JP2008239616A - Hdl (high density lipoprotein) enhancer - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide an HDL enhancer containing a compound with an excellent HDL enhancing action. <P>SOLUTION: The HDL enhancer comprises a compound represented by formula (I), pharmaceutically acceptable salt thereof or solvate thereof. (Ring Q is a (substituted) monocyclic aryl, a (substituted) monocyclic heteroaryl, a (substituted) fused aryl, a (substituted) fused heteroaryl, Y<SP>1</SP>is a single bond or -NR<SP>6</SP>-, etc., ring A is a (substituted) nonaromatic heterocyclic diyl, Z<SP>1</SP>is a single bond, O, S or NR<SP>9</SP>, ring B is a (substituted) aromatic cyclic diyl or (substituted) aromatic heterocyclic diyl, Y<SP>3</SP>is a single bond, a lower (substituted) (-O-)alkylene, or a (substituted) alkenylene, etc., Z<SP>2</SP>is a COOR<SP>3</SP>, etc). <P>COPYRIGHT: (C)2009,JPO&INPIT

Description

  The present invention relates to a compound having HDL-elevating activity and useful as a medicament. Moreover, it is related with the HDL raising agent containing those compounds.

  It is well known that the risk of suffering from arteriosclerosis, especially coronary artery disease such as myocardial infarction and angina, is increased by the increase in blood LDL. On the other hand, with regard to HDL, many epidemiological studies have shown that the lower the plasma concentration, the higher the coronary artery disease and the higher it decreases, and it works as a “protective factor” against arteriosclerosis. It is believed that And this is thought to be related to HDL playing a central role in the pathway of collecting cholesterol from the organ to the liver.

  In addition, it is known that low HDL increases the risk of arteriosclerosis regardless of whether or not LDL is elevated, and low HDL is considered to be a “risk factor” that should be noted more than high LDL. .

  The increase in LDL is considered not to have a significant public health contribution to the development of ischemic heart disease in Japan, and it is considered necessary to reanalyze the contribution of HDL. In addition, coronary artery stenosis in patients undergoing coronary angiography has a stronger correlation with triglycerides and HDL cholesterol than with total cholesterol and LDL cholesterol. Such a tendency is common in other reports, and HDL is considered to be a stronger controlling factor than LDL for arteriosclerosis.

  Therefore, the HDL elevating agent is effective for treating or preventing arteriosclerosis, particularly coronary artery diseases such as myocardial infarction and angina. In addition, hyperlipidemia, diabetes, hyperglycemia, insulin resistance, obesity, atherosclerosis, hypertension, syndrome X, inflammation, allergic diseases (inflammatory colitis, rheumatoid arthritis, chronic pancreatitis, multiple sclerosis , Glomerulosclerosis, psoriasis, etc.), osteoporosis, infertility, cancer, Alzheimer's disease, Parkinsonism, Graves' disease and the like are expected to be useful.

  The following compounds are known as compounds having a chemical structure similar to that used in the HDL-elevating agent of the present invention.

Patent Document 1 discloses that a benzothiazole derivative containing piperazine can be used as an anti-obesity drug or the like.
Patent Document 2 discloses benzothiazole derivatives or benzoxazole derivatives containing piperazine or piperidine as antiviral agents.

  Patent Document 3 discloses a benzoxazole derivative containing pyrrolidine as a PPARγ agonist. However, piperazine and compounds containing piperidine are not described.

  Patent Document 4 and Patent Document 5 disclose that a compound containing piperazine has an antiallergic action or the like.

  Non-Patent Document 1 discloses a compound containing piperazine as a glycoprotein IIb / IIIa antagonist. Patent Document 6 discloses a compound containing piperazine as a CB1 antagonist.

  In Patent Document 7 and Patent Document 8, compounds containing piperazine and piperidine are described as PPAR modulators. However, these compounds are characterized by having a sulfonyl group as a linker between piperazine and a phenyl group.

However, the above document does not describe any HDL raising action.
International Publication No. WO00 / 006558 Pamphlet European Patent No. 398425 specification International Publication No. WO97 / 31907 Pamphlet JP 05-345765 A JP 09-208570 A International Publication No. WO2006 / 060461 Pamphlet International Publication No. WO2004 / 092117 Pamphlet International Publication No. WO2005 / 115983 Pamphlet Bioorganic & Medical Chemistry Letters, 1998, Vol. 8, pp. 1531-1536

  An object of the present invention is to provide a compound having an excellent HDL raising action. Moreover, the HDL raising agent containing those compounds is provided.

  As a result of intensive studies, the present inventors have succeeded in synthesizing a compound having an excellent HDL raising action. As a means for finding the candidate compound, a computer-aided molecular design technique was used to search for a compound having a desired pharmacological activity. That is, the present inventors use a compound three-dimensional database automatic search program based on the three-dimensional structure of a peroxisome proliferator activated receptor whose structure is registered in PDB (Protein Data Bank), and use the compound three-dimensional database automatic search program. A compound that can be a PPAR agonist was selected by virtual screening. Subsequently, many derivatives were synthesized based on the structure of the selected compounds, and the synthesized derivatives were subjected to HDL-elevating action confirmation test, transcription activation test for PPARδ, α and γ, cytotoxicity test, etc. The present invention was completed by selecting a compound having a strong activity and a desired pharmacological activity and further synthesizing the derivative. The present inventor has also found that the compounds used in the present invention have an HDL-elevating action, have PPAR transcription activity, have little inhibition on drug metabolizing enzymes, and have good metabolic stability and water solubility. In addition, the compound used in the present invention has low toxicity and is considered to be sufficiently safe for use as a medicine.

環Ｑは置換されていてもよい単環アリール、置換されていてもよい単環ヘテロアリール、置換されていてもよい縮合アリールまたは置換されていてもよい縮合ヘテロアリール（但し、環Ｑは非置換１１Ｈ-ジベンズ[b, e]-アゼピン-6-イルではない）であり、
Ｙ^１は単結合、−ＮＲ^６−または−ＮＲ^６−ＣＯ−（ここでＲ^６は水素または置換されていてもよい低級アルキルである）であり、
但し、環Ｑが非置換単環アリールの場合、Ｙ^１は−ＮＲ^６−ＣＯ−であり、
環Ｑが単環アリールかつＹ^１が単結合の場合、環Ｑはハロゲン化アルキルで置換されたフェニルであり、
環Ａは置換されていてもよい非芳香族ヘテロ環ジイル（但し、Ｙ^１が単結合の場合、環Ｑは環Ａを構成する窒素原子と結合する）であり、
式：−Ｙ^２Ｚ¹−は

で示される基（但し、−Ｙ^２Ｚ¹−は−SO_２−ではなく、環Ｑが非置換ベンゾチアゾール-2-イルまたはベンゾオキサゾール-2-イルの場合、−Ｙ^２Ｚ¹−が−CH₂−CH₂−O−または−O−でない）であり、
Ｒ^７は各々独立して水素、置換されていてもよい低級アルキルまたは置換されていてもよいシクロアルキルであり、
Ｒ^８およびＲ^９は各々独立して水素または置換されていてもよい低級アルキルであり、
ｎは０〜３の整数であり、
Ｚ¹は単結合、−Ｏ−、−Ｓ−または−ＮＲ^９−（ここでＲ^９は水素、置換されていてもよい低級アルキル、置換されていてもよいアシル、置換されていてもよい低級アルキルスルホニルまたは置換されていてもよいアリールスルホニルである）であり、
環Ｂは置換されていてもよい芳香族炭素環ジイルまたは置換されていてもよい芳香族へテロ環ジイルであり、
Ｙ^３は単結合、置換されていてもよく、−Ｏ−が介在していてもよい低級アルキレン、−Ｏ−が介在していてもよいシクロアルキレンまたは置換されていてもよい低級アルケニレンであり、
Ｚ^２はＣＯＯＲ^３、Ｃ（＝ＮＲ^３）ＮＲ^１４ＯＲ^１５、ＣＯＮＨＣＮ、

（ここでＲ^３、Ｒ^１４およびＲ^１５は各々独立して水素、置換されていてもよい低級アルキル、置換されていてもよい低級アルケニル、置換されていてもよいアリールまたは置換されていてもよいヘテロアリールである）である、
（但し、式：−Ｙ^２Ｚ¹−が

で示される基であり、ｎが０であり、Ｚ¹が単結合の場合は除く）
で示される化合物、その製薬上許容される塩またはそれらの溶媒和物を含有するＨＤＬ上昇剤、
（２）環Ａが

［ここでＸ^４はＮまたはＣＲ^５（ここでＲ^５は水素または置換されていてもよい低級アルキルである）であり、Ｘ^５はＯ、Ｓ、ＮＲ^１６またはＣＲ^１７Ｒ^１８（ここでＲ^１６〜Ｒ^１８はそれぞれ独立して水素、置換されていてもよい低級アルキル、シアノ、置換されていてもよい非芳香族へテロ環式基、置換されていてもよいヘテロアリール、置換されていてもよいアミノ、置換されていてもよい低級アルコキシ、アリール低級アルキルまたは置換されていてもよいシクロアルキルである）である。但し、Ｘ^４がＣＲ^５かつＸ^５がＣＲ^１７Ｒ^１８の場合は除く。Ｒ^４は各々独立して、ハロゲン、置換されていてもよい低級アルキル、置換されていてもよい低級アルケニル、置換されていてもよい低級アルキニル、置換されていてもよい低級アルコキシまたは置換されていてもよいアリールであり、ｍは０〜２の整数である。Ｘ^４からの結合手はＹ^１と結合し、他方の結合手はＹ^２と結合する。Ｘ^５がＮＲ^１６またはＣＲ^１７Ｒ^１８の場合、該他方の結合手はＸ^５と結合していてもよい。］で示される基である、（１）記載の化合物、その製薬上許容される塩またはそれらの溶媒和物を含有するＨＤＬ上昇剤、
（３）環Ａが

［ここでＸ^４はＮまたはＣＲ^５（ここでＲ^５は水素または置換されていてもよい低級アルキルである）であり、Ｘ^５はＮＲ^１６またはＣＲ^１７Ｒ^１８（ここでＲ^１６〜Ｒ^１８はそれぞれ独立して水素、置換されていてもよい低級アルキル、シアノ、置換されていてもよい非芳香族へテロ環式基、置換されていてもよいヘテロアリール、置換されていてもよいアミノ、置換されていてもよい低級アルコキシ、アリール低級アルキルまたは置換されていてもよいシクロアルキルである）である。Ｒ^４は各々独立して、ハロゲン、置換されていてもよい低級アルキル、置換されていてもよい低級アルケニル、置換されていてもよい低級アルキニル、置換されていてもよい低級アルコキシまたは置換されていてもよいアリールであり、ｍは０〜２の整数である。Ｘ^４からの結合手はＹ^１と結合し、他方の結合手はＹ^２と結合する。該他方の結合手はＸ^５と結合していてもよい。］で示される基である、（１）記載の化合物、その製薬上許容される塩またはそれらの溶媒和物を含有するＨＤＬ上昇剤、
（４）環Ａが

（Ｒ^４は各々独立して、ハロゲン、置換されていてもよい低級アルキル、置換されていてもよい低級アルケニル、置換されていてもよい低級アルキニルまたは置換されていてもよい低級アルコキシであり、ｍは１または２の整数である。）で示される基である、（１）記載の化合物、その製薬上許容される塩またはそれらの溶媒和物を含有するＨＤＬ上昇剤、
（５）環Ａが

（Ｒ^１７は置換されていてもよい低級アルキル、シアノ、置換されていてもよい非芳香族へテロ環式基、置換されていてもよいヘテロアリール、置換されていてもよいアミノ、置換されていてもよい低級アルコキシ、アリール低級アルキルまたは置換されていてもよいシクロアルキルである。Ｎからの結合手はＹ^１と結合し、Ｃからの結合手はＹ^２と結合する。）で示される基である、（１）記載の化合物、その製薬上許容される塩またはそれらの溶媒和物を含有するＨＤＬ上昇剤、
（６）環Ａが

［ここでＸ^４はＮまたはＣＲ^５（ここでＲ^５は水素または置換されていてもよい低級アルキルである）であり、Ｘ^５はＮＲ^１６またはＣＲ^１７Ｒ^１８（ここでＲ^１６〜Ｒ^１８はそれぞれ独立して水素、置換されていてもよい低級アルキル、シアノ、置換されていてもよい非芳香族へテロ環式基、置換されていてもよいヘテロアリール、置換されていてもよいアミノ、置換されていてもよい低級アルコキシ、アリール低級アルキルまたは置換されていてもよいシクロアルキルである）である。但し、Ｘ^４がＣＲ^５かつＸ^５がＣＲ^１７Ｒ^１８の場合は除く。Ｒ^４は各々独立して、ハロゲン、置換されていてもよい低級アルキル、置換されていてもよい低級アルケニル、置換されていてもよい低級アルキニル、置換されていてもよい低級アルコキシまたは置換されていてもよいアリールであり、ｍは０〜２の整数である。Ｘ^４からの結合手はＹ^１と結合し、他方の結合手はＹ^２と結合する。該他方の結合手はＸ^５と結合していてもよい。］で示される基である、（１）記載の化合物、その製薬上許容される塩またはそれらの溶媒和物を含有するＨＤＬ上昇剤、
（７）環Ｑが置換された縮合ヘテロアリールである、（１）または（２）記載の化合物、その製薬上許容される塩またはそれらの溶媒和物を含有するＨＤＬ上昇剤、
（８）環Ｑが置換されたベンゾフリル、置換されたベンゾチエニル、置換されたベンゾピロリル、置換されたベンゾオキサゾリル、置換されたベンゾイソキサゾリル、置換されたベンゾチアゾリル、置換されたベンゾイソチアゾリル、置換されたベンゾイミダゾリルまたは置換されたベンゾピラゾリルである、（１）または（２）記載の化合物、その製薬上許容される塩またはそれらの溶媒和物を含有するＨＤＬ上昇剤、
（９）式：

が
式：

［式中、
Ｒ^１は水素、ハロゲン、ヒドロキシ、置換されていてもよい低級アルキル、置換されていてもよい低級アルケニル、置換されていてもよい低級アルキニル、置換されていてもよい低級アルコキシまたは置換されていてもよいアリールであり、
Ｒ^２はハロゲン、置換されていてもよいアルキル、置換されていてもよいアリール、置換されていてもよいアリールオキシ、置換されていてもよいアリールチオまたは置換されていてもよいヘテロアリールであり、または
Ｒ^１およびＲ^２は、隣接する炭素原子、Ｘ^１およびＸ^３を構成原子に含む５員環と一緒になって置換された縮合ヘテロアリールを形成してもよく、
Ｘ^１はＮまたはＣＲ^１０、
Ｘ^３はＮＲ^１１、ＯまたはＳ、
（ここでＲ^１０およびＲ^１１は各々独立して水素または置換されていてもよい低級アルキルである）である］で示される基である、（１）または（２）記載の化合物、その製薬上許容される塩またはそれらの溶媒和物を含有するＨＤＬ上昇剤、
（１０）式：

が
式：

［式中、
Ｒ^１は水素、ハロゲン、ヒドロキシ、置換されていてもよい低級アルキル、置換されていてもよい低級アルケニル、置換されていてもよい低級アルキニルまたは置換されていてもよい低級アルコキシであり、
Ｒ^２はハロゲン、置換されていてもよいアルキル、置換されていてもよいアリール、置換されていてもよいアリールオキシ、置換されていてもよいアリールチオまたは置換されていてもよいヘテロアリールであり、または
Ｒ^１およびＲ^２は、隣接する炭素原子、Ｘ^１およびＸ^３を構成原子に含む５員環と一緒になって置換された縮合ヘテロアリールを形成してもよく、
Ｘ^１はＮまたはＣＲ^１２、
Ｘ^３はＮＲ^１３、ＯまたはＳ、
（ここでＲ^１２およびＲ^１３は各々独立して水素または置換されていてもよい低級アルキルである）である］で示される基である、（１）または（２）記載の化合物、その製薬上許容される塩またはそれらの溶媒和物を含有するＨＤＬ上昇剤、
（１１）式：

が
式：

［式中、
Ｒ^１はそれぞれ独立して水素、ハロゲン、ヒドロキシ、置換されていてもよい低級アルキル、置換されていてもよい低級アルケニル、置換されていてもよい低級アルキニルまたは置換されていてもよい低級アルコキシであり、
Ｒ^２はハロゲン、置換されていてもよいアルキル、置換されていてもよいアリール、置換されていてもよいアリールオキシ、置換されていてもよいアリールチオまたは置換されていてもよいヘテロアリールであり、
Ｘ^１はＮまたはＣＲ^１９、
Ｘ^３はＮまたはＣＲ^２０
（ここでＲ^１９およびＲ^２０は各々独立して水素または置換されていてもよい低級アルキルである。但し、Ｘ^１またはＸ^３のいずれか一方はＮである。）である］で示される基である、（１）または（２）記載の化合物、その製薬上許容される塩またはそれらの溶媒和物を含有するＨＤＬ上昇剤、
（１２）式：−Ｙ^２Ｚ¹−が

で示される基であり、
Ｒ^８およびＲ^９が各々独立して水素または低級アルキルであり、
ｎが０〜２の整数であり、
Ｚ^１が単結合、−Ｏ−または−Ｓ−である、（１）または（２）記載の化合物、その製薬上許容される塩またはそれらの溶媒和物を含有するＨＤＬ上昇剤、
（１３）環Ｂが置換されていてもよいフェニレン、置換されていてもよいインドールジイル、置換されていてもよいベンゾフランジイル、置換されていてもよいベンゾチオフェンジイル、置換されていてもよいフランジイルまたは置換されていてもよいチオフェンジイルである、（１）または（２）記載の化合物、その製薬上許容される塩またはそれらの溶媒和物を含有するＨＤＬ上昇剤、
（１４）Ｙ^３が単結合、置換されていてもよい低級アルキレン、−Ｏ−置換されていてもよい低級アルキレンまたは置換されていてもよい低級アルケニレンである、（１）または（２）記載の化合物、その製薬上許容される塩またはそれらの溶媒和物を含有するＨＤＬ上昇剤、
（１５）Ｚ^２がＣＯＯＲ^３（ここでＲ^３は水素または置換されていてもよい低級アルキルである）である、（１）または（２）記載の化合物、その製薬上許容される塩またはそれらの溶媒和物を含有するＨＤＬ上昇剤、
（１６）式：

が
式：

［式中、
Ｒ^１は水素であり、
Ｒ^２は置換されていてもよいアリールであり、または
Ｒ^１およびＲ^２は隣接する炭素原子、Ｘ^１およびＸ^３を構成原子に含む５員環と一緒になって置換された縮合ヘテロアリールを形成してもよく、
Ｘ^１はＮまたはＣＲ^１０（ここでＲ^１０は水素である）であり、
Ｘ^３はＯまたはＳである］で示される基であり、
Ｙ^１が単結合であり、
環Ａが

［ここでＸ^４はＮであり、Ｘ^５はＮＲ^１６またはＣＲ^１７Ｒ^１８（ここでＲ^１６〜Ｒ^１８はそれぞれ独立して水素、置換されていてもよい低級アルキル、シアノ、置換されていてもよい非芳香族へテロ環式基、置換されていてもよいヘテロアリール、置換されていてもよいアミノ、置換されていてもよい低級アルコキシ、アリール低級アルキルまたは置換されていてもよいシクロアルキルである）である。Ｒ^４は各々独立して、ハロゲン、置換されていてもよい低級アルキル、置換されていてもよい低級アルケニル、置換されていてもよい低級アルキニル、置換されていてもよい低級アルコキシまたは置換されていてもよいアリールであり、ｍは０〜２の整数である。Ｘ^４からの結合手はＹ^１と結合し、他方の結合手はＹ^２と結合する。該他方の結合手はＸ^５と結合していてもよい。］で示される基であり、
式：−Ｙ^２Ｚ¹−が

で示される基であり、
Ｒ^８およびＲ^９が各々独立して水素または低級アルキルであり、
ｎが０〜２の整数であり、
Ｚ^１が単結合、−Ｏ−または−Ｓ−であり、
環Ｂが置換されていてもよいフェニレン（置換基としては、ハロゲン、低級アルキルまたは低級アルコキシ）、置換されていてもよいフランジイル（置換基としては、ハロゲン、低級アルキルまたは低級アルコキシ）または置換されていてもよいチオフェンジイル（置換基としては、ハロゲン、低級アルキルまたは低級アルコキシ）であり、
Ｙ^３が単結合、置換されていてもよい低級アルキレン（置換基としては、ハロゲンまたは低級アルキレン）、−Ｏ−置換されていてもよい低級アルキレン（置換基としては、低級アルキレンまたはハロゲン）、置換されていてもよい低級アルケニレン（置換基としては、低級アルキレンまたはハロゲン）であり、
Ｚ^２がＣＯＯＲ^３（ここでＲ^３は水素または低級アルキルである）である、（１）記載の化合物、その製薬上許容される塩またはそれらの溶媒和物を含有するＨＤＬ上昇剤、
（１７）式：

が
式：

（式中、
Ｒ^１はそれぞれ独立して水素、ハロゲン、ヒドロキシ、置換されていてもよい低級アルキル、置換されていてもよい低級アルケニル、置換されていてもよい低級アルキニルまたは置換されていてもよい低級アルコキシであり、
Ｒ^２は置換されていてもよいアルキルまたは置換されていてもよいアリールであり
Ｘ^１はＮまたはＣＲ^１９、
Ｘ^３はＮまたはＣＲ^２０
（ここでＲ^１９およびＲ^２０は各々独立して水素または置換されていてもよい低級アルキルである。但し、Ｘ^１またはＸ^３のいずれか一方はＮである。）である］で示される基であり、
Ｙ^１が単結合であり、
環Ａが

［ここでＸ^４はＮであり、Ｘ^５はＮＲ^１６またはＣＲ^１７Ｒ^１８（ここでＲ^１６〜Ｒ^１８はそれぞれ独立して水素、置換されていてもよい低級アルキル、シアノ、置換されていてもよい非芳香族へテロ環式基、置換されていてもよいヘテロアリール、置換されていてもよいアミノ、置換されていてもよい低級アルコキシ、アリール低級アルキルまたは置換されていてもよいシクロアルキルである）である。Ｒ^４は各々独立して、ハロゲン、置換されていてもよい低級アルキル、置換されていてもよい低級アルケニル、置換されていてもよい低級アルキニル、置換されていてもよい低級アルコキシまたは置換されていてもよいアリールであり、ｍは０〜２の整数である。Ｘ^４からの結合手はＹ^１と結合し、他方の結合手はＹ^２と結合する。該他方の結合手はＸ^５と結合していてもよい。］で示される基であり、
式：−Ｙ^２Ｚ¹−が

で示される基であり、
Ｒ^８およびＲ^９が各々独立して水素または低級アルキルであり、
ｎが０〜２の整数であり、
Ｚ^１が単結合、−Ｏ−または−Ｓ−であり、
環Ｂが置換されていてもよいフェニレン（置換基としては、ハロゲン、低級アルキルまたは低級アルコキシ）、置換されていてもよいフランジイル（置換基としては、ハロゲン、低級アルキルまたは低級アルコキシ）または置換されていてもよいチオフェンジイル（置換基としては、ハロゲン、低級アルキルまたは低級アルコキシ）であり、
Ｙ^３が単結合、置換されていてもよい低級アルキレン（置換基としては、ハロゲンまたは低級アルキレン）、−Ｏ−置換されていてもよい低級アルキレン（置換基としては、低級アルキレンまたはハロゲン）、置換されていてもよい低級アルケニレン（置換基としては、低級アルキレンまたはハロゲン）であり、
Ｚ^２がＣＯＯＲ^３（ここでＲ^３は水素または低級アルキルである）である、（１）記載の化合物、その製薬上許容される塩またはそれらの溶媒和物を含有するＨＤＬ上昇剤、
（１８）Ｙ^１が単結合であり、
環Ａが

（Ｒ^４は各々独立して、ハロゲン、置換されていてもよい低級アルキル、置換されていてもよい低級アルケニル、置換されていてもよい低級アルキニルまたは置換されていてもよい低級アルコキシであり、ｍは１または２の整数である。）で示される基であり、
式：−Ｙ^２Ｚ¹−が

で示される基であり、
Ｒ^８およびＲ^９が各々独立して水素または低級アルキルであり、
ｎが１〜２の整数であり、
Ｚ^１が単結合または−Ｏ−であり、
環Ｂが置換されていてもよいフェニレンであり、
Ｙ^３が置換されていてもよい低級アルキレン（置換基としては、ハロゲンまたは低級アルキレン）または−Ｏ−置換されていてもよい低級アルキレン（置換基としては、低級アルキレンまたはハロゲン）であり、
Ｚ^２がＣＯＯＲ^３（ここでＲ^３は水素または低級アルキルである）である、（１）記載の化合物、その製薬上許容される塩またはそれらの溶媒和物を含有するＨＤＬ上昇剤、
（１９）Ｙ^１が単結合であり、
環Ａが

（Ｒ^１７は置換されていてもよい低級アルキル、シアノ、置換されていてもよい非芳香族へテロ環式基、置換されていてもよいヘテロアリール、置換されていてもよいアミノ、置換されていてもよい低級アルコキシ、アリール低級アルキルまたは置換されていてもよいシクロアルキルである。Ｎからの結合手はＹ^１と結合し、Ｃからの結合手はＹ^２と結合する。）で示される基であり、
式：−Ｙ^２Ｚ¹−が

で示される基であり、
Ｒ^８およびＲ^９が各々独立して水素または低級アルキルであり、
ｎが２であり、
Ｚ^１が−Ｏ−であり、
環Ｂが置換されていてもよいフェニレンであり、
Ｙ^３が置換されていてもよい低級アルキレン（置換基としては、ハロゲンまたは低級アルキレン）または−Ｏ−置換されていてもよい低級アルキレン（置換基としては、低級アルキレンまたはハロゲン）であり、
Ｚ^２がＣＯＯＲ^３（ここでＲ^３は水素または低級アルキルである）である、（１）記載の化合物、その製薬上許容される塩またはそれらの溶媒和物を含有するＨＤＬ上昇剤、
を提供する。 The present invention
(1) Formula (I):

Ring Q is an optionally substituted monocyclic aryl, an optionally substituted monocyclic heteroaryl, an optionally substituted fused aryl or an optionally substituted heteroaryl (provided that ring Q is unsubstituted 11H-Dibenz [b, e] -azepin-6-yl)
Y ¹ is a single bond, —NR ⁶ — or —NR ⁶ —CO— (wherein R ⁶ is hydrogen or optionally substituted lower alkyl);
Provided that when ring Q is unsubstituted monocyclic aryl, Y ¹ is —NR ⁶ —CO—;
When ring Q is monocyclic aryl and Y ¹ is a single bond, ring Q is phenyl substituted with an alkyl halide;
Ring A is an optionally substituted non-aromatic heterocyclic diyl (provided that when Y ¹ is a single bond, ring Q is bonded to a nitrogen atom constituting ring A);
Formula: ^-Y 2 Z ¹ - is

(Wherein —Y ² Z ¹ — is not —SO ₂ —, and when ring Q is unsubstituted benzothiazol-2-yl or benzoxazol-2-yl, —Y ² Z ¹ — is — CH ₂ —CH ₂ —O— or not —O—),
Each R ⁷ is independently hydrogen, optionally substituted lower alkyl or optionally substituted cycloalkyl;
R ⁸ and R ⁹ are each independently hydrogen or optionally substituted lower alkyl,
n is an integer from 0 to 3,
Z ¹ is a single bond, —O—, —S— or —NR ⁹ — (wherein R ⁹ is hydrogen, optionally substituted lower alkyl, optionally substituted acyl, optionally substituted lower) Alkylsulfonyl or optionally substituted arylsulfonyl),
Ring B is an optionally substituted aromatic carbocyclic diyl or an optionally substituted aromatic heterocyclic diyl;
Y ³ is a single bond, which may be substituted, -O- may be interposed with lower alkylene, -O- may be interposed with cycloalkylene or optionally substituted lower alkenylene,
Z ² is COOR ³ , C (= NR ³ ) NR ¹⁴ OR ¹⁵ , CONHCN,

(Wherein R ³ , R ¹⁴ and R ¹⁵ are each independently hydrogen, optionally substituted lower alkyl, optionally substituted lower alkenyl, optionally substituted aryl, or optionally substituted. Is heteroaryl),
(However, the formula: ^-Y 2 Z ¹ - is

Except when n is 0 and Z ¹ is a single bond)
An HDL elevating agent containing a compound represented by the formula: pharmaceutically acceptable salts thereof or solvates thereof,
(2) Ring A is

[Wherein X ⁴ is N or CR ⁵ (where R ⁵ is hydrogen or optionally substituted lower alkyl) and X ⁵ is O, S, NR ¹⁶ or CR ¹⁷ R ¹⁸ (where R ⁵ is R ^{16 to} R ¹⁸ are each independently hydrogen, optionally substituted lower alkyl, cyano, optionally substituted non-aromatic heterocyclic group, optionally substituted heteroaryl, substituted It may be amino, optionally substituted lower alkoxy, aryl lower alkyl or optionally substituted cycloalkyl). However, the case where X ⁴ is CR ⁵ and X ⁵ is CR ¹⁷ R ¹⁸ is excluded. Each R ⁴ is independently halogen, optionally substituted lower alkyl, optionally substituted lower alkenyl, optionally substituted lower alkynyl, optionally substituted lower alkoxy, or substituted And m is an integer of 0-2. Bond from X ⁴ is bonded to Y ^1, the other bond is bound to Y ^2. When X ⁵ is NR ¹⁶ or CR ¹⁷ R ¹⁸ , the other bond may be bonded to X ⁵ . An HDL-elevating agent containing the compound according to (1), a pharmaceutically acceptable salt thereof, or a solvate thereof,
(3) Ring A is

[Where X ⁴ is N or CR ⁵ (where R ⁵ is hydrogen or optionally substituted lower alkyl) and X ⁵ is NR ¹⁶ or CR ¹⁷ R ¹⁸ (where R ^{16 to} R ¹⁸ Are each independently hydrogen, optionally substituted lower alkyl, cyano, optionally substituted non-aromatic heterocyclic group, optionally substituted heteroaryl, optionally substituted amino, Optionally substituted lower alkoxy, aryl lower alkyl or optionally substituted cycloalkyl). Each R ⁴ is independently halogen, optionally substituted lower alkyl, optionally substituted lower alkenyl, optionally substituted lower alkynyl, optionally substituted lower alkoxy, or substituted And m is an integer of 0-2. Bond from X ⁴ is bonded to Y ^1, the other bond is bound to Y ^2. Bonds of the other side may be bonded to X ^5. An HDL-elevating agent containing the compound according to (1), a pharmaceutically acceptable salt thereof, or a solvate thereof,
(4) Ring A is

(R ⁴ is each independently halogen, optionally substituted lower alkyl, optionally substituted lower alkenyl, optionally substituted lower alkynyl or optionally substituted lower alkoxy, m Is an integer of 1 or 2.) An HDL-elevating agent containing the compound according to (1), a pharmaceutically acceptable salt thereof, or a solvate thereof,
(5) Ring A is

(R ¹⁷ is optionally substituted lower alkyl, cyano, optionally substituted non-aromatic heterocyclic group, optionally substituted heteroaryl, optionally substituted amino, substituted A lower alkoxy group, an aryl lower alkyl group, or an optionally substituted cycloalkyl group, a bond from N is bonded to Y ^1, and a bond from C is bonded to Y ² . An HDL elevating agent containing the compound according to (1), a pharmaceutically acceptable salt thereof or a solvate thereof,
(6) Ring A is

[Where X ⁴ is N or CR ⁵ (where R ⁵ is hydrogen or optionally substituted lower alkyl) and X ⁵ is NR ¹⁶ or CR ¹⁷ R ¹⁸ (where R ^{16 to} R ¹⁸ Are each independently hydrogen, optionally substituted lower alkyl, cyano, optionally substituted non-aromatic heterocyclic group, optionally substituted heteroaryl, optionally substituted amino, Optionally substituted lower alkoxy, aryl lower alkyl or optionally substituted cycloalkyl). However, the case where X ⁴ is CR ⁵ and X ⁵ is CR ¹⁷ R ¹⁸ is excluded. Each R ⁴ is independently halogen, optionally substituted lower alkyl, optionally substituted lower alkenyl, optionally substituted lower alkynyl, optionally substituted lower alkoxy, or substituted And m is an integer of 0-2. Bond from X ⁴ is bonded to Y ^1, the other bond is bound to Y ^2. Bonds of the other side may be bonded to X ^5. An HDL-elevating agent containing the compound according to (1), a pharmaceutically acceptable salt thereof, or a solvate thereof,
(7) an HDL-elevating agent containing the compound according to (1) or (2), a pharmaceutically acceptable salt thereof or a solvate thereof, wherein the ring Q is a condensed heteroaryl substituted;
(8) Benzofuryl substituted with ring Q, substituted benzothienyl, substituted benzopyrrolyl, substituted benzoxazolyl, substituted benzoisoxazolyl, substituted benzothiazolyl, substituted benzoisothiazo An HDL-elevating agent containing a compound according to (1) or (2), a pharmaceutically acceptable salt thereof, or a solvate thereof, which is ril, substituted benzimidazolyl or substituted benzopyrazolyl,
(9) Formula:

Is the formula:

[Where:
R ¹ is hydrogen, halogen, hydroxy, optionally substituted lower alkyl, optionally substituted lower alkenyl, optionally substituted lower alkynyl, optionally substituted lower alkoxy, or optionally substituted Good aryl,
R ² is halogen, optionally substituted alkyl, optionally substituted aryl, optionally substituted aryloxy, optionally substituted arylthio, or optionally substituted heteroaryl, or R ¹ and R ² may form a substituted fused heteroaryl together with a 5-membered ring containing adjacent carbon atoms, X ¹ and X ³ as constituent atoms,
X ¹ is N or CR ¹⁰ ,
X ³ is NR ¹¹ , O or S,
(Wherein R ¹⁰ and R ¹¹ are each independently hydrogen or optionally substituted lower alkyl)], the compound according to (1) or (2), its pharmaceutical HDL raising agents containing acceptable salts or solvates thereof,
(10) Formula:

Is the formula:

[Where:
R ¹ is hydrogen, halogen, hydroxy, optionally substituted lower alkyl, optionally substituted lower alkenyl, optionally substituted lower alkynyl, or optionally substituted lower alkoxy,
R ² is halogen, optionally substituted alkyl, optionally substituted aryl, optionally substituted aryloxy, optionally substituted arylthio, or optionally substituted heteroaryl, or R ¹ and R ² may form a substituted fused heteroaryl together with a 5-membered ring containing adjacent carbon atoms, X ¹ and X ³ as constituent atoms,
X ¹ is N or CR ¹² ,
X ³ is NR ¹³ , O or S,
(Wherein R ¹² and R ¹³ are each independently hydrogen or optionally substituted lower alkyl)], the compound according to (1) or (2), its pharmaceutical HDL raising agents containing acceptable salts or solvates thereof,
(11) Formula:

Is the formula:

[Where:
R ¹ is independently hydrogen, halogen, hydroxy, optionally substituted lower alkyl, optionally substituted lower alkenyl, optionally substituted lower alkynyl, or optionally substituted lower alkoxy. ,
R ² is halogen, optionally substituted alkyl, optionally substituted aryl, optionally substituted aryloxy, optionally substituted arylthio or optionally substituted heteroaryl;
X ¹ is N or CR ¹⁹ ,
X ³ is N or CR ²⁰
Wherein R ¹⁹ and R ²⁰ are each independently hydrogen or optionally substituted lower alkyl, provided that either X ¹ or X ³ is N. An HDL-elevating agent containing the compound according to (1) or (2), a pharmaceutically acceptable salt thereof or a solvate thereof,
(12): ^-Y 2 Z ¹ - is

A group represented by
R ⁸ and R ⁹ are each independently hydrogen or lower alkyl,
n is an integer from 0 to 2,
An HDL-elevating agent containing a compound according to (1) or (2), a pharmaceutically acceptable salt thereof or a solvate thereof, wherein Z ¹ is a single bond, —O— or —S—;
(13) Ring B may be optionally substituted phenylene, optionally substituted indolediyl, optionally substituted benzofurandiyl, optionally substituted benzothiophenediyl, optionally substituted furandyl Or an HDL-elevating agent containing the compound according to (1) or (2), a pharmaceutically acceptable salt thereof, or a solvate thereof, which is an optionally substituted thiophenediyl;
(14) Y ³ is a single bond, optionally substituted lower alkylene, —O—optionally substituted lower alkylene or optionally substituted lower alkenylene, according to (1) or (2) An HDL elevating agent containing a compound, a pharmaceutically acceptable salt thereof or a solvate thereof,
(15) The compound according to (1) or (2), a pharmaceutically acceptable salt thereof or a compound thereof, wherein Z ² is COOR ³ (wherein R ³ is hydrogen or optionally substituted lower alkyl) An HDL raising agent containing a solvate of
(16) Formula:

Is the formula:

[Where:
R ¹ is hydrogen;
R ² is an optionally substituted aryl, or R ¹ and R ² are fused heteroaryl substituted together with a 5-membered ring containing adjacent carbon atoms, X ¹ and X ³ as constituent atoms. May form,
X ¹ is N or CR ¹⁰ (where R ¹⁰ is hydrogen);
X ³ is O or S],
Y ¹ is a single bond,
Ring A is

[Wherein X ⁴ is N and X ⁵ is NR ¹⁶ or CR ¹⁷ R ¹⁸ (where R ^{16 to} R ¹⁸ are each independently hydrogen, optionally substituted lower alkyl, cyano, substituted May be a non-aromatic heterocyclic group, an optionally substituted heteroaryl, an optionally substituted amino, an optionally substituted lower alkoxy, an aryl lower alkyl or an optionally substituted cycloalkyl; Yes). Each R ⁴ is independently halogen, optionally substituted lower alkyl, optionally substituted lower alkenyl, optionally substituted lower alkynyl, optionally substituted lower alkoxy, or substituted And m is an integer of 0-2. Bond from X ⁴ is bonded to Y ^1, the other bond is bound to Y ^2. Bonds of the other side may be bonded to X ^5. Is a group represented by
Formula: ^-Y 2 Z ¹ - is

A group represented by
R ⁸ and R ⁹ are each independently hydrogen or lower alkyl,
n is an integer from 0 to 2,
Z ¹ is a single bond, —O— or —S—,
Ring B may be substituted phenylene (substituent is halogen, lower alkyl or lower alkoxy), may be substituted furanyl (substituent is halogen, lower alkyl or lower alkoxy) or substituted Optionally substituted thiophenediyl (as a substituent, halogen, lower alkyl or lower alkoxy),
Y ³ is a single bond, optionally substituted lower alkylene (substituent is halogen or lower alkylene), -O-optionally substituted lower alkylene (substituent is lower alkylene or halogen), substituted Lower alkenylene which may be substituted (as the substituent, lower alkylene or halogen),
An HDL-elevating agent containing the compound according to (1), a pharmaceutically acceptable salt thereof or a solvate thereof, wherein Z ² is COOR ³ (wherein R ³ is hydrogen or lower alkyl);
(17) Formula:

Is the formula:

(Where
R ¹ is independently hydrogen, halogen, hydroxy, optionally substituted lower alkyl, optionally substituted lower alkenyl, optionally substituted lower alkynyl, or optionally substituted lower alkoxy. ,
R ² is alkyl which may be substituted or aryl which may be substituted, and X ¹ is N or CR ¹⁹ ,
X ³ is N or CR ²⁰
Wherein R ¹⁹ and R ²⁰ are each independently hydrogen or optionally substituted lower alkyl, provided that either X ¹ or X ³ is N. And
Y ¹ is a single bond,
Ring A is

[Wherein X ⁴ is N and X ⁵ is NR ¹⁶ or CR ¹⁷ R ¹⁸ (where R ^{16 to} R ¹⁸ are each independently hydrogen, optionally substituted lower alkyl, cyano, substituted May be a non-aromatic heterocyclic group, an optionally substituted heteroaryl, an optionally substituted amino, an optionally substituted lower alkoxy, an aryl lower alkyl or an optionally substituted cycloalkyl; Yes). Each R ⁴ is independently halogen, optionally substituted lower alkyl, optionally substituted lower alkenyl, optionally substituted lower alkynyl, optionally substituted lower alkoxy, or substituted And m is an integer of 0-2. Bond from X ⁴ is bonded to Y ^1, the other bond is bound to Y ^2. Bonds of the other side may be bonded to X ^5. Is a group represented by
Formula: ^-Y 2 Z ¹ - is

A group represented by
R ⁸ and R ⁹ are each independently hydrogen or lower alkyl,
n is an integer from 0 to 2,
Z ¹ is a single bond, —O— or —S—,
Ring B may be substituted phenylene (substituent is halogen, lower alkyl or lower alkoxy), may be substituted furanyl (substituent is halogen, lower alkyl or lower alkoxy) or substituted Optionally substituted thiophenediyl (as a substituent, halogen, lower alkyl or lower alkoxy),
Y ³ is a single bond, optionally substituted lower alkylene (substituent is halogen or lower alkylene), -O-optionally substituted lower alkylene (substituent is lower alkylene or halogen), substituted Lower alkenylene which may be substituted (as the substituent, lower alkylene or halogen),
An HDL-elevating agent containing the compound according to (1), a pharmaceutically acceptable salt thereof or a solvate thereof, wherein Z ² is COOR ³ (wherein R ³ is hydrogen or lower alkyl);
(18) Y ¹ is a single bond,
Ring A is

(R ⁴ is each independently halogen, optionally substituted lower alkyl, optionally substituted lower alkenyl, optionally substituted lower alkynyl or optionally substituted lower alkoxy, m Is an integer of 1 or 2.)
Formula: ^-Y 2 Z ¹ - is

A group represented by
R ⁸ and R ⁹ are each independently hydrogen or lower alkyl,
n is an integer of 1 to 2,
Z ¹ is a single bond or —O—,
Ring B is an optionally substituted phenylene,
Y ³ is optionally substituted lower alkylene (substituent is halogen or lower alkylene) or —O-substituted lower alkylene (substituent is lower alkylene or halogen);
An HDL-elevating agent containing the compound according to (1), a pharmaceutically acceptable salt thereof or a solvate thereof, wherein Z ² is COOR ³ (wherein R ³ is hydrogen or lower alkyl);
(19) Y ¹ is a single bond,
Ring A is

(R ¹⁷ is optionally substituted lower alkyl, cyano, optionally substituted non-aromatic heterocyclic group, optionally substituted heteroaryl, optionally substituted amino, substituted A lower alkoxy group which may be substituted, an aryl lower alkyl group or an optionally substituted cycloalkyl group, a bond from N is bonded to Y ^1, and a bond from C is bonded to Y ² . And
Formula: ^-Y 2 Z ¹ - is

A group represented by
R ⁸ and R ⁹ are each independently hydrogen or lower alkyl,
n is 2,
Z ¹ is —O—,
Ring B is an optionally substituted phenylene,
Y ³ is optionally substituted lower alkylene (substituent is halogen or lower alkylene) or —O-substituted lower alkylene (substituent is lower alkylene or halogen);
An HDL-elevating agent containing the compound according to (1), a pharmaceutically acceptable salt thereof or a solvate thereof, wherein Z ² is COOR ³ (wherein R ³ is hydrogen or lower alkyl);
I will provide a.

Furthermore, arteriosclerosis containing the above compound, pharmaceutically acceptable salt or solvate thereof, especially coronary artery disease such as myocardial infarction and angina, hyperlipidemia, diabetes, obesity, atherosclerosis A therapeutic and / or prophylactic agent for hyperglycemia and / or syndrome X is provided.
In addition, a method for increasing HDL characterized by administering the above compound, a pharmaceutically acceptable salt thereof or a solvate thereof, specifically arteriosclerosis, particularly coronary artery disease such as myocardial infarction or angina pectoris, high Methods of treating and / or preventing lipemia, diabetes, obesity, atherosclerosis, hyperglycemia and / or syndrome X are provided.

  As another aspect, a medicament for increasing HDL, particularly arteriosclerosis, especially coronary artery disease such as myocardial infarction and angina, hyperlipidemia, diabetes, obesity, atherosclerosis, hyperglycemia and / or syndrome There is provided use of the above compound, a pharmaceutically acceptable salt thereof or a solvate thereof for the manufacture of a medicament for the treatment and / or prevention of X.

  As will be apparent from the test results described below, the compound used in the present invention exhibits an HDL-elevating action and a PPAR agonistic action, and the compound used in the present invention is a pharmaceutical, particularly coronary arteries such as arteriosclerosis, especially myocardial infarction and angina. It is very useful as a medicament for the treatment and / or prevention of diseases, hyperlipidemia, diabetes, obesity, atherosclerosis, hyperglycemia and / or syndrome X.

Each term used in this specification is explained below. In addition, in this specification, each term has the same meaning, whether it is used alone or when used together with other terms.
“HDL” is an abbreviation for high density lipoprotein and means plasma lipoprotein having a density of 1.063 to 1.21 g / mL. Apolipoproteins (AI, A-II, C, E) are the main proteins. HDL has the effect of receiving cholesterol accumulated in peripheral tissues from cells and transferring it to the liver, and is thought to have anti-atherogenic effects.
In the present specification, “HDL increase” means an increase in HDL cholesterol. That is, the “HDL raising agent” means a drug having an action of raising HDL cholesterol. The “HDL raising agent” means a pharmaceutical composition having an HDL raising action.

“Monocyclic aryl” means a monocyclic aromatic carbocyclic group composed of 6 to 12 carbon atoms, and examples thereof include phenyl.
“Condensed aryl” refers to a monocyclic aromatic carbocyclic group consisting of 6 to 12 carbon atoms, to 1 to 4 monocyclic aromatic carbocycles (from 6 to 12 carbon atoms). A monocyclic aromatic carbocyclic ring) is condensed, and examples thereof include naphthyl, anthryl, phenanthryl and the like. Any ring may have a bond. Naphthyl is preferable.
“Aryl” means the above “monocyclic aryl” and the above “fused aryl”.
“Aralkyl” means the above “alkyl” substituted with 1 to 3 above “aryl”. Examples include benzyl, phenethyl, phenylpropyl, trityl and the like.

“Monocyclic heteroaryl” means a 4- to 8-membered monocyclic aromatic heterocyclic group having one or more heteroatoms arbitrarily selected from O, S and N in the ring, specifically Examples include pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazolyl, triazinyl, tetrazolyl, isoxazolyl, oxazolyl, oxadiazolyl, isothiazolyl, thiazolyl, thiadiazolyl, furyl, thienyl and the like. In particular, a 5-membered or 6-membered monocyclic aromatic heterocyclic group is preferable.
“Fused heteroaryl” refers to a monocyclic aromatic heterocycle derived from the above “monocyclic heteroaryl” and an aromatic carbocycle (aromatic carbocycle derived from the above “aryl”) or an aromatic heterocycle ( Means a group derived from a condensed aromatic heterocycle condensed with a 4- to 8-membered aromatic heterocycle having one or more heteroatoms arbitrarily selected from O, S and N in the ring; Isoindolyl, indazolyl, indolizinyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl, naphthyridinyl, quinoxalinyl, purinyl, pteridinyl, benzopyranyl, benzimidazolyl, benzisoxazolyl, benzoxazozolyl, benzoisothiazolyl, benzoisothiazolyl Benzothiazolyl, benzothiadiazolyl, benzof , Isobenzofuryl, benzothienyl, benzotriazolyl, imidazopyridyl, triazolopyridyl, imidazothiazolyl, pyrazinopyridazinyl, quinazolinyl, tetrahydroquinolyl, tetrahydrobenzothienyl, carbazolyl, acridinyl, xanthenyl, pheno Thiazinyl, phenoxathiinyl, phenoxazinyl, dibenzofuryl and the like can be mentioned. In the case of “fused heteroaryl”, any ring may have a bond. In particular, condensed heteroaryl in which a benzene ring is condensed to a 5-membered or 6-membered monocyclic aromatic heterocycle is preferable.
“Heteroaryl” means the above “monocyclic heteroaryl” and “fused heteroaryl”.
“Heteroaralkyl” means the above “alkyl” substituted with 1 to 3 of the above “heteroaryl”.
The “non-aromatic heterocyclic group” is a 4- to 8-membered monocyclic non-aromatic heterocyclic group having one or more hetero atoms arbitrarily selected from O, S and N in the ring, or the above “ The “monocyclic non-aromatic heterocyclic group” is an aromatic carbocycle (aromatic carbocycle derived from the above “aryl”), an aromatic heterocycle (heteroatom optionally selected from O, S and N) 4- to 8-membered aromatic heterocycle having one or more thereof), monocyclic non-aromatic heterocycle (monocyclic non-aromatic heterocycle derived from the above “monocyclic non-aromatic heterocyclic group”) , A fused non-aromatic heterocyclic group condensed with a cycloalkane (a ring derived from “cycloalkyl” below), specifically indolinyl, dioxanyl, thiranyl, oxiranyl, oxathiolanyl, azetidinyl, thianyl, Pyrrolidinyl, pyrrolinyl, imi Zorijiniru, imidazolinyl, pyrazolidinyl, pyrazolinyl, piperidyl, piperidino, piperazinyl, piperazino, morpholinyl, morpholino, oxadiazinyl, dihydropyridyl, and the like.
The “heterocyclic group” includes the above “heteroaryl” and the above “non-aromatic heterocyclic group”. For example, morpholino, piperidino, piperazino, furyl, thienyl, pyridyl and the like are included.

［ここで、Ｘ^４はＮまたはＣＲ^５（ここでＲ^５は水素または置換されていてもよい低級アルキルである）であり、Ｘ^５はＯ、Ｓ、ＮＲ^１６またはＣＲ^１７Ｒ^１８（ここでＲ^１６〜Ｒ^１８はそれぞれ独立して水素、置換されていてもよい低級アルキル、置換されていてもよい非芳香族へテロ環式基、置換されていてもよいヘテロアリール、置換されていてもよいアミノ、置換されていてもよい低級アルコキシ、アリール低級アルキルまたは置換されていてもよいシクロアルキルである）である。但し、Ｘ^４がＣＲ^５かつＸ^５がＣＲ^１７Ｒ^１８の場合は除く。Ｒ^４は各々独立して、ハロゲン、置換されていてもよい低級アルキル、置換されていてもよい低級アルケニル、置換されていてもよい低級アルキニル、置換されていてもよい低級アルコキシまたは置換されていてもよいアリールであり、ｍは０〜２の整数である。］
なお、上記において、Ｘ^４から伸びる結合手はＹ^１に結合し、他方の結合手はＹ^２に結合する。Ｘ^５がＮＲ^１６またはＣＲ^１７Ｒ^１８である場合、該他方の結合手がＸ^５に結合する場合も含まれる。該他方の結合手は、Ｘ^５に結合する場合が好ましい。 “Non-aromatic heterodiyl” means removing two hydrogen atoms from a 4- to 10-membered non-aromatic heterocycle having one or more heteroatoms arbitrarily selected from O, S and N in the ring A divalent group formed. The non-aromatic heterocycle may be crosslinked with alkylene. Preferred are piperidine diyl, piperazine diyl, morpholine diyl, dioxane diyl, pyrrolidine diyl, pyrroline diyl, imidazoline diyl, imidazolidine diyl and the like. For example, as the “non-aromatic heterocyclic diyl” of ring A, the following groups are exemplified.

[Wherein X ⁴ is N or CR ⁵ (where R ⁵ is hydrogen or optionally substituted lower alkyl) and X ⁵ is O, S, NR ¹⁶ or CR ¹⁷ R ¹⁸ (where R ^{16 to} R ¹⁸ are each independently hydrogen, an optionally substituted lower alkyl, an optionally substituted non-aromatic heterocyclic group, an optionally substituted heteroaryl, or an optionally substituted A good amino, an optionally substituted lower alkoxy, an aryl lower alkyl or an optionally substituted cycloalkyl). However, the case where X ⁴ is CR ⁵ and X ⁵ is CR ¹⁷ R ¹⁸ is excluded. Each R ⁴ is independently halogen, optionally substituted lower alkyl, optionally substituted lower alkenyl, optionally substituted lower alkynyl, optionally substituted lower alkoxy, or substituted And m is an integer of 0-2. ]
In the above, bonds extending from X ⁴ is bonded to Y ^1, the other bond is bonded to Y ^2. In the case where X ⁵ is NR ¹⁶ or CR ¹⁷ R ¹⁸ , the case where the other bond is bonded to X ⁵ is also included. Bonds of said other, when bound to X ⁵ are preferred.

（式中、各記号は、上記と同意義。） “When X ⁵ is NR ¹⁶ , the other bond is bonded to X ⁵ ” means the following.

(In the formula, each symbol has the same meaning as above.)

（式中、各記号は、上記と同意義。） “When X ⁵ is CR ¹⁷ R ¹⁸ , the other bond is bonded to X ⁵ ” means the following.

(In the formula, each symbol has the same meaning as above.)

  The “aromatic carbocyclic diyl” includes a divalent group formed by removing one hydrogen atom from the above “aryl”. Examples thereof include phenylene and naphthylene, and phenylene is preferable.

  The “aromatic heterocyclic diyl” includes a divalent group formed by removing one hydrogen atom from the above “heteroaryl”. Specifically, pyrrole diyl, imidazole diyl, pyrazole diyl, pyridine diyl, pyridazine diyl, pyrimidine diyl, pyrazine diyl, triazole diyl, triazine diyl, isoxazole diyl, oxazole diyl, oxadiazole diyl, isothiazole diyl, thiazole diyl, thiadiazole diyl , Flangedyl, thiophenediyl, indolediyl, benzofurandiyl, benzothiophenediyl and the like. Preferred are indolediyl, benzofurandiyl, benzothiophenediyl, frangiyl, and thiophenediyl, particularly monocyclic aromatic heterocyclic diyl, and further flangedyl (particularly furan-2,5-diyl). Thiophenediyl (particularly thiophene-2,5-diyl) is preferred.

  “Lower alkyl” includes linear or branched alkyl having 1 to 10 carbon atoms, preferably 1 to 6 carbon atoms, more preferably 1 to 4 carbon atoms, such as methyl, ethyl, n-propyl. , Isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, hexyl, isohexyl, n-heptyl, isoheptyl, n-octyl, isooctyl, n-nonyl and n-decyl, etc. Is mentioned.

  “Lower alkenyl” is a linear or branched alkenyl having 2 to 10 carbon atoms, preferably 2 to 6 carbon atoms, more preferably 2 to 4 carbon atoms, having one or more double bonds at any position. Is included. Specific examples include vinyl, propenyl, isopropenyl, butenyl, isobutenyl, prenyl, butadienyl, pentenyl, isopentenyl, pentadienyl, hexenyl, isohexenyl, hexadienyl, heptenyl, octenyl, nonenyl and decenyl.

  “Lower alkynyl” means linear or branched alkynyl having 2 to 10 carbon atoms, preferably 2 to 6 carbon atoms, more preferably 2 to 4 carbon atoms, specifically, ethynyl, Includes propynyl, butynyl, pentynyl, hexynyl, heptynyl, octynyl, nonynyl, decynyl and the like. These have one or more triple bonds at arbitrary positions, and may further have a double bond.

  “Cycloalkyl” includes cycloalkyl having 3 to 9, preferably 3 to 6 carbon atoms. Specific examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.

  “Cycloalkylene” includes cycloalkylene having 3 to 9, preferably 3 to 6 carbon atoms. Specific examples include cyclopropylene, cyclobutylene, cyclopentylene, cyclohexylene, cycloheptylene, and cyclooctylene. Particularly preferred is cyclopropylene.

で示される基等が挙げられる。 The “cycloalkylene optionally having —O—” means a cycloalkylene in which one or two —O— may be present at the terminal of the “cycloalkylene”. For example,

The group etc. which are shown are mentioned.

  “Acyl” means (a) carbonyl substituted with the above “alkyl” or carbonyl substituted with the above “alkenyl”, (b) carbonyl substituted with the “cycloalkyl”, (c) carbonyl substituted with the “aryl” And (d) formyl. Specific examples include formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, pivaloyl, hexanoyl, acryloyl, propioyl, methacryloyl, crotonoyl, cyclopropylcarbonyl, cyclohexylcarbonyl, cyclooctylcarbonyl and benzoyl.

  The “lower alkylene” includes linear or branched alkylene having 1 to 10 carbon atoms, preferably 1 to 6 carbon atoms, and more preferably 1 to 3 carbon atoms. Specific examples include methylene, ethylene, trimethylene, tetramethylene, pentamethylene, hexamethylene, methylmethylene, propylene, dimethylmethylene, 1,1-dimethylethylene, 1,2-dimethylethylene, and the like. Particularly preferred are methylene, ethylene and dimethylmethylene.

The “lower alkylene optionally having —O—” means alkylene in which 1 to 3 —O— may be present in a part of the “alkylene”. In addition, those in which —O— is present at the terminal of alkylene are also included. For _{example, -O-CH 2 -, -} CH 2 -O -, - CH 2 -O-CH 2 -, - O-CH 2 -CH 2 -, - CH 2 -CH 2 -O -, - O-CH (CH ₃ ) —, —O—C (CH ₃ ) ₂ —, —O—CH ₂ —CH ₂ —O—, —O—CH (CH ₃ ) —O—, —O—C (CH ₃ ) ₂ -O- and the like.
“Lower alkylene which may be substituted with —O-” means one in which —O— is present at the end of alkylene.

  “Lower alkenylene” means a linear or branched alkenylene having 2 to 10 carbon atoms, preferably 2 to 6 carbon atoms, more preferably 2 to 4 carbon atoms, having one or more double bonds at any position. Is included. For example, vinylene, propenylene and the like can be mentioned.

  “Halogen” includes fluorine, chlorine, bromine and iodine. Particularly preferred are fluorine, chlorine and bromine.

  The alkyl part of “lower alkoxy” has the same meaning as the above “lower alkyl”.

“Optionally substituted lower alkyl”, “optionally substituted lower alkylsulfonyl”, “optionally substituted lower alkenyl”, “optionally substituted lower alkynyl”, “substituted” Substituents of “lower alkylene”, “optionally substituted lower alkenylene”, “optionally substituted lower alkoxy”, and “optionally substituted acyl” include halogen, hydroxy, substituted Optionally substituted lower alkoxy, optionally substituted lower alkynyloxy, optionally substituted amino, mercapto, optionally substituted lower alkylthio, acyl, acyloxy, optionally substituted imino, carboxy, substituted Optionally substituted lower alkoxycarbonyl, optionally substituted carbamoyl, substituted Optionally substituted thiocarbamoyl, optionally substituted carbamoyloxy, optionally substituted thiocarbamoyloxy, optionally substituted sulfamoyl, optionally substituted lower alkylsulfonyl, optionally substituted lower Alkylsulfonyloxy, cyano, nitro, optionally substituted cycloalkyl, optionally substituted cycloalkyloxy, optionally substituted aryl, optionally substituted aryloxy, optionally substituted Arylthio, optionally substituted arylsulfonyl, optionally substituted arylsulfonyloxy, optionally substituted heterocyclic group, optionally substituted heterocyclic oxy, optionally substituted lower alkylene , Optionally substituted lower alkylenedio Shi, oxo and the like, may be substituted with one or more groups arbitrary position is selected from these. When the lower alkylene which may be substituted, or the lower alkylenedioxy which may be substituted is a substituent, two bonds may be bonded to one carbon atom to form a spiro ring, It may be bonded to different atoms and may form a ring together with adjacent carbon atoms.
The heterocyclic moiety of “heterocyclic oxy” is the same as the above “heterocyclic group”.

“Optionally substituted monocyclic aryl”, “optionally substituted monocyclic heteroaryl”, “optionally substituted aryl”, “optionally substituted aralkyl”, “substituted” May be aryloxy "," optionally substituted arylthio "," optionally substituted heteroaryl "," optionally substituted heteroaralkyl "," optionally substituted heteroaryloxy ", “Optionally substituted heteroarylthio”, “substituted fused aryl”, “substituted fused heteroaryl”, “optionally substituted arylsulfonyl”, “optionally substituted aromatic carbon” The substituents of “ring diyl”, “optionally substituted aromatic heterocyclic diyl” and “optionally substituted non-aromatic heterocyclic group” include substituted Optionally substituted lower alkyl, optionally substituted lower alkenyl, optionally substituted lower alkenyl, optionally substituted lower alkenyloxy, halogen, hydroxy, optionally substituted lower alkoxy, substituted Optionally substituted lower alkynyloxy, optionally substituted amino, mercapto, optionally substituted lower alkylthio, acyl, acyloxy, optionally substituted imino, carboxy, optionally substituted lower alkoxycarbonyl , Optionally substituted carbamoyl, optionally substituted thiocarbamoyl, optionally substituted carbamoyloxy, optionally substituted thiocarbamoyloxy, optionally substituted sulfamoyl, optionally substituted Good lower alkylsulfonyl, Optionally substituted lower alkylsulfonyloxy, cyano, nitro, optionally substituted cycloalkyl, optionally substituted cycloalkyloxy, optionally substituted aryl, optionally substituted aryloxy, Optionally substituted arylthio, optionally substituted arylsulfonyl, optionally substituted arylsulfonyloxy, optionally substituted heterocyclic group, optionally substituted heterocyclic oxy, substituted Lower alkylene which may be substituted, and lower alkylenedioxy which may be substituted may be mentioned, and any position may be substituted with one or more groups selected from these. When the lower alkylene which may be substituted or the lower alkylenedioxy which may be substituted is a substituent, they may be bonded to separate atoms to form a ring together with adjacent carbon atoms.
Among the above substituents, preferably, halogen, hydroxy, optionally substituted lower alkyl (the substituent is halogen, hydroxy), optionally substituted lower alkenyl (the substituent is halogen, Hydroxy), optionally substituted lower alkoxy (substituents are halogen, aryl), carboxy, lower alkoxycarbonyl, optionally substituted carbamoyl (substituents are lower alkyl, aryl), substituted May be amino (substituents are acyl, lower alkyl), mercapto, lower alkylthio, acyl, acyloxy, cyano, nitro, aryl, heterocyclic group, lower alkylene, lower alkylenedioxy, particularly halogen, Optionally substituted lower alkyl (substituent Gen) is preferable.
“Substituted benzofuryl”, “substituted benzothienyl”, “substituted benzopyrrolyl”, “substituted benzoxazolyl”, “substituted benzoisoxazolyl”, “substituted benzothiazolyl”, The substituents of “substituted benzoisothiazolyl”, “substituted benzimidazolyl”, and “substituted benzopyrazolyl” are the same as the substituents of the above “substituted condensed heteroaryl”.
The substituent of “optionally substituted phenylene” has the same meaning as the substituent of “optionally substituted aromatic carbocyclic diyl”.
"Optionally substituted indolediyl", "optionally substituted benzofurandiyl", "optionally substituted benzothiophenediyl", "optionally substituted furanyl", "substituted The substituent of “may be thiophenediyl” has the same meaning as the substituent of “optionally substituted aromatic heterocyclic diyl”.

  Substituents of “optionally substituted non-aromatic heterocyclic diyl” are halogen, hydroxy, optionally substituted lower alkoxy, optionally substituted lower alkynyloxy, optionally substituted amino, Mercapto, optionally substituted lower alkylthio, acyl, acyloxy, optionally substituted imino, carboxy, optionally substituted lower alkoxycarbonyl, optionally substituted carbamoyl, optionally substituted thio Carbamoyl, optionally substituted carbamoyloxy, optionally substituted thiocarbamoyloxy, optionally substituted sulfamoyl, optionally substituted lower alkylsulfonyl, optionally substituted lower alkylsulfonyloxy, Cyano, nitro, optionally substituted Chloroalkyl, optionally substituted cycloalkyloxy, optionally substituted aryl, optionally substituted aryloxy, optionally substituted arylthio, optionally substituted arylsulfonyl, substituted Arylsulfonyloxy which may be substituted, heterocyclic group which may be substituted, heterocyclic oxy which may be substituted, lower alkylene which may be substituted, lower alkylenedioxy which may be substituted, oxo And any position may be substituted with one or more groups selected from these. When the lower alkylene which may be substituted, or the lower alkylenedioxy which may be substituted is a substituent, two bonds may be bonded to one carbon atom to form a spiro ring, It may be bonded to different atoms and may form a ring together with adjacent carbon atoms.

  “Optionally substituted lower alkynyloxy”, “optionally substituted lower alkylthio”, “optionally substituted lower alkoxycarbonyl”, “optionally substituted lower alkylsulfonyloxy”, “substituted” Optionally substituted cycloalkyl "," optionally substituted cycloalkyloxy "," optionally substituted arylsulfonyl "," optionally substituted arylsulfonyloxy "," optionally substituted sulfonyloxy " The substituent of “good heterocyclic group”, “optionally substituted heterocyclic oxy”, and “optionally substituted lower alkylenedioxy” is the same as the substituent of the above “optionally substituted lower alkyl”. It is the same.

  “Optionally substituted amino”, “optionally substituted imino”, “optionally substituted carbamoyl”, “optionally substituted thiocarbamoyl”, “optionally substituted carbamoyloxy” Examples of the substituent of “optionally substituted thiocarbamoyloxy” and “optionally substituted sulfamoyl” include those similar to the above “optionally substituted lower alkyl”. These substituents may be mono- or di-substituted on the nitrogen atom. In particular, lower alkyl, aryl, heterocyclic group, acyl, lower alkoxycarbonyl, lower alkylsulfonyl, and arylsulfonyl are preferable.

  Below, the preferable aspect of each substituent of the compound shown by a formula (I) is demonstrated.

Ring Q is an optionally substituted monocyclic aryl, an optionally substituted monocyclic heteroaryl, an optionally substituted fused aryl or an optionally substituted fused heteroaryl, preferably at least substituted with one R ^2, may be further substituted monocyclic aryl, substituted with at least one of R ^2, each R ² is halogen further optionally substituted monocyclic heteroaryl (wherein Alkyl which may be substituted, aryl which may be substituted, aralkyl which may be substituted, aryloxy which may be substituted, arylthio which may be substituted, heteroaryl which may be substituted, Optionally substituted heteroaralkyl, optionally substituted heteroaryloxy or optionally substituted heteroaryl A Ruchio) a fused aryl or substituted fused heteroaryl substituted. In particular, monocyclic heteroaryl substituted with one R ² and further substituted (where R ² is halogen, optionally substituted alkyl, optionally substituted aryl), substituted Preferred are fused fused aryl or substituted fused heteroaryl.
“It may be further substituted” means that it may have a substituent in addition to the substituent R ² . The substituent may be the same substituent as R ² .
Substituted fused heteroaryls include substituted benzofuryl, substituted benzothienyl, substituted benzopyrrolyl, substituted benzoxazolyl, substituted benzoisoxazolyl, substituted benzothiazolyl, substituted Examples thereof include benzoisothiazolyl, substituted benzimidazolyl or substituted benzopyrazolyl, particularly preferably substituted benzothiazolyl (substituents are halogen, optionally substituted lower alkyl, optionally substituted lower Alkoxy, aryl, lower alkylsulfonyl, and optionally substituted carbamoyl).

［式中、
Ｒ^１は水素、ハロゲン、ヒドロキシ、置換されていてもよい低級アルキル、置換されていてもよい低級アルケニル、置換されていてもよい低級アルキニル、置換されていてもよい低級アルコキシまたは置換されていてもよいアリールであり、
Ｒ^２はハロゲン、置換されていてもよいアルキル、置換されていてもよいアリール、置換されていてもよいアリールオキシ、置換されていてもよいアリールチオまたは置換されていてもよいヘテロアリールであり、
または、Ｒ^１およびＲ^２は隣接する炭素原子と一緒になって置換されていてもよい環を形成してもよく、
Ｘ^１はＮまたはＣＲ^１０、
Ｘ^３はＮＲ^１１、ＯまたはＳ、
（ここでＲ^１０及びＲ^１１は各々独立して水素または置換されていてもよい低級アルキルである）である］で示される基、
式：

［式中、
Ｒ^１は水素、ハロゲン、ヒドロキシ、置換されていてもよい低級アルキル、置換されていてもよい低級アルケニル、置換されていてもよい低級アルキニルまたは置換されていてもよい低級アルコキシであり、
Ｒ^２はハロゲン、置換されていてもよいアルキル、置換されていてもよいアリール、置換されていてもよいアリールオキシ、置換されていてもよいアリールチオまたは置換されていてもよいヘテロアリールであり、
または、Ｒ^１およびＲ^２は隣接する炭素原子と一緒になって置換されていてもよい環を形成してもよく、
Ｘ^１はＮまたはＣＲ^１２、
Ｘ^３はＮＲ^１３、ＯまたはＳ、
（ここでＲ^１２およびＲ^１３は各々独立して水素または置換されていてもよい低級アルキルである）である］で示される基、または
式：

［式中、
Ｒ^１はそれぞれ独立して水素、ハロゲン、ヒドロキシ、置換されていてもよい低級アルキル、置換されていてもよい低級アルケニル、置換されていてもよい低級アルキニルまたは置換されていてもよい低級アルコキシであり、
Ｒ^２はハロゲン、置換されていてもよいアルキル、置換されていてもよいアリール、置換されていてもよいアリールオキシ、置換されていてもよいアリールチオまたは置換されていてもよいヘテロアリールであり、
Ｘ^１はＮまたはＣＲ^１９、
Ｘ^３はＮまたはＣＲ^２０
（ここでＲ^１９およびＲ^２０は各々独立して水素または置換されていてもよい低級アルキルである。但し、Ｘ^１またはＸ^３のいずれか一方はＮである。）である。］
で示される基が好ましい。 As the ring Q, the following are particularly preferable. formula:

[Where:
R ¹ is hydrogen, halogen, hydroxy, optionally substituted lower alkyl, optionally substituted lower alkenyl, optionally substituted lower alkynyl, optionally substituted lower alkoxy, or optionally substituted Good aryl,
R ² is halogen, optionally substituted alkyl, optionally substituted aryl, optionally substituted aryloxy, optionally substituted arylthio or optionally substituted heteroaryl;
Or R ¹ and R ² together with adjacent carbon atoms may form an optionally substituted ring;
X ¹ is N or CR ¹⁰ ,
X ³ is NR ¹¹ , O or S,
Wherein R ¹⁰ and R ¹¹ are each independently hydrogen or optionally substituted lower alkyl.]
formula:

[Where:
R ¹ is hydrogen, halogen, hydroxy, optionally substituted lower alkyl, optionally substituted lower alkenyl, optionally substituted lower alkynyl, or optionally substituted lower alkoxy,
R ² is halogen, optionally substituted alkyl, optionally substituted aryl, optionally substituted aryloxy, optionally substituted arylthio or optionally substituted heteroaryl;
Or R ¹ and R ² together with adjacent carbon atoms may form an optionally substituted ring;
X ¹ is N or CR ¹² ,
X ³ is NR ¹³ , O or S,
Wherein R ¹² and R ¹³ are each independently hydrogen or optionally substituted lower alkyl, or a group of the formula:

[Where:
R ¹ is independently hydrogen, halogen, hydroxy, optionally substituted lower alkyl, optionally substituted lower alkenyl, optionally substituted lower alkynyl, or optionally substituted lower alkoxy. ,
R ² is halogen, optionally substituted alkyl, optionally substituted aryl, optionally substituted aryloxy, optionally substituted arylthio or optionally substituted heteroaryl;
X ¹ is N or CR ¹⁹ ,
X ³ is N or CR ²⁰
(Wherein R ¹⁹ and R ²⁰ are each independently hydrogen or optionally substituted lower alkyl, provided that either X ¹ or X ³ is N). ]
Is preferred.

（Ｒは、置換されていてもよい低級アルキル、置換されていてもよい低級アルケニル、置換されていてもよい低級アルケニル、置換されていてもよい低級アルケニルオキシ、ハロゲン、ヒドロキシ、置換されていてもよい低級アルコキシ、置換されていてもよい低級アルキニルオキシ、置換されていてもよいアミノ、メルカプト、置換されていてもよい低級アルキルチオ、アシル、アシルオキシ、置換されていてもよいイミノ、カルボキシ、置換されていてもよい低級アルコキシカルボニル、置換されていてもよいカルバモイル、置換されていてもよいチオカルバモイル、置換されていてもよいカルバモイルオキシ、置換されていてもよいチオカルバモイルオキシ、置換されていてもよいスルファモイル、置換されていてもよい低級アルキルスルホニル、置換されていてもよい低級アルキルスルホニルオキシ、シアノ、ニトロ、置換されていてもよいシクロアルキル、置換されていてもよいシクロアルキルオキシ、置換されていてもよいアリール、置換されていてもよいアリールオキシ、置換されていてもよいアリールチオ、置換されていてもよいアリールスルホニル、置換されていてもよいアリールスルホニルオキシ、置換されていてもよいヘテロ環式基、置換されていてもよいヘテロ環オキシであり、Ｒ’は水素または上記Ｒと同意義である。ただし、Ｒ’が上記Ｒから選択される基である場合は、Ｒは水素でもよい。） As the “substituted condensed heteroaryl” of ring Q, the following embodiments are also preferred.

(R is optionally substituted lower alkyl, optionally substituted lower alkenyl, optionally substituted lower alkenyl, optionally substituted lower alkenyloxy, halogen, hydroxy, optionally substituted. Good lower alkoxy, optionally substituted lower alkynyloxy, optionally substituted amino, mercapto, optionally substituted lower alkylthio, acyl, acyloxy, optionally substituted imino, carboxy, substituted Lower alkoxycarbonyl which may be substituted, carbamoyl which may be substituted, thiocarbamoyl which may be substituted, carbamoyloxy which may be substituted, thiocarbamoyloxy which may be substituted, sulfamoyl which may be substituted , Optionally substituted lower alkyl Sulfonyl, optionally substituted lower alkylsulfonyloxy, cyano, nitro, optionally substituted cycloalkyl, optionally substituted cycloalkyloxy, optionally substituted aryl, optionally substituted Aryloxy, optionally substituted arylthio, optionally substituted arylsulfonyl, optionally substituted arylsulfonyloxy, optionally substituted heterocyclic group, optionally substituted heterocyclic oxy And R ′ has the same meaning as hydrogen or R. However, when R ′ is a group selected from R, R may be hydrogen.)

（Ｒ^１は水素、ハロゲン、ヒドロキシ、置換されていてもよい低級アルキル、置換されていてもよい低級アルケニル、置換されていてもよい低級アルキニル、置換されていてもよい低級アルコキシまたは置換されていてもよいアリールであり、Ｒ及びＲ’は各々独立して水素、ハロゲン、ヒドロキシ、置換されていてもよい低級アルコキシ、置換されていてもよい低級アルキニルオキシ、置換されていてもよいアミノ、メルカプト、置換されていてもよい低級アルキルチオ、アシル、アシルオキシ、置換されていてもよいイミノ、カルボキシ、置換されていてもよい低級アルコキシカルボニル、置換されていてもよいカルバモイル、置換されていてもよいチオカルバモイル、置換されていてもよいカルバモイルオキシ、置換されていてもよいチオカルバモイルオキシ、置換されていてもよいスルファモイル、置換されていてもよい低級アルキルスルホニル、置換されていてもよい低級アルキルスルホニルオキシ、シアノ、ニトロ、置換されていてもよいシクロアルキル、置換されていてもよいシクロアルキルオキシ、置換されていてもよいアリール、置換されていてもよいアリールオキシ、置換されていてもよいアリールチオ、置換されていてもよいアリールスルホニル、置換されていてもよいアリールスルホニルオキシ、置換されていてもよいヘテロ環式基、置換されていてもよいヘテロ環オキシ等である。） As the “monocyclic heteroaryl which is substituted with at least one R ² and may be further substituted” in the ring Q, the following embodiments are also preferable.

(R ¹ is hydrogen, halogen, hydroxy, optionally substituted lower alkyl, optionally substituted lower alkenyl, optionally substituted lower alkynyl, optionally substituted lower alkoxy, or optionally substituted R and R ′ are each independently hydrogen, halogen, hydroxy, optionally substituted lower alkoxy, optionally substituted lower alkynyloxy, optionally substituted amino, mercapto, Optionally substituted lower alkylthio, acyl, acyloxy, optionally substituted imino, carboxy, optionally substituted lower alkoxycarbonyl, optionally substituted carbamoyl, optionally substituted thiocarbamoyl, Optionally substituted carbamoyloxy, optionally substituted Ocarbamoyloxy, optionally substituted sulfamoyl, optionally substituted lower alkylsulfonyl, optionally substituted lower alkylsulfonyloxy, cyano, nitro, optionally substituted cycloalkyl, substituted Cycloalkyloxy which may be substituted, aryl which may be substituted, aryloxy which may be substituted, arylthio which may be substituted, arylsulfonyl which may be substituted, arylsulfonyloxy which may be substituted, A heterocyclic group which may be substituted, a heterocyclic oxy which may be substituted, etc.)

Y ¹ is a single bond, —NR ⁶ — or —NR ⁶ —CO— (wherein R ⁶ is hydrogen or optionally substituted lower alkyl), and a single bond is particularly preferred.

［ここでＸ^４はＮまたはＣＲ^５（ここでＲ^５は水素または置換されていてもよい低級アルキルである）であり、Ｘ^５はＯ、Ｓ、ＮＲ^１６またはＣＲ^１７Ｒ^１８（ここでＲ^１６〜Ｒ^１８はそれぞれ独立して水素、置換されていてもよい低級アルキル、シアノ、置換されていてもよい非芳香族へテロ環式基、置換されていてもよいヘテロアリール、置換されていてもよいアミノ、置換されていてもよい低級アルコキシ、アリール低級アルキルまたは置換されていてもよいシクロアルキルである）である。但し、Ｘ^４がＣＲ^５かつＸ^５がＣＲ^１７Ｒ^１８の場合は除く。Ｒ^４は各々独立して、ハロゲン、置換されていてもよい低級アルキル、置換されていてもよい低級アルケニル、置換されていてもよい低級アルキニル、置換されていてもよい低級アルコキシまたは置換されていてもよいアリールであり、ｍは０〜２の整数である。Ｘ^４からの結合手はＹ^１と結合し、他方の結合手はＹ^２と結合する。Ｘ^５がＮＲ^１６またはＣＲ^１７Ｒ^１８の場合、該他方の結合手はＸ^５と結合していてもよい。］で示される基が好ましい。より好ましくは、

［ここでＸ^４はＮまたはＣＲ^５（ここでＲ^５は水素または置換されていてもよい低級アルキルである）であり、Ｘ^５はＮＲ^１６またはＣＲ^１７Ｒ^１８（ここでＲ^１６〜Ｒ^１８はそれぞれ独立して水素、置換されていてもよい低級アルキル、シアノ、置換されていてもよい非芳香族へテロ環式基、置換されていてもよいヘテロアリール、置換されていてもよいアミノ、置換されていてもよい低級アルコキシ、アリール低級アルキルまたは置換されていてもよいシクロアルキルである）である。但し、Ｘ^４がＣＲ^５かつＸ^５がＣＲ^１７Ｒ^１８の場合は除く。Ｒ^４は各々独立して、ハロゲン、置換されていてもよい低級アルキル、置換されていてもよい低級アルケニル、置換されていてもよい低級アルキニル、置換されていてもよい低級アルコキシまたは置換されていてもよいアリールであり、ｍは０〜２の整数である。Ｘ^４からの結合手はＹ^１と結合し、他方の結合手はＹ^２と結合する。該他方の結合手はＸ^５と結合していてもよい。］で示される基である。さらに好ましくは、

［ここでＸ^４はＮであり、Ｘ^５はＮＲ^１６またはＣＲ^１７Ｒ^１８（ここでＲ^１６〜Ｒ^１８はそれぞれ独立して水素、置換されていてもよい低級アルキル、シアノ、置換されていてもよい非芳香族へテロ環式基、置換されていてもよいヘテロアリール、置換されていてもよいアミノ、置換されていてもよい低級アルコキシ、アリール低級アルキルまたは置換されていてもよいシクロアルキルである）である。Ｒ^４は各々独立して、ハロゲン、置換されていてもよい低級アルキル、置換されていてもよい低級アルケニル、置換されていてもよい低級アルキニル、置換されていてもよい低級アルコキシまたは置換されていてもよいアリールであり、ｍは０〜２の整数である。Ｘ^４からの結合手はＹ^１と結合し、他方の結合手はＹ^２と結合する。］で示される基である。特に、ｍは１〜２が好ましい。特に、Ｒ^４は各々独立して、置換されていてもよい低級アルキル、例えば、炭素数１〜４の直鎖または分枝状のアルキルが好ましい。さらに好ましくは、

（Ｒ^４は各々独立して、ハロゲン、置換されていてもよい低級アルキル、置換されていてもよい低級アルケニル、置換されていてもよい低級アルキニルまたは置換されていてもよい低級アルコキシであり、ｍは１または２の整数である。）で示される基である。または、

（Ｒ^１７は置換されていてもよい低級アルキル、シアノ、置換されていてもよい非芳香族へテロ環式基、置換されていてもよいヘテロアリール、置換されていてもよいアミノ、置換されていてもよい低級アルコキシ、アリール低級アルキルまたは置換されていてもよいシクロアルキルである。Ｎからの結合手はＹ^１と結合し、Ｃからの結合手はＹ^２と結合する。）で示される基である。 Ring A is an optionally substituted non-aromatic heterocyclic diyl (provided that when Y ¹ is a single bond, ring Q is bonded to the nitrogen atom constituting ring A),

[Wherein X ⁴ is N or CR ⁵ (where R ⁵ is hydrogen or optionally substituted lower alkyl) and X ⁵ is O, S, NR ¹⁶ or CR ¹⁷ R ¹⁸ (where R ⁵ is R ^{16 to} R ¹⁸ are each independently hydrogen, optionally substituted lower alkyl, cyano, optionally substituted non-aromatic heterocyclic group, optionally substituted heteroaryl, substituted It may be amino, optionally substituted lower alkoxy, aryl lower alkyl or optionally substituted cycloalkyl). However, the case where X ⁴ is CR ⁵ and X ⁵ is CR ¹⁷ R ¹⁸ is excluded. Each R ⁴ is independently halogen, optionally substituted lower alkyl, optionally substituted lower alkenyl, optionally substituted lower alkynyl, optionally substituted lower alkoxy, or substituted And m is an integer of 0-2. Bond from X ⁴ is bonded to Y ^1, the other bond is bound to Y ^2. When X ⁵ is NR ¹⁶ or CR ¹⁷ R ¹⁸ , the other bond may be bonded to X ⁵ . ] Is preferable. More preferably,

[Where X ⁴ is N or CR ⁵ (where R ⁵ is hydrogen or optionally substituted lower alkyl) and X ⁵ is NR ¹⁶ or CR ¹⁷ R ¹⁸ (where R ^{16 to} R ¹⁸ Are each independently hydrogen, optionally substituted lower alkyl, cyano, optionally substituted non-aromatic heterocyclic group, optionally substituted heteroaryl, optionally substituted amino, Optionally substituted lower alkoxy, aryl lower alkyl or optionally substituted cycloalkyl). However, the case where X ⁴ is CR ⁵ and X ⁵ is CR ¹⁷ R ¹⁸ is excluded. Each R ⁴ is independently halogen, optionally substituted lower alkyl, optionally substituted lower alkenyl, optionally substituted lower alkynyl, optionally substituted lower alkoxy, or substituted And m is an integer of 0-2. Bond from X ⁴ is bonded to Y ^1, the other bond is bound to Y ^2. Bonds of the other side may be bonded to X ^5. ]. More preferably,

[Wherein X ⁴ is N and X ⁵ is NR ¹⁶ or CR ¹⁷ R ¹⁸ (where R ^{16 to} R ¹⁸ are each independently hydrogen, optionally substituted lower alkyl, cyano, substituted May be a non-aromatic heterocyclic group, an optionally substituted heteroaryl, an optionally substituted amino, an optionally substituted lower alkoxy, an aryl lower alkyl or an optionally substituted cycloalkyl; Yes). Each R ⁴ is independently halogen, optionally substituted lower alkyl, optionally substituted lower alkenyl, optionally substituted lower alkynyl, optionally substituted lower alkoxy, or substituted And m is an integer of 0-2. Bond from X ⁴ is bonded to Y ^1, the other bond is bound to Y ^2. ]. In particular, m is preferably 1 to 2. In particular, each R ⁴ is preferably independently an optionally substituted lower alkyl, for example, a linear or branched alkyl having 1 to 4 carbon atoms. More preferably,

(R ⁴ is each independently halogen, optionally substituted lower alkyl, optionally substituted lower alkenyl, optionally substituted lower alkynyl or optionally substituted lower alkoxy, m Is an integer of 1 or 2.). Or

(R ¹⁷ is optionally substituted lower alkyl, cyano, optionally substituted non-aromatic heterocyclic group, optionally substituted heteroaryl, optionally substituted amino, substituted A lower alkoxy group, an aryl lower alkyl group, or an optionally substituted cycloalkyl group, a bond from N is bonded to Y ^1, and a bond from C is bonded to Y ² . It is.

