group or a pyridyl group (the phenyl group and the pyridyl group are , Unsubstituted or independently selected from the group consisting of a fluorine atom, a C _1-3 alkyl group (wherein the C _1-3 alkyl group is substituted by one or more fluorine atoms) and a cyano group. 27. A spiro compound according to any one of claims 1, 24 to 26, a tautomer of the compound, or Its pharmaceutically acceptable salt. T is the formula (VI-1) or (VI-2)

(Wherein L ⁴ represents a C _1-3 alkylene group, L ⁵ represents a single bond, R ⁸ and R ¹⁰ are each independently a phenyl group (the phenyl group is a C _4-6 alkyl group). 27. The spiro compound according to any one of claims 1, 24 to 26, a tautomer of the compound, or a pharmaceutically acceptable salt thereof. Salt that can be done. The spiro compound according to any one of claims 2 to 23, a tautomer of the compound, or a pharmaceutically acceptable salt thereof, wherein R ⁶ is a hydrogen atom.   30. The spiro compound according to any one of claims 1 to 3, 7, and 9 to 29, a tautomer of the compound, or a pharmaceutically acceptable salt thereof, wherein X is cyclohexylene.   30. The spiro compound according to any one of claims 1 or 2, 4 to 6, and 8 to 29, wherein X is a phenylene group, a pyridinediyl group, a pyrazinediyl group, a thiophenediyl group, or a thiazolediyl group. Sex or a pharmaceutically acceptable salt thereof.   32. An adiponectin receptor activator comprising the spiro compound according to any one of claims 1 to 31, a tautomer of the compound, or a pharmaceutically acceptable salt thereof as an active ingredient.   A prophylactic / therapeutic / ameliorating agent for a disease effective for activating the adiponectin receptor, comprising the adiponectin receptor activating agent according to claim 32 as an active ingredient.   A metabolic syndrome and a prophylactic or therapeutic drug for arteriosclerosis comprising the adiponectin receptor activator according to claim 32 as an active ingredient.   A medicament comprising the spiro compound according to any one of claims 1 to 31, a tautomer of the compound, or a pharmaceutically acceptable salt thereof as an active ingredient.