で示される基であり、
Ｒ^７は各々独立して水素、置換されていてもよい低級アルキルまたは置換されていてもよいシクロアルキルであり、
Ｒ^８およびＲ^９は各々独立して水素または置換されていてもよい低級アルキルであり、
ｎは０〜３の整数であり、
Ｚ¹は単結合、−Ｏ−、−Ｓ−または−ＮＲ^９−（ここでＲ^９は水素、置換されていてもよい低級アルキル、置換されていてもよいアシル、置換されていてもよい低級アルキルスルホニルまたは置換されていてもよいアリールスルホニルである）である。特に、

で示される基であり、Ｒ^８およびＲ^９が各々独立して水素または低級アルキルであり、ｎが０〜２の整数であり、
Ｚ^１が単結合、−Ｏ−または−Ｓ−で示される基が好ましい。 Formula: ^-Y 2 Z ¹ - is

A group represented by
Each R ⁷ is independently hydrogen, optionally substituted lower alkyl or optionally substituted cycloalkyl;
R ⁸ and R ⁹ are each independently hydrogen or optionally substituted lower alkyl,
n is an integer from 0 to 3,
Z ¹ is a single bond, —O—, —S— or —NR ⁹ — (wherein R ⁹ is hydrogen, optionally substituted lower alkyl, optionally substituted acyl, optionally substituted lower) Alkylsulfonyl or optionally substituted arylsulfonyl). In particular,

R ⁸ and R ⁹ are each independently hydrogen or lower alkyl, n is an integer of 0 to 2,
Z ¹ is preferably a single bond, a group represented by —O— or —S—.

［Ｒ^１７は水素、置換されていてもよい低級アルキル、シアノ、置換されていてもよい非芳香族へテロ環式基、置換されていてもよいヘテロアリール、置換されていてもよいアミノ、置換されていてもよい低級アルコキシ、アリール低級アルキルまたは置換されていてもよいシクロアルキルであり、Ｒ^６は水素または置換されていてもよい低級アルキルであり、Ｒ^７は水素、置換されていてもよい低級アルキルまたは置換されていてもよいシクロアルキルであり、Ｒ^４は各々独立して、ハロゲン、置換されていてもよい低級アルキル、置換されていてもよい低級アルケニル、置換されていてもよい低級アルキニル、置換されていてもよい低級アルコキシまたは置換されていてもよいアリールであり、Ｚ¹は単結合、Ｏ、ＳまたはＮＲ^９（ここでＲ^９は水素、置換されていてもよい低級アルキル、置換されていてもよいアシル、置換されていてもよい低級アルキルスルホニルまたは置換されていてもよいアリールスルホニルである）であり、ｎは０〜３の整数である。］
特に、Ｒ^１７は非芳香族へテロ環式基、例えば、ピロリジニル、ピペリジル、アゼパニル、モルホリニル等が好ましい。 As -Y ¹ -ring AY ² -Z ^1- , the following embodiments are also preferred.

[R ¹⁷ is hydrogen, optionally substituted lower alkyl, cyano, optionally substituted non-aromatic heterocyclic group, optionally substituted heteroaryl, optionally substituted amino, substituted Lower alkoxy, aryl lower alkyl, or optionally substituted cycloalkyl, R ⁶ is hydrogen or optionally substituted lower alkyl, and R ⁷ is hydrogen, optionally substituted. Lower alkyl or optionally substituted cycloalkyl, each R ⁴ independently represents halogen, optionally substituted lower alkyl, optionally substituted lower alkenyl, optionally substituted lower alkynyl , substituted an aryl which may be also substituted lower alkoxy or substituted, Z ¹ is a single bond, O, S or NR ⁹ ( R ⁹ In this hydrogen, optionally substituted lower alkyl, acyl which may be substituted, an unsubstituted or substituted lower optionally alkylsulfonyl or substituted optionally arylsulfonyl be), n is It is an integer of 0-3. ]
In particular, R ¹⁷ is preferably a non-aromatic heterocyclic group such as pyrrolidinyl, piperidyl, azepanyl, morpholinyl and the like.

  Ring B is an optionally substituted aromatic carbocyclic diyl or an optionally substituted aromatic heterocyclic diyl, and in particular, optionally substituted phenylene (substituents include halogen, lower alkyl Or lower alkoxy), optionally substituted furanyl (substituent is halogen, lower alkyl or lower alkoxy) or optionally substituted thiophenediyl (substituent is halogen, lower alkyl or lower alkoxy) Is preferred.

Y ³ is a single bond, which may be substituted, a lower alkylene which may be interposed with —O—, a cycloalkylene which may be interposed with —O— or a lower alkenylene which may be substituted; In particular, a single bond, optionally substituted lower alkylene (as a substituent, lower alkylene or halogen), -O-optionally substituted lower alkylene (as a substituent, lower alkylene or halogen), substituted An optionally substituted lower alkenylene (as a substituent, lower alkylene or halogen) is preferable.

（ここでＲ^３、Ｒ^１４およびＲ^１５は各々独立して水素、置換されていてもよい低級アルキル、置換されていてもよい低級アルケニル、置換されていてもよいアリールまたは置換されていてもよいヘテロアリールである）であり、特に、ＣＯＯＲ^３（ここでＲ^３は水素または置換されていてもよい低級アルキルである）が好ましい。 Z ² is COOR ³ , C (= NR ³ ) NR ¹⁴ OR ¹⁵ , CONHCN,

(Where R ³ , R ¹⁴ and R ¹⁵ are each independently hydrogen, optionally substituted lower alkyl, optionally substituted lower alkenyl, optionally substituted aryl, or optionally substituted. In particular, COOR ³ (wherein R ³ is hydrogen or optionally substituted lower alkyl).

［Ｚ¹は単結合、−Ｏ−、−Ｓ−または−ＮＲ^９−（ここでＲ^９は水素、置換されていてもよい低級アルキル、置換されていてもよいアシル、置換されていてもよい低級アルキルスルホニルまたは置換されていてもよいアリールスルホニルである）であり、Ｒ、Ｒ’及びＲ’’は各々独立して水素、ハロゲン、ヒドロキシ、置換されていてもよい低級アルコキシ、置換されていてもよい低級アルキニルオキシ、置換されていてもよいアミノ、メルカプト、置換されていてもよい低級アルキルチオ、アシル、アシルオキシ、置換されていてもよいイミノ、カルボキシ、置換されていてもよい低級アルコキシカルボニル、置換されていてもよいカルバモイル、置換されていてもよいチオカルバモイル、置換されていてもよいカルバモイルオキシ、置換されていてもよいチオカルバモイルオキシ、置換されていてもよいスルファモイル、置換されていてもよい低級アルキルスルホニル、置換されていてもよい低級アルキルスルホニルオキシ、シアノ、ニトロ、置換されていてもよいシクロアルキル、置換されていてもよいシクロアルキルオキシ、置換されていてもよいアリール、置換されていてもよいアリールオキシ、置換されていてもよいアリールチオ、置換されていてもよいアリールスルホニル、置換されていてもよいアリールスルホニルオキシ、置換されていてもよいヘテロ環式基、置換されていてもよいヘテロ環オキシ、置換されていてもよい低級アルキレン、置換されていてもよい低級アルキレンジオキシ、オキソである。］ As the -Z ¹ -ring BY ³ -Z ² , the following embodiments are also preferable.

[Z ¹ is a single bond, —O—, —S— or —NR ⁹ — (wherein R ⁹ is hydrogen, optionally substituted lower alkyl, optionally substituted acyl, optionally substituted. R, R ′ and R ″ are each independently hydrogen, halogen, hydroxy, optionally substituted lower alkoxy, substituted, or lower alkylsulfonyl or optionally substituted arylsulfonyl. May be substituted lower alkynyloxy, optionally substituted amino, mercapto, optionally substituted lower alkylthio, acyl, acyloxy, optionally substituted imino, carboxy, optionally substituted lower alkoxycarbonyl, substituted Optionally substituted carbamoyl, optionally substituted thiocarbamoyl, optionally substituted carbamoyloxy, Optionally substituted thiocarbamoyloxy, optionally substituted sulfamoyl, optionally substituted lower alkylsulfonyl, optionally substituted lower alkylsulfonyloxy, cyano, nitro, optionally substituted cycloalkyl , Optionally substituted cycloalkyloxy, optionally substituted aryl, optionally substituted aryloxy, optionally substituted arylthio, optionally substituted arylsulfonyl, optionally substituted Preferred arylsulfonyloxy, optionally substituted heterocyclic group, optionally substituted heterocyclic oxy, optionally substituted lower alkylene, optionally substituted lower alkylenedioxy, oxo. ]

  The compound used in the present invention includes a pharmaceutically acceptable salt capable of producing each compound. “Pharmaceutically acceptable salts” include, for example, salts of inorganic acids such as hydrochloric acid, sulfuric acid, nitric acid or phosphoric acid; salts of organic acids such as paratoluenesulfonic acid, methanesulfonic acid, oxalic acid or citric acid; ammonium, Examples include salts of organic bases such as trimethylammonium or triethylammonium; salts of alkali metals such as sodium or potassium; and salts of alkaline earth metals such as calcium or magnesium.

  The compound used in the present invention includes a solvate thereof, and may be coordinated with any number of solvent molecules with respect to compound (I). Hydrates are preferred.

  When compound (I) used in the present invention has an asymmetric carbon atom, it includes racemates and all stereoisomers (diastereomers, enantiomers, etc.). In addition, when the compound (I) used in the present invention has a double bond, the arrangement of substituents of the double bond includes any of the geometrical isomers.

Below, the general manufacturing method of the compound used for this invention is described.

（式中、Ｘはハロゲン等、他の記号は、上記（１）と同意義。） Process A

(In the formula, X is halogen, and other symbols are as defined in (1) above.)

This step is a method for producing a compound represented by the formula (C) by reacting a compound represented by the formula (A) with a compound represented by the formula (B).
This step is particularly preferably performed in the presence of a base. As the base, potassium carbonate, sodium carbonate, sodium hydrogen carbonate, sodium hydroxide, sodium hydride, triethylamine, N, N-diisopropylethylamine and the like can be used. As the reaction solvent, N, N-dimethylformamide, tetrahydrofuran, dioxane, methylene chloride, acetonitrile, dimethyl sulfoxide and the like can be used. The reaction can be carried out at room temperature to 100 ° C.
An acid addition salt can also be used as the compound (B). In that case, the amount of the base used in the reaction may be increased.

（式中、Ｘはハロゲン等、他の記号は、上記（１）と同意義。） Process B

(In the formula, X is halogen, and other symbols are as defined in (1) above.)

This step is a method for producing a compound represented by the formula (C) by reacting a compound represented by the formula (D) with a compound represented by the formula (E).
This step can be performed under the same conditions as in step B.

（式中、Ｘはハロゲン等、他の記号は、上記（１）と同意義。） Process C

(In the formula, X is halogen, and other symbols are as defined in (1) above.)

This step is a method for producing a compound represented by the formula (H) by reacting a compound represented by the formula (F) with a compound represented by the formula (G).
This step can be performed under the same conditions as in steps A and B.

（式中、Ｘはハロゲン等、他の記号は、上記（１）と同意義。） Process D

(In the formula, X is halogen, and other symbols are as defined in (1) above.)

This step is a method for producing a compound represented by the formula (L) by reacting a compound represented by the formula (J) with a compound represented by the formula (K).
This step can be performed under the same conditions as in Steps A, B, and C.

（式中、各記号は、上記（１）と同意義。） Process E

(In the formula, each symbol has the same meaning as in the above (1).)

This step is a method for producing a compound represented by the formula (O) by reacting a compound represented by the formula (M) with a compound represented by the formula (N).
This step is a Mitsunobu reaction and can be performed in the presence of ethyl azodicarboxylate and triphenylphosphine. Instead of ethyl azodicarboxylate, 1,1-azodicarbonyldipiperidine, N, N, N ′, N′-tetramethylazodicarboxamide and the like can be used. Further, tributylphosphine or the like can be used instead of triphenylphosphine. As the reaction solvent, tetrahydrofuran, toluene, benzene or the like can be used. The reaction can be performed at room temperature.

（式中、Ｘはハロゲン等、他の記号は、上記（１）と同意義。） Process F

(In the formula, X is halogen, and other symbols are as defined in (1) above.)

This step is a method for producing a compound represented by the formula (R) by reacting a compound represented by the formula (P) with a compound represented by the formula (Q).
This step can be performed under the same conditions as in Steps A, B, C, and D.

（式中、Ｘはハロゲン等、他の記号は、上記（１）と同意義。） Process G

(In the formula, X is halogen, and other symbols are as defined in (1) above.)

This step is a method for producing a compound represented by the formula (O) by reacting a compound represented by the formula (P) with a compound represented by the formula (S).
This step can be performed under the same conditions as in Steps A, B, C, D, and F.

When the compound obtained by any of the above methods is a COOR ³ ester, this compound can be hydrolyzed by a conventional method to obtain a carboxylic acid form of COOH.
If necessary, any substituent may be converted into a different substituent using a known organic synthesis reaction at an appropriate stage of the above production method.
For example, when any compound has a halogen, in a solvent such as DMF or tetrahydrofuran, a base such as sodium hydride or potassium hydride, an alkali metal hydroxide, an alkali metal hydrogen carbonate, an alkali metal carbonate, an organic base And the like, in the presence of a deoxidizing agent such as -20 ° C to 100 ° C, a compound in which the substituent is converted to lower alkoxy is obtained.
In addition, when any compound has alkyl hydroxy, an oxidizing agent such as pyridinium dichromate, Jones reagent, manganese dioxide, potassium permanganate, ruthenium tetroxide and the like and dimethylformamide, tetrahydrofuran, dichloromethane, benzene, acetone The compound in which the substituent is converted to carboxy is obtained by reacting in a solvent such as.

  If necessary, the amino or hydroxy of the compound may be protected by a conventional method at an appropriate stage, followed by reaction, and deprotected by treatment with an acid or base at an appropriate stage.

  The amino protecting group includes phthalimide, lower alkoxycarbonyl (butoxycarbonyl (Boc), etc.), lower alkenyloxycarbonyl, halogenoalkoxycarbonyl, aryl lower alkoxycarbonyl, trialkylsilyl, lower alkylsulfonyl, halogeno lower alkylsulfonyl, arylsulfonyl, lower Alkylcarbonyl, arylcarbonyl, aryl lower alkyl (benzyl, etc.) and the like can be used.

  Examples of the hydroxy protecting group include alkyl (t-butyl and the like), aralkyl (triphenylmethyl, benzyl), trialkylsilyl (t-butyldimethylsilyl, triisopropylsilyl and the like), alkyldiarylsilyl (t-butyldiphenylsilyl and the like), Triaralkylsilyl (such as tribenzylsilyl), alkoxyalkyl (such as methoxymethyl, 1-ethoxyethyl, 1-methyl-1-methoxyethyl), alkoxyalkoxyalkyl (such as methoxyethoxymethyl), alkylthioalkyl (such as methylthiomethyl), Tetrahydropyranyl (tetrahydropyran-2-yl, 4-methoxytetrahydropyran-4-yl etc.), tetrahydrothiopyranyl (tetrahydrothiopyran-2-yl etc.), tetrahydrofuranyl (tetrahydrofuran 2- yl, etc.), tetrahydrothiofuranyl (tetrahydrothiopyran-2-yl, etc.), aralkyloxyalkyl (benzyloxymethyl etc.) alkylsulfonyl, acyl, p- toluenesulfonyl, and the like.

  The deprotection reaction is a solvent such as tetrahydrofuran, dimethylformamide, diethyl ether, dichloromethane, toluene, benzene, xylene, cyclohexane, hexane, chloroform, ethyl acetate, butyl acetate, pentane, heptane, dioxane, acetone, acetonitrile or a mixed solvent thereof. A base such as hydrazine, pyridine, sodium hydroxide, or potassium hydroxide, or an acid such as hydrochloric acid, trifluoroacetic acid, or hydrofluoric acid may be used.

［式中、Ｒ^Ｘはアミノ保護基（例えば、ベンジル、tert-ブトキシカルボニル等）等であり、Ｘ^１０はハロゲンである。他の各記号の意味は前記と同意義である。］
化合物（Ｏ１）に、環Ｑを有する誘導体を塩基の存在下反応させ、化合物（Ｏ２）を得る。得られた化合物（Ｏ２）の保護基をはずし、化合物（Ｏ４）を反応させ、化合物（Ｏ５）を得る。
Process H

[Wherein R ^X is an amino protecting group (eg, benzyl, tert-butoxycarbonyl, etc.) and the like, and X ¹⁰ is halogen. The meanings of the other symbols are as defined above. ]
Compound (O1) is reacted with a derivative having ring Q in the presence of a base to obtain compound (O2). The protecting group of the obtained compound (O2) is removed, and the compound (O4) is reacted to obtain the compound (O5).

［式中、Ｒ^Ｘはアミノ保護基（例えば、ベンジル、tert-ブトキシカルボニル等）等であり、Ｒ^Ｙは低級アルキル等であり、Ｘ^１０はヒドロキシであり、Ｚ^１はＯ、Ｓ、ＮＲ^９である。他の各記号の意味は前記と同意義である。］
化合物（Ｐ１）に、塩基（たとえば、炭酸カリウム等）の存在下、式：Ｘ−Ｃ（Ｒ^８Ｒ^９）_ｎ−１−ＣＯＯＲ^Ｙで示される化合物を反応させ、化合物（Ｐ２）を得る。溶媒としては、ジメチルホルムアミド等を使用することができる。
得られた化合物（Ｐ２）を還元し、化合物（Ｐ３）を得ることができる。還元は、水素化リチウムアルミニウム等を用いて行うことができる。
得られた化合物（Ｐ３）をメシルクロリド等と反応させ、Ｘ^１０を脱離基に変換し、環Ｂを有する化合物とカップリングする。
その後、Ｒ^Ｘの脱保護を行い、化合物（ｐ５）を得、次に、フェニルイソシアネート誘導体等を反応させ、化合物（Ｐ６）を得る。
なお、環Ｑを有する化合物を反応させて、化合物（Ｐ７）に導くこともできる。
また、化合物（Ｐ３）のＸ^１０をハロゲンに変換し、環Ｂを有する化合物を反応させることにより、Ｚ^１が−Ｓ−や−ＮＲ^９−の化合物も得ることができる。 Process I

[Wherein, R ^X is an amino protecting group (eg, benzyl, tert-butoxycarbonyl, etc.), R ^Y is lower alkyl, X ¹⁰ is hydroxy, Z ¹ is O, S, NR ⁹ It is. The meanings of the other symbols are as defined above. ]
Compound (P1) is reacted with a compound represented by the formula: X—C (R ⁸ R ⁹ ) _n−1 —COOR ^Y in the presence of a base (for example, potassium carbonate and the like) to obtain compound (P2). As the solvent, dimethylformamide or the like can be used.
The obtained compound (P2) can be reduced to obtain the compound (P3). The reduction can be performed using lithium aluminum hydride or the like.
The obtained compound (P3) is reacted with mesyl chloride and the like, it converts X ¹⁰ to a leaving group, for coupling a compound having a ring B.
Thereafter, R ^X is deprotected to obtain the compound (p5), and then reacted with a phenyl isocyanate derivative or the like to obtain the compound (P6).
In addition, the compound which has the ring Q can be made to react, and it can also guide | induced to a compound (P7).
In addition, a compound in which Z ¹ is —S— or —NR ⁹ — can be obtained by converting X ¹⁰ of compound (P3) to halogen and reacting the compound having ring B.

［式中、Ｒ^Ｘはアミノ保護基（例えば、ベンジル、tert-ブトキシカルボニル等）等であり、Ｒ^Ｙは低級アルキル等であり、Ｘ^１０はヒドロキシまたはハロゲンであり、Ｚ^１は−Ｏ−、−Ｓ−、−ＮＲ^９−である。他の各記号の意味は前記と同意義である。］
化合物（Ｑ１）から化合物（Ｑ２）に誘導し、ＣＯＯＲ^Ｙを還元する。還元は、水素化リチウムアルミニウム等で行うことができる。次ぎに、Ｒ^Ｘの脱保護を行う、保護基がベンジル基の場合、接触還元等により脱保護を行うことができる。脱保護の後、環Ｑを有する化合物を塩基(たとえば、炭酸カリウム)の存在下で反応させ、化合物（Ｑ4）を得る。次に、得られた化合物（Ｑ４）に環Ｂを有する化合物を反応させ、化合物（Ｏ５）を得る。なお、化合物（Ｑ４）のＸ^１０をハロゲンに変換し、環Ｂを有する化合物を反応させることにより、Ｚ^１が−Ｓ−や−ＮＲ^９−の化合物も得ることができる。 Process J

Wherein R ^X is an amino protecting group (eg, benzyl, tert-butoxycarbonyl, etc.), R ^Y is lower alkyl, etc., X ¹⁰ is hydroxy or halogen, Z ¹ is —O—, -S-, -NR < ⁹ >-. The meanings of the other symbols are as defined above. ]
From compound (Q1) to compound (Q2), COOR ^Y is reduced. The reduction can be performed with lithium aluminum hydride or the like. Next, the deprotection of R ^X, when the protecting group is a benzyl group, can be deprotected by catalytic reduction or the like. After deprotection, the compound having ring Q is reacted in the presence of a base (for example, potassium carbonate) to obtain compound (Q4). Next, the compound (Q4) obtained is reacted with a compound having a ring B to obtain a compound (O5). A compound in which Z ¹ is —S— or —NR ⁹ — can also be obtained by converting X ¹⁰ of compound (Q4) to halogen and reacting the compound having ring B.

The HDL elevating agent of the present invention effectively acts on all HDL-related diseases, but is particularly effective for treating or preventing arteriosclerosis, particularly coronary artery diseases such as myocardial infarction and angina. Also, hyperlipidemia, dyslipidemia, dyslipidemia, low HDL disease, hyper LDL disease, hyper VLDL disease, hyper TG disease, diabetes, hyperglycemia, insulin resistance, obesity, bulimia nervosa, atheromatous Arteriosclerosis, hypertension, syndrome X, ischemic disease, inflammation, allergic disease (inflammatory colitis, rheumatoid arthritis, chronic pancreatitis, multiple sclerosis, glomerulosclerosis, psoriasis, eczema, etc.), osteoporosis, It is effective for the prevention and / or treatment of infertility, cancer (breast cancer, colon cancer, colon cancer, ovarian cancer, lung cancer, etc.), Alzheimer's disease, Parkinsonism, and Graves' disease.
Furthermore, the compounds used in the present invention are: a) weak CYP enzyme inhibition b) high water solubility c) good pharmacokinetics such as high bioavailability d) low toxicity such as anemia-inducing action e) metabolic stability It has excellent characteristics such as high.

  The HDL elevating agent of the present invention can be administered either orally or parenterally. Oral administration may be prepared and administered in a commonly used dosage form such as tablets, granules, powders, capsules, pills, liquids, syrups, buccals or sublinguals according to conventional methods. For parenteral administration, any commonly used dosage forms such as injections such as intramuscular administration and intravenous administration, suppositories, percutaneous absorption agents, inhalants and the like can be suitably administered. Since the compound used in the present invention has high oral absorbability, it can be suitably used as an oral preparation.

The HDL-elevating agent of the present invention comprises various pharmaceutical additives such as excipients, binders, wetting agents, disintegrants, lubricants, diluents and the like suitable for the dosage form of the compound used in the present invention. Can be mixed as necessary to obtain a pharmaceutical preparation. In the case of an injection, it may be sterilized with an appropriate carrier to form a preparation.
Specifically, the excipients are lactose, sucrose, glucose, starch, calcium carbonate or crystalline cellulose, and the binders are methyl cellulose, carboxymethyl cellulose, hydroxypropyl cellulose, gelatin or polyvinyl. Examples of disintegrants include pyrrolidone, carboxymethylcellulose, sodium carboxymethylcellulose, starch, sodium alginate, agar powder or sodium lauryl sulfate, and lubricants include talc, magnesium stearate, or macrogol. It is done. As a suppository base, cacao butter, macrogol, methyl cellulose, or the like can be used. In addition, when preparing as a liquid or emulsion or suspension injection, add commonly used solubilizers, suspending agents, emulsifiers, stabilizers, preservatives, isotonic agents, etc. In the case of oral administration, a flavoring agent, a fragrance or the like may be added.

  The dose of the HDL elevating agent of the present invention is preferably set in consideration of the patient's age, weight, type and degree of illness, administration route, etc. 100 mg / kg / day, preferably in the range of 0.1-10 mg / kg / day. In the case of parenteral administration, although it varies greatly depending on the administration route, it is usually 0.005 to 10 mg / kg / day, preferably 0.01 to 1 mg / kg / day. This may be administered once to several times a day.

  Examples of the compounds used in the present invention will be shown below to explain the present invention in more detail, but these do not limit the present invention.

収率：88％, ¹H-NMR (CDCl₃): δ7.41 (1H, dd, J=8.5, 2.0Hz), 7.45 (1H, d, J=8.5Hz), 7.95 (1H, d, J=2.0Hz).

参考例２

収率：90％, ¹H-NMR (CDCl₃): δ7.60 (1H, dd, J=8.5, 2.0Hz),7.82 (1H, d, J=8.5Hz), 7.93 (1H, d, J=2.0Hz).

参考例３

収率：76％, 1H-NMR(CDCl₃): δ7.23 (1H, td, J=8.0, 2.5Hz), 7.48 (1H, dd, J=8.0, 2.5Hz), 7.91 (1H, dd, J=8.0, 4.0Hz).

参考例４

収率：65％, 1H-NMR(CDCl3): δ7.73 (1H, d, J=7.0Hz), 7.82 (1H, d, J=9.0Hz).

参考例５

収率：89％, 1H-NMR(CDCl3): δ7.78 (1H, d, J=6.5Hz), 8.06 (1H, d, J=10.5Hz).

参考例６

収率：66％, 1H-NMR(CDCl3): δ8.00 (1H, d, J=8.5Hz), 8.17 (1H, d, J=8.5Hz), 8.45 (1H, s), 8.89 (1H, s).
The compounds described in Reference Examples 1 to 6 were obtained using the methods described in US Patent Application Publication No. 2004/0224997 and International Publication No. 95/22531.
Reference example 1

Yield: 88%, ¹ H-NMR (CDCl ₃ ): δ7.41 (1H, dd, J = 8.5, 2.0Hz), 7.45 (1H, d, J = 8.5Hz), 7.95 (1H, d, J = 2.0Hz).

Reference example 2

Yield: 90%, ¹ H-NMR (CDCl ₃ ): δ 7.60 (1H, dd, J = 8.5, 2.0Hz), 7.82 (1H, d, J = 8.5Hz), 7.93 (1H, d, J = 2.0Hz).

Reference example 3

Yield: 76%, 1H-NMR (CDCl ₃ ): δ7.23 (1H, td, J = 8.0, 2.5Hz), 7.48 (1H, dd, J = 8.0, 2.5Hz), 7.91 (1H, dd, J = 8.0, 4.0Hz).

Reference example 4

Yield: 65%, 1H-NMR (CDCl3): δ 7.73 (1H, d, J = 7.0Hz), 7.82 (1H, d, J = 9.0Hz).

Reference Example 5

Yield: 89%, 1H-NMR (CDCl3): δ 7.78 (1H, d, J = 6.5Hz), 8.06 (1H, d, J = 10.5Hz).

Reference Example 6

Yield: 66%, 1H-NMR (CDCl3): δ8.00 (1H, d, J = 8.5Hz), 8.17 (1H, d, J = 8.5Hz), 8.45 (1H, s), 8.89 (1H, s).

2-アミノ-5-フェニルチアゾール（ジャーナル・オブ・メディシナル・ケミストリー、 1983年26巻(８) 1158-1163 に記載）1.00g（5.67mmol）、塩化銅（II）二水和物1.94g（11.3mmol）、濃塩酸8ml及び酢酸8mlの混合物に氷冷下、亜硝酸ナトリウム0.47g（6.80mmol）を加え40℃で1時間撹拌した。反応液を室温に戻した後、水及びクロロホルムを加え抽出した。有機層を飽和食塩水で洗浄、無水硫酸ナトリウムで乾燥した後、減圧下溶媒を留去した。残渣をシリカゲルカラムクロマトグラフィー（塩化メチレン）で精製し、2-クロロ-5-フェニルチアゾールを淡黄色結晶として0.68g（62％）得た。
¹H-NMR(CDCl₃): δ7.32-7.53 (5H, m), 7.71 (1H, s). Reference Example 7
Production of 2-chloro-5-phenylthiazole

2-amino-5-phenylthiazole (Journal of Medicinal Chemistry, 1983 26 (8) 1158-1163) 1.00 g (5.67 mmol), copper (II) chloride dihydrate 1.94 g (11.3 mmol), 8 ml of concentrated hydrochloric acid and 8 ml of acetic acid were added with 0.47 g (6.80 mmol) of sodium nitrite under ice cooling, followed by stirring at 40 ° C. for 1 hour. After returning the reaction solution to room temperature, water and chloroform were added for extraction. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (methylene chloride) to obtain 0.68 g (62%) of 2-chloro-5-phenylthiazole as pale yellow crystals.
¹ H-NMR (CDCl ₃ ): δ7.32-7.53 (5H, m), 7.71 (1H, s).

3-(メトキシメトキシ)-4-メチルベンジルアルコール（国際公開第２００４／０２２５５１号パンフレットに記載）9.80g（53.78mmol）、トリエチルアミン7.90ml（56.47mmol）、無水THF50mlの混合物に氷冷下、メタンスルホニルクロリド4.40ml（56.47mmol）を滴下した後、同温で1.5時間撹拌した。析出結晶を濾別し、濾液を減圧下濃縮した後、残渣にシアン化ナトリウム7.91g（0.161mol）及び無水N,N-ジメチルホルムアミド50mlを加え、室温下3日間撹拌した。反応液に水及び酢酸エチルを加え抽出した後、有機層を飽和食塩水で洗浄、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、残渣をシリカゲルカラムクロマトグラフィー（ヘキサン：酢酸エチル＝3：1）で精製し、[3-(メトキシメトキシ)-4-メチルフェニル]アセトニトリルを褐色油状物として7.87g（77％）得た。
¹H-NMR(CDCl₃): δ2.23 (3H, s), 3.49 (3H, s), 3.70 (2H, s), 5.21 (2H, s), 6.89 (1H, dd, J=7.5, 1.5Hz), 6.98 (1H, d, J=1.5Hz), 7.14 (1H, d, J=7.5Hz).

参考例９
3-(メトキシメトキシ)-4-メチルフェニル酢酸の製造

[3-(メトキシメトキシ)-4-メチルフェニル]アセトニトリル7.87g（41.2mmol）、水酸化ナトリウム8.30g（210mmol）、水30ml及びエタノール70mlの混合物を5時間加熱還流した。反応液を減圧下濃縮し、水及び酢酸エチルを加え逆抽出した後、水層に2N-塩酸水溶液を加えPH＝7とした。酢酸エチルを加え抽出した後、有機層を飽和食塩水で洗浄、無水硫酸ナトリウムで乾燥した。減圧下溶媒を留去し、3-(メトキシメトキシ)-4-メチルフェニル酢酸を淡褐色油状物として5.52g（64％）得た。
¹H-NMR(CDCl₃): δ2.22 (3H, s), 3.48 (3H, s), 3.59 (2H, s), 5.19 (2H, s), 6.83 (1H, dd, J=7.5, 1.5Hz), 6.95 (1H, d, J=1.5Hz), 7.13 (1H, d, J=7.5Hz), 9.83 (1H, brs).

参考例１０
[3-ヒドロキシ-4-メチルフェニル]酢酸エチルの製造

[3-(メトキシメトキシ)-4-メチル]フェニル酢酸5.52g（26.3mmol）、濃塩酸2ml及びエタノール20mlの混合物を3時間加熱撹拌した。空冷後、反応液を減圧下濃縮し、残渣に飽和炭酸水素ナトリウム水溶液を加え、PH＝7とした後、酢酸エチルを加え抽出した。有機層を飽和食塩水で洗浄、無水硫酸ナトリウムで乾燥した後、減圧下溶媒を留去した。残渣をシリカゲルカラムクロマトグラフィー（ヘキサン：酢酸エチル＝3：1）で精製し、3-ヒドロキシ-4-メチルフェニル酢酸エチルを淡黄色油状物として2.40g（47％）得た。
¹H-NMR(CDCl₃): δ1.26 (3H, t, J=7Hz), 2.21 (3H, s), 3.53 (2H, s), 4.14 (2H, q, J=7Hz), 5.13 (1H, s), 6.72 (1H, s), 6.74 (1H, d, J=7.5Hz), 7.05 (1H, d, J=7.5Hz).

参考例１１
2-クロロ-5-(メトキシエトキシ)トルエンの製造

4-クロロ-3-メチルクレゾール15.0g（0.105mol）、N,N-ジイソプロピルエチルアミン23.3ml（0.137mol）及びTHF150mlの混合物に室温下、クロロメチルメチルエーテル9.50ml（0.126mol）を滴下し、60℃で27.5時間撹拌した。反応液を氷水に注ぎ、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄、無水硫酸ナトリウムで乾燥した後、減圧下溶媒を留去した。残渣をシリカゲルカラムクロマトグラフィー（ヘキサン：酢酸エチル＝5：1）で精製し、2-クロロ-5-(メトキシエトキシ)トルエンを赤褐色油状物として17.7g（90％）得た。
¹H-NMR(CDCl₃): δ2.34 (3H, s), 3.47 (3H, s), 5.13 (2H, s), 6.81 (1H, dd, J=8.5, 3.0Hz), 6.92 (1H, d, J=3.0Hz), 7.22 (1H, d, J=8.5Hz).

参考例１２
[2-クロロ-5-(メトキシメトキシ)フェニル]アセトニトリルの製造

2-クロロ-5-(メトキシエトキシ)トルエン5.00g（26.8mmol）、N-ブロモスクシンイミド4.77ｇ（26.8mmol）、2,2-アゾビス（イソブチロニトリル）0.09g（0.53mmol）及び四塩化炭素25ｍlの混合物を2時間加熱還流した。空冷後、沈殿を濾去した後、濾液を減圧下濃縮した。残渣にシアン化ナトリウム2.77g（80.4mol）及び無水N,N-ジメチルホルムアミド30ｍlを加え、室温下2時間撹拌した。反応液に水及び酢酸エチルを加え抽出した後、有機層を飽和食塩水で洗浄、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、残渣をシリカゲルカラムクロマトグラフィー（ヘキサン：酢酸エチル＝6：1→4：1）で精製し、[2-クロロ-5-(メトキシメトキシ)フェニル]アセトニトリルを無色油状物として2.64g（47％）得た。
¹H-NMR(CDCl₃): δ3.48 (3H, s), 3.80 (2H, s), 5.17 (2H, s), 6.99 (1H, dd, J=9.0, 3.0Hz), 7.19 (1H, d, J=3.0Hz), 7.32 (1H, d, J=9.0Hz).

参考例１３
[2-クロロ-5-ヒドロキシフェニル]酢酸エチルの製造

[２-クロロ-5-(メトキシメトキシ)フェニル]アセトニトリル2.60g（12.3mmol）、水酸化ナトリウム2.46g（61.5mmol）、水10.4ml及びエタノール33.8mlの混合物を80℃で3時間撹拌した。空冷後、減圧下溶媒を留去し、残渣に水及び2N-塩酸水溶液を加え酸性とした後、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄、無水硫酸ナトリウムで乾燥した後、減圧下溶媒を留去した。残渣に濃塩酸0.65ｍｌ及びエタノール15ｍｌを加え80℃で8時間撹拌した。空冷後、反応液を減圧下濃縮し、残渣をシリカゲルカラムクロマトグラフィー（ヘキサン：酢酸エチル＝2：1）で精製し、[2-クロロ-5-ヒドロキシフェニル]酢酸エチルを無色油状物として0.69g（26％）得た。
¹H-NMR(CDCl₃): δ1.28 (3H, t, J=7.0Hz), 3.70 (2H, s), 4.20 (2H, q, J=7.0Hz), 5.66 (1H, s), 6.64 (1H, dd, J=8.5, 3.0Hz), 6.73 (1H, d, J=3.0Hz), 7.18 (1H, d, J=8.5Hz).

参考例１４
[3-ブロモメチル5-メチル]フェノキシアセテートの製造

国際公開第２００４／０２２５５１号パンフレットの参考例７７に記載の方法に従い合成した。
¹H-NMR(CDCl₃); δ2.29 (3H, s), 2.35 (3H, s), 4.44 (2H, s), 6.85 (1H, s), 6.94 (1H, s), 7.08 (1H, s).

参考例１５
3-ブロモメチル-5-メチル安息香酸メチルの製造

3,5-ジメチル安息香酸メチル5.00g（30.5mmol）、N-ブロモスクシンイミド5.69g（32.0mmol）、2,2-アゾビス（イソブチロニトリル）0.10g（0.61mmol）の四塩化炭素25mlの混合物を1時間加熱還流した。空冷後、沈殿物を濾去した後、濾液を減圧下濃縮した。残渣をシリカゲルカラムクロマトグラフィー（ヘキサン：酢酸エチル＝10：1）で精製し、3-ブロモメチル-5-メチル安息香酸メチルを無色油状物として3.78ｇ（51％）得た。
¹H-NMR(CDCl₃): δ2.40 (3H, s), 3.92 (3H, s), 4.49 (2H, s), 7.40 (1H, s), 7.79 (1H, s), 7.89 (1H, s). Reference Example 8
Preparation of [3- (methoxymethoxy) -4-methylphenyl] acetonitrile

3- (Methoxymethoxy) -4-methylbenzyl alcohol (described in WO 2004/022551 pamphlet) 9.80 g (53.78 mmol), triethylamine 7.90 ml (56.47 mmol), anhydrous THF 50 ml in a mixture of ice-cooled methanesulfonyl After dropwise addition of 4.40 ml (56.47 mmol) of chloride, the mixture was stirred at the same temperature for 1.5 hours. Precipitated crystals were filtered off, and the filtrate was concentrated under reduced pressure. To the residue were added 7.91 g (0.161 mol) of sodium cyanide and 50 ml of anhydrous N, N-dimethylformamide, and the mixture was stirred at room temperature for 3 days. Water and ethyl acetate were added to the reaction solution for extraction, and the organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 3: 1) to give 7.87 g of [3- (methoxymethoxy) -4-methylphenyl] acetonitrile as a brown oil. (77%) obtained.
¹ H-NMR (CDCl ₃ ): δ2.23 (3H, s), 3.49 (3H, s), 3.70 (2H, s), 5.21 (2H, s), 6.89 (1H, dd, J = 7.5, 1.5 Hz), 6.98 (1H, d, J = 1.5Hz), 7.14 (1H, d, J = 7.5Hz).

Reference Example 9
Production of 3- (methoxymethoxy) -4-methylphenylacetic acid

A mixture of [3- (methoxymethoxy) -4-methylphenyl] acetonitrile 7.87 g (41.2 mmol), sodium hydroxide 8.30 g (210 mmol), water 30 ml and ethanol 70 ml was heated to reflux for 5 hours. The reaction solution was concentrated under reduced pressure, water and ethyl acetate were added and back-extracted, and then 2N-hydrochloric acid aqueous solution was added to the aqueous layer to obtain PH = 7. After extraction with ethyl acetate, the organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain 5.52 g (64%) of 3- (methoxymethoxy) -4-methylphenylacetic acid as a light brown oil.
¹ H-NMR (CDCl ₃ ): δ2.22 (3H, s), 3.48 (3H, s), 3.59 (2H, s), 5.19 (2H, s), 6.83 (1H, dd, J = 7.5, 1.5 Hz), 6.95 (1H, d, J = 1.5Hz), 7.13 (1H, d, J = 7.5Hz), 9.83 (1H, brs).

Reference Example 10
Production of ethyl [3-hydroxy-4-methylphenyl] acetate

A mixture of 5.52 g (26.3 mmol) of [3- (methoxymethoxy) -4-methyl] phenylacetic acid, 2 ml of concentrated hydrochloric acid and 20 ml of ethanol was heated and stirred for 3 hours. After air cooling, the reaction mixture was concentrated under reduced pressure, saturated aqueous sodium hydrogen carbonate solution was added to the residue to PH = 7, and ethyl acetate was added for extraction. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 3: 1) to obtain 2.40 g (47%) of ethyl 3-hydroxy-4-methylphenylacetate as a pale yellow oil.
¹ H-NMR (CDCl ₃ ): δ1.26 (3H, t, J = 7Hz), 2.21 (3H, s), 3.53 (2H, s), 4.14 (2H, q, J = 7Hz), 5.13 (1H , s), 6.72 (1H, s), 6.74 (1H, d, J = 7.5Hz), 7.05 (1H, d, J = 7.5Hz).

Reference Example 11
Production of 2-chloro-5- (methoxyethoxy) toluene

To a mixture of 1-5.0 g (0.105 mol) of 4-chloro-3-methylcresol, 23.3 ml (0.137 mol) of N, N-diisopropylethylamine and 150 ml of THF, 9.50 ml (0.126 mol) of chloromethyl methyl ether was added dropwise at room temperature. The mixture was stirred at ° C for 27.5 hours. The reaction mixture was poured into ice water and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 5: 1) to obtain 17.7 g (90%) of 2-chloro-5- (methoxyethoxy) toluene as a reddish brown oil.
¹ H-NMR (CDCl ₃ ): δ 2.34 (3H, s), 3.47 (3H, s), 5.13 (2H, s), 6.81 (1H, dd, J = 8.5, 3.0Hz), 6.92 (1H, d, J = 3.0Hz), 7.22 (1H, d, J = 8.5Hz).

Reference Example 12
Preparation of [2-chloro-5- (methoxymethoxy) phenyl] acetonitrile

2-chloro-5- (methoxyethoxy) toluene 5.00 g (26.8 mmol), N-bromosuccinimide 4.77 g (26.8 mmol), 2,2-azobis (isobutyronitrile) 0.09 g (0.53 mmol) and carbon tetrachloride 25 ml of the mixture was heated to reflux for 2 hours. After air cooling, the precipitate was filtered off, and the filtrate was concentrated under reduced pressure. To the residue were added 2.77 g (80.4 mol) of sodium cyanide and 30 ml of anhydrous N, N-dimethylformamide, and the mixture was stirred at room temperature for 2 hours. Water and ethyl acetate were added to the reaction solution for extraction, and the organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 6: 1 → 4: 1) to give [2-chloro-5- (methoxymethoxy) phenyl] acetonitrile as a colorless oil 2.64 g (47%) was obtained as a product.
¹ H-NMR (CDCl ₃ ): δ3.48 (3H, s), 3.80 (2H, s), 5.17 (2H, s), 6.99 (1H, dd, J = 9.0, 3.0Hz), 7.19 (1H, d, J = 3.0Hz), 7.32 (1H, d, J = 9.0Hz).

Reference Example 13
Production of ethyl [2-chloro-5-hydroxyphenyl] acetate

A mixture of [2-chloro-5- (methoxymethoxy) phenyl] acetonitrile 2.60 g (12.3 mmol), sodium hydroxide 2.46 g (61.5 mmol), water 10.4 ml and ethanol 33.8 ml was stirred at 80 ° C. for 3 hours. After air cooling, the solvent was distilled off under reduced pressure. The residue was acidified with water and 2N-hydrochloric acid aqueous solution, and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. To the residue, 0.65 ml of concentrated hydrochloric acid and 15 ml of ethanol were added and stirred at 80 ° C. for 8 hours. After air cooling, the reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 2: 1) to give 0.69 g of ethyl [2-chloro-5-hydroxyphenyl] acetate as a colorless oil. (26%) obtained.
¹ H-NMR (CDCl ₃ ): δ1.28 (3H, t, J = 7.0Hz), 3.70 (2H, s), 4.20 (2H, q, J = 7.0Hz), 5.66 (1H, s), 6.64 (1H, dd, J = 8.5, 3.0Hz), 6.73 (1H, d, J = 3.0Hz), 7.18 (1H, d, J = 8.5Hz).

Reference Example 14
Production of [3-bromomethyl 5-methyl] phenoxyacetate

The compound was synthesized according to the method described in Reference Example 77 of WO 2004/022551 pamphlet.
¹ H-NMR (CDCl ₃ ); δ 2.29 (3H, s), 2.35 (3H, s), 4.44 (2H, s), 6.85 (1H, s), 6.94 (1H, s), 7.08 (1H, s).

Reference Example 15
Production of methyl 3-bromomethyl-5-methylbenzoate

Mixture of 5.00 g (30.5 mmol) of methyl 3,5-dimethylbenzoate, 5.69 g (32.0 mmol) of N-bromosuccinimide and 0.10 g (0.61 mmol) of 2,2-azobis (isobutyronitrile) in 25 ml of carbon tetrachloride Was heated to reflux for 1 hour. After air cooling, the precipitate was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 10: 1) to obtain 3.78 g (51%) of methyl 3-bromomethyl-5-methylbenzoate as a colorless oil.
¹ H-NMR (CDCl ₃ ): δ 2.40 (3H, s), 3.92 (3H, s), 4.49 (2H, s), 7.40 (1H, s), 7.79 (1H, s), 7.89 (1H, s).

収率：56％, ¹H-NMR(CDCl₃): δ3.93 (3H, s), 4.61 (2H, s), 7.47 (1H, d, J=8.5Hz), 7.91 (1H, dd, J=8.5, 2Hz), 8.11 (1H, d, J=2Hz).

参考例１７

収率：75％,¹H-NMR(CDCl₃): δ2.33 (3H, s), 4.40 (2H, s), 7.08 (1H, s), 7.10 (1H, s), 7.18 (1H, s).
Thereafter, the compounds described in Reference Examples 16 and 17 were obtained in the same manner as Reference Example 15.
Reference Example 16

Yield: 56%, ¹ H-NMR (CDCl ₃ ): δ3.93 (3H, s), 4.61 (2H, s), 7.47 (1H, d, J = 8.5Hz), 7.91 (1H, dd, J = 8.5, 2Hz), 8.11 (1H, d, J = 2Hz).

Reference Example 17

Yield: 75%, ¹ H-NMR (CDCl ₃ ): δ2.33 (3H, s), 4.40 (2H, s), 7.08 (1H, s), 7.10 (1H, s), 7.18 (1H, s ).

(3-ブロモメチル-5−クロロ)トルエン1.67g（7.62mmol）、シアン化ナトリウム0.42g（8.51mmol）及び無水N, N-ジメチルホルムアミド15mlの混合物を40℃下で2時間撹拌した。反応液に水及び酢酸エチルを加え抽出し、有機層を飽和食塩水で洗浄、無水硫酸ナトリウムで乾燥した後、減圧下溶媒を留去した。残渣をシリカゲルカラムクロマトグラフィー（塩化メチレン）で精製し、[（3-クロロ-5-メチル）フェニル]アセトニトリルを淡黄色油状物質として0.75ｇ（59％）得た。
¹H-NMR(CDCl₃): δ2.35 (3H, s), 3.69 (2H, s), 7.04 (1H, s), 7.12 (1H, s), 7.14 (1H, s).

参考例１９
(3-クロロ-5-メチル)フェニル酢酸エチルの製造

[(3-クロロ-5-メチルフェニル)]アセトニトリル0.38g（2.29mmol）に2N水酸化ナトリウム水溶液2.1ml及びエタノール5mlを加え80℃で1時間撹拌した。反応液を減圧下濃縮し、残渣に水及び2N-HCl水溶液を加え中性とした後、酢酸エチルを加え抽出した。有機層を飽和食塩水で洗浄、無水硫酸ナトリウムで乾燥した後、減圧下溶媒を留去し、無色結晶を得た。これに濃硫酸0.02ml、エタノール2mlを加え、5時間加熱還流撹拌した。反応液を減圧下濃縮し、残渣に水及び2N-水酸化ナトリウム水溶液を加え中性とした後、酢酸エチルを加え抽出した。有機層を飽和食塩水で洗浄、無水硫酸ナトリウムで乾燥した後、減圧下溶媒を留去した。残渣をシリカゲルカラムクロマトグラフィー（ヘキサン：酢酸エチル＝6：1）で精製し、3-クロロ-5-メチルフェニル酢酸エチルを無色油状物質として0.31g（63％）得た。
¹H-NMR(CDCl₃): δ1.26 (3H, t, J = 7.2 Hz), 2.32 (3H, s), 3.53 (2H, s), 4.16 (2H, q, J = 7.2 Hz), 6.97 (1H, s), 7.08 (2H, s).

参考例２０
[3-ブロモメチル-5-クロロ]フェニル酢酸エチルの製造

3-クロロ-5-メチルフェニル酢酸エチル0.20g（0.958mol）、N-ブロモスクシンイミド0.21g（1.21mmol）、2,2-アゾビス（イソブチロニトリル）0.01g（0.037mmol）の四塩化炭素2mlの混合物を2時間加熱還流した。空冷後、沈殿物を濾去した後、濾液を減圧下濃縮した。残渣をシリカゲルカラムクロマトグラフィー（ヘキサン：酢酸エチル＝20：1）で精製し、3-ブロモメチル-5-クロロフェニル酢酸エチルを無色油状物として0.16ｇ（57％）得た。
¹H-NMR(CDCl₃): δ1.27 (3H, t, J = 7.2 Hz), 3.58 (2H, s), 4.17 (2H, t, J = 7.2 Hz), 4.42 (2H, s), 7.20 (1H, s), 7.22 (1H, s), 7.30 (1H, s). Reference Example 18
Preparation of [(3-Chloro-5-methyl) phenyl] acetonitrile

A mixture of 1.67 g (7.62 mmol) of (3-bromomethyl-5-chloro) toluene, 0.42 g (8.51 mmol) of sodium cyanide and 15 ml of anhydrous N, N-dimethylformamide was stirred at 40 ° C. for 2 hours. Water and ethyl acetate were added to the reaction solution for extraction. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (methylene chloride) to obtain 0.75 g (59%) of [(3-chloro-5-methyl) phenyl] acetonitrile as a pale yellow oily substance.
¹ H-NMR (CDCl ₃ ): δ 2.35 (3H, s), 3.69 (2H, s), 7.04 (1H, s), 7.12 (1H, s), 7.14 (1H, s).

Reference Example 19
Production of ethyl (3-chloro-5-methyl) phenylacetate

To 0.38 g (2.29 mmol) of [(3-chloro-5-methylphenyl)] acetonitrile, 2.1 ml of 2N sodium hydroxide aqueous solution and 5 ml of ethanol were added and stirred at 80 ° C. for 1 hour. The reaction mixture was concentrated under reduced pressure, and the residue was neutralized with water and 2N-HCl aqueous solution, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give colorless crystals. To this was added 0.02 ml of concentrated sulfuric acid and 2 ml of ethanol, and the mixture was heated to reflux with stirring for 5 hours. The reaction mixture was concentrated under reduced pressure, and the residue was neutralized with water and 2N-aqueous sodium hydroxide solution, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 6: 1) to obtain 0.31 g (63%) of ethyl 3-chloro-5-methylphenylacetate as a colorless oil.
¹ H-NMR (CDCl ₃ ): δ1.26 (3H, t, J = 7.2 Hz), 2.32 (3H, s), 3.53 (2H, s), 4.16 (2H, q, J = 7.2 Hz), 6.97 (1H, s), 7.08 (2H, s).

Reference Example 20
Preparation of ethyl [3-bromomethyl-5-chloro] phenylacetate

Carbon tetrachloride 2 ml of ethyl 3-chloro-5-methylphenylacetate 0.20 g (0.958 mol), 0.21 g (1.21 mmol) of N-bromosuccinimide, 0.01 g (0.037 mmol) of 2,2-azobis (isobutyronitrile) The mixture was heated to reflux for 2 hours. After air cooling, the precipitate was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 20: 1) to obtain 0.16 g (57%) of ethyl 3-bromomethyl-5-chlorophenylacetate as a colorless oil.
¹ H-NMR (CDCl ₃ ): δ 1.27 (3H, t, J = 7.2 Hz), 3.58 (2H, s), 4.17 (2H, t, J = 7.2 Hz), 4.42 (2H, s), 7.20 (1H, s), 7.22 (1H, s), 7.30 (1H, s).

収率：56％, 1H-NMR(CDCl3): δ1.26 (3H, t, J=7.0Hz), 3.61 (2H, s), 4.16 (2H, q, J=7.0Hz), 4.48 (2H, s), 7.18-7.38 (4H, m).

参考例２２

収率：70％, 1H-NMR(CDCl3): δ1.28 (3H, t, J=7Hz), 3.51 (3H, s), 3.59 (2H, s), 4.17 (2H, q, J=7Hz), 4.45 (2H, s), 7.04 (1H, s), 7.12 (2H, s).
Similarly, the compounds described in Reference Examples 21 and 22 were synthesized.
Reference Example 21

Yield: 56%, 1H-NMR (CDCl3): δ1.26 (3H, t, J = 7.0Hz), 3.61 (2H, s), 4.16 (2H, q, J = 7.0Hz), 4.48 (2H, s), 7.18-7.38 (4H, m).

Reference Example 22

Yield: 70%, 1H-NMR (CDCl3): δ1.28 (3H, t, J = 7Hz), 3.51 (3H, s), 3.59 (2H, s), 4.17 (2H, q, J = 7Hz) , 4.45 (2H, s), 7.04 (1H, s), 7.12 (2H, s).

4-ヒドロキシ-3-メチル安息香酸3.01g (19.78mmol)、濃硫酸0.20ml及びエタノール40mlの混合物を6時間加熱還流した。反応液を減圧下濃縮し、残渣に水及び2N-水酸化ナトリウム水溶液を加え中性とした後、酢酸エチルを加え抽出した。有機層を飽和食塩水で洗浄、無水硫酸ナトリウムで乾燥した後、減圧下溶媒を留去し、4-ヒドロキシ-3-メチル安息香酸エチルを黄色結晶として3.40g (95%)得た。
¹H-NMR(CDCl₃): δ1.38 (3H, t, J = 7.2 Hz), 2.28 (3H, s), 4.35 (2H, q, J = 7.2Hz), 5.75 (1H, s), 6.81 (1H, d, J = 8.1 Hz), 8.40 (1H, d, J = 8.1 Hz), 7.84 (1H, s).

参考例２４
4-(メトキシメトキシ)-3-メチル安息香酸エチルの製造

4-ヒドロキシ-3-メチル安息香酸エチル2.15g (11.93mmol)、メトキシメトキシクロリド1.60ml(21.2mmol)、 ジイソプロピルエチルアミン4.10ml(23.9mmol)及びTHF40mlの混合物を60℃で9時間加熱撹拌した。空冷後、反応液に水及び酢酸エチルを加え抽出し、有機層を飽和食塩水で洗浄、無水硫酸ナトリウムで乾燥した後、減圧下溶媒を留去した。残渣をシリカゲルカラムクロマトグラフィー（ヘキサン：酢酸エチル＝20：1）で精製し、4-(メトキシメトキシ)-3-メチル安息香酸エチルを無色油状物として1.94g（73％）得た。
¹H-NMR(CDCl₃): δ1.38 (3H, t, J = 7.2 Hz), 2.27 (3H, s), 3.49 (3H, s), 4.34 (2H, q, J = 7.2 Hz), 5.26 (2H, s), 7.05 (1H, d, J = 9.3 Hz), 7.84-7.86 (2H, m).

参考例２５
[4-(メトキシメトキシ)-3-メチル]ベンジルアルコールの製造

水素化リチウムアルミニウム0.26g (6.76mmol)の無水THF 5mlの懸濁液に4-(メトキシメトキシ)-3-メチル安息香酸エチル1.02g (4.55mmol)及び無水THF 10ml の混合物を0℃で滴下した。同温で1時間撹拌後、反応液に2N-水酸化ナトリウム水溶液を滴下し、残渣を濾去した。濾液に酢酸エチル及び飽和食塩水を加え分液後、有機層を無水硫酸ナトリウムで乾燥した後、減圧下溶媒を留去した。残渣をシリカゲルカラムクロマトグラフィー（ヘキサン：酢酸エチル＝3：1）で精製し、[4-(メトキシメトキシ)-3-メチル]ベンジルアルコールを無色油状物として0.80g（97％）得た。
¹H-NMR(CDCl₃): δ1.63 (1H, brs), 2.25 (3H, s), 3.48 (3H, s), 4.59 (2H, d, J = 3.9 Hz), 5.20 (2H, s), 7.01-7.17 (3H, m)

参考例２６
5-クロロメチル-2-（メトキシメトキシ）トルエンの製造

[4-(メトキシメトキシ)-3-メチル]ベンジルアルコール0.49g（2.69 mmol）、トリエチルアミン0.42ml（3.01mmol）、塩化メチレン14mlの混合物に氷冷下、メタンスルホニルクロリド0.23ml（2.97mmol）を滴下した後、4.5時間撹拌した。反応液を減圧下濃縮し、残渣をシリカゲルカラムクロマトグラフィー（ヘキサン：酢酸エチル＝6：1）で精製し、5-クロロメチル-2-（メトキシメトキシ）トルエンを淡褐色油状物として0.53g（99％）得た。
¹H-NMR(CDCl₃): δ2.25 (3H, s), 3.48 (3H, s), 4.54 (2H, s), 5.20 (2H, s), 7.02 (1H, d, J = 8.4 Hz), 7.14-7.18 (2H, m).

参考例２７
シンセティク コミュニケイションズ 2004年 34巻 4111-4118を参考に以下の化合物を合成した。
２−（N−クロロアセトアミド）ブタン酸メチルの合成

２−アミノブタン酸10.0ｇ（96.97mmmol）のメタノール65ｍl溶液に氷冷下、塩化チオニル30ｍl（411.28mmol）を滴下後、室温下18時間攪拌した。反応液を減圧下濃縮し、残渣にジイソプロピルエーテル20ｍlを加え減圧下共沸後、無色結晶を得た。
上記結晶5.00ｇに水15ｍl及び炭酸水素ナトリウム6.66ｇ（79.28mmol）を加え、氷冷下、クロロアセチルクロリド2.6ml（32.64mmol）のトルエン10ml溶液を滴下後、室温下18時間攪拌した。反応液を分液後、有機層を無水硫酸ナトリウムで乾燥した後、減圧下溶媒を留去した。残渣をシリカゲルカラムクロマトグラフィー（ヘキサン：酢酸エチル＝2：1）で精製し、２−（N−クロロアセトアミド）ブタン酸メチルを無色油状物として4.75ｇ（75％）得た。
1H-NMR(CDCl3): δ0.94 (3 H, t, J = 7.2 Hz), 1.74-1.86 (1 H, m), 1.8-2.02 (1 H, m), 3.78 (3 H, s), 4.08 (2 H, s), 4.59 (1 H, q, J = 6.6 Hz), 7.07 (1 H, s). Reference Example 23
Production of ethyl 4-hydroxy-3-methylbenzoate

A mixture of 3.01 g (19.78 mmol) of 4-hydroxy-3-methylbenzoic acid, 0.20 ml of concentrated sulfuric acid and 40 ml of ethanol was heated to reflux for 6 hours. The reaction mixture was concentrated under reduced pressure, and the residue was neutralized with water and 2N-aqueous sodium hydroxide solution, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to obtain 3.40 g (95%) of ethyl 4-hydroxy-3-methylbenzoate as yellow crystals.
¹ H-NMR (CDCl ₃ ): δ1.38 (3H, t, J = 7.2 Hz), 2.28 (3H, s), 4.35 (2H, q, J = 7.2 Hz), 5.75 (1H, s), 6.81 (1H, d, J = 8.1 Hz), 8.40 (1H, d, J = 8.1 Hz), 7.84 (1H, s).

Reference Example 24
Preparation of ethyl 4- (methoxymethoxy) -3-methylbenzoate

A mixture of 2.15 g (11.93 mmol) of ethyl 4-hydroxy-3-methylbenzoate, 1.60 ml (21.2 mmol) of methoxymethoxy chloride, 4.10 ml (23.9 mmol) of diisopropylethylamine and 40 ml of THF was stirred with heating at 60 ° C. for 9 hours. After air cooling, water and ethyl acetate were added to the reaction solution for extraction. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 20: 1) to obtain 1.94 g (73%) of ethyl 4- (methoxymethoxy) -3-methylbenzoate as a colorless oil.
¹ H-NMR (CDCl ₃ ): δ1.38 (3H, t, J = 7.2 Hz), 2.27 (3H, s), 3.49 (3H, s), 4.34 (2H, q, J = 7.2 Hz), 5.26 (2H, s), 7.05 (1H, d, J = 9.3 Hz), 7.84-7.86 (2H, m).

Reference Example 25
Preparation of [4- (methoxymethoxy) -3-methyl] benzyl alcohol

To a suspension of 0.26 g (6.76 mmol) of lithium aluminum hydride in 5 ml of anhydrous THF, a mixture of 1.02 g (4.55 mmol) of ethyl 4- (methoxymethoxy) -3-methylbenzoate and 10 ml of anhydrous THF was added dropwise at 0 ° C. . After stirring at the same temperature for 1 hour, 2N-aqueous sodium hydroxide solution was added dropwise to the reaction solution, and the residue was removed by filtration. Ethyl acetate and saturated brine were added to the filtrate, and the mixture was separated. The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 3: 1) to obtain 0.80 g (97%) of [4- (methoxymethoxy) -3-methyl] benzyl alcohol as a colorless oil.
¹ H-NMR (CDCl ₃ ): δ1.63 (1H, brs), 2.25 (3H, s), 3.48 (3H, s), 4.59 (2H, d, J = 3.9 Hz), 5.20 (2H, s) , 7.01-7.17 (3H, m)

Reference Example 26
Production of 5-chloromethyl-2- (methoxymethoxy) toluene

Methanesulfonyl chloride 0.23 ml (2.97 mmol) was added dropwise to a mixture of [4- (methoxymethoxy) -3-methyl] benzyl alcohol 0.49 g (2.69 mmol), triethylamine 0.42 ml (3.01 mmol) and methylene chloride 14 ml under ice cooling. And stirred for 4.5 hours. The reaction mixture was concentrated under reduced pressure, the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 6: 1), and 0.53 g (99%) of 5-chloromethyl-2- (methoxymethoxy) toluene as a pale brown oily substance. %)Obtained.
¹ H-NMR (CDCl ₃ ): δ2.25 (3H, s), 3.48 (3H, s), 4.54 (2H, s), 5.20 (2H, s), 7.02 (1H, d, J = 8.4 Hz) , 7.14-7.18 (2H, m).

Reference Example 27
The following compounds were synthesized with reference to Synthetic Communications 2004 Volume 34 4111-4118.
Synthesis of methyl 2- (N-chloroacetamido) butanoate

To a solution of 10.0 g (96.97 mmol) of 2-aminobutanoic acid in 65 mL of methanol was added dropwise 30 mL (411.28 mmol) of thionyl chloride under ice cooling, followed by stirring at room temperature for 18 hours. The reaction solution was concentrated under reduced pressure, 20 ml of diisopropyl ether was added to the residue and azeotroped under reduced pressure to obtain colorless crystals.
To 5.00 g of the above crystals, 15 ml of water and 6.66 g (79.28 mmol) of sodium hydrogen carbonate were added, and a solution of 2.6 ml (32.64 mmol) of chloroacetyl chloride in 10 ml of toluene was added dropwise under ice cooling, followed by stirring at room temperature for 18 hours. After separating the reaction solution, the organic layer was dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 2: 1) to obtain 4.75 g (75%) of methyl 2- (N-chloroacetamido) butanoate as a colorless oil.
1H-NMR (CDCl3): δ0.94 (3 H, t, J = 7.2 Hz), 1.74-1.86 (1 H, m), 1.8-2.02 (1 H, m), 3.78 (3 H, s), 4.08 (2 H, s), 4.59 (1 H, q, J = 6.6 Hz), 7.07 (1 H, s).

収率：74％, 1H-NMR(CDCl3): δ0.94 (3H, t, J=7.5Hz), 1.70-2.00 (2H, m), 3.78 (3H, s), 4.09 (2H, s), 4.54-4.63 (1H, m), 7.10 (1H, brs).

参考例２９

収率：70％, 1H-NMR(CDCl3): δ0.94 (3H, t, J=7.5Hz), 1.65-2.00 (2H, m), 3.78 (3H, s), 4.11 (2H, s) 4.50-4.65 (1H, m), 7.09 (1H, brs).

参考例３０

収率：97％, 1H-NMR(CDCl3): δ0.95 (3 H, t, J = 7.2 Hz), 1.26-1.41 (2 H, m), 1.66-1.78 (1 H, m), 1.81-1.89 (1 H, m), 3.77 (3 H, s), 4.08 (2 H, s), 4.62 (1 H, dt, J = 7.8 Hz), 7.03 (1 H, s)

参考例３１

収率：91％, 1H-NMR(CDCl3): δ0.95 (3 H, t, J = 7.5 Hz), 1.24-1.43 (2 H, m), 1.66-1.78 (1 H, m), 1.81-1.93 (1 H, m), 3.77(3H, s),4.08 (2 H, s), 4.62 (1 H, q, J = 7.5 Hz),7.02 (1 H, s)

参考例３２

収率：99％, 1H-NMR(CDCl3): δ0.91 (3H, t, J=7Hz), 1.23-1.40 (4H, m), 1.67-1.80 (1H, m), 1.81-1.96 (1H, m), 3.77 (3H, s), 4.08 (2H, s), 4.57-4.65 (1H, m), 7.03 (1H, brs).

参考例３３

収率：86％, 1H-NMR(CDCl3): δ0.91 (3H, t, J=7Hz), 1.23-1.40 (4H, m), 1.65-1.80 (1H, m), 1.82-1.95 (1H, m), 3.77 (3H, s), 4.08 (2H, s), 4.55-4.65 (1H, m), 7.02 (1H, brs).

参考例３４

収率：93％, 1H-NMR(CDCl3): δ0.96 (6 H, d, J = 6.0 Hz), 1.58-1.74 (3H, m), 3.76 (3 H, s), 4.08 (2 H, s), 4.66 (1 H, t, J = 8.4 Hz), 6.90 (1 H, br)

参考例３５

収率：quant.％, 1H-NMR(CDCl3): δ0.96 (6H, d, J=6.0Hz), 1.54-1.78 (3H, m), 3.76 (3H, s), 4.08 (2H, s), 4.60-4.70 (1H, m), 6.83-6.95 (1H, m).

参考例３６

収率：93％, 1H-NMR(CDCl3): δ0.95 (6H, d, J=6Hz), 1.56-1.75 (3H, m), 3.76 (3H, s), 4.08 (2H, s), 4.60-4.70 (1H, m), 6.93 (1H, brs).

参考例３７

収率：90％, 1H-NMR(CDCl3): δ0.96 (6H, t, J=6.5Hz), 2.16-2.30 (1H, m), 3.77 (3H, s), 4.10 (2H, s), 4.51-4.60 (1H, m), 7.04 (1H, brs). Similarly, the compounds described in Reference Examples 28 to 37 were obtained.
Reference Example 28

Yield: 74%, 1H-NMR (CDCl3): δ0.94 (3H, t, J = 7.5Hz), 1.70-2.00 (2H, m), 3.78 (3H, s), 4.09 (2H, s), 4.54-4.63 (1H, m), 7.10 (1H, brs).

Reference Example 29

Yield: 70%, 1H-NMR (CDCl3): δ0.94 (3H, t, J = 7.5Hz), 1.65-2.00 (2H, m), 3.78 (3H, s), 4.11 (2H, s) 4.50 -4.65 (1H, m), 7.09 (1H, brs).

Reference Example 30

Yield: 97%, 1H-NMR (CDCl3): δ 0.95 (3 H, t, J = 7.2 Hz), 1.26-1.41 (2 H, m), 1.66-1.78 (1 H, m), 1.81- 1.89 (1 H, m), 3.77 (3 H, s), 4.08 (2 H, s), 4.62 (1 H, dt, J = 7.8 Hz), 7.03 (1 H, s)

Reference Example 31

Yield: 91%, 1H-NMR (CDCl3): δ 0.95 (3 H, t, J = 7.5 Hz), 1.24-1.43 (2 H, m), 1.66-1.78 (1 H, m), 1.81- 1.93 (1 H, m), 3.77 (3H, s), 4.08 (2 H, s), 4.62 (1 H, q, J = 7.5 Hz), 7.02 (1 H, s)

Reference Example 32

Yield: 99%, 1H-NMR (CDCl3): δ 0.91 (3H, t, J = 7Hz), 1.23-1.40 (4H, m), 1.67-1.80 (1H, m), 1.81-1.96 (1H, m), 3.77 (3H, s), 4.08 (2H, s), 4.57-4.65 (1H, m), 7.03 (1H, brs).

Reference Example 33

Yield: 86%, 1H-NMR (CDCl3): δ0.91 (3H, t, J = 7Hz), 1.23-1.40 (4H, m), 1.65-1.80 (1H, m), 1.82-1.95 (1H, m), 3.77 (3H, s), 4.08 (2H, s), 4.55-4.65 (1H, m), 7.02 (1H, brs).

Reference Example 34

Yield: 93%, 1H-NMR (CDCl3): δ 0.96 (6 H, d, J = 6.0 Hz), 1.58-1.74 (3H, m), 3.76 (3 H, s), 4.08 (2 H, s), 4.66 (1 H, t, J = 8.4 Hz), 6.90 (1 H, br)

Reference Example 35

Yield: quant.%, 1H-NMR (CDCl3): δ0.96 (6H, d, J = 6.0Hz), 1.54-1.78 (3H, m), 3.76 (3H, s), 4.08 (2H, s) , 4.60-4.70 (1H, m), 6.83-6.95 (1H, m).

Reference Example 36

Yield: 93%, 1H-NMR (CDCl3): δ 0.95 (6H, d, J = 6Hz), 1.56-1.75 (3H, m), 3.76 (3H, s), 4.08 (2H, s), 4.60 -4.70 (1H, m), 6.93 (1H, brs).

Reference Example 37

Yield: 90%, 1H-NMR (CDCl3): δ0.96 (6H, t, J = 6.5Hz), 2.16-2.30 (1H, m), 3.77 (3H, s), 4.10 (2H, s), 4.51-4.60 (1H, m), 7.04 (1H, brs).

２−（N−クロロアセトアミド）ブタン酸メチル4.00g（20.71mmol）、トリエチルアミン8.8ml（63.14mmol）、ベンジルアミン2.8ml（25.64mmol）及びメタノール45mlの混合物を16時間加熱還流攪拌した。反応液を減圧下濃縮し、残渣に水及び酢酸エチルを加え抽出後、有機層に1N塩酸水溶液を加え分液後、有機層に炭酸水素ナトリウム水溶液を加え中性とした後、有機層を飽和食塩水で洗浄後、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、残渣をジイソプロピルエーテルで洗浄し１−ベンジル−３−エチルピペラジン−２,５−ジオンを無色結晶として1.58ｇ（33％）得た。
1H-NMR(CDCl3): δ0.98 (3 H, t, J = 7.2 Hz), 1.71-2.02 (2 H, m), 3.84 (2 H, dd, J = 0.9, 5.1 Hz), 4.03-4.08 (1 H, m), 4.51 (1 H, d, J = 14.4 Hz), 4.71 (1 H, d, J = 14.4 Hz), 7.25-7.36 (5 H, m) Reference Example 38
Synthesis of 1-benzyl-3-ethylpiperazine-2,5-dione

A mixture of methyl 2- (N-chloroacetamido) butanoate 4.00 g (20.71 mmol), triethylamine 8.8 ml (63.14 mmol), benzylamine 2.8 ml (25.64 mmol) and methanol 45 ml was heated and stirred for 16 hours. The reaction mixture was concentrated under reduced pressure, and water and ethyl acetate were added to the residue for extraction. After 1N hydrochloric acid solution was added to the organic layer for liquid separation, the organic layer was neutralized by adding aqueous sodium hydrogen carbonate solution, and then the organic layer was saturated. After washing with brine, it was dried over anhydrous sodium sulfate. After evaporating the solvent under reduced pressure, the residue was washed with diisopropyl ether to obtain 1.58 g (33%) of 1-benzyl-3-ethylpiperazine-2,5-dione as colorless crystals.
1H-NMR (CDCl3): δ0.98 (3 H, t, J = 7.2 Hz), 1.71-2.02 (2 H, m), 3.84 (2 H, dd, J = 0.9, 5.1 Hz), 4.03-4.08 (1 H, m), 4.51 (1 H, d, J = 14.4 Hz), 4.71 (1 H, d, J = 14.4 Hz), 7.25-7.36 (5 H, m)

収率：44％, 1H-NMR(CDCl3): δ0.98 (3H, t, J=7.5Hz), 1.83-2.03 (2H, m), 3.83 (2H, d, J=5.5Hz), 4.00-4.10 (1H, m), 4.50 (1H, d, J=14.5Hz), 4.71 (1H, d, J=14.5Hz), 7.05 (1H, brs), 7.23-7.40 (5H, m).

参考例４０

収率：32％, 1H-NMR(CDCl3): δ0.98 (3H, t, J=7.5Hz), 1.85-2.05 (2H, m), 3.83 (2H, dd, J=6, 1Hz), 4.02-4.10 (1H, m), 4.50 (1H, d, J=14.5Hz), 4.71 (1H, d, J=14.5Hz), 6.95 (1H, brs), 7.20-7.40 (5H, m).

参考例４１

収率：41％, 1H-NMR(CDCl3): δ0.97 (3 H, t, J = 7.2 Hz), 1.36-1.48 (2 H, m), 1.82-1.90 (2 H, m), 3.83 (2 H, dd, J = 0.9, 5.4 Hz), 4.07 (1 H, td, J = 2.6, 5.7 Hz), 4.60 (2 H, dd, J = 14.1, 39.9 Hz), 7.24-7.38 (5 H, m)

参考例４２

収率：45％, 1H-NMR(CDCl3): δ0.97 (3 H, t, J = 7.2 Hz), 1.36-1.48 (2 H, m), 1.82-1.90 (2 H, m), 3.83 (2 H, dd, J = 0.9, 5.4 Hz), 4.04-4.09 (1 H, m), 4.53 (1 H, d, J = 14.4 Hz), 4.67 (1 H, d, J = 14.4 Hz), 7.24-7.39 (5 H, m)

参考例４３

収率：49％, 1H-NMR(CDCl3): δ0.85-1.00 (3H, m), 1.24-1.45 (4H, m), 1.80-1.96 (2H, m), 3.83 (2H, d, J=6Hz), 4.02-4.12 (1H, m), 4.53 (1H, d, J=14.5Hz), 4.67 (1H, d, J=14.5Hz), 6.68 (1H, brs), 7.21-7.40 (5H, m).

参考例４４

収率：43％, 1H-NMR(CDCl3): δ0.85-0.95 (3H, m), 1.30-1.50 (4H, m), 1.80-1.98 (2H, m), 3.72-3.91 (2H, m), 4.04-4.10 (1H, m), 4.53 (1H, d, J=14.5Hz), 4.67 (1H, d, J=14.5Hz), 6.45 (1H, brs), 7.23-7.40 (5H, m).

参考例４５

収率：34％, 1H-NMR(CDCl3): δ0.97 (6 H, dd, J = 6.0, 8.1 Hz), 1.61-1.73 (2 H, m), 1.76-1.88 (1 H, m), 3.83 (2 H, d, J = 6.3 Hz), 4.02-4.07 (1 H, m), 4.59 (2 H, q, J = 14.7 Hz), 6.65 (1 H, s), 7.23-7.35 (5 H, m)

参考例４６

収率：55％, 1H-NMR(CDCl3): δ0.96 (3H, d, J=6.5Hz), 0.98 (3H, d, J=6.5Hz), 1.58-1.89 (3H, m), 3.80 (1H, d, J=17.5Hz), 3.83(1H, d, J=17.5Hz), 4.01-4.10 (1H, m), 4.55 (1H, d, J=14.5Hz), 4.65 (1H, d, J=14.5Hz), 6.66 (1H, s), 7.21-7.40 (5H, m).

参考例４７

収率：50％, 1H-NMR(CDCl3): δ0.90-1.05 (6H, m), 1.58-1.90 (3H, m), 3.83 (2H, d, J=6.5Hz), 4.02-4.10 (1H, m), 4.54 (1H, d, J=14.5Hz), 4.65 (1H, d, J=14.5Hz), 6.75 (1H, brs), 7.20-7.40 (5H, m).

参考例４８

収率：12％, 1H-NMR(CDCl3): δ0.88 (3H, d, J=6.5Hz), 1.02 (3H, d, J=6.5Hz), 2.42-2.55 (1H, m), 3.83 (2H, d, J=11Hz), 3.90-3.96 (1H, m), 4.45 (1H, d, J=14Hz), 4.77 (1H, d, J=14Hz), 6.43 (1H, brs), 7.21-7.45 (5H, m). Similarly, the compounds of Reference Examples 39 to 48 were obtained.
Reference Example 39

Yield: 44%, 1H-NMR (CDCl3): δ0.98 (3H, t, J = 7.5Hz), 1.83-2.03 (2H, m), 3.83 (2H, d, J = 5.5Hz), 4.00- 4.10 (1H, m), 4.50 (1H, d, J = 14.5Hz), 4.71 (1H, d, J = 14.5Hz), 7.05 (1H, brs), 7.23-7.40 (5H, m).

Reference Example 40

Yield: 32%, 1H-NMR (CDCl3): δ 0.98 (3H, t, J = 7.5Hz), 1.85-2.05 (2H, m), 3.83 (2H, dd, J = 6, 1Hz), 4.02 -4.10 (1H, m), 4.50 (1H, d, J = 14.5Hz), 4.71 (1H, d, J = 14.5Hz), 6.95 (1H, brs), 7.20-7.40 (5H, m).

Reference Example 41

Yield: 41%, 1H-NMR (CDCl3): δ 0.97 (3 H, t, J = 7.2 Hz), 1.36-1.48 (2 H, m), 1.82-1.90 (2 H, m), 3.83 ( 2 H, dd, J = 0.9, 5.4 Hz), 4.07 (1 H, td, J = 2.6, 5.7 Hz), 4.60 (2 H, dd, J = 14.1, 39.9 Hz), 7.24-7.38 (5 H, m)

Reference Example 42

Yield: 45%, 1H-NMR (CDCl3): δ 0.97 (3 H, t, J = 7.2 Hz), 1.36-1.48 (2 H, m), 1.82-1.90 (2 H, m), 3.83 ( 2 H, dd, J = 0.9, 5.4 Hz), 4.04-4.09 (1 H, m), 4.53 (1 H, d, J = 14.4 Hz), 4.67 (1 H, d, J = 14.4 Hz), 7.24 -7.39 (5 H, m)

Reference Example 43

Yield: 49%, 1H-NMR (CDCl3): δ0.85-1.00 (3H, m), 1.24-1.45 (4H, m), 1.80-1.96 (2H, m), 3.83 (2H, d, J = 6Hz), 4.02-4.12 (1H, m), 4.53 (1H, d, J = 14.5Hz), 4.67 (1H, d, J = 14.5Hz), 6.68 (1H, brs), 7.21-7.40 (5H, m ).

Reference Example 44

Yield: 43%, 1H-NMR (CDCl3): δ0.85-0.95 (3H, m), 1.30-1.50 (4H, m), 1.80-1.98 (2H, m), 3.72-3.91 (2H, m) , 4.04-4.10 (1H, m), 4.53 (1H, d, J = 14.5Hz), 4.67 (1H, d, J = 14.5Hz), 6.45 (1H, brs), 7.23-7.40 (5H, m).

Reference Example 45

Yield: 34%, 1H-NMR (CDCl3): δ 0.97 (6 H, dd, J = 6.0, 8.1 Hz), 1.61-1.73 (2 H, m), 1.76-1.88 (1 H, m), 3.83 (2 H, d, J = 6.3 Hz), 4.02-4.07 (1 H, m), 4.59 (2 H, q, J = 14.7 Hz), 6.65 (1 H, s), 7.23-7.35 (5 H , m)

Reference Example 46

Yield: 55%, 1H-NMR (CDCl3): δ 0.96 (3H, d, J = 6.5Hz), 0.98 (3H, d, J = 6.5Hz), 1.58-1.89 (3H, m), 3.80 ( 1H, d, J = 17.5Hz), 3.83 (1H, d, J = 17.5Hz), 4.01-4.10 (1H, m), 4.55 (1H, d, J = 14.5Hz), 4.65 (1H, d, J = 14.5Hz), 6.66 (1H, s), 7.21-7.40 (5H, m).

Reference Example 47

Yield: 50%, 1H-NMR (CDCl3): δ0.90-1.05 (6H, m), 1.58-1.90 (3H, m), 3.83 (2H, d, J = 6.5Hz), 4.02-4.10 (1H , m), 4.54 (1H, d, J = 14.5Hz), 4.65 (1H, d, J = 14.5Hz), 6.75 (1H, brs), 7.20-7.40 (5H, m).

Reference Example 48

Yield: 12%, 1H-NMR (CDCl3): δ0.88 (3H, d, J = 6.5Hz), 1.02 (3H, d, J = 6.5Hz), 2.42-2.55 (1H, m), 3.83 ( 2H, d, J = 11Hz), 3.90-3.96 (1H, m), 4.45 (1H, d, J = 14Hz), 4.77 (1H, d, J = 14Hz), 6.43 (1H, brs), 7.21-7.45 (5H, m).

水素化リチウムアルミニウム0.87g（22.9mmol）の無水THF 20mlの懸濁液に氷冷下、１−ベンジル−３−エチルピペラジン−２,５−ジオン1.50g（6.46mmol）の無水THF（10ml）溶液を滴下した。室温下18時間撹拌後、氷冷下、水0.25ml及びTHF5ml混合液及び2N-水酸化ナトリウム水溶液0.5mlを順次滴下後、室温下1時間撹拌した。水酸化アルミニウムを濾去した後、濾液を減圧下濃縮した。残渣に酢酸エチル及び飽和食塩水を加え分液した後、有機層を無水硫酸ナトリウムで乾燥した。減圧下溶媒を留去後、１−ベンジル−３−エチルピペラジンを淡黄色油状物として1.29g（98％）得た。
1H-NMR(CDCl3): δ0.90 (3 H, t, J = 7.5 Hz), 1.30-1.40 (2 H, m), 1.70 (1 H, t, J = 10.8 Hz), 2.01 (1 H, dt, J = 3.6, 10.8 Hz) , 2.61-2.70 (1 H, m), 2.73-2.89 (2 H, m), 2.92-3.00 (1 H, m), 3.49 (2 H, dt, J = 6.9 Hz), 3.68 (1 H, t, J = 5.7 Hz), 7.23-7.31 (5 H, m) Reference Example 49
Synthesis of 1-benzyl-3-ethylpiperazine

A solution of 0.87 g (22.9 mmol) of lithium aluminum hydride in 20 ml of anhydrous THF under ice cooling and a solution of 1.50 g (6.46 mmol) of 1-benzyl-3-ethylpiperazine-2,5-dione in anhydrous THF (10 ml) Was dripped. After stirring at room temperature for 18 hours, 0.25 ml of water and 5 ml of THF and 0.5 ml of 2N-sodium hydroxide aqueous solution were successively added dropwise under ice cooling, followed by stirring at room temperature for 1 hour. After aluminum hydroxide was removed by filtration, the filtrate was concentrated under reduced pressure. Ethyl acetate and saturated brine were added to the residue for liquid separation, and the organic layer was dried over anhydrous sodium sulfate. After evaporating the solvent under reduced pressure, 1.29 g (98%) of 1-benzyl-3-ethylpiperazine as a pale yellow oil was obtained.
1H-NMR (CDCl3): δ0.90 (3 H, t, J = 7.5 Hz), 1.30-1.40 (2 H, m), 1.70 (1 H, t, J = 10.8 Hz), 2.01 (1 H, dt, J = 3.6, 10.8 Hz), 2.61-2.70 (1 H, m), 2.73-2.89 (2 H, m), 2.92-3.00 (1 H, m), 3.49 (2 H, dt, J = 6.9 Hz), 3.68 (1 H, t, J = 5.7 Hz), 7.23-7.31 (5 H, m)

収率：96％, 1H-NMR(CDCl3): δ0.90 (3H, t, J=7.5Hz), 1.29-1.36(2H, m), 1.70 (1H, t, J=10.5Hz), 2.01 (1H, td, J=11, 3.5Hz), 2.60-3.00 (5H, m), 3.46 (1H, d, J=13Hz), 3.53 (1H, d, J=13Hz), 7.20-7.40 (5H, m).

参考例５１

収率：89％, 1H-NMR(CDCl3): δ0.90 (3H, t, J=7.5Hz), 1.35 (2H, quant, J=7.5Hz), 1.70 (1H, t, J=10.5Hz), 2.01 (1H, td, J=11, 3.5Hz), 2.60-3.00 (5H, m), 3.46 (1H, d, J=13Hz), 3.53 (1H, d, J=13Hz), 7.20-7.40 (5H, m).

参考例５２

収率：73％, 1H-NMR(CDCl3): δ0.89 (3 H, t, J = 6.9 Hz), 1.29-1.40 (4 H, m), 1.69 (1 H, t, J = 9.9 Hz), 2.00 (1 H, td, J = 3.6, 10.5 Hz), 2.73-2.99 (5 H, m), 3.49 (2 H, d, J = 5.4 Hz), 7.21-7.35 (5 H, m)

参考例５３

収率：68％, 1H-NMR(CDCl3): δ0.89 (3 H, t, J = 6.8 Hz), 1.26-1.40 (4 H, m), 1.69 (1 H, t, J = 9.9 Hz), 2.00 (1 H, td, J = 3.6, 10.8 Hz), 2.72-2.95 (5 H, m), 3.49 (2 H, d, J = 5.1 Hz), 7.23-7.32 (5 H, m)

参考例５４

収率：quant.％, 1H-NMR(CDCl3): δ0.88 (3H, t, J=6.5Hz), 1.20-1.40 (6H, m), 1.50 (1H, brs), 1.70 (1H, t, J=10Hz), 2.00 (1H, td, J=11, 4Hz), 2.65-3.00 (5H, m), 3.46 (1H, d, J=13Hz), 3.52 (1H, d, J=13Hz), 7.20-7.40 (5H, m).

参考例５５

収率：quant.％, 1H-NMR(CDCl3): δ0.88 (3H, d, J=6.5Hz), 1.20-1.39 (6H, m), 1.70 (1H, t, J=10Hz), 2.00 (1H, td, J=11, 4Hz), 2.65-3.00 (5H, m), 3.46 (1H, d, J=13Hz), 3.52 (1H, d, J=13Hz), 7.20-7.40 (5H, m).

参考例５６

収率：88％, 1H-NMR(CDCl3): δ0.88 (6 H, dd, J = 5.1, 6.6 Hz), 1.09-1.26 (2 H, m), 1.59-1.72 (3 H, m), 2.00 (1 H, dt, J = 3.9, 10.8 Hz), 2.74-2.84 (3 H, m), 2.88-2.94 (2 H, m), 3.49 (2 H, d, J = 7.5 Hz), 7.31 (3 H, s), 7.32 (2 H, s)

参考例５７

収率：quant. ％, 1H-NMR(CDCl3): δ0.87 (3H, d, J=6.5Hz), 0.89 (3H, d, J=6.5Hz), 1.05-1.29 (2H, m), 1.57-1.74 (2H, m), 2.00 (1H, td, J=10.5, 4.0Hz), 2.70-2.99 (5H, m), 3.43 (1H, d, J=13.0Hz), 3.50 (1H, d, J=13.0Hz), 7.20-7.38 (5H, m).

参考例５８

収率：90％, 1H-NMR(CDCl3): δ0.87 (3H, d, J=5Hz), 0.89 (3H, d, J=5Hz), 1.16-1.30 (2H, m), 1.58-1.74 (2H, m), 2.00 (1H, td, J=11, 4Hz), 2.70-3.00 (5H, m), 3.45 (1H, d, J=13Hz), 3.52 (1H, d, J=13Hz), 7.20-7.40 (5H, m).

参考例５９

収率：92％, 1H-NMR(CDCl3): δ0.88 (3H, d, J=6.5Hz), 0.93 (3H, d, J=6.5Hz), 1.55 (1H, sextet, J=6.5Hz), 1.78 (1H, t, J=10.5Hz), 1.97 (1H, td, J=11, 3.5Hz), 2.67-3.03 (5H, m), 3.44 (1H, d, J=13Hz), 3.56 (1H, d, J=13Hz), 7.20-7.40 (5H, m).

参考例６０

収率：80％, 1H-NMR(CDCl3): δ0.91 (3H, d, J=7.0Hz), 0.94 (3H, d, J=7.0Hz), 1.43-1.60 (1H, m), 2.27-2.37 (1H, m), 2.38-2.48 (1H, m), 2.65-2.85 (2H, m), 2.86-2.94 (1H, m), 2.96-3.06 (2H, m). Similarly, the compounds described in Reference Examples 50 to 60 were obtained.
Reference Example 50

Yield: 96%, 1H-NMR (CDCl3): δ0.90 (3H, t, J = 7.5Hz), 1.29-1.36 (2H, m), 1.70 (1H, t, J = 10.5Hz), 2.01 ( 1H, td, J = 11, 3.5Hz), 2.60-3.00 (5H, m), 3.46 (1H, d, J = 13Hz), 3.53 (1H, d, J = 13Hz), 7.20-7.40 (5H, m ).

Reference Example 51

Yield: 89%, 1H-NMR (CDCl3): δ0.90 (3H, t, J = 7.5Hz), 1.35 (2H, quant, J = 7.5Hz), 1.70 (1H, t, J = 10.5Hz) , 2.01 (1H, td, J = 11, 3.5Hz), 2.60-3.00 (5H, m), 3.46 (1H, d, J = 13Hz), 3.53 (1H, d, J = 13Hz), 7.20-7.40 ( 5H, m).

Reference Example 52

Yield: 73%, 1H-NMR (CDCl3): δ0.89 (3 H, t, J = 6.9 Hz), 1.29-1.40 (4 H, m), 1.69 (1 H, t, J = 9.9 Hz) , 2.00 (1 H, td, J = 3.6, 10.5 Hz), 2.73-2.99 (5 H, m), 3.49 (2 H, d, J = 5.4 Hz), 7.21-7.35 (5 H, m)

Reference Example 53

Yield: 68%, 1H-NMR (CDCl3): δ 0.89 (3 H, t, J = 6.8 Hz), 1.26-1.40 (4 H, m), 1.69 (1 H, t, J = 9.9 Hz) , 2.00 (1 H, td, J = 3.6, 10.8 Hz), 2.72-2.95 (5 H, m), 3.49 (2 H, d, J = 5.1 Hz), 7.23-7.32 (5 H, m)

Reference Example 54

Yield: quant.%, 1H-NMR (CDCl3): δ0.88 (3H, t, J = 6.5Hz), 1.20-1.40 (6H, m), 1.50 (1H, brs), 1.70 (1H, t, J = 10Hz), 2.00 (1H, td, J = 11, 4Hz), 2.65-3.00 (5H, m), 3.46 (1H, d, J = 13Hz), 3.52 (1H, d, J = 13Hz), 7.20 -7.40 (5H, m).

Reference Example 55

Yield: quant.%, 1H-NMR (CDCl3): δ0.88 (3H, d, J = 6.5Hz), 1.20-1.39 (6H, m), 1.70 (1H, t, J = 10Hz), 2.00 ( 1H, td, J = 11, 4Hz), 2.65-3.00 (5H, m), 3.46 (1H, d, J = 13Hz), 3.52 (1H, d, J = 13Hz), 7.20-7.40 (5H, m) .

Reference Example 56

Yield: 88%, 1H-NMR (CDCl3): δ 0.88 (6 H, dd, J = 5.1, 6.6 Hz), 1.09-1.26 (2 H, m), 1.59-1.72 (3 H, m), 2.00 (1 H, dt, J = 3.9, 10.8 Hz), 2.74-2.84 (3 H, m), 2.88-2.94 (2 H, m), 3.49 (2 H, d, J = 7.5 Hz), 7.31 ( 3 H, s), 7.32 (2 H, s)

Reference Example 57

Yield: quant.%, 1H-NMR (CDCl3): δ0.87 (3H, d, J = 6.5Hz), 0.89 (3H, d, J = 6.5Hz), 1.05-1.29 (2H, m), 1.57 -1.74 (2H, m), 2.00 (1H, td, J = 10.5, 4.0Hz), 2.70-2.99 (5H, m), 3.43 (1H, d, J = 13.0Hz), 3.50 (1H, d, J = 13.0Hz), 7.20-7.38 (5H, m).

Reference Example 58

Yield: 90%, 1H-NMR (CDCl3): δ0.87 (3H, d, J = 5Hz), 0.89 (3H, d, J = 5Hz), 1.16-1.30 (2H, m), 1.58-1.74 ( 2H, m), 2.00 (1H, td, J = 11, 4Hz), 2.70-3.00 (5H, m), 3.45 (1H, d, J = 13Hz), 3.52 (1H, d, J = 13Hz), 7.20 -7.40 (5H, m).

Reference Example 59

Yield: 92%, 1H-NMR (CDCl3): δ0.88 (3H, d, J = 6.5Hz), 0.93 (3H, d, J = 6.5Hz), 1.55 (1H, sextet, J = 6.5Hz) , 1.78 (1H, t, J = 10.5Hz), 1.97 (1H, td, J = 11, 3.5Hz), 2.67-3.03 (5H, m), 3.44 (1H, d, J = 13Hz), 3.56 (1H , d, J = 13Hz), 7.20-7.40 (5H, m).

Reference Example 60

Yield: 80%, 1H-NMR (CDCl3): δ0.91 (3H, d, J = 7.0Hz), 0.94 (3H, d, J = 7.0Hz), 1.43-1.60 (1H, m), 2.27- 2.37 (1H, m), 2.38-2.48 (1H, m), 2.65-2.85 (2H, m), 2.86-2.94 (1H, m), 2.96-3.06 (2H, m).

１−ベンジル−３−エチルピペラジン1.16g（5.68 mmol）、5％パラジウム-炭素 0.11g、トリフルオロ酢酸1.1ml（14.8mmol）及びメタノール30ml混合物を室温下、水素ガス存在下１７時間攪拌した。反応液を濾過した後、濾液を減圧下濃縮した。残渣をジイソプロピルエーテルで洗浄後、３−エチルピペラジン・2トリフルオロ酢酸塩を無色結晶として1.65g（85％）得た。
1H-NMR(D2O): δ0.74 (3 H, t, J = 7.5 Hz), 1.44-1.54 (2 H, m), 2.90 (1 H, dd, J = 12.0 Hz), 3.07-3.15 (2 H, m), 3.20-3.34 (1 H, m), 3.43-3.51 (3 H, m)
Reference Example 61
Synthesis of 3-ethylpiperazine-2 trifluoroacetate

A mixture of 1.16 g (5.68 mmol) of 1-benzyl-3-ethylpiperazine, 0.11 g of 5% palladium-carbon, 1.1 ml (14.8 mmol) of trifluoroacetic acid and 30 ml of methanol was stirred at room temperature for 17 hours in the presence of hydrogen gas. After the reaction solution was filtered, the filtrate was concentrated under reduced pressure. The residue was washed with diisopropyl ether, and 1.65 g (85%) of 3-ethylpiperazine-2trifluoroacetate was obtained as colorless crystals.
1H-NMR (D2O): δ0.74 (3 H, t, J = 7.5 Hz), 1.44-1.54 (2 H, m), 2.90 (1 H, dd, J = 12.0 Hz), 3.07-3.15 (2 H, m), 3.20-3.34 (1 H, m), 3.43-3.51 (3 H, m)

収率：88％, 1H-NMR(DMSO-d6): δ0.94 (3H, t, J=7.5Hz), 1.60 (2H, quant, J=7.5Hz), 2.93 (1H, t, J=12.5Hz), 3.00-3.65 (6H, m), 9.24 (2H, brs).

参考例６３

収率：80％, 1H-NMR(DMSO-d6): δ0.94 (3H, t, J=7.5Hz), 1.61 (2H, quant, J=7.5Hz), 2.93 (1H, t, J=12.5Hz), 3.00-3.60 (6H, m), 9.27 (2H, brs).

参考例６４

収率：59％, 1H-NMR(D2O): δ0.76 (3 H, t, J = 7.5 Hz), 1.25 (2 H, m), 1.53 (2 H, q, J = 7.5 Hz), 3.00 (1 H, t, J = 12.9 Hz), 3.13-3.29 (2 H, m), 3.39-3.48 (1 H, m), 3.52-3.59 (3 H, m)

参考例６５

収率：61％, 1H-NMR(D2O): δ0.79 (3 H, t, J = 7.2 Hz), 1.22-1.35 (2 H, m), 1.52-1.60 (2 H, m), 3.03 (1 H, dd, J = 12.2 Hz), 3.16-3.32 (2 H, m), 3.40-3.51 (1 H, m), 3.55-3.63 (3 H, m)

参考例６６

収率：76％, 1H-NMR(DMSO-d6): δ0.88 (3H, t, J=7Hz), 1.20-1.40 (4H, m), 1.48-1.70 (2H, m), 2.96 (1H, t, J=12.5Hz), 3.05-3.28 (2H, m), 3.30-3.44 (1H, m), 3.45-3.60 (3H, m), 9.39 (2H, brs).

参考例６７

収率：74％, 1H-NMR(DMSO-d6): δ0.87 (3H, t, J=7.5Hz), 1.20-1.40 (4H, m), 1.45-1.67 (2H, m), 2.94 (1H, t, J=7Hz), 3.16 (2H, quant, J=12.5Hz), 3.29-2.65 (4H, m), 9.35 (2H, brs).

参考例６８

収率：78％, 1H-NMR(D2O): δ0.82 (6 H, dd, J = 1.8, 6.0 Hz), 1.49 (2 H, t, J = 6.9 Hz), 1.54-1.65(1 H, m), 3.06 (1 H, dd, J = 11.7 Hz), 3.20-3.37 (2 H, m), 3.48-3.55 (1 H, m), 3.57-3.66 (3 H, m)

参考例６９

1H-NMR(CDCl3): δ0.87 (3H, d, J=6.5Hz), 0.89 (3H, d, J=6.5Hz), 1.44 (2H, t, J=7.0Hz), 1.61-1.78 (1H, m), 2.85-3.00 (1H, m), 3.03-3.32 (2H, m), 3.35-3.59 (4H, m), 9.34 (2H, brs).

参考例７０

収率：82％, 1H-NMR(DMSO-d6): 0.88 (6H, t, J=6.5Hz), 1.43 (2H, t, J=6.5Hz), 1.70 (1H, quant, J=6.5Hz), 2.90 (1H, t, J=13Hz), 3.00-3.28 (2H, m), 3.35-3.55 (4H, m), 9.17 (2H, brs).

参考例７１

収率：49％, 1H-NMR(DMSO-d6): 0.94 (3H, d, J=7Hz), 0.98 (3H, d, J=7Hz), 1.84-1.98 (1H, m), 2.94 (1H, t, J=12.5Hz), 3.05-3.25 (3H, m), 3.47 (2H, d, J=10.5Hz), 3.52 (1H, d, J=15Hz), 9.12 (2H, brs). Similarly, the compounds described in Reference Examples 62 to 71 were obtained.
Reference Example 62

Yield: 88%, 1H-NMR (DMSO-d6): δ 0.94 (3H, t, J = 7.5Hz), 1.60 (2H, quant, J = 7.5Hz), 2.93 (1H, t, J = 12.5 Hz), 3.00-3.65 (6H, m), 9.24 (2H, brs).

Reference Example 63

Yield: 80%, 1H-NMR (DMSO-d6): δ 0.94 (3H, t, J = 7.5Hz), 1.61 (2H, quant, J = 7.5Hz), 2.93 (1H, t, J = 12.5 Hz), 3.00-3.60 (6H, m), 9.27 (2H, brs).

Reference Example 64

Yield: 59%, 1H-NMR (D2O): δ 0.76 (3 H, t, J = 7.5 Hz), 1.25 (2 H, m), 1.53 (2 H, q, J = 7.5 Hz), 3.00 (1 H, t, J = 12.9 Hz), 3.13-3.29 (2 H, m), 3.39-3.48 (1 H, m), 3.52-3.59 (3 H, m)

Reference Example 65

Yield: 61%, 1H-NMR (D2O): δ 0.79 (3 H, t, J = 7.2 Hz), 1.22-1.35 (2 H, m), 1.52-1.60 (2 H, m), 3.03 ( 1 H, dd, J = 12.2 Hz), 3.16-3.32 (2 H, m), 3.40-3.51 (1 H, m), 3.55-3.63 (3 H, m)

Reference Example 66

Yield: 76%, 1H-NMR (DMSO-d6): δ0.88 (3H, t, J = 7Hz), 1.20-1.40 (4H, m), 1.48-1.70 (2H, m), 2.96 (1H, t, J = 12.5Hz), 3.05-3.28 (2H, m), 3.30-3.44 (1H, m), 3.45-3.60 (3H, m), 9.39 (2H, brs).

Reference Example 67

Yield: 74%, 1H-NMR (DMSO-d6): δ0.87 (3H, t, J = 7.5Hz), 1.20-1.40 (4H, m), 1.45-1.67 (2H, m), 2.94 (1H , t, J = 7Hz), 3.16 (2H, quant, J = 12.5Hz), 3.29-2.65 (4H, m), 9.35 (2H, brs).

Reference Example 68

Yield: 78%, 1H-NMR (D2O): δ 0.82 (6 H, dd, J = 1.8, 6.0 Hz), 1.49 (2 H, t, J = 6.9 Hz), 1.54-1.65 (1 H, m), 3.06 (1 H, dd, J = 11.7 Hz), 3.20-3.37 (2 H, m), 3.48-3.55 (1 H, m), 3.57-3.66 (3 H, m)

Reference Example 69

1H-NMR (CDCl3): δ0.87 (3H, d, J = 6.5Hz), 0.89 (3H, d, J = 6.5Hz), 1.44 (2H, t, J = 7.0Hz), 1.61-1.78 (1H , m), 2.85-3.00 (1H, m), 3.03-3.32 (2H, m), 3.35-3.59 (4H, m), 9.34 (2H, brs).

Reference Example 70

Yield: 82%, 1H-NMR (DMSO-d6): 0.88 (6H, t, J = 6.5Hz), 1.43 (2H, t, J = 6.5Hz), 1.70 (1H, quant, J = 6.5Hz) , 2.90 (1H, t, J = 13Hz), 3.00-3.28 (2H, m), 3.35-3.55 (4H, m), 9.17 (2H, brs).

Reference Example 71

Yield: 49%, 1H-NMR (DMSO-d6): 0.94 (3H, d, J = 7Hz), 0.98 (3H, d, J = 7Hz), 1.84-1.98 (1H, m), 2.94 (1H, t, J = 12.5Hz), 3.05-3.25 (3H, m), 3.47 (2H, d, J = 10.5Hz), 3.52 (1H, d, J = 15Hz), 9.12 (2H, brs).

３−エチルピペラジン・2トリフルオロ酢酸塩0.51ｇ（1.47 mmol）及びアセトニトリル10ｍｌの混合物に室氷冷下、トリエチルアミン0.62ｍｌ（4.45mmol）及び二炭酸ジ-ｔ-ブチル0.35ｇ（1.59mmol）を加え、室温下17時間攪拌した。反応液を減圧下濃縮後、残渣に酢酸エチル及び水を加え抽出した。有機層を飽和食塩水で洗浄後、無水硫酸ナトリウムで乾燥した。減圧下溶媒を留去後、残渣をシリカゲルカラムクロマトグラフィー（クロロホルム：メタノール＝20：1）で精製し、1-tert-ブトキシカルボニル-３−エチルピペラジンを無色結晶として0.27ｇ（85％）得た。
1H-NMR(CDCl3): δ 1.03 (3 H, t, J = 7.5 Hz), 1.47 (9 H, s), 1.60-1.81 (2 H, m), 2.96 (3 H, br), 3.26 (2 H, d, J = 12.6 Hz), 4.08 (2 H, d, J = 14.1 Hz) Reference Example 72
Synthesis of 1-tert-butoxycarbonyl-3-ethylpiperazine

To a mixture of 0.51 g (1.47 mmol) of 3-ethylpiperazine · 2 trifluoroacetate and 10 ml of acetonitrile, 0.62 ml (4.45 mmol) of triethylamine and 0.35 g (1.59 mmol) of di-t-butyl dicarbonate were added under room ice cooling. The mixture was stirred at room temperature for 17 hours. The reaction mixture was concentrated under reduced pressure, and the residue was extracted with ethyl acetate and water. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (chloroform: methanol = 20: 1) to obtain 0.27 g (85%) of 1-tert-butoxycarbonyl-3-ethylpiperazine as colorless crystals. .
1H-NMR (CDCl3): δ 1.03 (3 H, t, J = 7.5 Hz), 1.47 (9 H, s), 1.60-1.81 (2 H, m), 2.96 (3 H, br), 3.26 (2 H, d, J = 12.6 Hz), 4.08 (2 H, d, J = 14.1 Hz)

収率：99％, 1H-NMR(CDCl3): 0.95 (3H, t, J=7.5Hz), 1.30-1.45 (2H, m), 1.46 (9H, s), 1.67 (1H, brs), 2.30-2.55 (2H, m), 2.68-2.90 (2H, m), 2.91-3.01 (1H, m), 3.80-4.05 (2H, m).

参考例７４

収率：80％, 1H-NMR(CDCl3): 0.95 (3H, t, J=7.5Hz), 1.30-1.45 (2H, m), 1.46 (9H, s), 1.69 (1H, brs), 2.30-2.55 (2H, m), 2.68-2.88 (2H, m), 2.90-3.00 (1H, m), 3.85-4.02 (2H, m).

参考例７５

収率：quant.％, 1H-NMR(CDCl3, 328 K): 0.94 (3 H, t, J = 6.9 Hz), 1.29-1.46 (4 H, m), 1.46 (9 H, s), 2.64-2.86 (3 H, m), 2.96-3.14 (2 H, m), 3.64-4.04 (2 H, m)

参考例７６

収率：quant.％, 1H-NMR(CDCl3, 328 K): 0.94 (3 H, t, J = 6.9 Hz), 1.36-1.60 (4 H, m), 1.47 (9 H, s), 2.82-2.93 (3 H, m), 3.12-3.21 (2 H, m), 3.99-4.10 (2 H, m)

参考例７７

収率：96％, 1H-NMR(CDCl3): 0.90 (3H, t, J=6Hz), 1.25-1.40 (6H, m), 1.46 (9H, s), 1.54 (1H, brs), 2.30-2.60 (2H, m), 2.67-2.86 (2H, m), 2.90-2.99 (1H, m), 3.80-4.05 (2H, m).

参考例７８

収率：94％, 1H-NMR(CDCl3): 0.85-0.95 (3H, m), 1.25-1.40 (6H, m), 1.46 (9H, s), 1.56 (1H, brs), 2.30-3.00 (5H, m), 3.80-4.05 (2H, m).

参考例７９

収率：90％, 1H-NMR(CDCl3): 0.94 (6 H, dd, J = 3.3, 6.3 Hz), 1.47 (9 H, s), 1.43-1.54 (2 H, m), 1.68-1.79 (1 H, m), 2.97 (2 H, dt, J = 3.3, 12.3 Hz), 3.08 (1 H, br), 3.22-3.28 (2 H, m), 4.08 (2 H, d, J = 13.8 Hz)

参考例８０

収率：74％, 1H-NMR(CDCl3): 0.90 (3H, d, J=6.5Hz), 0.93 (3H, d, J=6.5Hz), 1.11-1.30 (2H, m), 1.47 (9H, s), 1.60-1.78 (1H, m), 2.41 (1H, brs), 2.56-2.87 (3H, m), 2.90-3.00 (1H, m), 3.82-4.03 (2H, m).

参考例８１

収率：99％, 1H-NMR(CDCl3): 0.92 (6H, t, J=7Hz), 1.15-1.30 (2H, m), 1.46 (9H, s), 1.47 (1H, brs), 1.62-1.76 (1H, m), 2.30-2.52 (1H, m), 2.58-3.00 (4H, m), 3.82-4.04 (2H, m).

参考例８２

収率：59％, 1H-NMR(CDCl3): 0.95 (3H, d, J=13.5Hz), 0.96 (3H, d, J=13.5Hz), 1.46 (9H, s), 1.47-1.69 (1H, m), 2.22-2.35 (1H, m), 2.38-2.63 (1H, brs), 2.65-2.86 (2H, m), 2.93-3.04 (1H, m), 3.80-4.17 (2H, m).

参考例８３

収率：75％, 1H-NMR(CDCl3): 0.94 (3H, d, J=2.5Hz), 0.96 (3H, d, J=2.5Hz), 1.46 (9H, s), 1.53-1.70 (2H, m), 2.24-2.35 (1H, m), 2.36-2.65 (1H, m), 2.66-2.86 (2H, m), 2.93-3.04 (1H, m), 3.80-4.16 (2H, m). Similarly, the compounds described in Reference Examples 73 to 83 were obtained.
Reference Example 73

Yield: 99%, 1H-NMR (CDCl3): 0.95 (3H, t, J = 7.5Hz), 1.30-1.45 (2H, m), 1.46 (9H, s), 1.67 (1H, brs), 2.30- 2.55 (2H, m), 2.68-2.90 (2H, m), 2.91-3.01 (1H, m), 3.80-4.05 (2H, m).

Reference Example 74

Yield: 80%, 1H-NMR (CDCl3): 0.95 (3H, t, J = 7.5Hz), 1.30-1.45 (2H, m), 1.46 (9H, s), 1.69 (1H, brs), 2.30- 2.55 (2H, m), 2.68-2.88 (2H, m), 2.90-3.00 (1H, m), 3.85-4.02 (2H, m).

Reference Example 75

Yield: quant.%, 1H-NMR (CDCl3, 328 K): 0.94 (3 H, t, J = 6.9 Hz), 1.29-1.46 (4 H, m), 1.46 (9 H, s), 2.64- 2.86 (3 H, m), 2.96-3.14 (2 H, m), 3.64-4.04 (2 H, m)

Reference Example 76

Yield: quant.%, 1H-NMR (CDCl3, 328 K): 0.94 (3 H, t, J = 6.9 Hz), 1.36-1.60 (4 H, m), 1.47 (9 H, s), 2.82- 2.93 (3 H, m), 3.12-3.21 (2 H, m), 3.99-4.10 (2 H, m)

Reference Example 77

Yield: 96%, 1H-NMR (CDCl3): 0.90 (3H, t, J = 6Hz), 1.25-1.40 (6H, m), 1.46 (9H, s), 1.54 (1H, brs), 2.30-2.60 (2H, m), 2.67-2.86 (2H, m), 2.90-2.99 (1H, m), 3.80-4.05 (2H, m).

Reference Example 78

Yield: 94%, 1H-NMR (CDCl3): 0.85-0.95 (3H, m), 1.25-1.40 (6H, m), 1.46 (9H, s), 1.56 (1H, brs), 2.30-3.00 (5H , m), 3.80-4.05 (2H, m).

Reference Example 79

Yield: 90%, 1H-NMR (CDCl3): 0.94 (6 H, dd, J = 3.3, 6.3 Hz), 1.47 (9 H, s), 1.43-1.54 (2 H, m), 1.68-1.79 ( 1 H, m), 2.97 (2 H, dt, J = 3.3, 12.3 Hz), 3.08 (1 H, br), 3.22-3.28 (2 H, m), 4.08 (2 H, d, J = 13.8 Hz )

Reference Example 80

Yield: 74%, 1H-NMR (CDCl3): 0.90 (3H, d, J = 6.5Hz), 0.93 (3H, d, J = 6.5Hz), 1.11-1.30 (2H, m), 1.47 (9H, s), 1.60-1.78 (1H, m), 2.41 (1H, brs), 2.56-2.87 (3H, m), 2.90-3.00 (1H, m), 3.82-4.03 (2H, m).

Reference Example 81

Yield: 99%, 1H-NMR (CDCl3): 0.92 (6H, t, J = 7Hz), 1.15-1.30 (2H, m), 1.46 (9H, s), 1.47 (1H, brs), 1.62-1.76 (1H, m), 2.30-2.52 (1H, m), 2.58-3.00 (4H, m), 3.82-4.04 (2H, m).

Reference Example 82

Yield: 59%, 1H-NMR (CDCl3): 0.95 (3H, d, J = 13.5Hz), 0.96 (3H, d, J = 13.5Hz), 1.46 (9H, s), 1.47-1.69 (1H, m), 2.22-2.35 (1H, m), 2.38-2.63 (1H, brs), 2.65-2.86 (2H, m), 2.93-3.04 (1H, m), 3.80-4.17 (2H, m).

Reference Example 83

Yield: 75%, 1H-NMR (CDCl3): 0.94 (3H, d, J = 2.5Hz), 0.96 (3H, d, J = 2.5Hz), 1.46 (9H, s), 1.53-1.70 (2H, m), 2.24-2.35 (1H, m), 2.36-2.65 (1H, m), 2.66-2.86 (2H, m), 2.93-3.04 (1H, m), 3.80-4.16 (2H, m).

2,6-ジクロロベンゾチアゾール1.00g（4.90mmol）、1-ピペラジンtert-ブチルエステル0.96g（5.15mmol）、炭酸カリウム0.71g（5.15mmol）及び無水N,N-ジメチルホルムアミド10mlの混合物を室温下14時間撹拌した後、50℃で3時間撹拌した。反応液に水を加え、析出結晶を濾取した後、ジイソプロピルエーテルで洗浄し、4-(6-クロロベンゾチアゾール-2-イル)ピペラジン-1-カルボン酸tert-ブチルエステルを淡褐色結晶として1.50g（87％）得た。
¹H-NMR(DMSO-d₆): δ1.43 (9H, s), 3.44-3.53 (4H, m), 3.55-3.60 (4H, m), 7.30 (1H, dd, J=8, 2Hz), 7.44 (1H, d, J=8Hz), 7.93 (1H, d, J=2Hz). Reference Example 84
Preparation of 4- (6-chlorobenzothiazol-2-yl) piperazine-1-carboxylic acid tert-butyl ester

A mixture of 1.00 g (4.90 mmol) of 2,6-dichlorobenzothiazole, 0.96 g (5.15 mmol) of 1-piperazine tert-butyl ester, 0.71 g (5.15 mmol) of potassium carbonate and 10 ml of anhydrous N, N-dimethylformamide at room temperature After stirring for 14 hours, the mixture was stirred at 50 ° C. for 3 hours. Water was added to the reaction solution, and the precipitated crystals were collected by filtration and washed with diisopropyl ether to give 4- (6-chlorobenzothiazol-2-yl) piperazine-1-carboxylic acid tert-butyl ester as a light brown crystal in 1.50. g (87%) was obtained.
¹ H-NMR (DMSO-d ₆ ): δ1.43 (9H, s), 3.44-3.53 (4H, m), 3.55-3.60 (4H, m), 7.30 (1H, dd, J = 8, 2Hz) , 7.44 (1H, d, J = 8Hz), 7.93 (1H, d, J = 2Hz).

収率：97％, ¹H-NMR(CDCl₃); δ1.42 (9H, d, J=8.4Hz), 2.01-2.07 (2H, m), 3.36 (1H, t, J=6.0Hz), 3.44 (1H, t, J = 5.7Hz) 3.63-3.76(6H, m) 7.24 (1H, dd, J=8.7, 2.1Hz), 7.43(1H, d, J=8.4Hz), 7.55 (1H, d, J=2.4Hz).

参考例８６

収率：51％, ¹H-NMR(DMSO-d₆): δ1.43 (9H, s), 3.44-3.53 (4H, m), 3.55-3.65 (4H, m), 7.58 (2H, s), 8.27 (1H,s)

参考例８７

収率：47％, ¹H-NMR(CDCl₃): δ1.44 (9H, s), 2.06 (2H, quant, J=6Hz), 3.35-3.50 (2H, m), 3.60-3.85 (6H, m), 7.50-7.60 (2H, m), 7.85 (1H, s).

参考例８８

収率：43％, ¹H-NMR(CDCl₃): δ1.29 (3H, d, J=7Hz), 1.49 (9H,s), 2.85-3.10 (1H,m), 3.10-3.30 (1H,m), 3.40 (1H, td, J=13, 3.5Hz), 3.75-4.25 (4H, m), 7.24 (1H, dd, J=8.5, 2Hz), 7.44 (1H, d, J=8.5Hz), 7.56 (1H, d, J=2Hz).

参考例８９

収率：69％, ¹H-NMR (CDCl₃): δ1.16 (3H, d, J=6 Hz), 1.76 (1H, brs), 2.80 (1H, dd, J=12, 12 Hz), 2.90-2.95 (1H,m), 3.00 (1H, dd, J=12,3 Hz), 3.15 (1H, td, J=12,3 Hz), 3.21 (1H, dd, J=12,3 Hz), 3.84-4.00 (2H, m), 7.24 (1H, dd, J= 8.5, 2.5Hz), 7.44 (1H, d, J=8.5 Hz), 7.56 (1H, d, J=2.5Hz).

参考例９０

収率：90％,¹H-NMR(CDCl₃): δ1.15 (6H, d, J=6 Hz), 1.61 (1H, brs), 2.73 (2H, dd, J=12.5, 10 Hz), 2.95-3.10 (2H, m), 3.94 (2H, dd, J=12.5, 2.5Hz), 7.23 (1H, dd, J=8.5, 2Hz), 7.42 (1H, d, J=2Hz), 7.55 (1H, d, J=8.5Hz).

参考例９１

収率：40％,¹H-NMR(CDCl₃): δ1.27 (3H, d, J=7Hz), 1.37 (3H, d, J=7Hz), 2.64 (1H, dd, J=12, 2.5Hz), 3.20-3.35 (1H, m), 3.42 (1H, dd, J=12, 4.5Hz), 3.50-3.65 (2H, m), 4.10-4.25 (1H, m), 7.23 (1H, dd, J=8.5, 2Hz), 7.42 (1H, d, J=8.5Hz), 7.54 (1H, d, J=2Hz).

参考例９２

収率：87％, 1H-NMR(CDCl3): δ1.16 (3H, d, J=6Hz), 1.62 (1H, brs), 2.84 (1H, t, J=10.5Hz), 2.90-3.00 (1H, m), 3.01 (1H, dd, J=12, 3Hz), 3.14 (1H, dt, J=12, 2.5Hz), 3.25 (1H, td, J=12, 3.5Hz), 4.01 (2H, t, J=12Hz), 7.52 (1H, d, J=8.5Hz), 7.57 (1H, d, J=8.5Hz), 7.85 (1H, s).

参考例９３

収率：8％, 1H-NMR(CDCl3): δ1.27 (3H, d, J=6.5Hz), 1.40 (3H, d, J=6.5Hz), 1.65 (1H, brs), 2.66 (1H, dd, J=13, 2Hz), 3.25-3.40 (1H, m), 3.43 (1H, dd, J=13, 4.5Hz), 3.61 (2H, d, J=3Hz), 4.20-4.28 (1H, m), 7.51 (1H, d, J=8.5Hz), 7.56 (1H, d, J=8.5Hz), 7.84 (1H, s).

参考例９４

収率：38％, 1H-NMR(CDCl3): δ1.16 (6H, d, J=6.5Hz), 1.54 (1H, brs), 2.76 (1H, d, J=12.5Hz), 2.80 (1H, d, J=12.5Hz), 2.95-3.08 (2H, m), 3.95-4.03 (2H, m), 7.52 (1H, d, J=8.5Hz), 7.57 (1H, d, J=8.5Hz), 7.85 (1H, s).

参考例９５

収率：71％, 1H-NMR(CDCl3): δ1.15 (3 H, d, J = 6.3 Hz), 2.80 (1 H, dd, J = 12.3 Hz), 2.88-3.02 (2 H, m), 3.08-3.23 (2 H, m), 3.94 (2 H, dd, J = 12.3 Hz), 7.24 (1 H, dd, J = 2.1, 8.7 Hz), 7.43 (1 H, d, J = 8.7 Hz), 7.56 (1 H, d, J = 2.1 Hz)

参考例９６

収率：77％,1H-NMR(CDCl3): δ1.15 (3 H, d, J = 6.0 Hz), 2.80 (1 H, dd, J = 12.3 Hz), 2.89-3.02 (2 H, m), 3.10-3.23 (2 H, m), 3.95 (2 H, t, J = 12.3 Hz), 7.24 (1 H, dd, J = 2.4, 8.4 Hz), 7.44 (1 H, d, J = 8.4Hz), 7.56 (1 H, d, J = 2.4 Hz)

参考例９７

収率：48％, 1H-NMR(CDCl3): δ1.16 (3 H, d, J = 6.0 Hz), 2.86 (1 H, d, J = 12.0 Hz), 2.88-3.03 (2 H, m), 3.11-3.16 (1 H, m), 3.23 (1 H, dt, J = 3.3, 12.0 Hz), 4.01 (2 H, t, J = 12.6 Hz), 7.51-7.59 (2 H, m), 7.85 (1 H, s)

参考例９８

収率：63％, 1H-NMR(CDCl3): δ1.01 (3 H, t, J = 7.2 Hz), 1.44-1.53 (2 H, m), 2.67-2.76 (1 H, m), 2.80-2.88 (1 H, m), 2.91-3.00 (1 H, m), 3.10-3.20 (2 H, m), 3.91-4.01 (2 H, m), 7.24 (1 H, dd, J = 2.1, 8.7 Hz), 7.43 (1 H, d, J = 8.7 Hz), 7.55 (1 H, d, J = 2.1 Hz), 8.02 (1 H, s)

参考例９９

収率：quant.％, 1H-NMR(CDCl3): δ1.16 (3H, d, J=6Hz), 1.75 (1H, brs), 2.80-3.05 (3H, m), 3.08-3.18 (1H, m), 3.25 (1H, dd, J=12, 3.5Hz), 4.00 (2H, t, J=12Hz), 7.53 (1H, d, J=8.5Hz), 7.55 (1H, d, J=8.5Hz), 7.85 (1H, s).

参考例１００

収率：quant.％, 1H-NMR(CDCl3): δ1.98 (1H, brs), 3.06-3.30 (3H, m), 3.38 (1H, dd, J=12, 3.5Hz), 3.93 (1H, dd, J=10.5, 3Hz), 4.05-4.18 (2H, m), 7.30-7.60 (7H, m), 7.86 (1H, s).

参考例１０１

収率：quant.％, 1H-NMR(CDCl3): δ1.02 (3H, t, J=7.5Hz), 1.38-1.60 (2H, m), 1.75 (1H, brs), 2.65-2.80 (1H, m), 2.85-3.00 (2H, m), 3.10-3.20 (1H, m), 3.25 (1H, td, J=12, 3.5Hz), 3.95-4.10 (2H, m), 7.52 (1H, dd, J=8.5, 1.5Hz), 7.57 (1H, d, J=8.5Hz), 7.85 (1H, d, J=1.5Hz).

参考例１０２

収率：93％, 1H-NMR(CDCl3): δ1.02 (3H, t, J=7.5Hz), 1.38-1.60 (2H, m), 1.78 (1H, brs), 2.67-2.78 (1H, m), 2.82-3.03 (2H, m), 3.09-3.32 (2H, m), 3.95-4.10 (2H, m), 7.52 (1H, d, J= 8.5 Hz), 7.70 (1H, d, J=8.5Hz), 7.85 (1H, s).

参考例１０３

収率：quant. ％, 1H-NMR(CDCl3): δ1.02 (3H, t, J=7.5Hz), 1.38-1.60 (2H, m), 1.83 (1H, brs), 2.65-2.78 (1H, m), 2.85-3.03 (2H, m), 3.10-3.18 (1H, m), 3.24 (1H, td, J=12, 3.5Hz), 3.93-4.10 (2H, m), 7.52 (1H, dd, J=8.5, 1.5Hz), 7.57 (1H, d, J=8.5Hz), 7.85 (1H, d, J=1.5Hz).

参考例１０４

収率：84％, 1H-NMR(CDCl3): δ0.90-1.05 (3H, m), 1.35-1.54 (4H, m), 1.55-1.66 (2H, m), 2.75-3.02 (3H, m), 3.14 (1H, dt, J=12, 2Hz), 3.25 (1H, td, J=12.5, 3.5Hz), 4.01 (1H, t, J=11.5Hz), 7.52 (1H, dd, J=8.5, 1.5Hz), 7.57 (1H, d, J=8.5Hz), 7.85 (1H, d, J=1.5Hz).

参考例１０５

収率：87％, 1H-NMR(CDCl3): δ0.96-0.99 (3 H, m), 1.42-1.50 (4 H, m), 2.83-3.01 (3 H, m), 3.12-3.29 (2 H, m), 4.01 (2 H, t, J = 9.9 Hz), 7.51-7.59 (2 H, m), 7.85 (1 H, s), 8.02 (1 H, s)

参考例１０６

収率：quant. ％, 1H-NMR(CDCl3): δ0.94 (3H, t, J=7.5Hz), 1.29-1.54 (6H, m), 1.56-1.70 (2H, m), 2.73-3.05 (3H, m), 3.13 (1H, dt, J=12, 2Hz), 3.25 (1H, td, J=12, 3.5Hz), 4.01 (1H, t, J=10Hz), 7.52 (1H, dd, J=8.5, 1.5Hz), 7.57 (1H, d, J=8.5Hz), 7.85 (1H, d, J=1.5Hz).

参考例１０７

収率：56％, 1H-NMR(CDCl3): δ0.95 (6 H, dd, J = 6.6, 8.4 Hz), 1.25-1.33 (2 H, m), 1.71-1.80 (1 H, m), 2.77-2.92 (2 H, m), 2.96-3.00 (1 H, m), 3.10-3.24 (2 H, m), 3.95 (2 H, d, J = 10.5 Hz), 7.24 (1 H, dd, J = 2.1, 8.4 Hz), 7.44 (1 H, d, J = 8.4 Hz), 7.56 (1 H, d, J = 2.1 Hz)

参考例１０８

収率：quant. ％, 1H-NMR(CDCl3): δ0.93 (3H, d, J=6.5Hz), 0.96 (3H, d, J=6.5Hz), 1.26-1.35 (2H, m), 1.68 (1H, brs), 1.69-1.83 (1H, m), 2.73-3.03 (3H, m), 3.07-3.25 (2H, m), 3.90-4.00 (2H, m), 7.23 (1H, dd, J=8.5, 2Hz), 7.44 (1H, d, J=8.5Hz), 7.55 (1H, d, J=2Hz).

参考例１０９

収率：quant.％, 1H-NMR(CDCl3): δ0.93 (3H, d, J=6.5Hz), 0.96 (3H, d, J=6.5Hz), 1.20-1.38 (2H, m), 1.60-1.84 (2H, m), 2.72-3.03 (2H, m), 3.05-3.26 (2H, m), 3.87-4.02 (2H, m), 7.23 (1H, dd, J=8.5, 2.0Hz), 7.43 (1H, d, J=8.5Hz), 7.55 (1H, d, J=2.0Hz).

参考例１１０

収率：quant.％, 1H-NMR(CDCl3): δ0.94 (3H, d, J=6.5Hz), 0.97 (3H, d J=6.5Hz), 1.27-1.37 (2H, m), 1.66 (1H, brs), 1.70-1.83 (1H, m), 2.80-3.03 (3H, m), 3.09-3.30 (2H, m), 3.95-4.05 (2H, m), 7.52 (1H, d, J=8.5Hz), 7.57 (1H, d, J=8.5Hz), 7.85 (1H, s).

参考例１１１

収率：91 ％, 1H-NMR(CDCl3): δ0.94 (3H, d, J=6.5Hz), 0.97 (3H, d, J=6.5Hz), 1.27-1.36 (2H, m), 1.62-1.84 (2H, m), 2.81-3.03 (2H, m), 3.09-3.30 (2H, m), 3.94-4.07 (2H, m), 7.52 (1H, d, J=8.5 Hz), 7.57 (1H, d, J=8.5Hz), 7.85 (1H, s).

参考例１１２

収率：91 ％, 1H-NMR(CDCl3): δ1.16 (3H, d, J=6Hz), 1.58 (1H, brs), 2.80-3.03 (3H, m), 3.07-3.17 (1H, m), 3.24 (1H, td, J=12, 3.5Hz), 3.99 (2H, t, J=11Hz), 7.26 (1H, d, J=12Hz), 7.75 (1H, d, J=6.5Hz).

参考例１１３

収率：91 ％, 1H-NMR(CDCl3): δ1.02 (3H, t, J=7.5Hz), 1.37-1.62 (2H, m), 1.90 (1H, brs), 2.64-2.78 (1H, m), 2.84-3.03 (2H, m), 3.10-3.20 (1H, m), 3.21-3.32 (1H, m), 3.92-4.09 (2H, m), 7.27 (1H, d, J=12.5Hz), 7.76 (1H, d, J=6.5Hz).

参考例１１４

収率：75％, 1H-NMR(CDCl3): δ1.32 (3H, d, J=6.5Hz), 1.50 (9H, s), 2.90-3.30 (2H, m), 3.44 (1H, td, J=12.5, 3.5Hz), 3.80-4.40 (4H, m), 7.53 (1H, dd, J=8.5, 1.5Hz), 7.57 (1H, d, J=8.5Hz), 7.86 (1H, d, J=1.5Hz).

参考例１１５

収率：61％, 1H-NMR(CDCl3): δ1.29 (3H, d, J=6Hz), 1.49 (9H, s), 2.90-3.30 (2H, m), 3.34-3.48 (1H, m), 3.80-4.30 (4H, m), 7.25 (1H, dd, J=8.5, 2Hz), 7.44 (1H, d, J=8.5Hz), 7.57 (1H, d, J=2Hz).

参考例１１６

収率：31％, 1H-NMR(CDCl3): δ1.30 (3H, d, J=6.5Hz), 1.49 (9H, s), 2.91-3.29 (2H, m), 3.33-3.47 (1H, m), 3.76-4.34 (4H, m), 7.25 (1H, dd, J=8.5, 2.0Hz), 7.44 (1H, d, J=8.5Hz), 7.57 (1H, d, J=2.0Hz).

参考例１１７

収率：65％, 1H-NMR(CDCl3): δ1.31 (3H, d, J=6.5Hz), 1.50 (9H, s), 2.90-3.30 (2H, m), 3.44 (1H, td, J=12.5, 3.5Hz), 3.85-4.35 (4H, m), 7.53 (1H, dd, J=8.5, 1.5Hz), 7.58 (1H, d, J=8.5Hz), 7.86 (1H, d, J=1.5Hz).

参考例１１８

収率：50％, 1H-NMR(CDCl3): δ1.32 (3H, d, J=6.5Hz), 1.50 (9H, s), 2.85-3.27 (2H, m), 3.32-3.52 (1H, m), 3.82-4.38 (4H, m), 7.54 (1H, d, J=8.5Hz), 7.58(1H, d, J=8.5 Hz),7.86 (1H, s).

参考例１１９

収率：22％, 1H-NMR(CDCl3): δ1.00 (3H, t, J=7.5Hz), 1.49 (9H, s), 1.63-1.78 (2H, m), 2.83-3.17 (2H, m), 3.26-3.41 (1H, m), 3.82-4.31 (4H, m), 7.23 (1H, dd, J=8.5, 2.0Hz), 7.41 (1H, d, J=8.5Hz), 7.53 (1H, d, J=2.0Hz).

参考例１２０

収率：41％, 1H-NMR(CDCl3): δ1.00 (3H, t, J=7.5Hz), 1.49 (9H, s), 1.72 (2H, quant, J=7.5Hz), 2.90-3.20 (3H, m), 3.26-3.42 (1H, m), 3.85-4.00 (2H, m), 4.10-4.30 (1H, m), 7.24 (1H, dd, J=8.5, 2Hz), 7.41 (1H, d, J=8.5Hz), 7.55 (1H, d, J=2Hz).

参考例１２１

収率：25％, 1H-NMR(CDCl3): δ1.00 (3H, t, J=7.5Hz), 1.49 (9H, s), 1.63-1.78 (2H, m), 2.82-3.19 (2H, m), 3.26-3.43 (1H, m), 3.80-4.30 (4H, m), 7.23 (1H, dd, J=8.5, 2.0Hz), 7.41 (1H, d, J=8.5Hz), 7.54 (1H, d, J=2.0Hz).

参考例１２２

収率：67％, 1H-NMR(CDCl3): δ1.01 (3H, t, J=7.5Hz), 1.49 (9H, s), 1.68-1.80 (2H, m), 2.90-3.20 (2H, m), 3.32-3.46 (1H, m), 3.90-4.32 (4H, m), 7.54 (1H, d, J=8.5Hz), 7.55 (1H, d, J=8.5Hz), 7.85 (1H, s).

参考例１２３

収率：60％, 1H-NMR(CDCl3): δ1.01 (3H, t, J=7.5Hz), 1.49 (9H, s), 1.74 (2H, quant, J=7.5Hz), 2.90-3.20 (2H, m), 3.33-3.46 (1H, m), 3.92-4.31 (4H, m), 7.50-7.58 (2H, m), 7.85 (1H, s).

参考例１２４

収率：43％, 1H-NMR(CDCl3): δ0.96 (3H, t, J=7.0Hz), 1.25-1.75 (4H, m), 1.49 (9H, s), 2.84-3.18 (2H, m), 3.36 (1H, td, J=12.5, 3.0Hz), 3.85-4.32 (4H, m), 7.24 (1H, dd, J=8.5, 2.0Hz), 7.41 (1H, d, J=8.5Hz), 7.55 (1H, d, J=2.0Hz).

参考例１２５

収率：33％, 1H-NMR(CDCl3, 328 K): δ0.96 (3 H, t, J = 7.2 Hz), 1.36-1.49 (2 H, m), 1.49 (9 H, s), 1.59-1.71(2 H, m), 2.98 (1 H, t, J = 11.1 Hz), 3.10 (1 H, d, J = 11.1 Hz), 3.36 (1 H, dt, J = 3.3, 13.2 Hz), 3.93-4.12 (4 H, m), 7.22 (1 H, s), 7.41 (1 H, d, J = 8.4 Hz), 7.54 (1 H, s)

参考例１２６

収率：40％, 1H-NMR(CDCl3): δ0.97 (3H, t, J=7.0Hz), 1.20-1.55 (2H, m), 1.50 (9H, s), 1.56-1.77 (2H, m), 2.83-3.21 (2H, m), 3.40 (1H, td, J=13.0, 3.0Hz), 3.88-4.35 (4H, m), 7.52 (1H, d, J=8.5Hz), 7.56 (1H, d, J=8.5Hz), 7.84 (1H, s).

参考例１２７

収率：64％, 1H-NMR(CDCl3, 328 K): δ0.97 (3 H, t, J = 7.2 Hz), 1.27-1.49 (2 H, m), 1.49 (9 H, s), 1.69 (2 H, br), 2.99 (1 H, t, J = 11.7 Hz), 3.11 (1 H, d, J = 12.6 Hz), 3.39 (1 H, td, J = 12.6 Hz), 3.97-4.14 (4 H, m), 7.53 (2 H, s, J = Hz), 7.83 (1 H, s)

参考例１２８

収率：18％, 1H-NMR(CDCl3): δ0.85-0.97 (3H, m), 1.30-1.45 (4H, m), 1.49 (9H, s), 1.59-1.75 (2H, m), 2.86-3.19 (2H, m), 3.30-3.43 (1H, m), 3.90-4.30 (4H, m), 7.24 (1H, dd, J=8.5, 2Hz), 7.42 (1H, d, J=8.5Hz), 7.55 (1H, d, J=2Hz).

参考例１２９

収率：50％, 1H-NMR(CDCl3): δ0.84-0.98 (3H, m), 1.25-1.75 (15H, m), 2.85-3.20 (2H, m), 3.30-3.45 (1H, m), 3.90-4.30 (4H, m), 7.24 (1H, dd, J=9, 2Hz), 7.42 (1H, d, J=9Hz), 7.55 (1H, d, J=2Hz).

参考例１３０

収率：58％, 1H-NMR(CDCl3): δ0.85-0.97 (3H, m), 1.30-1.45 (4H, m), 1.50 (9H, s), 1.63-1.78 (2H, m), 2.85-3.20 (2H, m), 3.33-3.43 (1H, m), 3.95-4.35 (4H, m), 7.50-7.58 (2H, m), 7.85 (1H, s).

参考例１３１

収率：11％, 1H-NMR(CDCl3): δ0.92 (3H, d, J=6.5Hz), 1.13 (3H, d, J=6.5Hz), 1.49 (9H, s), 2.07-2.27 (1H, m), 2.70-3.15 (2H, m), 3.25-3.44 (1H, m), 3.59-3.75 (1H, m), 3.95-4.46 (3H, m), 7.52 (1H, s), 7.53 (1H, s), 7.83 (1H, s).

参考例１３２

収率：31％, 1H-NMR(CDCl3): δ0.91(3H, d, J=6.5Hz), 1.13 (3H, d, J=6.5Hz), 1.49 (9H, s), 2.12-2.24 (1H, m), 2.84-3.13 (2H, m), 3.27-3.43 (1H, m), 3.60-3.75 (1H, m), 4.02-4.40 (3H, m), 7.53 (2H, s), 7.83 (1H, s).

参考例１３３

収率：26％, 1H-NMR(CDCl3): δ0.98 (3H, d, J=6.5Hz), 1.00 (3H, d, J=6.5Hz), 1.33-1.75 (3H, m), 1.49 (9H, s), 2.84-3.22 (2H, m), 3.37 (1H, td, J=13.0, 3.5Hz), 3.88-4.32 (4H, m), 7.24 (1H, dd, J=8.5, 2.0Hz), 7.42 (1H, d, J=8.5Hz), 7.56 (1H, d, J=2.0Hz).

参考例１３４

収率：54％, 1H-NMR(CDCl3): δ0.90-1.05 (6H, m), 1.35-1.48 (2H, m), 1.49 (9H, s), 1.58-1.73 (1H, m), 2.85-3.20 (2H, m), 3.30-3.43 (1H, m), 3.90-4.30 (4H, m), 7.35 (1H, dd, J=8.5, 2Hz), 7.41 (1H, d, J=8.5Hz), 7.57 (1H, d, J=2Hz).

参考例１３５

収率：43％, 1H-NMR(CDCl3): δ0.99 (3H, d, J=6.5Hz), 1.00 (3H, d, J=6.5Hz), 1.37-1.52 (1H, m), 1.49 (9H, s), 1.57-1.75 (2H, m), 2.84-3.23 (2H, m), 3.40 (1H, td, J=13.0, 3.5.Hz), 3.94-4.35 (4H, m), 7.48-7.58 (2H, m), 7.85 (1H, s).

参考例１３６

収率：57％, 1H-NMR(CDCl3, 328 K): δ1.00 (6 H, t, J = 6.0 Hz), 1.40-1.52 (1 H, m), 1.49 (9 H, s), 1.60-1.69 (2 H, m), 2.99 (1 H, t, J = 10.8 Hz), 3.12 (1 H, d, J = 10.8 Hz), 3.40 (1 H, dt, J = 3.6, 12.9 Hz), 3.98-4.13 (4 H, m), 7.49-7.56 (2 H, m), 7.84 (1 H, s)

参考例１３７

収率：46％, 1H-NMR(CDCl3): δ1.10 (3H, d, J=7.0Hz), 1.26 (3H, d, J=7.0Hz), 2.98 (1H, td, J=12.5, 3.5Hz), 3.06-3.17 (2H, m), 3.35 (1H, td, J=12.5, 3.5Hz), 3.75-3.93 (1H, m), 4.00-4.18 (1H, m), 7.46-7.62 (2H, m), 7.85(1H, s).

参考例１３８

収率：96％, 1H-NMR(CDCl3): δ1.49 (9H, s), 3.54-3.70 (8H, m), 7.29 (1H, d, J=7.0Hz), 7.78 (1H, d, J=11.5Hz).

参考例１３９

収率：90％, 1H-NMR(CDCl3): δ1.43 (9H, s), 2.00-2.13 (2H, m), 3.32-3.54 (2H, m), 3.62-3.89 (6H, m), 7.28 (1H, d, J=7.0Hz), 7.75 (1H, d, J=11.5Hz).

参考例１４０

収率：64％, 1H-NMR(CDCl3): δ1.32 (3H, d, J=7.0Hz), 1.50 (9H, s), 2.94-3.15 (2H, m), 3.44 (1H, td, J=12.5, 3.5Hz), 3.77-4.42 (4H, m), 7.28 (1H, d, J=12.0Hz), 7.77 (1H, d, J=7.0Hz).

参考例１４１

収率：57％, 1H-NMR(CDCl3): δ1.32 (3H, d, J=7.0Hz), 1.50 (9H, s), 2.88-3.32 (2H, m), 3.45 (1H, td, J=12.5, 3.5Hz), 3.75-4.36 (4H, m), 7.29 (1H, d, J=12.0Hz), 7.77 (1H, d, J=7.0Hz).

参考例１４２

収率：93％, 1H-NMR(CDCl3): δ1.17 (6H, d, J=6.0Hz), 2.76 (1H, d, J=12.5Hz), 2.81 (1H, d, J=12.5Hz), 2.94-3.08 (2H, m), 3.97 (2H, d, J=12.5Hz), 7.27 (1H, d, J= 11.5 Hz), 7.75 (1H, d, J=7.0Hz).

参考例１４３

収率：55％, 1H-NMR(CDCl3): δ1.49 (9H, s), 3.43-3.66 (8H, m), 7.22 (1H, t, J=7.5Hz), 7.33 (2H, t, J=7.5Hz), 7.41 (1H, s), 7.43 (2H, d, J=7.5Hz).

参考例１４４

収率：78％, 1H-NMR(CDCl3): δ1.49 (9H, s), 3.55-3.67 (8H, m), 7.10 (1H, td, J=8.0, 1.0Hz), 7.31 (1H, td, J=8.0, 1.0Hz), 7.57 (1H, dd, J=8.0, 1.0Hz), 7.61 (1H, dd, J=8.0, 1.0Hz).

参考例１４５

収率：42％, H-NMR(CDCl3): δ1.00 (3H, t, J=7.5Hz), 1.49 (9H, s), 1.64-1.79 (2H, m), 2.85-3.19 (2H, m), 3.28-3.44 (1H, m), 3.83-4.33 (4H, m), 7.27 (1H, d, J=10.0Hz), 7.55 (1H, d, J=7.0Hz).

参考例１４６

収率：60％, 1H-NMR(CDCl3): δ1.50 (9H, s), 3.55-3.68 (4H, m), 3.73-3.85 (4H, m), 7.37-7.47 (1H, m), 7.59 (1H, td, J=8.0, 1.0Hz), 7.69 (1H, dd, J=8.0, 1.0Hz), 7.89 (1H, dd, J=8.0, 1.0Hz), 8.58 (1H, s).

参考例１４７

収率：60％, 1H-NMR(CDCl3): δ1.50 (9H, s), 3.56-3.67 (4H, m), 3.73-3.84 (4H, m), 7.53 (1H, dd, J=9.0, 2.0Hz), 7.62 (1H, d, J=9.0Hz), 7.88 (1H, d, J=2.0Hz), 8.57 (1H, s).

参考例１４８

収率：70％, 1H-NMR(CDCl3): δ1.20 (3H, d, J=6.5Hz), 2.68 (1H, dd, J=13.0, 10.5Hz), 2.86-3.22 (4H, m), 4.37-4.48 (2H, m), 7.35-7.44 (1H, m), 7.53-7.62 (1H, m), 7.68 (1H, dd, J=8.5, 1.5Hz), 7.88 (1H, dd, J=8.5, 1.5Hz), 8.58 (1H, s).

参考例１４９

収率：27％, 1H-NMR(CDCl3): δ1.50 (9H, s), 3.53-3.64 (4H, m), 3.68-3.78 (4H, m), 6.98 (1H, d, J=9.0Hz), 7.25 (1H, td, J=8.0, 1.5Hz), 7.55 (1H, td, J=8.0, 1.5Hz), 7.61 (1H, d, J=8.0Hz), 7.71 (1H, d, J=8.0Hz), 7.92 (1H, d, J=9.0Hz)

参考例１５０

収率：51％, 1H-NMR(CDCl3): δ1.20 (6H, d, J=6.0Hz), 2.58 (1H, d, J=12.5Hz), 2.62 (1H, d, J=12.5Hz), 2.93-3.07 (2H, m), 4.43 (2H, dd, J=12.5, 2.0Hz), 7.38 (1H, td, J=8.5, 1.5Hz), 7.57 (1H, td, J=8.5, 1.5Hz), 7.68 (1H, dd, J=8.5, 1.5Hz), 7.87 (1H, dd, J=8.5, 1.5Hz), 8.58 (1H, s).

参考例１５１

収率：88％, 1H-NMR(CDCl3): δ1.20 (6H, d, J=6.5Hz), 2.58 (1H, d, J=13.0Hz), 2.62 (1H, d, J=13.0Hz), 2.92-3.07 (2H, m), 4.42 (2H, dd, J=13.0, 2.0Hz), 7.50 (1H, dd, J=9.0, 2.0Hz), 7.60 (1H, d, J=9.0Hz), 7.85 (1H, d, J=2.0Hz), 8.57 (1H, s).

参考例１５２

収率：quant.％, 1H-NMR(CDCl3): δ1.21 (6H, d, J=6.0Hz), 2.62 (1H, d, J=12.5Hz), 2.66 (1H, d, J=12.5Hz), 2.92-3.06 (2H, m), 4.49 (2H, dd, J=12.5, 2.0Hz), 7.71-7.75 (2H, m), 8.14 (1H, s), 8.63 (1H, s).

参考例１５３

収率：52％, 1H-NMR(CDCl3): δ1.31 (3H, d, J=6.5Hz), 1.51 (9H, s), 2.95-3.19 (1H, m), 3.21-3.31 (1H, m), 3.32-3.45 (1H, m), 3.92-4.41 (3H, m), 4.68-4.82 (1H, m), 7.72 (1H, s), 7.73 (1H, s), 8.17 (1H, s), 8.60 (1H, s).

参考例１５４

収率：72％, 1H-NMR(CDCl3): δ1.50 (9H, s), 2.73 (3H, s), 3.37-3.46 (4H, m), 3.62-3.70 (4H, m), 7.76 (1H, d, J=9.0Hz), 7.89 (1H, d, J=9.0Hz), 8.19 (1H, s). Thereafter, the compounds described in Reference Examples 85 to 154 were obtained in the same manner as in Reference Example 84.
Reference Example 85

Yield: 97%, ¹ H-NMR (CDCl ₃ ); δ1.42 (9H, d, J = 8.4Hz), 2.01-2.07 (2H, m), 3.36 (1H, t, J = 6.0Hz), 3.44 (1H, t, J = 5.7Hz) 3.63-3.76 (6H, m) 7.24 (1H, dd, J = 8.7, 2.1Hz), 7.43 (1H, d, J = 8.4Hz), 7.55 (1H, d , J = 2.4Hz).

Reference Example 86

Yield: 51%, ¹ H-NMR (DMSO-d ₆ ): δ1.43 (9H, s), 3.44-3.53 (4H, m), 3.55-3.65 (4H, m), 7.58 (2H, s) , 8.27 (1H, s)

Reference Example 87

Yield: 47%, ¹ H-NMR (CDCl ₃ ): δ1.44 (9H, s), 2.06 (2H, quant, J = 6Hz), 3.35-3.50 (2H, m), 3.60-3.85 (6H, m), 7.50-7.60 (2H, m), 7.85 (1H, s).

Reference Example 88

Yield: 43%, ¹ H-NMR (CDCl ₃ ): δ 1.29 (3H, d, J = 7Hz), 1.49 (9H, s), 2.85-3.10 (1H, m), 3.10-3.30 (1H, m), 3.40 (1H, td, J = 13, 3.5Hz), 3.75-4.25 (4H, m), 7.24 (1H, dd, J = 8.5, 2Hz), 7.44 (1H, d, J = 8.5Hz) , 7.56 (1H, d, J = 2Hz).

Reference Example 89

Yield: 69%, ¹ H-NMR (CDCl ₃ ): δ1.16 (3H, d, J = 6 Hz), 1.76 (1H, brs), 2.80 (1H, dd, J = 12, 12 Hz), 2.90-2.95 (1H, m), 3.00 (1H, dd, J = 12,3 Hz), 3.15 (1H, td, J = 12,3 Hz), 3.21 (1H, dd, J = 12,3 Hz) , 3.84-4.00 (2H, m), 7.24 (1H, dd, J = 8.5, 2.5Hz), 7.44 (1H, d, J = 8.5 Hz), 7.56 (1H, d, J = 2.5Hz).

Reference Example 90

Yield: 90%, ¹ H-NMR (CDCl ₃ ): δ 1.15 (6H, d, J = 6 Hz), 1.61 (1H, brs), 2.73 (2H, dd, J = 12.5, 10 Hz), 2.95-3.10 (2H, m), 3.94 (2H, dd, J = 12.5, 2.5Hz), 7.23 (1H, dd, J = 8.5, 2Hz), 7.42 (1H, d, J = 2Hz), 7.55 (1H , d, J = 8.5Hz).

Reference Example 91

Yield: 40%, ¹ H-NMR (CDCl ₃ ): δ 1.27 (3H, d, J = 7Hz), 1.37 (3H, d, J = 7Hz), 2.64 (1H, dd, J = 12, 2.5 Hz), 3.20-3.35 (1H, m), 3.42 (1H, dd, J = 12, 4.5Hz), 3.50-3.65 (2H, m), 4.10-4.25 (1H, m), 7.23 (1H, dd, J = 8.5, 2Hz), 7.42 (1H, d, J = 8.5Hz), 7.54 (1H, d, J = 2Hz).

Reference Example 92

Yield: 87%, 1H-NMR (CDCl3): δ1.16 (3H, d, J = 6Hz), 1.62 (1H, brs), 2.84 (1H, t, J = 10.5Hz), 2.90-3.00 (1H , m), 3.01 (1H, dd, J = 12, 3Hz), 3.14 (1H, dt, J = 12, 2.5Hz), 3.25 (1H, td, J = 12, 3.5Hz), 4.01 (2H, t , J = 12Hz), 7.52 (1H, d, J = 8.5Hz), 7.57 (1H, d, J = 8.5Hz), 7.85 (1H, s).

Reference Example 93

Yield: 8%, 1H-NMR (CDCl3): δ 1.27 (3H, d, J = 6.5Hz), 1.40 (3H, d, J = 6.5Hz), 1.65 (1H, brs), 2.66 (1H, dd, J = 13, 2Hz), 3.25-3.40 (1H, m), 3.43 (1H, dd, J = 13, 4.5Hz), 3.61 (2H, d, J = 3Hz), 4.20-4.28 (1H, m ), 7.51 (1H, d, J = 8.5Hz), 7.56 (1H, d, J = 8.5Hz), 7.84 (1H, s).

Reference Example 94

Yield: 38%, 1H-NMR (CDCl3): δ 1.16 (6H, d, J = 6.5Hz), 1.54 (1H, brs), 2.76 (1H, d, J = 12.5Hz), 2.80 (1H, d, J = 12.5Hz), 2.95-3.08 (2H, m), 3.95-4.03 (2H, m), 7.52 (1H, d, J = 8.5Hz), 7.57 (1H, d, J = 8.5Hz), 7.85 (1H, s).

Reference Example 95

Yield: 71%, 1H-NMR (CDCl3): δ 1.15 (3 H, d, J = 6.3 Hz), 2.80 (1 H, dd, J = 12.3 Hz), 2.88-3.02 (2 H, m) , 3.08-3.23 (2 H, m), 3.94 (2 H, dd, J = 12.3 Hz), 7.24 (1 H, dd, J = 2.1, 8.7 Hz), 7.43 (1 H, d, J = 8.7 Hz ), 7.56 (1 H, d, J = 2.1 Hz)

Reference Example 96

Yield: 77%, 1H-NMR (CDCl3): δ 1.15 (3 H, d, J = 6.0 Hz), 2.80 (1 H, dd, J = 12.3 Hz), 2.89-3.02 (2 H, m) , 3.10-3.23 (2 H, m), 3.95 (2 H, t, J = 12.3 Hz), 7.24 (1 H, dd, J = 2.4, 8.4 Hz), 7.44 (1 H, d, J = 8.4 Hz ), 7.56 (1 H, d, J = 2.4 Hz)

Reference Example 97

Yield: 48%, 1H-NMR (CDCl3): δ 1.16 (3 H, d, J = 6.0 Hz), 2.86 (1 H, d, J = 12.0 Hz), 2.88-3.03 (2 H, m) , 3.11-3.16 (1 H, m), 3.23 (1 H, dt, J = 3.3, 12.0 Hz), 4.01 (2 H, t, J = 12.6 Hz), 7.51-7.59 (2 H, m), 7.85 (1 H, s)

Reference Example 98

Yield: 63%, 1H-NMR (CDCl3): δ1.01 (3 H, t, J = 7.2 Hz), 1.44-1.53 (2 H, m), 2.67-2.76 (1 H, m), 2.80- 2.88 (1 H, m), 2.91-3.00 (1 H, m), 3.10-3.20 (2 H, m), 3.91-4.01 (2 H, m), 7.24 (1 H, dd, J = 2.1, 8.7 Hz), 7.43 (1 H, d, J = 8.7 Hz), 7.55 (1 H, d, J = 2.1 Hz), 8.02 (1 H, s)

Reference Example 99

Yield: quant.%, 1H-NMR (CDCl3): δ1.16 (3H, d, J = 6Hz), 1.75 (1H, brs), 2.80-3.05 (3H, m), 3.08-3.18 (1H, m ), 3.25 (1H, dd, J = 12, 3.5Hz), 4.00 (2H, t, J = 12Hz), 7.53 (1H, d, J = 8.5Hz), 7.55 (1H, d, J = 8.5Hz) , 7.85 (1H, s).

Reference Example 100

Yield: quant.%, 1H-NMR (CDCl3): δ1.98 (1H, brs), 3.06-3.30 (3H, m), 3.38 (1H, dd, J = 12, 3.5Hz), 3.93 (1H, dd, J = 10.5, 3Hz), 4.05-4.18 (2H, m), 7.30-7.60 (7H, m), 7.86 (1H, s).

Reference Example 101

Yield: quant.%, 1H-NMR (CDCl3): δ1.02 (3H, t, J = 7.5Hz), 1.38-1.60 (2H, m), 1.75 (1H, brs), 2.65-2.80 (1H, m), 2.85-3.00 (2H, m), 3.10-3.20 (1H, m), 3.25 (1H, td, J = 12, 3.5Hz), 3.95-4.10 (2H, m), 7.52 (1H, dd, J = 8.5, 1.5Hz), 7.57 (1H, d, J = 8.5Hz), 7.85 (1H, d, J = 1.5Hz).

Reference Example 102

Yield: 93%, 1H-NMR (CDCl3): δ1.02 (3H, t, J = 7.5Hz), 1.38-1.60 (2H, m), 1.78 (1H, brs), 2.67-2.78 (1H, m ), 2.82-3.03 (2H, m), 3.09-3.32 (2H, m), 3.95-4.10 (2H, m), 7.52 (1H, d, J = 8.5 Hz), 7.70 (1H, d, J = 8.5 Hz), 7.85 (1H, s).

Reference Example 103

Yield: quant.%, 1H-NMR (CDCl3): δ1.02 (3H, t, J = 7.5Hz), 1.38-1.60 (2H, m), 1.83 (1H, brs), 2.65-2.78 (1H, m), 2.85-3.03 (2H, m), 3.10-3.18 (1H, m), 3.24 (1H, td, J = 12, 3.5Hz), 3.93-4.10 (2H, m), 7.52 (1H, dd, J = 8.5, 1.5Hz), 7.57 (1H, d, J = 8.5Hz), 7.85 (1H, d, J = 1.5Hz).

Reference Example 104

Yield: 84%, 1H-NMR (CDCl3): δ0.90-1.05 (3H, m), 1.35-1.54 (4H, m), 1.55-1.66 (2H, m), 2.75-3.02 (3H, m) , 3.14 (1H, dt, J = 12, 2Hz), 3.25 (1H, td, J = 12.5, 3.5Hz), 4.01 (1H, t, J = 11.5Hz), 7.52 (1H, dd, J = 8.5, 1.5Hz), 7.57 (1H, d, J = 8.5Hz), 7.85 (1H, d, J = 1.5Hz).

Reference Example 105

Yield: 87%, 1H-NMR (CDCl3): δ0.96-0.99 (3 H, m), 1.42-1.50 (4 H, m), 2.83-3.01 (3 H, m), 3.12-3.29 (2 H, m), 4.01 (2 H, t, J = 9.9 Hz), 7.51-7.59 (2 H, m), 7.85 (1 H, s), 8.02 (1 H, s)

Reference Example 106

Yield: quant.%, 1H-NMR (CDCl3): δ0.94 (3H, t, J = 7.5Hz), 1.29-1.54 (6H, m), 1.56-1.70 (2H, m), 2.73-3.05 ( 3H, m), 3.13 (1H, dt, J = 12, 2Hz), 3.25 (1H, td, J = 12, 3.5Hz), 4.01 (1H, t, J = 10Hz), 7.52 (1H, dd, J = 8.5, 1.5Hz), 7.57 (1H, d, J = 8.5Hz), 7.85 (1H, d, J = 1.5Hz).

Reference Example 107

Yield: 56%, 1H-NMR (CDCl3): δ 0.95 (6 H, dd, J = 6.6, 8.4 Hz), 1.25-1.33 (2 H, m), 1.71-1.80 (1 H, m), 2.77-2.92 (2 H, m), 2.96-3.00 (1 H, m), 3.10-3.24 (2 H, m), 3.95 (2 H, d, J = 10.5 Hz), 7.24 (1 H, dd, J = 2.1, 8.4 Hz), 7.44 (1 H, d, J = 8.4 Hz), 7.56 (1 H, d, J = 2.1 Hz)

Reference Example 108

Yield: quant.%, 1H-NMR (CDCl3): δ0.93 (3H, d, J = 6.5Hz), 0.96 (3H, d, J = 6.5Hz), 1.26-1.35 (2H, m), 1.68 (1H, brs), 1.69-1.83 (1H, m), 2.73-3.03 (3H, m), 3.07-3.25 (2H, m), 3.90-4.00 (2H, m), 7.23 (1H, dd, J = 8.5, 2Hz), 7.44 (1H, d, J = 8.5Hz), 7.55 (1H, d, J = 2Hz).

Reference Example 109

Yield: quant.%, 1H-NMR (CDCl3): δ0.93 (3H, d, J = 6.5Hz), 0.96 (3H, d, J = 6.5Hz), 1.20-1.38 (2H, m), 1.60 -1.84 (2H, m), 2.72-3.03 (2H, m), 3.05-3.26 (2H, m), 3.87-4.02 (2H, m), 7.23 (1H, dd, J = 8.5, 2.0Hz), 7.43 (1H, d, J = 8.5Hz), 7.55 (1H, d, J = 2.0Hz).

Reference Example 110

Yield: quant.%, 1H-NMR (CDCl3): δ 0.94 (3H, d, J = 6.5Hz), 0.97 (3H, d J = 6.5Hz), 1.27-1.37 (2H, m), 1.66 ( 1H, brs), 1.70-1.83 (1H, m), 2.80-3.03 (3H, m), 3.09-3.30 (2H, m), 3.95-4.05 (2H, m), 7.52 (1H, d, J = 8.5 Hz), 7.57 (1H, d, J = 8.5Hz), 7.85 (1H, s).

Reference Example 111

Yield: 91%, 1H-NMR (CDCl3): δ 0.94 (3H, d, J = 6.5Hz), 0.97 (3H, d, J = 6.5Hz), 1.27-1.36 (2H, m), 1.62- 1.84 (2H, m), 2.81-3.03 (2H, m), 3.09-3.30 (2H, m), 3.94-4.07 (2H, m), 7.52 (1H, d, J = 8.5 Hz), 7.57 (1H, d, J = 8.5Hz), 7.85 (1H, s).

Reference Example 112

Yield: 91%, 1H-NMR (CDCl3): δ 1.16 (3H, d, J = 6Hz), 1.58 (1H, brs), 2.80-3.03 (3H, m), 3.07-3.17 (1H, m) , 3.24 (1H, td, J = 12, 3.5Hz), 3.99 (2H, t, J = 11Hz), 7.26 (1H, d, J = 12Hz), 7.75 (1H, d, J = 6.5Hz).

Reference Example 113

Yield: 91%, 1H-NMR (CDCl3): δ1.02 (3H, t, J = 7.5Hz), 1.37-1.62 (2H, m), 1.90 (1H, brs), 2.64-2.78 (1H, m ), 2.84-3.03 (2H, m), 3.10-3.20 (1H, m), 3.21-3.32 (1H, m), 3.92-4.09 (2H, m), 7.27 (1H, d, J = 12.5Hz), 7.76 (1H, d, J = 6.5Hz).

Reference Example 114

Yield: 75%, 1H-NMR (CDCl3): δ1.32 (3H, d, J = 6.5Hz), 1.50 (9H, s), 2.90-3.30 (2H, m), 3.44 (1H, td, J = 12.5, 3.5Hz), 3.80-4.40 (4H, m), 7.53 (1H, dd, J = 8.5, 1.5Hz), 7.57 (1H, d, J = 8.5Hz), 7.86 (1H, d, J = 1.5Hz).

Reference Example 115

Yield: 61%, 1H-NMR (CDCl3): δ 1.29 (3H, d, J = 6Hz), 1.49 (9H, s), 2.90-3.30 (2H, m), 3.34-3.48 (1H, m) , 3.80-4.30 (4H, m), 7.25 (1H, dd, J = 8.5, 2Hz), 7.44 (1H, d, J = 8.5Hz), 7.57 (1H, d, J = 2Hz).

Reference Example 116

Yield: 31%, 1H-NMR (CDCl3): δ1.30 (3H, d, J = 6.5Hz), 1.49 (9H, s), 2.91-3.29 (2H, m), 3.33-3.47 (1H, m ), 3.76-4.34 (4H, m), 7.25 (1H, dd, J = 8.5, 2.0Hz), 7.44 (1H, d, J = 8.5Hz), 7.57 (1H, d, J = 2.0Hz).

Reference Example 117

Yield: 65%, 1H-NMR (CDCl3): δ1.31 (3H, d, J = 6.5Hz), 1.50 (9H, s), 2.90-3.30 (2H, m), 3.44 (1H, td, J = 12.5, 3.5Hz), 3.85-4.35 (4H, m), 7.53 (1H, dd, J = 8.5, 1.5Hz), 7.58 (1H, d, J = 8.5Hz), 7.86 (1H, d, J = 1.5Hz).

Reference Example 118

Yield: 50%, 1H-NMR (CDCl3): δ1.32 (3H, d, J = 6.5Hz), 1.50 (9H, s), 2.85-3.27 (2H, m), 3.32-3.52 (1H, m ), 3.82-4.38 (4H, m), 7.54 (1H, d, J = 8.5Hz), 7.58 (1H, d, J = 8.5 Hz), 7.86 (1H, s).

Reference Example 119

Yield: 22%, 1H-NMR (CDCl3): δ1.00 (3H, t, J = 7.5Hz), 1.49 (9H, s), 1.63-1.78 (2H, m), 2.83-3.17 (2H, m ), 3.26-3.41 (1H, m), 3.82-4.31 (4H, m), 7.23 (1H, dd, J = 8.5, 2.0Hz), 7.41 (1H, d, J = 8.5Hz), 7.53 (1H, d, J = 2.0Hz).

Reference Example 120

Yield: 41%, 1H-NMR (CDCl3): δ1.00 (3H, t, J = 7.5Hz), 1.49 (9H, s), 1.72 (2H, quant, J = 7.5Hz), 2.90-3.20 ( 3H, m), 3.26-3.42 (1H, m), 3.85-4.00 (2H, m), 4.10-4.30 (1H, m), 7.24 (1H, dd, J = 8.5, 2Hz), 7.41 (1H, d , J = 8.5Hz), 7.55 (1H, d, J = 2Hz).

Reference Example 121

Yield: 25%, 1H-NMR (CDCl3): δ1.00 (3H, t, J = 7.5Hz), 1.49 (9H, s), 1.63-1.78 (2H, m), 2.82-3.19 (2H, m ), 3.26-3.43 (1H, m), 3.80-4.30 (4H, m), 7.23 (1H, dd, J = 8.5, 2.0Hz), 7.41 (1H, d, J = 8.5Hz), 7.54 (1H, d, J = 2.0Hz).

Reference Example 122

Yield: 67%, 1H-NMR (CDCl3): δ1.01 (3H, t, J = 7.5Hz), 1.49 (9H, s), 1.68-1.80 (2H, m), 2.90-3.20 (2H, m ), 3.32-3.46 (1H, m), 3.90-4.32 (4H, m), 7.54 (1H, d, J = 8.5Hz), 7.55 (1H, d, J = 8.5Hz), 7.85 (1H, s) .

Reference Example 123

Yield: 60%, 1H-NMR (CDCl3): δ1.01 (3H, t, J = 7.5Hz), 1.49 (9H, s), 1.74 (2H, quant, J = 7.5Hz), 2.90-3.20 ( 2H, m), 3.33-3.46 (1H, m), 3.92-4.31 (4H, m), 7.50-7.58 (2H, m), 7.85 (1H, s).

Reference Example 124

Yield: 43%, 1H-NMR (CDCl3): δ0.96 (3H, t, J = 7.0Hz), 1.25-1.75 (4H, m), 1.49 (9H, s), 2.84-3.18 (2H, m ), 3.36 (1H, td, J = 12.5, 3.0Hz), 3.85-4.32 (4H, m), 7.24 (1H, dd, J = 8.5, 2.0Hz), 7.41 (1H, d, J = 8.5Hz) , 7.55 (1H, d, J = 2.0Hz).

Reference Example 125

Yield: 33%, 1H-NMR (CDCl3, 328 K): δ 0.96 (3 H, t, J = 7.2 Hz), 1.36-1.49 (2 H, m), 1.49 (9 H, s), 1.59 -1.71 (2 H, m), 2.98 (1 H, t, J = 11.1 Hz), 3.10 (1 H, d, J = 11.1 Hz), 3.36 (1 H, dt, J = 3.3, 13.2 Hz), 3.93-4.12 (4 H, m), 7.22 (1 H, s), 7.41 (1 H, d, J = 8.4 Hz), 7.54 (1 H, s)

Reference Example 126

Yield: 40%, 1H-NMR (CDCl3): δ0.97 (3H, t, J = 7.0Hz), 1.20-1.55 (2H, m), 1.50 (9H, s), 1.56-1.77 (2H, m ), 2.83-3.21 (2H, m), 3.40 (1H, td, J = 13.0, 3.0Hz), 3.88-4.35 (4H, m), 7.52 (1H, d, J = 8.5Hz), 7.56 (1H, d, J = 8.5Hz), 7.84 (1H, s).

Reference Example 127

Yield: 64%, 1H-NMR (CDCl3, 328 K): δ 0.97 (3 H, t, J = 7.2 Hz), 1.27-1.49 (2 H, m), 1.49 (9 H, s), 1.69 (2 H, br), 2.99 (1 H, t, J = 11.7 Hz), 3.11 (1 H, d, J = 12.6 Hz), 3.39 (1 H, td, J = 12.6 Hz), 3.97-4.14 ( 4 H, m), 7.53 (2 H, s, J = Hz), 7.83 (1 H, s)

Reference Example 128

Yield: 18%, 1H-NMR (CDCl3): δ0.85-0.97 (3H, m), 1.30-1.45 (4H, m), 1.49 (9H, s), 1.59-1.75 (2H, m), 2.86 -3.19 (2H, m), 3.30-3.43 (1H, m), 3.90-4.30 (4H, m), 7.24 (1H, dd, J = 8.5, 2Hz), 7.42 (1H, d, J = 8.5Hz) , 7.55 (1H, d, J = 2Hz).

Reference Example 129

Yield: 50%, 1H-NMR (CDCl3): δ0.84-0.98 (3H, m), 1.25-1.75 (15H, m), 2.85-3.20 (2H, m), 3.30-3.45 (1H, m) , 3.90-4.30 (4H, m), 7.24 (1H, dd, J = 9, 2Hz), 7.42 (1H, d, J = 9Hz), 7.55 (1H, d, J = 2Hz).

Reference Example 130

Yield: 58%, 1H-NMR (CDCl3): δ0.85-0.97 (3H, m), 1.30-1.45 (4H, m), 1.50 (9H, s), 1.63-1.78 (2H, m), 2.85 -3.20 (2H, m), 3.33-3.43 (1H, m), 3.95-4.35 (4H, m), 7.50-7.58 (2H, m), 7.85 (1H, s).

Reference Example 131

Yield: 11%, 1H-NMR (CDCl3): δ 0.92 (3H, d, J = 6.5Hz), 1.13 (3H, d, J = 6.5Hz), 1.49 (9H, s), 2.07-2.27 ( 1H, m), 2.70-3.15 (2H, m), 3.25-3.44 (1H, m), 3.59-3.75 (1H, m), 3.95-4.46 (3H, m), 7.52 (1H, s), 7.53 ( 1H, s), 7.83 (1H, s).

Reference Example 132

Yield: 31%, 1H-NMR (CDCl3): δ 0.91 (3H, d, J = 6.5Hz), 1.13 (3H, d, J = 6.5Hz), 1.49 (9H, s), 2.12-2.24 ( 1H, m), 2.84-3.13 (2H, m), 3.27-3.43 (1H, m), 3.60-3.75 (1H, m), 4.02-4.40 (3H, m), 7.53 (2H, s), 7.83 ( 1H, s).

Reference Example 133

Yield: 26%, 1H-NMR (CDCl3): δ 0.98 (3H, d, J = 6.5Hz), 1.00 (3H, d, J = 6.5Hz), 1.33-1.75 (3H, m), 1.49 ( 9H, s), 2.84-3.22 (2H, m), 3.37 (1H, td, J = 13.0, 3.5Hz), 3.88-4.32 (4H, m), 7.24 (1H, dd, J = 8.5, 2.0Hz) , 7.42 (1H, d, J = 8.5Hz), 7.56 (1H, d, J = 2.0Hz).

Reference Example 134

Yield: 54%, 1H-NMR (CDCl3): δ0.90-1.05 (6H, m), 1.35-1.48 (2H, m), 1.49 (9H, s), 1.58-1.73 (1H, m), 2.85 -3.20 (2H, m), 3.30-3.43 (1H, m), 3.90-4.30 (4H, m), 7.35 (1H, dd, J = 8.5, 2Hz), 7.41 (1H, d, J = 8.5Hz) , 7.57 (1H, d, J = 2Hz).

Reference Example 135

Yield: 43%, 1H-NMR (CDCl3): δ0.99 (3H, d, J = 6.5Hz), 1.00 (3H, d, J = 6.5Hz), 1.37-1.52 (1H, m), 1.49 ( 9H, s), 1.57-1.75 (2H, m), 2.84-3.23 (2H, m), 3.40 (1H, td, J = 13.0, 3.5.Hz), 3.94-4.35 (4H, m), 7.48-7.58 (2H, m), 7.85 (1H, s).

Reference Example 136

Yield: 57%, 1H-NMR (CDCl3, 328 K): δ1.00 (6 H, t, J = 6.0 Hz), 1.40-1.52 (1 H, m), 1.49 (9 H, s), 1.60 -1.69 (2 H, m), 2.99 (1 H, t, J = 10.8 Hz), 3.12 (1 H, d, J = 10.8 Hz), 3.40 (1 H, dt, J = 3.6, 12.9 Hz), 3.98-4.13 (4 H, m), 7.49-7.56 (2 H, m), 7.84 (1 H, s)

Reference Example 137

Yield: 46%, 1H-NMR (CDCl3): δ1.10 (3H, d, J = 7.0Hz), 1.26 (3H, d, J = 7.0Hz), 2.98 (1H, td, J = 12.5, 3.5 Hz), 3.06-3.17 (2H, m), 3.35 (1H, td, J = 12.5, 3.5Hz), 3.75-3.93 (1H, m), 4.00-4.18 (1H, m), 7.46-7.62 (2H, m), 7.85 (1H, s).

Reference Example 138

Yield: 96%, 1H-NMR (CDCl3): δ 1.49 (9H, s), 3.54-3.70 (8H, m), 7.29 (1H, d, J = 7.0Hz), 7.78 (1H, d, J = 11.5Hz).

Reference Example 139

Yield: 90%, 1H-NMR (CDCl3): δ1.43 (9H, s), 2.00-2.13 (2H, m), 3.32-3.54 (2H, m), 3.62-3.89 (6H, m), 7.28 (1H, d, J = 7.0Hz), 7.75 (1H, d, J = 11.5Hz).

Reference Example 140

Yield: 64%, 1H-NMR (CDCl3): δ1.32 (3H, d, J = 7.0Hz), 1.50 (9H, s), 2.94-3.15 (2H, m), 3.44 (1H, td, J = 12.5, 3.5Hz), 3.77-4.42 (4H, m), 7.28 (1H, d, J = 12.0Hz), 7.77 (1H, d, J = 7.0Hz).

Reference Example 141

Yield: 57%, 1H-NMR (CDCl3): δ1.32 (3H, d, J = 7.0Hz), 1.50 (9H, s), 2.88-3.32 (2H, m), 3.45 (1H, td, J = 12.5, 3.5Hz), 3.75-4.36 (4H, m), 7.29 (1H, d, J = 12.0Hz), 7.77 (1H, d, J = 7.0Hz).

Reference Example 142

Yield: 93%, 1H-NMR (CDCl3): δ 1.17 (6H, d, J = 6.0Hz), 2.76 (1H, d, J = 12.5Hz), 2.81 (1H, d, J = 12.5Hz) , 2.94-3.08 (2H, m), 3.97 (2H, d, J = 12.5Hz), 7.27 (1H, d, J = 11.5 Hz), 7.75 (1H, d, J = 7.0Hz).

Reference Example 143

Yield: 55%, 1H-NMR (CDCl3): δ 1.49 (9H, s), 3.43-3.66 (8H, m), 7.22 (1H, t, J = 7.5Hz), 7.33 (2H, t, J = 7.5Hz), 7.41 (1H, s), 7.43 (2H, d, J = 7.5Hz).

Reference Example 144

Yield: 78%, 1H-NMR (CDCl3): δ 1.49 (9H, s), 3.55-3.67 (8H, m), 7.10 (1H, td, J = 8.0, 1.0Hz), 7.31 (1H, td , J = 8.0, 1.0Hz), 7.57 (1H, dd, J = 8.0, 1.0Hz), 7.61 (1H, dd, J = 8.0, 1.0Hz).

Reference Example 145

Yield: 42%, H-NMR (CDCl3): δ1.00 (3H, t, J = 7.5Hz), 1.49 (9H, s), 1.64-1.79 (2H, m), 2.85-3.19 (2H, m ), 3.28-3.44 (1H, m), 3.83-4.33 (4H, m), 7.27 (1H, d, J = 10.0Hz), 7.55 (1H, d, J = 7.0Hz).

Reference Example 146

Yield: 60%, 1H-NMR (CDCl3): δ1.50 (9H, s), 3.55-3.68 (4H, m), 3.73-3.85 (4H, m), 7.37-7.47 (1H, m), 7.59 (1H, td, J = 8.0, 1.0Hz), 7.69 (1H, dd, J = 8.0, 1.0Hz), 7.89 (1H, dd, J = 8.0, 1.0Hz), 8.58 (1H, s).

Reference Example 147

Yield: 60%, 1H-NMR (CDCl3): δ1.50 (9H, s), 3.56-3.67 (4H, m), 3.73-3.84 (4H, m), 7.53 (1H, dd, J = 9.0, 2.0Hz), 7.62 (1H, d, J = 9.0Hz), 7.88 (1H, d, J = 2.0Hz), 8.57 (1H, s).

Reference Example 148

Yield: 70%, 1H-NMR (CDCl3): δ 1.20 (3H, d, J = 6.5Hz), 2.68 (1H, dd, J = 13.0, 10.5Hz), 2.86-3.22 (4H, m), 4.37-4.48 (2H, m), 7.35-7.44 (1H, m), 7.53-7.62 (1H, m), 7.68 (1H, dd, J = 8.5, 1.5Hz), 7.88 (1H, dd, J = 8.5 , 1.5Hz), 8.58 (1H, s).

Reference Example 149

Yield: 27%, 1H-NMR (CDCl3): δ1.50 (9H, s), 3.53-3.64 (4H, m), 3.68-3.78 (4H, m), 6.98 (1H, d, J = 9.0Hz ), 7.25 (1H, td, J = 8.0, 1.5Hz), 7.55 (1H, td, J = 8.0, 1.5Hz), 7.61 (1H, d, J = 8.0Hz), 7.71 (1H, d, J = 8.0Hz), 7.92 (1H, d, J = 9.0Hz)

Reference Example 150

Yield: 51%, 1H-NMR (CDCl3): δ 1.20 (6H, d, J = 6.0Hz), 2.58 (1H, d, J = 12.5Hz), 2.62 (1H, d, J = 12.5Hz) , 2.93-3.07 (2H, m), 4.43 (2H, dd, J = 12.5, 2.0Hz), 7.38 (1H, td, J = 8.5, 1.5Hz), 7.57 (1H, td, J = 8.5, 1.5Hz) ), 7.68 (1H, dd, J = 8.5, 1.5Hz), 7.87 (1H, dd, J = 8.5, 1.5Hz), 8.58 (1H, s).

Reference Example 151

Yield: 88%, 1H-NMR (CDCl3): δ 1.20 (6H, d, J = 6.5Hz), 2.58 (1H, d, J = 13.0Hz), 2.62 (1H, d, J = 13.0Hz) , 2.92-3.07 (2H, m), 4.42 (2H, dd, J = 13.0, 2.0Hz), 7.50 (1H, dd, J = 9.0, 2.0Hz), 7.60 (1H, d, J = 9.0Hz), 7.85 (1H, d, J = 2.0Hz), 8.57 (1H, s).

Reference Example 152

Yield: quant.%, 1H-NMR (CDCl3): δ1.21 (6H, d, J = 6.0Hz), 2.62 (1H, d, J = 12.5Hz), 2.66 (1H, d, J = 12.5Hz) ), 2.92-3.06 (2H, m), 4.49 (2H, dd, J = 12.5, 2.0Hz), 7.71-7.75 (2H, m), 8.14 (1H, s), 8.63 (1H, s).

Reference Example 153

Yield: 52%, 1H-NMR (CDCl3): δ1.31 (3H, d, J = 6.5Hz), 1.51 (9H, s), 2.95-3.19 (1H, m), 3.21-3.31 (1H, m ), 3.32-3.45 (1H, m), 3.92-4.41 (3H, m), 4.68-4.82 (1H, m), 7.72 (1H, s), 7.73 (1H, s), 8.17 (1H, s), 8.60 (1H, s).

Reference Example 154

Yield: 72%, 1H-NMR (CDCl3): δ1.50 (9H, s), 2.73 (3H, s), 3.37-3.46 (4H, m), 3.62-3.70 (4H, m), 7.76 (1H , d, J = 9.0Hz), 7.89 (1H, d, J = 9.0Hz), 8.19 (1H, s).

4N-塩酸-ジオキサン溶液に4-(6-クロロベンゾチアゾール-2-イル)ピペラジン-1-カルボン酸tert-ブチルエステル1.50g（4.239mmol）を加え、60℃で1時間撹拌した。反応液を減圧下濃縮した後、残渣を酢酸エチルで洗浄し、4-(6-クロロベンゾチアゾール-2-イル)ピペラジン2塩酸塩を無色結晶として1.40g（100％）得た。
¹H-NMR(DMSO-d₆): δ3.15-3.25 (4H, m), 3.84 (4H, t, J=5Hz), 6.88 (1H, brs), 7.34 (1H, dd, J=8.5, 2Hz), 7.50 (1H, d, J=8.5Hz), 7.99 (1H, d, J=2Hz), 9.71 (2H, brs). Reference Example 155
Preparation of 4- (6-chlorobenzothiazol-2-yl) piperazine dihydrochloride

To the 4N-hydrochloric acid-dioxane solution was added 1.50 g (4.239 mmol) of 4- (6-chlorobenzothiazol-2-yl) piperazine-1-carboxylic acid tert-butyl ester, and the mixture was stirred at 60 ° C. for 1 hour. The reaction mixture was concentrated under reduced pressure, and the residue was washed with ethyl acetate to obtain 1.40 g (100%) of 4- (6-chlorobenzothiazol-2-yl) piperazine dihydrochloride as colorless crystals.
¹ H-NMR (DMSO-d ₆ ): δ 3.15-3.25 (4H, m), 3.84 (4H, t, J = 5Hz), 6.88 (1H, brs), 7.34 (1H, dd, J = 8.5, 2Hz), 7.50 (1H, d, J = 8.5Hz), 7.99 (1H, d, J = 2Hz), 9.71 (2H, brs).

収率：100％, ¹H-NMR(DMSO-d₆)：δ2.13-2.20 (2H, m), 3.20-3.22, (2H, m), 3.33-3.35 (2H, m), 3.68-3.72 (2H, m), 3.98-4.00 (2H, m), 7.33 (1H, dd, J =8.7Hz, 2.4Hz),7.47 (1H, d, J = 9.0Hz ), 7.97 (1H, d, J=2.1Hz), 9.35 (2H, br-s).

参考例１５７

収率：99％, ¹H-NMR(DMSO-d₆)：δ3.26 (4H, t, J=5Hz), 3.90 (4H, t, J=5Hz), 7.64 (2H, s), 8.34 (1H, s), 8.65 (1H, brs), 9.77 (2H, s).

参考例１５８

収率：99％, ¹H-NMR(DMSO-d₆)：δ2.10-2.25 (2H, m), 3.20-3.30 (2H, m), 3.30-3.40 (2H, m), 3.70-3.80 (2H, m), 4.00-4.10 (2H, m), 6.64 (1H, brs), 7.60 (2H, s), 8.30 (1H, s), 9.47 (2H, s).

参考例１５９

収率：91％, ¹H-NMR(DMSO-d₆)：δ1.39 (3H, d, J=7Hz), 3.03-3.18 (1H, m), 3.25-3.40 (4H, m), 3.95-4.05 (1H, m), 4.44-4.55 (1H, m), 7.34 (1H, dd, J=8.5, 2Hz), 7.49 (1H, d, J=8.5Hz), 7.96 (1H, d, J=2Hz), 9.09 (1H, brs), 9.55 (2H, brs).

参考例１６０

収率：82％, 1H-NMR(CDCl3): δ1.40 (3H, d, J=6.5Hz), 1.67 (1H, brs), 2.77-2.95 (2H, m), 3.05-3.15 (2H, m), 3.40 (1H, td, J=12.5, 3.5Hz), 3.87 (1H, dd, J=12.5, 3.5Hz), 4.15-4.30 (1H, m), 7.51 (1H, dd, J=8.5, 1Hz), 7.56 (1H, d, J=8.5Hz), 7.84 (1H, d, J=1Hz).

参考例１６１

収率：quant. ％, 1H-NMR(DMSO-d6): δ1.42 (3H, d, J=7Hz), 2.95-3.15 (1H, m), 3.15-3.40 (3H, m), 3.48-3.65 (1H, m), 3.95 (1H, m), 4.40-4.55 (1H, m), 7.33 (1H, dd, J=8.5, 2Hz), 7.48 (1H, d, J=8.5Hz), 7.98 (1H, d, J=2Hz), 8.16 (1H, brs), 9.51 (1H, brs), 9.94 (1H, brs).

参考例１６２

収率：94％, 1H-NMR(DMSO-d6): δ1.42 (3H, d, J=7.0Hz), 2.98-3.15 (1H, m), 3.16-3.38 (3H, m), 3.47-3.63 (1H, m), 3.96-4.08 (1H, m), 4.40-4.53 (1H, m), 5.10 (1H, s), 7.33 (1H, dd, J=8.5, 2.0Hz), 7.49 (1H, d, J=8.5Hz), 7.97 (1H, d, J=2.0Hz), 9.35-9.53 (1H, br), 9.82-9.98 (1H, br).

参考例１６３

収率：100％, 1H-NMR(CDCl3): δ1.40 (3H, d, J=7Hz), 2.84-2.96 (2H, m), 3.05-3.15 (2H, m), 3.39 (1H, dt, J=12.5, 3.5Hz), 3.88 (1H, dd, J=12.5, 2.5Hz), 4.15-4.25 (1H, m), 7.52 (1H, dd, J=8.5, 1.5Hz), 7.56 (1H, d, J=8.5Hz), 7.85 (1H, d, J=1.5Hz).

参考例１６４

収率：80％, 1H-NMR(DMSO-d6): δ1.41 (3H, d, J=7.0Hz), 3.00-3.17 (1H, m), 3.18-3.38 (3H, m), 3.49-3.64 (1H, m), 4.05-4.14 (1H, m), 4.45-4.58 (1H, m), 6.03 (1H, brs) 7.61 (2H, m), 8.31 (1H, s), 9.25-9.50 (1H, m), 9.73-9.92 (1H, m).

参考例１６５

収率：71％, 1H-NMR(DMSO-d6): δ0.91 (3H, t, J=7.5Hz), 1.80-1.96 (2H, m), 3.01-3.16 (1H, m), 3.17-3.42 (3H, m), 3.43-3.59 (1H, m), 4.08-4.27 (2H, m), 4.43 (1H, s), 7.33 (1H, dd, J=8.5, 2.0Hz), 7.46 (1H, d, J=8.5Hz), 7.94 (1H, d, J=2.0Hz), 9.22-9.44 (1H, m), 9.60-9.75 (1H, m).

参考例１６６

収率：99％, 1H-NMR(CDCl3): δ0.98 (3H, t, J=7.5Hz), 1.63 (1H, brs), 1.88 (2H, quant, J=7.5Hz), 2.88 (1H, td, J=12, 3.5Hz), 2.95-3.10 (3H, m), 3.34 (1H, td, J=12.5, 3.5Hz), 3.77-3.86 (1H, m), 3.90-4.00 (1H, m), 7.22 (1H, dd, J=8.5, 2Hz), 7.40 (1H, d, J=8.5Hz), 7.53 (1H, d, J=2Hz).

参考例１６７

収率：quant.％1H-NMR(DMSO-d6): δ0.90 (3H, t, J=7.5Hz), 1.84-2.05 (2H, m), 2.94-3.62 (5H, m), 4.07-4.26 (2H, m), 6.71 (1H, brs), 7.32 (1H, dd, J=8.5, 2.0Hz), 7.46 (1H, d, J=8.5Hz), 7.96 (1H, d, J=2.0Hz), 9.35-9.58 (1H, m), 9.73-9.95 (1H, m).

参考例１６８

収率：quant.％, 1H-NMR(CDCl3): δ0.98 (3H, t, J=7.5Hz), 1.61 (1H, brs), 1.90 (2H, quant, J=7.5Hz), 2.89 (1H, td, J=12, 3.5Hz), 2.95-3.13 (3H, m), 3.37 (1H, td, J=12.5, 3.5Hz), 3.83-3.94 (1H, m), 3.95-4.06 (1H, m), 7.45-7.56 (2H, m), 7.83 (1H, s).

参考例１６９

収率：quant.％, 1H-NMR(CDCl3): δ0.98 (3H, t, J=7.5Hz), 1.72 (1H, brs), 1.91 (2H, quant, J=7.5Hz), 2.89 (1H, td, J=12.5, 3.5Hz), 2.95-3.13 (3H, m), 3.38 (1H, td, J=12.5, 3.5Hz), 3.84-3.95 (1H, m), 3.95-4.08 (1H, m), 7.50 (1H, d, J=8.5Hz), 7.54 (1H, d, J=8.5Hz), 7.83 (1H, s).

参考例１７０

収率：quant.％, 1H-NMR(DMSO-d6): δ0.92 (3H, t, J=7.0Hz), 1.20-1.45 (2H, m), 1.78-1.92 (2H, q, J=7.5Hz), 2.97-3.38 (4H, m), 3.42-3.59 (1H, m), 4.04-4.17 (1H, m), 4.22-4.34 (1H, m), 5.64 (1H, br), 7.31 (1H, dd, J=8.5, 2.5Hz), 7.45 (1H, d, J=8.5Hz), 7.96 (1H, d, J=2.5Hz), 9.04-9.20 (1H, m), 9.50-9.64 (1H, m).

参考例１７１

収率：quant.％, 1H-NMR(CDCl3): δ0.99 (3 H, t, J = 6.6 Hz), 1.26-1.49 (4 H, m), 2.11 (2 H, br), 3.63-3.83 (3 H, m), 4.10 (1 H, br), 4.51 (1 H, br), 4.64 (1 H, br), 7.22 (1 H, s), 7.56-7.63 (2 H, m)

参考例１７２

収率：quant.％, 1H-NMR(DMSO-d6): δ0.93 (3H, t, J=7.5Hz), 1.18-1.46 (2H, m), 1.80-1.95 (2H, m), 3.00-3.40 (4H, m), 3.45-3.62 (1H, m), 4.12-4.24 (1H, m), 4.29-4.42 (1H, m), 7.54-7.65 (2H, m), 8.31 (1H, s), 9.14-9.32 (1H, m), 9.60-9.72 (1H, m).

参考例１７３

収率：quant.％, 1H-NMR(CDCl3): δ1.00 (3 H, t, J = 6.0 Hz), 1.26-1.54 (4 H, m), 2.17 (2 H, br), 3.63-3.86 (3 H, m), 4.11 (1 H, br), 4.54 (1 H, br), 4.70 (1 H, br), 7.50 (1 H, d, J = 7.5 Hz), 7.72 (1 H, d, J = 7.5 Hz), 7.91 (1 H, s)

参考例１７４

収率：quant.％, 1H-NMR(DMSO-d6): δ0.87 (3H, t, J=7Hz), 1.20-1.39 (4H, m), 1.78-1.95 (2H, m), 3.00-3.15 (1H, m), 3.15-3.40 (3H, m), 3.42-3.55 (1H, m), 4.07-4.20 (1H, m), 4.20-4.30 (1H, m), 4.55 (1H, brs), 7.31 (1H, dd, J=8.5, 2Hz), 7.44 (1H, d, J=8.5Hz), 7.95 (1H, d, J=2Hz), 9.00 (1H, brs), 9.48 (1H, brs).

参考例１７５

収率：quant.％, 1H-NMR(DMSO-d6): δ0.87 (3H, t, J=7Hz), 1.18-1.40 (4H, m), 1.77-1.98 (2H, m), 2.95-3.14 (1H, m), 3.14-3.37 (3H, m), 3.40-3.51 (1H, m), 4.08-4.20 (1H, m), 4.20-4.31 (1H, m), 6.89 (1H, brs), 7.31 (1H, dd, J=8.5, 2Hz), 7.44 (1H, d, J=8.5Hz), 7.95 (1H, d, J=2Hz), 9.25 (1H, brs), 9.62 (1H, brs).

参考例１７６

収率：quant.％, 1H-NMR(DMSO-d6): δ0.85-0.90 (3H, m), 1.20-1.40 (4H, m), 1.85-2.00 (2H, m), 3.00-3.59 (5H, m), 4.15-4.23 (1H, m), 4.24-4.35 (1H, m), 7.60 (2H, s), 8.29 (1H, s), 9.36 (2H, brs), 9.75 (1H, s).

参考例１７７

収率：quant.％, 1H-NMR(DMSO-d6): δ0.86 (3H, d, J=6.5Hz), 1.04 (3H, d, J=6.5Hz), 3.00-3.35 (4H, m), 3.38-3.60 (2H, m), 3.87-4.02 (1H, m), 4.16-4.31 (1H, m), 5.20 (1H, br), 7.57 (1H, d, J=8.5Hz), 7.61 (1H, d, J=8.5Hz), 8.29 (1H, s), 9.05-9.22 (1H, m), 9.37-9.50 (1H, m).

参考例１７８

収率：93％, H-NMR(DMSO-d6): δ0.86 (3H, d, J=6.5Hz), 1.00 (3H, d, J=6.5Hz), 2.50-2.60 (1H, m), 3.03-3.31 (3H, m), 3.44-3.60 (2H, m), 3.90-4.00 (1H, m), 4.20-4.30 (1H, m), 7.54-7.63 (2H, m), 8.29 (1H, s), 9.23 (1H, brs), 9.48 (2H, brs).

参考例１７９

収率：96％, 1H-NMR(DMSO-d6): δ0.95 (6H, d, J=6.5Hz), 1.50-1.90 (3H, m), 2.96-3.37 (4H, m), 3.40-3.60 (1H, m), 4.03-4.16 (1H, m), 4.27-4.40 (1H, m), 6.30 (1H, br), 7.32 (1H, dd, J=8.5, 2.0Hz), 7.45 (1H, d, J=8.5Hz), 7.97 (1H, d, J=2.0Hz), 9.10-9.32 (1H, m), 9.52-9.75 (1H, m).

参考例１８０

収率：quant. ％, 1H-NMR(DMSO-d6): δ0.94 (6H, d, J=6.5Hz), 1.52-1.94 (3H, m), 2.95-3.35 (4H, m), 3.45-3.57 (1H, m), 4.04-4.16 (1H, m), 4.29-4.40 (1H, m), 7.32 (1H, dd, J=8.5, 2Hz), 7.45 (1H, d, J=8.5Hz), 7.97 (1H, d, J=2Hz), 9.45 (1H, brs), 9.81 (1H, brs), 9.84 (1H, brs).

参考例１８１

収率：quant. ％, 1H-NMR(DMSO-d6): δ0.96 (6H, d, J=6.5Hz), 1.50-1.90 (3H, m), 2.99-3.39 (4H, m), 3.46-3.63 (1H, m), 4.08-4.22 (1H, m), 4.35-4.48 (1H, m), 6.11(1H, brs), 7.60 (2H, s), 8.31 (1H, s), 9.10-9.29 (1H, m), 9.54-9.67 (1H, m).

参考例１８２

収率：97％, 1H-NMR(CDCl3): δ1.04 (6 H, s), 1.68 (1 H, br), 1.98 (1 H, br), 2.07 (1 H, br), 3.54 (3 H, br), 3.71 (1 H, br), 3.98 (1 H, s), 4.46 (2 H, br), 7.52 (1 H, d, J = 7.5 Hz), 7.65 (1 H, d, J = 7.5 Hz), 7.90 (1 H, s)

参考例１８３

収率：94％, 1H-NMR(DMSO-d6): δ3.24 (4H, t, J=5.0Hz), 3.74 (4H, t, J=5.0Hz), 5.12 (1H, s), 7.26 (1H, t, J=7.5Hz), 7.39 (2H, t, J=7.5Hz), 7.51 (2H, d, J=7.5Hz), 7.71 (1H, s), 9.58 (2H, s).

参考例１８４

収率：96％, 1H-NMR(DMSO-d6): δ3.17-3.34 (4H, m), 3.83-3.96 (4H, m), 5.12 (1H, brs), 7.55 (1H, d, J=12.5Hz), 8.36 (1H, d, J=7.5Hz), 9.69(2H, brs).

参考例１８５

収率：92％, 1H-NMR(DMSO-d6): δ2.14-2.27 (2H, m), 3.16-3.30 (2H, m), 3.31-3.43 (2H, m), 3.66-3.84 (2H, m), 3.97-4.13 (2H, m), 4.78 (1H, brs), 7.53 (1H, d, J=12.5Hz), 8.32 (1H, d, J=7.5Hz), 9.53 (2H, brs).

参考例１８６

収率：89％, 1H-NMR(CDCl3): δ1.44 (3H, d, J=7.0Hz), 3.00-3.13 (1H, m), 3.14-3.40 (3H, m), 3.53-3.69 (1H, m), 4.02-4.15 (1H, m), 4.46-4.60 (1H, m), 6.90 (1H, brs), 7.55 (1H, d, J=12.5Hz), 8.35 (1H, d, J=7.0Hz), 9.50 (1H, br), 9.94 (1H, br).

参考例１８７

収率：83％, 1H-NMR(DMSO-d6): δ1.44 (3H, d, J=7.0Hz), 3.01-3.19 (1H, m), 3.20-3.45 (3H, m), 3.51-3.70 (1H, m), 4.01-4.16 (1H, m), 4.45-4.62 (1H, m), 5.95 (1H, brs), 7.55 (1H, d, J=12.5Hz), 8.35 (1H, d, J=7.5Hz), 9.49 (1H, br), 9.89 (1H, br).

参考例１８８

収率：83％, 1H-NMR(DMSO-d6): δ0.90 (3H, t, J=7.5Hz), 1.80-2.00 (2H, m), 2.97-3.40 (4H, m), 3.41-3.56 (1H, m), 4.06-4.26 (2H, m), 7.49 (1H, d, J=10.5Hz), 8.10 (1H, d, J=7.5Hz), 9.02-9.25 (1H, m), 9.43-9.65 (1H, m).

参考例１８９

収率：quant.％, 1H-NMR(DMSO-d6): δ3.16-3.32 (4H, m), 3.98-4.12 (4H, m), 7.42-7.51 (1H, m), 7.60-7.72 (2H, m), 7.88 (1H, d, J=8.0Hz), 8.90 (1H, s), 9.54 (2H, s).

参考例１９０

収率：92％, 1H-NMR(DMSO-d6): δ2.19-3.32 (4H, m), 3.80-3.90 (4H, m), 7.15 (1H, td, J=8.0, 1.0Hz), 7.34 (1H, td, J=8.0, 1.0Hz), 7.54 (1H, dd, J=8.0, 1.0Hz), 7.85 (1H, dd, J=8.0, 1.0Hz), 9.65 (2H, s).

参考例１９１

収率：91％, 1H-NMR(DMSO-d6): δ3.30 (4H, s), 3.80 (1H, br), 4.16 (4H, s), 7.38-7.60 (2H, m), 7.68-7.81 (1H, m), 7.84-7.97 (1H, m), 8.16 (1H, br), 8.32-8.52 (1H, m), 9.57 (2H, brs).

参考例１９２

収率：63％, 1H-NMR(DMSO-d6): δ3.24 (4H, s), 3.87 (1H, brs), 4.03 (4H, s), 7.66 (2H, s), 7.93 (1H, s), 8.92 (1H, s), 9.38 (2H, brs).

参考例１９３

収率：82％, 1H-NMR(DMSO-d6): δ2.71 (3H, s), 3.24-3.35 (4H, m), 3.62-3.73 (4H, m), 7.91 (1H, d, J=9.0Hz), 7.97 (1H, d, J=9.0Hz), 8.23 (1H, s), 9.32 (2H, brs).

参考例１９４

収率：80％, 1H-NMR(DMSO-d6): δ1.39 (3H, d, J=7.0Hz), 3.00-3.16 (1H, m), 3.18-3.54 (5H, m), 4.68 (1H, d, J=14.0Hz), 5.05-5.17 (1H, m), 7.79 (1H, d, J=8.5Hz), 7.89 (1H, d, J=8.5Hz), 8.20 (1H, s), 8.97 (1H, s), 9.19 (1H, brs), 9.53 (1H, brs). Thereafter, the compounds described in Reference Examples 156 to 194 were obtained in the same manner as in Reference Example 155.
Reference Example 156

Yield: 100%, ¹ H-NMR (DMSO-d ₆ ): δ2.13-2.20 (2H, m), 3.20-3.22, (2H, m), 3.33-3.35 (2H, m), 3.68-3.72 (2H, m), 3.98-4.00 (2H, m), 7.33 (1H, dd, J = 8.7Hz, 2.4Hz), 7.47 (1H, d, J = 9.0Hz), 7.97 (1H, d, J = 2.1Hz), 9.35 (2H, br-s).

Reference Example 157

Yield: 99%, ¹ H-NMR (DMSO-d ₆ ): δ 3.26 (4H, t, J = 5Hz), 3.90 (4H, t, J = 5Hz), 7.64 (2H, s), 8.34 ( 1H, s), 8.65 (1H, brs), 9.77 (2H, s).

Reference Example 158

Yield: 99%, ¹ H-NMR (DMSO-d ₆ ): δ 2.10-2.25 (2H, m), 3.20-3.30 (2H, m), 3.30-3.40 (2H, m), 3.70-3.80 ( 2H, m), 4.00-4.10 (2H, m), 6.64 (1H, brs), 7.60 (2H, s), 8.30 (1H, s), 9.47 (2H, s).

Reference Example 159

Yield: 91%, ¹ H-NMR (DMSO-d ₆ ): δ 1.39 (3H, d, J = 7Hz), 3.03-3.18 (1H, m), 3.25-3.40 (4H, m), 3.95- 4.05 (1H, m), 4.44-4.55 (1H, m), 7.34 (1H, dd, J = 8.5, 2Hz), 7.49 (1H, d, J = 8.5Hz), 7.96 (1H, d, J = 2Hz ), 9.09 (1H, brs), 9.55 (2H, brs).

Reference Example 160

Yield: 82%, 1H-NMR (CDCl3): δ 1.40 (3H, d, J = 6.5Hz), 1.67 (1H, brs), 2.77-2.95 (2H, m), 3.05-3.15 (2H, m ), 3.40 (1H, td, J = 12.5, 3.5Hz), 3.87 (1H, dd, J = 12.5, 3.5Hz), 4.15-4.30 (1H, m), 7.51 (1H, dd, J = 8.5, 1Hz ), 7.56 (1H, d, J = 8.5Hz), 7.84 (1H, d, J = 1Hz).

Reference Example 161

Yield: quant.%, 1H-NMR (DMSO-d6): δ1.42 (3H, d, J = 7Hz), 2.95-3.15 (1H, m), 3.15-3.40 (3H, m), 3.48-3.65 (1H, m), 3.95 (1H, m), 4.40-4.55 (1H, m), 7.33 (1H, dd, J = 8.5, 2Hz), 7.48 (1H, d, J = 8.5Hz), 7.98 (1H , d, J = 2Hz), 8.16 (1H, brs), 9.51 (1H, brs), 9.94 (1H, brs).

Reference Example 162

Yield: 94%, 1H-NMR (DMSO-d6): δ1.42 (3H, d, J = 7.0Hz), 2.98-3.15 (1H, m), 3.16-3.38 (3H, m), 3.47-3.63 (1H, m), 3.96-4.08 (1H, m), 4.40-4.53 (1H, m), 5.10 (1H, s), 7.33 (1H, dd, J = 8.5, 2.0Hz), 7.49 (1H, d , J = 8.5Hz), 7.97 (1H, d, J = 2.0Hz), 9.35-9.53 (1H, br), 9.82-9.98 (1H, br).

Reference Example 163

Yield: 100%, 1H-NMR (CDCl3): δ1.40 (3H, d, J = 7Hz), 2.84-2.96 (2H, m), 3.05-3.15 (2H, m), 3.39 (1H, dt, J = 12.5, 3.5Hz), 3.88 (1H, dd, J = 12.5, 2.5Hz), 4.15-4.25 (1H, m), 7.52 (1H, dd, J = 8.5, 1.5Hz), 7.56 (1H, d , J = 8.5Hz), 7.85 (1H, d, J = 1.5Hz).

Reference Example 164

Yield: 80%, 1H-NMR (DMSO-d6): δ1.41 (3H, d, J = 7.0Hz), 3.00-3.17 (1H, m), 3.18-3.38 (3H, m), 3.49-3.64 (1H, m), 4.05-4.14 (1H, m), 4.45-4.58 (1H, m), 6.03 (1H, brs) 7.61 (2H, m), 8.31 (1H, s), 9.25-9.50 (1H, m), 9.73-9.92 (1H, m).

Reference Example 165

Yield: 71%, 1H-NMR (DMSO-d6): δ0.91 (3H, t, J = 7.5Hz), 1.80-1.96 (2H, m), 3.01-3.16 (1H, m), 3.17-3.42 (3H, m), 3.43-3.59 (1H, m), 4.08-4.27 (2H, m), 4.43 (1H, s), 7.33 (1H, dd, J = 8.5, 2.0Hz), 7.46 (1H, d , J = 8.5Hz), 7.94 (1H, d, J = 2.0Hz), 9.22-9.44 (1H, m), 9.60-9.75 (1H, m).

Reference Example 166

Yield: 99%, 1H-NMR (CDCl3): δ0.98 (3H, t, J = 7.5Hz), 1.63 (1H, brs), 1.88 (2H, quant, J = 7.5Hz), 2.88 (1H, td, J = 12, 3.5Hz), 2.95-3.10 (3H, m), 3.34 (1H, td, J = 12.5, 3.5Hz), 3.77-3.86 (1H, m), 3.90-4.00 (1H, m) , 7.22 (1H, dd, J = 8.5, 2Hz), 7.40 (1H, d, J = 8.5Hz), 7.53 (1H, d, J = 2Hz).

Reference Example 167

Yield: quant.% 1H-NMR (DMSO-d6): δ 0.90 (3H, t, J = 7.5Hz), 1.84-2.05 (2H, m), 2.94-3.62 (5H, m), 4.07-4.26 (2H, m), 6.71 (1H, brs), 7.32 (1H, dd, J = 8.5, 2.0Hz), 7.46 (1H, d, J = 8.5Hz), 7.96 (1H, d, J = 2.0Hz) , 9.35-9.58 (1H, m), 9.73-9.95 (1H, m).

Reference Example 168

Yield: quant.%, 1H-NMR (CDCl3): δ0.98 (3H, t, J = 7.5Hz), 1.61 (1H, brs), 1.90 (2H, quant, J = 7.5Hz), 2.89 (1H , td, J = 12, 3.5Hz), 2.95-3.13 (3H, m), 3.37 (1H, td, J = 12.5, 3.5Hz), 3.83-3.94 (1H, m), 3.95-4.06 (1H, m ), 7.45-7.56 (2H, m), 7.83 (1H, s).

Reference Example 169

Yield: quant.%, 1H-NMR (CDCl3): δ0.98 (3H, t, J = 7.5Hz), 1.72 (1H, brs), 1.91 (2H, quant, J = 7.5Hz), 2.89 (1H , td, J = 12.5, 3.5Hz), 2.95-3.13 (3H, m), 3.38 (1H, td, J = 12.5, 3.5Hz), 3.84-3.95 (1H, m), 3.95-4.08 (1H, m ), 7.50 (1H, d, J = 8.5Hz), 7.54 (1H, d, J = 8.5Hz), 7.83 (1H, s).

Reference Example 170

Yield: quant.%, 1H-NMR (DMSO-d6): δ0.92 (3H, t, J = 7.0Hz), 1.20-1.45 (2H, m), 1.78-1.92 (2H, q, J = 7.5 Hz), 2.97-3.38 (4H, m), 3.42-3.59 (1H, m), 4.04-4.17 (1H, m), 4.22-4.34 (1H, m), 5.64 (1H, br), 7.31 (1H, dd, J = 8.5, 2.5Hz), 7.45 (1H, d, J = 8.5Hz), 7.96 (1H, d, J = 2.5Hz), 9.04-9.20 (1H, m), 9.50-9.64 (1H, m ).

Reference Example 171

Yield: quant.%, 1H-NMR (CDCl3): δ0.99 (3 H, t, J = 6.6 Hz), 1.26-1.49 (4 H, m), 2.11 (2 H, br), 3.63-3.83 (3 H, m), 4.10 (1 H, br), 4.51 (1 H, br), 4.64 (1 H, br), 7.22 (1 H, s), 7.56-7.63 (2 H, m)

Reference Example 172

Yield: quant.%, 1H-NMR (DMSO-d6): δ0.93 (3H, t, J = 7.5Hz), 1.18-1.46 (2H, m), 1.80-1.95 (2H, m), 3.00- 3.40 (4H, m), 3.45-3.62 (1H, m), 4.12-4.24 (1H, m), 4.29-4.42 (1H, m), 7.54-7.65 (2H, m), 8.31 (1H, s), 9.14-9.32 (1H, m), 9.60-9.72 (1H, m).

Reference Example 173

Yield: quant.%, 1H-NMR (CDCl3): δ1.00 (3 H, t, J = 6.0 Hz), 1.26-1.54 (4 H, m), 2.17 (2 H, br), 3.63-3.86 (3 H, m), 4.11 (1 H, br), 4.54 (1 H, br), 4.70 (1 H, br), 7.50 (1 H, d, J = 7.5 Hz), 7.72 (1 H, d , J = 7.5 Hz), 7.91 (1 H, s)

Reference Example 174

Yield: quant.%, 1H-NMR (DMSO-d6): δ0.87 (3H, t, J = 7Hz), 1.20-1.39 (4H, m), 1.78-1.95 (2H, m), 3.00-3.15 (1H, m), 3.15-3.40 (3H, m), 3.42-3.55 (1H, m), 4.07-4.20 (1H, m), 4.20-4.30 (1H, m), 4.55 (1H, brs), 7.31 (1H, dd, J = 8.5, 2Hz), 7.44 (1H, d, J = 8.5Hz), 7.95 (1H, d, J = 2Hz), 9.00 (1H, brs), 9.48 (1H, brs).

Reference Example 175

Yield: quant.%, 1H-NMR (DMSO-d6): δ0.87 (3H, t, J = 7Hz), 1.18-1.40 (4H, m), 1.77-1.98 (2H, m), 2.95-3.14 (1H, m), 3.14-3.37 (3H, m), 3.40-3.51 (1H, m), 4.08-4.20 (1H, m), 4.20-4.31 (1H, m), 6.89 (1H, brs), 7.31 (1H, dd, J = 8.5, 2Hz), 7.44 (1H, d, J = 8.5Hz), 7.95 (1H, d, J = 2Hz), 9.25 (1H, brs), 9.62 (1H, brs).

Reference Example 176

Yield: quant.%, 1H-NMR (DMSO-d6): δ0.85-0.90 (3H, m), 1.20-1.40 (4H, m), 1.85-2.00 (2H, m), 3.00-3.59 (5H , m), 4.15-4.23 (1H, m), 4.24-4.35 (1H, m), 7.60 (2H, s), 8.29 (1H, s), 9.36 (2H, brs), 9.75 (1H, s).

Reference Example 177

Yield: quant.%, 1H-NMR (DMSO-d6): δ0.86 (3H, d, J = 6.5Hz), 1.04 (3H, d, J = 6.5Hz), 3.00-3.35 (4H, m) , 3.38-3.60 (2H, m), 3.87-4.02 (1H, m), 4.16-4.31 (1H, m), 5.20 (1H, br), 7.57 (1H, d, J = 8.5Hz), 7.61 (1H , d, J = 8.5Hz), 8.29 (1H, s), 9.05-9.22 (1H, m), 9.37-9.50 (1H, m).

Reference Example 178

Yield: 93%, H-NMR (DMSO-d6): δ 0.86 (3H, d, J = 6.5Hz), 1.00 (3H, d, J = 6.5Hz), 2.50-2.60 (1H, m), 3.03-3.31 (3H, m), 3.44-3.60 (2H, m), 3.90-4.00 (1H, m), 4.20-4.30 (1H, m), 7.54-7.63 (2H, m), 8.29 (1H, s ), 9.23 (1H, brs), 9.48 (2H, brs).

Reference Example 179

Yield: 96%, 1H-NMR (DMSO-d6): δ 0.95 (6H, d, J = 6.5Hz), 1.50-1.90 (3H, m), 2.96-3.37 (4H, m), 3.40-3.60 (1H, m), 4.03-4.16 (1H, m), 4.27-4.40 (1H, m), 6.30 (1H, br), 7.32 (1H, dd, J = 8.5, 2.0Hz), 7.45 (1H, d , J = 8.5Hz), 7.97 (1H, d, J = 2.0Hz), 9.10-9.32 (1H, m), 9.52-9.75 (1H, m).

Reference Example 180

Yield: quant.%, 1H-NMR (DMSO-d6): δ 0.94 (6H, d, J = 6.5Hz), 1.52-1.94 (3H, m), 2.95-3.35 (4H, m), 3.45- 3.57 (1H, m), 4.04-4.16 (1H, m), 4.29-4.40 (1H, m), 7.32 (1H, dd, J = 8.5, 2Hz), 7.45 (1H, d, J = 8.5Hz), 7.97 (1H, d, J = 2Hz), 9.45 (1H, brs), 9.81 (1H, brs), 9.84 (1H, brs).

Reference Example 181

Yield: quant.%, 1H-NMR (DMSO-d6): δ0.96 (6H, d, J = 6.5Hz), 1.50-1.90 (3H, m), 2.99-3.39 (4H, m), 3.46- 3.63 (1H, m), 4.08-4.22 (1H, m), 4.35-4.48 (1H, m), 6.11 (1H, brs), 7.60 (2H, s), 8.31 (1H, s), 9.10-9.29 ( 1H, m), 9.54-9.67 (1H, m).

Reference Example 182

Yield: 97%, 1H-NMR (CDCl3): δ1.04 (6 H, s), 1.68 (1 H, br), 1.98 (1 H, br), 2.07 (1 H, br), 3.54 (3 H, br), 3.71 (1 H, br), 3.98 (1 H, s), 4.46 (2 H, br), 7.52 (1 H, d, J = 7.5 Hz), 7.65 (1 H, d, J = 7.5 Hz), 7.90 (1 H, s)

Reference Example 183

Yield: 94%, 1H-NMR (DMSO-d6): δ 3.24 (4H, t, J = 5.0Hz), 3.74 (4H, t, J = 5.0Hz), 5.12 (1H, s), 7.26 ( 1H, t, J = 7.5Hz), 7.39 (2H, t, J = 7.5Hz), 7.51 (2H, d, J = 7.5Hz), 7.71 (1H, s), 9.58 (2H, s).

Reference Example 184

Yield: 96%, 1H-NMR (DMSO-d6): δ3.17-3.34 (4H, m), 3.83-3.96 (4H, m), 5.12 (1H, brs), 7.55 (1H, d, J = 12.5Hz), 8.36 (1H, d, J = 7.5Hz), 9.69 (2H, brs).

Reference Example 185

Yield: 92%, 1H-NMR (DMSO-d6): δ2.14-2.27 (2H, m), 3.16-3.30 (2H, m), 3.31-3.43 (2H, m), 3.66-3.84 (2H, m), 3.97-4.13 (2H, m), 4.78 (1H, brs), 7.53 (1H, d, J = 12.5Hz), 8.32 (1H, d, J = 7.5Hz), 9.53 (2H, brs).

Reference Example 186

Yield: 89%, 1H-NMR (CDCl3): δ1.44 (3H, d, J = 7.0Hz), 3.00-3.13 (1H, m), 3.14-3.40 (3H, m), 3.53-3.69 (1H , m), 4.02-4.15 (1H, m), 4.46-4.60 (1H, m), 6.90 (1H, brs), 7.55 (1H, d, J = 12.5Hz), 8.35 (1H, d, J = 7.0 Hz), 9.50 (1H, br), 9.94 (1H, br).

Reference Example 187

Yield: 83%, 1H-NMR (DMSO-d6): δ1.44 (3H, d, J = 7.0Hz), 3.01-3.19 (1H, m), 3.20-3.45 (3H, m), 3.51-3.70 (1H, m), 4.01-4.16 (1H, m), 4.45-4.62 (1H, m), 5.95 (1H, brs), 7.55 (1H, d, J = 12.5Hz), 8.35 (1H, d, J = 7.5Hz), 9.49 (1H, br), 9.89 (1H, br).

Reference Example 188

Yield: 83%, 1H-NMR (DMSO-d6): δ0.90 (3H, t, J = 7.5Hz), 1.80-2.00 (2H, m), 2.97-3.40 (4H, m), 3.41-3.56 (1H, m), 4.06-4.26 (2H, m), 7.49 (1H, d, J = 10.5Hz), 8.10 (1H, d, J = 7.5Hz), 9.02-9.25 (1H, m), 9.43- 9.65 (1H, m).

Reference Example 189

Yield: quant.%, 1H-NMR (DMSO-d6): δ3.16-3.32 (4H, m), 3.98-4.12 (4H, m), 7.42-7.51 (1H, m), 7.60-7.72 (2H , m), 7.88 (1H, d, J = 8.0Hz), 8.90 (1H, s), 9.54 (2H, s).

Reference Example 190

Yield: 92%, 1H-NMR (DMSO-d6): δ2.19-3.32 (4H, m), 3.80-3.90 (4H, m), 7.15 (1H, td, J = 8.0, 1.0Hz), 7.34 (1H, td, J = 8.0, 1.0Hz), 7.54 (1H, dd, J = 8.0, 1.0Hz), 7.85 (1H, dd, J = 8.0, 1.0Hz), 9.65 (2H, s).

Reference Example 191

Yield: 91%, 1H-NMR (DMSO-d6): δ 3.30 (4H, s), 3.80 (1H, br), 4.16 (4H, s), 7.38-7.60 (2H, m), 7.68-7.81 (1H, m), 7.84-7.97 (1H, m), 8.16 (1H, br), 8.32-8.52 (1H, m), 9.57 (2H, brs).

Reference Example 192

Yield: 63%, 1H-NMR (DMSO-d6): δ3.24 (4H, s), 3.87 (1H, brs), 4.03 (4H, s), 7.66 (2H, s), 7.93 (1H, s ), 8.92 (1H, s), 9.38 (2H, brs).

Reference Example 193

Yield: 82%, 1H-NMR (DMSO-d6): δ2.71 (3H, s), 3.24-3.35 (4H, m), 3.62-3.73 (4H, m), 7.91 (1H, d, J = 9.0Hz), 7.97 (1H, d, J = 9.0Hz), 8.23 (1H, s), 9.32 (2H, brs).

Reference Example 194

Yield: 80%, 1H-NMR (DMSO-d6): δ1.39 (3H, d, J = 7.0Hz), 3.00-3.16 (1H, m), 3.18-3.54 (5H, m), 4.68 (1H , d, J = 14.0Hz), 5.05-5.17 (1H, m), 7.79 (1H, d, J = 8.5Hz), 7.89 (1H, d, J = 8.5Hz), 8.20 (1H, s), 8.97 (1H, s), 9.19 (1H, brs), 9.53 (1H, brs).

4-(6-クロロベンゾチアゾール-2-イル)ピペラジン2塩酸塩3.00g（9.18mmol）、3-(ブロモメチル)安息香酸メチル2.31g（10.1mmol）、炭酸カリウム3.81g（27.6mmol）及び無水N,N-ジメチルホルムアミド30mlの混合物を室温下14時間撹拌した。反応液に水を加え、析出結晶を濾取後、ジイソプロピルエーテルで洗浄し3-[[4-(6-クロロベンゾチアゾール-2-イル)ピペラジン-1-イル]メチル]安息香酸メチルを無色結晶として3.06g（83％）得た。
¹H-NMR(CDCl₃): δ2.58 (4H, t, J=5Hz), 3.61 (2H, s), 3.64 (4H, t, J=5Hz), 3.93 (3H, s), 7.23 (1H, dd, J=8.5, 2Hz), 7.35-7.45 (1H, m), 7.43 (1H, d, J=8.5Hz), 7.55 (1H, d, J=2Hz), 7.55-7.60 (1H, m), 7.96 (1H, d, J=7.5Hz), 8.01 (1H, s). Example 1
Preparation of methyl 3-[[4- (6-chlorobenzothiazol-2-yl) piperazin-1-yl] methyl] benzoate

4- (6-Chlorobenzothiazol-2-yl) piperazine dihydrochloride 3.00 g (9.18 mmol), methyl 3- (bromomethyl) benzoate 2.31 g (10.1 mmol), potassium carbonate 3.81 g (27.6 mmol) and anhydrous N Then, a mixture of 30 ml of N-dimethylformamide was stirred at room temperature for 14 hours. Water was added to the reaction mixture, and the precipitated crystals were collected by filtration and washed with diisopropyl ether to give methyl 3-[[4- (6-chlorobenzothiazol-2-yl) piperazin-1-yl] methyl] benzoate as colorless crystals. As a result, 3.06 g (83%) was obtained.
¹ H-NMR (CDCl ₃ ): δ2.58 (4H, t, J = 5Hz), 3.61 (2H, s), 3.64 (4H, t, J = 5Hz), 3.93 (3H, s), 7.23 (1H , dd, J = 8.5, 2Hz), 7.35-7.45 (1H, m), 7.43 (1H, d, J = 8.5Hz), 7.55 (1H, d, J = 2Hz), 7.55-7.60 (1H, m) , 7.96 (1H, d, J = 7.5Hz), 8.01 (1H, s).

収率：88％, ¹H-NMR(CDCl₃): δ2.01-2.05(2H, m), 2.69 (2H, t, J=5.4Hz), 2.80-2.83 (2H, m), 3.67(2H, s) 3.72-3.78 (4H, m), 3.92 (3H, s), 7.23 (1H, dd, J= 8.7Hz, 2.1Hz), 7.37-7.44 (2H, m), 7.53(1H, s), 7.55 (1H, d, J =2.1Hz ), 7.94 ( 1H, d, J = 7.5Hz ), 7.99 (1H, s).

実施例３

収率：73％,¹H-NMR(CDCl₃): δ2.60 (4 H, t, J=5 Hz), 3.62 (2H, s), 3.67 (4H, t, J=5 Hz), 3.97 (3H, s), 7.43 (1H, t, J= 7.5 Hz), 7.50-7.60 (3 H, m), 7.85 (1H, s), 7.97 (1H, d, J= 7.5 Hz), 8.02 (1H, s).

実施例４

収率：q.y, ¹H-NMR(CDCl₃): δ2.00-2.20 (2H, m), 2.70 (2H, t, J=5.5 Hz), 2.83 (2H, t, J= 5.5 Hz), 3.69 (2H, s), 3.70-3.85 (4H, m), 3.92 (3H, s), 7.40 (1H,t, J=7.5Hz), 7.50-7.60 (3H, m), 7.84 (1H, s), 7.94 (1H, d, J=7.5Hz), 7.99 (1H, s).

実施例５

収率：97％,¹H-NMR(CDCl₃): δ1.41 (3H, d, J= 6 Hz), 2.28 (1H, td,J= 11.5, 3.5 Hz), 2.36 (1H, dd, J=11.5, 3.5 Hz), 2.69 (1H, d, J= 11.5 Hz), 2.90 (1H, d, J= 11.5 Hz), 3.40-3.55 (2H, m), 3.63 (1H,d, J=12.5Hz), 3.80-3.90 (1H, m), 3.93 (3H, s), 4.10-4.25 (1H, m), 7.22 (1H, dd, J=8.5, 2 Hz), 7.42 (1H, d, J= 8.5 Hz), 7.43 (1H, t, J= 7.5 Hz), 7.54 (1H, d, J= 2 Hz), 7.58 (1H, d, J= 7.5 Hz), 7.95 (1H, d, J= 7.5 Hz), 8.02 (1H, s).

実施例６

収率：q.y,¹H-NMR(CDCl₃): δ1.23 (3H, d, J= 6 Hz), 2.25-2.35 (1H, m), 2.60-2.73 (1H, m), 2.73-2.82 (1H, m), 3.17 (1H, dd, J= 12.5, 9 Hz), 3.33 (1H, d, J= 13.5 Hz), 3.35-3.45 (1H, m), 3.65-3.75 (1H, m), 3.85-3.90 (1H, m), 3.93 (3H, s), 4.08 (1H, d, J=13.5 Hz), 7.22 (1H, dd, J= 8.5, 2 Hz), 7.41 (1H, t, J= 7.5 Hz), 7.43 (1H, d, J= 8.5 Hz), 7.54 (1H, d, J= 2 Hz), 7.56 (1H, d, J= 7.5 Hz), 7.94 (1H, d, J= 7.5 Hz), 8.01 (1H, s).

実施例７

収率：83%, ¹H-NMR(CDCl₃): δ1.15 (6H, d, J=6Hz), 2.75-2.85 (2H, m), 3.06 (2H, dd, J=13, 12.5Hz), 3.80-3.92 (4H,m),3.92(3H,s),7.24 (1H, dd, J=8.5, 2Hz), 7.37 (1H, d, J= 7.5Hz), 7.43 (1H, d, J= 8.5 Hz), 7.55 (1H, d, J= 2 Hz), 7.62 (1H, d, J= 7.5 Hz), 7.89 (1H, d, J= 7.5 Hz), 8.04 (1H, s).

実施例８

収率：79%, ¹H-NMR(CDCl₃): δ1.10 (3H, d, J=6.5Hz),1.38 (3H, d, J=6.5Hz), 2.31 (1H, d, J= 12 Hz), 2.91 (1H, dd, J= 12,4 Hz), 3.10-3.20 (1H, m), 3.59 (2H, t, J= 14 Hz), 3.71 (2H, t, J=14 Hz), 3.93 (3H, s), 4.16-4.28 (1H, m), 7.22 (1H, dd, J= 8.5, 2 Hz), 7.42 (1H, d, J= 8.5 Hz), 7.43 (1H, d, J= 7.5 Hz), 7.53 (1H, d, J= 2 Hz), 7.61 (1H, d, J= 7.5 Hz), 7.95 (1H, d, J= 7.5 Hz), 8.06 (1H, s).

実施例９

収率92%, ¹H-NMR(CDCl₃): δ2.45 (3H, s), 2.58 (4H, t, J=5Hz), 3.55 (2H, s), 3.61 (4H, t, J=5Hz), 3.91 (3H, s), 7.23 (1H, dd, J=8.5, 2 Hz), 7.24 (1H, d, J=8 Hz), 7.43 (1H, d, J= 8.5Hz), 7.55 (1H, d, J=2 Hz), 7.87 (1H, dd, J=8, 1.5Hz), 7.92 (1H, d, J=1.5Hz).

実施例１０

収率93%,¹H-NMR(CDCl₃): δ2.66 (4H, t, J= 5 Hz), 3.66 (4H, t, J=5 Hz), 3.71 (2H, s), 3.96 (3H, s), 7.24 (1H, dd, J=8.5, 2 Hz), 7.44 (1H, d, J=8.5 Hz), 7.45 (1H, d, J=8 Hz), 7.55 (1H, d, J=2 Hz), 7.88 (1H, dd, J= 8,2 Hz), 8.15 (1H, d, J=2 Hz).

実施例１１

収率79%, ¹H-NMR(CDCl₃): δ1.99-2.05 (2H, m), 2.40 (3H, s), 2.69 (2H, t, J =5.1Hz), 2.79-2.82 (2H, m), 3.61 (2H, s), 3.71-3.75 (4H, m), 3.90 (3H, s), 7.21-7.25 (2H, m), 7.42 (1H, d, J =8.4Hz), 7.55 (1H, d, J = 2.4Hz ), 7.38-7.87 (1H, m), 7.92 (1H, s).

実施例１２

収率79%, ¹H-NMR(CDCl₃): δ2.03-2.10 (2H, m), 2.75 (2H, t, J=5.4Hz), 2.87-2.90 (2H, m), 3.73-3.80 (6H, m), 3.92 (3H, s), 7.22-7.26 (1H, m), 7.41(1H, s), 7.44 (1H, s), 7.55 (1H, d, J=2.1Hz ), 7.87 (1H, dd, J =8.4Hz, 2.1Hz), 8.15 ( 1H, d, J = 2.1Hz ).

実施例１３

収率90%, ¹H-NMR(CDCl₃): δ2.38 (3H, s), 2.57 (4H, t, J=5Hz), 3.51 (2H, s), 3.64 (4H, t, J=5Hz), 3.92 (3H, s), 7.23 (1H, dd, J=8.5, 2Hz),7.37(1H,s), 7.43 (1H, d, J=8.5Hz), 7.55 (1H, d, J=2Hz), 7.78 (1H, s), 7.80 (1H, s).

実施例１４

収率90%, ¹H-NMR(CDCl₃): δ1.59 (3H, s), 2.00-2.06 (2H, m), 2.39 (3H, s), 2.69 (2H, t, J= 5.4 Hz), 2.79-2.82 (2H, m), 3.64 (2H, s) 3.74-3.77 (4H,m), 7.23 (1H, dd, J=8.4 Hz, 1.8 Hz), 7.35 (1H, s), 7.42 (1H, d, J=8.4Hz), 7.55 (1H, d, J=1.8Hz), 7.75 ( 1H, s), 7.78 (1H, s).

実施例１５

¹H-NMR(CDCl₃): δ2.65 (4H, t, J=5.1Hz), 3.64-3.67 (4H, m), 3.78 (2H, s), 3.88 (3H, s), 6.93 (1H, d, J=3.3Hz), 7.24 (1H, dd, J=8.7,2.1Hz), 7.44 (1H, d, J=8.7Hz), 7.56 (1H, d, J=2.1Hz), 7.67 (1H, d, J=3.3Hz).

実施例１６

収率65%, ¹H-NMR(CDCl₃): δ2.01-2.08 (2H, m), 2.71-2.75 (2H,m), 2.85-2.89 (2H, m), 3.72-3.76 (2H, m), 3.79-3.82 (2H, m), 3.86 (2H, s), 3.87 (3H, s), 6.89 (1H, d, J= 3.9 Hz), 7.23 (1H, dd, J= 8.7 Hz, 2.1 Hz), 7.42 (1H, d, J=8.7Hz), 7.55 (1H, d, J=2.4Hz ), 7.65 (1H, d, J=3.9Hz).

実施例１７

¹H-NMR(CDCl₃): δ1.37 (3H, t, J= 7 Hz), 2.65 (4H, t, J= 5 Hz), 3.65 (4H, t, J= 5 Hz), 3.69 (2H, s), 4.36 (2H, q, J= 7 Hz), 6.37 (1H, d, J= 3.5 Hz), 7.13 (1H, d, J=3.5Hz), 7.24 (1H, dd, J=8.5, 2Hz), 7.43 (1H, d, J=8.5Hz), 7.55 (1H, d, J=2Hz).

実施例１８

¹H-NMR(CDCl₃): δ2.56-2.60 (4H, m), 3.62-3.66 (6H, m), 3.92 (3H, s), 7.24 (1H, dd, J=8.7, 2.1Hz), 7.42-7.44 (3H, m), 7.55 (1H, d, J=2.1Hz), 8.01 (2H, d, J=8.4Hz).

実施例１９

収率76%, ¹H-NMR(CDCl₃): δ2.41(3H,s), 2.59 (4H, t, J= 5 Hz), 3.58 (2H,s),3.69(4 H,t, J=5 Hz), 3.96 (3H, s), 7.37 (1H, s), 7.50-7.60 (2H, m), 7.79 (1H, s), 7.80 (1H, s), 7.85 (1H, s).

実施例２０

収率74%, ¹H-NMR(CDCl₃): δ2.00-2.10 (2H, m), 2.38 (3H, s), 2.70 (2H, t, J=5Hz), 2.82 (2H, t, J=5Hz), 3.65 (2H, s), 3.70-3.90 (4H, m), 3.91 (3H, s), 7.34 (1H, s), 7.50-7.60 (2H, m), 7.75 (1H, s), 7.79 (1H, s), 7.85 (1H, s).

実施例２１

収率98%, 1H-NMR(CDCl3): δ1.24 (3H, d, J=6.5Hz), 2.25-2.37 (1H, m), 2.64-2.75 (1H, m), 2.75-2.83 (1H, m), 3.23 (1H, dd, J=13, 9Hz), 3.29 (1H, d, J=13.5Hz), 3.40-3.50 (1H, m), 3.70-3.80 (1H, m), 3.87-3.95 (1H, m), 3.93 (3H, s), 4.08 (1H, d, J=13.5Hz), 7.42 (1H, t, J=7.5Hz), 7.50-7.60 (3H, m), 7.84 (1H, s), 7.95 (1H, d, J=8Hz), 8.01 (1H, s).

実施例２２

収率85%, 1H-NMR(CDCl3): δ1.24 (3H, d, J=6.5Hz), 2.23-2.35 (1H, m), 2.41 (3H, s), 2.60-2.73 (1H, m), 2.80 (1H, dt, J=12, 3.5 Hz), 3.21 (1H, d, J=13 Hz), 3.24 (1H, d, J=13.5Hz), 3.39-3.50 (1H, m), 3.70-3.80 (1H, m), 3.91 (3H, s), 3.91-3.95 (1H, m), 4.05 (1H, d, J=13.5Hz), 7.36 (1H, s), 7.51 (1H, d, J=8.5Hz), 7.55 (1H, d, J=8.5Hz), 7.77 (1H, s), 7.80 (1H, s), 7.84 (1H, s).

実施例２３

収率96%, 1H-NMR(CDCl3): δ1.24 (3 H, d, J = 6.3 Hz), 2.24-2.32 (1 H, m), 2.40 (3 H, s), 2.63-2.68 (1 H, m), 2.78 (1 H, dt, J = 3.6, 12.0 Hz), 3.17 (1 H, dd, J = 9.0 Hz), 3.22 (1 H, d, J = 13.2 Hz), 3.35-3.43 (1 H, m), 3.71 (1 H, dt, J = 3.3, 12.6 Hz), 3.88 (1 H, dd, J = 3.0, 15.0 Hz), 3.91 (3 H, s), 4.05 (1 H, d, J = 13.2 Hz), 7.23 (1 H, dd, J = 2.4, 8.4 Hz), 7.36 (1 H, s), 7.43 (1 H, d, J = 8.4 Hz), 7.54 (1 H, d, J = 2.4 Hz, 7.76 (1 H, s), 7.79 (1 H, s)

実施例２４

収率98%, 1H-NMR(CDCl3): δ1.24 (3 H, d, J = 6.3 Hz), 2.28 (1H, ddd, J = 3.3, 8.7, 9.6 Hz), 2.40 (3 H, s), 2.62-2.68 (1 H, m), 2.78 (1 H, dt, J = 3.6, 12.0 Hz), 3.17 (1 H, dd, J = 8.7, 12.6 Hz), 3.22 (1 H, d, J = 12.9 Hz), 3.39 (1 H, m), 3.71 (1 H, d, 12.3 Hz), 3.88 (1 H, dd, 3.3, 13.2 Hz), 3.92 (3 H, s), 4.05 (1 H, d, J = 13.2 Hz), 7.23 (1 H, dd, J = 2.1, 8.4 Hz), 7.36 (1 H, s), 7.43 (1 H, d, J = 8.4 Hz), 7.54(1 H, d, J = 2.1 Hz), 7.76 (1 H, s), 7.79 (1 H, s)

実施例２５

収率86%, 1H-NMR(CDCl3): δ1.11 (6H, d, J=6Hz), 2.40 (3H, s), 2.70-2.85 (2H, m), 3.00-3.15 (2H, m), 3.83 (2H, s), 3.83-3.90 (2H, m), 3.91 (3H, s), 7.23 (1H, dd, J=8.5, 2Hz), 7.40 (1H, s), 7.43 (1H, d, J=8.5Hz), 7.55 (1H, d, J=2Hz), 7.72 (1H, s), 7.84 (1H, s).

実施例２６

収率67%, 1H-NMR(CDCl3): δ1.13 (6H, d, J=6.5Hz), 2.40 (3H, s), 2.75-2.88 (2H, m), 3.05-3.18 (2H, m), 3.84 (2H, s), 3.91 (3H, s), 3.91-3.95 (2H, m), 7.40 (1H, s), 7.52 (1H, d, J=8.5Hz), 7.57 (1H, d, J=8.5Hz), 7.72 (1H, s), 7.84 (2H, s).

実施例２７

収率75%, 1H-NMR(CDCl3): δ1.42 (3H, d, J=6.5Hz), 2.26 (1H, td, J=11.5, 3.5Hz), 2.36 (1H, dd, J=11.5, 3.5Hz), 2.41 (3H, s), 2.65-2.75 (1H, m), 2.85-2.95 (1H, m), 3.47 (1H, d, J=13.5Hz), 3.48-3.55 (1H, m), 3.60 (1H, d, J=13.5Hz), 3.80-3.90 (1H, m), 3.91 (3H, s), 4.20-4.30 (1H, m), 7.38 (1H, s), 7.51 (1H, dd, J=8.5, 2Hz), 7.56 (1H, d, J=8.5Hz), 7.77 (1H, s), 7.83 (1H, d, J=2Hz), 7.84 (1H, s).

実施例２８

収率78%, 1H-NMR(CDCl3): δ1.24 (3H, t, J=6.0Hz), 2.24-2.36 (1H, m), 2.41 (3H, s), 2.61-2.73 (1H, m), 2.75-2.84 (1H, m), 3.21 (1H, d, J=13.0Hz), 3.24 (1H, d, J=13.5Hz), 3.38-3.51 (1H, m), 3.71-3.82 (1H, m), 3.88-3.98 (1H, m), 3.92 (3H, s), 4.05 (1H, d, J=13.0Hz), 7.36 (1H, s), 7.51 (1H, d, J=8.5), 7.56 (1H, d, J=8.5Hz), 7.77 (1H, s), 7.80 (1H, s), 7.84 (1H, s).

実施例２９

収率58%,¹H-NMR(DMSO-d₆): δ2.25 (3H, s), 2.31 (3H, s), 2.51 (4H, t, J= 5 Hz), 3.51 (2H, s), 3.57 (4H, t, J= 5 Hz), 6.85 (1H, s), 6.89 (1H, s), 7.04 (1H, s), 7.28 (1H, dd, J=8.5, 2.5Hz), 7.42 (1H, d, J=8.5Hz), 7.91 (1H, d, J=2.5Hz).

実施例３０

収率89%, ¹H-NMR(CDCl₃): δ1.99-2.06 (2H, m), 2.29 (3H, s), 2.34 (3H, s), 2.68 (2H, t, J=5.7Hz), 2.78-2.82 (2H, m ), 3.61 (2H, s ), 3.72-3.78 (4H, m), 6.79 (1H, s ), 6.88 (1H, s), 6.98 (1H, s), 7.22 (1H, dd, J =7.5Hz, 3.3Hz), 7.42(1H, d, J =6.3Hz), 7.54 (1H, d, J =2.1Hz).

実施例３１

収率71%, ¹H-NMR(CDCl₃): δ2.30 (3H, s), 2.36 (3H, s), 2.59 (4H, t, J=5Hz), 3.53 (2H, s), 3.68 (4H, t, J=5Hz), 6.83 (1H,s), 6.90 (1H, s), 7.02 (1H,s), 7.50-7.60 (2H,m), 7.85 (1H, s).

実施例３２

収率65%, ¹H-NMR(CDCl₃): δ1.95-2.10 (2H, m), 2.28 (3H, s), 2.34 (3H, s), 2.69 (2H, t, J=5Hz), 2.83 (2H, t, J=5Hz), 3.61 (2H, s), 3.70-3.85 (4H, m), 6.80 (1H, s), 6.89 (1H, s), 6.99 (1H, s), 7.48-7.60 (2H, m), 7.85 (1H, s).

実施例３３

収率69%, ¹H-NMR(CDCl₃): δ2.31 (3H, s), 2.57 (4H, t, J = 5.1 Hz), 3.55 (2H,s), 3.63 (4H, t, J = 5.1Hz), 7.06 (2H,d,J =8.1 Hz),7.24 (1H, dd, J =8.4, 2.1Hz), 7.35 (2H, d, J = 8.1Hz), 7.43 (1H, d, J = 8.4 Hz), 7.55 (1H, d, J = 2.1 Hz).

実施例３４

収率56%, 1H-NMR(CDCl3): δ1.22 (3H, d, J=6Hz), 2.24-2.35 (1H, m), 2.29 (3H, s), 2.35 (3H, s), 2.62-2.72 (1H, m), 2.83 (1H, dt, J=12, 4Hz), 3.15-3.25 (2H, m), 3.40-3.50 (1H, m), 3.70-3.80 (1H, m), 3.87-3.95 (1H, m), 4.03 (1H, d, J=13.5Hz), 6.81 (1H, s), 6.90 (1H, s), 7.01 (1H, s), 7.52 (1H, d, J=8.5Hz), 7.56 (1H, d, J=8.5Hz), 7.84 (1H, s).

実施例３５

収率41%, 1H-NMR(CDCl3): δ1.10 (6H, d, J=6Hz), 2.29 (3H, s), 2.34 (3H, s), 2.70-2.85 (2H, m), 3.00-3.10 (2H, m), 3.79 (2H, s), 3.80-3.90 (2H, m), 6.76 (1H, s), 6.95 (1H, s), 7.02 (1H, s), 7.23 (1H, dd, J=8.5, 2Hz), 7.43 (1H, d, J=8.5Hz), 7.55 (1H, d, J=2Hz).

実施例３６

収率63%, 1H-NMR(CDCl3): δ1.11 (6H, d, J=6Hz), 2.30 (3H, s), 2.35 (3H, s), 2.70-2.86 (2H, m), 3.00-3.15 (2H, m), 3.80 (2H, s), 3.85-3.95 (2H, m), 6.77 (1H, s), 6.95 (1H, s), 7.02 (1H, s), 7.52 (1H, d, J=8.5Hz), 7.57 (1H, d, J=8.5Hz), 7.85 (1H, s).

実施例３７

収率53%, 1H-NMR(CDCl3): δ1.02 (3H, t, J=7.5Hz), 1.55-1.78 (2H, m), 2.30 (3H, s), 2.30-2.35 (1H, m), 2.36 (3H, s), 2.49-2.60 (1H, m), 2.78-2.90 (1H, m), 3.26 (1H, d, J=13.5Hz), 3.38-3.46 (1H, m), 3.46-3.58 (1H, m), 3.63-3.72 (1H, m), 3.85 (1H, dd, J=13, 3.5Hz), 3.98 (1H, d, J=13.5Hz), 6.81 (1H, s), 6.91 (1H, s), 7.02 (1H, s), 7.51 (1H, dd, J=8.5, 1.5Hz), 7.56 (1H, d, J=8.5Hz), 7.84 ３(1H, d, J=1.5Hz)

実施例３８

収率69%, 1H-NMR(CDCl3): δ2.25-2.35 (1H, m), 2.30 (3H, s), 2.34 (3H, s), 2.86 (1H, d, J=13.5Hz), 3.02 (1H, d, J=11.5Hz), 3.25-3.50 (3H, m), 3.82 (1H, d, J=13.5Hz), 4.00-4.10 (2H, m), 6.79 (1H, s), 6.82 (1H, s), 6.93 (1H, s), 7.30-7.45 (3H, m), 7.48-7.55 (4H, m), 7.84 (1H, d, J=0.5Hz).

実施例３９

収率48%, 1H-NMR(CDCl3): δ1.40 (3H, d, J=6.5Hz), 2.15-2.30 (2H, m), 2.31 (3H, s), 2.36 (3H, s), 2.68-2.75 (1H, m), 2.85-2.95 (1H, m), 3.38-3.60 (3H, m), 3.80-3.90 (1H, m), 4.15-4.25 (1H, m), 6.81 (1H, s), 6.92 (1H, s), 7.02 (1H, s), 7.23 (1H, dd, J=8.5, 2Hz), 7.42 (1H, d, J=8.5Hz), 7.54 (1H, d, J=2Hz).

実施例４０

収率81%, 1H-NMR(CDCl3): δ1.42 (3H, d, J=6.5Hz), 2.18-2.29 (1H, m), 2.30 (3H, s), 2.30-2.35 (1H, m), 2.36 (3H, s), 2.75 (1H, d, J=11.5Hz), 2.92 (1H, d, J=11.5Hz), 3.43 (1H, d, J=13.5Hz), 3.52 (1H, td, J=12.5, 3.5Hz), 3.57 (1H, d, J=13.5Hz), 3.91 (1H, d, J=12.5Hz), 4.17-4.30 (1H, m), 6.81 (1H, s), 6.92 (1H, s), 7.02 (1H, s), 7.51 (1H, d, J=8.5Hz), 7.55 (1H, d, J=8.5Hz), 7.84 (1H, s).

実施例４１

収率57%, 1H-NMR(CDCl3): δ1.42 (3H, d, J=6.5Hz), 2.18-2.38 (2H, m), 2.30 (3H, s), 2.36 (3H, s), 2.70-2.80 (1H, m), 2.86-2.97 (1H, m), 3.38-3.61 (3H, m), 3.85-3.97 (1H, m), 4.17-4.30 (1H, m), 6.82 (1H, s), 6.92 (1H, s), 7.03 (1H, s), 7.48-7.59 (2H, m), 7.84 (1H, s).

実施例４２

収率63%, 1H-NMR(CDCl3): δ1.02 (3H, t, J=7.5Hz), 1.60-1.75 (2H, m), 2.30 (3H, s), 2.30-2.35 (1H, m), 2.36 (3H, s), 2.48-2.58 (1H, m), 2.79-2.90 (1H, m), 3.26 (1H, d, J=13.5Hz), 3.38-3.58 (2H, m), 3.63-3.73 (1H, m), 3.80-3.90 (1H, m), 3.98 (1H, d, J=13.5Hz), 6.81 (1H, s), 6.91 (1H, s), 7.02 (1H, s), 7.51 (1H, d, J=8.5Hz), 7.55 (1H, d, J=8.5Hz), 7.84 (1H, s).

実施例４３

収率79%, 1H-NMR(CDCl3): δ1.02 (3H, t, J=7.5Hz), 1.57-1.80 (2H, m), 2.21 (3H, s), 2.21-2.35 (1H, m), 2.36 (3H, s), 2.50-2.60 (1H, m), 2.80-2.90 (1H, m), 3.26 (1H, d, J=13.5Hz), 3.38-3.60 (2H, m), 3.63-3.74 (1H, m), 3.85 (1H, dd, J=12.5, 3.5Hz), 3.98 (1H, d, J=13.5Hz), 6.81 (1H, s), 6.91 (1H, s), 7.02 (1H, s), 7.53 (1H, d, J=8.5Hz), 7.55 (1H, d, J=8.5Hz), 7.84 (1H, s).

実施例４４

収率63%, 1H-NMR(CDCl3): δ1.20 (3H, t, J=7.5Hz), 1.30-1.70 (4H, m), 2.29 (3H, s), 2.29-2.35 (1H, m), 2.36 (3H, s), 2.55-2.65 (1H, m), 2.79-2.89 (1H, m), 3.28 (1H, d, J=13.5Hz), 3.41 (1H, dd, J=13, 7.5Hz), 3.50-3.60 (1H, m), 3.60-3.70 (1H, m), 3.84 (1H, dd, J=13, 3Hz), 3.97 (1H, d, J=13.5Hz), 6.81 (1H, s), 6.90 (1H, s), 7.02 (1H, s), 7.51 (1H, dd, J=8.5, 1.5Hz), 7.56 (1H, d, J=8.5Hz), 7.83 (1H, d, J=1.5Hz).

実施例４５

収率62%, 1H-NMR(CDCl3): δ0.95 (3 H, t, J = 7.2 Hz), 1.36-1.43 (2 H, m), 1.50-1.66 (2 H, m), 2.30 (3 H, s), 2.35 (3 H, s), 2.32-2.39 (1H, m), 2.58-2.63 (1 H, m), 2.80-2.87 (1 H, m), 3.28 (1 H, d, J = 13.5 Hz), 3.41 (1 H, dd, J = 7.5, 12.6 Hz), 3.50-3.59 (1 H, m), 3.62-3.68 (1 H, m), 3.84 (1 H, dd, J = 3.0, 12.6 Hz), 3.97 (1 H, d, J = 13.5 Hz), 6.81 (1 H, s), 6.90 (1 H, s), 7.01 (1 H, s), 7.53-7.55 (2 H, m), 7.83 (1 H, s)

実施例４６

収率70%, 1H-NMR(CDCl3): δ0.93 (3H, t, J=7.5Hz), 1.23-1.75 (6H, m), 2.30 (3H, s), 2.30-2.34 (1H, m), 2.35 (3H, s), 2.54-2.64 (1H, m), 2.79-2.89 (1H, m), 3.27 (1H, d, J=13.5Hz), 3.41 (1H, dd, J=12.5, 7.5Hz), 3.49-3.60 (1H, m), 3.61-3.71 (1H, m), 3.84 (1H, dd, J=12.5, 2.5Hz), 3.97 (1H, d, J=13.5Hz), 6.81 (1H, s), 6.90 (1H, s), 7.02 (1H, s), 7.51 (1H, dd, J=8.5, 1.5Hz), 7.56 (1H, d, J=8.5Hz), 7.84 (1H, d, J=1.5Hz).

実施例４７

収率69%, 1H-NMR(CDCl3): δ0.91 (3H, d, J=6.5Hz), 0.95 (3H, d, J=6.5Hz), 1.33-1.45 (1H, m), 1.45-1.58 (1H, m), 1.62-1.77 (1H, m), 2.29 (3H, s), 2.35 (3H, s), 2.36-2.45 (1H, m), 2.62-2.73 (1H, m), 2.77-2.88 (1H, m), 3.33 (1H, d, J=13.5Hz), 3.35 (1H, dd, J=13, 7Hz), 3.58 (2H, t, J=5.5Hz), 3.75 (1H, dd, J=13, 3.5Hz), 3.90 (1H, d, J=13.5Hz), 6.80 (1H, s), 6.90 (1H, s), 7.02 (1H, s), 7.23 (1H, dd, J=8.5, 2Hz), 7.42 (1H, d, J=8.5Hz), 7.54 (1H, d, J=2Hz).

実施例４８

収率49%, 1H-NMR(CDCl3): δ0.92 (3H, d, J=6.5Hz), 0.95 (3H, d, J=6.5Hz), 1.32-1.60 (2H, m), 1.62-1.78 (1H, m), 2.29 (3H, s), 2.31-2.46 (1H, m), 2.35 (3H, s), 2.62-2.72 (1H, m), 2.75-2.88 (1H, m), 3.29-3.42 (2H, m), 3.58 (2H, t, J=5.0Hz), 3.75 (1H, dd, J=13.0, 3.5Hz), 3.90 (1H, d, J=13.5Hz), 6.80 (1H, s), 6.91 (1H, s), 7.02 (1H, s), 7.23 (1H, dd, J=8.5, 2.0Hz), 7.43 (1H, d, J=8.5Hz), 7.54 (1H, d, J=2.0Hz).

実施例４９

収率72%, 1H-NMR(CDCl3): δ0.92 (3H, d, J=7.5Hz), 0.95 (3H, d, J=7.5Hz), 1.33-1.45 (1H, m), 1.46-1.60 (1H, m), 1.64-1.78 (1H, m), 2.30 (3H, s), 2.35 (3H, s), 2.36-2.46 (1H, m), 2.63-2.75 (1H, m), 2.77-2.88 (1H, m), 3.35 (1H, d, J=13.5Hz), 3.40 (1H, dd, J=13, 6.5Hz), 3.55-3.70 (2H, m), 3.79 (1H, dd, J=12, 3Hz), 3.90 (1H, d, J=13.5Hz), 6.81 (1H, s), 6.91 (1H, s), 7.02 (1H, s), 7.51 (1H, dd, J=8.5, 1.5Hz), 7.55 (1H, d, J=8.5Hz), 7.83 (1H, d, J=1.5Hz).

実施例５０

収率65%, 1H-NMR(CDCl3): δ1.98-2.08 (2H, m), 2.28 (3H, s), 2.34 (3H, s), 2.65-2.74 (2H, m), 2.78-2.85 (2H, m), 3.61 (2H, s), 3.65-3.88 (4H, m), 6.80 (1H, s), 6.88 (1H, s), 6.99 (1H, s), 7.27 (1H, d, J=12.0Hz), 7.75 (1H, d, J=7.0Hz).

実施例５１

収率57%, 1H-NMR(CDCl3): δ1.11 (6H, d, J=6.0Hz), 2.29 (3H, s), 2.34 (3H, s), 2.71-2.86 (2H, m), 3.07 (1H, d, J=13.0Hz), 3.10 (1H, d, J=13.0Hz), 3.79 (2H, s), 3.88 (2H, d, J=13.0Hz), 6.77 (1H, s), 6.96 (1H, s), 7.01 (1H, s), 7.26 (1H, d, J=11.5Hz), 7.73 (1H, d, J=7.0Hz).

実施例５２

収率57%, 1H-NMR(CDCl3): δ1.21 (3H, d, J=6Hz), 2.24-2.29 (1H, m), 2.30 (3H, s), 2.36 (3H, s), 2.60-2.72 (1H, m), 2.83 (1H, dt, J=12, 3.5Hz), 3.18 (1H, d, J=13.5Hz), 3.18-3.25 (1H, m), 3.48-3.51 (1H, m), 3.67-3.80 (1H, m), 3.85-3.95 (1H, m), 4.02 (1H, d, J=13.5Hz), 6.81 (1H, s), 6.90 (1H, s), 7.01 (1H, s), 7.26 (1H, d, J=12Hz), 7.73 (1H, d, J=7Hz).

実施例５３

収率65%, 1H-NMR(CDCl3): δ1.02 (3H, t, J=7.5Hz), 1.50-1.78 (2H, m), 2.26-2.42 (1H, m), 2.30 (3H, s), 2.36 (3H, s), 2.48-2.59 (1H, m), 2.78-2.89 (1H, m), 3.27 (1H, d, J=13.5Hz), 3.38-3.58 (2H, m), 3.61-3.72 (1H, m), 3.78-3.89 (1H, m), 3.98 (1H, d, J=13.5Hz), 6.81 (1H, s), 6.90 (1H, s), 7.01 (1H, s), 7.26 (1H, d, J=12.0Hz), 7.74 (1H, d, J=7.0Hz).

実施例５４

収率61%, 1H-NMR(CDCl3): δ2.29 (3H, s), 2.36 (3H, s), 2.58 (4H, t, J=5.0Hz), 3.52 (2H, s), 3.53 (4H, t, J=5.0Hz), 6.82 (1H, s), 6.90 (1H, s), 7.02 (1H, s), 7.17-7.24 (1H, m), 7.27-7.37 (2H, m), 7.38-7.47 (3H, m).

実施例５５

収率49%, 1H-NMR(CDCl3): δ1.15 (6H, d, J=6.0Hz), 2.30 (3H, s), 2.35 (3H, s), 2.68-2.83 (2H, m), 2.94 (1H, d, J=13.0Hz), 2.97 (1H, d, J=13.0Hz), 3.80 (2H, s), 4.33 (2H, d, J=14.0Hz), 6.76 (1H, s), 6.97 (1H, s), 7.04 (1H, s), 7.34-7.43 (1H, m), 7.52-7.61 (1H, m), 7.67 (1H, d, J=8.0, 1.5Hz), 7.87 (1H, dd, J=8.0, 1.5Hz), 8.56 (1H, s)

実施例５６

収率56%, 1H-NMR(CDCl3): δ1.21 (3H, d, J=6.0Hz), 1.18-2.30 (1H, m), 2.28 (3H, s), 2.35 (3H, s), 2.52-2.65 (1H, m ), 2.78-2.89 (1H, m), 3.05-3.20 (2H, m), 3.27-3.41 (1H, m), 3.97-4.12 (2H, m), 4.15-4.25 (1H, m), 6.80 (1H, s), 6.92 (1H, s), 7.01 (1H, s), 7.32-7.40 (1H, m), 7.50-7.59 (1H, m), 7.67 (1H, dd, J=8.0, 1.5Hz), 7.87 (1H, dd, J=8.0, 1.5Hz), 8.53 (1H, s).

実施例５７

収率55%, 1H-NMR(CDCl3): δ1.14 (6H, d, J=6.0Hz), 2.29 (3H, s), 2.35 (3H, s), 2.68-2.82 (2H, m), 2.94 (1H, d, J=13.0Hz), 2.98 (1H, d, J=13.0Hz), 3.80 (2H, s), 4.30 (2H, d, J=13.0Hz), 6.76 (1H, s), 6.97 (1H, s), 7.03 (1H, s), 7.50 (1H, dd, J=9.0, 2.5Hz), 7.59 (1H, d, J=9.0Hz), 7.85 (1H, d, J=2.5Hz), 8.54 (1H, s).

実施例５８

収率34%, 1H-NMR(CDCl3): δ1.13 (6H, d, J=6.0Hz), 2.28 (3H, s), 2.34 (3H, s), 2.65-2.79 (2H, m), 2.95 (1H, d, J=13.0Hz), 2.98 (1H, d, J=13.0Hz), 3.78 (2H, s), 4.34 (2H, d, J=13.0Hz), 6.77 (1H, s), 6.98 (1H, s), 7.02 (1H, s), 7.67-7.73 (2H, m), 8.13 (1H, s), 8.58 (1H, s).

実施例５９

収率92%, ¹H-NMR(CDCl₃): δ2.25 (3H, s), 2.56 (4H, t, J = 5.1 Hz), 3.48 (2H, s), 3.50 (3H, s), 3.63 (4H, t, J = 5.1 Hz), 5.20 (2H, s), 7.00 (1H, d), 7.08 (1H, d, 8.1 Hz), 7.12 (1H, s), 7.23 (1H, dd, J = 8.7, 2.1 Hz), 7.43 (1H, d, J = 8.7 Hz), 7.53 (1H, d, 2.1 Hz).

実施例６０

収率90%, ¹H-NMR(CDCl₃): δ1.98-2.05 (2H, m), 2.24 (3H, s), 2.68 (2H, t, J = 5.4 Hz), 2.79 (2H, t, J = 4.8 Hz), 3.49 (3H, s), 3.55 (2H,s), 3.71-3.78 (4H,m), 5.19 (2H, s), 6.98 (1H,s),7.07(2H,m),7.22 (1H, dd, 8.7, 2.1Hz), 7.42 (1H,d,J =8.7Hz),7.54(1H, d, J = 2.1Hz).

実施例６１

収率60%, ¹H-NMR(CDCl₃): δ2.57 (4H, t, J = 5.1 Hz), 3.48 (3H, s), 3.50 (2H, s), 3.64 (4H, t, J=5.1Hz), 5.17 (2H, s), 6.91 (1H, s), 6.97-7.01 (2H, m), 7.24 (1H, dd, 8.7, 2.1Hz), 7.44 (1H, d, J = 8.7 Hz), 7.56 (1H, d, J = 2.1Hz).

実施例６２

収率70%, 1H-NMR(CDCl3): δ1.22 (3H, d, J=6.5Hz), 2.24 (3H, s), 2.24-2.35 (1H, m), 2.60-2.70 (1H, m), 2.78-2.88 (1H, m), 3.19 (1H, dt, J=13, 4.5Hz), 3.24 (1H, d, J=13Hz), 3.38-3.50 (1H, m), 3.50 (3H, s), 3.70-3.80 (1H, m), 3.85-3.93 (1H, m), 4.01 (1H, d, J=13Hz), 5.21 (2H, s), 6.89 (1H, d, J=7.5Hz), 7.02 (1H, s), 7.10 (1H, d, J=7.5Hz), 7.50 (1H, d, J=8.5Hz), 7.53 (1H, d, J=8.5Hz), 7.83 (1H, s).

実施例６３

収率92%, 1H-NMR(CDCl3): δ1.22 (3 H, d, J = 6.0 Hz), 2.23-2.33 (1 H, m), 2.33 (3 H, s), 2.60-2.67 (1 H, m), 2.83 (1 H, dt, J = 3.3, 12.0 Hz), 3.16 (2 H, dd, J = 4.2, 13.2 Hz), 3.44-3.35 (1 H, m), 3.49 (3 H, s), 3.71 (1 H, d, J = 12.0 Hz), 3.86 (1 H, dd, J = 2.1, 12.6 Hz), 3.99 (1 H, d, J = 13.2 Hz), 5.17 (2 H, s), 6.77 (1 H, s), 6.80 (1 H, s), 6.83 (1 H, s), 7.23 (1 H, dd, J = 2.1, 8.7 Hz), 7.42 (1 H, d, J = 8.7 Hz), 7.54 (1 H, d, J = 2.1 Hz)

実施例６４

収率95%, 1H-NMR(CDCl3): δ1.22 (3 H, d, J = 6.0 Hz), 2.25-2.31 (1 H, m), 2.33 (3 H, s), 2.60-2.67 (1 H, m), 2.83 (1 H, dt, J = 3.6, 12.0 Hz), 3.16 (2 H, dt, J = 3.6, 13.5 Hz), 3.44-3.35 (1 H, m), 3.49 (3 H, s), 3.71 (1 H, dt, J = 3.0, 12.3 Hz), 3.86 (1 H, ddd, J = 1.5, 3.6, 12.6 Hz), 3.99 (1 H, d, J = 13.5 Hz), 5.16 (2 H, s), 6.77 (1 H, s), 6.80 (1 H, s), 6.83 (1 H, s), 7.23 (1 H, dd, J = 2.1, 8.7 Hz), 7.42 (1 H, d, J = 8.7 Hz), 7.54 (1 H, d, J = 2.1 Hz),

実施例６５

収率38%, ¹H-NMR(CDCl₃): δ1.27 (3H, t, J=7.2 Hz), 2.57 (4H, t, J=4.8Hz), 3.52 (2H, s), 3.59 (2H, s), 3.64 (4H, t, J = 4.8Hz), 4.17 (2H, q, J=7.2Hz), 7.14 (1H, s), 7.20 (1H, s), 7.23 (1H, dd, J=7.8, 2.4Hz), 7.26 (1H, s), 7.43(1H,d, J= 7.8Hz), 7.56 (1H, d, J=2.4Hz).

実施例６６

収率60%, ¹H-NMR(CDCl₃): δ1.26 (3H, t, J = 7.2 Hz), 1.98-2.06 (2H, m), 2.68 (2H, t, J = 5.4Hz), 2.80 (2H, t, J = 5.4 Hz), 3.56 (2H, s), 3.60 (2H, s), 3.71-3.78 (4H, m), 4.16 (2H, q, J = 7.2Hz), 7.12 (1H, s), 7.18 (1H, s), 7.23 (1H, dd, J= 8.4, 2.1Hz), 7.25 (1H, s), 7.42 (1H, d, J = 8.4Hz), 7.55 (1H, d, J = 2.1Hz)

実施例６７

収率89%, ¹H-NMR(CDCl₃): δ1.26 (3H, t, J=7Hz),2.57(4H,t,J=5Hz),3.55(2H,s),3.61 2H, s),3.62(4H,t,J=5Hz),4.15(2H,q,J=7Hz),7.23 (1H,dd,J=8.5,2Hz),7.25-7.35 (4H, m), 7.42 (1H,d,J=8.5Hz),7.55(1H,d, J=2Hz).

実施例６８

収率 79%, 1H-NMR(CDCl3): δ1.13 (6H, d, J=6Hz), 1.25 (3H, t, J=7Hz), 2.73-2.90 (2H, m), 3.05-3.15 (2H, m), 3.61 (2H, s), 3.85 (2H, s), 3.85-3.95(2H, m), 4.14 (2H, q, J=7Hz), 7.10-7.35 (4H, m), 7.52 (1H, d, J=8.5Hz), 7.56 (1H, d, J=8.5Hz), 7.84 (1H, s).

実施例６９

収率 54%, 1H-NMR(CDCl3): δ1.09 (6H, d, J=6.5Hz), 1.26 (3H, t, J=7Hz), 2.70-2.95 (2H, m), 3.10 (2H, dd, J=13, 13Hz), 3.58 (2H, s), 3.78 (2H, s), 3.86-3.96 (2H, m), 4.15 (2H, q, J=7Hz), 7.14 (1H, s), 7.17 (1H, s), 7.33 (1H, s), 7.53 (1H, d, J=8.5Hz), 7.57 (1H, d, J=8.5Hz), 7.85 (1H, s).

実施例７０

収率 71%, 1H-NMR(CDCl3): δ1.08 (3H, d, J=6.5Hz), 1.25 (3H, t, J=7Hz), 1.40 (3H, d, J=6.5Hz), 2.25-2.35 (1H, m), 2.90 (1H, dd, J=12, 4Hz), 3.10-3.20 (1H, m), 3.52 (1H, d, J=13.5Hz), 3.62 (2H, s), 3.63-3.78 (3H, m), 4.16 (2H, q, J=7Hz), 4.20-4.35 (1H, m), 7.20-7.35 (4H, m), 7.45-7.56 (2H ,m), 7.82 (1H, s).

実施例７１

収率 92%, 1H-NMR(CDCl3): δ1.23 (3H, d, J=6Hz), 1.25 (3H, t, J=7Hz), 2.23-2.35 (1H, m), 2.60-2.75 (1H, m), 2.83 (1H, dt, J=12, 4Hz), 3.20 (1H, d, J=12.5Hz), 3.22 (1H, d, J=13Hz), 3.38-3.50 (1H, m), 3.62 (2H, s), 3.70-3.80 (1H, m), 3.85-3.95 (1H, m), 4.05 (1H, d, J=13Hz), 4.16 (2H, q, J=7Hz), 7.15-7.35 (4H, m), 7.45-7.60 (2H, m), 7.84 (1H, s).

実施例７２

収率88%, 1H-NMR(CDCl3): δ1.23 (3 H, t, J = 7.2 Hz), 1.26 (3 H, t, J = 6.9 Hz), 2.27 (1 H, ddd, J = 3.3, 8.7, 9.9 Hz), 2.61-2.67 (1 H, m), 2.80 (1 H, dt, J = 3.3, 11.7 Hz), 3.21 (2 H, d, J = 13.5 Hz), 3.34-3.43 (1 H, m), 3.62 (2 H, s), 3.71 (1 H, d, J = 12.6 Hz), 3.87 (1 H, dd, J = 2.1, 12.6 Hz), 4.05 (1 H, d, J = 13.5 Hz), 4.16 (2 H, q, J = 7.2 Hz), 7.18-7.32 (5 H, m), 7.42 (1 H, d, J = 8.7 Hz), 7.54 (1 H, d, J = 2.4 Hz)

実施例７３

収率93%, 1H-NMR(CDCl3): δ1.24 (3 H, t, J = 6.0 Hz), 1.26 (3 H, t, J = 7.2 Hz), 2.27 (1 H, ddd, J = 3.3, 8.7, 9.9 Hz), 2.62-2.67 (1 H, m), 2.80 (1 H, dt, J = 3.6, 12.0 Hz), 3.21 (2 H, d, J = 13.5 Hz), 3.39-3.42 (1 H, m), 3.62 (2 H, s), 3.71 (1 H, dt, J = 12.0 Hz), 3.87 (1 H, dd, J = 2.1, 12.6 Hz), 4.06 (1 H, d, J = 13.5 Hz), 4.16 (2 H, q, J = 7.2 Hz), 7.18-7.32 (5 H, m), 7.42 (1 H, d, J = 8.4 Hz), 7.54 (1 H, d, J = 2.1 Hz)

実施例７４

収率 82%, 1H-NMR(CDCl3): δ1.23 (3H, d, J=6Hz), 1.26 (3H, t, J=7Hz), 2.20-2.35 (1H, m), 2.34 (3H, s), 2.58-2.71 (1H, m), 2.82 (1H, dt, J=12, 4Hz), 3.16 (1H, d, J=13.5Hz), 3.16-3.25 (1H, m), 3.38-3.50 (1H, m), 3.58 (2H, s), 3.70-3.80 (1H, m), 3.86-3.96 (1H, m), 4.03 (1H, d, J=13.5Hz), 4.15 (2H, q, J=7Hz), 7.01 (1H, s), 7.05 (2H, s), 7.51 (1H, d, J=8.5Hz), 7.55 (1H, d, J=8.5Hz), 7.84 (1H, s).

実施例７５

収率92%, 1H-NMR(CDCl3): δ1.02 (3 H, t, J = 7.2 Hz), 1.26 (3 H, t, J = 7.2 Hz), 1.61-1.74 (2 H, m), 2.29-2.37 (1 H, m), 2.50-2.55 (1 H, m), 2.79-2.84 (1 H, m), 3.29 (1 H, d, J = 13.5 Hz), 3.37 (1 H, dd, J = 8.1, 12.9 Hz), 3.40-3.50 (1 H, m), 3.62 (3 H, s), 3.80 (1 H, dd, J = 3.3, 12.9 Hz), 4.01 (1 H, d, J = 13.5 Hz), 4.16 (2 H, t, J = 7.2 Hz), 7.18 (5 H, m), 7.42 (1 H, d, J = 8.7 Hz), 7.54 (1 H, d, J = 2.1 Hz)

実施例７６

収率90%, 1H-NMR(CDCl3): δ0.93 (6 H, dd, J = 6.3, 11.7 Hz), 1.26 (3 H, t, J = 7.2 Hz), 1.35-1.44 (1 H, m), 1.50-1.56 (1 H, m), 1.65-1.76 (1 H, m), 2.37-2.44 (1 H, m), 2.67-2.72 (1 H, m), 2.78-2.85 (1 H, m), 3.36 (1 H, d, J = 12.9 Hz), 3.39 (1 H, d, J = 13.2 Hz), 3.58 (2 H, t, J = 4.8 Hz), 3.61 (2 H, s), 3.75 (1 H, dd, J = 3.3, 12.9 Hz), 3.93 (1 H, d, J = 13.2 Hz), 4.16 (2 H, q, J = 7.2 Hz), 7.17-7.31 (5 H, m), 7.42 (1 H, d, J = 8.7 Hz), 7.54 (1 H, d, J = 1.8 Hz)

実施例７７

収率 68%, 1H-NMR(CDCl3): δ1.26 (3H, t, J=7Hz), 1.42 (3H, d, J=6.5Hz), 2.25 (1H, td, J=11.5, 3.5Hz), 2.32 (1H, dd, J=11.5, 4Hz), 2.74 (1H, d, J=11.5Hz), 2.91 (1H, dt, J=11.5, 2Hz), 3.46 (1H, d, J=13.5Hz), 3.52 (1H, td, J=11.5, 4Hz), 3.59 (1H, d, J=13.5Hz), 3.62 (2H, s), 3.85-4.00 (1H, m), 4.15 (2H, q, J=7Hz), 4.20-4.30 (1H, m), 7.15-7.33 (4H, m), 7.51 (1H, d, J=8.5Hz), 7.55 (1H, d, J=8.5Hz), 7.84 (1H, s).

実施例７８

収率 86%, 1H-NMR(CDCl3): δ1.25 (3H, t, J=7Hz), 1.40 (3H, d, J=6.5Hz), 2.24 (1H, td, J=11.5, 3.5Hz), 2.33 (1H, dd, J=11.5, 3.5Hz), 2.72 (1H, d, J=11Hz), 2.91 (1H, d, J=11Hz), 3.43 (1H, d, J=13.5Hz), 3.49 (1H, td, J=11.5, 3.5Hz), 3.59 (1H, d, J=13.5Hz), 3.62 (2H, s), 3.80-3.90 (1H, m), 4.10-4.18 (1H, m), 4.19 (2H, q, J=7Hz), 7.15-7.35 (5H, m), 7.42 (1H, d, J=7.5Hz), 7.54 (1H, d, J=2Hz).

実施例７９

収率 71%, 1H-NMR(CDCl3): δ1.26 (3H, t, J=7.0Hz), 1.40 (3H, d, J=7.0Hz), 2.17-2.38 (2H, m), 2.68-2.77 (1H, m), 2.88-2.96 (1H, m), 3.41-3.67 (5H, m), 3.82-3.92 (1H, m), 4.07-4.23 (1H, m), 4.16 (2H, q, J=7.0Hz), 7.16-7.34 (5H, m), 7.42 (1H, d, J=8.5Hz), 7.54 (1H, d, J=2.0Hz).

実施例８０

収率 85%, 1H-NMR(CDCl3): δ1.26 (3H, t, J=7Hz), 1.40 (3H, d, J=6.5Hz), 2.23 (1H, td, J=11.5, 3.5Hz), 2.27-2.33 (1H, m), 2.34 (3H, s), 2.72 (1H, d, J=11.5Hz), 2.90 (1H, d, J=11.5Hz), 3.41 (1H, d, J=13.5Hz), 3.45-3.54 (1H, m), 3.55 (1H, d, J=13.5Hz), 3.58 (2H, s), 3.85 (1H, d, J=12Hz), 4.10-4.15 (1H, m), 4.16 (2H, q, J=7Hz), 7.01 (1H, s), 7.07 (1H, s), 7.08 (1H, s), 7.22 (1H, dd, J=8.5, 2Hz), 7.42 (1H, d, J=8.5Hz), 7.54 (1H, d, J=2Hz).

実施例８１

収率 74%, 1H-NMR(CDCl3): δ1.26 (3H, t, J=7.0Hz), 1.40 (3H, d, J=7.0Hz), 2.16-2.37 (5H, m), 2.68-2.77 (1H, m), 2.86-2.96 (1H, m), 3.36-3.62 (5H, m), 3.80-3.90 (1H, m), 4.15 (3H, m), 7.01 (1H, s), 7.04-7.10 (2H, m), 7.23 (1H, dd, J=8.5, 2.0Hz), 7.42 (1H, d, J=8.5Hz), 7.54 (1H, d, J=2.0Hz).

実施例８２

収率 83%, 1H-NMR(CDCl3): δ1.26 (3H, t, J=7Hz), 1.42 (3H, d, J=6.5Hz), 2.25 (1H, dt, J=12.5, 3.5Hz), 2.33 (1H, dd, J=11, 3.5Hz), 2.73 (1H, d, J=11Hz), 2.93 (1H, d, J=11Hz), 3.42-3.60 (3H, m), 3.62 (2H, s), 3.85-3.97 (1H, m), 4.16 (2H, q, J=7Hz), 4.18-4.28 (1H, m), 7.18-7.35 (4H, m), 7.51 (1H, d, J=8.5Hz), 7.56 (1H, d, J=8.5Hz), 7.84 (1H, s).

実施例８３

収率 72%, 1H-NMR(CDCl3): δ1.26 (3H, t, J=7.0Hz), 1.42 (3H, d, J=6.5Hz), 2.25 (1H, td, J=11.5, 3.5Hz), 2.34 (1H, dd, J=11.5, 3.5Hz), 2.74 (1H, d, J=11.5Hz), 2.93 (1H, d, J=11.5Hz), 3.42-3.66 (5H, m), 3.91 (1H, d, J=11.5Hz), 4.08-4.29 (3H, m), 7.16-7.35 (4H, m), 7.47-7.60 (2H, m), 7.84 (1H, s).

実施例８４

収率 74%, 1H-NMR(CDCl3): δ1.26 (3H, t, J=7Hz), 1.42 (3H, d, J=6.5Hz), 2.18-2.34 (2H, m), 2.35 (3H, s), 2.74 (1H, d, J=11Hz), 2.92 (1H, d, J=11.5Hz), 3.42 (1H, d, J=13.5Hz), 3.53 (1H, td, J=11.5, 3.5Hz), 3.56 (1H, d, J=13.5Hz), 3.58 (2H, s), 3.91 (1H, d, J=12Hz), 4.15 (2H, q, J=7Hz), 4.15-4.30 (1H, m), 7.02 (1H, s), 7.07 (1H, s), 7.09 (1H, s), 7.51 (1H, d, J=8.5Hz), 7.55 (1H, d, J=8.5Hz), 7.84 (1H, s).

実施例８５

収率 69%, 1H-NMR(CDCl3): δ1.26 (3H, t, J=7.0Hz), 1.43 (3H, d, J=6.5Hz), 2.17-2.39 (5H, m), 2.70-2.79 (1H, m), 2.87-2.97 (1H, m), 3.43 (1H, d, J=13.0Hz), 3.46-3.62 (4H, m), 3.85-3.97 (1H, m), 4.16 (2H, q, J=7.0Hz), 4.17-4.29 (1H, m), 7.02 (1H, s), 7.05-7.11 (2H, m), 7.47-7.59 (2H, m), 7.84 (1H, s).

実施例８６

収率 86%, 1H-NMR(CDCl3): δ1.27 (3H, t, J=7Hz), 1.43 (3H, d, J=6.5Hz), 2.26 (1H, td, J=12, 3.5Hz), 2.36 (1H, dd, J=11, 3.5Hz), 2.72 (1H, d, J=11Hz), 2.91 (1H, d, J=11Hz), 3.44 (1H, d, J=13.5Hz), 3.52 (1H, td, J=12.5, 3.5Hz), 3.55 (1H, d, J=13.5Hz), 3.59 (2H, s), 3.86-3.96 (1H, m), 4.16 (2H, q, J=7Hz), 4.20-4.30 (1H, m), 7.17 (1H, s), 7.20 (1H, s), 7.29 (1H, s), 7.51 (1H, d, J=8.5Hz), 7.56 (1H, d, J=8.5Hz), 7.84 (1H, s).

実施例８７

収率 41%, 1H-NMR(CDCl3): δ0.87 (3H, t, J=7.5Hz), 1.26 (3H, t, J=7.0Hz), 1.80-2.02 (2H, m), 2.16-2.30 (2H, m), 2.79-2.94 (2H, m), 3.38-3.52 (2H, m), 3.54-3.65 (3H, m), 3.76-3.88 (1H, m), 3.94-4.06 (1H, m), 4.15 (2H, q, J=7.0Hz), 7.15-7.34 (5H, m), 7.39 (1H, d, J=8.5Hz), 7.52 (1H, d, J=2.0Hz).

実施例８８

収率 79%, 1H-NMR(CDCl3): δ0.87 (3H, t, J=7.5Hz), 1.26 (3H, t, J=7Hz), 1.85-2.00 (2H, m), 2.18-2.29 (2H, m), 2.80-2.84 (2H, m), 3.42 (1H, d, J=13.5Hz), 3.44 (1H, td, J=12.5, 3.5Hz), 3.59 (1H, d, J=13.5Hz), 3.62 (2H, s), 3.70-3.86 (1H, m), 3.95-4.05 (1H, m), 4.15 (2H, q, J=7Hz), 7.15-7.33 (5H, m), 7.39 (1H, d, J=8.5Hz), 7.52 (1H, d, J=2Hz).

実施例８９

収率 25%, 1H-NMR(CDCl3): δ0.88 (3H, t, J=7.5Hz), 1.26 (3H, t, J=7Hz), 1.83-2.03 (2H, m), 2.22 (2H, td, J=12.5, 3.5Hz), 2.34 (3H, s), 2.80-2.92 (2H, m), 3.38 (1H, d, J=13.5Hz), 3.45 (1H, td, J=12.5, 3.5Hz), 3.55 (1H, d, J=13.5Hz), 3.57 (2H, s), 3.75-3.88 (1H, m), 3.95-4.03 (1H, m), 4.15 (2H, q, J=7Hz), 7.01 (1H, s), 7.05 (1H, s), 7.06 (1H, s), 7.21 (1H, dd, J=8.5, 2Hz), 7.39 (1H, d, J=8.5Hz), 7.52 (1H, d, J=2Hz).

実施例９０

収率 67%, 1H-NMR(CDCl3): δ0.88 (3H, t, J=7.5Hz), 1.26 (3H, t, J=7.0Hz), 1.80-2.03 (2H, m), 2.22 (2H, td, J=11.5, 3.5Hz), 2.34 (3H, s), 2.80-2.93 (2H, m), 3.38 (1H, d, J=13.0Hz), 3.46 (1H, td, J=12.5, 3.0Hz), 3.56 (1H, d, J=13.0Hz), 3.57 (2H, s), 3.76-3.87 (1H, m), 3.94-4.05 (1H, m), 4.15 (2H, q, J=7.0Hz), 7.01 (1H, s), 7.06 (2H, s), 7.22 (1H, dd, J=8.5, 2.0Hz), 7.39 (1H, d, J=8.5Hz), 7.52 (1H, d, J=2.0Hz).

実施例９１

収率 80%, 1H-NMR(CDCl3): δ0.88 (3H, t, J=7.5Hz), 1.26 (3H, t, J=7Hz), 1.96 (2H, quant, J=7.5Hz), 2.19-2.30 (2H, m), 2.82-2.95 (2H, m), 3.44 (1H, d, J=13.5Hz), 3.49 (1H, td, J=12.5, 3.5Hz), 3.59 (1H, d, J=13.5Hz), 3.62 (2H, s), 3.73-3.83 (1H, m), 4.00-4.10 (1H, m), 4.17 (2H, q, J=7Hz), 7.15-7.33 (4H, m), 7.48-7.55 (2H, m), 7.82 (1H, s).

実施例９２

収率 53%, 1H-NMR(CDCl3): δ0.89 (3H, t, J=7.5Hz), 1.20 (3H, t, J=7Hz), 1.87-2.03 (2H, m), 2.24 (2H, td, J=11, 3.5Hz), 2.34 (3H, s), 2.82-2.95 (2H, m), 3.38 (1H, d, J=13Hz), 3.49 (1H, td, J=13, 3.5Hz), 3.56 (1H, d, J=13Hz), 3.57 (2H, s), 3.80-3.95 (1H, m), 4.00-4.10 (1H, m), 4.16 (2H, q, J=7Hz), 7.01 (1H, s), 7.05 (1H, s), 7.06 (1H, s), 7.48-7.55 (2H, m), 7.82 (1H, s).

実施例９３

収率 74%, 1H-NMR(CDCl3): δ0.90 (3H, t, J=7.5Hz), 1.27 (3H, t, J=7Hz), 1.94 (2H, quant, J=7.5Hz), 2.20-2.32 (2H, m), 2.80-2.93 (2H, m), 3.41 (1H, d, J=13.5Hz), 3.49 (1H, td, J=12.5, 3.5Hz), 3.55 (1H, d, J=13.5Hz), 3.59 (2H, s), 3.85-3.95 (1H, m), 4.00-4.10 (1H, m), 4.17 (2H, q, J=7Hz), 7.14 (1H, s), 7.20 (1H, s), 7.28 (1H, s), 7.45-7.56 (2H, m), 7.82 (1H, s).

実施例９４

収率85%, 1H-NMR(CDCl3): δ0.88 (3H, t, J=7.5Hz), 1.20 (3H, t, J=7Hz), 1.94 (2H, quant, J=7.5Hz), 2.19-2.30 (2H, m), 2.80-2.95 (2H, m), 3.43 (1H, d, J=13.5Hz), 3.51 (1H, td, J=12.5, 3.5Hz), 3.59 (1H, d, J=13.5Hz), 3.62 (2H, s), 3.80-3.95 (1H, m), 4.00-4.10 (1H, m), 4.15 (2H, q, J=7Hz), 7.15-7.33 (4H, m), 7.50 (1H, d, J=8.5Hz), 7.52 (1H, d, J=8.5Hz), 7.82 (1H, s).

実施例９５

収率73%, 1H-NMR(CDCl3): δ0.88 (3H, t, J=7.5Hz), 1.26 (3H, t, J=7Hz), 1.95 (2H, quant, J=7.5Hz), 2.15-2.28 (2H, m), 2.34 (3H, s), 2.82-2.93 (2H, m), 3.39 (1H, d, J=13.5Hz), 3.48 (1H, td, J=12.5, 3.5Hz), 3.55 (1H, d, J=13.5Hz), 3.57 (2H, s), 3.80-3.95 (1H, m), 3.98-4.10 (1H, m), 4.15 (2H, q, J=7Hz), 7.01 (1H, s), 7.06 (2H, s), 7.52(2H, s), 7.82 (1H, s).

実施例９６

収率67%, 1H-NMR(CDCl3): δ0.93 (3H, t, J=7.5Hz), 1.19-1.35 (2H, m), 1.26 (3H, t, J=7.0Hz), 1.73-2.00 (2H, m), 2.15-2.30 (2H, m), 2.81 (1H, d, J=11.5Hz), 2.88 (1H, d, J=11.0Hz), 3.42 (1H, d, J=13.5Hz), 3.46 (1H, td, J=12.5, 3.5Hz), 3.58 (1H, d, J=13.5Hz), 3.61 (2H, s), 3.84-4.05 (2H, m), 4.16 (2H, q, J=7.0Hz), 7.14-7.34 (5H, m), 7.39 (1H, d, J=8.5Hz), 7.52 (1H, d, J=2.0Hz).

実施例９７

収率64%, 1H-NMR(CDCl3): δ0.93 (3 H, t, J = 7.2 Hz), 1.21-1.31 (5 H, m), 1.78-1.96 (2 H, m), 2.19-2.28 (2 H, m), 2.81 (1 H, d, J = 11.4 Hz), 2.88(1 H, d, J = 11.4 Hz), 3.42 (1 H, d, J = 13.2 Hz), 3.47 (1 H, td, J = 3.3, 12.6 Hz), 3.59 (1 H, d, J = 13.2 Hz), 3.62 (2 H, s), 3.90 (1 H, s), 4.00 (1 H, d, J = 12.6 Hz), 4.16 (2 H, q, J = 7.2 Hz), 7.19-7.33 (5 H, m), 7.39 (1 H, d, J = 8.4 Hz), 7.53 (1 H, d, J = 2.1 Hz)

実施例９８

収率 58%, 1H-NMR(CDCl3): δ0.34 (3H, t, J=7.0Hz), 1.19-1.35 (2H, m), 1.26 (3H, t, J=7.0Hz), 1.72-2.02 (2H, m), 2.15-2.29 (2H, m), 2.34 (3H, s), 2.81 (1H, d, J=11.5Hz), 2.89 (1H, d, J=11.5Hz), 3.37 (1H, d, J=13.5Hz), 3.47 (1H, td, J=13.5, 3.0Hz), 3.57 (1H, d, J=13.5Hz), 3.57 (2H, s), 3.83-3.93 (1H, m), 3.94-4.04 (1H, m), 4.16 (2H, q, J=7.0Hz), 7.01 (1H, s), 7.05 (2H, s), 7.22 (1H, dd, J=8.5, 2.0Hz), 7.39 (1H, d, J=8.5Hz), 7.52(1H, d, J=2.0Hz).

実施例９９

収率68%, 1H-NMR(CDCl3): δ0.94 (3 H, t, J = 7.5 Hz), 1.24-1.31 (5 H, m), 1.73-1.85 (1 H, m), 1.89-2.01 (1 H, m), 2.17-2.27 (2 H, m), 2.34 (3 H, s), 2.81 (1 H, d, J = 11.4 Hz), 2.88 (1 H, d, J = 11.1 Hz), 3.37 (1 H, d, J = 13.5 Hz), 3.47 (1 H, dt, J = 3.3, 12.6 Hz), 3.57 (1 H, d, J = 13.5 Hz), 3.57 (2 H, s), 3.89 (1 H, s), 3.99 (1 H, d, J = 12.0 Hz), 4.16 (2 H, q, J = 7.2 Hz), 7.01 (1 H, s), 7.06 (2 H, s), 7.22 (1 H, dd, J = 2.1, 8.4 Hz), 7.39 (1 H, d, J = 8.4 Hz), 7.52 (1 H, d, J = 2.1 Hz)

実施例１００

収率69%, 1H-NMR(CDCl3): δ0.93 (3H, t, J=7.0Hz), 1.18-1.35 (2H, m), 1.26 (3H, t, J=7.0Hz), 1.76-1.99 (2H, m), 2.16-2.29 (2H, m), 2.82 (1H, d, J=11.5Hz), 2.89 (1H, d, J=11.5Hz), 3.42 (1H, d, J=13.5Hz), 3.49 (1H, td, J=13.0, 3.5Hz), 3.59 (1H, d, J=13.5Hz), 3.62 (2H, s), 3.90-4.09 (2H, m), 4.16 (2H, q, J=7.0Hz), 7.15-7.34 (4H, m), 7.49 (1H, d, J=8.5Hz), 7.53 (1H, d, J=8.5Hz), 7.81 (1H, s).

実施例１０１

収率80%, 1H-NMR(CDCl3): δ0.94 (3 H, t, J = 7.2 Hz), 1.24-1.31 (5 H, m), 1.83-1.91 (2 H, m), 2.20-2.29 (2 H, m), 2.83 (1 H, d, J = 11.4 Hz), 2.90 (1 H, d, J = 11.4 Hz), 3.34 (1 H, d, J = 13.5 Hz), 3.50 (1 H, td, J = 3.6, 12.6 Hz), 3.60 (1 H, d, J = 13.5 Hz), 3.62 (2 H, s), 3.97 (1 H, s), 4.05 (1 H, d, J = 12.6 Hz), 4.16 (2 H, q, J = 7.2 Hz), 7.19-7.33 (4 H, m), 7.51 (2 H, s), 7.82 (1 H, s)

実施例１０２

収率79%, 1H-NMR(CDCl3): δ0.87 (3H, t, J=7Hz), 1.15-1.40 (7H, m), 1.74-2.00 (2H, m), 2.17-2.29 (2H, m), 2.77-2.94 (2H, m), 3.41 (1H, d, J=13.5Hz), 3.46 (1H, td, J=13, 3.5Hz), 3.59 (1H, d, J=13.5Hz), 3.61 (2H, s), 3.80-3.93 (1H, m), 3.95-4.08 (1H, m), 4.16 (2H, q, J=7Hz), 7.15-7.32 (5H, m), 7.39 (1H, d, J=9Hz), 7.52 (1H, d, J=2Hz).

実施例１０３

収率75%, 1H-NMR(CDCl3): δ0.87 (3H, t, J=7Hz), 1.15-1.40 (7H, m), 1.76-2.01 (2H, m), 2.20-2.30 (2H, m), 2.77-2.93 (2H, m), 3.42 (1H, d, J=13.5Hz), 3.46 (1H, td, J=13, 3.5Hz), 3.59 (1H, d, J=13.5Hz), 3.61 (2H, s), 3.80-3.92 (1H, m), 3.95-4.06 (1H, m), 4.16 (2H, q, J=7Hz), 7.16-7.33 (5H, m), 7.39 (1H, d, J=9Hz), 7.52 (1H, d, J=2Hz).

実施例１０４

収率75%, 1H-NMR(CDCl3): δ0.88 (3H, t, J=7Hz), 1.15-1.40 (7H, m), 1.75-2.03 (2H, m), 2.17-2.30 (2H, m), 2.34 (3H, s), 2.80-2.96 (2H, m), 3.37 (1H, d, J=13.5Hz), 3.50 (1H, td, J=13, 3.5Hz), 3.57 (2H, s), 3.58 (1H, d, J=13.5Hz), 3.85-4.00 (1H, m), 4.00-4.10 (1H, m), 4.15 (2H, q, J=7Hz), 7.01 (1H, s), 7.05 (1H, s), 7.07 (1H, s), 7.45-7.55 (2H, m), 7.82 (1H, s).

実施例１０５

収率44%, 1H-NMR(CDCl3): δ0.90 (3H, d, J=6.5Hz), 0.91 (3H, d, J=6.5Hz), 1.26 (3H, t, J=7.0Hz), 2.12 (1H, dd, J=11.5, 3.5Hz), 2.23 (1H, td, J=11.5, 3.5Hz), 2.34 (3H, s), 2.56-2.72 (1H, m), 2.88 (1H, d, J=11.5Hz), 2.98 (1H, d, J=11.5Hz), 3.34 (1H, d, J=13.0Hz), 3.40-3.65 (2H, m), 3.56 (1H, d, J=13.0Hz), 3.57 (2H, s), 4.08-4.22 (1H, m), 4.15 (2H, q, J=7.0Hz), 7.01 (1H, s), 7.05 (2H, s), 7.49 (2H, s), 7.79 (1H, s).

実施例１０６

収率70%, 1H-NMR(CDCl3): δ0.90 (3H, d, J=2.5Hz), 0.91 (3H, d, J=2.5Hz), 1.26 (3H, t, J=7Hz), 2.12 (1H, dd, J=11.5, 3.5Hz), 2.23 (1H, td, J=11.5, 3.5Hz), 2.34 (3H, s), 2.55-2.73 (1H, m), 2.88 (1H, d, J=9.5Hz), 2.98 (1H, d, =9.5Hz), 3.34 (1H, d, J=13Hz), 3.40-3.54 (1H, m), 3.56 (1H, d, J=13Hz), 3.57 (2H, s), 3.57-3.60 (1H, m), 4.11-4.15 (1H, m), 4.16 (2H, q, J=7Hz), 7.01 (1H, s), 7.04 (1H, s), 7.05 (1H, s), 7.49-7.50 (2H, m), 7.79 (1H, s).

実施例１０７

収率73%, 1H-NMR(CDCl3): δ0.93 (6H, d, J=6.5Hz), 1.26 (3H, t, J=7.0Hz), 1.32-1.53 (1H, m), 1.54-1.67 (1H, m), 1.85-1.98 (1H, m), 2.24 (2H, td, J=11.5, 3.5Hz), 2.79 (1H, d, J=11.5Hz), 2.89 (1H, d, J=11.5Hz), 3.40 (1H, d, J=13.5Hz), 3.47 (1H, td, J=13.0, 3.5Hz), 3.61 (1H, d, J=13.5Hz), 3.61 (2H, s), 3.88-4.08 (2H, m), 4.16 (2H, q, J=7.0Hz), 7.15-7.33 (5H, m), 7.39 (1H, d, J=8.5Hz), 7.53 (1H, d, J=2.0Hz).

実施例１０８

収率81%, 1H-NMR(CDCl3): δ0.93 (6H, d, J=6.5Hz), 1.26 (3H, t, J=7Hz), 1.38-1.47 (1H, m), 1.55-1.67 (1H, m), 1.85-1.96 (1H, m), 2.19-2.30 (2H, m), 2.78 (1H, d, J=11.5Hz), 2.88 (1H, d, J=11.5Hz), 3.40 (1H, d, J=13.5Hz), 3.47 (1H, td, J=13, 3.5Hz), 3.60 (1H, d, J=13.5Hz), 3.61 (2H, s), 3.90-4.08 (2H, m), 4.15 (2H, q, J=7Hz), 7.15-7.35 (5H, m), 7.39 (1H, d, J=8.5Hz), 7.53 (1H, d, J=2Hz).

実施例１０９

収率63%, 1H-NMR(CDCl3): δ0.93 (3H, d, J=6.5Hz), 0.94 (3H, d, J=6.5Hz), 1.26 (3H, t, J=7.0Hz), 1.36-1.64 (2H, m), 1.88-2.02 (1H, m), 2.13-2.44 (2H, m), 2.34 (3H, s), 2.79 (1H, d, J=11.0Hz), 2.89 (1H, d, J=11.0Hz), 3.35 (1H, d, J=13.5Hz), 3.41-3.68 (2H, m), 3.57 (2H, s), 3.86-4.09 (2H, m), 4.16 (2H, q, J=7.0Hz), 7.01 (1H, s), 7.04 (1H, s), 7.06 (1H, s), 7.22 (1H, dd, J=8.5, 2.0Hz), 7.39 (1H, d, J=8.5Hz), 7.53 (1H, d, J=2.0Hz).

実施例１１０

収率81%, 1H-NMR(CDCl3): δ0.92 (3H, d, J=3Hz), 0.95 (3H, d, J=3Hz), 1.26 (3H, t, J=7Hz), 1.39-1.65 (2H, m), 1.90-2.02 (1H, m), 2.15-2.32 (2H, m), 2.34 (3H, s), 2.78 (1H, d, J=11.5Hz), 2.89 (1H, d, J=11.5Hz), 3.35 (1H, d, J=13.5Hz), 3.48 (1H, td, J=13, 3.5Hz), 3.57 (2H, s), 3.59 (1H, d, J=13.5Hz), 3.86-4.08 (2H, m), 4.15 (2H, q, J=7Hz), 7.01 (1H, s), 7.04 (1H, s), 7.06 (1H, s), 7.21 (1H, dd, J=8.5, 2Hz), 7.39 (1H, d, J=8.5Hz), 7.53 (1H, d, J=2Hz).

実施例１１１

収率47%, 1H-NMR(CDCl3): δ0.94 (3H, d, J=6.5Hz), 0.95 (3H, d, J=6.5Hz), 1.27 (3H, t, J=7.0Hz), 1.38-1.67 (2H, m), 1.89-2.04 (1H, m), 2.14-2.38 (2H, m), 2.34 (3H, s), 2.80 (1H, d, J=11.5Hz), 2.90 (1H, d, J=11.5Hz), 3.35 (1H, d, J=13.5Hz), 3.44-3.64 (2H, m), 3.57 (2H, s), 3.94-4.21 (2H, m), 4.16 (2H, q, J=7.0Hz), 7.01 (1H, s), 7.06 (2H, s), 7.49 (1H, d, J=8.5Hz), 7.53 (1H, d, J=8.5Hz), 7.82 (1H, s).

実施例１１２

収率80%, 1H-NMR(CDCl3): δ0.94 (6 H, dd, J = 3.0, 6.3 Hz), 1.26 (3 H, t, J = 7.2 Hz), 1.44-1.48 (1 H, m), 1.56-1.62 (1 H, m), 1.91-2.00 (1 H, m), 2.18-2.26 (2 H, m), 2.34 (3 H, s), 2.80 (1 H, d, J = 11.4 Hz), 2.91 (1 H, d, J = 11.4 Hz), 3.36 (1H, d, J=13.2Hz), 3.52 (1 H, dt, J = 3.6, 12.6 Hz), 3.57 (2 H, s), 3.60 (1H, d, J=13.2Hz), 4.04 (2 H, br), 4.16 (2 H, q, J = 7.2 Hz), 7.01 (1 H, s), 7.04 (1 H, s), 7.06 (1 H,s), 7.2 (2 H, s), 7.83 (1 H,s)

実施例１１３

収率69%, 1H-NMR(CDCl3): δ1.26 (3H, t, J=7.0Hz), 2.59 (4H, t, J=5.0Hz), 3.57 (2H, s), 3.62 (2H, s), 3.68 (4H, t, J=5.0Hz), 4.16 (2H, q, J=7.0Hz), 7.18-7.34 (5H, m), 7.75 (1H, d, J=7.0Hz).

実施例１１４

収率72%, 1H-NMR(CDCl3): δ1.26 (3H, t, J=7.0Hz), 2.34 (3H, s), 2.58 (4H, t, J=5.0Hz), 3.52 (2H, s), 3.58 (2H, s), 3.68 (4H, t, J=5.0Hz), 4.16 (2H, q, J=7.0Hz), 7.00-7.12 (3H, m), 7.26 (1H, d, J=11.5Hz), 7.75 (1H, d, J=7.0Hz).

実施例１１５

収率41%, 1H-NMR(CDCl3): δ1.25 (3H, t, J=7.0Hz), 1.96-2.08 (2H, m), 2.32 (3H, s), 2.69 (2H, t, J=5.0Hz), 2.75-2.85 (2H, m), 3.56 (2H, s), 3.60 (2H, s), 3.61-3.89 (4H, m), 4.15 (2H, q, J=7.0Hz), 6.50-7.07 (3H, m), 7.26 (1H, d, J=12.0Hz), 7.73 (1H, d, J=7.0Hz).

実施例１１６

収率80%, 1H-NMR(CDCl3): δ1.23 (3H, d, J=6Hz), 1.26 (3H, t, J=7Hz), 2.23-2.33 (1H, m), 2.34 (3H, s), 2.69-2.70 (1H, m), 2.82 (1H, dt, J=12, 4Hz), 3.17 (1H, d, J=13Hz), 3.18-3.26 (1H, m), 3.36-3.48 (1H, m), 3.58 (2H, s), 3.70-3.80 (1H, m), 3.85-3.95 (1H, m), 4.02 (1H, d, J=13Hz), 4.13 (2H, q, J=7Hz), 7.01 (1H, s), 7.04 (1H, s), 7.05 (1H, s), 7.26 (1H, d, J=12Hz), 7.73 (1H, d, J=7Hz).

実施例１１７

収率63%, 1H-NMR(CDCl3): δ1.26 (3H, t, J=7.0Hz), 1.43 (3H, d, J=7.0Hz), 2.17-2.37 (2H, m), 2.34 (3H, s), 2.71-2.79 (1H, m), 2.87-2.98 (1H, m), 3.43 (1H, d, J=13.0Hz), 3.46-3.60 (2H, m), 3.58 (2H, s), 3.83-3.94 (1H, m), 4.15-4.28 (1H, m), 4.16 (2H, q, J=7.0Hz), 7.02 (1H, s), 7.06 (1H, s), 7.08 (1H, s), 7.26 (1H, d, J=11.5Hz), 7.74 (1H, d, J=7.0Hz).

実施例１１８

収率60%, 1H-NMR(CDCl3): δ1.26 (3H, t, J=7.0Hz), 1.43 (3H, d, J=7.0Hz), 2.16-2.36 (2H, m), 2.34 (3H, s), 2.70-2.79 (1H, m), 2.87-2.98 (1H, m), 3.43 (1H, d, J=13.0Hz), 3.45-3.61 (4H, m), 3.84-3.94 (1H, m), 4.14-4.28 (1H, m), 4.16 (2H, q, J=7.0Hz), 7.01 (1H, s), 7.04-7.12 (2H, m), 7.26 (1H, d, J=11.5Hz), 7.74 (1H, d, J=7.0Hz).

実施例１１９

収率90%, 1H-NMR(CDCl3): δ0.87 (3H, t, J=7.5Hz), 1.25 (3H, t, J=7.0Hz), 1.82-2.03 (2H, m), 2.14-2.53 (2H, m), 2.33 (3H, s), 2.78-2.93 (2H, m), 3.37 (1H, d, J=13.5Hz), 3.45 (1H, td, J=12.5, 3.5Hz), 3.55 (1H, d, J=13.5Hz), 3.57 (2H, s), 3.76-3.88 (1H, m), 3.90-4.03 (1H, m), 4.15 (2H, q, J=7.0Hz), 7.00 (1H, s), 7.03-7.09 (2H, m), 7.24 (1H, d, J=10.5Hz), 7.49 (1H, d, J=7.0Hz).

実施例１２０

収率18%, 1H-NMR(CDCl3): δ1.20 (3H, d, J=6.5Hz), 1.25 (3H, t, J=7.0Hz), 1.36 (3H, d, J=6.5Hz), 2.15 (1H, td, J=12.0, 3.5Hz), 2.60-2.72 (1H, m), 2.74-2.84 (1H, m), 2.98 (1H, d, J=13.5Hz), 3.40 (1H, td, J=12.5, 3.5Hz), 3.62 (2H, s), 3.67-3.81 (1H, m), 4.03-4.22 (4H, m), 7.13-7.34 (4H, m), 7.50 (1H, dd, J=8.5, 1.5Hz), 7.55 (1H, d, J=8.5Hz), 7.82 (1H, d, J=1.5Hz).

実施例１２１

収率73%, 1H-NMR(CDCl3): δ1.26 (3H, t, J=7.0Hz), 2.58 (4H, t, J=5.0Hz), 3.54 (4H, t, J=5.0Hz), 3.56 (2H, s), 3.62 (2H, s), 4.16 (2H, q, J=7.0Hz), 7.17-7.24 (2H, m), 7.25-7.37 (5H, m), 7.39-7.45 (2H, m), 7.40 (1H, s).

実施例１２２

収率56%, 1H-NMR(CDCl3): δ1.26 (3H, t, J=7.0Hz), 2.61 (4H, t, J=5.0Hz), 3.57 (2H, s), 3.63 (2H, s), 3.81 (4H, t, J=5.0), 4.16 (2H, q, J=7.0Hz), 7.14-7.34 (4H, m), 7.35-7.43 (1H, m), 7.53-7.62 (1H, m), 7.68 (1H, dd, J=8.0, 1.5Hz), 7.87 (1H, dd, J=8.0, 1.5Hz), 8.57 (1H, s).

実施例１２３

収率70%, 1H-NMR(CDCl3): δ1.26 (3H, t, J=7.0Hz), 2.58 (4H, t, J=5.0Hz), 3.56 (2H, s), 3.62 (2H, s), 3.65 (4H, t, J=5.0Hz), 4.16 (2H, q, J=7.0Hz), 7.07 (1H, t, J=7.5Hz), 7.16-7.34 (5H, m), 7.55 (1H, d, J=8.0Hz), 7.59 (1H, d, J=8.0Hz).

実施例１２４

収率66%, 1H-NMR(CDCl3): δ1.26 (3H, t, J=7.0Hz), 2.59 (4H, t, J=5.0Hz), 3.57 (2H, s), 3.63 (2H, s), 3.76 (4H, t, J=5.0Hz), 4.16 (2H, q, J=7.0Hz), 6.97 (1H, d, J=9.0Hz), 7.17-7.38 (5H, m), 7.48-7.64 (2H, m), 7.69 (1H, d, J=8.5Hz), 7.88 (1H, d, J=9.0Hz).

実施例１２５

収率88%, 1H-NMR(CDCl3): δ1.26 (3H, t, J=7.0Hz), 2.60 (4H, t, J=5.0Hz), 3.57 (2H, s), 3.63 (2H, s), 3.80 (4H, t, J=5.0Hz), 4.16 (2H, q, J=7.0Hz), 7.16-7.35 (4H, m), 7.50 (1H, dd, J=90, 2.5Hz), 7.59 (1H, d, J=9.0Hz), 7.85 (1H, d, J=2.5Hz), 8.55 (1H, s).

実施例１２６

収率80%, 1H-NMR(CDCl3): δ1.26 (3H, t, J=7.0Hz), 1.39 (3H, d, J=7.0Hz), 2.20 (1H, t, J=11.5, 3.5Hz), 2.25-2.37 (4H, m), 2.82 (1H, d, J=11.5Hz), 3.00 (1H, d, J=11.5Hz), 3.31-3.46 (2H, m), 3.53-3.63 (3H, m), 4.16 (2H, q, J=7.0Hz), 4.33-4.43 (1H, m), 4.64-4.77 (1H, m), 7.02 (1H, s), 7.09 (1H, s), 7.11 (1H, s), 7.70 (2H, s), 8.14 (1H, s), 8.58 (1H, s).

実施例１２７

収率90%, 1H-NMR(CDCl3): δ1.26 (3H, t, J=7.0Hz), 2.66 (4H, t, J=5.0Hz), 2.70 (3H, s), 3.47 (4H, t, J=5.0Hz), 3.60 (2H, s), 3.63 (2H, s), 4.16 (2H, q, J=7.0Hz), 7.16-7.34 (4H, m), 7.74 (1H, d, J=8.5Hz), 7.87 (1H, d, J=8.5Hz), 8.16 (1H, s). Thereafter, the compounds described in Examples 2 to 127 were obtained in the same manner as in Example 1.
Example 2

Yield: 88%, ¹ H-NMR (CDCl _Three ): δ2.01-2.05 (2H, m), 2.69 (2H, t, J = 5.4Hz), 2.80-2.83 (2H, m), 3.67 (2H, s) 3.72-3.78 (4H, m), 3.92 (3H, s), 7.23 (1H, dd, J = 8.7Hz, 2.1Hz), 7.37-7.44 (2H, m), 7.53 (1H, s), 7.55 (1H, d, J = 2.1Hz), 7.94 (1H, d, J = 7.5Hz), 7.99 (1H, s).

Example 3

Yield: 73%, ¹ H-NMR (CDCl _Three ): δ2.60 (4 H, t, J = 5 Hz), 3.62 (2H, s), 3.67 (4H, t, J = 5 Hz), 3.97 (3H, s), 7.43 (1H, t, J = 7.5 Hz), 7.50-7.60 (3 H, m), 7.85 (1H, s), 7.97 (1H, d, J = 7.5 Hz), 8.02 (1H, s).

Example 4

Yield: qy, ¹ H-NMR (CDCl _Three ): δ2.00-2.20 (2H, m), 2.70 (2H, t, J = 5.5 Hz), 2.83 (2H, t, J = 5.5 Hz), 3.69 (2H, s), 3.70-3.85 (4H, m), 3.92 (3H, s), 7.40 (1H, t, J = 7.5Hz), 7.50-7.60 (3H, m), 7.84 (1H, s), 7.94 (1H, d, J = 7.5Hz), 7.99 (1H, s).

Example 5

Yield: 97%, ¹ H-NMR (CDCl _Three ): δ1.41 (3H, d, J = 6 Hz), 2.28 (1H, td, J = 11.5, 3.5 Hz), 2.36 (1H, dd, J = 11.5, 3.5 Hz), 2.69 (1H, d, J = 11.5 Hz), 2.90 (1H, d, J = 11.5 Hz), 3.40-3.55 (2H, m), 3.63 (1H, d, J = 12.5Hz), 3.80-3.90 (1H, m), 3.93 ( 3H, s), 4.10-4.25 (1H, m), 7.22 (1H, dd, J = 8.5, 2 Hz), 7.42 (1H, d, J = 8.5 Hz), 7.43 (1H, t, J = 7.5 Hz ), 7.54 (1H, d, J = 2 Hz), 7.58 (1H, d, J = 7.5 Hz), 7.95 (1H, d, J = 7.5 Hz), 8.02 (1H, s).

Example 6

Yield: qy, ¹ H-NMR (CDCl _Three ): δ1.23 (3H, d, J = 6 Hz), 2.25-2.35 (1H, m), 2.60-2.73 (1H, m), 2.73-2.82 (1H, m), 3.17 (1H, dd, J = 12.5, 9 Hz), 3.33 (1H, d, J = 13.5 Hz), 3.35-3.45 (1H, m), 3.65-3.75 (1H, m), 3.85-3.90 (1H, m), 3.93 (3H, s), 4.08 (1H, d, J = 13.5 Hz), 7.22 (1H, dd, J = 8.5, 2 Hz), 7.41 (1H, t, J = 7.5 Hz), 7.43 (1H, d, J = 8.5 Hz), 7.54 (1H, d, J = 2 Hz), 7.56 (1H, d, J = 7.5 Hz), 7.94 (1H, d, J = 7.5 Hz), 8.01 (1H, s).

Example 7

Yield: 83%, ¹ H-NMR (CDCl _Three ): δ1.15 (6H, d, J = 6Hz), 2.75-2.85 (2H, m), 3.06 (2H, dd, J = 13, 12.5Hz), 3.80-3.92 (4H, m), 3.92 (3H , s), 7.24 (1H, dd, J = 8.5, 2Hz), 7.37 (1H, d, J = 7.5Hz), 7.43 (1H, d, J = 8.5 Hz), 7.55 (1H, d, J = 2 Hz), 7.62 (1H, d, J = 7.5 Hz), 7.89 (1H, d, J = 7.5 Hz), 8.04 (1H, s).

Example 8

Yield: 79%, ¹ H-NMR (CDCl _Three ): δ1.10 (3H, d, J = 6.5Hz), 1.38 (3H, d, J = 6.5Hz), 2.31 (1H, d, J = 12 Hz), 2.91 (1H, dd, J = 12, 4 Hz), 3.10-3.20 (1H, m), 3.59 (2H, t, J = 14 Hz), 3.71 (2H, t, J = 14 Hz), 3.93 (3H, s), 4.16-4.28 (1H, m), 7.22 (1H, dd, J = 8.5, 2 Hz), 7.42 (1H, d, J = 8.5 Hz), 7.43 (1H, d, J = 7.5 Hz), 7.53 (1H, d, J = 2 Hz), 7.61 (1H, d, J = 7.5 Hz), 7.95 (1H, d, J = 7.5 Hz), 8.06 (1H, s).

Example 9

92% yield, ¹ H-NMR (CDCl _Three ): δ2.45 (3H, s), 2.58 (4H, t, J = 5Hz), 3.55 (2H, s), 3.61 (4H, t, J = 5Hz), 3.91 (3H, s), 7.23 (1H , dd, J = 8.5, 2 Hz), 7.24 (1H, d, J = 8 Hz), 7.43 (1H, d, J = 8.5 Hz), 7.55 (1H, d, J = 2 Hz), 7.87 (1H , dd, J = 8, 1.5Hz), 7.92 (1H, d, J = 1.5Hz).

Example 10

93% yield, ¹ H-NMR (CDCl _Three ): δ2.66 (4H, t, J = 5 Hz), 3.66 (4H, t, J = 5 Hz), 3.71 (2H, s), 3.96 (3H, s), 7.24 (1H, dd, J = 8.5, 2 Hz), 7.44 (1H, d, J = 8.5 Hz), 7.45 (1H, d, J = 8 Hz), 7.55 (1H, d, J = 2 Hz), 7.88 (1H, dd, J = 8,2 Hz), 8.15 (1H, d, J = 2 Hz).

Example 11

79% yield, ¹ H-NMR (CDCl _Three ): δ1.99-2.05 (2H, m), 2.40 (3H, s), 2.69 (2H, t, J = 5.1Hz), 2.79-2.82 (2H, m), 3.61 (2H, s), 3.71- 3.75 (4H, m), 3.90 (3H, s), 7.21-7.25 (2H, m), 7.42 (1H, d, J = 8.4Hz), 7.55 (1H, d, J = 2.4Hz), 7.38-7.87 (1H, m), 7.92 (1H, s).

Example 12

79% yield, ¹ H-NMR (CDCl _Three ): δ2.03-2.10 (2H, m), 2.75 (2H, t, J = 5.4Hz), 2.87-2.90 (2H, m), 3.73-3.80 (6H, m), 3.92 (3H, s), 7.22-7.26 (1H, m), 7.41 (1H, s), 7.44 (1H, s), 7.55 (1H, d, J = 2.1Hz), 7.87 (1H, dd, J = 8.4Hz, 2.1Hz), 8.15 (1H, d, J = 2.1Hz).

Example 13

90% yield, ¹ H-NMR (CDCl _Three ): δ2.38 (3H, s), 2.57 (4H, t, J = 5Hz), 3.51 (2H, s), 3.64 (4H, t, J = 5Hz), 3.92 (3H, s), 7.23 (1H , dd, J = 8.5, 2Hz), 7.37 (1H, s), 7.43 (1H, d, J = 8.5Hz), 7.55 (1H, d, J = 2Hz), 7.78 (1H, s), 7.80 (1H , s).

Example 14

90% yield, ¹ H-NMR (CDCl _Three ): δ1.59 (3H, s), 2.00-2.06 (2H, m), 2.39 (3H, s), 2.69 (2H, t, J = 5.4 Hz), 2.79-2.82 (2H, m), 3.64 ( 2H, s) 3.74-3.77 (4H, m), 7.23 (1H, dd, J = 8.4 Hz, 1.8 Hz), 7.35 (1H, s), 7.42 (1H, d, J = 8.4 Hz), 7.55 (1H , d, J = 1.8Hz), 7.75 (1H, s), 7.78 (1H, s).

Example 15

¹ H-NMR (CDCl _Three ): δ2.65 (4H, t, J = 5.1Hz), 3.64-3.67 (4H, m), 3.78 (2H, s), 3.88 (3H, s), 6.93 (1H, d, J = 3.3Hz) , 7.24 (1H, dd, J = 8.7, 2.1Hz), 7.44 (1H, d, J = 8.7Hz), 7.56 (1H, d, J = 2.1Hz), 7.67 (1H, d, J = 3.3Hz) .

Example 16

Yield 65%, ¹ H-NMR (CDCl _Three ): δ2.01-2.08 (2H, m), 2.71-2.75 (2H, m), 2.85-2.89 (2H, m), 3.72-3.76 (2H, m), 3.79-3.82 (2H, m), 3.86 (2H, s), 3.87 (3H, s), 6.89 (1H, d, J = 3.9 Hz), 7.23 (1H, dd, J = 8.7 Hz, 2.1 Hz), 7.42 (1H, d, J = 8.7 Hz ), 7.55 (1H, d, J = 2.4Hz), 7.65 (1H, d, J = 3.9Hz).

Example 17

¹ H-NMR (CDCl _Three ): δ1.37 (3H, t, J = 7 Hz), 2.65 (4H, t, J = 5 Hz), 3.65 (4H, t, J = 5 Hz), 3.69 (2H, s), 4.36 (2H , q, J = 7 Hz), 6.37 (1H, d, J = 3.5 Hz), 7.13 (1H, d, J = 3.5 Hz), 7.24 (1H, dd, J = 8.5, 2 Hz), 7.43 (1H, d, J = 8.5Hz), 7.55 (1H, d, J = 2Hz).

Example 18

¹ H-NMR (CDCl _Three ): δ2.56-2.60 (4H, m), 3.62-3.66 (6H, m), 3.92 (3H, s), 7.24 (1H, dd, J = 8.7, 2.1Hz), 7.42-7.44 (3H, m ), 7.55 (1H, d, J = 2.1Hz), 8.01 (2H, d, J = 8.4Hz).

Example 19

76% yield, ¹ H-NMR (CDCl _Three ): δ2.41 (3H, s), 2.59 (4H, t, J = 5 Hz), 3.58 (2H, s), 3.69 (4 H, t, J = 5 Hz), 3.96 (3H, s), 7.37 (1H, s), 7.50-7.60 (2H, m), 7.79 (1H, s), 7.80 (1H, s), 7.85 (1H, s).

Example 20

Yield 74%, ¹ H-NMR (CDCl _Three ): δ2.00-2.10 (2H, m), 2.38 (3H, s), 2.70 (2H, t, J = 5Hz), 2.82 (2H, t, J = 5Hz), 3.65 (2H, s), 3.70 -3.90 (4H, m), 3.91 (3H, s), 7.34 (1H, s), 7.50-7.60 (2H, m), 7.75 (1H, s), 7.79 (1H, s), 7.85 (1H, s ).

Example 21

Yield 98%, 1H-NMR (CDCl3): δ1.24 (3H, d, J = 6.5Hz), 2.25-2.37 (1H, m), 2.64-2.75 (1H, m), 2.75-2.83 (1H, m), 3.23 (1H, dd, J = 13, 9Hz), 3.29 (1H, d, J = 13.5Hz), 3.40-3.50 (1H, m), 3.70-3.80 (1H, m), 3.87-3.95 ( 1H, m), 3.93 (3H, s), 4.08 (1H, d, J = 13.5Hz), 7.42 (1H, t, J = 7.5Hz), 7.50-7.60 (3H, m), 7.84 (1H, s ), 7.95 (1H, d, J = 8Hz), 8.01 (1H, s).

Example 22

Yield 85%, 1H-NMR (CDCl3): δ1.24 (3H, d, J = 6.5Hz), 2.23-2.35 (1H, m), 2.41 (3H, s), 2.60-2.73 (1H, m) , 2.80 (1H, dt, J = 12, 3.5 Hz), 3.21 (1H, d, J = 13 Hz), 3.24 (1H, d, J = 13.5Hz), 3.39-3.50 (1H, m), 3.70- 3.80 (1H, m), 3.91 (3H, s), 3.91-3.95 (1H, m), 4.05 (1H, d, J = 13.5Hz), 7.36 (1H, s), 7.51 (1H, d, J = 8.5Hz), 7.55 (1H, d, J = 8.5Hz), 7.77 (1H, s), 7.80 (1H, s), 7.84 (1H, s).

Example 23

Yield 96%, 1H-NMR (CDCl3): δ1.24 (3 H, d, J = 6.3 Hz), 2.24-2.32 (1 H, m), 2.40 (3 H, s), 2.63-2.68 (1 H, m), 2.78 (1 H, dt, J = 3.6, 12.0 Hz), 3.17 (1 H, dd, J = 9.0 Hz), 3.22 (1 H, d, J = 13.2 Hz), 3.35-3.43 ( 1 H, m), 3.71 (1 H, dt, J = 3.3, 12.6 Hz), 3.88 (1 H, dd, J = 3.0, 15.0 Hz), 3.91 (3 H, s), 4.05 (1 H, d , J = 13.2 Hz), 7.23 (1 H, dd, J = 2.4, 8.4 Hz), 7.36 (1 H, s), 7.43 (1 H, d, J = 8.4 Hz), 7.54 (1 H, d, J = 2.4 Hz, 7.76 (1 H, s), 7.79 (1 H, s)

Example 24

Yield 98%, 1H-NMR (CDCl3): δ1.24 (3 H, d, J = 6.3 Hz), 2.28 (1H, ddd, J = 3.3, 8.7, 9.6 Hz), 2.40 (3 H, s) , 2.62-2.68 (1 H, m), 2.78 (1 H, dt, J = 3.6, 12.0 Hz), 3.17 (1 H, dd, J = 8.7, 12.6 Hz), 3.22 (1 H, d, J = 12.9 Hz), 3.39 (1 H, m), 3.71 (1 H, d, 12.3 Hz), 3.88 (1 H, dd, 3.3, 13.2 Hz), 3.92 (3 H, s), 4.05 (1 H, d , J = 13.2 Hz), 7.23 (1 H, dd, J = 2.1, 8.4 Hz), 7.36 (1 H, s), 7.43 (1 H, d, J = 8.4 Hz), 7.54 (1 H, d, J = 2.1 Hz), 7.76 (1 H, s), 7.79 (1 H, s)

Example 25

Yield 86%, 1H-NMR (CDCl3): δ1.11 (6H, d, J = 6Hz), 2.40 (3H, s), 2.70-2.85 (2H, m), 3.00-3.15 (2H, m), 3.83 (2H, s), 3.83-3.90 (2H, m), 3.91 (3H, s), 7.23 (1H, dd, J = 8.5, 2Hz), 7.40 (1H, s), 7.43 (1H, d, J = 8.5Hz), 7.55 (1H, d, J = 2Hz), 7.72 (1H, s), 7.84 (1H, s).

Example 26

Yield 67%, 1H-NMR (CDCl3): δ1.13 (6H, d, J = 6.5Hz), 2.40 (3H, s), 2.75-2.88 (2H, m), 3.05-3.18 (2H, m) , 3.84 (2H, s), 3.91 (3H, s), 3.91-3.95 (2H, m), 7.40 (1H, s), 7.52 (1H, d, J = 8.5Hz), 7.57 (1H, d, J = 8.5Hz), 7.72 (1H, s), 7.84 (2H, s).

Example 27

Yield 75%, 1H-NMR (CDCl3): δ1.42 (3H, d, J = 6.5Hz), 2.26 (1H, td, J = 11.5, 3.5Hz), 2.36 (1H, dd, J = 11.5, 3.5Hz), 2.41 (3H, s), 2.65-2.75 (1H, m), 2.85-2.95 (1H, m), 3.47 (1H, d, J = 13.5Hz), 3.48-3.55 (1H, m), 3.60 (1H, d, J = 13.5Hz), 3.80-3.90 (1H, m), 3.91 (3H, s), 4.20-4.30 (1H, m), 7.38 (1H, s), 7.51 (1H, dd, J = 8.5, 2Hz), 7.56 (1H, d, J = 8.5Hz), 7.77 (1H, s), 7.83 (1H, d, J = 2Hz), 7.84 (1H, s).

Example 28

Yield 78%, 1H-NMR (CDCl3): δ1.24 (3H, t, J = 6.0Hz), 2.24-2.36 (1H, m), 2.41 (3H, s), 2.61-2.73 (1H, m) , 2.75-2.84 (1H, m), 3.21 (1H, d, J = 13.0Hz), 3.24 (1H, d, J = 13.5Hz), 3.38-3.51 (1H, m), 3.71-3.82 (1H, m ), 3.88-3.98 (1H, m), 3.92 (3H, s), 4.05 (1H, d, J = 13.0Hz), 7.36 (1H, s), 7.51 (1H, d, J = 8.5), 7.56 ( 1H, d, J = 8.5Hz), 7.77 (1H, s), 7.80 (1H, s), 7.84 (1H, s).

Example 29

Yield 58%, ¹ H-NMR (DMSO-d ₆ ): δ2.25 (3H, s), 2.31 (3H, s), 2.51 (4H, t, J = 5 Hz), 3.51 (2H, s), 3.57 (4H, t, J = 5 Hz), 6.85 (1H, s), 6.89 (1H, s), 7.04 (1H, s), 7.28 (1H, dd, J = 8.5, 2.5Hz), 7.42 (1H, d, J = 8.5Hz), 7.91 (1H, d, J = 2.5Hz).

Example 30

Yield 89%, ¹ H-NMR (CDCl _Three ): δ1.99-2.06 (2H, m), 2.29 (3H, s), 2.34 (3H, s), 2.68 (2H, t, J = 5.7Hz), 2.78-2.82 (2H, m), 3.61 ( 2H, s), 3.72-3.78 (4H, m), 6.79 (1H, s), 6.88 (1H, s), 6.98 (1H, s), 7.22 (1H, dd, J = 7.5Hz, 3.3Hz), 7.42 (1H, d, J = 6.3Hz), 7.54 (1H, d, J = 2.1Hz).

Example 31

71% yield, ¹ H-NMR (CDCl _Three ): δ2.30 (3H, s), 2.36 (3H, s), 2.59 (4H, t, J = 5Hz), 3.53 (2H, s), 3.68 (4H, t, J = 5Hz), 6.83 (1H , s), 6.90 (1H, s), 7.02 (1H, s), 7.50-7.60 (2H, m), 7.85 (1H, s).

Example 32

Yield 65%, ¹ H-NMR (CDCl _Three ): δ1.95-2.10 (2H, m), 2.28 (3H, s), 2.34 (3H, s), 2.69 (2H, t, J = 5Hz), 2.83 (2H, t, J = 5Hz), 3.61 (2H, s), 3.70-3.85 (4H, m), 6.80 (1H, s), 6.89 (1H, s), 6.99 (1H, s), 7.48-7.60 (2H, m), 7.85 (1H, s ).

Example 33

69% yield, ¹ H-NMR (CDCl _Three ): δ2.31 (3H, s), 2.57 (4H, t, J = 5.1 Hz), 3.55 (2H, s), 3.63 (4H, t, J = 5.1 Hz), 7.06 (2H, d, J = 8.1 Hz), 7.24 (1H, dd, J = 8.4, 2.1 Hz), 7.35 (2H, d, J = 8.1 Hz), 7.43 (1H, d, J = 8.4 Hz), 7.55 (1H, d, J = 2.1 Hz).

Example 34

Yield 56%, 1H-NMR (CDCl3): δ1.22 (3H, d, J = 6Hz), 2.24-2.35 (1H, m), 2.29 (3H, s), 2.35 (3H, s), 2.62- 2.72 (1H, m), 2.83 (1H, dt, J = 12, 4Hz), 3.15-3.25 (2H, m), 3.40-3.50 (1H, m), 3.70-3.80 (1H, m), 3.87-3.95 (1H, m), 4.03 (1H, d, J = 13.5Hz), 6.81 (1H, s), 6.90 (1H, s), 7.01 (1H, s), 7.52 (1H, d, J = 8.5Hz) , 7.56 (1H, d, J = 8.5Hz), 7.84 (1H, s).

Example 35

Yield 41%, 1H-NMR (CDCl3): δ1.10 (6H, d, J = 6Hz), 2.29 (3H, s), 2.34 (3H, s), 2.70-2.85 (2H, m), 3.00- 3.10 (2H, m), 3.79 (2H, s), 3.80-3.90 (2H, m), 6.76 (1H, s), 6.95 (1H, s), 7.02 (1H, s), 7.23 (1H, dd, J = 8.5, 2Hz), 7.43 (1H, d, J = 8.5Hz), 7.55 (1H, d, J = 2Hz).

Example 36

Yield 63%, 1H-NMR (CDCl3): δ1.11 (6H, d, J = 6Hz), 2.30 (3H, s), 2.35 (3H, s), 2.70-2.86 (2H, m), 3.00- 3.15 (2H, m), 3.80 (2H, s), 3.85-3.95 (2H, m), 6.77 (1H, s), 6.95 (1H, s), 7.02 (1H, s), 7.52 (1H, d, J = 8.5Hz), 7.57 (1H, d, J = 8.5Hz), 7.85 (1H, s).

Example 37

Yield 53%, 1H-NMR (CDCl3): δ1.02 (3H, t, J = 7.5Hz), 1.55-1.78 (2H, m), 2.30 (3H, s), 2.30-2.35 (1H, m) , 2.36 (3H, s), 2.49-2.60 (1H, m), 2.78-2.90 (1H, m), 3.26 (1H, d, J = 13.5Hz), 3.38-3.46 (1H, m), 3.46-3.58 (1H, m), 3.63-3.72 (1H, m), 3.85 (1H, dd, J = 13, 3.5Hz), 3.98 (1H, d, J = 13.5Hz), 6.81 (1H, s), 6.91 ( 1H, s), 7.02 (1H, s), 7.51 (1H, dd, J = 8.5, 1.5Hz), 7.56 (1H, d, J = 8.5Hz), 7.84 3 (1H, d, J = 1.5Hz)

Example 38

Yield 69%, 1H-NMR (CDCl3): δ2.25-2.35 (1H, m), 2.30 (3H, s), 2.34 (3H, s), 2.86 (1H, d, J = 13.5Hz), 3.02 (1H, d, J = 11.5Hz), 3.25-3.50 (3H, m), 3.82 (1H, d, J = 13.5Hz), 4.00-4.10 (2H, m), 6.79 (1H, s), 6.82 ( 1H, s), 6.93 (1H, s), 7.30-7.45 (3H, m), 7.48-7.55 (4H, m), 7.84 (1H, d, J = 0.5Hz).

Example 39

Yield 48%, 1H-NMR (CDCl3): δ1.40 (3H, d, J = 6.5Hz), 2.15-2.30 (2H, m), 2.31 (3H, s), 2.36 (3H, s), 2.68 -2.75 (1H, m), 2.85-2.95 (1H, m), 3.38-3.60 (3H, m), 3.80-3.90 (1H, m), 4.15-4.25 (1H, m), 6.81 (1H, s) , 6.92 (1H, s), 7.02 (1H, s), 7.23 (1H, dd, J = 8.5, 2Hz), 7.42 (1H, d, J = 8.5Hz), 7.54 (1H, d, J = 2Hz) .

Example 40

Yield 81%, 1H-NMR (CDCl3): δ1.42 (3H, d, J = 6.5Hz), 2.18-2.29 (1H, m), 2.30 (3H, s), 2.30-2.35 (1H, m) , 2.36 (3H, s), 2.75 (1H, d, J = 11.5Hz), 2.92 (1H, d, J = 11.5Hz), 3.43 (1H, d, J = 13.5Hz), 3.52 (1H, td, J = 12.5, 3.5Hz), 3.57 (1H, d, J = 13.5Hz), 3.91 (1H, d, J = 12.5Hz), 4.17-4.30 (1H, m), 6.81 (1H, s), 6.92 ( 1H, s), 7.02 (1H, s), 7.51 (1H, d, J = 8.5Hz), 7.55 (1H, d, J = 8.5Hz), 7.84 (1H, s).

Example 41

Yield 57%, 1H-NMR (CDCl3): δ1.42 (3H, d, J = 6.5Hz), 2.18-2.38 (2H, m), 2.30 (3H, s), 2.36 (3H, s), 2.70 -2.80 (1H, m), 2.86-2.97 (1H, m), 3.38-3.61 (3H, m), 3.85-3.97 (1H, m), 4.17-4.30 (1H, m), 6.82 (1H, s) , 6.92 (1H, s), 7.03 (1H, s), 7.48-7.59 (2H, m), 7.84 (1H, s).

Example 42

Yield 63%, 1H-NMR (CDCl3): δ1.02 (3H, t, J = 7.5Hz), 1.60-1.75 (2H, m), 2.30 (3H, s), 2.30-2.35 (1H, m) , 2.36 (3H, s), 2.48-2.58 (1H, m), 2.79-2.90 (1H, m), 3.26 (1H, d, J = 13.5Hz), 3.38-3.58 (2H, m), 3.63-3.73 (1H, m), 3.80-3.90 (1H, m), 3.98 (1H, d, J = 13.5Hz), 6.81 (1H, s), 6.91 (1H, s), 7.02 (1H, s), 7.51 ( 1H, d, J = 8.5Hz), 7.55 (1H, d, J = 8.5Hz), 7.84 (1H, s).

Example 43

Yield 79%, 1H-NMR (CDCl3): δ1.02 (3H, t, J = 7.5Hz), 1.57-1.80 (2H, m), 2.21 (3H, s), 2.21-2.35 (1H, m) , 2.36 (3H, s), 2.50-2.60 (1H, m), 2.80-2.90 (1H, m), 3.26 (1H, d, J = 13.5Hz), 3.38-3.60 (2H, m), 3.63-3.74 (1H, m), 3.85 (1H, dd, J = 12.5, 3.5Hz), 3.98 (1H, d, J = 13.5Hz), 6.81 (1H, s), 6.91 (1H, s), 7.02 (1H, s), 7.53 (1H, d, J = 8.5Hz), 7.55 (1H, d, J = 8.5Hz), 7.84 (1H, s).

Example 44

Yield 63%, 1H-NMR (CDCl3): δ1.20 (3H, t, J = 7.5Hz), 1.30-1.70 (4H, m), 2.29 (3H, s), 2.29-2.35 (1H, m) , 2.36 (3H, s), 2.55-2.65 (1H, m), 2.79-2.89 (1H, m), 3.28 (1H, d, J = 13.5Hz), 3.41 (1H, dd, J = 13, 7.5Hz ), 3.50-3.60 (1H, m), 3.60-3.70 (1H, m), 3.84 (1H, dd, J = 13, 3Hz), 3.97 (1H, d, J = 13.5Hz), 6.81 (1H, s ), 6.90 (1H, s), 7.02 (1H, s), 7.51 (1H, dd, J = 8.5, 1.5Hz), 7.56 (1H, d, J = 8.5Hz), 7.83 (1H, d, J = 1.5Hz).

Example 45

Yield 62%, 1H-NMR (CDCl3): δ 0.95 (3 H, t, J = 7.2 Hz), 1.36-1.43 (2 H, m), 1.50-1.66 (2 H, m), 2.30 (3 H, s), 2.35 (3 H, s), 2.32-2.39 (1H, m), 2.58-2.63 (1 H, m), 2.80-2.87 (1 H, m), 3.28 (1 H, d, J = 13.5 Hz), 3.41 (1 H, dd, J = 7.5, 12.6 Hz), 3.50-3.59 (1 H, m), 3.62-3.68 (1 H, m), 3.84 (1 H, dd, J = 3.0 , 12.6 Hz), 3.97 (1 H, d, J = 13.5 Hz), 6.81 (1 H, s), 6.90 (1 H, s), 7.01 (1 H, s), 7.53-7.55 (2 H, m ), 7.83 (1 H, s)

Example 46

Yield 70%, 1H-NMR (CDCl3): δ0.93 (3H, t, J = 7.5Hz), 1.23-1.75 (6H, m), 2.30 (3H, s), 2.30-2.34 (1H, m) , 2.35 (3H, s), 2.54-2.64 (1H, m), 2.79-2.89 (1H, m), 3.27 (1H, d, J = 13.5Hz), 3.41 (1H, dd, J = 12.5, 7.5Hz ), 3.49-3.60 (1H, m), 3.61-3.71 (1H, m), 3.84 (1H, dd, J = 12.5, 2.5Hz), 3.97 (1H, d, J = 13.5Hz), 6.81 (1H, s), 6.90 (1H, s), 7.02 (1H, s), 7.51 (1H, dd, J = 8.5, 1.5Hz), 7.56 (1H, d, J = 8.5Hz), 7.84 (1H, d, J = 1.5Hz).

Example 47

Yield 69%, 1H-NMR (CDCl3): δ 0.91 (3H, d, J = 6.5Hz), 0.95 (3H, d, J = 6.5Hz), 1.33-1.45 (1H, m), 1.45-1.58 (1H, m), 1.62-1.77 (1H, m), 2.29 (3H, s), 2.35 (3H, s), 2.36-2.45 (1H, m), 2.62-2.73 (1H, m), 2.77-2.88 (1H, m), 3.33 (1H, d, J = 13.5Hz), 3.35 (1H, dd, J = 13, 7Hz), 3.58 (2H, t, J = 5.5Hz), 3.75 (1H, dd, J = 13, 3.5Hz), 3.90 (1H, d, J = 13.5Hz), 6.80 (1H, s), 6.90 (1H, s), 7.02 (1H, s), 7.23 (1H, dd, J = 8.5, 2Hz), 7.42 (1H, d, J = 8.5Hz), 7.54 (1H, d, J = 2Hz).

Example 48

Yield 49%, 1H-NMR (CDCl3): δ0.92 (3H, d, J = 6.5Hz), 0.95 (3H, d, J = 6.5Hz), 1.32-1.60 (2H, m), 1.62-1.78 (1H, m), 2.29 (3H, s), 2.31-2.46 (1H, m), 2.35 (3H, s), 2.62-2.72 (1H, m), 2.75-2.88 (1H, m), 3.29-3.42 (2H, m), 3.58 (2H, t, J = 5.0Hz), 3.75 (1H, dd, J = 13.0, 3.5Hz), 3.90 (1H, d, J = 13.5Hz), 6.80 (1H, s) , 6.91 (1H, s), 7.02 (1H, s), 7.23 (1H, dd, J = 8.5, 2.0Hz), 7.43 (1H, d, J = 8.5Hz), 7.54 (1H, d, J = 2.0 Hz).

Example 49

Yield 72%, 1H-NMR (CDCl3): δ 0.92 (3H, d, J = 7.5Hz), 0.95 (3H, d, J = 7.5Hz), 1.33-1.45 (1H, m), 1.46-1.60 (1H, m), 1.64-1.78 (1H, m), 2.30 (3H, s), 2.35 (3H, s), 2.36-2.46 (1H, m), 2.63-2.75 (1H, m), 2.77-2.88 (1H, m), 3.35 (1H, d, J = 13.5Hz), 3.40 (1H, dd, J = 13, 6.5Hz), 3.55-3.70 (2H, m), 3.79 (1H, dd, J = 12 , 3Hz), 3.90 (1H, d, J = 13.5Hz), 6.81 (1H, s), 6.91 (1H, s), 7.02 (1H, s), 7.51 (1H, dd, J = 8.5, 1.5Hz) , 7.55 (1H, d, J = 8.5Hz), 7.83 (1H, d, J = 1.5Hz).

Example 50

Yield 65%, 1H-NMR (CDCl3): δ1.98-2.08 (2H, m), 2.28 (3H, s), 2.34 (3H, s), 2.65-2.74 (2H, m), 2.78-2.85 ( 2H, m), 3.61 (2H, s), 3.65-3.88 (4H, m), 6.80 (1H, s), 6.88 (1H, s), 6.99 (1H, s), 7.27 (1H, d, J = 12.0Hz), 7.75 (1H, d, J = 7.0Hz).

Example 51

Yield 57%, 1H-NMR (CDCl3): δ1.11 (6H, d, J = 6.0Hz), 2.29 (3H, s), 2.34 (3H, s), 2.71-2.86 (2H, m), 3.07 (1H, d, J = 13.0Hz), 3.10 (1H, d, J = 13.0Hz), 3.79 (2H, s), 3.88 (2H, d, J = 13.0Hz), 6.77 (1H, s), 6.96 (1H, s), 7.01 (1H, s), 7.26 (1H, d, J = 11.5Hz), 7.73 (1H, d, J = 7.0Hz).

Example 52

Yield 57%, 1H-NMR (CDCl3): δ1.21 (3H, d, J = 6Hz), 2.24-2.29 (1H, m), 2.30 (3H, s), 2.36 (3H, s), 2.60- 2.72 (1H, m), 2.83 (1H, dt, J = 12, 3.5Hz), 3.18 (1H, d, J = 13.5Hz), 3.18-3.25 (1H, m), 3.48-3.51 (1H, m) , 3.67-3.80 (1H, m), 3.85-3.95 (1H, m), 4.02 (1H, d, J = 13.5Hz), 6.81 (1H, s), 6.90 (1H, s), 7.01 (1H, s ), 7.26 (1H, d, J = 12Hz), 7.73 (1H, d, J = 7Hz).

Example 53

Yield 65%, 1H-NMR (CDCl3): δ1.02 (3H, t, J = 7.5Hz), 1.50-1.78 (2H, m), 2.26-2.42 (1H, m), 2.30 (3H, s) , 2.36 (3H, s), 2.48-2.59 (1H, m), 2.78-2.89 (1H, m), 3.27 (1H, d, J = 13.5Hz), 3.38-3.58 (2H, m), 3.61-3.72 (1H, m), 3.78-3.89 (1H, m), 3.98 (1H, d, J = 13.5Hz), 6.81 (1H, s), 6.90 (1H, s), 7.01 (1H, s), 7.26 ( 1H, d, J = 12.0Hz), 7.74 (1H, d, J = 7.0Hz).

Example 54

Yield 61%, 1H-NMR (CDCl3): δ 2.29 (3H, s), 2.36 (3H, s), 2.58 (4H, t, J = 5.0Hz), 3.52 (2H, s), 3.53 (4H , t, J = 5.0Hz), 6.82 (1H, s), 6.90 (1H, s), 7.02 (1H, s), 7.17-7.24 (1H, m), 7.27-7.37 (2H, m), 7.38- 7.47 (3H, m).

Example 55

Yield 49%, 1H-NMR (CDCl3): δ 1.15 (6H, d, J = 6.0Hz), 2.30 (3H, s), 2.35 (3H, s), 2.68-2.83 (2H, m), 2.94 (1H, d, J = 13.0Hz), 2.97 (1H, d, J = 13.0Hz), 3.80 (2H, s), 4.33 (2H, d, J = 14.0Hz), 6.76 (1H, s), 6.97 (1H, s), 7.04 (1H, s), 7.34-7.43 (1H, m), 7.52-7.61 (1H, m), 7.67 (1H, d, J = 8.0, 1.5Hz), 7.87 (1H, dd , J = 8.0, 1.5Hz), 8.56 (1H, s)

Example 56

Yield 56%, 1H-NMR (CDCl3): δ1.21 (3H, d, J = 6.0Hz), 1.18-2.30 (1H, m), 2.28 (3H, s), 2.35 (3H, s), 2.52 -2.65 (1H, m), 2.78-2.89 (1H, m), 3.05-3.20 (2H, m), 3.27-3.41 (1H, m), 3.97-4.12 (2H, m), 4.15-4.25 (1H, m), 6.80 (1H, s), 6.92 (1H, s), 7.01 (1H, s), 7.32-7.40 (1H, m), 7.50-7.59 (1H, m), 7.67 (1H, dd, J = 8.0, 1.5Hz), 7.87 (1H, dd, J = 8.0, 1.5Hz), 8.53 (1H, s).

Example 57

Yield 55%, 1H-NMR (CDCl3): δ 1.14 (6H, d, J = 6.0Hz), 2.29 (3H, s), 2.35 (3H, s), 2.68-2.82 (2H, m), 2.94 (1H, d, J = 13.0Hz), 2.98 (1H, d, J = 13.0Hz), 3.80 (2H, s), 4.30 (2H, d, J = 13.0Hz), 6.76 (1H, s), 6.97 (1H, s), 7.03 (1H, s), 7.50 (1H, dd, J = 9.0, 2.5Hz), 7.59 (1H, d, J = 9.0Hz), 7.85 (1H, d, J = 2.5Hz) , 8.54 (1H, s).

Example 58

Yield 34%, 1H-NMR (CDCl3): δ1.13 (6H, d, J = 6.0Hz), 2.28 (3H, s), 2.34 (3H, s), 2.65-2.79 (2H, m), 2.95 (1H, d, J = 13.0Hz), 2.98 (1H, d, J = 13.0Hz), 3.78 (2H, s), 4.34 (2H, d, J = 13.0Hz), 6.77 (1H, s), 6.98 (1H, s), 7.02 (1H, s), 7.67-7.73 (2H, m), 8.13 (1H, s), 8.58 (1H, s).

Example 59

92% yield, ¹ H-NMR (CDCl _Three ): δ2.25 (3H, s), 2.56 (4H, t, J = 5.1 Hz), 3.48 (2H, s), 3.50 (3H, s), 3.63 (4H, t, J = 5.1 Hz), 5.20 (2H, s), 7.00 (1H, d), 7.08 (1H, d, 8.1 Hz), 7.12 (1H, s), 7.23 (1H, dd, J = 8.7, 2.1 Hz), 7.43 (1H, d, J = 8.7 Hz), 7.53 (1H, d, 2.1 Hz).

Example 60

90% yield, ¹ H-NMR (CDCl _Three ): δ1.98-2.05 (2H, m), 2.24 (3H, s), 2.68 (2H, t, J = 5.4 Hz), 2.79 (2H, t, J = 4.8 Hz), 3.49 (3H, s) , 3.55 (2H, s), 3.71-3.78 (4H, m), 5.19 (2H, s), 6.98 (1H, s), 7.07 (2H, m), 7.22 (1H, dd, 8.7, 2.1Hz), 7.42 (1H, d, J = 8.7Hz), 7.54 (1H, d, J = 2.1Hz).

Example 61

Yield 60%, ¹ H-NMR (CDCl _Three ): δ2.57 (4H, t, J = 5.1 Hz), 3.48 (3H, s), 3.50 (2H, s), 3.64 (4H, t, J = 5.1Hz), 5.17 (2H, s), 6.91 (1H, s), 6.97-7.01 (2H, m), 7.24 (1H, dd, 8.7, 2.1Hz), 7.44 (1H, d, J = 8.7 Hz), 7.56 (1H, d, J = 2.1Hz) .

Example 62

Yield 70%, 1H-NMR (CDCl3): δ1.22 (3H, d, J = 6.5Hz), 2.24 (3H, s), 2.24-2.35 (1H, m), 2.60-2.70 (1H, m) , 2.78-2.88 (1H, m), 3.19 (1H, dt, J = 13, 4.5Hz), 3.24 (1H, d, J = 13Hz), 3.38-3.50 (1H, m), 3.50 (3H, s) , 3.70-3.80 (1H, m), 3.85-3.93 (1H, m), 4.01 (1H, d, J = 13Hz), 5.21 (2H, s), 6.89 (1H, d, J = 7.5Hz), 7.02 (1H, s), 7.10 (1H, d, J = 7.5Hz), 7.50 (1H, d, J = 8.5Hz), 7.53 (1H, d, J = 8.5Hz), 7.83 (1H, s).

Example 63

Yield 92%, 1H-NMR (CDCl3): δ1.22 (3 H, d, J = 6.0 Hz), 2.23-2.33 (1 H, m), 2.33 (3 H, s), 2.60-2.67 (1 H, m), 2.83 (1 H, dt, J = 3.3, 12.0 Hz), 3.16 (2 H, dd, J = 4.2, 13.2 Hz), 3.44-3.35 (1 H, m), 3.49 (3 H, s), 3.71 (1 H, d, J = 12.0 Hz), 3.86 (1 H, dd, J = 2.1, 12.6 Hz), 3.99 (1 H, d, J = 13.2 Hz), 5.17 (2 H, s ), 6.77 (1 H, s), 6.80 (1 H, s), 6.83 (1 H, s), 7.23 (1 H, dd, J = 2.1, 8.7 Hz), 7.42 (1 H, d, J = 8.7 Hz), 7.54 (1 H, d, J = 2.1 Hz)

Example 64

Yield 95%, 1H-NMR (CDCl3): δ1.22 (3 H, d, J = 6.0 Hz), 2.25-2.31 (1 H, m), 2.33 (3 H, s), 2.60-2.67 (1 H, m), 2.83 (1 H, dt, J = 3.6, 12.0 Hz), 3.16 (2 H, dt, J = 3.6, 13.5 Hz), 3.44-3.35 (1 H, m), 3.49 (3 H, s), 3.71 (1 H, dt, J = 3.0, 12.3 Hz), 3.86 (1 H, ddd, J = 1.5, 3.6, 12.6 Hz), 3.99 (1 H, d, J = 13.5 Hz), 5.16 ( 2 H, s), 6.77 (1 H, s), 6.80 (1 H, s), 6.83 (1 H, s), 7.23 (1 H, dd, J = 2.1, 8.7 Hz), 7.42 (1 H, d, J = 8.7 Hz), 7.54 (1 H, d, J = 2.1 Hz),

Example 65

Yield 38%, ¹ H-NMR (CDCl _Three ): δ1.27 (3H, t, J = 7.2 Hz), 2.57 (4H, t, J = 4.8 Hz), 3.52 (2H, s), 3.59 (2H, s), 3.64 (4H, t, J = 4.8Hz), 4.17 (2H, q, J = 7.2Hz), 7.14 (1H, s), 7.20 (1H, s), 7.23 (1H, dd, J = 7.8, 2.4Hz), 7.26 (1H, s) , 7.43 (1H, d, J = 7.8Hz), 7.56 (1H, d, J = 2.4Hz).

Example 66

Yield 60%, ¹ H-NMR (CDCl _Three ): δ1.26 (3H, t, J = 7.2 Hz), 1.98-2.06 (2H, m), 2.68 (2H, t, J = 5.4 Hz), 2.80 (2H, t, J = 5.4 Hz), 3.56 (2H, s), 3.60 (2H, s), 3.71-3.78 (4H, m), 4.16 (2H, q, J = 7.2Hz), 7.12 (1H, s), 7.18 (1H, s), 7.23 ( 1H, dd, J = 8.4, 2.1Hz), 7.25 (1H, s), 7.42 (1H, d, J = 8.4Hz), 7.55 (1H, d, J = 2.1Hz)

Example 67

Yield 89%, ¹ H-NMR (CDCl _Three ): δ1.26 (3H, t, J = 7Hz), 2.57 (4H, t, J = 5Hz), 3.55 (2H, s), 3.61 2H, s), 3.62 (4H, t, J = 5Hz), 4.15 (2H, q, J = 7Hz), 7.23 (1H, dd, J = 8.5,2Hz), 7.25-7.35 (4H, m), 7.42 (1H, d, J = 8.5Hz), 7.55 (1H, d , J = 2Hz).

Example 68

Yield 79%, 1H-NMR (CDCl3): δ1.13 (6H, d, J = 6Hz), 1.25 (3H, t, J = 7Hz), 2.73-2.90 (2H, m), 3.05-3.15 (2H , m), 3.61 (2H, s), 3.85 (2H, s), 3.85-3.95 (2H, m), 4.14 (2H, q, J = 7Hz), 7.10-7.35 (4H, m), 7.52 (1H , d, J = 8.5Hz), 7.56 (1H, d, J = 8.5Hz), 7.84 (1H, s).

Example 69

Yield 54%, 1H-NMR (CDCl3): δ1.09 (6H, d, J = 6.5Hz), 1.26 (3H, t, J = 7Hz), 2.70-2.95 (2H, m), 3.10 (2H, dd, J = 13, 13Hz), 3.58 (2H, s), 3.78 (2H, s), 3.86-3.96 (2H, m), 4.15 (2H, q, J = 7Hz), 7.14 (1H, s), 7.17 (1H, s), 7.33 (1H, s), 7.53 (1H, d, J = 8.5Hz), 7.57 (1H, d, J = 8.5Hz), 7.85 (1H, s).

Example 70

Yield 71%, 1H-NMR (CDCl3): δ1.08 (3H, d, J = 6.5Hz), 1.25 (3H, t, J = 7Hz), 1.40 (3H, d, J = 6.5Hz), 2.25 -2.35 (1H, m), 2.90 (1H, dd, J = 12, 4Hz), 3.10-3.20 (1H, m), 3.52 (1H, d, J = 13.5Hz), 3.62 (2H, s), 3.63 -3.78 (3H, m), 4.16 (2H, q, J = 7Hz), 4.20-4.35 (1H, m), 7.20-7.35 (4H, m), 7.45-7.56 (2H, m), 7.82 (1H, s).

Example 71

Yield 92%, 1H-NMR (CDCl3): δ1.23 (3H, d, J = 6Hz), 1.25 (3H, t, J = 7Hz), 2.23-2.35 (1H, m), 2.60-2.75 (1H , m), 2.83 (1H, dt, J = 12, 4Hz), 3.20 (1H, d, J = 12.5Hz), 3.22 (1H, d, J = 13Hz), 3.38-3.50 (1H, m), 3.62 (2H, s), 3.70-3.80 (1H, m), 3.85-3.95 (1H, m), 4.05 (1H, d, J = 13Hz), 4.16 (2H, q, J = 7Hz), 7.15-7.35 ( 4H, m), 7.45-7.60 (2H, m), 7.84 (1H, s).

Example 72

Yield 88%, 1H-NMR (CDCl3): δ1.23 (3 H, t, J = 7.2 Hz), 1.26 (3 H, t, J = 6.9 Hz), 2.27 (1 H, ddd, J = 3.3 , 8.7, 9.9 Hz), 2.61-2.67 (1 H, m), 2.80 (1 H, dt, J = 3.3, 11.7 Hz), 3.21 (2 H, d, J = 13.5 Hz), 3.34-3.43 (1 H, m), 3.62 (2 H, s), 3.71 (1 H, d, J = 12.6 Hz), 3.87 (1 H, dd, J = 2.1, 12.6 Hz), 4.05 (1 H, d, J = 13.5 Hz), 4.16 (2 H, q, J = 7.2 Hz), 7.18-7.32 (5 H, m), 7.42 (1 H, d, J = 8.7 Hz), 7.54 (1 H, d, J = 2.4 Hz)

Example 73

Yield 93%, 1H-NMR (CDCl3): δ1.24 (3 H, t, J = 6.0 Hz), 1.26 (3 H, t, J = 7.2 Hz), 2.27 (1 H, ddd, J = 3.3 , 8.7, 9.9 Hz), 2.62-2.67 (1 H, m), 2.80 (1 H, dt, J = 3.6, 12.0 Hz), 3.21 (2 H, d, J = 13.5 Hz), 3.39-3.42 (1 H, m), 3.62 (2 H, s), 3.71 (1 H, dt, J = 12.0 Hz), 3.87 (1 H, dd, J = 2.1, 12.6 Hz), 4.06 (1 H, d, J = 13.5 Hz), 4.16 (2 H, q, J = 7.2 Hz), 7.18-7.32 (5 H, m), 7.42 (1 H, d, J = 8.4 Hz), 7.54 (1 H, d, J = 2.1 Hz)

Example 74

Yield 82%, 1H-NMR (CDCl3): δ1.23 (3H, d, J = 6Hz), 1.26 (3H, t, J = 7Hz), 2.20-2.35 (1H, m), 2.34 (3H, s ), 2.58-2.71 (1H, m), 2.82 (1H, dt, J = 12, 4Hz), 3.16 (1H, d, J = 13.5Hz), 3.16-3.25 (1H, m), 3.38-3.50 (1H , m), 3.58 (2H, s), 3.70-3.80 (1H, m), 3.86-3.96 (1H, m), 4.03 (1H, d, J = 13.5Hz), 4.15 (2H, q, J = 7Hz ), 7.01 (1H, s), 7.05 (2H, s), 7.51 (1H, d, J = 8.5Hz), 7.55 (1H, d, J = 8.5Hz), 7.84 (1H, s).

Example 75

Yield 92%, 1H-NMR (CDCl3): δ1.02 (3 H, t, J = 7.2 Hz), 1.26 (3 H, t, J = 7.2 Hz), 1.61-1.74 (2 H, m), 2.29-2.37 (1 H, m), 2.50-2.55 (1 H, m), 2.79-2.84 (1 H, m), 3.29 (1 H, d, J = 13.5 Hz), 3.37 (1 H, dd, J = 8.1, 12.9 Hz), 3.40-3.50 (1 H, m), 3.62 (3 H, s), 3.80 (1 H, dd, J = 3.3, 12.9 Hz), 4.01 (1 H, d, J = 13.5 Hz), 4.16 (2 H, t, J = 7.2 Hz), 7.18 (5 H, m), 7.42 (1 H, d, J = 8.7 Hz), 7.54 (1 H, d, J = 2.1 Hz)

Example 76

Yield 90%, 1H-NMR (CDCl3): δ0.93 (6 H, dd, J = 6.3, 11.7 Hz), 1.26 (3 H, t, J = 7.2 Hz), 1.35-1.44 (1 H, m ), 1.50-1.56 (1 H, m), 1.65-1.76 (1 H, m), 2.37-2.44 (1 H, m), 2.67-2.72 (1 H, m), 2.78-2.85 (1 H, m ), 3.36 (1 H, d, J = 12.9 Hz), 3.39 (1 H, d, J = 13.2 Hz), 3.58 (2 H, t, J = 4.8 Hz), 3.61 (2 H, s), 3.75 (1 H, dd, J = 3.3, 12.9 Hz), 3.93 (1 H, d, J = 13.2 Hz), 4.16 (2 H, q, J = 7.2 Hz), 7.17-7.31 (5 H, m), 7.42 (1 H, d, J = 8.7 Hz), 7.54 (1 H, d, J = 1.8 Hz)

Example 77

Yield 68%, 1H-NMR (CDCl3): δ1.26 (3H, t, J = 7Hz), 1.42 (3H, d, J = 6.5Hz), 2.25 (1H, td, J = 11.5, 3.5Hz) , 2.32 (1H, dd, J = 11.5, 4Hz), 2.74 (1H, d, J = 11.5Hz), 2.91 (1H, dt, J = 11.5, 2Hz), 3.46 (1H, d, J = 13.5Hz) , 3.52 (1H, td, J = 11.5, 4Hz), 3.59 (1H, d, J = 13.5Hz), 3.62 (2H, s), 3.85-4.00 (1H, m), 4.15 (2H, q, J = 7Hz), 4.20-4.30 (1H, m), 7.15-7.33 (4H, m), 7.51 (1H, d, J = 8.5Hz), 7.55 (1H, d, J = 8.5Hz), 7.84 (1H, s ).

Example 78

Yield 86%, 1H-NMR (CDCl3): δ1.25 (3H, t, J = 7Hz), 1.40 (3H, d, J = 6.5Hz), 2.24 (1H, td, J = 11.5, 3.5Hz) , 2.33 (1H, dd, J = 11.5, 3.5Hz), 2.72 (1H, d, J = 11Hz), 2.91 (1H, d, J = 11Hz), 3.43 (1H, d, J = 13.5Hz), 3.49 (1H, td, J = 11.5, 3.5Hz), 3.59 (1H, d, J = 13.5Hz), 3.62 (2H, s), 3.80-3.90 (1H, m), 4.10-4.18 (1H, m), 4.19 (2H, q, J = 7Hz), 7.15-7.35 (5H, m), 7.42 (1H, d, J = 7.5Hz), 7.54 (1H, d, J = 2Hz).

Example 79

Yield 71%, 1H-NMR (CDCl3): δ1.26 (3H, t, J = 7.0Hz), 1.40 (3H, d, J = 7.0Hz), 2.17-2.38 (2H, m), 2.68-2.77 (1H, m), 2.88-2.96 (1H, m), 3.41-3.67 (5H, m), 3.82-3.92 (1H, m), 4.07-4.23 (1H, m), 4.16 (2H, q, J = 7.0Hz), 7.16-7.34 (5H, m), 7.42 (1H, d, J = 8.5Hz), 7.54 (1H, d, J = 2.0Hz).

Example 80

Yield 85%, 1H-NMR (CDCl3): δ1.26 (3H, t, J = 7Hz), 1.40 (3H, d, J = 6.5Hz), 2.23 (1H, td, J = 11.5, 3.5Hz) , 2.27-2.33 (1H, m), 2.34 (3H, s), 2.72 (1H, d, J = 11.5Hz), 2.90 (1H, d, J = 11.5Hz), 3.41 (1H, d, J = 13.5 Hz), 3.45-3.54 (1H, m), 3.55 (1H, d, J = 13.5Hz), 3.58 (2H, s), 3.85 (1H, d, J = 12Hz), 4.10-4.15 (1H, m) , 4.16 (2H, q, J = 7Hz), 7.01 (1H, s), 7.07 (1H, s), 7.08 (1H, s), 7.22 (1H, dd, J = 8.5, 2Hz), 7.42 (1H, d, J = 8.5Hz), 7.54 (1H, d, J = 2Hz).

Example 81

Yield 74%, 1H-NMR (CDCl3): δ1.26 (3H, t, J = 7.0Hz), 1.40 (3H, d, J = 7.0Hz), 2.16-2.37 (5H, m), 2.68-2.77 (1H, m), 2.86-2.96 (1H, m), 3.36-3.62 (5H, m), 3.80-3.90 (1H, m), 4.15 (3H, m), 7.01 (1H, s), 7.04-7.10 (2H, m), 7.23 (1H, dd, J = 8.5, 2.0Hz), 7.42 (1H, d, J = 8.5Hz), 7.54 (1H, d, J = 2.0Hz).

Example 82

Yield 83%, 1H-NMR (CDCl3): δ1.26 (3H, t, J = 7Hz), 1.42 (3H, d, J = 6.5Hz), 2.25 (1H, dt, J = 12.5, 3.5Hz) , 2.33 (1H, dd, J = 11, 3.5Hz), 2.73 (1H, d, J = 11Hz), 2.93 (1H, d, J = 11Hz), 3.42-3.60 (3H, m), 3.62 (2H, s), 3.85-3.97 (1H, m), 4.16 (2H, q, J = 7Hz), 4.18-4.28 (1H, m), 7.18-7.35 (4H, m), 7.51 (1H, d, J = 8.5 Hz), 7.56 (1H, d, J = 8.5Hz), 7.84 (1H, s).

Example 83

Yield 72%, 1H-NMR (CDCl3): δ1.26 (3H, t, J = 7.0Hz), 1.42 (3H, d, J = 6.5Hz), 2.25 (1H, td, J = 11.5, 3.5Hz ), 2.34 (1H, dd, J = 11.5, 3.5Hz), 2.74 (1H, d, J = 11.5Hz), 2.93 (1H, d, J = 11.5Hz), 3.42-3.66 (5H, m), 3.91 (1H, d, J = 11.5Hz), 4.08-4.29 (3H, m), 7.16-7.35 (4H, m), 7.47-7.60 (2H, m), 7.84 (1H, s).

Example 84

Yield 74%, 1H-NMR (CDCl3): δ1.26 (3H, t, J = 7Hz), 1.42 (3H, d, J = 6.5Hz), 2.18-2.34 (2H, m), 2.35 (3H, s), 2.74 (1H, d, J = 11Hz), 2.92 (1H, d, J = 11.5Hz), 3.42 (1H, d, J = 13.5Hz), 3.53 (1H, td, J = 11.5, 3.5Hz ), 3.56 (1H, d, J = 13.5Hz), 3.58 (2H, s), 3.91 (1H, d, J = 12Hz), 4.15 (2H, q, J = 7Hz), 4.15-4.30 (1H, m ), 7.02 (1H, s), 7.07 (1H, s), 7.09 (1H, s), 7.51 (1H, d, J = 8.5Hz), 7.55 (1H, d, J = 8.5Hz), 7.84 (1H , s).

Example 85

Yield 69%, 1H-NMR (CDCl3): δ1.26 (3H, t, J = 7.0Hz), 1.43 (3H, d, J = 6.5Hz), 2.17-2.39 (5H, m), 2.70-2.79 (1H, m), 2.87-2.97 (1H, m), 3.43 (1H, d, J = 13.0Hz), 3.46-3.62 (4H, m), 3.85-3.97 (1H, m), 4.16 (2H, q , J = 7.0Hz), 4.17-4.29 (1H, m), 7.02 (1H, s), 7.05-7.11 (2H, m), 7.47-7.59 (2H, m), 7.84 (1H, s).

Example 86

Yield 86%, 1H-NMR (CDCl3): δ1.27 (3H, t, J = 7Hz), 1.43 (3H, d, J = 6.5Hz), 2.26 (1H, td, J = 12, 3.5Hz) , 2.36 (1H, dd, J = 11, 3.5Hz), 2.72 (1H, d, J = 11Hz), 2.91 (1H, d, J = 11Hz), 3.44 (1H, d, J = 13.5Hz), 3.52 (1H, td, J = 12.5, 3.5Hz), 3.55 (1H, d, J = 13.5Hz), 3.59 (2H, s), 3.86-3.96 (1H, m), 4.16 (2H, q, J = 7Hz ), 4.20-4.30 (1H, m), 7.17 (1H, s), 7.20 (1H, s), 7.29 (1H, s), 7.51 (1H, d, J = 8.5Hz), 7.56 (1H, d, J = 8.5Hz), 7.84 (1H, s).

Example 87

Yield 41%, 1H-NMR (CDCl3): δ0.87 (3H, t, J = 7.5Hz), 1.26 (3H, t, J = 7.0Hz), 1.80-2.02 (2H, m), 2.16-2.30 (2H, m), 2.79-2.94 (2H, m), 3.38-3.52 (2H, m), 3.54-3.65 (3H, m), 3.76-3.88 (1H, m), 3.94-4.06 (1H, m) , 4.15 (2H, q, J = 7.0Hz), 7.15-7.34 (5H, m), 7.39 (1H, d, J = 8.5Hz), 7.52 (1H, d, J = 2.0Hz).

Example 88

Yield 79%, 1H-NMR (CDCl3): δ0.87 (3H, t, J = 7.5Hz), 1.26 (3H, t, J = 7Hz), 1.85-2.00 (2H, m), 2.18-2.29 ( 2H, m), 2.80-2.84 (2H, m), 3.42 (1H, d, J = 13.5Hz), 3.44 (1H, td, J = 12.5, 3.5Hz), 3.59 (1H, d, J = 13.5Hz ), 3.62 (2H, s), 3.70-3.86 (1H, m), 3.95-4.05 (1H, m), 4.15 (2H, q, J = 7Hz), 7.15-7.33 (5H, m), 7.39 (1H , d, J = 8.5Hz), 7.52 (1H, d, J = 2Hz).

Example 89

Yield 25%, 1H-NMR (CDCl3): δ0.88 (3H, t, J = 7.5Hz), 1.26 (3H, t, J = 7Hz), 1.83-2.03 (2H, m), 2.22 (2H, td, J = 12.5, 3.5Hz), 2.34 (3H, s), 2.80-2.92 (2H, m), 3.38 (1H, d, J = 13.5Hz), 3.45 (1H, td, J = 12.5, 3.5Hz ), 3.55 (1H, d, J = 13.5Hz), 3.57 (2H, s), 3.75-3.88 (1H, m), 3.95-4.03 (1H, m), 4.15 (2H, q, J = 7Hz), 7.01 (1H, s), 7.05 (1H, s), 7.06 (1H, s), 7.21 (1H, dd, J = 8.5, 2Hz), 7.39 (1H, d, J = 8.5Hz), 7.52 (1H, d, J = 2Hz).

Example 90

Yield 67%, 1H-NMR (CDCl3): δ0.88 (3H, t, J = 7.5Hz), 1.26 (3H, t, J = 7.0Hz), 1.80-2.03 (2H, m), 2.22 (2H , td, J = 11.5, 3.5Hz), 2.34 (3H, s), 2.80-2.93 (2H, m), 3.38 (1H, d, J = 13.0Hz), 3.46 (1H, td, J = 12.5, 3.0 Hz), 3.56 (1H, d, J = 13.0Hz), 3.57 (2H, s), 3.76-3.87 (1H, m), 3.94-4.05 (1H, m), 4.15 (2H, q, J = 7.0Hz ), 7.01 (1H, s), 7.06 (2H, s), 7.22 (1H, dd, J = 8.5, 2.0Hz), 7.39 (1H, d, J = 8.5Hz), 7.52 (1H, d, J = 2.0Hz).

Example 91

Yield 80%, 1H-NMR (CDCl3): δ0.88 (3H, t, J = 7.5Hz), 1.26 (3H, t, J = 7Hz), 1.96 (2H, quant, J = 7.5Hz), 2.19 -2.30 (2H, m), 2.82-2.95 (2H, m), 3.44 (1H, d, J = 13.5Hz), 3.49 (1H, td, J = 12.5, 3.5Hz), 3.59 (1H, d, J = 13.5Hz), 3.62 (2H, s), 3.73-3.83 (1H, m), 4.00-4.10 (1H, m), 4.17 (2H, q, J = 7Hz), 7.15-7.33 (4H, m), 7.48-7.55 (2H, m), 7.82 (1H, s).

Example 92

Yield 53%, 1H-NMR (CDCl3): δ0.89 (3H, t, J = 7.5Hz), 1.20 (3H, t, J = 7Hz), 1.87-2.03 (2H, m), 2.24 (2H, td, J = 11, 3.5Hz), 2.34 (3H, s), 2.82-2.95 (2H, m), 3.38 (1H, d, J = 13Hz), 3.49 (1H, td, J = 13, 3.5Hz) , 3.56 (1H, d, J = 13Hz), 3.57 (2H, s), 3.80-3.95 (1H, m), 4.00-4.10 (1H, m), 4.16 (2H, q, J = 7Hz), 7.01 ( 1H, s), 7.05 (1H, s), 7.06 (1H, s), 7.48-7.55 (2H, m), 7.82 (1H, s).

Example 93

Yield 74%, 1H-NMR (CDCl3): δ0.90 (3H, t, J = 7.5Hz), 1.27 (3H, t, J = 7Hz), 1.94 (2H, quant, J = 7.5Hz), 2.20 -2.32 (2H, m), 2.80-2.93 (2H, m), 3.41 (1H, d, J = 13.5Hz), 3.49 (1H, td, J = 12.5, 3.5Hz), 3.55 (1H, d, J = 13.5Hz), 3.59 (2H, s), 3.85-3.95 (1H, m), 4.00-4.10 (1H, m), 4.17 (2H, q, J = 7Hz), 7.14 (1H, s), 7.20 ( 1H, s), 7.28 (1H, s), 7.45-7.56 (2H, m), 7.82 (1H, s).

Example 94

Yield 85%, 1H-NMR (CDCl3): δ0.88 (3H, t, J = 7.5Hz), 1.20 (3H, t, J = 7Hz), 1.94 (2H, quant, J = 7.5Hz), 2.19 -2.30 (2H, m), 2.80-2.95 (2H, m), 3.43 (1H, d, J = 13.5Hz), 3.51 (1H, td, J = 12.5, 3.5Hz), 3.59 (1H, d, J = 13.5Hz), 3.62 (2H, s), 3.80-3.95 (1H, m), 4.00-4.10 (1H, m), 4.15 (2H, q, J = 7Hz), 7.15-7.33 (4H, m), 7.50 (1H, d, J = 8.5Hz), 7.52 (1H, d, J = 8.5Hz), 7.82 (1H, s).

Example 95

Yield 73%, 1H-NMR (CDCl3): δ0.88 (3H, t, J = 7.5Hz), 1.26 (3H, t, J = 7Hz), 1.95 (2H, quant, J = 7.5Hz), 2.15 -2.28 (2H, m), 2.34 (3H, s), 2.82-2.93 (2H, m), 3.39 (1H, d, J = 13.5Hz), 3.48 (1H, td, J = 12.5, 3.5Hz), 3.55 (1H, d, J = 13.5Hz), 3.57 (2H, s), 3.80-3.95 (1H, m), 3.98-4.10 (1H, m), 4.15 (2H, q, J = 7Hz), 7.01 ( 1H, s), 7.06 (2H, s), 7.52 (2H, s), 7.82 (1H, s).

Example 96

Yield 67%, 1H-NMR (CDCl3): δ0.93 (3H, t, J = 7.5Hz), 1.19-1.35 (2H, m), 1.26 (3H, t, J = 7.0Hz), 1.73-2.00 (2H, m), 2.15-2.30 (2H, m), 2.81 (1H, d, J = 11.5Hz), 2.88 (1H, d, J = 11.0Hz), 3.42 (1H, d, J = 13.5Hz) , 3.46 (1H, td, J = 12.5, 3.5Hz), 3.58 (1H, d, J = 13.5Hz), 3.61 (2H, s), 3.84-4.05 (2H, m), 4.16 (2H, q, J = 7.0Hz), 7.14-7.34 (5H, m), 7.39 (1H, d, J = 8.5Hz), 7.52 (1H, d, J = 2.0Hz).

Example 97

Yield 64%, 1H-NMR (CDCl3): δ0.93 (3 H, t, J = 7.2 Hz), 1.21-1.31 (5 H, m), 1.78-1.96 (2 H, m), 2.19-2.28 (2 H, m), 2.81 (1 H, d, J = 11.4 Hz), 2.88 (1 H, d, J = 11.4 Hz), 3.42 (1 H, d, J = 13.2 Hz), 3.47 (1 H , td, J = 3.3, 12.6 Hz), 3.59 (1 H, d, J = 13.2 Hz), 3.62 (2 H, s), 3.90 (1 H, s), 4.00 (1 H, d, J = 12.6 Hz), 4.16 (2 H, q, J = 7.2 Hz), 7.19-7.33 (5 H, m), 7.39 (1 H, d, J = 8.4 Hz), 7.53 (1 H, d, J = 2.1 Hz )

Example 98

Yield 58%, 1H-NMR (CDCl3): δ0.34 (3H, t, J = 7.0Hz), 1.19-1.35 (2H, m), 1.26 (3H, t, J = 7.0Hz), 1.72-2.02 (2H, m), 2.15-2.29 (2H, m), 2.34 (3H, s), 2.81 (1H, d, J = 11.5Hz), 2.89 (1H, d, J = 11.5Hz), 3.37 (1H, d, J = 13.5Hz), 3.47 (1H, td, J = 13.5, 3.0Hz), 3.57 (1H, d, J = 13.5Hz), 3.57 (2H, s), 3.83-3.93 (1H, m), 3.94-4.04 (1H, m), 4.16 (2H, q, J = 7.0Hz), 7.01 (1H, s), 7.05 (2H, s), 7.22 (1H, dd, J = 8.5, 2.0Hz), 7.39 (1H, d, J = 8.5Hz), 7.52 (1H, d, J = 2.0Hz).

Example 99

Yield 68%, 1H-NMR (CDCl3): δ 0.94 (3 H, t, J = 7.5 Hz), 1.24-1.31 (5 H, m), 1.73-1.85 (1 H, m), 1.89-2.01 (1 H, m), 2.17-2.27 (2 H, m), 2.34 (3 H, s), 2.81 (1 H, d, J = 11.4 Hz), 2.88 (1 H, d, J = 11.1 Hz) , 3.37 (1 H, d, J = 13.5 Hz), 3.47 (1 H, dt, J = 3.3, 12.6 Hz), 3.57 (1 H, d, J = 13.5 Hz), 3.57 (2 H, s), 3.89 (1 H, s), 3.99 (1 H, d, J = 12.0 Hz), 4.16 (2 H, q, J = 7.2 Hz), 7.01 (1 H, s), 7.06 (2 H, s), 7.22 (1 H, dd, J = 2.1, 8.4 Hz), 7.39 (1 H, d, J = 8.4 Hz), 7.52 (1 H, d, J = 2.1 Hz)

Example 100

Yield 69%, 1H-NMR (CDCl3): δ0.93 (3H, t, J = 7.0Hz), 1.18-1.35 (2H, m), 1.26 (3H, t, J = 7.0Hz), 1.76-1.99 (2H, m), 2.16-2.29 (2H, m), 2.82 (1H, d, J = 11.5Hz), 2.89 (1H, d, J = 11.5Hz), 3.42 (1H, d, J = 13.5Hz) , 3.49 (1H, td, J = 13.0, 3.5Hz), 3.59 (1H, d, J = 13.5Hz), 3.62 (2H, s), 3.90-4.09 (2H, m), 4.16 (2H, q, J = 7.0Hz), 7.15-7.34 (4H, m), 7.49 (1H, d, J = 8.5Hz), 7.53 (1H, d, J = 8.5Hz), 7.81 (1H, s).

Example 101

Yield 80%, 1H-NMR (CDCl3): δ 0.94 (3 H, t, J = 7.2 Hz), 1.24-1.31 (5 H, m), 1.83-1.91 (2 H, m), 2.20-2.29 (2 H, m), 2.83 (1 H, d, J = 11.4 Hz), 2.90 (1 H, d, J = 11.4 Hz), 3.34 (1 H, d, J = 13.5 Hz), 3.50 (1 H , td, J = 3.6, 12.6 Hz), 3.60 (1 H, d, J = 13.5 Hz), 3.62 (2 H, s), 3.97 (1 H, s), 4.05 (1 H, d, J = 12.6 Hz), 4.16 (2 H, q, J = 7.2 Hz), 7.19-7.33 (4 H, m), 7.51 (2 H, s), 7.82 (1 H, s)

Example 102

Yield 79%, 1H-NMR (CDCl3): δ0.87 (3H, t, J = 7Hz), 1.15-1.40 (7H, m), 1.74-2.00 (2H, m), 2.17-2.29 (2H, m ), 2.77-2.94 (2H, m), 3.41 (1H, d, J = 13.5Hz), 3.46 (1H, td, J = 13, 3.5Hz), 3.59 (1H, d, J = 13.5Hz), 3.61 (2H, s), 3.80-3.93 (1H, m), 3.95-4.08 (1H, m), 4.16 (2H, q, J = 7Hz), 7.15-7.32 (5H, m), 7.39 (1H, d, J = 9Hz), 7.52 (1H, d, J = 2Hz).

Example 103

Yield 75%, 1H-NMR (CDCl3): δ0.87 (3H, t, J = 7Hz), 1.15-1.40 (7H, m), 1.76-2.01 (2H, m), 2.20-2.30 (2H, m ), 2.77-2.93 (2H, m), 3.42 (1H, d, J = 13.5Hz), 3.46 (1H, td, J = 13, 3.5Hz), 3.59 (1H, d, J = 13.5Hz), 3.61 (2H, s), 3.80-3.92 (1H, m), 3.95-4.06 (1H, m), 4.16 (2H, q, J = 7Hz), 7.16-7.33 (5H, m), 7.39 (1H, d, J = 9Hz), 7.52 (1H, d, J = 2Hz).

Example 104

Yield 75%, 1H-NMR (CDCl3): δ0.88 (3H, t, J = 7Hz), 1.15-1.40 (7H, m), 1.75-2.03 (2H, m), 2.17-2.30 (2H, m ), 2.34 (3H, s), 2.80-2.96 (2H, m), 3.37 (1H, d, J = 13.5Hz), 3.50 (1H, td, J = 13, 3.5Hz), 3.57 (2H, s) , 3.58 (1H, d, J = 13.5Hz), 3.85-4.00 (1H, m), 4.00-4.10 (1H, m), 4.15 (2H, q, J = 7Hz), 7.01 (1H, s), 7.05 (1H, s), 7.07 (1H, s), 7.45-7.55 (2H, m), 7.82 (1H, s).

Example 105

Yield 44%, 1H-NMR (CDCl3): δ 0.90 (3H, d, J = 6.5Hz), 0.91 (3H, d, J = 6.5Hz), 1.26 (3H, t, J = 7.0Hz), 2.12 (1H, dd, J = 11.5, 3.5Hz), 2.23 (1H, td, J = 11.5, 3.5Hz), 2.34 (3H, s), 2.56-2.72 (1H, m), 2.88 (1H, d, J = 11.5Hz), 2.98 (1H, d, J = 11.5Hz), 3.34 (1H, d, J = 13.0Hz), 3.40-3.65 (2H, m), 3.56 (1H, d, J = 13.0Hz) , 3.57 (2H, s), 4.08-4.22 (1H, m), 4.15 (2H, q, J = 7.0Hz), 7.01 (1H, s), 7.05 (2H, s), 7.49 (2H, s), 7.79 (1H, s).

Example 106

Yield 70%, 1H-NMR (CDCl3): δ0.90 (3H, d, J = 2.5Hz), 0.91 (3H, d, J = 2.5Hz), 1.26 (3H, t, J = 7Hz), 2.12 (1H, dd, J = 11.5, 3.5Hz), 2.23 (1H, td, J = 11.5, 3.5Hz), 2.34 (3H, s), 2.55-2.73 (1H, m), 2.88 (1H, d, J = 9.5Hz), 2.98 (1H, d, = 9.5Hz), 3.34 (1H, d, J = 13Hz), 3.40-3.54 (1H, m), 3.56 (1H, d, J = 13Hz), 3.57 (2H , s), 3.57-3.60 (1H, m), 4.11-4.15 (1H, m), 4.16 (2H, q, J = 7Hz), 7.01 (1H, s), 7.04 (1H, s), 7.05 (1H , s), 7.49-7.50 (2H, m), 7.79 (1H, s).

Example 107

Yield 73%, 1H-NMR (CDCl3): δ0.93 (6H, d, J = 6.5Hz), 1.26 (3H, t, J = 7.0Hz), 1.32-1.53 (1H, m), 1.54-1.67 (1H, m), 1.85-1.98 (1H, m), 2.24 (2H, td, J = 11.5, 3.5Hz), 2.79 (1H, d, J = 11.5Hz), 2.89 (1H, d, J = 11.5 Hz), 3.40 (1H, d, J = 13.5Hz), 3.47 (1H, td, J = 13.0, 3.5Hz), 3.61 (1H, d, J = 13.5Hz), 3.61 (2H, s), 3.88- 4.08 (2H, m), 4.16 (2H, q, J = 7.0Hz), 7.15-7.33 (5H, m), 7.39 (1H, d, J = 8.5Hz), 7.53 (1H, d, J = 2.0Hz ).

Example 108

Yield 81%, 1H-NMR (CDCl3): δ0.93 (6H, d, J = 6.5Hz), 1.26 (3H, t, J = 7Hz), 1.38-1.47 (1H, m), 1.55-1.67 ( 1H, m), 1.85-1.96 (1H, m), 2.19-2.30 (2H, m), 2.78 (1H, d, J = 11.5Hz), 2.88 (1H, d, J = 11.5Hz), 3.40 (1H , d, J = 13.5Hz), 3.47 (1H, td, J = 13, 3.5Hz), 3.60 (1H, d, J = 13.5Hz), 3.61 (2H, s), 3.90-4.08 (2H, m) , 4.15 (2H, q, J = 7Hz), 7.15-7.35 (5H, m), 7.39 (1H, d, J = 8.5Hz), 7.53 (1H, d, J = 2Hz).

Example 109

Yield 63%, 1H-NMR (CDCl3): δ0.93 (3H, d, J = 6.5Hz), 0.94 (3H, d, J = 6.5Hz), 1.26 (3H, t, J = 7.0Hz), 1.36-1.64 (2H, m), 1.88-2.02 (1H, m), 2.13-2.44 (2H, m), 2.34 (3H, s), 2.79 (1H, d, J = 11.0Hz), 2.89 (1H, d, J = 11.0Hz), 3.35 (1H, d, J = 13.5Hz), 3.41-3.68 (2H, m), 3.57 (2H, s), 3.86-4.09 (2H, m), 4.16 (2H, q , J = 7.0Hz), 7.01 (1H, s), 7.04 (1H, s), 7.06 (1H, s), 7.22 (1H, dd, J = 8.5, 2.0Hz), 7.39 (1H, d, J = 8.5Hz), 7.53 (1H, d, J = 2.0Hz).

Example 110

Yield 81%, 1H-NMR (CDCl3): δ0.92 (3H, d, J = 3Hz), 0.95 (3H, d, J = 3Hz), 1.26 (3H, t, J = 7Hz), 1.39-1.65 (2H, m), 1.90-2.02 (1H, m), 2.15-2.32 (2H, m), 2.34 (3H, s), 2.78 (1H, d, J = 11.5Hz), 2.89 (1H, d, J = 11.5Hz), 3.35 (1H, d, J = 13.5Hz), 3.48 (1H, td, J = 13, 3.5Hz), 3.57 (2H, s), 3.59 (1H, d, J = 13.5Hz), 3.86-4.08 (2H, m), 4.15 (2H, q, J = 7Hz), 7.01 (1H, s), 7.04 (1H, s), 7.06 (1H, s), 7.21 (1H, dd, J = 8.5 , 2Hz), 7.39 (1H, d, J = 8.5Hz), 7.53 (1H, d, J = 2Hz).

Example 111

Yield 47%, 1H-NMR (CDCl3): δ0.94 (3H, d, J = 6.5Hz), 0.95 (3H, d, J = 6.5Hz), 1.27 (3H, t, J = 7.0Hz), 1.38-1.67 (2H, m), 1.89-2.04 (1H, m), 2.14-2.38 (2H, m), 2.34 (3H, s), 2.80 (1H, d, J = 11.5Hz), 2.90 (1H, d, J = 11.5Hz), 3.35 (1H, d, J = 13.5Hz), 3.44-3.64 (2H, m), 3.57 (2H, s), 3.94-4.21 (2H, m), 4.16 (2H, q , J = 7.0Hz), 7.01 (1H, s), 7.06 (2H, s), 7.49 (1H, d, J = 8.5Hz), 7.53 (1H, d, J = 8.5Hz), 7.82 (1H, s ).

Example 112

Yield 80%, 1H-NMR (CDCl3): δ0.94 (6 H, dd, J = 3.0, 6.3 Hz), 1.26 (3 H, t, J = 7.2 Hz), 1.44-1.48 (1 H, m ), 1.56-1.62 (1 H, m), 1.91-2.00 (1 H, m), 2.18-2.26 (2 H, m), 2.34 (3 H, s), 2.80 (1 H, d, J = 11.4 Hz), 2.91 (1 H, d, J = 11.4 Hz), 3.36 (1H, d, J = 13.2 Hz), 3.52 (1 H, dt, J = 3.6, 12.6 Hz), 3.57 (2 H, s) , 3.60 (1H, d, J = 13.2Hz), 4.04 (2 H, br), 4.16 (2 H, q, J = 7.2 Hz), 7.01 (1 H, s), 7.04 (1 H, s), 7.06 (1 H, s), 7.2 (2 H, s), 7.83 (1 H, s)

Example 113

Yield 69%, 1H-NMR (CDCl3): δ1.26 (3H, t, J = 7.0Hz), 2.59 (4H, t, J = 5.0Hz), 3.57 (2H, s), 3.62 (2H, s ), 3.68 (4H, t, J = 5.0Hz), 4.16 (2H, q, J = 7.0Hz), 7.18-7.34 (5H, m), 7.75 (1H, d, J = 7.0Hz).

Example 114

Yield 72%, 1H-NMR (CDCl3): δ1.26 (3H, t, J = 7.0Hz), 2.34 (3H, s), 2.58 (4H, t, J = 5.0Hz), 3.52 (2H, s ), 3.58 (2H, s), 3.68 (4H, t, J = 5.0Hz), 4.16 (2H, q, J = 7.0Hz), 7.00-7.12 (3H, m), 7.26 (1H, d, J = 11.5Hz), 7.75 (1H, d, J = 7.0Hz).

Example 115

Yield 41%, 1H-NMR (CDCl3): δ1.25 (3H, t, J = 7.0Hz), 1.96-2.08 (2H, m), 2.32 (3H, s), 2.69 (2H, t, J = 5.0Hz), 2.75-2.85 (2H, m), 3.56 (2H, s), 3.60 (2H, s), 3.61-3.89 (4H, m), 4.15 (2H, q, J = 7.0Hz), 6.50- 7.07 (3H, m), 7.26 (1H, d, J = 12.0Hz), 7.73 (1H, d, J = 7.0Hz).

Example 116

Yield 80%, 1H-NMR (CDCl3): δ1.23 (3H, d, J = 6Hz), 1.26 (3H, t, J = 7Hz), 2.23-2.33 (1H, m), 2.34 (3H, s ), 2.69-2.70 (1H, m), 2.82 (1H, dt, J = 12, 4Hz), 3.17 (1H, d, J = 13Hz), 3.18-3.26 (1H, m), 3.36-3.48 (1H, m), 3.58 (2H, s), 3.70-3.80 (1H, m), 3.85-3.95 (1H, m), 4.02 (1H, d, J = 13Hz), 4.13 (2H, q, J = 7Hz), 7.01 (1H, s), 7.04 (1H, s), 7.05 (1H, s), 7.26 (1H, d, J = 12Hz), 7.73 (1H, d, J = 7Hz).

Example 117

Yield 63%, 1H-NMR (CDCl3): δ1.26 (3H, t, J = 7.0Hz), 1.43 (3H, d, J = 7.0Hz), 2.17-2.37 (2H, m), 2.34 (3H , s), 2.71-2.79 (1H, m), 2.87-2.98 (1H, m), 3.43 (1H, d, J = 13.0Hz), 3.46-3.60 (2H, m), 3.58 (2H, s), 3.83-3.94 (1H, m), 4.15-4.28 (1H, m), 4.16 (2H, q, J = 7.0Hz), 7.02 (1H, s), 7.06 (1H, s), 7.08 (1H, s) , 7.26 (1H, d, J = 11.5Hz), 7.74 (1H, d, J = 7.0Hz).

Example 118

Yield 60%, 1H-NMR (CDCl3): δ1.26 (3H, t, J = 7.0Hz), 1.43 (3H, d, J = 7.0Hz), 2.16-2.36 (2H, m), 2.34 (3H , s), 2.70-2.79 (1H, m), 2.87-2.98 (1H, m), 3.43 (1H, d, J = 13.0Hz), 3.45-3.61 (4H, m), 3.84-3.94 (1H, m ), 4.14-4.28 (1H, m), 4.16 (2H, q, J = 7.0Hz), 7.01 (1H, s), 7.04-7.12 (2H, m), 7.26 (1H, d, J = 11.5Hz) , 7.74 (1H, d, J = 7.0Hz).

Example 119

Yield 90%, 1H-NMR (CDCl3): δ0.87 (3H, t, J = 7.5Hz), 1.25 (3H, t, J = 7.0Hz), 1.82-2.03 (2H, m), 2.14-2.53 (2H, m), 2.33 (3H, s), 2.78-2.93 (2H, m), 3.37 (1H, d, J = 13.5Hz), 3.45 (1H, td, J = 12.5, 3.5Hz), 3.55 ( 1H, d, J = 13.5Hz), 3.57 (2H, s), 3.76-3.88 (1H, m), 3.90-4.03 (1H, m), 4.15 (2H, q, J = 7.0Hz), 7.00 (1H , s), 7.03-7.09 (2H, m), 7.24 (1H, d, J = 10.5Hz), 7.49 (1H, d, J = 7.0Hz).

Example 120

Yield 18%, 1H-NMR (CDCl3): δ 1.20 (3H, d, J = 6.5Hz), 1.25 (3H, t, J = 7.0Hz), 1.36 (3H, d, J = 6.5Hz), 2.15 (1H, td, J = 12.0, 3.5Hz), 2.60-2.72 (1H, m), 2.74-2.84 (1H, m), 2.98 (1H, d, J = 13.5Hz), 3.40 (1H, td, J = 12.5, 3.5Hz), 3.62 (2H, s), 3.67-3.81 (1H, m), 4.03-4.22 (4H, m), 7.13-7.34 (4H, m), 7.50 (1H, dd, J = 8.5, 1.5Hz), 7.55 (1H, d, J = 8.5Hz), 7.82 (1H, d, J = 1.5Hz).

Example 121

Yield 73%, 1H-NMR (CDCl3): δ1.26 (3H, t, J = 7.0Hz), 2.58 (4H, t, J = 5.0Hz), 3.54 (4H, t, J = 5.0Hz), 3.56 (2H, s), 3.62 (2H, s), 4.16 (2H, q, J = 7.0Hz), 7.17-7.24 (2H, m), 7.25-7.37 (5H, m), 7.39-7.45 (2H, m), 7.40 (1H, s).

Example 122

Yield 56%, 1H-NMR (CDCl3): δ1.26 (3H, t, J = 7.0Hz), 2.61 (4H, t, J = 5.0Hz), 3.57 (2H, s), 3.63 (2H, s ), 3.81 (4H, t, J = 5.0), 4.16 (2H, q, J = 7.0Hz), 7.14-7.34 (4H, m), 7.35-7.43 (1H, m), 7.53-7.62 (1H, m ), 7.68 (1H, dd, J = 8.0, 1.5Hz), 7.87 (1H, dd, J = 8.0, 1.5Hz), 8.57 (1H, s).

Example 123

Yield 70%, 1H-NMR (CDCl3): δ1.26 (3H, t, J = 7.0Hz), 2.58 (4H, t, J = 5.0Hz), 3.56 (2H, s), 3.62 (2H, s ), 3.65 (4H, t, J = 5.0Hz), 4.16 (2H, q, J = 7.0Hz), 7.07 (1H, t, J = 7.5Hz), 7.16-7.34 (5H, m), 7.55 (1H , d, J = 8.0Hz), 7.59 (1H, d, J = 8.0Hz).

Example 124

Yield 66%, 1H-NMR (CDCl3): δ1.26 (3H, t, J = 7.0Hz), 2.59 (4H, t, J = 5.0Hz), 3.57 (2H, s), 3.63 (2H, s ), 3.76 (4H, t, J = 5.0Hz), 4.16 (2H, q, J = 7.0Hz), 6.97 (1H, d, J = 9.0Hz), 7.17-7.38 (5H, m), 7.48-7.64 (2H, m), 7.69 (1H, d, J = 8.5Hz), 7.88 (1H, d, J = 9.0Hz).

Example 125

Yield 88%, 1H-NMR (CDCl3): δ1.26 (3H, t, J = 7.0Hz), 2.60 (4H, t, J = 5.0Hz), 3.57 (2H, s), 3.63 (2H, s ), 3.80 (4H, t, J = 5.0Hz), 4.16 (2H, q, J = 7.0Hz), 7.16-7.35 (4H, m), 7.50 (1H, dd, J = 90, 2.5Hz), 7.59 (1H, d, J = 9.0Hz), 7.85 (1H, d, J = 2.5Hz), 8.55 (1H, s).

Example 126

Yield 80%, 1H-NMR (CDCl3): δ1.26 (3H, t, J = 7.0Hz), 1.39 (3H, d, J = 7.0Hz), 2.20 (1H, t, J = 11.5, 3.5Hz ), 2.25-2.37 (4H, m), 2.82 (1H, d, J = 11.5Hz), 3.00 (1H, d, J = 11.5Hz), 3.31-3.46 (2H, m), 3.53-3.63 (3H, m), 4.16 (2H, q, J = 7.0Hz), 4.33-4.43 (1H, m), 4.64-4.77 (1H, m), 7.02 (1H, s), 7.09 (1H, s), 7.11 (1H , s), 7.70 (2H, s), 8.14 (1H, s), 8.58 (1H, s).

Example 127

Yield 90%, 1H-NMR (CDCl3): δ1.26 (3H, t, J = 7.0Hz), 2.66 (4H, t, J = 5.0Hz), 2.70 (3H, s), 3.47 (4H, t , J = 5.0Hz), 3.60 (2H, s), 3.63 (2H, s), 4.16 (2H, q, J = 7.0Hz), 7.16-7.34 (4H, m), 7.74 (1H, d, J = 8.5Hz), 7.87 (1H, d, J = 8.5Hz), 8.16 (1H, s).

[3-(メトキシメトキシ)-4-メチル]ベンジルアルコール（国際公開第２００４／０２２５５１号パンフレットの参考例68に記載）1.23g（6.75 mmol）、トリエチルアミン0.55ml（7.09mmol）及びTHF 12mlの混合物に氷冷下、メタンスルホニルクロリド0.55ml（7.09mmol）を滴下した後、1時間撹拌した。反応液を減圧下濃縮した後、残渣に4-(6-クロロベンゾチアゾール-2-イル)ピペラジン2塩酸塩 2.10g（6.43 mmol）、炭酸カリウム2.67g（19.3mmol）及び無水N,N-ジメチルホルムアミド20mlを加え、室温下14時間撹拌した。反応液に水を加え、析出結晶を濾取後、ジイソプロピルエーテルで洗浄し6-クロロ-2-[4-(3-メトキシメトキシ-4-メチルベンジル)ピペラジン-1-イル]ベンゾチアゾールを無色結晶として1.70g（63％）得た。
¹H-NMR(CDCl₃): δ2.24 (3H, s), 2.57 (4H, t, J=5Hz), 3.50 (3H, s), 3.52 (2H, s), 3.63 (4H, t, J=5Hz), 5.22 (2H, s), 6.89 (1H, d, J=7.5Hz), 7.03 (1H, s), 7.10 (1H, d, J=7.5Hz), 7.23 (1H, dd, J=8.5, 2Hz), 7.45 (1H, d, J=8.5Hz), 7.59 (1H, d, J=2Hz).

実施例１２９
3-[4-[(6-クロロベンゾチアゾール-2-イル)ピペラジン-1-イル]メチル]ベンジルアルコールの製造

水素化リチウムアルミニウム0.52g（13.7mmol）の無水THF 27mlの懸濁液に氷冷下、3-[[4-(6-クロロベンゾチアゾール-2-イル)ピペラジン-1-イル]メチル]安息香酸メチル2.76g（6.87mmol）の無水THF（27ml）溶液を滴下した。室温下1時間撹拌後、氷冷下、水0.25ml及びTHF5ml混合液及び2N-水酸化ナトリウム水溶液0.5mlを順次滴下後、室温下1時間撹拌した。水酸化アルミニウムを濾去した後、濾液を減圧下濃縮した。残渣に酢酸エチル及び飽和食塩水を加え分液した後、有機層を無水硫酸ナトリウムで乾燥した。減圧下溶媒を留去し、黄色結晶を得た。ジイソプロピルエーテルで洗浄後、3-[4-[(6-クロロベンゾチアゾール-2-イル)ピペラジン-1-イル]メチル]ベンジルアルコールを淡黄色結晶として2.35g（92％）得た。
¹H-NMR(CDCl₃): 1.83 (1H, t, J=5.5Hz), 2.57 (4H, t, J=5Hz), 3.51 (2H, s), 3.63 (4H, t, J=5Hz), 4.71 (2H, d, J=5.5Hz), 7.23 (1H, dd, J=8.5, 2Hz), 7.25-7.38 (4H, m), 7.42 (1H, d, J=8.5Hz), 7.55 (1H, d. J=2Hz). Example 128
Preparation of 6-chloro-2- [4- (3-methoxymethoxy-4-methylbenzyl) piperazin-1-yl] benzothiazole

[3- (methoxymethoxy) -4-methyl] benzyl alcohol (described in Reference Example 68 of WO 2004/022551 pamphlet) 1.23 g (6.75 mmol), triethylamine 0.55 ml (7.09 mmol) and THF 12 ml in a mixture Under ice cooling, 0.55 ml (7.09 mmol) of methanesulfonyl chloride was added dropwise, followed by stirring for 1 hour. After the reaction solution was concentrated under reduced pressure, 4- (6-chlorobenzothiazol-2-yl) piperazine dihydrochloride 2.10 g (6.43 mmol), potassium carbonate 2.67 g (19.3 mmol) and anhydrous N, N-dimethyl were added to the residue. 20 ml of formamide was added and stirred at room temperature for 14 hours. Water was added to the reaction solution, and the precipitated crystals were collected by filtration and washed with diisopropyl ether to give 6-chloro-2- [4- (3-methoxymethoxy-4-methylbenzyl) piperazin-1-yl] benzothiazole as colorless crystals. 1.70 g (63%) was obtained.
¹ H-NMR (CDCl ₃ ): δ2.24 (3H, s), 2.57 (4H, t, J = 5Hz), 3.50 (3H, s), 3.52 (2H, s), 3.63 (4H, t, J = 5Hz), 5.22 (2H, s), 6.89 (1H, d, J = 7.5Hz), 7.03 (1H, s), 7.10 (1H, d, J = 7.5Hz), 7.23 (1H, dd, J = 8.5, 2Hz), 7.45 (1H, d, J = 8.5Hz), 7.59 (1H, d, J = 2Hz).

Example 129
Preparation of 3- [4-[(6-chlorobenzothiazol-2-yl) piperazin-1-yl] methyl] benzyl alcohol

3-[[4- (6-Chlorobenzothiazol-2-yl) piperazin-1-yl] methyl] benzoic acid in a suspension of 0.52 g (13.7 mmol) of lithium aluminum hydride in 27 ml of anhydrous THF under ice-cooling A solution of 2.76 g (6.87 mmol) of methyl in anhydrous THF (27 ml) was added dropwise. After stirring at room temperature for 1 hour, 0.25 ml of water and 5 ml of THF and 0.5 ml of 2N-sodium hydroxide aqueous solution were successively added dropwise under ice cooling, followed by stirring at room temperature for 1 hour. After aluminum hydroxide was removed by filtration, the filtrate was concentrated under reduced pressure. Ethyl acetate and saturated brine were added to the residue for liquid separation, and the organic layer was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain yellow crystals. After washing with diisopropyl ether, 2.35 g (92%) of 3- [4-[(6-chlorobenzothiazol-2-yl) piperazin-1-yl] methyl] benzyl alcohol was obtained as pale yellow crystals.
¹ H-NMR (CDCl ₃ ): 1.83 (1H, t, J = 5.5Hz), 2.57 (4H, t, J = 5Hz), 3.51 (2H, s), 3.63 (4H, t, J = 5Hz), 4.71 (2H, d, J = 5.5Hz), 7.23 (1H, dd, J = 8.5, 2Hz), 7.25-7.38 (4H, m), 7.42 (1H, d, J = 8.5Hz), 7.55 (1H, d.J = 2Hz).

収率：100％, ¹H-NMR(CDCl₃); δ1.65 (1H, brs), 1.98-2.05 (2H, m), 2.70 (2H, t, J=5.1Hz), 2.79-2.82 (2H, m), 3.65 (2H, s), 3.71-3.77 (4H, m), 4.69 (2H, s), 7.23 (1H, dd, J=8.7Hz, 2.4Hz), 7.26-7.34 (4H, m), 7.43 (1H, d, J=8.4Hz), 7.55 (1H, d, J=2.1Hz).

実施例１３１

収率：100％, ¹H-NMR(CDCl₃); δ1.26 (1H, brs), 2.59 (4H, t, J=5Hz), 3.58 (2H, s), 3.68 (4H, t, J=5Hz), 4.72 (2H, s), 7.20-7.40 (4H, m), 7.50-7.60 (2H, m), 7.84 (1H, s).

実施例１３２

収率：60％,¹H-NMR(DMSO-d₆): δ1.88-1.99 (2H, m), 2.58-2.67 (2H, m), 2.74-2.84 (2H, m), 3.62 (2H,s),3.63-3.85(4H,m),4.47(2H,d, J=5.5Hz), 5.16 (1H, t, J=5.5Hz), 7.13-7.20 (2H, m), 7.22-7.30 (2H, m), 7.52-7.57 (2H, m), 8.22 (1H, s).

実施例１３３

収率：96％¹H-NMR(CDCl₃); δ1.41 (3H, d, J=6.5Hz), 1.63 (1H, brs), 2.25 (1H, td, J=11.5, 3.5Hz), 2.33 (1H, dd, J=11.5, 3.5Hz), 2.72 (1H, d, J=11.5Hz), 2.86-2.95 (1H, m), 3.47 (1H, td, J=12.5, 3.5Hz), 3.48 (1H, d, J=13.5Hz), 3.60 (1H, d, J=13.5Hz), 3.85 (1H, d, J=12.5Hz), 4.10-4.25 (1H, m), 4.72 (2H, s), 7.22 (1H, dd, J=8.5, 2Hz), 7.25-7.40 (4H, m), 7.42 (1H, d, J=8.5Hz), 7.54 (1H, d, J=2Hz).

実施例１３４

収率：98％, ¹H-NMR(CDCl₃); δ1.23 (3H, d, J=6.5Hz), 1.55-1.70 (1H, m), 2.22-2.32 (1H, m), 2.60-2.70 (1H, m), 2.75-2.85 (1H, m), 3.10-3.20 (1H, m), 3.22 (1H, d, J=13.5Hz), 3.35-3.45 (1H, m ), 3.65-3.75 (1H, m), 3.83-3.90 (1H, m), 4.06 (1H, d, J=13.5Hz), 4.71 (2H, s), 7.20-7.35 (5H, m), 7.42 (1H, d, J=8.5Hz), 7.54 (1H, d, J=2Hz).

実施例１３５

収率：q.y., ¹H-NMR(CDCl₃); δ1.12 (6H, d, J=6Hz), 1.64 (1H, brs), 2.75-2.85 (2H, m), 3.05 (2H, dd, J=13, 12.5Hz), 3.85 (2H, s), 3.80-3.90 (2H, m), 4.70 (2H, s), 7.23 (1H, dd, J=8.5, 2Hz), 7.25-7.28 (1H, m), 7.30-7.35 (2H, m), 7.38 (1H, s), 7.42 (1H, d, J=8.5Hz), 7.55 (1H, d, J=2Hz).

実施例１３６

収率：q.y.,¹H-NMR(CDCl₃); δ1.08 (3H, d, J=6.5 Hz), 1.38 (3H, d, J=6.5Hz), 1.74 (1H, brs), 2.33 (1H, d, J=11.5Hz), 2.89 (1H, dd, J=11.5, 4Hz), 3.06-3.19 (1H,m), 3.53 (1H, d, J=14.5Hz), 3.60-3.75 (3H, m), 4.15-4.28 (1H, m), 4.70 (2H, s), 7.21 (1H, dd, J=8.5, 2Hz), 7.25-7.35 (4H, m), 7.40 (1H, d, J=8.5Hz), 7.53 (1H, d, J=2Hz).

実施例１３７

収率：60％, ¹H-NMR(CDCl₃); δ1.71 (1H, brs), 2.38 (3H, s), 2.58 (4H, t, J=5Hz), 3.52 (2H, s), 3.61 (4H,t,J=5Hz), 4.67 (2H, s), 7.15 -7.20 (2H, m), 7.23 (1H, dd, J=8.5, 2Hz), 7.25-7.28 (1H, m), 7.43 (1H, d, J=8.5Hz),7.55 (1H, d, J=2Hz).

実施例１３８

収率：39％,¹H-NMR(CDCl₃); δ1.80 (1H, brs), 2.65 (4H,t,J=5Hz),3.65 (4H, t, J=5Hz), 3.68 (2H, s), 4.70 (2H, s), 7.23 (1H, dd, J=8,2Hz), 7.24 (1H, dd, 8.5, 2Hz), 7.36 (1H, d, J=8Hz), 7.42 (1H, d, J=8.5 Hz), 7.48 (1H, d, J=2Hz), 7.55 (1H, d, J=2Hz).

実施例１３９

収率：92％,¹H-NMR(CDCl₃); δ1.66-1.73, (1H, br-s), 1.97-2.04 (2H, m), 2.33 (3H, s), 2.69 (2H, t, J=5.4Hz), 2.78-2.81 (2H, m), 3.59 (2H, s), 3.70-3.75 (4H, m), 4.65 (2H, s), 7.16-7.17 (2H, m), 7.23 (1H, dd, J=8.7Hz, 2.1Hz), 7.28 (1H, s), 7.43 (1H, d, J=8.7Hz), 7.55 (1H, d, J=2.4Hz).

実施例１４０

収率：100％, ¹H-NMR(CDCl₃); δ1.70-1.88 (1H, br-s), 1.98-2.07 (2H, m), 2.75 (2H, t, J= 5.4Hz), 2.84-2.89 (2H, m), 3.72-3.84 (6H, m), 4.68 (2H, s), 7.17-7.25 (2H, m), 7.33 (1H, d, J=8.1Hz), 7.44 (1H, d, J=8.1Hz), 7.50 ( 1H, d, J=2.1Hz), 7.55 (1H, d, J =2.4Hz).

実施例１４１

収率：30％, ¹H-NMR(CDCl₃); δ1.90 (1H, brs), 2.62(4H,t,J=5Hz),3.64(4H,t,J=5Hz), 3.74 (2H, s), 4.79 (2H, s), 6.79 (1H, d, J=3.5Hz), 6.85 (1H, d, J=3.5Hz), 7.23 (1H, dd, J=8.5, 2Hz), 7.43 (1H, d, J=8.5Hz), 7.55 (1H, d, J=2Hz).

実施例１４２

収率：80％, ¹H-NMR(CDCl₃); δ1.86 (1H, s), 2.00-2.07 (2H, m), 2.71-2.74 (2H, m), 2.84-2.87 (2H, m), 3.73 (2H, t, J=6.0Hz), 3.77-3.80 (2H, m), 3.82 (2H, s), 4.78 (2H, s), 6.76 (1H, d, J =3.3Hz), 6.84 (1H, d, J =3.3Hz), 7.23 (1H, dd, J=8.7, 2.4Hz), 7.42 (1H, d, J=9.0Hz), 7.55 (1H, d, J =2.4Hz).

実施例１４３

収率：90％, ¹H-NMR(CDCl₃); δ1.81 (1H, brs), 2.36 (3H, s), 2.57 (4H, t, J=5Hz), 3.53 (2H, s), 3.63 (4H, t, J=5Hz), 4.67 (2H, s), 7.08 (1H, s), 7.11 (1H, s), 7.13 (1H, s), 7.23 (1H, dd, J=8.5, 2Hz),7.43(1H,d,J=8.5Hz),7.55 (1H, d, J=2Hz).

実施例１４４

収率：q. y, ¹H-NMR(CDCl₃); δ1.79 (1H, t, J=4.5Hz), 2.36 (3H, s), 2.59 (4H, t, J=5Hz), 3.54 (2H, s), 3.68 (4H, t, J=5Hz), 4.67 (2H, d, J=4.5Hz), 7.09 (1H, s), 7.11 (1H, s), 7.14 (1H, s), 7.45-7.60 (2H, m), 7.84 (1H, s).

実施例１４５

収率：93％, ¹H-NMR(CDCl₃); δ1.70 (1H, s), 1.99-2.06 (2H, m), 2.35 (3H, s), 2.70 (2H, t, J=5.4Hz), 2.79-2.82 (2H, m), 3.61 (2H, s), 3.71-3.77 (4H, m), 4.65 ( 2H, s), 7.07 (1H, s), 7.09 (1H, s), 7.13 (1H, s), 7.23 (1H, dd, J=8.7Hz, J=2.1Hz ), 7.43 (1H,d, J =8.7Hz), 7.55 (1H, d, J =2.1Hz).

実施例１４６

収率：q. y, ¹H-NMR(CDCl₃); δ1.77 (1H, brs), 1.95-2.10 (2H, m), 2.34 (3H, s), 2.68 (2H, t, J=5.5Hz), 2.82 (2H, t, J=5.5Hz), 3.61 (2H, s), 3.70-3.85 (4H, m), 4.65 (2H, s), 7.06 (1H, s), 7.08 (1H, s), 7.13 (1H, s), 7.45-7.60 (2H, m), 7.84 (1H, s).

実施例１４７

収率：80％,¹H-NMR(DMSO-d₆): δ1.59 (1H, brs), 2.57 (4H, t, J=5Hz), 2.88 (2H, t, J=6.5Hz), 3.55 (2H, s), 3.63 (4H, t, J=5Hz), 3.88 (2H, t, J=6.5Hz), 7.20 (2H, d, J=7.5Hz), 7.26 (1H, dd, J=8.5, 2Hz), 7.29 (2H, d, J=7.5Hz), 7.43 (1H, d, J=8.5Hz), 7.55 (1H, d, J=2Hz).

実施例１４８

収率：46％,1H-NMR(CDCl3): δ1.14 (6H, d, J=6Hz), 1.68 (1H, brs), 2.30 (3H, s), 2.70-2.87 (2H, m), 3.03-3.15 (2H, m), 3.82 (2H, s), 3.85-3.95 (2H, m), 4.66 (2H, s), 7.05 (1H, s), 7.11 (1H, s), 7.17 (1H, s), 7.51 (1H, d, J=8.5Hz), 7.55 (1H, d, J=8.5Hz), 7.84 (1H, s).

実施例１４９

収率：95％,1H-NMR(CDCl3): δ1.24 (3H, d, J=6Hz), 1.69 (1H, brs), 2.20-2.35 (1H, m), 2.36 (3H, s), 2.60-2.72 (1H, m), 2.82 (1H, dt, J=12, 3.5Hz), 3.15-3.25 (2H, m), 3.35-3.48 (1H, m), 3.70-3.80 (1H, m), 3.85-3.95 (1H, m), 4.04 (1H, d, J=13.5Hz), 4.67 (2H, s), 7.00-7.15 (3H, m), 7.52 (1H, dd, J=8.5, 1Hz), 7.56 (1H, d, J=8.5Hz), 7.83 (1H, d, J=1Hz).

実施例１５０

収率：quant.％,1H-NMR(DMSO-d6): δ1.30 (3H, d, J=7Hz), 2.05-2.25 (2H, m), 2.27 (3H, s), 2.65-2.75 (1H, m), 2.80-2.95 (1H, m), 3.30-3.85 (3H, m), 4.15-4.30 (1H, m), 4.43 (2H, d, J=5.5Hz), 4.48 (1H, t, J=5Hz), 5.21 (1H, t, J=5.5Hz), 7.00 (2H, s), 7.06 (1H, s), 7.54 (2H, s), 8.19 (1H, s).

実施例１５１

収率：45％,1H-NMR(CDCl3): δ1.23 (3 H, d, J = 6.3 Hz), 2.26 (1 H, ddd, J = 3.3, 9.5, 12.3 Hz), 2.36 (3 H, s), 2.60-2.66 (1 H, m), 2.80 (1 H, dt, J = 3.3, 12.0 Hz), 3.17 (2 H, d, J = 13.2 Hz), 3.20-3.33 (1 H, m), 3.71 (1 H, dt, J = 2.1, 12.0 Hz), 3.87 (1 H, dd, J = 2.1, 12.6 Hz), 4.03 (1 H, d, J = 13.2 Hz), 4.67 (2 H, s), 7.09 (2 H, s), 7.14 (1 H, s), 7.23 (1 H, dd, J = 2.1, 8.4 Hz), 7.42 (1 H, d, J = 8.4 Hz), 7.54 (1 H, d, J = 2.1 Hz)

実施例１５２

収率：54％,1H-NMR(CDCl3): δ1.24 (3 H ,d, J = 6.3 Hz), 2.23-2.31 (1 H, m), 2.36 (3 H, s), 2.60-2.66 (1 H, m), 2.81 (1 H, dt, J = 3.3, 11.7 Hz), 3.18 (2 H, d, J = 12.9 Hz), 3.34-3.42 (1 H, m), 3.71 (1 H, d, J = 12.9 Hz), 3.87 (1 H, d, J = 10.2 Hz), 4.04 (1 H, d, J = 13.5 Hz), 4.67 (2 H, s), 7.09 (2 H, s), 7.14 (1 H, s), 7.23 (1 H, dd, J = 2.4, 8.4 Hz), 7.43 (1 H, d, J = 8.4 Hz), 7.55 (1 H, d, J = 2.4 Hz)

実施例１５３

収率：84％,1H-NMR(CDCl3): δ1.24 (3H, d, J=6.0Hz), 1.63-1.73 (1H, m), 2.23-2.34 (1H, m), 2.37 (3H, s), 2.59-2.72 (1H, m), 2.78-2.88 (1H, m), 3.15-3.26 (1H, m), 3.19 (1H, d, J=13.0Hz), 3.37-3.48 (1H, m), 3.72-3.83 (1H, m), 3.86-3.97 (1H, m), 4.04 (1H, d, J=13.0Hz), 4.67 (2H, d, J=4.5Hz), 7.07-7.17 (3H, m), 7.48-7.59 (2H, m), 7.84 (1H, s). Thereafter, the compounds described in Examples 130 to 153 were obtained in the same manner as in Example 129.
Example 130

Yield: 100%, ¹ H-NMR (CDCl ₃ ); δ1.65 (1H, brs), 1.98-2.05 (2H, m), 2.70 (2H, t, J = 5.1Hz), 2.79-2.82 (2H , m), 3.65 (2H, s), 3.71-3.77 (4H, m), 4.69 (2H, s), 7.23 (1H, dd, J = 8.7Hz, 2.4Hz), 7.26-7.34 (4H, m) , 7.43 (1H, d, J = 8.4Hz), 7.55 (1H, d, J = 2.1Hz).

Example 131

Yield: 100%, ¹ H-NMR (CDCl ₃ ); δ1.26 (1H, brs), 2.59 (4H, t, J = 5Hz), 3.58 (2H, s), 3.68 (4H, t, J = 5Hz), 4.72 (2H, s), 7.20-7.40 (4H, m), 7.50-7.60 (2H, m), 7.84 (1H, s).

Example 132

Yield: 60%, ¹ H-NMR (DMSO-d ₆ ): δ1.88-1.99 (2H, m), 2.58-2.67 (2H, m), 2.74-2.84 (2H, m), 3.62 (2H, s), 3.63-3.85 (4H, m), 4.47 (2H, d, J = 5.5Hz), 5.16 (1H, t, J = 5.5Hz), 7.13-7.20 (2H, m), 7.22-7.30 (2H , m), 7.52-7.57 (2H, m), 8.22 (1H, s).

Example 133

Yield: 96% ¹ H-NMR (CDCl ₃ ); δ1.41 (3H, d, J = 6.5Hz), 1.63 (1H, brs), 2.25 (1H, td, J = 11.5, 3.5Hz), 2.33 (1H, dd, J = 11.5, 3.5Hz), 2.72 (1H, d, J = 11.5Hz), 2.86-2.95 (1H, m), 3.47 (1H, td, J = 12.5, 3.5Hz), 3.48 ( 1H, d, J = 13.5Hz), 3.60 (1H, d, J = 13.5Hz), 3.85 (1H, d, J = 12.5Hz), 4.10-4.25 (1H, m), 4.72 (2H, s), 7.22 (1H, dd, J = 8.5, 2Hz), 7.25-7.40 (4H, m), 7.42 (1H, d, J = 8.5Hz), 7.54 (1H, d, J = 2Hz).

Example 134

Yield: 98%, ¹ H-NMR (CDCl ₃ ); δ1.23 (3H, d, J = 6.5Hz), 1.55-1.70 (1H, m), 2.22-2.32 (1H, m), 2.60-2.70 (1H, m), 2.75-2.85 (1H, m), 3.10-3.20 (1H, m), 3.22 (1H, d, J = 13.5Hz), 3.35-3.45 (1H, m), 3.65-3.75 (1H , m), 3.83-3.90 (1H, m), 4.06 (1H, d, J = 13.5Hz), 4.71 (2H, s), 7.20-7.35 (5H, m), 7.42 (1H, d, J = 8.5 Hz), 7.54 (1H, d, J = 2Hz).

Example 135

Yield: qy, ¹ H-NMR (CDCl ₃ ); δ1.12 (6H, d, J = 6Hz), 1.64 (1H, brs), 2.75-2.85 (2H, m), 3.05 (2H, dd, J = 13, 12.5Hz), 3.85 (2H, s), 3.80-3.90 (2H, m), 4.70 (2H, s), 7.23 (1H, dd, J = 8.5, 2Hz), 7.25-7.28 (1H, m ), 7.30-7.35 (2H, m), 7.38 (1H, s), 7.42 (1H, d, J = 8.5Hz), 7.55 (1H, d, J = 2Hz).

Example 136

Yield: qy, ¹ H-NMR (CDCl ₃ ); δ1.08 (3H, d, J = 6.5 Hz), 1.38 (3H, d, J = 6.5 Hz), 1.74 (1H, brs), 2.33 (1H , d, J = 11.5Hz), 2.89 (1H, dd, J = 11.5, 4Hz), 3.06-3.19 (1H, m), 3.53 (1H, d, J = 14.5Hz), 3.60-3.75 (3H, m ), 4.15-4.28 (1H, m), 4.70 (2H, s), 7.21 (1H, dd, J = 8.5, 2Hz), 7.25-7.35 (4H, m), 7.40 (1H, d, J = 8.5Hz ), 7.53 (1H, d, J = 2Hz).

Example 137

Yield: 60%, ¹ H-NMR (CDCl ₃ ); δ1.71 (1H, brs), 2.38 (3H, s), 2.58 (4H, t, J = 5Hz), 3.52 (2H, s), 3.61 (4H, t, J = 5Hz), 4.67 (2H, s), 7.15 -7.20 (2H, m), 7.23 (1H, dd, J = 8.5, 2Hz), 7.25-7.28 (1H, m), 7.43 ( 1H, d, J = 8.5Hz), 7.55 (1H, d, J = 2Hz).

Example 138

Yield: 39%, ¹ H-NMR (CDCl ₃ ); δ 1.80 (1H, brs), 2.65 (4H, t, J = 5Hz), 3.65 (4H, t, J = 5Hz), 3.68 (2H, s), 4.70 (2H, s), 7.23 (1H, dd, J = 8,2Hz), 7.24 (1H, dd, 8.5, 2Hz), 7.36 (1H, d, J = 8Hz), 7.42 (1H, d , J = 8.5 Hz), 7.48 (1H, d, J = 2Hz), 7.55 (1H, d, J = 2Hz).

Example 139

Yield: 92%, ¹ H-NMR (CDCl ₃ ); δ1.66-1.73, (1H, br-s), 1.97-2.04 (2H, m), 2.33 (3H, s), 2.69 (2H, t , J = 5.4Hz), 2.78-2.81 (2H, m), 3.59 (2H, s), 3.70-3.75 (4H, m), 4.65 (2H, s), 7.16-7.17 (2H, m), 7.23 ( 1H, dd, J = 8.7Hz, 2.1Hz), 7.28 (1H, s), 7.43 (1H, d, J = 8.7Hz), 7.55 (1H, d, J = 2.4Hz).

Example 140

Yield: 100%, ¹ H-NMR (CDCl ₃ ); δ 1.70-1.88 (1H, br-s), 1.98-2.07 (2H, m), 2.75 (2H, t, J = 5.4Hz), 2.84 -2.89 (2H, m), 3.72-3.84 (6H, m), 4.68 (2H, s), 7.17-7.25 (2H, m), 7.33 (1H, d, J = 8.1Hz), 7.44 (1H, d , J = 8.1Hz), 7.50 (1H, d, J = 2.1Hz), 7.55 (1H, d, J = 2.4Hz).

Example 141

Yield: 30%, ¹ H-NMR (CDCl ₃ ); δ1.90 (1H, brs), 2.62 (4H, t, J = 5Hz), 3.64 (4H, t, J = 5Hz), 3.74 (2H, s), 4.79 (2H, s), 6.79 (1H, d, J = 3.5Hz), 6.85 (1H, d, J = 3.5Hz), 7.23 (1H, dd, J = 8.5, 2Hz), 7.43 (1H , d, J = 8.5Hz), 7.55 (1H, d, J = 2Hz).

Example 142

Yield: 80%, ¹ H-NMR (CDCl ₃ ); δ1.86 (1H, s), 2.00-2.07 (2H, m), 2.71-2.74 (2H, m), 2.84-2.87 (2H, m) , 3.73 (2H, t, J = 6.0Hz), 3.77-3.80 (2H, m), 3.82 (2H, s), 4.78 (2H, s), 6.76 (1H, d, J = 3.3Hz), 6.84 ( 1H, d, J = 3.3Hz), 7.23 (1H, dd, J = 8.7, 2.4Hz), 7.42 (1H, d, J = 9.0Hz), 7.55 (1H, d, J = 2.4Hz).

Example 143

Yield: 90%, ¹ H-NMR (CDCl ₃ ); δ1.81 (1H, brs), 2.36 (3H, s), 2.57 (4H, t, J = 5Hz), 3.53 (2H, s), 3.63 (4H, t, J = 5Hz), 4.67 (2H, s), 7.08 (1H, s), 7.11 (1H, s), 7.13 (1H, s), 7.23 (1H, dd, J = 8.5, 2Hz) , 7.43 (1H, d, J = 8.5Hz), 7.55 (1H, d, J = 2Hz).

Example 144

Yield: q, y, ¹ H-NMR (CDCl ₃ ); δ 1.79 (1H, t, J = 4.5Hz), 2.36 (3H, s), 2.59 (4H, t, J = 5Hz), 3.54 2H, s), 3.68 (4H, t, J = 5Hz), 4.67 (2H, d, J = 4.5Hz), 7.09 (1H, s), 7.11 (1H, s), 7.14 (1H, s), 7.45 -7.60 (2H, m), 7.84 (1H, s).

Example 145

Yield: 93%, ¹ H-NMR (CDCl ₃ ); δ 1.70 (1H, s), 1.99-2.06 (2H, m), 2.35 (3H, s), 2.70 (2H, t, J = 5.4Hz ), 2.79-2.82 (2H, m), 3.61 (2H, s), 3.71-3.77 (4H, m), 4.65 (2H, s), 7.07 (1H, s), 7.09 (1H, s), 7.13 ( 1H, s), 7.23 (1H, dd, J = 8.7Hz, J = 2.1Hz), 7.43 (1H, d, J = 8.7Hz), 7.55 (1H, d, J = 2.1Hz).

Example 146

Yield: q. Y, ¹ H-NMR (CDCl ₃ ); δ1.77 (1H, brs), 1.95-2.10 (2H, m), 2.34 (3H, s), 2.68 (2H, t, J = 5.5 Hz), 2.82 (2H, t, J = 5.5Hz), 3.61 (2H, s), 3.70-3.85 (4H, m), 4.65 (2H, s), 7.06 (1H, s), 7.08 (1H, s ), 7.13 (1H, s), 7.45-7.60 (2H, m), 7.84 (1H, s).

Example 147

Yield: 80%, ¹ H-NMR (DMSO-d ₆ ): δ1.59 (1H, brs), 2.57 (4H, t, J = 5Hz), 2.88 (2H, t, J = 6.5Hz), 3.55 (2H, s), 3.63 (4H, t, J = 5Hz), 3.88 (2H, t, J = 6.5Hz), 7.20 (2H, d, J = 7.5Hz), 7.26 (1H, dd, J = 8.5 , 2Hz), 7.29 (2H, d, J = 7.5Hz), 7.43 (1H, d, J = 8.5Hz), 7.55 (1H, d, J = 2Hz).

Example 148

Yield: 46%, 1H-NMR (CDCl3): δ 1.14 (6H, d, J = 6Hz), 1.68 (1H, brs), 2.30 (3H, s), 2.70-2.87 (2H, m), 3.03 -3.15 (2H, m), 3.82 (2H, s), 3.85-3.95 (2H, m), 4.66 (2H, s), 7.05 (1H, s), 7.11 (1H, s), 7.17 (1H, s ), 7.51 (1H, d, J = 8.5Hz), 7.55 (1H, d, J = 8.5Hz), 7.84 (1H, s).

Example 149

Yield: 95%, 1H-NMR (CDCl3): δ1.24 (3H, d, J = 6Hz), 1.69 (1H, brs), 2.20-2.35 (1H, m), 2.36 (3H, s), 2.60 -2.72 (1H, m), 2.82 (1H, dt, J = 12, 3.5Hz), 3.15-3.25 (2H, m), 3.35-3.48 (1H, m), 3.70-3.80 (1H, m), 3.85 -3.95 (1H, m), 4.04 (1H, d, J = 13.5Hz), 4.67 (2H, s), 7.00-7.15 (3H, m), 7.52 (1H, dd, J = 8.5, 1Hz), 7.56 (1H, d, J = 8.5Hz), 7.83 (1H, d, J = 1Hz).

Example 150

Yield: quant.%, 1H-NMR (DMSO-d6): δ 1.30 (3H, d, J = 7Hz), 2.05-2.25 (2H, m), 2.27 (3H, s), 2.65-2.75 (1H , m), 2.80-2.95 (1H, m), 3.30-3.85 (3H, m), 4.15-4.30 (1H, m), 4.43 (2H, d, J = 5.5Hz), 4.48 (1H, t, J = 5Hz), 5.21 (1H, t, J = 5.5Hz), 7.00 (2H, s), 7.06 (1H, s), 7.54 (2H, s), 8.19 (1H, s).

Example 151

Yield: 45%, 1H-NMR (CDCl3): δ1.23 (3 H, d, J = 6.3 Hz), 2.26 (1 H, ddd, J = 3.3, 9.5, 12.3 Hz), 2.36 (3 H, s), 2.60-2.66 (1 H, m), 2.80 (1 H, dt, J = 3.3, 12.0 Hz), 3.17 (2 H, d, J = 13.2 Hz), 3.20-3.33 (1 H, m) , 3.71 (1 H, dt, J = 2.1, 12.0 Hz), 3.87 (1 H, dd, J = 2.1, 12.6 Hz), 4.03 (1 H, d, J = 13.2 Hz), 4.67 (2 H, s ), 7.09 (2 H, s), 7.14 (1 H, s), 7.23 (1 H, dd, J = 2.1, 8.4 Hz), 7.42 (1 H, d, J = 8.4 Hz), 7.54 (1 H , d, J = 2.1 Hz)

Example 152

Yield: 54%, 1H-NMR (CDCl3): δ1.24 (3 H, d, J = 6.3 Hz), 2.23-2.31 (1 H, m), 2.36 (3 H, s), 2.60-2.66 ( 1 H, m), 2.81 (1 H, dt, J = 3.3, 11.7 Hz), 3.18 (2 H, d, J = 12.9 Hz), 3.34-3.42 (1 H, m), 3.71 (1 H, d , J = 12.9 Hz), 3.87 (1 H, d, J = 10.2 Hz), 4.04 (1 H, d, J = 13.5 Hz), 4.67 (2 H, s), 7.09 (2 H, s), 7.14 (1 H, s), 7.23 (1 H, dd, J = 2.4, 8.4 Hz), 7.43 (1 H, d, J = 8.4 Hz), 7.55 (1 H, d, J = 2.4 Hz)

Example 153

Yield: 84%, 1H-NMR (CDCl3): δ1.24 (3H, d, J = 6.0Hz), 1.63-1.73 (1H, m), 2.23-2.34 (1H, m), 2.37 (3H, s ), 2.59-2.72 (1H, m), 2.78-2.88 (1H, m), 3.15-3.26 (1H, m), 3.19 (1H, d, J = 13.0Hz), 3.37-3.48 (1H, m), 3.72-3.83 (1H, m), 3.86-3.97 (1H, m), 4.04 (1H, d, J = 13.0Hz), 4.67 (2H, d, J = 4.5Hz), 7.07-7.17 (3H, m) , 7.48-7.59 (2H, m), 7.84 (1H, s).

3-[4-[(6-クロロベンゾチアゾール-2-イル)ピペラジン-1-イル]メチル]ベンジルアルコール2.35ｇ（6.29mmol）に室温下、塩化チオニル12mlを加え60℃で1時間撹拌した。反応液を減圧下濃縮し、得られた残渣に氷水及び10％水酸化ナトリウム水溶液を加え、中性とした。得られた結晶を濾取し、6-クロロ-[4-(3-クロロメチルベンジル)ピペラジン-1-イル]ベンゾチアゾール1塩酸塩を無色結晶として2.50ｇ（93％）を得た。
¹H-NMR(DMSO-d₆): δ3.20-3.30 (2H, m), 3.35-3.45 (2H, m), 3.55-3.75 (2H, m), 4.10-4.25 (2H, m), 4.35-4.40 (2H, m), 4.80 (2H, s), 7.34 (1H, dd, J=8.5, 2Hz), 7.45-7.60 (3H, m), 7.60-7.70 (2H, m), 8.00 (1H, d, J=2Hz), 11.45 (1H, brs). Example 154
Preparation of 6-chloro- [4- (3-chloromethylbenzyl) piperazin-1-yl] benzothiazole monohydrochloride

To 2.35 g (6.29 mmol) of 3- [4-[(6-chlorobenzothiazol-2-yl) piperazin-1-yl] methyl] benzyl alcohol was added 12 ml of thionyl chloride at room temperature, and the mixture was stirred at 60 ° C. for 1 hour. The reaction mixture was concentrated under reduced pressure, and ice water and 10% aqueous sodium hydroxide solution were added to the resulting residue to neutralize it. The obtained crystals were collected by filtration to obtain 2.50 g (93%) of 6-chloro- [4- (3-chloromethylbenzyl) piperazin-1-yl] benzothiazole monohydrochloride as colorless crystals.
¹ H-NMR (DMSO-d ₆ ): δ3.20-3.30 (2H, m), 3.35-3.45 (2H, m), 3.55-3.75 (2H, m), 4.10-4.25 (2H, m), 4.35 -4.40 (2H, m), 4.80 (2H, s), 7.34 (1H, dd, J = 8.5, 2Hz), 7.45-7.60 (3H, m), 7.60-7.70 (2H, m), 8.00 (1H, d, J = 2Hz), 11.45 (1H, brs).

収率：77％, ¹H-NMR(CDCl₃); δ1.99-2.06 (2H, m), 2.69 (2H, t, J=5.4Hz), 2.80-2.83 (2H, m), 3.65 (2H, s), 3.72-3.79 (4H, m), 4.58 (2H, s), 7.21-7.31 (4H, m), 7.36 (1H, s), 7.42 (1H, d, J=8.4Hz), 7.55 (1H, d, J =2.4Hz).

実施例１５６

収率：77％, ¹H-NMR(CDCl₃); δ2.60 (4H, t, J=5Hz), 3.59 (2H, s), 3.70 (4H, t, J=5Hz), 4.60 (2H, s), 7.25-7.40 (4H, m), 7.50-7.60 (2H, m), 7.85 (1H, s).

実施例１５７

収率：95％, ¹H-NMR(CDCl₃); δ1.95-2.12 (2H, m), 2.61-2.71 (2H, m), 2.77-2.88 (2H, m), 3.66 (2H, s), 3.68-3.90 (4H,m), 4.58 (2H, s), 7.22-7.40 (4H, m), 7.48-7.60 (2H, m), 7.85 (1H, s).

実施例１５８

収率：95％, ¹H-NMR(CDCl₃); δ1.41 (3H, d, J=6.5Hz), 2.25 (1H, td, J=11, 3Hz), 2.34 (1H, dd, J=11, 3Hz), 2.71 (1H, d, J=11Hz), 2.92 (1H, d, J=11Hz), 3.47 (1H, d, J=13.5Hz), 3.49 (1H, td, J=12, 3Hz), 3.62 (1H, d, J=13.5Hz), 3.87(1H, d, J=12Hz), 4.15-4.25 (1H, m), 4.60 (2H, s), 7.22 (1H, dd, J=8.5, 2Hz), 7.30-7.38 (3H, m), 7.38-7.42 (1H, m), 7.42 (1H, d, J=8.5Hz), 7.54 (1H, d, J=2Hz)

実施例１５９

収率：63％, ¹H-NMR(CDCl₃); δ1.23 (3H, d, J=6Hz), 2.24-2.34 (1H, m), 2.60-2.73 (1H, m), 2.75-2.85 (1H, m), 3.13-3.23 (1H, m), 3.22 (1H, d, J=13.5Hz), 3.34-3.44 (1H, m ), 3.66-3.76 (1H, m), 3.84-3.92 (1H, m), 4.06 (1H, d, J=13.5Hz), 4.60 (2H, s), 7.23 (1H, dd, J=8.5, 2Hz), 7.25-7.40 (4H, m), 7.43 (1H, d, J=8.5Hz), 7.55 (1H, d, J=2Hz).

実施例１６０

収率：71％, ¹H-NMR(CDCl₃); δ1.11 (6H, d, J=6Hz), 2.70-2.85 (2H, m), 3.06 (2H, dd, J=13, 13Hz), 3.84 (2H, s), 3.85-3.90 (2H, m), 4.60 (2H, s), 7.20-7.45 (6H, m ), 7.55 (1H, d, J=2Hz).

実施例１６１

収率：90％, ¹H-NMR(CDCl₃); δ1.09 (3H, d, J=6.5Hz), 1.39 (3H, d, J=6.5Hz), 2.32 (1H, d, J=10.5Hz), 2.89 (1H, dd, J=12, 4Hz), 3.08-3.20 (1H, m), 3.52 (1H, d, J=13.5Hz), 3.64 (1H, d, J=12Hz), 3.70 (1H, d, J=13.5Hz), 3.73 (1H, dd, J=12, 4Hz), 4.15-4.30 (1H, m), 4.60 (2H, s), 7.23 (1H, dd, J=8.5, 2Hz), 7.25-7.35 (3H, m), 7.41 (1H, d, J=8.5Hz), 7.44 (1H, s), 7.53 (1H, d, J=2Hz).

実施例１６２

収率：85％, ¹H-NMR(CDCl₃); δ2.38 (3H, s), 2.58 (4H, t, J=5Hz), 3.52 (2H, s), 3.63 (4H, t, J=5Hz), 4.60 (2H, s), 7.15 -7.30 (4H, m), 7.44 (1H, d, J=8Hz), 7.56 (1H, d, J=2Hz).

実施例１６３

収率：68％, ¹H-NMR(CDCl₃); δ2.66 (4H, t, J=5Hz), 3.66 (4H, t, J=5Hz), 3.68 (2H, s), 4.58 (2H, s), 720-7.25 (2H, m), 7.37 (1H, d, J=8Hz), 7.44 (1H, d, J=8.5Hz), 7.55 (1H, d, J=2Hz), 7.56 (1H, d, J=2Hz).

実施例１６４

収率：99％, ¹H-NMR(CDCl₃); δ1.97-2.05 (2H, m), 2.33 (3H, s), 2.67 (2H, t, J=5.4Hz), 2.79-2.82 (2H, m), 3.58 (2H, s), 3.72-3.77 (4H, m), 4.56 (2H, s), 7.12-7.25 (3H, m), 7.30 (1H, d, J=1.8Hz), 7.42 (1H, d, J=8.4Hz), 7.55 (1H, d, J=2.4Hz).

実施例１６５

収率：81％, ¹H-NMR(CDCl₃); δ2.01-2.09 (2H, m), 2.75 (2H, t, J=5.1Hz ), 2.87-2.90 (2H, m), 3.74-3.83 (6H, m), 4.54 (2H, s), 7.20-7.25 (2H, m), 7.33 (1H, d, J=8.4Hz), 7.43 (1H, d, J= 9.0Hz), 7.52 (1H, d, J =2.1Hz), 7.55 (1H, d, J=2.1Hz).

実施例１６６

収率：85％, ¹H-NMR(CDCl₃); δ2.36 (3H, s), 2.58 (4H, t, J=5Hz), 3.53 (2H, s), 3.64 (4H, t, J=5Hz), 4.56 (2H, s), 7.12 (1H, s), 7.13 (1H, s), 7.17 (1H, s), 7.23 (1H, dd, J=8.5, 2Hz), 7.43 (1H, d, J=8.5Hz), 7.55 (1H, d, J=2Hz).

実施例１６７

収率：91％, ¹H-NMR(CDCl₃); δ1.98-2.06 (2H, m), 2.34 (3H, s), 2.69 (2H, t, J=5.4Hz), 2.78-2.83 (2H, m), 3.61 (2H, s), 3.72-3.78 (4H, m), 4.55 (2H, s), 7.09-7.11(2H, m), 7.14 (1H, s), 7.23 (1H, dd, J=8.4, 2.1Hz), 7.43 (1H, d, J=8.7Hz), 7.55 (1H, d, J =2.1Hz).

実施例１６８

収率：45％, ¹H-NMR(DMSO-d₆): δ2.55 (4H, t, J=5Hz), 3.57 (4H, t, J=5Hz), 3.74 (2H, s), 4.99 (2H, s), 6.86 (1H, d, J=3.5Hz), 7.04 (1H, d, J=3.5Hz), 7.28 (1H, dd, J=8.5, 2Hz), 7.42 (1H, d, J=8.5Hz), 7.91 (1H, d, J=2Hz).

実施例１６９

収率：45％, ¹H-NMR(CDCl₃); δ2.00-2.07 (2H, m), 2.71-2.74 (2H, m), 2.84-2.87 (2H, m), 3.73 (2H, t, J=6.0Hz), 3.75-3.81 (2H, m), 3.81(2H, s), 4.76 (2H, s), 6.73 (1H, d, J=3.3Hz), 6.91 (1H, d, J=3.3Hz), 7.23 (1H, dd, J=8.7, 2.4Hz), 7.42 (1H, d, J=8.4Hz), 7.55 (1H, d, J=2.1Hz).

実施例１７０

収率：59％, ¹H-NMR(CDCl₃); δ2.37 (3H, s), 2.59 (4H, t, J=5Hz), 3.54 (2H, s), 3.69 (4H, t, J=5Hz), 4.57 (2H, s), 7.12 (1H, s), 7.13 (1H, s), 7.17 (1H, s), 7.50-7.60 (2H, m), 7.85 (1H, s).

実施例１７１

収率：71％, ¹H-NMR(CDCl₃); δ1.95-2.10 (2H, m), 2.34 (3H, s), 2.70 (2H, t, J=5.5Hz), 2.82 (2H, t, J=5.5Hz), 3.61 (2H, s), 3.70-3.90 (4H, m), 4.54 (2H, s), 7.05-7.14 (2H, m), 7.15 (1H, s), 7.48-7.60 (2H, m), 7.85 (1H, s).

実施例１７２

収率：77％, ¹H-NMR(CDCl₃); δ2.57 (4H, t, J=5Hz), 3.07 (2H, t, J=7.5Hz), 3.55 (2H, s), 3.63 (4H, t, J=5Hz), 3.72 (2H, t, J=7.5Hz), 7.19 (2H, d, J=8Hz), 7.23 (1H, dd, J=8.5, 2Hz), 7.29 (2H, d, J=8Hz), 7.43 (1H, d, J=8.5Hz), 7.55 (1H, d, J=2Hz).

実施例１７３

収率：91％, 1H-NMR(CDCl3): δ1.12 (6H, d, J=6Hz), 2.35 (3H, s), 2.68-2.86 (2H, m), 3.05-3.15 (2H, m), 3.81 (2H, s), 3.85-3.98 (2H, m), 4.56 (2H, s), 7.07 (1H, s), 7.14 (1H, s), 7.21 (1H, s), 7.52 (1H, d, J=8.5Hz), 7.57 (1H, d, J=8.5Hz), 7.84 (1H, s).

実施例１７４

収率：74％, 1H-NMR(CDCl3): δ1.24 (3H, d, J=6Hz), 2.23-2.35 (1H, m), 2.36 (3H, s), 2.60-2.70 (1H, m), 2.80 (1H, dt, J=13, 3.5Hz), 3.17 (1H, d, J=13.5Hz), 3.18-3.26 (1H, m), 3.38-3.50 (1H, m), 3.72-3.80 (1H, m), 3.87-3.95 (1H, m), 4.03 (1H, d, J=13.5Hz), 4.56 (2H, s), 7.11 (2H, s), 7.17 (1H, s), 7.53 (1H, d, J=8.5Hz), 7.56 (1H, d, J=8.5Hz), 7.84 (1H, s).

実施例１７５

収率：81％, 1H-NMR(CDCl3): δ1.43 (3H, d, J=6.5Hz), 2.26 (1H, td, J=11.5, 3.5Hz), 2.30-2.36 (1H, m), 2.37 (3H, s), 2.73 (1H, d, J=11.5Hz), 2.93 (1H, d, J=11.5Hz), 3.43 (1H, d, J=13.5Hz), 3.54 (1H, td, J=12.5, 3.5Hz), 3.58 (1H, d, J=13.5Hz), 3.85-3.98 (1H, m), 4.20-4.30 (1H, m), 4.57 (2H, s), 7.12 (2H, s), 7.21 (1H, s), 7.51 (1H, dd, J=8.5, 1.5Hz), 7.56 (1H, d, J=8.5Hz), 7.84 (1H, d, J=1.5Hz).

実施例１７６

収率：83％, 1H-NMR(CDCl3): δ1.23 (3 H, d, J = 6.0 Hz), 2.23-2.31 (1 H, m), 2.36 (3 H, s), 2.61-2.83 (1 H, m), 2.80 (1 H, dt, J = 3.6, 11.7 Hz), 3.13-3.20 (2 H, m), 3.35-3.43 (1 H, m), 3.72 (1 H, dt, J = 2.7 Hz), 3.87 (1 H, dd, J = 1.8, 12.3 Hz), 4.03 (1 H, d, J = 13.2 Hz), 4.56 (2 H, s), 7.11 (2 H, s), 7.16 (1 H, s), 7.23 (1 H, dd, J = 2.1, 8.7 Hz), 7.43 (1 H, d, J = 8.7 Hz), 7.54 (1 H, d, J = 2.1 Hz)

実施例１７７

収率：77％, 1H-NMR(CDCl3): δ1.23 (3 H, d, J = 6.0 Hz), 2.27 (1 H, ddd, J = 3.3, 8.7, 9.9 Hz), 2.35 (3 H, s), 2.61-2.67 (1 H, m), 2.80 (1 H, dt, J = 3.6, 12.0 Hz), 3.13-3.20 (2 H, m), 3.35-3.43 (1 H, m), 3.72 (1 H, d, J = 12.6 Hz), 3.87 (1 H, dd, J = 1.8, 12.6 Hz), 4.03 (1 H, d, J = 13.2 Hz), 4.56 (2 H, s), 7.11 (2 H, s), 7.16 (1 H, s), 7.23 (1 H, dd, J = 1.8, 8.7 Hz), 7.53 (1 H, d, J = 8.7 Hz), 7.54 (1 H, d, J = 1.8 Hz)

実施例１７８

収率：60％, 1H-NMR(CDCl3): δ1.24 (3H, d, J=6.0Hz), 2.23-2.34 (1H, m), 2.36 (3H, s), 2.60-2.72 (1H, m), 2.77-2.87 (1H, m), 3.14-3.27 (2H, m), 3.38-3.51 (1H, m), 3.72-3.82 (1H, m), 3.87-3.98 (1H, m), 4.04 (1H, d, J=13.0Hz), 4.56 (2H, s), 7.12 (2H, s), 7.17 (1H, s), 7.48-7.59 (2H, m), 7.84 (1H, s). The compounds described in Examples 155 to 178 were obtained in the same manner as in Example 154.
Example 155

Yield: 77%, ¹ H-NMR (CDCl ₃ ); δ1.99-2.06 (2H, m), 2.69 (2H, t, J = 5.4Hz), 2.80-2.83 (2H, m), 3.65 (2H , s), 3.72-3.79 (4H, m), 4.58 (2H, s), 7.21-7.31 (4H, m), 7.36 (1H, s), 7.42 (1H, d, J = 8.4Hz), 7.55 ( (1H, d, J = 2.4Hz).

Example 156

Yield: 77%, ¹ H-NMR (CDCl ₃ ); δ 2.60 (4H, t, J = 5Hz), 3.59 (2H, s), 3.70 (4H, t, J = 5Hz), 4.60 (2H, s), 7.25-7.40 (4H, m), 7.50-7.60 (2H, m), 7.85 (1H, s).

Example 157

Yield: 95%, ¹ H-NMR (CDCl ₃ ); δ1.95-2.12 (2H, m), 2.61-2.71 (2H, m), 2.77-2.88 (2H, m), 3.66 (2H, s) , 3.68-3.90 (4H, m), 4.58 (2H, s), 7.22-7.40 (4H, m), 7.48-7.60 (2H, m), 7.85 (1H, s).

Example 158

Yield: 95%, ¹ H-NMR (CDCl ₃ ); δ1.41 (3H, d, J = 6.5Hz), 2.25 (1H, td, J = 11, 3Hz), 2.34 (1H, dd, J = 11, 3Hz), 2.71 (1H, d, J = 11Hz), 2.92 (1H, d, J = 11Hz), 3.47 (1H, d, J = 13.5Hz), 3.49 (1H, td, J = 12, 3Hz ), 3.62 (1H, d, J = 13.5Hz), 3.87 (1H, d, J = 12Hz), 4.15-4.25 (1H, m), 4.60 (2H, s), 7.22 (1H, dd, J = 8.5 , 2Hz), 7.30-7.38 (3H, m), 7.38-7.42 (1H, m), 7.42 (1H, d, J = 8.5Hz), 7.54 (1H, d, J = 2Hz)

Example 159

Yield: 63%, ¹ H-NMR (CDCl ₃ ); δ1.23 (3H, d, J = 6Hz), 2.24-2.34 (1H, m), 2.60-2.73 (1H, m), 2.75-2.85 ( 1H, m), 3.13-3.23 (1H, m), 3.22 (1H, d, J = 13.5Hz), 3.34-3.44 (1H, m), 3.66-3.76 (1H, m), 3.84-3.92 (1H, m), 4.06 (1H, d, J = 13.5Hz), 4.60 (2H, s), 7.23 (1H, dd, J = 8.5, 2Hz), 7.25-7.40 (4H, m), 7.43 (1H, d, J = 8.5Hz), 7.55 (1H, d, J = 2Hz).

Example 160

Yield: 71%, ¹ H-NMR (CDCl ₃ ); δ1.11 (6H, d, J = 6Hz), 2.70-2.85 (2H, m), 3.06 (2H, dd, J = 13, 13Hz), 3.84 (2H, s), 3.85-3.90 (2H, m), 4.60 (2H, s), 7.20-7.45 (6H, m), 7.55 (1H, d, J = 2Hz).

Example 161

Yield: 90%, ¹ H-NMR (CDCl ₃ ); δ 1.09 (3H, d, J = 6.5 Hz), 1.39 (3H, d, J = 6.5 Hz), 2.32 (1H, d, J = 10.5 Hz), 2.89 (1H, dd, J = 12, 4Hz), 3.08-3.20 (1H, m), 3.52 (1H, d, J = 13.5Hz), 3.64 (1H, d, J = 12Hz), 3.70 ( 1H, d, J = 13.5Hz), 3.73 (1H, dd, J = 12, 4Hz), 4.15-4.30 (1H, m), 4.60 (2H, s), 7.23 (1H, dd, J = 8.5, 2Hz ), 7.25-7.35 (3H, m), 7.41 (1H, d, J = 8.5Hz), 7.44 (1H, s), 7.53 (1H, d, J = 2Hz).

Example 162

Yield: 85%, ¹ H-NMR (CDCl ₃ ); δ2.38 (3H, s), 2.58 (4H, t, J = 5Hz), 3.52 (2H, s), 3.63 (4H, t, J = 5Hz), 4.60 (2H, s), 7.15 -7.30 (4H, m), 7.44 (1H, d, J = 8Hz), 7.56 (1H, d, J = 2Hz).

Example 163

Yield: 68%, ¹ H-NMR (CDCl ₃ ); δ2.66 (4H, t, J = 5Hz), 3.66 (4H, t, J = 5Hz), 3.68 (2H, s), 4.58 (2H, s), 720-7.25 (2H, m), 7.37 (1H, d, J = 8Hz), 7.44 (1H, d, J = 8.5Hz), 7.55 (1H, d, J = 2Hz), 7.56 (1H, d, J = 2Hz).

Example 164

Yield: 99%, ¹ H-NMR (CDCl ₃ ); δ1.97-2.05 (2H, m), 2.33 (3H, s), 2.67 (2H, t, J = 5.4Hz), 2.79-2.82 (2H , m), 3.58 (2H, s), 3.72-3.77 (4H, m), 4.56 (2H, s), 7.12-7.25 (3H, m), 7.30 (1H, d, J = 1.8Hz), 7.42 ( 1H, d, J = 8.4Hz), 7.55 (1H, d, J = 2.4Hz).

Example 165

Yield: 81%, ¹ H-NMR (CDCl ₃ ); δ2.01-2.09 (2H, m), 2.75 (2H, t, J = 5.1Hz), 2.87-2.90 (2H, m), 3.74-3.83 (6H, m), 4.54 (2H, s), 7.20-7.25 (2H, m), 7.33 (1H, d, J = 8.4Hz), 7.43 (1H, d, J = 9.0Hz), 7.52 (1H, d, J = 2.1Hz), 7.55 (1H, d, J = 2.1Hz).

Example 166

Yield: 85%, ¹ H-NMR (CDCl ₃ ); δ 2.36 (3H, s), 2.58 (4H, t, J = 5Hz), 3.53 (2H, s), 3.64 (4H, t, J = 5Hz), 4.56 (2H, s), 7.12 (1H, s), 7.13 (1H, s), 7.17 (1H, s), 7.23 (1H, dd, J = 8.5, 2Hz), 7.43 (1H, d, J = 8.5Hz), 7.55 (1H, d, J = 2Hz).

Example 167

Yield: 91%, ¹ H-NMR (CDCl ₃ ); δ1.98-2.06 (2H, m), 2.34 (3H, s), 2.69 (2H, t, J = 5.4Hz), 2.78-2.83 (2H , m), 3.61 (2H, s), 3.72-3.78 (4H, m), 4.55 (2H, s), 7.09-7.11 (2H, m), 7.14 (1H, s), 7.23 (1H, dd, J = 8.4, 2.1Hz), 7.43 (1H, d, J = 8.7Hz), 7.55 (1H, d, J = 2.1Hz).

Example 168

Yield: 45%, ¹ H-NMR (DMSO-d ₆ ): δ2.55 (4H, t, J = 5Hz), 3.57 (4H, t, J = 5Hz), 3.74 (2H, s), 4.99 ( 2H, s), 6.86 (1H, d, J = 3.5Hz), 7.04 (1H, d, J = 3.5Hz), 7.28 (1H, dd, J = 8.5, 2Hz), 7.42 (1H, d, J = 8.5Hz), 7.91 (1H, d, J = 2Hz).

Example 169

Yield: 45%, ¹ H-NMR (CDCl ₃ ); δ2.00-2.07 (2H, m), 2.71-2.74 (2H, m), 2.84-2.87 (2H, m), 3.73 (2H, t, J = 6.0Hz), 3.75-3.81 (2H, m), 3.81 (2H, s), 4.76 (2H, s), 6.73 (1H, d, J = 3.3Hz), 6.91 (1H, d, J = 3.3 Hz), 7.23 (1H, dd, J = 8.7, 2.4Hz), 7.42 (1H, d, J = 8.4Hz), 7.55 (1H, d, J = 2.1Hz).

Example 170

Yield: 59%, ¹ H-NMR (CDCl ₃ ); δ2.37 (3H, s), 2.59 (4H, t, J = 5Hz), 3.54 (2H, s), 3.69 (4H, t, J = 5Hz), 4.57 (2H, s), 7.12 (1H, s), 7.13 (1H, s), 7.17 (1H, s), 7.50-7.60 (2H, m), 7.85 (1H, s).

Example 171

Yield: 71%, ¹ H-NMR (CDCl ₃ ); δ1.95-2.10 (2H, m), 2.34 (3H, s), 2.70 (2H, t, J = 5.5Hz), 2.82 (2H, t , J = 5.5Hz), 3.61 (2H, s), 3.70-3.90 (4H, m), 4.54 (2H, s), 7.05-7.14 (2H, m), 7.15 (1H, s), 7.48-7.60 ( 2H, m), 7.85 (1H, s).

Example 172

Yield: 77%, ¹ H-NMR (CDCl ₃ ); δ2.57 (4H, t, J = 5Hz), 3.07 (2H, t, J = 7.5Hz), 3.55 (2H, s), 3.63 (4H , t, J = 5Hz), 3.72 (2H, t, J = 7.5Hz), 7.19 (2H, d, J = 8Hz), 7.23 (1H, dd, J = 8.5, 2Hz), 7.29 (2H, d, J = 8Hz), 7.43 (1H, d, J = 8.5Hz), 7.55 (1H, d, J = 2Hz).

Example 173

Yield: 91%, 1H-NMR (CDCl3): δ1.12 (6H, d, J = 6Hz), 2.35 (3H, s), 2.68-2.86 (2H, m), 3.05-3.15 (2H, m) , 3.81 (2H, s), 3.85-3.98 (2H, m), 4.56 (2H, s), 7.07 (1H, s), 7.14 (1H, s), 7.21 (1H, s), 7.52 (1H, d , J = 8.5Hz), 7.57 (1H, d, J = 8.5Hz), 7.84 (1H, s).

Example 174

Yield: 74%, 1H-NMR (CDCl3): δ1.24 (3H, d, J = 6Hz), 2.23-2.35 (1H, m), 2.36 (3H, s), 2.60-2.70 (1H, m) , 2.80 (1H, dt, J = 13, 3.5Hz), 3.17 (1H, d, J = 13.5Hz), 3.18-3.26 (1H, m), 3.38-3.50 (1H, m), 3.72-3.80 (1H , m), 3.87-3.95 (1H, m), 4.03 (1H, d, J = 13.5Hz), 4.56 (2H, s), 7.11 (2H, s), 7.17 (1H, s), 7.53 (1H, d, J = 8.5Hz), 7.56 (1H, d, J = 8.5Hz), 7.84 (1H, s).

Example 175

Yield: 81%, 1H-NMR (CDCl3): δ1.43 (3H, d, J = 6.5Hz), 2.26 (1H, td, J = 11.5, 3.5Hz), 2.30-2.36 (1H, m), 2.37 (3H, s), 2.73 (1H, d, J = 11.5Hz), 2.93 (1H, d, J = 11.5Hz), 3.43 (1H, d, J = 13.5Hz), 3.54 (1H, td, J = 12.5, 3.5Hz), 3.58 (1H, d, J = 13.5Hz), 3.85-3.98 (1H, m), 4.20-4.30 (1H, m), 4.57 (2H, s), 7.12 (2H, s) , 7.21 (1H, s), 7.51 (1H, dd, J = 8.5, 1.5Hz), 7.56 (1H, d, J = 8.5Hz), 7.84 (1H, d, J = 1.5Hz).

Example 176

Yield: 83%, 1H-NMR (CDCl3): δ1.23 (3 H, d, J = 6.0 Hz), 2.23-2.31 (1 H, m), 2.36 (3 H, s), 2.61-2.83 ( 1 H, m), 2.80 (1 H, dt, J = 3.6, 11.7 Hz), 3.13-3.20 (2 H, m), 3.35-3.43 (1 H, m), 3.72 (1 H, dt, J = 2.7 Hz), 3.87 (1 H, dd, J = 1.8, 12.3 Hz), 4.03 (1 H, d, J = 13.2 Hz), 4.56 (2 H, s), 7.11 (2 H, s), 7.16 ( 1 H, s), 7.23 (1 H, dd, J = 2.1, 8.7 Hz), 7.43 (1 H, d, J = 8.7 Hz), 7.54 (1 H, d, J = 2.1 Hz)

Example 177

Yield: 77%, 1H-NMR (CDCl3): δ1.23 (3 H, d, J = 6.0 Hz), 2.27 (1 H, ddd, J = 3.3, 8.7, 9.9 Hz), 2.35 (3 H, s), 2.61-2.67 (1 H, m), 2.80 (1 H, dt, J = 3.6, 12.0 Hz), 3.13-3.20 (2 H, m), 3.35-3.43 (1 H, m), 3.72 ( 1 H, d, J = 12.6 Hz), 3.87 (1 H, dd, J = 1.8, 12.6 Hz), 4.03 (1 H, d, J = 13.2 Hz), 4.56 (2 H, s), 7.11 (2 H, s), 7.16 (1 H, s), 7.23 (1 H, dd, J = 1.8, 8.7 Hz), 7.53 (1 H, d, J = 8.7 Hz), 7.54 (1 H, d, J = 1.8 Hz)

Example 178

Yield: 60%, 1H-NMR (CDCl3): δ1.24 (3H, d, J = 6.0Hz), 2.23-2.34 (1H, m), 2.36 (3H, s), 2.60-2.72 (1H, m ), 2.77-2.87 (1H, m), 3.14-3.27 (2H, m), 3.38-3.51 (1H, m), 3.72-3.82 (1H, m), 3.87-3.98 (1H, m), 4.04 (1H , d, J = 13.0Hz), 4.56 (2H, s), 7.12 (2H, s), 7.17 (1H, s), 7.48-7.59 (2H, m), 7.84 (1H, s).

6-クロロ-[4-(3-クロロメチルベンジル)ピペラジン-1-イル]ベンゾチアゾール1塩酸塩 0.50g（1.27mmol）、シアン化ナトリウム0.19g（3.82mmol）の無水N,N-ジメチルホルムアミド5mlの混合物を40℃で1.5時間撹拌した。空冷後、反応液に水及び酢酸エチルを加え抽出した後、有機層を飽和食塩水で洗浄、無水硫酸ナトリウムで乾燥した。減圧下溶媒を留去し、得られた結晶をジイソプロピルエーテルで洗浄し{3-[[4-(6-クロロベンゾチアゾール-2-イル)ピペラジン-1-イル]メチル]フェニル}アセトニトリルを淡褐色結晶として0.35g（72％）を得た。
¹H-NMR(CDCl₃): δ2.58 (4H, t, J=5Hz), 3.57 (2H, s), 3.67 (4H, t, J=5Hz), 3.77 (2H, s), 7.24 (1H, dd, J=8.5, 2Hz), 7.25-7.40 (4H, m), 7.43 (1H, d, J=8.5Hz), 7.55 (1H, d, J=2Hz). Example 179
Preparation of {3-[[4- (6-Chlorobenzothiazol-2-yl) piperazin-1-yl] methyl] phenyl} acetonitrile

6-chloro- [4- (3-chloromethylbenzyl) piperazin-1-yl] benzothiazole monohydrochloride 0.50 g (1.27 mmol), sodium cyanide 0.19 g (3.82 mmol) in anhydrous N, N-dimethylformamide 5 ml The mixture was stirred at 40 ° C. for 1.5 hours. After air cooling, water and ethyl acetate were added to the reaction solution for extraction, and the organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the resulting crystals were washed with diisopropyl ether and {3-[[4- (6-chlorobenzothiazol-2-yl) piperazin-1-yl] methyl] phenyl} acetonitrile was pale brown 0.35 g (72%) was obtained as crystals.
¹ H-NMR (CDCl ₃ ): δ2.58 (4H, t, J = 5Hz), 3.57 (2H, s), 3.67 (4H, t, J = 5Hz), 3.77 (2H, s), 7.24 (1H , dd, J = 8.5, 2Hz), 7.25-7.40 (4H, m), 7.43 (1H, d, J = 8.5Hz), 7.55 (1H, d, J = 2Hz).

収率：95％, ¹H-NMR(CDCl₃); δ1.98-2.06 (2H, m), 2.69 (2H, t, J=5.4Hz), 2.79-2.83 (2H, m), 3.65 (2H, s) 3.72-3.80 (6H, m), 7.21-7.25 (2H, m), 7.29-7.33 (3H, m), 7.43 (1H, d, J=8.7Hz), 7.55 (1H, d, J=2.4Hz).

実施例１８１

収率：99％, ¹H-NMR(CDCl₃); δ2.59 (4H, t, J=5Hz), 3.58 (2H, s), 3.69(4H, t, J=5Hz), 3.77 (2H, s), 7.20-7.40 (4H, m), 7.50-7.60 (2H, m), 7.85 (1H, d, J=0.5Hz).

実施例１８２

収率：74％, ¹H-NMR(CDCl₃); δ1.98-2.10 (2H, m), 2.64-2.74 (2H, m), 2.77-2.88 (2H, m), 3.65 (2H, s), 3.68-3.90 (4H, m), 3.74 (2H, s), 7.18-7.38 (4H, m), 7.48-7.59 (2H, m), 7.84 (1H, s).

実施例１８３

収率：68％, ¹H-NMR(CDCl₃); δ1.41 (3H, d, J=6.5Hz), 2.26 (1H, td, J=11, 2.5Hz), 2.35 (1H, dd, J=11, 4Hz), 2.71 (1H, d, J=11Hz), 2.89 (1H, d, J=11Hz), 3.47 (1H, d, J=13Hz), 3.50 (1H, td, J=13, 3Hz), 3.61 (1H, d, J=13Hz), 3.77 (2H, s), 3.87(1H, d, J=13Hz), 4.15-4.25 (1H, m), 7.23 (1H, dd, J=8.5, 2Hz), 7.25-7.30 (1H, m), 7.30-7.40 (3H, m), 7.42 (1H, d, J=8.5Hz), 7.55 (1H, d, J=2Hz).

実施例１８４

収率：86％, ¹H-NMR(CDCl₃); δ1.23 (3H, d, J=6.5Hz), 2.23-2.35 (1H, m), 2.58-2.72 (1H, m), 2.72-2.85 (1H, m), 3.10-3.20 (1H, m), 3.22 (1H, d, J=13.5Hz), 3.33-3.45 (1H, m ), 3.60-3.75 (1H, m), 3.76 (2H, s), 3.83-3.93 (1H, m), 4.06 (1H, d, J=13.5Hz), 7.23 (1H, dd, J=8.5, 2Hz), 7.25-7.35 (4H, m), 7.43 (1H, d, J=8.5Hz), 7.55 (1H, d, J=2Hz).

実施例１８５

収率：59％, ¹H-NMR(CDCl₃); δ1.10 (6H, d, J=6Hz), 2.70-2.85 (2H, m), 3.05 (2H, dd, J=13, 13Hz), 3.76 (2H, s), 3.83 (2H, s), 3.88 (2H, dd, J=13, 2Hz), 7.18 (1H, d, J=7Hz), 7.25 (1H, dd, J=8.5, 2Hz), 7.30-7.40 (3H, m), 7.43 (1H, d, J=8.5Hz), 7.55 (1H, d, J=2Hz).

実施例１８６

収率：97％, ¹H-NMR(CDCl₃); δ1.09 (3H, d, J=6.5Hz), 1.39 (3H, d, J=6.5Hz), 2.31 (1H, d, J=11.5Hz), 2.90 (1H, dd, J=11.5, 4Hz), 3.08-3.20 (1H, m), 3.53 (1H, t, J=14Hz), 3.64 (1H, d, J=12.5Hz), 3.70 (1H, d, J=14Hz), 3.72 (1H, dd, J=12.5, 4Hz), 3.76 (2H, s), 4.18-4.30 (1H, m), 7.21 (1H, dd, J=8.5, 2Hz), 7.21-7.25 (1H, m), 7.30-7.40 (3H, m), 7.41 (1H, d, J=8.5Hz), 7.53 (1H, d, J=2Hz).

実施例１８７

収率：35％, ¹H-NMR(CDCl₃); δ2.37 (3H, s), 2.58 (4H, t, J=5Hz), 3.52 (2H, s), 3.63 (4H, t, J=5Hz), 3.73 (2H, s), 7.10 -7.30 (4H, m), 7.43 (1H, d, J=8.5Hz), 7.55 (1H, d, J=2Hz).

実施例１８８

収率：69％, ¹H-NMR(CDCl₃); δ2.65 (4H, t, J=5Hz), 3.66 (4H, t, J=5Hz), 3.68 (2H, s), 3.76 (2H, s), 7.19 (1H, dd, J=8, 2Hz), 7.24 (1H, dd, 8.5, 2Hz), 7.38 (1H, d, J=8Hz), 7.44 (1H, d, J=8.5Hz), 7.51 (1H, d, J=2Hz), 7.56 (1H, d, J=2Hz).

実施例１８９

収率：78％, ¹H-NMR(CDCl₃); δ1.99-2.05 (2H, m), 2.32 (3H, s), 2.67 (2H, t, J=5.4Hz), 2.79-2.83 (2H, m), 3.58 (2H, s), 3.70 (2H, s), 3.72-3.78 (4H, m), 7.13-7.14 (2H, m), 7.21-7.26 (2H, m), 7.42 (1H, d, J=8.4Hz), 7.55 (1H, d, J=2.1Hz).

実施例１９０

収率：99％, ¹H-NMR(CDCl₃); δ2.03-2.07 (2H, m), 2.75 (2H, t, J=5.4Hz), 2.87-2.90 (2H, m), 3.70 (2H, s), 3.75 (2H, s), 3.75 (2H, t, J=6.0Hz), 3.82 (2H, t, J= 5.1Hz), 7.16 (1H, dd, J=8.1, 2.1Hz), 7.23 (1H, dd, J=8.4Hz, 2.1Hz), 7.35 (1H, d, J=8.4Hz), 7.42 (1H, d, J =8.4Hz), 7.49 (1H, d, J=2.4Hz), 7.56 (1H, d, J=2.1Hz).

実施例１９１

収率：78％, ¹H-NMR(CDCl₃); δ2.36 (3H, s), 2.57 (4H, t, J=5Hz), 3.51 (2H, s), 3.64 (4H, t, J=5Hz), 3.72 (2H, s), 7.06 (1H, s), 7.10 (1H, s), 7.11 (1H, s), 7.23 (1H, dd, J=8.5, 2Hz), 7.42 (1H, d, J=8.5Hz), 7.55 (1H, d, J=2Hz).

実施例１９２

収率：q. y, ¹H-NMR(CDCl₃); δ1.99-2.06 (2H, m), 2.35 (3H, s), 2.67 (2H, t, J=5.4Hz ), 2.78-2.82 (2H, m), 3.60 (2H, s), 3.70-3.78 (6H, m), 7.04 (1H, s), 7.09 (2H, s), 7.23 (1H, dd, J=8. 7, 2.1Hz), 7.43 (1H, d, J=8.7Hz), 7.55 (1H, d, J=2.1Hz).

実施例１９３

収率：68％, ¹H-NMR(CDCl₃); δ2.50-2.60 (4H, m), 3.50-3.60 (4H, m), 3.72 (2H, s), 4.24 (2H, s), 6.88 (1H, d, J=3Hz), 6.91 (1H, d, J=3Hz), 7.28 (1H, dd, J=8.5, 1.5Hz), 7.42 (1H, d, J=8.5Hz), 7.91 (1H, d, J=1.5Hz).

実施例１９４

収率：32％, ¹H-NMR(CDCl₃); δ1.99-2.07 (2H, m), 2.70-2.74 (2H, m), 2.83-2.87 (2H, m), 3.73 (2H, t, J=6.0Hz), 3.77-3.80 (2H, m), 3.80 (2H, s), 3.86 (2H, s), 6.76 ( 1H, d, J=3.3Hz), 6.88 (1H, td, J=3.3, 0.9Hz), 7.23 (1H, dd, J= 8.7, 2.1Hz), 7.42 (1H, d, J=8.4Hz), 7.55 (1H, d, J=2.4Hz).

実施例１９５

収率：93％, ¹H-NMR(CDCl₃); δ2.27 (3H, s), 2.58 (4H, t, J=5Hz), 3.53 (2H, s), 3.69 (4H, t, J=5Hz), 3.72 (2H, s), 7.07 (1H, s), 7.11 (1H, s), 7.12 (1H, s), 7.52 (1H, d, J=8.5Hz), 7.57 (1H, d, J=8.5Hz), 7.85 (1H, s).

実施例１９６

収率：86％, ¹H-NMR(CDCl₃); δ1.95-2.10 (2H, m), 2.34 (3H, s), 2.69 (2H, t, J=5.5Hz), 2.82 (2H, t, J=5.5Hz), 3.61 (2H, s), 3.69 (2H, s), 3.70-3.90 (4H, m), 7.04 (1H, s), 7.08 (1H, s), 7.09 (1H, s), 7.51 (1H, d, J=8.5Hz), 7.56 (1H, d, J=8.5Hz), 7.85 (1H, s).

実施例１９７

収率：85％, ¹H-NMR(DMSO-d₆): δ2.45-2.55 (4H, m), 2.81 (2H, t, J=5Hz), 2.87 (2H, t, J=5Hz), 3.52 (2H, s), 3.56 (4H, t, J=5.5Hz), 7.20-7.35 (5H, m), 7.42 (1H, d, J=8.5Hz), 7.91 (1H, d, J=2Hz).

実施例１９８

収率：84％, 1H-NMR(CDCl3): δ1.12 (6H, d, J=6Hz), 2.36 (3H, s), 2.75-2.87 (2H, m), 3.10 (1H, d, J=13Hz), 3.13 (1H, d, J=13Hz), 3.71 (2H, s), 3.79 (2H, s), 3.92 (2H, dd, J=13, 2Hz), 7.00 (1H, s), 7.14 (1H, s), 7.16 (1H, s), 7.52 (1H, dd, J=8.5, 1Hz), 7.57 (1H, d, J=8.5Hz), 7.84 (1H, d, J=1Hz).

実施例１９９

収率：86％, 1H-NMR(CDCl3): δ1.23 (3H, d, J=6Hz), 2.20-2.35 (1H, m), 2.36 (3H, s), 2.61-2.73 (1H, m), 2.80 (1H, dt, J=12, 3.5Hz), 3.15-3.28 (2H, m), 3.40-3.50 (1H, m), 3.71 (2H, s), 3.71-3.81 (1H, m), 3.87-3.97 (1H, m), 4.02 (1H, d, J=13.5Hz), 7.05 (1H, s), 7.11 (2H, s), 7.50 (1H, d, J=8.5Hz), 7.56 (1H, d, J=8.5Hz), 7.84 (1H, s)

実施例２００

収率：79％, 1H-NMR(CDCl3): δ1.43 (3H, d, J=6.5Hz), 2.26 (1H, td, J=11.5, 3.5Hz), 2.30-2.33 (1H, m), 2.34 (3H, s), 2.72 (1H, d, J=11Hz), 2.91 (1H, d, J=11.5Hz), 3.45 (1H, d, J=13.5Hz), 3.54 (1H, td, J=13, 3.5Hz), 3.58 (1H, d, J=13.5Hz), 3.72 (2H, s), 3.92 (1H, d, J=13Hz), 4.20-4.30 (1H, m), 7.06 (1H, s), 7.13 (1H, s), 7.15 (1H, s), 7.51 (1H, d, J=8.5Hz), 7.56 (1H, d, J=8.5Hz), 7.84 (1H, s).

実施例２０１

収率：90％, 1H-NMR(CDCl3): δ1.22 (3 H, d, J = 6.3 Hz), 2.23-2.32 (1 H, m), 2.36 (3 H, s), 2.59-2.69 (1 H, m), 2.78 (1 H, dt, J = 3.6, 8.1 Hz), 3.17 (2 H, dt, J = 3.6, 13.5 Hz), 3.35-3.44 (1 H, m), 3.70-3.75 (1 H, m), 3.71 (2 H, s), 3.85-3.90 (1 H, m), 4.02 (1 H, s), 7.05 (1 H, s), 7.11 (2 H, s), 7.23 (1 H, dd, J = 2.1, 8.7 Hz), 7.43 (1 H, d, J = 8.7 Hz), 7.55 (1 H, d, J = 2.1 Hz)

実施例２０２

収率：98％, 1H-NMR(CDCl3): δ1.22 (3 H, d, J = 6.3 Hz), 2.23-2.32 (1 H, m), 2.36 (3 H, s), 2.62-2.66 (1 H, m), 2.78 (1 H, dt, J = 3.9, 11.7 Hz), 3.17 (2 H, dt, J = 3.9, 13.5 Hz), 3.35-3.44 (1 H, m), 3.71 (2 H, s), 3.70-3.74 (1 H, m), 3.87 (1 H, dd, J = 2.1, 12.6 Hz), 4.02 (1 H, d, J = 13.5 Hz), 7.05 (1 H, s), 7.11 (2 H, s), 7.23 (1 H, dd, J = 2.1, 8.4 Hz), 7.43 (1 H, d, J = 8.4 Hz), 7.55 (1H, d, J = 2.1 Hz)

実施例２０３

収率：85％, 1H-NMR(CDCl3): δ1.24 (3H, d, J=6.5Hz), 2.23-2.34 (1H, m), 2.37 (3H, s), 2.60-2.73 (1H, m), 2.80 (1H, dt, J=12.0, 3.5Hz), 3.13-3.27 (2H, m), 3.39-3.51 (1H, m), 3.70-3.83 (3H, m), 3.87-3.97 (1H, m), 4.03 (1H, d, J=13.5Hz), 7.06 (1H, s), 7.11 (2H, s), 7.48-7.59 (2H, m), 7.84 (1H, s). Thereafter, the compounds described in Examples 180 to 203 were obtained in the same manner as in Example 179.
Example 180

Yield: 95%, ¹ H-NMR (CDCl ₃ ); δ1.98-2.06 (2H, m), 2.69 (2H, t, J = 5.4Hz), 2.79-2.83 (2H, m), 3.65 (2H , s) 3.72-3.80 (6H, m), 7.21-7.25 (2H, m), 7.29-7.33 (3H, m), 7.43 (1H, d, J = 8.7Hz), 7.55 (1H, d, J = 2.4Hz).

Example 181

Yield: 99%, ¹ H-NMR (CDCl ₃ ); δ 2.59 (4H, t, J = 5Hz), 3.58 (2H, s), 3.69 (4H, t, J = 5Hz), 3.77 (2H, s), 7.20-7.40 (4H, m), 7.50-7.60 (2H, m), 7.85 (1H, d, J = 0.5Hz).

Example 182

Yield: 74%, ¹ H-NMR (CDCl ₃ ); δ1.98-2.10 (2H, m), 2.64-2.74 (2H, m), 2.77-2.88 (2H, m), 3.65 (2H, s) , 3.68-3.90 (4H, m), 3.74 (2H, s), 7.18-7.38 (4H, m), 7.48-7.59 (2H, m), 7.84 (1H, s).

Example 183

Yield: 68%, ¹ H-NMR (CDCl ₃ ); δ1.41 (3H, d, J = 6.5Hz), 2.26 (1H, td, J = 11, 2.5Hz), 2.35 (1H, dd, J = 11, 4Hz), 2.71 (1H, d, J = 11Hz), 2.89 (1H, d, J = 11Hz), 3.47 (1H, d, J = 13Hz), 3.50 (1H, td, J = 13, 3Hz ), 3.61 (1H, d, J = 13Hz), 3.77 (2H, s), 3.87 (1H, d, J = 13Hz), 4.15-4.25 (1H, m), 7.23 (1H, dd, J = 8.5, 2Hz), 7.25-7.30 (1H, m), 7.30-7.40 (3H, m), 7.42 (1H, d, J = 8.5Hz), 7.55 (1H, d, J = 2Hz).

Example 184

Yield: 86%, ¹ H-NMR (CDCl ₃ ); δ1.23 (3H, d, J = 6.5Hz), 2.23-2.35 (1H, m), 2.58-2.72 (1H, m), 2.72-2.85 (1H, m), 3.10-3.20 (1H, m), 3.22 (1H, d, J = 13.5Hz), 3.33-3.45 (1H, m), 3.60-3.75 (1H, m), 3.76 (2H, s ), 3.83-3.93 (1H, m), 4.06 (1H, d, J = 13.5Hz), 7.23 (1H, dd, J = 8.5, 2Hz), 7.25-7.35 (4H, m), 7.43 (1H, d , J = 8.5Hz), 7.55 (1H, d, J = 2Hz).

Example 185

Yield: 59%, ¹ H-NMR (CDCl ₃ ); δ1.10 (6H, d, J = 6Hz), 2.70-2.85 (2H, m), 3.05 (2H, dd, J = 13, 13Hz), 3.76 (2H, s), 3.83 (2H, s), 3.88 (2H, dd, J = 13, 2Hz), 7.18 (1H, d, J = 7Hz), 7.25 (1H, dd, J = 8.5, 2Hz) , 7.30-7.40 (3H, m), 7.43 (1H, d, J = 8.5Hz), 7.55 (1H, d, J = 2Hz).

Example 186

Yield: 97%, ¹ H-NMR (CDCl ₃ ); δ 1.09 (3H, d, J = 6.5 Hz), 1.39 (3H, d, J = 6.5 Hz), 2.31 (1H, d, J = 11.5 Hz), 2.90 (1H, dd, J = 11.5, 4Hz), 3.08-3.20 (1H, m), 3.53 (1H, t, J = 14Hz), 3.64 (1H, d, J = 12.5Hz), 3.70 ( 1H, d, J = 14Hz), 3.72 (1H, dd, J = 12.5, 4Hz), 3.76 (2H, s), 4.18-4.30 (1H, m), 7.21 (1H, dd, J = 8.5, 2Hz) , 7.21-7.25 (1H, m), 7.30-7.40 (3H, m), 7.41 (1H, d, J = 8.5Hz), 7.53 (1H, d, J = 2Hz).

Example 187

Yield: 35%, ¹ H-NMR (CDCl ₃ ); δ2.37 (3H, s), 2.58 (4H, t, J = 5Hz), 3.52 (2H, s), 3.63 (4H, t, J = 5Hz), 3.73 (2H, s), 7.10 -7.30 (4H, m), 7.43 (1H, d, J = 8.5Hz), 7.55 (1H, d, J = 2Hz).

Example 188

Yield: 69%, ¹ H-NMR (CDCl ₃ ); δ 2.65 (4H, t, J = 5Hz), 3.66 (4H, t, J = 5Hz), 3.68 (2H, s), 3.76 (2H, s), 7.19 (1H, dd, J = 8, 2Hz), 7.24 (1H, dd, 8.5, 2Hz), 7.38 (1H, d, J = 8Hz), 7.44 (1H, d, J = 8.5Hz), 7.51 (1H, d, J = 2Hz), 7.56 (1H, d, J = 2Hz).

Example 189

Yield: 78%, ¹ H-NMR (CDCl ₃ ); δ1.99-2.05 (2H, m), 2.32 (3H, s), 2.67 (2H, t, J = 5.4Hz), 2.79-2.83 (2H , m), 3.58 (2H, s), 3.70 (2H, s), 3.72-3.78 (4H, m), 7.13-7.14 (2H, m), 7.21-7.26 (2H, m), 7.42 (1H, d , J = 8.4Hz), 7.55 (1H, d, J = 2.1Hz).

Example 190

Yield: 99%, ¹ H-NMR (CDCl ₃ ); δ2.03-2.07 (2H, m), 2.75 (2H, t, J = 5.4Hz), 2.87-2.90 (2H, m), 3.70 (2H , s), 3.75 (2H, s), 3.75 (2H, t, J = 6.0Hz), 3.82 (2H, t, J = 5.1Hz), 7.16 (1H, dd, J = 8.1, 2.1Hz), 7.23 (1H, dd, J = 8.4Hz, 2.1Hz), 7.35 (1H, d, J = 8.4Hz), 7.42 (1H, d, J = 8.4Hz), 7.49 (1H, d, J = 2.4Hz), 7.56 (1H, d, J = 2.1Hz).

Example 191

Yield: 78%, ¹ H-NMR (CDCl ₃ ); δ 2.36 (3H, s), 2.57 (4H, t, J = 5Hz), 3.51 (2H, s), 3.64 (4H, t, J = 5Hz), 3.72 (2H, s), 7.06 (1H, s), 7.10 (1H, s), 7.11 (1H, s), 7.23 (1H, dd, J = 8.5, 2Hz), 7.42 (1H, d, J = 8.5Hz), 7.55 (1H, d, J = 2Hz).

Example 192

Yield: q. Y, ¹ H-NMR (CDCl ₃ ); δ1.99-2.06 (2H, m), 2.35 (3H, s), 2.67 (2H, t, J = 5.4Hz), 2.78-2.82 ( 2H, m), 3.60 (2H, s), 3.70-3.78 (6H, m), 7.04 (1H, s), 7.09 (2H, s), 7.23 (1H, dd, J = 8, 7, 2.1Hz) , 7.43 (1H, d, J = 8.7Hz), 7.55 (1H, d, J = 2.1Hz).

Example 193

Yield: 68%, ¹ H-NMR (CDCl ₃ ); δ2.50-2.60 (4H, m), 3.50-3.60 (4H, m), 3.72 (2H, s), 4.24 (2H, s), 6.88 (1H, d, J = 3Hz), 6.91 (1H, d, J = 3Hz), 7.28 (1H, dd, J = 8.5, 1.5Hz), 7.42 (1H, d, J = 8.5Hz), 7.91 (1H , d, J = 1.5Hz).

Example 194

Yield: 32%, ¹ H-NMR (CDCl ₃ ); δ1.99-2.07 (2H, m), 2.70-2.74 (2H, m), 2.83-2.87 (2H, m), 3.73 (2H, t, J = 6.0Hz), 3.77-3.80 (2H, m), 3.80 (2H, s), 3.86 (2H, s), 6.76 (1H, d, J = 3.3Hz), 6.88 (1H, td, J = 3.3 0.9Hz), 7.23 (1H, dd, J = 8.7, 2.1Hz), 7.42 (1H, d, J = 8.4Hz), 7.55 (1H, d, J = 2.4Hz).

Example 195

Yield: 93%, ¹ H-NMR (CDCl ₃ ); δ2.27 (3H, s), 2.58 (4H, t, J = 5Hz), 3.53 (2H, s), 3.69 (4H, t, J = 5Hz), 3.72 (2H, s), 7.07 (1H, s), 7.11 (1H, s), 7.12 (1H, s), 7.52 (1H, d, J = 8.5Hz), 7.57 (1H, d, J = 8.5Hz), 7.85 (1H, s).

Example 196

Yield: 86%, ¹ H-NMR (CDCl ₃ ); δ1.95-2.10 (2H, m), 2.34 (3H, s), 2.69 (2H, t, J = 5.5Hz), 2.82 (2H, t , J = 5.5Hz), 3.61 (2H, s), 3.69 (2H, s), 3.70-3.90 (4H, m), 7.04 (1H, s), 7.08 (1H, s), 7.09 (1H, s) , 7.51 (1H, d, J = 8.5Hz), 7.56 (1H, d, J = 8.5Hz), 7.85 (1H, s).

Example 197

Yield: 85%, ¹ H-NMR (DMSO-d ₆ ): δ2.45-2.55 (4H, m), 2.81 (2H, t, J = 5Hz), 2.87 (2H, t, J = 5Hz), 3.52 (2H, s), 3.56 (4H, t, J = 5.5Hz), 7.20-7.35 (5H, m), 7.42 (1H, d, J = 8.5Hz), 7.91 (1H, d, J = 2Hz) .

Example 198

Yield: 84%, 1H-NMR (CDCl3): δ1.12 (6H, d, J = 6Hz), 2.36 (3H, s), 2.75-2.87 (2H, m), 3.10 (1H, d, J = 13Hz), 3.13 (1H, d, J = 13Hz), 3.71 (2H, s), 3.79 (2H, s), 3.92 (2H, dd, J = 13, 2Hz), 7.00 (1H, s), 7.14 ( 1H, s), 7.16 (1H, s), 7.52 (1H, dd, J = 8.5, 1Hz), 7.57 (1H, d, J = 8.5Hz), 7.84 (1H, d, J = 1Hz).

Example 199

Yield: 86%, 1H-NMR (CDCl3): δ1.23 (3H, d, J = 6Hz), 2.20-2.35 (1H, m), 2.36 (3H, s), 2.61-2.73 (1H, m) , 2.80 (1H, dt, J = 12, 3.5Hz), 3.15-3.28 (2H, m), 3.40-3.50 (1H, m), 3.71 (2H, s), 3.71-3.81 (1H, m), 3.87 -3.97 (1H, m), 4.02 (1H, d, J = 13.5Hz), 7.05 (1H, s), 7.11 (2H, s), 7.50 (1H, d, J = 8.5Hz), 7.56 (1H, d, J = 8.5Hz), 7.84 (1H, s)

Example 200

Yield: 79%, 1H-NMR (CDCl3): δ1.43 (3H, d, J = 6.5Hz), 2.26 (1H, td, J = 11.5, 3.5Hz), 2.30-2.33 (1H, m), 2.34 (3H, s), 2.72 (1H, d, J = 11Hz), 2.91 (1H, d, J = 11.5Hz), 3.45 (1H, d, J = 13.5Hz), 3.54 (1H, td, J = 13, 3.5Hz), 3.58 (1H, d, J = 13.5Hz), 3.72 (2H, s), 3.92 (1H, d, J = 13Hz), 4.20-4.30 (1H, m), 7.06 (1H, s ), 7.13 (1H, s), 7.15 (1H, s), 7.51 (1H, d, J = 8.5Hz), 7.56 (1H, d, J = 8.5Hz), 7.84 (1H, s).

Example 201

Yield: 90%, 1H-NMR (CDCl3): δ1.22 (3 H, d, J = 6.3 Hz), 2.23-2.32 (1 H, m), 2.36 (3 H, s), 2.59-2.69 ( 1 H, m), 2.78 (1 H, dt, J = 3.6, 8.1 Hz), 3.17 (2 H, dt, J = 3.6, 13.5 Hz), 3.35-3.44 (1 H, m), 3.70-3.75 ( 1 H, m), 3.71 (2 H, s), 3.85-3.90 (1 H, m), 4.02 (1 H, s), 7.05 (1 H, s), 7.11 (2 H, s), 7.23 ( 1 H, dd, J = 2.1, 8.7 Hz), 7.43 (1 H, d, J = 8.7 Hz), 7.55 (1 H, d, J = 2.1 Hz)

Example 202

Yield: 98%, 1H-NMR (CDCl3): δ1.22 (3 H, d, J = 6.3 Hz), 2.23-2.32 (1 H, m), 2.36 (3 H, s), 2.62-2.66 ( 1 H, m), 2.78 (1 H, dt, J = 3.9, 11.7 Hz), 3.17 (2 H, dt, J = 3.9, 13.5 Hz), 3.35-3.44 (1 H, m), 3.71 (2 H , s), 3.70-3.74 (1 H, m), 3.87 (1 H, dd, J = 2.1, 12.6 Hz), 4.02 (1 H, d, J = 13.5 Hz), 7.05 (1 H, s), 7.11 (2 H, s), 7.23 (1 H, dd, J = 2.1, 8.4 Hz), 7.43 (1 H, d, J = 8.4 Hz), 7.55 (1H, d, J = 2.1 Hz)

Example 203

Yield: 85%, 1H-NMR (CDCl3): δ1.24 (3H, d, J = 6.5Hz), 2.23-2.34 (1H, m), 2.37 (3H, s), 2.60-2.73 (1H, m ), 2.80 (1H, dt, J = 12.0, 3.5Hz), 3.13-3.27 (2H, m), 3.39-3.51 (1H, m), 3.70-3.83 (3H, m), 3.87-3.97 (1H, m ), 4.03 (1H, d, J = 13.5Hz), 7.06 (1H, s), 7.11 (2H, s), 7.48-7.59 (2H, m), 7.84 (1H, s).

水素化ナトリウム0.15g（60%, 3.81mmol）の無水THF懸濁液に氷冷下、マロン酸ジエチル0.58ml（3.81mmol）を滴下し、室温下30分撹拌した。反応液に6-クロロ-[4-(3-クロロメチルベンジル)ピペラジン-1-イル]ベンゾチアゾール1塩酸塩0.50g（1.27mmol）を加入し、同温下14.5時間撹拌した後、50℃で38時間撹拌した。反応液に水及び酢酸エチルを加え抽出した後、有機層を飽和食塩水で洗浄、無水硫酸ナトリウムで乾燥した。減圧下溶媒を留去し、残渣をシリカゲルカラムクロマトグラフィー（ヘキサン：酢酸エチル＝3：1）で精製し、2-{3-[4-(6-クロロベンゾチアゾール-2-イル)ピペラジン-1-イルメチル]ベンジル}マロン酸ジエチルを無色油状物として0.38ｇ（58％）得た。
¹H-NMR(DMSO-d₆): δ1.10 (6H, t, J=7Hz), 2.49 (4H, t, J=5Hz), 3.08 (2H, d, J=8Hz), 3.50 (2H, s), 3.56 (4H, t, J=5Hz), 3.81 (1H, t, J=8Hz), 4.06 (4H, q, J=7Hz), 7.10-7.20 (3H, m), 7.24 (1H, d, J=7.5Hz), 7.28 (1H, dd, J=8.5, 2Hz), 7.42 (1H, d, J=8.5Hz), 7.91 (1H, d, J=2Hz). Example 204
Preparation of diethyl 2- {3- [4- (6-chlorobenzothiazol-2-yl) piperazin-1-ylmethyl] benzyl} malonate

To an anhydrous THF suspension of sodium hydride 0.15 g (60%, 3.81 mmol), 0.58 ml (3.81 mmol) of diethyl malonate was added dropwise under ice cooling, followed by stirring at room temperature for 30 minutes. To the reaction solution was added 0.50 g (1.27 mmol) of 6-chloro- [4- (3-chloromethylbenzyl) piperazin-1-yl] benzothiazole monohydrochloride, and the mixture was stirred at the same temperature for 14.5 hours. Stir for 38 hours. Water and ethyl acetate were added to the reaction solution for extraction, and the organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 3: 1) to give 2- {3- [4- (6-chlorobenzothiazol-2-yl) piperazine-1 There was obtained 0.38 g (58%) of diethyl -ylmethyl] benzyl} malonate as a colorless oil.
¹ H-NMR (DMSO-d ₆ ): δ1.10 (6H, t, J = 7Hz), 2.49 (4H, t, J = 5Hz), 3.08 (2H, d, J = 8Hz), 3.50 (2H, s), 3.56 (4H, t, J = 5Hz), 3.81 (1H, t, J = 8Hz), 4.06 (4H, q, J = 7Hz), 7.10-7.20 (3H, m), 7.24 (1H, d , J = 7.5Hz), 7.28 (1H, dd, J = 8.5, 2Hz), 7.42 (1H, d, J = 8.5Hz), 7.91 (1H, d, J = 2Hz).

収率：46％, ¹H-NMR(CDCl₃); δ1.26 (6H, t, J=7Hz), 2.59 (4H, t, J=5Hz), 3.38 (2H, d, J=7.5Hz), 3.60-3.68 (5H, m), 3.69 (2H, s), 4.24 (4H, q, J=7Hz), 6.68 (1H, d, J=3Hz), 6.71 (1H, d, J=3Hz), 7.25 (1H, dd, J=9, 2Hz), 7.43 (1H, d, J=9Hz), 7.55 (1H, d, J=2Hz).

実施例２０６

収率：5％, ¹H-NMR(CDCl₃); δ1.21-1.32 (6H, m), 2.00-2.05 (2H, m), 2.70 (2H, t, J= 5.4Hz), 2.81-2.84 (2H, m), 3.36-3.38 (2H, m), 3.62-3.82 (7H, m), 4.14-4.24 (4H, m), 6.65-6.68 (2H, m), 7.22 (1H, dd, J=9.0, 1.8Hz), 7.42 (1H, d, J=8.4Hz), 7.54 (1H, d, J=1.8Hz). Thereafter, the compounds described in Examples 205 and 206 were obtained in the same manner as in Example 204.
Example 205

Yield: 46%, ¹ H-NMR (CDCl ₃ ); δ1.26 (6H, t, J = 7Hz), 2.59 (4H, t, J = 5Hz), 3.38 (2H, d, J = 7.5Hz) , 3.60-3.68 (5H, m), 3.69 (2H, s), 4.24 (4H, q, J = 7Hz), 6.68 (1H, d, J = 3Hz), 6.71 (1H, d, J = 3Hz), 7.25 (1H, dd, J = 9, 2Hz), 7.43 (1H, d, J = 9Hz), 7.55 (1H, d, J = 2Hz).

Example 206

Yield: 5%, ¹ H-NMR (CDCl ₃ ); δ1.21-1.32 (6H, m), 2.00-2.05 (2H, m), 2.70 (2H, t, J = 5.4Hz), 2.81-2.84 (2H, m), 3.36-3.38 (2H, m), 3.62-3.82 (7H, m), 4.14-4.24 (4H, m), 6.65-6.68 (2H, m), 7.22 (1H, dd, J = 9.0, 1.8Hz), 7.42 (1H, d, J = 8.4Hz), 7.54 (1H, d, J = 1.8Hz).

2,6-ジクロロベンゾチアゾール3.00g(14.7mmol)、4-ピペリジンエタノール2.09g (16.2mmol)、炭酸カリウム2.33g (16.2mmol)及び無水N,N-ジメチルホルムアミド15mlの混合物を室温下16時間撹拌した。反応液に水及び酢酸エチルを加え抽出し、有機層を飽和食塩水で洗浄、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、結晶をジイソプロピルエーテルで洗浄し6-クロロ-2-[4-(2-ヒドロキシエチル)ピペリジン-１-イル]ベンゾチアゾールを緑色結晶として2.92g（67％）得た。
¹H-NMR(CDCl₃): δ1.26-1.44 (3H, m), 1.57 (2H, q, J=6.5Hz), 1.68-1.91 (3H, m), 3.06-3.19 (2H, m), 3.74 (2H, q, J=6.5Hz), 4.07-4.17 (2H, m), 7.22 (1H, dd, J=8.5, 2.0Hz), 7.42 (1H, d, J=8.5Hz), 7.54 (1H, d, J=2.0Hz). Reference Example 195
Preparation of 6-chloro-2- [4- (2-hydroxyethyl) piperidin-1-yl] benzothiazole

A mixture of 3.00 g (14.7 mmol) of 2,6-dichlorobenzothiazole, 2.09 g (16.2 mmol) of 4-piperidineethanol, 2.33 g (16.2 mmol) of potassium carbonate and 15 ml of anhydrous N, N-dimethylformamide was stirred at room temperature for 16 hours. did. Water and ethyl acetate were added to the reaction solution for extraction, and the organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After evaporating the solvent under reduced pressure, the crystals were washed with diisopropyl ether to give 2.92 g (67%) of 6-chloro-2- [4- (2-hydroxyethyl) piperidin-1-yl] benzothiazole as green crystals. It was.
¹ H-NMR (CDCl ₃ ): δ1.26-1.44 (3H, m), 1.57 (2H, q, J = 6.5Hz), 1.68-1.91 (3H, m), 3.06-3.19 (2H, m), 3.74 (2H, q, J = 6.5Hz), 4.07-4.17 (2H, m), 7.22 (1H, dd, J = 8.5, 2.0Hz), 7.42 (1H, d, J = 8.5Hz), 7.54 (1H , d, J = 2.0Hz).

収率：64％, ¹H-NMR(CDCl₃); δ1.60-1.75 (3H, m), 1.95-2.18 (2H, m), 3.34-3.48 (2H, m), 3.87-4.10 (3H, m), 7.23 (1H, dd, J=8.5, 2Hz), 7.43 (1H, d, J=8.5Hz), 7.53 (1H, d, J=2Hz).

参考例１９７

収率：100％, ¹H-NMR(DMSO-d₆): δ1.15-1.25 (2H, m), 1.60-1.75 (1H, m), 1.75-1.85 (2H, m), 3.05-3.20 (2H, m), 3.25-3.30 (2H, m), 3.95-4.10 (2H, m), 4.56 (1H, brs), 7.27 (1H, dd, J=8.5, 2Hz), 7.40 (1H, d, J=8.5Hz), 7.88 (1H,d, J=2Hz).

参考例１９８

収率：95％, ¹H-NMR(CDCl₃); δ1.65 (1H, s), 2.60-2.67 (6H, m), 3.63-3.69 (6H, m), 7.23 (1H, d, J=8.5, 2.0Hz), 7.44 (1H, d ,J=8.5Hz), 7.57 (1H, d, J=2.0Hz).

参考例１９９

収率：99％, ¹H-NMR(CDCl₃); δ2.00-2.07 (2H, m), 2.69 (2H, t, J=5.1Hz ), 2.76 (2H, t, J=5.4Hz), 2.89-2.93 (2H, m), 2.96 (1H, s), 3.60 (2H, t, J=5.4Hz), 3.73 (2H, t, J= 6.0Hz), 3.80-3.83 (2H, m), 7.24 (1H, dd, J=7.8, 2.1Hz), 7.42 ( 1H, d, J=8.7Hz), 7.55 (1H, d, J=2.1Hz).

参考例２００

収率：48％, ¹H-NMR(CDCl₃); δ1.28-1.46 (2H, m), 1.58 (2H, q, J=6.5Hz), 1.72-1.94 (3H, m), 3.11-3.24 (2H, m), 3.76 (2H, t, J=6.5Hz), 4.11-4.22 (2H, m), 7.48-7.57 (2H, m), 7.83 (1H, s).

参考例２０１

収率：70％, ¹H-NMR(DMSO-d₆): δ2.49 (2H, t, J=6Hz), 2.57 (4H, t, J=5Hz), 3.55 (2H, t, J=6Hz), 3.62 (4H, t, J=5Hz), 4.51 (1H, brs), 7.57 (2H, s), 8.25 (1H, s).

参考例２０２

収率：85％, ¹H-NMR(DMSO-d₆): δ1.83-1.90 (2H, m), 2.55 (2H, t, J=5.5Hz), 2.67 (2H, t, J=5Hz), 2.87 (2H, t, J=5Hz), 3.47 (2H, q, J=5.5Hz), 3.60-3.80 (4H, m), 4.39 (1H, t, J=5.5Hz), 7.55 (1H, s), 7.95 (1H, s), 8.21 (1H, s).

参考例２０３

収率：63％, ¹H-NMR(CDCl₃); δ1.23-1.44 (3H, m), 1.53-1.63 (2H, m), 1.68-1.90 (3H, m), 3.08-3.20 (2H, m), 3.75 (2H, q, J=6.0Hz), 4.08-4.18 (2H, m), 7.02 (1H, dd, J=8.5, 2.0Hz), 7.46 (1H, d, J=8.5Hz), 7.49 (1H, d, J=2.0Hz).

参考例２０４

収率：36％, ¹H-NMR(CDCl₃); δ1.25-1.45 (3H, m), 1.57 (2H, q, J =6.5Hz), 1.70-1.91 (3H, m), 3.08-3.23 (2H, m), 3.75 (2H, t, J=6.5Hz), 4.08-4.21 (2H, m), 7.04 (1H, dd, J=8.0, 1.0Hz), 7.21 (1H, t, J=8.0Hz), 7.39 (1H, dd, J=8.0, 1.0Hz).

参考例２０５

収率：52％, ¹H-NMR(CDCl₃); δ1.26 (1H, t, J=6.5Hz), 1.27-1.44 (2H, m), 1.57 (2H, q, J=6.5Hz), 1.68-1.91 (3H, m), 3.06-3.19 (2H, m), 3.75 (2H, q, J=6.5Hz), 4.05-4.19 (2H, m), 7.35-7.40 (2H, m), 7.68 (1H, s).

参考例２０６

収率：31％, ¹H-NMR(CDCl₃); δ1.22 (1H, t, J=5.0Hz), 1.27-1.45 (2H, m), 1.57 (2H, q, J=5.0Hz), 1.65-1.90 (3H, m), 2.38 (3H, s), 3.03-3.19 (2H, m), 3.75 (2H, q, J=5.0Hz), 4.06-4.17 (2H, m), 7.08 (1H, d, J=8.0Hz), 7.39 (1H, s), 7.42 (1H, d, J=8.0Hz).

参考例２０７

収率：9％, ¹H-NMR(CDCl₃); δ1.23-1.45 (3H, m), 1.52-1.64 (2H, m), 1.67-1.94 (3H, m), 3.40-3.22 (2H, m), 3.68-3.83 (2H, m), 4.03-4.17( 2H, m), 7.00 (1H, td, J=8.5, 2.5Hz), 7.29 (1H, dd, J=8.5, 2.5Hz), 7.40 (1H, dd, J=8.5, 4.0Hz).

参考例２０８

収率：48％, ¹H-NMR(DMSO-d₆): δ1.12-1.29 (2H, m), 1.40 (2H, q, J=6.5Hz), 1.57-1.81 (3H, m), 2.95-3.10 (2H, m), 3.47 (2H, q, J=6.5Hz), 3.84-3.97 (2H, m), 4.40 (1H, t, J=6.5Hz), 7.20 (1H, t, J=7.5Hz), 7.35 (2H, t, J=7.5Hz), 7.44 (2H, d, J=7.5Hz), 7.57 (1H, s).

参考例２０９

収率：88％, 1H-NMR(CDCl3): δ1.14-1.32 (2H, m), 1.40 (2H, q, J=6.5Hz), 1.54-1.83 (3H, m), 2.95-3.08 (2H, m), 3.47 (2H, q, J=6.5Hz), 3.88-4.00 (2H, m), 4.40 (1H, t, J=6.5Hz), 7.22 (1H, s), 7.27 (1H, t, J=7.5Hz), 7.38 (2H, t, J=7.5Hz), 7.87 (2H, d, J=7.5Hz).

参考例２１０

収率：71％, 1H-NMR(DMSO-d6): δ1.82-1.93 (2H, m), 2.55 (2H, t, J=6.0Hz), 2.62-2.70 (2H, m), 2.78-2.86 (2H, m), 3.47 (2H, q, J=6.0Hz), 3.59 (2H, t, J=6.0Hz), 3.61-3.68 (2H, m), 4.38 (1H, t, J=6.0Hz), 7.18 (1H, t, J=7.5Hz), 7.34 (2H, t, J=7.5Hz), 7.45 (2H, d, J=7.5Hz), 7.57 (1H, s).

参考例２１１

収率：93％, 1H-NMR(DMSO-d6): δ1.80-2.01 (2H, m), 2.57 (2H, t, J=6.0Hz), 2.64-2.77 (2H, m), 2.82-2.96 (2H, m), 3.42-3.53 (2H, m), 3.45-3.94 (4H, br), 4.34-4.46 (1H, m), 7.45 (1H, d, J=7.0Hz), 8.23 (1H, d, J=12.5Hz). Thereafter, the compounds described in Reference Examples 196 to 211 were obtained in the same manner as in Reference Example 195.
Reference Example 196

Yield: 64%, ¹ H-NMR (CDCl ₃ ); δ 1.60-1.75 (3H, m), 1.95-2.18 (2H, m), 3.34-3.48 (2H, m), 3.87-4.10 (3H, m), 7.23 (1H, dd, J = 8.5, 2Hz), 7.43 (1H, d, J = 8.5Hz), 7.53 (1H, d, J = 2Hz).

Reference Example 197

Yield: 100%, ¹ H-NMR (DMSO-d ₆ ): δ1.15-1.25 (2H, m), 1.60-1.75 (1H, m), 1.75-1.85 (2H, m), 3.05-3.20 ( 2H, m), 3.25-3.30 (2H, m), 3.95-4.10 (2H, m), 4.56 (1H, brs), 7.27 (1H, dd, J = 8.5, 2Hz), 7.40 (1H, d, J = 8.5Hz), 7.88 (1H, d, J = 2Hz).

Reference Example 198

Yield: 95%, ¹ H-NMR (CDCl ₃ ); δ 1.65 (1H, s), 2.60-2.67 (6H, m), 3.63-3.69 (6H, m), 7.23 (1H, d, J = 8.5, 2.0Hz), 7.44 (1H, d, J = 8.5Hz), 7.57 (1H, d, J = 2.0Hz).

Reference Example 199

Yield: 99%, ¹ H-NMR (CDCl ₃ ); δ2.00-2.07 (2H, m), 2.69 (2H, t, J = 5.1 Hz), 2.76 (2H, t, J = 5.4 Hz), 2.89-2.93 (2H, m), 2.96 (1H, s), 3.60 (2H, t, J = 5.4Hz), 3.73 (2H, t, J = 6.0Hz), 3.80-3.83 (2H, m), 7.24 (1H, dd, J = 7.8, 2.1Hz), 7.42 (1H, d, J = 8.7Hz), 7.55 (1H, d, J = 2.1Hz).

Reference Example 200

Yield: 48%, ¹ H-NMR (CDCl ₃ ); δ1.28-1.46 (2H, m), 1.58 (2H, q, J = 6.5Hz), 1.72-1.94 (3H, m), 3.11-3.24 (2H, m), 3.76 (2H, t, J = 6.5Hz), 4.11-4.22 (2H, m), 7.48-7.57 (2H, m), 7.83 (1H, s).

Reference Example 201

Yield: 70%, ¹ H-NMR (DMSO-d ₆ ): δ 2.49 (2H, t, J = 6Hz), 2.57 (4H, t, J = 5Hz), 3.55 (2H, t, J = 6Hz ), 3.62 (4H, t, J = 5Hz), 4.51 (1H, brs), 7.57 (2H, s), 8.25 (1H, s).

Reference Example 202

Yield: 85%, ¹ H-NMR (DMSO-d ₆ ): δ1.83-1.90 (2H, m), 2.55 (2H, t, J = 5.5Hz), 2.67 (2H, t, J = 5Hz) , 2.87 (2H, t, J = 5Hz), 3.47 (2H, q, J = 5.5Hz), 3.60-3.80 (4H, m), 4.39 (1H, t, J = 5.5Hz), 7.55 (1H, s ), 7.95 (1H, s), 8.21 (1H, s).

Reference Example 203

Yield: 63%, ¹ H-NMR (CDCl ₃ ); δ1.23-1.44 (3H, m), 1.53-1.63 (2H, m), 1.68-1.90 (3H, m), 3.08-3.20 (2H, m), 3.75 (2H, q, J = 6.0Hz), 4.08-4.18 (2H, m), 7.02 (1H, dd, J = 8.5, 2.0Hz), 7.46 (1H, d, J = 8.5Hz), 7.49 (1H, d, J = 2.0Hz).

Reference Example 204

Yield: 36%, ¹ H-NMR (CDCl ₃ ); δ1.25-1.45 (3H, m), 1.57 (2H, q, J = 6.5Hz), 1.70-1.91 (3H, m), 3.08-3.23 (2H, m), 3.75 (2H, t, J = 6.5Hz), 4.08-4.21 (2H, m), 7.04 (1H, dd, J = 8.0, 1.0Hz), 7.21 (1H, t, J = 8.0 Hz), 7.39 (1H, dd, J = 8.0, 1.0Hz).

Reference Example 205

Yield: 52%, ¹ H-NMR (CDCl ₃ ); δ1.26 (1H, t, J = 6.5Hz), 1.27-1.44 (2H, m), 1.57 (2H, q, J = 6.5Hz), 1.68-1.91 (3H, m), 3.06-3.19 (2H, m), 3.75 (2H, q, J = 6.5Hz), 4.05-4.19 (2H, m), 7.35-7.40 (2H, m), 7.68 ( 1H, s).

Reference Example 206

Yield: 31%, ¹ H-NMR (CDCl ₃ ); δ1.22 (1H, t, J = 5.0Hz), 1.27-1.45 (2H, m), 1.57 (2H, q, J = 5.0Hz), 1.65-1.90 (3H, m), 2.38 (3H, s), 3.03-3.19 (2H, m), 3.75 (2H, q, J = 5.0Hz), 4.06-4.17 (2H, m), 7.08 (1H, d, J = 8.0Hz), 7.39 (1H, s), 7.42 (1H, d, J = 8.0Hz).

Reference Example 207

Yield: 9%, ¹ H-NMR (CDCl ₃ ); δ1.23-1.45 (3H, m), 1.52-1.64 (2H, m), 1.67-1.94 (3H, m), 3.40-3.22 (2H, m), 3.68-3.83 (2H, m), 4.03-4.17 (2H, m), 7.00 (1H, td, J = 8.5, 2.5Hz), 7.29 (1H, dd, J = 8.5, 2.5Hz), 7.40 (1H, dd, J = 8.5, 4.0Hz).

Reference Example 208

Yield: 48%, ¹ H-NMR (DMSO-d ₆ ): δ1.12-1.29 (2H, m), 1.40 (2H, q, J = 6.5Hz), 1.57-1.81 (3H, m), 2.95 -3.10 (2H, m), 3.47 (2H, q, J = 6.5Hz), 3.84-3.97 (2H, m), 4.40 (1H, t, J = 6.5Hz), 7.20 (1H, t, J = 7.5 Hz), 7.35 (2H, t, J = 7.5Hz), 7.44 (2H, d, J = 7.5Hz), 7.57 (1H, s).

Reference Example 209

Yield: 88%, 1H-NMR (CDCl3): δ1.14-1.32 (2H, m), 1.40 (2H, q, J = 6.5Hz), 1.54-1.83 (3H, m), 2.95-3.08 (2H , m), 3.47 (2H, q, J = 6.5Hz), 3.88-4.00 (2H, m), 4.40 (1H, t, J = 6.5Hz), 7.22 (1H, s), 7.27 (1H, t, J = 7.5Hz), 7.38 (2H, t, J = 7.5Hz), 7.87 (2H, d, J = 7.5Hz).

Reference Example 210

Yield: 71%, 1H-NMR (DMSO-d6): δ1.82-1.93 (2H, m), 2.55 (2H, t, J = 6.0Hz), 2.62-2.70 (2H, m), 2.78-2.86 (2H, m), 3.47 (2H, q, J = 6.0Hz), 3.59 (2H, t, J = 6.0Hz), 3.61-3.68 (2H, m), 4.38 (1H, t, J = 6.0Hz) , 7.18 (1H, t, J = 7.5Hz), 7.34 (2H, t, J = 7.5Hz), 7.45 (2H, d, J = 7.5Hz), 7.57 (1H, s).

Reference Example 211

Yield: 93%, 1H-NMR (DMSO-d6): δ1.80-2.01 (2H, m), 2.57 (2H, t, J = 6.0Hz), 2.64-2.77 (2H, m), 2.82-2.96 (2H, m), 3.42-3.53 (2H, m), 3.45-3.94 (4H, br), 4.34-4.46 (1H, m), 7.45 (1H, d, J = 7.0Hz), 8.23 (1H, d , J = 12.5Hz).

6-クロロ-2-[4-(2-ヒドロキシエチル)ピペリジン-１-イル]ベンゾチアゾール1.20g（4.03mmol）に塩化チオニル10mlを加え60℃で1時間撹拌した。反応液を氷水にあけた後、5N水酸化ナトリウム水溶液で中和し、析出結晶を濾取した。結晶をジイソプロピルエーテルで洗浄し、6-クロロ-2-[4-(2-クロロエチル)ピペリジン-1-イル]ベンゾチアゾールを無色結晶として0.98g（77％）を得た。
¹H-NMR(CDCl₃): δ 1.25-1.44 (2H, m), 1.70-1.94 (5H, m), 3.08-3.22 (2H, m), 3.62 (2H, t, J=6.5Hz), 4.07-4.20 (2H, m), 7.23 (1H, dd, J=8.5, 2.0Hz), 7.43 (1H, d, J=8.5Hz), 7.55 (1H, d, J=2.0).
Reference Example 212
Preparation of 6-chloro-2- [4- (2-chloroethyl) piperidin-1-yl] benzothiazole

10 ml of thionyl chloride was added to 1.20 g (4.03 mmol) of 6-chloro-2- [4- (2-hydroxyethyl) piperidin-1-yl] benzothiazole, and the mixture was stirred at 60 ° C. for 1 hour. The reaction solution was poured into ice water, neutralized with 5N aqueous sodium hydroxide solution, and the precipitated crystals were collected by filtration. The crystals were washed with diisopropyl ether to obtain 0.98 g (77%) of 6-chloro-2- [4- (2-chloroethyl) piperidin-1-yl] benzothiazole as colorless crystals.
¹ H-NMR (CDCl ₃ ): δ 1.25-1.44 (2H, m), 1.70-1.94 (5H, m), 3.08-3.22 (2H, m), 3.62 (2H, t, J = 6.5Hz), 4.07 -4.20 (2H, m), 7.23 (1H, dd, J = 8.5, 2.0Hz), 7.43 (1H, d, J = 8.5Hz), 7.55 (1H, d, J = 2.0).

収率：q. y, ¹H-NMR(DMSO-d₆): δ1.20-1.42 (2H, m), 1.80-2.00 (3H, m), 3.10-3.25 (2H, m), 3.60 (2H, d, J=6.5Hz), 4.00-4.10 (2H, m), 7.28 (1H, dd, J=8.5, 2Hz), 7.41 (1H, d, J=8.5Hz), 7.90 (1H, d, J=2Hz).

参考例２１４

収率：95％, ¹H-NMR(CDCl₃); δ2.63-2.72 (4H, m), 2.80 (2H, t, J=7.0Hz), 3.58-3.73 (6H, m), 7.23 (1H, dd, J=8.5, 2.0Hz), 7.44 (1H, d, J=8.5Hz), 7.56 (1H, d, J=2.0Hz).

参考例２１５

収率：58％, ¹H-NMR(CDCl₃); δ1.98-2.06 (2H, m), 2.78 (2H, t, J=5.4Hz), 2.90-2.96 (4H, m), 3.56 (2H, t, J=7.2Hz), 3.72 (2H, t, J =6.0Hz), 3.78-3.81 (2H, m), 7.23 (1H, dd, J=8.4, 2.1Hz), 7.42 (1H, d, J =8.4Hz), 7.55 (1H, d, J=2.1Hz).

参考例２１６

収率：68％, ¹H-NMR(CDCl₃); δ1.25-1.43 (2H, m), 1.70-1.94 (5H, m), 3.08-3.22 (2H, m), 3.62 (2H, t, J=6.5Hz), 4.08-4.22 (2H, m), 7.03 (1H, dd, J=8.5, 2.0Hz), 7.46 (1H, d, J=8.5Hz), 7.52 (1H, d, J=2.0Hz).

参考例２１７

収率：90％, ¹H-NMR(CDCl₃); δ1.26-1.44 (2H, m), 1.71-1.93 (5H, m), 3.08-3.23 (2H, m), 3.62 (2H, t, J=6.5Hz), 4.10-4.22 (2H, m), 7.04 (1H, d, J=8.0Hz), 7.22 (1H, t, J=8.0Hz), 7.40 (1H, d, J=8.0Hz).

参考例２１８

収率：95％, ¹H-NMR(CDCl₃); δ1.25-1.43 (2H, m), 1.71-1.92 (5H, m), 3.07-3.23 (2H, m), 3.61 (2H, t, J=6.5Hz), 4.06-4.21 (2H, m), 7.35-7.43 (2H, m), 7.69 (1H, s).

参考例２１９

収率：65％, ¹H-NMR(CDCl₃); δ1.22-1.41 (2H, m), 1.68-1.90 (5H, m), 2.38 (3H, s), 3.02-3.18 (2H, m), 3.59 (2H, t, J=6.5Hz), 4.05-4.18 (2H, m), 7.06-7.12 (1H, m), 7.36-7.39 (1H, m), 7.43 (1H, d, J=8.0Hz).

参考例２２０

収率：91％, ¹H-NMR(CDCl₃); δ1.27-1.45 (2H, m), 1.72-1.95 (5H, m), 3.12-3.27 (2H, m), 3.62 (2H, t, J=6.5Hz), 4.12-4.26 (2H, m), 7.49-7.59 (2H, m), 7.84 (1H, s).

参考例２２１

収率：42％, ¹H-NMR(CDCl₃); δ2.68 (4H, t, J=5Hz), 2.81 (2H, t, J=7Hz), 3.63 (2H, t, J=7Hz), 3.71 (4H, t, J=5Hz), 7.53 (1H, d, J=8.5Hz), 7.58 (1H, d, J=8.5Hz), 7.86 (1H, s).

参考例２２２

収率：23％, ¹H-NMR(CDCl₃); δ1.94-2.07 (2H, m), 2.70-2.80 (2H, m), 2.83-2.99 (4H, m), 3.50-3.58 (2H, m), 3.64-3.88 (4H, m), 7.48-7.60 (2H, m), 7.84 (1H, s).

参考例２２３

収率：89％, ¹H-NMR(CDCl₃); δ1.27-1.44 (2H, m), 1.72-1.88 (5H, m), 2.99-3.13 (2H, m), 3.62 (2H, t, J=6.5Hz), 3.99-4.10 (2H, m), 7.17-7.24 (1H, m), 7.30-7.37 (2H, m), 7.38-7.45 (3H ,m).

参考例２２４

収率：35％, 1H-NMR(DMSO-d6): δ1.81-1.94 (2H, m), 2.66-2.76 (2H, m), 2.77-2.93 (4H, m), 3.55-3.72 (6H, m), 7.18 (1H, t, J=7.5Hz), 7.34 (2H, t, J=7.5Hz), 7.44 (2H, d, J=7.5Hz), 7.57 (1H, s).

参考例２２５

収率：quant. ％, 1H-NMR(CDCl3): δ1.95-2.10 (2H, m), 2.73-2.84 (2H, m), 2.85-3.01 (4H, m), 3.56 (2H, t, J=7.0Hz), 3.66-3.89 (4H, m), 7.27 (1H, d, J=11.5Hz), 7.75 (1H, d, J=7.0Hz). Hereinafter, the compounds described in Reference Examples 213 to 225 were obtained in the same manner as in Reference Example 212.
Reference Example 213

Yield: q. Y, ¹ H-NMR (DMSO-d ₆ ): δ1.20-1.42 (2H, m), 1.80-2.00 (3H, m), 3.10-3.25 (2H, m), 3.60 (2H , d, J = 6.5Hz), 4.00-4.10 (2H, m), 7.28 (1H, dd, J = 8.5, 2Hz), 7.41 (1H, d, J = 8.5Hz), 7.90 (1H, d, J = 2Hz).

Reference Example 214

Yield: 95%, ¹ H-NMR (CDCl ₃ ); δ2.63-2.72 (4H, m), 2.80 (2H, t, J = 7.0Hz), 3.58-3.73 (6H, m), 7.23 (1H , dd, J = 8.5, 2.0Hz), 7.44 (1H, d, J = 8.5Hz), 7.56 (1H, d, J = 2.0Hz).

Reference Example 215

Yield: 58%, ¹ H-NMR (CDCl ₃ ); δ1.98-2.06 (2H, m), 2.78 (2H, t, J = 5.4Hz), 2.90-2.96 (4H, m), 3.56 (2H , t, J = 7.2Hz), 3.72 (2H, t, J = 6.0Hz), 3.78-3.81 (2H, m), 7.23 (1H, dd, J = 8.4, 2.1Hz), 7.42 (1H, d, J = 8.4Hz), 7.55 (1H, d, J = 2.1Hz).

Reference Example 216

Yield: 68%, ¹ H-NMR (CDCl ₃ ); δ1.25-1.43 (2H, m), 1.70-1.94 (5H, m), 3.08-3.22 (2H, m), 3.62 (2H, t, J = 6.5Hz), 4.08-4.22 (2H, m), 7.03 (1H, dd, J = 8.5, 2.0Hz), 7.46 (1H, d, J = 8.5Hz), 7.52 (1H, d, J = 2.0 Hz).

Reference Example 217

Yield: 90%, ¹ H-NMR (CDCl ₃ ); δ1.26-1.44 (2H, m), 1.71-1.93 (5H, m), 3.08-3.23 (2H, m), 3.62 (2H, t, J = 6.5Hz), 4.10-4.22 (2H, m), 7.04 (1H, d, J = 8.0Hz), 7.22 (1H, t, J = 8.0Hz), 7.40 (1H, d, J = 8.0Hz) .

Reference Example 218

Yield: 95%, ¹ H-NMR (CDCl ₃ ); δ1.25-1.43 (2H, m), 1.71-1.92 (5H, m), 3.07-3.23 (2H, m), 3.61 (2H, t, J = 6.5Hz), 4.06-4.21 (2H, m), 7.35-7.43 (2H, m), 7.69 (1H, s).

Reference Example 219

Yield: 65%, ¹ H-NMR (CDCl ₃ ); δ1.22-1.41 (2H, m), 1.68-1.90 (5H, m), 2.38 (3H, s), 3.02-3.18 (2H, m) , 3.59 (2H, t, J = 6.5Hz), 4.05-4.18 (2H, m), 7.06-7.12 (1H, m), 7.36-7.39 (1H, m), 7.43 (1H, d, J = 8.0Hz ).

Reference Example 220

Yield: 91%, ¹ H-NMR (CDCl ₃ ); δ1.27-1.45 (2H, m), 1.72-1.95 (5H, m), 3.12-3.27 (2H, m), 3.62 (2H, t, J = 6.5Hz), 4.12-4.26 (2H, m), 7.49-7.59 (2H, m), 7.84 (1H, s).

Reference Example 221

Yield: 42%, ¹ H-NMR (CDCl ₃ ); δ 2.68 (4H, t, J = 5Hz), 2.81 (2H, t, J = 7Hz), 3.63 (2H, t, J = 7Hz), 3.71 (4H, t, J = 5Hz), 7.53 (1H, d, J = 8.5Hz), 7.58 (1H, d, J = 8.5Hz), 7.86 (1H, s).

Reference Example 222

Yield: 23%, ¹ H-NMR (CDCl ₃ ); δ1.94-2.07 (2H, m), 2.70-2.80 (2H, m), 2.83-2.99 (4H, m), 3.50-3.58 (2H, m), 3.64-3.88 (4H, m), 7.48-7.60 (2H, m), 7.84 (1H, s).

Reference Example 223

Yield: 89%, ¹ H-NMR (CDCl ₃ ); δ1.27-1.44 (2H, m), 1.72-1.88 (5H, m), 2.99-3.13 (2H, m), 3.62 (2H, t, J = 6.5Hz), 3.99-4.10 (2H, m), 7.17-7.24 (1H, m), 7.30-7.37 (2H, m), 7.38-7.45 (3H, m).

Reference Example 224

Yield: 35%, 1H-NMR (DMSO-d6): δ1.81-1.94 (2H, m), 2.66-2.76 (2H, m), 2.77-2.93 (4H, m), 3.55-3.72 (6H, m), 7.18 (1H, t, J = 7.5Hz), 7.34 (2H, t, J = 7.5Hz), 7.44 (2H, d, J = 7.5Hz), 7.57 (1H, s).

Reference Example 225

Yield: quant.%, 1H-NMR (CDCl3): δ1.95-2.10 (2H, m), 2.73-2.84 (2H, m), 2.85-3.01 (4H, m), 3.56 (2H, t, J = 7.0Hz), 3.66-3.89 (4H, m), 7.27 (1H, d, J = 11.5Hz), 7.75 (1H, d, J = 7.0Hz).

4-(6-クロロベンゾチアゾール-2-イル)ピペラジン2塩酸塩0.50g（1.53mmol）、トリエチルアミン0.32ml（2.25mmol）、無水THF10mlの混合物に氷冷下、クロロアセチルクロリド0.18ml（2.25mmol）を滴下した後、室温下24時間撹拌した。反応液に水及び酢酸エチルを加え抽出し、有機層を飽和食塩水で洗浄、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、結晶をヘキサンで洗浄し2-クロロ-1-[4-(6-クロロベンゾチアゾール-2-イル)ピペラジン-1-イル]エタン-１-オンを褐色結晶として0.15g（30％）得た。
¹H-NMR(CDCl₃): δ3.61-3.81 (8H, m), 4.12 (2H, s), 7.28 (1H, dd, J=8.5, 2.0Hz), 7.47 (1H, d, J=8.5Hz), 7.60 (1H, d, J=2.0Hz).

参考例２２７
[（6-クロロベンゾチアゾール-2-イル）ピペリジン-4-イル]メタンスルホネートの製造

1-（6-クロロベンゾチアゾール-2-イル）ピペリジン-4-オール1.43ｇ（5.32mmol）、トリエチルアミン0.78ml（5.59mmol）、無水THF30mlの混合物に氷冷下、メタンスルホニルクロリド0.43ml（5.59mmol）を滴下した後、室温下30分間撹拌した。反応液を減圧下濃縮し、残渣に水を加えた後、結晶を濾取し、[（6-クロロベンゾチアゾール-1-イル）ピペリジン-4-イル]メタンスルホネートを淡褐色結晶として1.66g（90％）得た。
¹H-NMR(CDCl₃): δ1.97-2.20 (4H, m), 3.08 (3H, s), 3.57-3.68 (2H, m), 3.80-3.91 (2H, m), 4.97-5.08 (1H, m), 7.25 (1H, dd, J=8.5, 2.0Hz), 7.44 (1H, d, J=8.5Hz), 7.57 (1H, d, J=2.0Hz).

実施例２０７
3-｛2-[1-(6-クロロベンゾチアゾール-2-イル)ピペリジン-4-イル]エトキシ｝安息香酸エチル

6-クロロ-2-[4-(2-クロロエチル)ピペリジン-1-イル]ベンゾチアゾール0.50g（1.59mmol）、炭酸セシウム0.78g(2.39mmol)、3-ヒドロキシ安息香酸エチル0.40g（2.39mmol）及び無水N,N-ジメチルホルムアミド5mlの混合物を60℃で9時間撹拌した。 反応液を室温に戻し、水及び酢酸エチルを加え抽出した。有機層を飽和食塩水で洗浄、無水硫酸ナトリウムで乾燥し減圧下溶媒を留去した後、残渣をシリカゲルカラムクロマトグラフィー（塩化メチレン）で精製し、3-｛2-[1-(6-クロロベンゾチアゾール-2-イル)ピペリジン-4-イル]エトキシ安息香酸エチルを無色結晶として0.43g（62％）得た。
¹H-NMR(CDCl₃): δ1.30-1.51 (5H, m), 1.74-1.97 (5H, m), 3.09-3.22 (2H, m), 4.04-4.18 (4H, m), 4.38 (2H, q, J=7.0Hz), 7.09 (1H, dd, J=8.0, 1.5Hz), 7.23 (1H, dd, J=8.5, 2.0Hz), 7.35 (1H, t, J=8.0Hz), 7.42 (1H, d, J=8.5Hz), 7.52-7.58 (2H, m), 7.65 (1H, dd, J=8.0, 1.5Hz). Reference Example 226
Preparation of 2-chloro-1- [4- (6-chlorobenzothiazol-2-yl) piperazin-1-yl] ethane-1-one

4- (6-Chlorobenzothiazol-2-yl) piperazine dihydrochloride 0.50g (1.53mmol), triethylamine 0.32ml (2.25mmol), anhydrous THF 10ml under ice-cooling, chloroacetyl chloride 0.18ml (2.25mmol) After dropwise addition, the mixture was stirred at room temperature for 24 hours. Water and ethyl acetate were added to the reaction solution for extraction, and the organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After removing the solvent under reduced pressure, the crystals were washed with hexane to give 2-chloro-1- [4- (6-chlorobenzothiazol-2-yl) piperazin-1-yl] ethane-1-one as brown crystals 0.15 g (30%) was obtained.
¹ H-NMR (CDCl ₃ ): δ3.61-3.81 (8H, m), 4.12 (2H, s), 7.28 (1H, dd, J = 8.5, 2.0Hz), 7.47 (1H, d, J = 8.5 Hz), 7.60 (1H, d, J = 2.0Hz).

Reference Example 227
Preparation of [(6-Chlorobenzothiazol-2-yl) piperidin-4-yl] methanesulfonate

To a mixture of 1- (6-chlorobenzothiazol-2-yl) piperidin-4-ol 1.43 g (5.32 mmol), triethylamine 0.78 ml (5.59 mmol) and anhydrous THF 30 ml under ice-cooling, methanesulfonyl chloride 0.43 ml (5.59 mmol) ) Was added dropwise, followed by stirring at room temperature for 30 minutes. The reaction solution was concentrated under reduced pressure, water was added to the residue, and the crystals were collected by filtration to obtain 1.66 g ([6-chlorobenzothiazol-1-yl) piperidin-4-yl] methanesulfonate as light brown crystals ( 90%).
¹ H-NMR (CDCl ₃ ): δ1.97-2.20 (4H, m), 3.08 (3H, s), 3.57-3.68 (2H, m), 3.80-3.91 (2H, m), 4.97-5.08 (1H , m), 7.25 (1H, dd, J = 8.5, 2.0Hz), 7.44 (1H, d, J = 8.5Hz), 7.57 (1H, d, J = 2.0Hz).

Example 207
3- {2- [1- (6-Chlorobenzothiazol-2-yl) piperidin-4-yl] ethoxy} ethyl benzoate

6-chloro-2- [4- (2-chloroethyl) piperidin-1-yl] benzothiazole 0.50 g (1.59 mmol), cesium carbonate 0.78 g (2.39 mmol), ethyl 3-hydroxybenzoate 0.40 g (2.39 mmol) And 5 ml of anhydrous N, N-dimethylformamide were stirred at 60 ° C. for 9 hours. The reaction solution was returned to room temperature and extracted by adding water and ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (methylene chloride) to give 3- {2- [1- (6-chloro 0.43 g (62%) of ethyl benzothiazol-2-yl) piperidin-4-yl] ethoxybenzoate was obtained as colorless crystals.
¹ H-NMR (CDCl ₃ ): δ1.30-1.51 (5H, m), 1.74-1.97 (5H, m), 3.09-3.22 (2H, m), 4.04-4.18 (4H, m), 4.38 (2H , q, J = 7.0Hz), 7.09 (1H, dd, J = 8.0, 1.5Hz), 7.23 (1H, dd, J = 8.5, 2.0Hz), 7.35 (1H, t, J = 8.0Hz), 7.42 (1H, d, J = 8.5Hz), 7.52-7.58 (2H, m), 7.65 (1H, dd, J = 8.0, 1.5Hz).

収率：39％,¹H-NMR(CDCl₃); δ1.40 (3H, t, J= 7.0 Hz), 1.92-2.16 (4H, m), 3.60-3.72 (2H, m), 3.80-3.92 (2H, m), 4.38 (2H, q, J=7.0Hz), 4.65-4.74 (1H, m), 7.13 (1H, m), 7.24 (1H, dd, J=8.5, 2.0Hz), 7.37 (1H, t, J=8.0Hz), 7.44 (1H, d, J=8.5Hz), 7.56 (1H, d, J=2.0Hz), 7.58-7.63 (1H, m), 7.67 (1H, m).

実施例２０９

収率：16％,¹H-NMR(CDCl₃); δ1.26 (3H, t, J= 7.0Hz), 1.90-2.12 (4H, m), 3.56-3.70 (4H, m), 3.78-3.90 (2H, m), 4.16 (2H, q, J=7.0Hz), 4.61 (1H, m), 6.80-6.93 (3H, m), 7.20-7.28 (2H, m), 7.43 (1H, d, J=8.5Hz), 7.55 (1H, d, J=2.0Hz).

実施例２１０

収率：39％,¹H-NMR(CDCl₃); δ1.34 (3H, t, J=7Hz), 1.45-1.65 (2H, m), 1.95-2.10 (2H, m), 2.10-2.25 (1H, m), 3.10-3.30 (2H, m), 3.92 (2H, d, J=6Hz), 4.15-4.25 (2H, m), 4.32 (2H, q, J=7Hz), 6.93 (1H, d, J=7.5Hz), 6.98 (1H, td, J=7.5, 1Hz), 7.24 (1H, dd, J=8.5, 2Hz), 7.43 (1H, d, J=8.5Hz), 7.46 (1H, td, J=7.5, 1Hz), 7.55 (1H, d, J=2Hz), 7.80 (1H, dd, J=7.5, 1Hz).

実施例２１１

収率：39％,¹H-NMR(CDCl₃); δ1.40 (3H, t, J= 7Hz), 1.45-1.60 (2H, m), 1.95-2.05 (2H, m), 2.05-2.20(1H,m),3.10-3.25(2H,m),3.90 (2H, d, J=6Hz), 4.15-4.25 (2H, m), 4.37 (2H, q, J=7Hz),7.09(1H, dd, J=8, 1.5Hz), 7.23 (1H, dd, J=8.5, 2Hz), 7.34 (1H, t, J=8Hz), 7.43 (1H, d, J=8.5Hz), 7.55 (1H, d, J=1.5Hz), 7.56 (1H, d, J=2Hz), 7.64 (1H, dd, J=8, 1.5Hz)

実施例２１２

収率：52％, ¹H-NMR(CDCl₃); δ1.38 (3H, t, J=7Hz), 1.45-1.60 (2H, m), 1.90-2.05 (2H, m), 2.05-2.20 (1H, m), 3.10-3.25 (2H,m), 3.90 (2H, d, J=6Hz), 4.10-4.25 (2H, m), 4.35 (2H, q, J=7Hz), 6.89 (2H, d, J=9Hz), 7.24 (1H, dd, J=8.5, 2Hz), 7.43 (1H, d, J=8.5Hz), 7.55 (1H, d, J=2Hz), 7.99 (2H, d, J=9Hz).

実施例２１３

収率：63％, ¹H-NMR(DMSO-d₆): δ1.25-1.45 (2H, m), 1.70-1.85 (1H, m), 1.85-2.00 (2H, m), 3.03 (2H, d, J=7Hz), 3.08-3.24 (2H, m), 3.86 (3H, s), 3.95-4.10 (2H, m), 7.27 (1H, dd, J=8.5, 2Hz), 7.40 (1H, d, J=8.5Hz), 7.48 (1H, t, J=8Hz), 7.64 (1H, d, J=8Hz), 7.75 (1H, d, J=8Hz), 7.84 (1H, s), 7.88 (1H, d, J=2Hz).

実施例２１４

収率：79％,¹H-NMR(CDCl₃); δ1.30-1.50 (2H,m), 1.75-2.00 (1H, m), 1.95-2.05 (2H, m), 2.89 (2H, d, J=7Hz), 3.05-3.18 (2H, m), 3.60 (2H, s), 3.70 (3H, s), 4.05-4.20 (2H, m), 7.20-7.30 (5H, m), 7.42 (1H, d, J=8.5Hz), 7.54(1H,d, J=2Hz).

実施例２１５

収率：86％,¹H-NMR(CDCl₃); δ1.25-1.50 (5H,m),1.77-2.00(5H,m),3.06-3.23(2H, m), 4.05-4.20(4H, m), 4.35(2H, q, J=7.0Hz), 6.93-7.04 (2H, m), 7.22 (1H, dd, J=8.5, 2.0Hz), 7.37-7.49 (2H, m), 7.54 (1H, d, J=2.0Hz), 7.78 (1H, dd, J=8.0, 1.5Hz).

実施例２１６

収率：65％,¹H-NMR(CDCl₃); δ1.34-1.53 (5H,m),1.76-1.98(5H,m),3.09-3.24(2H, m), 4.06-4.23(4H, m), 4.35(2H, q, J=7.0Hz), 6.91 (2H, d, J=8.5Hz), 7.23 (1H, dd, J=8.5, 2.0Hz), 7.42 (1H, d, J=8.5Hz), 7.55(1H, d, J=2.0Hz), 8.00 (2H, d, J=8.5Hz).

実施例２１７

収率：72％,¹H-NMR(CDCl₃); δ1.40(3H, t, J= 7.0Hz), 1.33-1.52 (2H, m), 1.79-1.98 (5H, m), 2.27 (3H, s), 3.08-3.21 (2H, m), 4.07-4.18 (4H, m), 4.37 (2H, q, J=7.0Hz), 7.19 (1H, dd, J=7.5, 1.5Hz), 7.23 (1H, dd, J=8.5, 2.0Hz), 7.42 (1H, d, J=8.5Hz), 7.47 (1H, d, J=1.5Hz), 7.55(1H, d, J=2.0Hz), 7.57(1H, dd, J=7.5, 1.5Hz).

実施例２１８

収率：46％,¹H-NMR(CDCl₃); δ1.24 (3H, t, J= 7.0Hz), 1.23-1.44 (2H, m), 1.67-1.92 (5H, m), 3.02-3.16 (2H, m), 3.57 (2H, s), 3.98 (2H, t, J=6.0Hz), 4.02-4.15 (2H, m), 4.14 (2H, q, J= 7.0Hz), 6.75-6.90 (3H, m), 7.16-7.26 (2H, m), 7.41 (1H, d, J=8.5Hz), 7.51 (1H, d, J=2.0Hz).

実施例２１９

収率：17％,¹H-NMR(CDCl₃); δ1.23-1.44 (2H, m), 1.67-1.90 (5H, m), 3.02-3.16 (2H, m), 3.55 (2H, s), 3.67 (3H, s), 3.98 (2H, t, J=6.0Hz), 4.02-4.14 (2H,m), 6.84 (2H, d, J= 8.5Hz), 7.18 (2H, d, J=8.5Hz), 7.20(1H, dd, J=8.5, 2.0Hz), 7.40 (1H, d, J=8.5Hz), 7.51 (1H, d, J=2.0).

実施例２２０

収率：58％,¹H-NMR(CDCl₃); δ1.23 (3H, t, J= 7.0Hz), 1.33-1.50 (2H, m), 1.74-1.96 (5H, m), 2.60 (2H, t, J=8.0Hz), 2.95 (2H, t, J=8.0Hz), 3.08-3.22 (2H, m), 4.02-4.19 (6H, m), 6.83 (1H, d, J=7.5Hz), 6.88 (1H, td, J=7.5, 1.0Hz), 7.14-7.20 (2H, m), 7.23 (1H, dd, J=8.5, 2.0Hz), 7.42 (1H, d, J=8.5Hz), 7.55 (1H, d, J=2.0Hz).

実施例２２１

収率：71％, ¹H-NMR(CDCl₃); δ1.24 (3H, t, J=7.0Hz),1.31-1.49(2H,m), 1.73-1.95 (5H, m), 2.62 (2H, t, J=8.0Hz), 2.93 (2H, t, J=8.0 Hz), 3.08-3.21 (2H, m), 4.02 (2H, t, J=6.0Hz), 4.07-4.20 (2H, m), 4.13 (2H, q, J=7.0Hz), 6.71-6.84 (3H, m), 7.16-7.25 (2H, m), 7.42 (1H, d, J=8.5Hz), 7.54 (1H, d, J=2.0Hz).

実施例２２２

収率：58％,¹H-NMR(CDCl₃); δ1.30-1.47 (2H, m), 1.72-1.95 (5H, m), 2.60 (2H, t, J=8.0Hz), 2.90 (2H, t, J=8.0Hz), 3.08-3.20 (2H, m), 3.67 (3H, s), 4.01 (2H, t, J=6.0Hz), 4.06-4.18 (2H, m), 6.82 (2H, d, J=8.5Hz), 7.12 (2H, d, J=8.5Hz), 7.23 (1H, dd, J=8.5, 2.0Hz), 7.42 (1H, d, J=8.5Hz), 7.54 (1H, d, J=2.0Hz).

実施例２２３

収率：58％, ¹H-NMR(CDCl₃); δ1.24-1.43 (2H, m), 1.61-1.92 (5H, m), 2.97-3.20 (4H, m), 3.93 (3H, s), 4.06-4.18 (2H, m), 7.23 (1H,dd,J=8.5,2.0Hz),7.36(1H,t, J=7.5Hz), 7.41 (1H, d, J=8.5Hz), 7.49 (1H, dt, J=7.5, 1.5Hz), 7.54 (1H, d, J=2.0Hz), 7.84 (1H, dt, J=7.5, 1.5Hz), 7.98 (1H, t, J=1.5Hz).

実施例２２４

収率：45％, ¹H-NMR(DMSO-d₆): δ1.12-1.30 (2H, m), 1.50-1.61 (2H, m), 1.65-1.86 (3H, m), 2.96-3.21 (4H, m), 3.61 (3H, s), 3.67 (2H, s), 3.94-4.07 (2H, m), 7.06 (1H, d, J=7.0Hz), 7.18-7.32 (4H, m), 7.39 (1H, d, J=8.5Hz), 7.88 (1H, d, J=2.0 Hz).

実施例２２５

収率：50％, ¹H-NMR(CDCl₃): δ1.26 (3H, t, J=7.2Hz),1.39-1.46(2H,m), 1.73-1.80 (1H, m), 1.89 (3H, d, J=12.3 Hz), 2.31 (3H, s), 3.54 (3H, s), 4.01 (2H, t, J=6.0 Hz), 4.05-4.15 (2H, m), 4.15 (2H, q, J=7.2Hz), 4.10-4.12 (2H, m), 6.58-6.67 (2H, m), 6.69 (1H, m), 7.22 (1H, dd, J=8.7, 2.1 Hz), 7.42 (1H, d, J=8.7 Hz), 7.54 (1H, d, J=2.1Hz).

実施例２２６

収率：53％, ¹H-NMR(CDCl₃); δ1.26 (3H, t, J= 7.0Hz), 1.31-1.51 (2H, m), 1.76-1.98 (5H, m), 3.07-3.23 (2H, m), 3.57 (2H, s), 4.04-4.20 (6H, m), 6.81 (1H, dd, J=7.5, 1.5Hz), 6.87 (1H, d, J=1.5Hz),7.19-7.34 (2H, m), 7.42 (1H, d, J=8.5Hz), 7.53 (1H, d, J=2.0Hz).

実施例２２７

収率：93％, ¹H-NMR(CDCl₃); δ1.26 (3H, t, J=7Hz), 1.30-1.50 (1H, m), 1.75-2.00 (4H, m), 3.05-3.23 (2H, m), 3.55 (2H, s), 4.05-4.15 (6H, m), 4.18 (2H, q, J=7Hz), 6.75-6.85 (1H, m), 6.91(1H, dd, J=8, 2Hz), 6.92 (1H, dd, J=11,2Hz),7.22 (1H, dd, J=8.5, 2Hz), 7.42 (1H, d, J=8.5Hz), 7.54 (1H, d, J=2Hz).

実施例２２８

収率：67％, ¹H-NMR(CDCl₃); δ1.39 (3H, t, J=7.0Hz),2.77(4H, t, J=5.0Hz), 2.93 (2H, t, J=5.5Hz), 3.65 (4H,t,J=5.0Hz), 4.21 (2H,t,J=5.5Hz),4.35 (2H,q,J=7.0Hz),6.98(1H, d, J=7.5Hz), 7.00 (1H, t, J=7.5Hz), 7.24 (1H, dd, J=8.5, 2.0Hz), 7.44 (1H, d, J=8.5Hz), 7.46 (1H, t, J=7.5Hz), 7.56 (1H, d, J=2.0Hz), 7.79 (1H, dd, J=7.5, 2.0Hz).

実施例２２９

収率：76％, ¹H-NMR(CDCl₃); δ1.40 (3H, t, J=7.0Hz),2.73( 4H, t, J=5.0Hz), 2.90 (2H, t, J=5.5Hz), 3.67 (4H, t, J=5.0Hz), 4.19 (2H, t, J=5.5Hz), 4.38 (2H, q, J=7.0Hz), 7.11 (1H, dd, J=8.0, 2.5Hz), 7.24 (1H, dd, J=8.5, 2.0Hz), 7.35 (1H, t, J=8.0Hz), 7.44 (1H, d, J=8.5Hz), 7.56 (1H, d, J=2.0Hz), 7.58 (1H, s), 7.66 (1H, dd, J=8.0, 2.5Hz).

実施例２３０

収率：82％, ¹H-NMR(CDCl₃); δ1.38 (3H, t, J=7.0Hz), 2.73 (4H, t, J=5.0Hz), 2.90 (2H, t, J=5.5Hz), 3.66 (4H, t, J=5.0Hz), 4.19 (2H, t, J=5.5Hz), 4.35 (2H, q, J=7.0Hz), 6.93 (2H, d, J=9.0Hz), 7.24 (1H, dd, J=8.5, 2.0Hz), 7.43 (1H, d, J=8.5Hz), 7.56 (1H, d, J=2.0Hz), 8.00 (2H, d, J=9.0Hz).

実施例２３１

収率：18％, ¹H-NMR(CDCl₃); δ1.27-1.48 (2H, m), 1.64-1.95 (5H, m), 3.05-3.19 (2H,m), 3.84 (3H, s), 4.06-4.19 (4H, m), 6.22 (1H, d, J=4.0Hz), 7.22 (1H, dd, J=8.5, 2.0Hz), 7.42 (1H, d, J=8.5Hz), 7.51-7.27 (2H, m).

実施例２３２

収率：46％, ¹H-NMR(CDCl₃); δ1.26 (3H, t, J=7.0Hz),2.72(4H, t, J=5.0Hz), 2.87 (2H, t, J=5.5Hz), 3.58 (2H, s), 3.66 (4H, t, J=5.0Hz),4.14(2H,t, J=5.5Hz),4.15(2H,q, J=7.0Hz),6.79-6.91(3H,m),7.23(1H,d,J=8.0Hz), 7.24 (1H, dd, J=8.5, 2.0Hz), 7.44 (1H, d, J=8.5Hz), 7.56 (1H, d, J=2.0Hz).

実施例２３３

収率：81％, ¹H-NMR(CDCl₃); δ1.32-1.51 (5H, m), 1.74-1.99 (5H, m), 3.11-3.27 (2H, m), 4.04-4.24 (4H, m), 4.38 (2H, q, J=7.0Hz), 7.06-7.13 (1H, m), 7.35 (1H, t, J=8.0Hz), 7.48-7.57 (3H, m), 7.65 (1H, d, J=8.0Hz), 7.84 (1H, s).

実施例２３４

収率：58％, ¹H-NMR(CDCl₃); δ1.26 (3H, t, J=7.0Hz), 1.31-1.50 (2H, m), 1.72-1.98 (5H, m), 3.12-3.25 (2H, m), 3.59 (2H, s), 4.04 (2H, t, J=6.0Hz), 4.10-4.24 (4H, m), 6.77-6.91 (3H, m), 7.23 (1H, t, J=7.5Hz), 7.48-7.59 (2H, m), 7.84 (1H,s).

実施例２３５

収率：51％,¹H-NMR(DMSO-d₆): δ1.26 (3H, t, J=7Hz),2.20(3H,s),2.77(4H,t, J=5Hz), 2.92 (2H, t, J=5.5Hz), 3.56 (2H, s), 3.70 (4H, t, J=5Hz), 4.13 (2H, t, J=5.5Hz), 4.16 (2H, q, J=7Hz), 6.75-6.80 (2H, m), 7.08 (1H, d, J=7Hz), 7.52 (1H, dd, J=8.5, 1.5Hz), 7.55 (1H, d, J=8.5Hz), 7.85 (1H, d, J=0.5Hz).

実施例２３６

収率：49％, ¹H-NMR(CDCl₃); δ1.26 (3H, t, J=7.0Hz),1.32-1.51(2H,m), 1.78-2.00 (5H, m), 3.12-3.27 (2H, m), 3.57 (2H, s), 4.05-4.24 (6H, m), 6.81 (1H, dd, J=8.0, 2.0Hz), 6.87 (1H, d, J=2.0Hz), 7.30 (1H, d, J=8.0Hz), 7.47-7.59 (2H, m), 7.83 (1H, s).

実施例２３７

収率：39％,¹H-NMR(CDCl₃); δ1.27 (3H, t, J= 7.0Hz), 1.30-1.48 (2H, m), 1.72-1.94 (5H, m), 3.08-3.21 (2H, m), 3.72 (2H, s), 3.97-4.04 (2H, m), 4.07-4.19 (2H, m), 4.19 (2H, q, J=7.0Hz), 6.76 (1H, dd, J=8.5, 3.0Hz), 6.84 (1H, d, J=3.0Hz), 7.23 (1H, dd, J=8.5, 2.0Hz), 7.27 (1H, d, J=8.5Hz), 7.42 (1H, d, J=8.5Hz), 7.54 (1H, d, J=2.0Hz).

実施例２３８

収率：69％,¹H-NMR(CDCl₃); δ2.00-2.08 (2H, m), 2.84 (2H, t, J=8.4Hz), 2.96-3.02 (4H, m), 3.59 (2H, s), 3.69 (3H, s), 3.73 (2H, t, J=6.0Hz), 3.79-3.84 (2H, m), 4.07 (2H, t, J=5.4Hz), 6.79-6.88 (3H, m), 7.20-7.27 (2H, m), 7.43 (1H, d, J=8.4Hz), 7.55 (1H, d, J=2.1Hz).

実施例２３９

収率：49％,¹H-NMR(CDCl₃); δ1.25 (3H, t, J= 7Hz), 1.98-2.08 (2H, m), 2.18 (3H, s), 2.82-2.90 (2H,m),2.98-3.05(4H, m), 3.55 (2H, s), 3.73 (2H, t, J=5.5Hz), 3.75-3.85 (2H, m), 4.05-4.10(2H,m), 4.15 (2H, q, J=7Hz), 6.74(1H,s),6.76 (1H,d,J=7.5Hz),7.07 (1H, d, 7.5Hz), 7.22 (1H, dd, J=8.5, 2Hz), 7.43 (1H, d, J=8.5Hz), 7.54 (1H, d, J=2Hz).

実施例２４０

収率：45％,¹H-NMR(CDCl₃); δ1.25 (3H, t, J= 7Hz), 1.95-2.10(2H, m), 2.88(2H, t, J=5.5 Hz), 3.00-3.10 (4H, m), 3.55 (2H, s), 3.73 (2H, t, J=5.5Hz), 3.75-3.85 (2H, m), 4.10-4.15 (2H, m), 4.15 (2H, q, J=7Hz), 6.80 (1H, dd, J=8, 2Hz), 6.85 (1H, d, J=2Hz), 7.22 (1H, dd, J=8.5, 2.5Hz), 7.29 (1H, d, J=8Hz), 7.42 (1H, d, J=8.5Hz), 7.54 (1H, d, J=2.5Hz).

実施例２４１

収率：74％,¹H-NMR(CDCl₃); δ1.25 (3H, t, J=7.0Hz),1.20-2.11(2H,m),2.79-2.90(2H,
m), 2.93-3.06(4H, m), 3.57(2H, s), 3.69-3.90 (4H, m), 4.04-4.12(2H, m), 4.15(2H, q, J=7.0 Hz), 6.76-6.90 (3H, m), 7.22(1H, t, J=8.0Hz), 7.48-7.59 (2H, m), 7.84 (1H, s).

実施例２４２

収率：42％,¹H-NMR(CDCl₃); δ1.25(3H,t,J= 7.0Hz), 1.99-2.09 (2H, m), 2.86-2.94 (2H, m), 3.02-3.12 (4H, m), 3.55 (2H, s), 3.69-3.90 (4H, m), 4.10-4.20 (4H, m), 6.81 (1H, dd, J= 8.0, 2.0Hz), 6.87(1H, d, J=2.0Hz), 7.29(1H, d, J=8.0Hz), 7.48-7.59 (2H, m), 7.84 (1H, s).

実施例２４３

収率：51％,¹H-NMR(CDCl₃); δ1.31-1.49 (5H,m), 1.75-1.96 (5H, m), 3.09-3.22 (2H,m), 4.05-4.19 (4H, m), 4.38 (2H, q, J=7.0Hz), 7.02 (1H, dd, J=8.0, 2.0Hz), 7.09 (1H, ddd, J=8.0, 2.5, 1.0Hz), 7.35 (1H, t, J=8.0Hz), 7.47 (1H, d, J=8.0Hz), 7.50 (1H, d, J=2.0Hz), 7.56 (1H, dd, J=2.5, 1.5Hz), 7.65 (1H, dt, J=8.0, 1.5, 1.0Hz).

実施例２４４

収率：44％,¹H-NMR(CDCl₃); δ1.26 (3H, t, J= 6.5Hz), 130-1.48 (2H, m), 1.72-1.95 (5H, m), 3.08-3.21 (2H, m), 3.58 (2H, s), 4.03 (2H, t, J=6.0Hz), 4.08-4.21 (2H, m), 4.15 (2H, q, J=6.5Hz), 6.76-6.90 (3H, m), 7.02 (1H, dd, J=8.5, 2.0Hz), 7.22 (1H, d, J=7.5Hz), 7.47 (1H, d, J=8.5Hz), 7.50 (1H, d, J=2.0Hz).

実施例２４５

収率：57％,¹H-NMR(CDCl₃); δ1.26 (3H, t, J= 7.0Hz),1.31-1.48(2H,m),1.71-1.96(5H, m), 3.09-3.22 (2H, m), 3.58 (2H, s), 4.03 (2H, t, J=6.0Hz), 4.09-4.21 (4H, m), 6.77-6.91 (3H, m), 7.03 (1H, dd, J=8.0, 1.0Hz), 7.17-7.28 (2H, m), 7.40 (1H, dd, J=8.0, 1.0Hz).

実施例２４６

収率：81％,¹H-NMR(CDCl₃); δ1.32-1.50 (5H, m), 1.75-1.95(5H, m), 3.09-3.21(2H, m), 4.05-4.18(4H, m), 4.38(2H, q, J=7.0Hz), 7.06-7.12 (1H, m), 7.32-7.39 (3H, m), 7.54-7.58 (1H, m), 7.62-7.67 (1H, m), 7.67-7.69 (1H, m).

実施例２４７

収率：44％,¹H-NMR(CDCl₃); δ1.26 (3H, t, J=7.0Hz), 1.31-1.48 (2H, m), 1.73-1.96 (5H, m), 3.08-3.20 (2H, m), 3.58 (2H, s), 4.00-4.18 (4H, m), 4.16 (2H, q, J=7.0Hz), 6.78-6.90 (3H, m), 7.20-7.28 (1H, m), 7.36 (2H, m), 7.69 (1H, m).

実施例２４８

収率：48％,¹H-NMR(CDCl₃); δ1.26 (3H, t, J= 7.0Hz), 1.30-1.49 (2H, m), 1.72-1.95 (5H, m), 2.39 (3H, s), 3.06-3.19 (2H, m), 3.58 (2H, s), 3.98-4.21 (6H, m), 6.77-6.91 (3H, m), 7.06-7.12 (1H, m), 7.23 (1H, t, J=7.5Hz), 7.37-7.47 (2H, m).

実施例２４９

収率：54％,¹H-NMR(CDCl₃); δ1.25 (3H, t, J= 7.0Hz), 3.56-3.82(10H, m), 4.14(2H, q, J=7.0Hz), 4.74(2H, s), 6.83-6.96(3H, m), 7.22-7.29(2H, m), 7.45(1H, d, J=8.5Hz), 7.58(1H, d, J=2.0Hz).

実施例２５０

収率：49％,¹H-NMR(CDCl₃); δ1.26(3H,t,J= 7.0Hz), 1.31-1.50(2H, m), 1.73-1.93(5H, m), 2.99-3.12(2H, m), 3.58(2H, s), 3.98-4.09 (4H,m), 4.15 (2H, q, J=7.0Hz), 6.78-6.90 (3H, m), 7.16-7.47 (7H, m).

実施例２５１

収率：54％,¹H-NMR(CDCl₃); δ1.26 (3H, t, J= 7.0Hz), 1.35-1.52(2H, m), 1.78-1.97(5H, m), 3.01-3.14(2H, m), 3.58(2H, s), 3.99-4.21 (6H, m), 6.81(1H, dd, J=8.0, 2.0Hz), 6.87(1H, d, J=2.0Hz), 7.16-7.24(1H, m), 7.27-7.37 (3H, m), 7.38-7.47 (3H, m).

実施例２５２

収率：58％,1H-NMR(DMSO-d6): δ1.18 (3H, t, J=7.0Hz), 1.83-1.95 (2H, m), 2.74-2.84 (2H, m), 2.89-3.01 (4H, m), 3.56-3.72 (6H, m), 4.08 (2H, q, J=7.0Hz), 4.09-4.17 (2H, m), 6.84 (1H, dd, J=8.0, 1.5Hz), 7.09 (1H, d, J=1.5Hz), 7.18 (1H, t, J=7.5Hz), 7.29-7.38 (3H, m), 7.44 (2H, d, J=7.5Hz), 7.57 (1H, s).

実施例２５３

収率：31％,1H-NMR(CDCl3): δ1.24 (3H, t, J=7.0Hz), 1.95-2.08 (2H, m), 2.88 (2H, t, J=5.5Hz), 2.98-3.12 (4H, m), 3.55 (2H, s), 3.60-3.90 (4H, m), 4.06-4.19 (4H, m), 6.79 (1H, dd, J=8.0, 1.5Hz), 6.86 (1H, d, J=1.5Hz), 7.25 (1H, d, J=12.0Hz), 7.27 (1H, d, J=8.0Hz), 7.72 (1H, d, J=7.0Hz). Thereafter, the compounds described in Examples 208 to 253 were obtained in the same manner as in Example 207.
Example 208

Yield: 39%, ¹ H-NMR (CDCl ₃ ); δ1.40 (3H, t, J = 7.0 Hz), 1.92-2.16 (4H, m), 3.60-3.72 (2H, m), 3.80-3.92 (2H, m), 4.38 (2H, q, J = 7.0Hz), 4.65-4.74 (1H, m), 7.13 (1H, m), 7.24 (1H, dd, J = 8.5, 2.0Hz), 7.37 ( 1H, t, J = 8.0Hz), 7.44 (1H, d, J = 8.5Hz), 7.56 (1H, d, J = 2.0Hz), 7.58-7.63 (1H, m), 7.67 (1H, m).

Example 209

Yield: 16%, ¹ H-NMR (CDCl ₃ ); δ1.26 (3H, t, J = 7.0Hz), 1.90-2.12 (4H, m), 3.56-3.70 (4H, m), 3.78-3.90 (2H, m), 4.16 (2H, q, J = 7.0Hz), 4.61 (1H, m), 6.80-6.93 (3H, m), 7.20-7.28 (2H, m), 7.43 (1H, d, J = 8.5Hz), 7.55 (1H, d, J = 2.0Hz).

Example 210

Yield: 39%, ¹ H-NMR (CDCl ₃ ); δ1.34 (3H, t, J = 7Hz), 1.45-1.65 (2H, m), 1.95-2.10 (2H, m), 2.10-2.25 ( 1H, m), 3.10-3.30 (2H, m), 3.92 (2H, d, J = 6Hz), 4.15-4.25 (2H, m), 4.32 (2H, q, J = 7Hz), 6.93 (1H, d , J = 7.5Hz), 6.98 (1H, td, J = 7.5, 1Hz), 7.24 (1H, dd, J = 8.5, 2Hz), 7.43 (1H, d, J = 8.5Hz), 7.46 (1H, td , J = 7.5, 1Hz), 7.55 (1H, d, J = 2Hz), 7.80 (1H, dd, J = 7.5, 1Hz).

Example 211

Yield: 39%, ¹ H-NMR (CDCl ₃ ); δ 1.40 (3H, t, J = 7Hz), 1.45-1.60 (2H, m), 1.95-2.05 (2H, m), 2.05-2.20 ( 1H, m), 3.10-3.25 (2H, m), 3.90 (2H, d, J = 6Hz), 4.15-4.25 (2H, m), 4.37 (2H, q, J = 7Hz), 7.09 (1H, dd , J = 8, 1.5Hz), 7.23 (1H, dd, J = 8.5, 2Hz), 7.34 (1H, t, J = 8Hz), 7.43 (1H, d, J = 8.5Hz), 7.55 (1H, d , J = 1.5Hz), 7.56 (1H, d, J = 2Hz), 7.64 (1H, dd, J = 8, 1.5Hz)

Example 212

Yield: 52%, ¹ H-NMR (CDCl ₃ ); δ 1.38 (3H, t, J = 7Hz), 1.45-1.60 (2H, m), 1.90-2.05 (2H, m), 2.05-2.20 ( 1H, m), 3.10-3.25 (2H, m), 3.90 (2H, d, J = 6Hz), 4.10-4.25 (2H, m), 4.35 (2H, q, J = 7Hz), 6.89 (2H, d , J = 9Hz), 7.24 (1H, dd, J = 8.5, 2Hz), 7.43 (1H, d, J = 8.5Hz), 7.55 (1H, d, J = 2Hz), 7.99 (2H, d, J = 9Hz).

Example 213

Yield: 63%, ¹ H-NMR (DMSO-d ₆ ): δ1.25-1.45 (2H, m), 1.70-1.85 (1H, m), 1.85-2.00 (2H, m), 3.03 (2H, d, J = 7Hz), 3.08-3.24 (2H, m), 3.86 (3H, s), 3.95-4.10 (2H, m), 7.27 (1H, dd, J = 8.5, 2Hz), 7.40 (1H, d , J = 8.5Hz), 7.48 (1H, t, J = 8Hz), 7.64 (1H, d, J = 8Hz), 7.75 (1H, d, J = 8Hz), 7.84 (1H, s), 7.88 (1H , d, J = 2Hz).

Example 214

Yield: 79%, ¹ H-NMR (CDCl ₃ ); δ1.30-1.50 (2H, m), 1.75-2.00 (1H, m), 1.95-2.05 (2H, m), 2.89 (2H, d, J = 7Hz), 3.05-3.18 (2H, m), 3.60 (2H, s), 3.70 (3H, s), 4.05-4.20 (2H, m), 7.20-7.30 (5H, m), 7.42 (1H, d, J = 8.5Hz), 7.54 (1H, d, J = 2Hz).

Example 215

Yield: 86%, ¹ H-NMR (CDCl ₃ ); δ1.25-1.50 (5H, m), 1.77-2.00 (5H, m), 3.06-3.23 (2H, m), 4.05-4.20 (4H, m), 4.35 (2H, q, J = 7.0Hz), 6.93-7.04 (2H, m), 7.22 (1H, dd, J = 8.5, 2.0Hz), 7.37-7.49 (2H, m), 7.54 (1H , d, J = 2.0Hz), 7.78 (1H, dd, J = 8.0, 1.5Hz).

Example 216

Yield: 65%, ¹ H-NMR (CDCl ₃ ); δ1.34-1.53 (5H, m), 1.76-1.98 (5H, m), 3.09-3.24 (2H, m), 4.06-4.23 (4H, m), 4.35 (2H, q, J = 7.0Hz), 6.91 (2H, d, J = 8.5Hz), 7.23 (1H, dd, J = 8.5, 2.0Hz), 7.42 (1H, d, J = 8.5 Hz), 7.55 (1H, d, J = 2.0Hz), 8.00 (2H, d, J = 8.5Hz).

Example 217

Yield: 72%, ¹ H-NMR (CDCl ₃ ); δ1.40 (3H, t, J = 7.0Hz), 1.33-1.52 (2H, m), 1.79-1.98 (5H, m), 2.27 (3H , s), 3.08-3.21 (2H, m), 4.07-4.18 (4H, m), 4.37 (2H, q, J = 7.0Hz), 7.19 (1H, dd, J = 7.5, 1.5Hz), 7.23 ( 1H, dd, J = 8.5, 2.0Hz), 7.42 (1H, d, J = 8.5Hz), 7.47 (1H, d, J = 1.5Hz), 7.55 (1H, d, J = 2.0Hz), 7.57 ( (1H, dd, J = 7.5, 1.5Hz).

Example 218

Yield: 46%, ¹ H-NMR (CDCl ₃ ); δ1.24 (3H, t, J = 7.0Hz), 1.23-1.44 (2H, m), 1.67-1.92 (5H, m), 3.02-3.16 (2H, m), 3.57 (2H, s), 3.98 (2H, t, J = 6.0Hz), 4.02-4.15 (2H, m), 4.14 (2H, q, J = 7.0Hz), 6.75-6.90 ( 3H, m), 7.16-7.26 (2H, m), 7.41 (1H, d, J = 8.5Hz), 7.51 (1H, d, J = 2.0Hz).

Example 219

Yield: 17%, ¹ H-NMR (CDCl ₃ ); δ1.23-1.44 (2H, m), 1.67-1.90 (5H, m), 3.02-3.16 (2H, m), 3.55 (2H, s) , 3.67 (3H, s), 3.98 (2H, t, J = 6.0Hz), 4.02-4.14 (2H, m), 6.84 (2H, d, J = 8.5Hz), 7.18 (2H, d, J = 8.5 Hz), 7.20 (1H, dd, J = 8.5, 2.0Hz), 7.40 (1H, d, J = 8.5Hz), 7.51 (1H, d, J = 2.0).

Example 220

Yield: 58%, ¹ H-NMR (CDCl ₃ ); δ1.23 (3H, t, J = 7.0Hz), 1.33-1.50 (2H, m), 1.74-1.96 (5H, m), 2.60 (2H , t, J = 8.0Hz), 2.95 (2H, t, J = 8.0Hz), 3.08-3.22 (2H, m), 4.02-4.19 (6H, m), 6.83 (1H, d, J = 7.5Hz) , 6.88 (1H, td, J = 7.5, 1.0Hz), 7.14-7.20 (2H, m), 7.23 (1H, dd, J = 8.5, 2.0Hz), 7.42 (1H, d, J = 8.5Hz), 7.55 (1H, d, J = 2.0Hz).

Example 221

Yield: 71%, ¹ H-NMR (CDCl ₃ ); δ1.24 (3H, t, J = 7.0Hz), 1.31-1.49 (2H, m), 1.73-1.95 (5H, m), 2.62 (2H , t, J = 8.0Hz), 2.93 (2H, t, J = 8.0 Hz), 3.08-3.21 (2H, m), 4.02 (2H, t, J = 6.0Hz), 4.07-4.20 (2H, m) , 4.13 (2H, q, J = 7.0Hz), 6.71-6.84 (3H, m), 7.16-7.25 (2H, m), 7.42 (1H, d, J = 8.5Hz), 7.54 (1H, d, J = 2.0Hz).

Example 222

Yield: 58%, ¹ H-NMR (CDCl ₃ ); δ1.30-1.47 (2H, m), 1.72-1.95 (5H, m), 2.60 (2H, t, J = 8.0Hz), 2.90 (2H , t, J = 8.0Hz), 3.08-3.20 (2H, m), 3.67 (3H, s), 4.01 (2H, t, J = 6.0Hz), 4.06-4.18 (2H, m), 6.82 (2H, d, J = 8.5Hz), 7.12 (2H, d, J = 8.5Hz), 7.23 (1H, dd, J = 8.5, 2.0Hz), 7.42 (1H, d, J = 8.5Hz), 7.54 (1H, d, J = 2.0Hz).

Example 223

Yield: 58%, ¹ H-NMR (CDCl ₃ ); δ1.24-1.43 (2H, m), 1.61-1.92 (5H, m), 2.97-3.20 (4H, m), 3.93 (3H, s) , 4.06-4.18 (2H, m), 7.23 (1H, dd, J = 8.5,2.0Hz), 7.36 (1H, t, J = 7.5Hz), 7.41 (1H, d, J = 8.5Hz), 7.49 ( 1H, dt, J = 7.5, 1.5Hz), 7.54 (1H, d, J = 2.0Hz), 7.84 (1H, dt, J = 7.5, 1.5Hz), 7.98 (1H, t, J = 1.5Hz).

Example 224

Yield: 45%, ¹ H-NMR (DMSO-d ₆ ): δ1.12-1.30 (2H, m), 1.50-1.61 (2H, m), 1.65-1.86 (3H, m), 2.96-3.21 ( 4H, m), 3.61 (3H, s), 3.67 (2H, s), 3.94-4.07 (2H, m), 7.06 (1H, d, J = 7.0Hz), 7.18-7.32 (4H, m), 7.39 (1H, d, J = 8.5Hz), 7.88 (1H, d, J = 2.0 Hz).

Example 225

Yield: 50%, ¹ H-NMR (CDCl ₃ ): δ1.26 (3H, t, J = 7.2Hz), 1.39-1.46 (2H, m), 1.73-1.80 (1H, m), 1.89 (3H , d, J = 12.3 Hz), 2.31 (3H, s), 3.54 (3H, s), 4.01 (2H, t, J = 6.0 Hz), 4.05-4.15 (2H, m), 4.15 (2H, q, J = 7.2Hz), 4.10-4.12 (2H, m), 6.58-6.67 (2H, m), 6.69 (1H, m), 7.22 (1H, dd, J = 8.7, 2.1 Hz), 7.42 (1H, d , J = 8.7 Hz), 7.54 (1H, d, J = 2.1 Hz).

Example 226

Yield: 53%, ¹ H-NMR (CDCl ₃ ); δ1.26 (3H, t, J = 7.0Hz), 1.31-1.51 (2H, m), 1.76-1.98 (5H, m), 3.07-3.23 (2H, m), 3.57 (2H, s), 4.04-4.20 (6H, m), 6.81 (1H, dd, J = 7.5, 1.5Hz), 6.87 (1H, d, J = 1.5Hz), 7.19- 7.34 (2H, m), 7.42 (1H, d, J = 8.5Hz), 7.53 (1H, d, J = 2.0Hz).

Example 227

Yield: 93%, ¹ H-NMR (CDCl ₃ ); δ1.26 (3H, t, J = 7Hz), 1.30-1.50 (1H, m), 1.75-2.00 (4H, m), 3.05-3.23 ( 2H, m), 3.55 (2H, s), 4.05-4.15 (6H, m), 4.18 (2H, q, J = 7Hz), 6.75-6.85 (1H, m), 6.91 (1H, dd, J = 8 , 2Hz), 6.92 (1H, dd, J = 11,2Hz), 7.22 (1H, dd, J = 8.5, 2Hz), 7.42 (1H, d, J = 8.5Hz), 7.54 (1H, d, J = 2Hz).

Example 228

Yield: 67%, ¹ H-NMR (CDCl ₃ ); δ 1.39 (3H, t, J = 7.0 Hz), 2.77 (4H, t, J = 5.0 Hz), 2.93 (2H, t, J = 5.5 Hz), 3.65 (4H, t, J = 5.0Hz), 4.21 (2H, t, J = 5.5Hz), 4.35 (2H, q, J = 7.0Hz), 6.98 (1H, d, J = 7.5Hz) , 7.00 (1H, t, J = 7.5Hz), 7.24 (1H, dd, J = 8.5, 2.0Hz), 7.44 (1H, d, J = 8.5Hz), 7.46 (1H, t, J = 7.5Hz) , 7.56 (1H, d, J = 2.0Hz), 7.79 (1H, dd, J = 7.5, 2.0Hz).

Example 229

Yield: 76%, ¹ H-NMR (CDCl ₃ ); δ 1.40 (3H, t, J = 7.0Hz), 2.73 (4H, t, J = 5.0Hz), 2.90 (2H, t, J = 5.5 Hz), 3.67 (4H, t, J = 5.0Hz), 4.19 (2H, t, J = 5.5Hz), 4.38 (2H, q, J = 7.0Hz), 7.11 (1H, dd, J = 8.0, 2.5 Hz), 7.24 (1H, dd, J = 8.5, 2.0Hz), 7.35 (1H, t, J = 8.0Hz), 7.44 (1H, d, J = 8.5Hz), 7.56 (1H, d, J = 2.0 Hz), 7.58 (1H, s), 7.66 (1H, dd, J = 8.0, 2.5Hz).

Example 230

Yield: 82%, ¹ H-NMR (CDCl ₃ ); δ 1.38 (3H, t, J = 7.0Hz), 2.73 (4H, t, J = 5.0Hz), 2.90 (2H, t, J = 5.5 Hz), 3.66 (4H, t, J = 5.0Hz), 4.19 (2H, t, J = 5.5Hz), 4.35 (2H, q, J = 7.0Hz), 6.93 (2H, d, J = 9.0Hz) , 7.24 (1H, dd, J = 8.5, 2.0Hz), 7.43 (1H, d, J = 8.5Hz), 7.56 (1H, d, J = 2.0Hz), 8.00 (2H, d, J = 9.0Hz) .

Example 231

Yield: 18%, ¹ H-NMR (CDCl ₃ ); δ1.27-1.48 (2H, m), 1.64-1.95 (5H, m), 3.05-3.19 (2H, m), 3.84 (3H, s) , 4.06-4.19 (4H, m), 6.22 (1H, d, J = 4.0Hz), 7.22 (1H, dd, J = 8.5, 2.0Hz), 7.42 (1H, d, J = 8.5Hz), 7.51- 7.27 (2H, m).

Example 232

Yield: 46%, ¹ H-NMR (CDCl ₃ ); δ1.26 (3H, t, J = 7.0 Hz), 2.72 (4H, t, J = 5.0 Hz), 2.87 (2H, t, J = 5.5 Hz), 3.58 (2H, s), 3.66 (4H, t, J = 5.0Hz), 4.14 (2H, t, J = 5.5Hz), 4.15 (2H, q, J = 7.0Hz), 6.79-6.91 ( 3H, m), 7.23 (1H, d, J = 8.0Hz), 7.24 (1H, dd, J = 8.5, 2.0Hz), 7.44 (1H, d, J = 8.5Hz), 7.56 (1H, d, J = 2.0Hz).

Example 233

Yield: 81%, ¹ H-NMR (CDCl ₃ ); δ1.32-1.51 (5H, m), 1.74-1.99 (5H, m), 3.11-3.27 (2H, m), 4.04-4.24 (4H, m), 4.38 (2H, q, J = 7.0Hz), 7.06-7.13 (1H, m), 7.35 (1H, t, J = 8.0Hz), 7.48-7.57 (3H, m), 7.65 (1H, d , J = 8.0Hz), 7.84 (1H, s).

Example 234

Yield: 58%, ¹ H-NMR (CDCl ₃ ); δ1.26 (3H, t, J = 7.0Hz), 1.31-1.50 (2H, m), 1.72-1.98 (5H, m), 3.12-3.25 (2H, m), 3.59 (2H, s), 4.04 (2H, t, J = 6.0Hz), 4.10-4.24 (4H, m), 6.77-6.91 (3H, m), 7.23 (1H, t, J = 7.5Hz), 7.48-7.59 (2H, m), 7.84 (1H, s).

Example 235

Yield: 51%, ¹ H-NMR (DMSO-d ₆ ): δ 1.26 (3H, t, J = 7Hz), 2.20 (3H, s), 2.77 (4H, t, J = 5Hz), 2.92 ( 2H, t, J = 5.5Hz), 3.56 (2H, s), 3.70 (4H, t, J = 5Hz), 4.13 (2H, t, J = 5.5Hz), 4.16 (2H, q, J = 7Hz) , 6.75-6.80 (2H, m), 7.08 (1H, d, J = 7Hz), 7.52 (1H, dd, J = 8.5, 1.5Hz), 7.55 (1H, d, J = 8.5Hz), 7.85 (1H , d, J = 0.5Hz).

Example 236

Yield: 49%, ¹ H-NMR (CDCl ₃ ); δ1.26 (3H, t, J = 7.0Hz), 1.32-1.51 (2H, m), 1.78-2.00 (5H, m), 3.12-3.27 (2H, m), 3.57 (2H, s), 4.05-4.24 (6H, m), 6.81 (1H, dd, J = 8.0, 2.0Hz), 6.87 (1H, d, J = 2.0Hz), 7.30 ( 1H, d, J = 8.0Hz), 7.47-7.59 (2H, m), 7.83 (1H, s).

Example 237

Yield: 39%, ¹ H-NMR (CDCl ₃ ); δ 1.27 (3H, t, J = 7.0Hz), 1.30-1.48 (2H, m), 1.72-1.94 (5H, m), 3.08-3.21 (2H, m), 3.72 (2H, s), 3.97-4.04 (2H, m), 4.07-4.19 (2H, m), 4.19 (2H, q, J = 7.0Hz), 6.76 (1H, dd, J = 8.5, 3.0Hz), 6.84 (1H, d, J = 3.0Hz), 7.23 (1H, dd, J = 8.5, 2.0Hz), 7.27 (1H, d, J = 8.5Hz), 7.42 (1H, d , J = 8.5Hz), 7.54 (1H, d, J = 2.0Hz).

Example 238

Yield: 69%, ¹ H-NMR (CDCl ₃ ); δ2.00-2.08 (2H, m), 2.84 (2H, t, J = 8.4Hz), 2.96-3.02 (4H, m), 3.59 (2H , s), 3.69 (3H, s), 3.73 (2H, t, J = 6.0Hz), 3.79-3.84 (2H, m), 4.07 (2H, t, J = 5.4Hz), 6.79-6.88 (3H, m), 7.20-7.27 (2H, m), 7.43 (1H, d, J = 8.4Hz), 7.55 (1H, d, J = 2.1Hz).

Example 239

Yield: 49%, ¹ H-NMR (CDCl ₃ ); δ1.25 (3H, t, J = 7Hz), 1.98-2.08 (2H, m), 2.18 (3H, s), 2.82-2.90 (2H, m), 2.98-3.05 (4H, m), 3.55 (2H, s), 3.73 (2H, t, J = 5.5Hz), 3.75-3.85 (2H, m), 4.05-4.10 (2H, m), 4.15 (2H, q, J = 7Hz), 6.74 (1H, s), 6.76 (1H, d, J = 7.5Hz), 7.07 (1H, d, 7.5Hz), 7.22 (1H, dd, J = 8.5, 2Hz ), 7.43 (1H, d, J = 8.5Hz), 7.54 (1H, d, J = 2Hz).

Example 240

Yield: 45%, ¹ H-NMR (CDCl ₃ ); δ1.25 (3H, t, J = 7Hz), 1.95-2.10 (2H, m), 2.88 (2H, t, J = 5.5 Hz), 3.00 -3.10 (4H, m), 3.55 (2H, s), 3.73 (2H, t, J = 5.5Hz), 3.75-3.85 (2H, m), 4.10-4.15 (2H, m), 4.15 (2H, q , J = 7Hz), 6.80 (1H, dd, J = 8, 2Hz), 6.85 (1H, d, J = 2Hz), 7.22 (1H, dd, J = 8.5, 2.5Hz), 7.29 (1H, d, J = 8Hz), 7.42 (1H, d, J = 8.5Hz), 7.54 (1H, d, J = 2.5Hz).

Example 241

Yield: 74%, ¹ H-NMR (CDCl ₃ ); δ1.25 (3H, t, J = 7.0 Hz), 1.20-2.11 (2H, m), 2.79-2.90 (2H,
m), 2.93-3.06 (4H, m), 3.57 (2H, s), 3.69-3.90 (4H, m), 4.04-4.12 (2H, m), 4.15 (2H, q, J = 7.0 Hz), 6.76 -6.90 (3H, m), 7.22 (1H, t, J = 8.0Hz), 7.48-7.59 (2H, m), 7.84 (1H, s).

Example 242

Yield: 42%, ¹ H-NMR (CDCl ₃ ); δ1.25 (3H, t, J = 7.0 Hz), 1.99-2.09 (2H, m), 2.86-2.94 (2H, m), 3.02-3.12 (4H, m), 3.55 (2H, s), 3.69-3.90 (4H, m), 4.10-4.20 (4H, m), 6.81 (1H, dd, J = 8.0, 2.0Hz), 6.87 (1H, d , J = 2.0Hz), 7.29 (1H, d, J = 8.0Hz), 7.48-7.59 (2H, m), 7.84 (1H, s).

Example 243

Yield: 51%, ¹ H-NMR (CDCl ₃ ); δ1.31-1.49 (5H, m), 1.75-1.96 (5H, m), 3.09-3.22 (2H, m), 4.05-4.19 (4H, m), 4.38 (2H, q, J = 7.0Hz), 7.02 (1H, dd, J = 8.0, 2.0Hz), 7.09 (1H, ddd, J = 8.0, 2.5, 1.0Hz), 7.35 (1H, t , J = 8.0Hz), 7.47 (1H, d, J = 8.0Hz), 7.50 (1H, d, J = 2.0Hz), 7.56 (1H, dd, J = 2.5, 1.5Hz), 7.65 (1H, dt , J = 8.0, 1.5, 1.0Hz).

Example 244

Yield: 44%, ¹ H-NMR (CDCl ₃ ); δ 1.26 (3H, t, J = 6.5 Hz), 130-1.48 (2H, m), 1.72-1.95 (5H, m), 3.08-3.21 (2H, m), 3.58 (2H, s), 4.03 (2H, t, J = 6.0Hz), 4.08-4.21 (2H, m), 4.15 (2H, q, J = 6.5Hz), 6.76-6.90 ( 3H, m), 7.02 (1H, dd, J = 8.5, 2.0Hz), 7.22 (1H, d, J = 7.5Hz), 7.47 (1H, d, J = 8.5Hz), 7.50 (1H, d, J = 2.0Hz).

Example 245

Yield: 57%, ¹ H-NMR (CDCl ₃ ); δ1.26 (3H, t, J = 7.0 Hz), 1.31-1.48 (2H, m), 1.71-1.96 (5H, m), 3.09-3.22 (2H, m), 3.58 (2H, s), 4.03 (2H, t, J = 6.0Hz), 4.09-4.21 (4H, m), 6.77-6.91 (3H, m), 7.03 (1H, dd, J = 8.0, 1.0Hz), 7.17-7.28 (2H, m), 7.40 (1H, dd, J = 8.0, 1.0Hz).

Example 246

Yield: 81%, ¹ H-NMR (CDCl ₃ ); δ1.32-1.50 (5H, m), 1.75-1.95 (5H, m), 3.09-3.21 (2H, m), 4.05-4.18 (4H, m), 4.38 (2H, q, J = 7.0Hz), 7.06-7.12 (1H, m), 7.32-7.39 (3H, m), 7.54-7.58 (1H, m), 7.62-7.67 (1H, m) , 7.67-7.69 (1H, m).

Example 247

Yield: 44%, ¹ H-NMR (CDCl ₃ ); δ 1.26 (3H, t, J = 7.0Hz), 1.31-1.48 (2H, m), 1.73-1.96 (5H, m), 3.08-3.20 (2H, m), 3.58 (2H, s), 4.00-4.18 (4H, m), 4.16 (2H, q, J = 7.0Hz), 6.78-6.90 (3H, m), 7.20-7.28 (1H, m ), 7.36 (2H, m), 7.69 (1H, m).

Example 248

Yield: 48%, ¹ H-NMR (CDCl ₃ ); δ1.26 (3H, t, J = 7.0Hz), 1.30-1.49 (2H, m), 1.72-1.95 (5H, m), 2.39 (3H , s), 3.06-3.19 (2H, m), 3.58 (2H, s), 3.98-4.21 (6H, m), 6.77-6.91 (3H, m), 7.06-7.12 (1H, m), 7.23 (1H , t, J = 7.5Hz), 7.37-7.47 (2H, m).

Example 249

Yield: 54%, ¹ H-NMR (CDCl ₃ ); δ1.25 (3H, t, J = 7.0Hz), 3.56-3.82 (10H, m), 4.14 (2H, q, J = 7.0Hz), 4.74 (2H, s), 6.83-6.96 (3H, m), 7.22-7.29 (2H, m), 7.45 (1H, d, J = 8.5Hz), 7.58 (1H, d, J = 2.0Hz).

Example 250

Yield: 49%, ¹ H-NMR (CDCl ₃ ); δ 1.26 (3H, t, J = 7.0 Hz), 1.31-1.50 (2H, m), 1.73-1.93 (5H, m), 2.99-3.12 (2H, m), 3.58 (2H, s), 3.98-4.09 (4H, m), 4.15 (2H, q, J = 7.0Hz), 6.78-6.90 (3H, m), 7.16-7.47 (7H, m ).

Example 251

Yield: 54%, ¹ H-NMR (CDCl ₃ ); δ 1.26 (3H, t, J = 7.0 Hz), 1.35-1.52 (2H, m), 1.78-1.97 (5H, m), 3.01-3.14 (2H, m), 3.58 (2H, s), 3.99-4.21 (6H, m), 6.81 (1H, dd, J = 8.0, 2.0Hz), 6.87 (1H, d, J = 2.0Hz), 7.16- 7.24 (1H, m), 7.27-7.37 (3H, m), 7.38-7.47 (3H, m).

Example 252

Yield: 58%, 1H-NMR (DMSO-d6): δ 1.18 (3H, t, J = 7.0Hz), 1.83-1.95 (2H, m), 2.74-2.84 (2H, m), 2.89-3.01 (4H, m), 3.56-3.72 (6H, m), 4.08 (2H, q, J = 7.0Hz), 4.09-4.17 (2H, m), 6.84 (1H, dd, J = 8.0, 1.5Hz), 7.09 (1H, d, J = 1.5Hz), 7.18 (1H, t, J = 7.5Hz), 7.29-7.38 (3H, m), 7.44 (2H, d, J = 7.5Hz), 7.57 (1H, s ).

Example 253

Yield: 31%, 1H-NMR (CDCl3): δ1.24 (3H, t, J = 7.0Hz), 1.95-2.08 (2H, m), 2.88 (2H, t, J = 5.5Hz), 2.98- 3.12 (4H, m), 3.55 (2H, s), 3.60-3.90 (4H, m), 4.06-4.19 (4H, m), 6.79 (1H, dd, J = 8.0, 1.5Hz), 6.86 (1H, d, J = 1.5Hz), 7.25 (1H, d, J = 12.0Hz), 7.27 (1H, d, J = 8.0Hz), 7.72 (1H, d, J = 7.0Hz).

6-クロロ-2-[4-(2-ヒドロキシエチル)ピペリジン-１-イル]ベンゾチアゾール0.17g （0.562mmol）、[3-ヒドロキシ-2-メチル]フェニル酢酸エチル(国際公開第２００４／０２２５５１号パンフレットの参考例67に記載)0.11g（0.552mmol）、1,1-アゾジカルボニルジピペリジン0.21g（0.844mmol）、無水THF6mlの混合物にアルゴン中、氷冷下トリブチルホスフィン0.21ml（0.841mmol）を滴下した。反応液を同温で2.5時間撹拌した後、水及び酢酸エチルを加え抽出した。有機層を飽和食塩水で洗浄、無水硫酸ナトリウムで乾燥し、減圧下溶媒を留去した後、残渣をシリカゲルカラムクロマトグラフィー（ヘキサン：酢酸エチル＝10：1→5：1）で精製し3-{2-[(6-クロロベンゾチアゾール-2-イル)ピペリジン-4-イル]エトキシ}-2-メチルフェニル酢酸エチルを無色油状物質として0.16g（59％）得た。
¹H-NMR(CDCl₃): δ1.26 (3H, t, J = 7.2 Hz), 1.38-1.47 (2H, m), 1.78-1.93 (5H, m), 2.18 (3H, s), 3.14 (2H, td, J = 12.6, 2.4Hz), 3.64 (2H, s), 4.02 (2H, t, J = 5.7 Hz), 4.10-4.16 (2H, m), 4.15 (2H, t, J = 7.2 Hz), 6.80 (2H, q, J = 7.8 Hz), 7.11 (1H, t, J = 7.8 Hz), 7.23 (1H, dd, J = 8.4, 1.8Hz), 7.42 (1H, d, J = 8.4 Hz), 7.54 (1H, d, J = 1.8 Hz). Example 254
Preparation of ethyl 3- {2-[(6-chlorobenzothiazol-2-yl) piperidin-4-yl] ethoxy} -2-methylphenylacetate

6-chloro-2- [4- (2-hydroxyethyl) piperidin-1-yl] benzothiazole 0.17 g (0.562 mmol), ethyl [3-hydroxy-2-methyl] phenylacetate (WO 2004/022551) (Described in Reference Example 67 in the pamphlet) 0.11 g (0.552 mmol), 1,1-azodicarbonyldipiperidine 0.21 g (0.844 mmol), anhydrous THF 6 ml in argon, 0.21 ml (0.841 mmol) of tributylphosphine under ice-cooling Was dripped. The reaction solution was stirred at the same temperature for 2.5 hours, and then extracted by adding water and ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 10: 1 → 5: 1). Obtained 0.16 g (59%) of ethyl {2-[(6-chlorobenzothiazol-2-yl) piperidin-4-yl] ethoxy} -2-methylphenylacetate as a colorless oil.
¹ H-NMR (CDCl ₃ ): δ1.26 (3H, t, J = 7.2 Hz), 1.38-1.47 (2H, m), 1.78-1.93 (5H, m), 2.18 (3H, s), 3.14 ( 2H, td, J = 12.6, 2.4Hz), 3.64 (2H, s), 4.02 (2H, t, J = 5.7 Hz), 4.10-4.16 (2H, m), 4.15 (2H, t, J = 7.2 Hz ), 6.80 (2H, q, J = 7.8 Hz), 7.11 (1H, t, J = 7.8 Hz), 7.23 (1H, dd, J = 8.4, 1.8 Hz), 7.42 (1H, d, J = 8.4 Hz) ), 7.54 (1H, d, J = 1.8 Hz).

収率：39％, ¹H-NMR(CDCl₃); δ1.26 (3H, t, J=7.0Hz), 1.28-1.50 (2H, m), 1.70-1.98 (5H, m), 3.04-3.21 (2H, m), 3.58 (2H, s), 3.97-4.22 (4H, m), 4.15 (2H, q, J=7.0Hz), 6.75-6.92 (3H, m), 7.00 (1H, td, J=9.0 ,3.0Hz), 7.23 (1H, t, J=8.0Hz), 7.29 (1H, dd, J=9.0, 3.0Hz), 7.44 (1H, dd, J=9.0, 5.0Hz).

実施例２５６

収率：22％, 1H-NMR(CDCl3): δ1.24 (3H, t, J=7.0Hz), 1.26-1.50 (2H, m), 1.68-1.92 (5H, m), 2.94-3.09 (2H, m), 3.58 (2H, m), 3.94-4.13 (4H, m), 4.14 (2H, q, J=7.0Hz), 6.72 (1H, s), 6.75-6.93 (3H, m), 7.24 (2H, m), 7.35 (2H, t, J=7.0Hz), 7.83 (2H, d, J=7.0Hz). Thereafter, the compounds described in Examples 255 and 256 were obtained in the same manner as in Example 254.
Example 255

Yield: 39%, ¹ H-NMR (CDCl ₃ ); δ1.26 (3H, t, J = 7.0Hz), 1.28-1.50 (2H, m), 1.70-1.98 (5H, m), 3.04-3.21 (2H, m), 3.58 (2H, s), 3.97-4.22 (4H, m), 4.15 (2H, q, J = 7.0Hz), 6.75-6.92 (3H, m), 7.00 (1H, td, J = 9.0, 3.0Hz), 7.23 (1H, t, J = 8.0Hz), 7.29 (1H, dd, J = 9.0, 3.0Hz), 7.44 (1H, dd, J = 9.0, 5.0Hz).

Example 256

Yield: 22%, 1H-NMR (CDCl3): δ1.24 (3H, t, J = 7.0Hz), 1.26-1.50 (2H, m), 1.68-1.92 (5H, m), 2.94-3.09 (2H , m), 3.58 (2H, m), 3.94-4.13 (4H, m), 4.14 (2H, q, J = 7.0Hz), 6.72 (1H, s), 6.75-6.93 (3H, m), 7.24 ( 2H, m), 7.35 (2H, t, J = 7.0Hz), 7.83 (2H, d, J = 7.0Hz).

3-{2-[(6-ブロモベンゾチアゾール-2-イル)ピペリジン-4-イル]エトキシ}フェニル酢酸エチル0.30g（0.596mmol）、フェニルボロン酸0.09g(0.775mmol)、テトラキス（トリフェニルホスフィン）パラジウム（０）0.03g（0.03mmol）、炭酸セシウム0.25g（0.775mmol）及びジオキサン3mlの混合物をアルゴン中3時間加熱還流撹拌した。反応液を室温に戻した後、減圧下濃縮した。残渣をシリカゲルカラムクロマトグラフィー（ヘキサン：酢酸エチル＝3：1）で精製し、3-{2-[（6-フェニルベンゾチアゾール-2-イル）ピペリジン-4-イル]エトキシ}フェニル酢酸エチルを無色結晶として0.08g（26％）得た。
1H-NMR(CDCl3): δ 1.25 (3H, t, J=7.0Hz), 1.28-1.48 (2H, m), 1.66-1.96 (5H, m), 3.04-3.21 (2H, m), 3.57 (2H, s), 3.94-4.07 (2H, m), 4.08-4.25 (4H, m), 6.73-6.92 (3H, m), 7.17-7.34 (2H, m), 7.36-7.47 (2H, m), 7.48-7.64 (4H, m), 7.79 (1H, d, J=2.0Hz).

実施例２５８
3-{[4-(6-クロロベンゾチアゾール-2-イル)ピペラジン-1-イル]メチル}-5-メチルフェノールの製造

酢酸3-{[4-（6-クロロベンゾチアゾール-2-イル）ピペラジン-1-イル]メチル}-5-メチルフェニルエステル1.97ｇ(4.88mmol)、2N-水酸化ナトリウム水溶液(10ml)及びメタノール(20ml)の混合物を40℃で1時間撹拌した。減圧下溶媒を留去し、残渣に水及び2N-塩酸水溶液を加え中性とした後、酢酸エチルを加え抽出した。有機層を飽和食塩水で洗浄、無水硫酸ナトリウムで乾燥した後、減圧下溶媒を留去した。残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル）で精製し、3-{[4-(6-クロロベンゾチアゾール-2-イル)ピペラジン-1-イル]メチル}-5-メチルフェノールを無色無晶型固体として1.83g（100％）得た。
¹H-NMR(CDCl3): δ2.29 (3H, s), 2.57 (4H, t, J=5Hz), 3.47 (2H, s), 3.67 (4H, t, J=5Hz), 6.59 (1H, s), 6.67 (2H, s), 7.23 (1H, dd, J=8.5, 2Hz), 7.45 (1H, d, J=8.5Hz), 7.55 (1H, d, J=2Hz). Example 257
Preparation of ethyl 3- {2-[(6-phenylbenzothiazol-2-yl) piperidin-4-yl] ethoxy} phenylacetate

3- {2-[(6-Bromobenzothiazol-2-yl) piperidin-4-yl] ethoxy} phenyl acetate 0.30 g (0.596 mmol), phenylboronic acid 0.09 g (0.775 mmol), tetrakis (triphenylphosphine) ) A mixture of 0.03 g (0.03 mmol) of palladium (0), 0.25 g (0.775 mmol) of cesium carbonate and 3 ml of dioxane was stirred under reflux for 3 hours under argon. The reaction solution was returned to room temperature and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 3: 1) and ethyl 3- {2-[(6-phenylbenzothiazol-2-yl) piperidin-4-yl] ethoxy} phenylacetate was colorless. As a crystal, 0.08 g (26%) was obtained.
1H-NMR (CDCl3): δ 1.25 (3H, t, J = 7.0Hz), 1.28-1.48 (2H, m), 1.66-1.96 (5H, m), 3.04-3.21 (2H, m), 3.57 (2H , s), 3.94-4.07 (2H, m), 4.08-4.25 (4H, m), 6.73-6.92 (3H, m), 7.17-7.34 (2H, m), 7.36-7.47 (2H, m), 7.48 -7.64 (4H, m), 7.79 (1H, d, J = 2.0Hz).

Example 258
Preparation of 3-{[4- (6-Chlorobenzothiazol-2-yl) piperazin-1-yl] methyl} -5-methylphenol

Acetic acid 3-{[4- (6-chlorobenzothiazol-2-yl) piperazin-1-yl] methyl} -5-methylphenyl ester 1.97 g (4.88 mmol), 2N aqueous sodium hydroxide solution (10 ml) and methanol (20 ml) of the mixture was stirred at 40 ° C. for 1 hour. The solvent was evaporated under reduced pressure, and the residue was neutralized with water and 2N-hydrochloric acid aqueous solution, and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate) to give 3-{[4- (6-chlorobenzothiazol-2-yl) piperazin-1-yl] methyl} -5-methylphenol as a colorless amorphous solid As a result, 1.83 g (100%) was obtained.
¹ H-NMR (CDCl3): δ 2.29 (3H, s), 2.57 (4H, t, J = 5Hz), 3.47 (2H, s), 3.67 (4H, t, J = 5Hz), 6.59 (1H, s), 6.67 (2H, s), 7.23 (1H, dd, J = 8.5, 2Hz), 7.45 (1H, d, J = 8.5Hz), 7.55 (1H, d, J = 2Hz).

収率：85％, ¹H-NMR(CDCl₃); δ1.74 (1H, brs), 1.96-2.05 (2H, m), 2.26 (3H, s), 2.67 (2H, t, J=5.1Hz), 2.75-2.79 (2H, m), 3.52 (2H, s), 3.68-3.74 (4H, m), 6.55 (1H, s), 6.61 (1H, s), 6.65 (1H, s), 7.22 (1H, dd, J=8.7, 2.1Hz), 7.43 (1H, d, J=8.4Hz), 7.54 (1H, d, J=2.1Hz).

実施例２６０

収率：100％, ¹H-NMR(CDCl₃); δ2.29 (3H, s), 2.61 (4H, t, J=5Hz), 3.50 (2H, s), 3.71 (4H, t, J=5Hz), 6.60 (1H, s), 6.69 (2H, s), 7.52 (1H, d, J=7.5Hz), 7.58 (1H, d, J=7.5Hz), 7.85 (1H, s).

実施例２６１

収率：71％, ¹H-NMR(CDCl₃); δ2.00-2.10 (2H, m), 2.28 (3H, s), 2.65-2.75 (2H, m), 2.80-2.90 (2H, m), 3.57 (2H, s), 3.70-3.90 (4H, m), 6.56 (1H, s), 6.65-6.70 (2H, m), 7.45-7.60 (2H, m), 7.85 (1H, s).

実施例２６２

収率：99％, 1H-NMR(CDCl3): δ1.22 (3H, d, J=6Hz), 1.64 (1H, brs), 2.25-2.29 (1H, m), 2.30 (3H, s), 2.60-2.70 (1H, m), 2.80-2.83 (1H, m), 3.13 (1H, d, J=13.5Hz), 3.17-3.25 (1H, m), 3.40-3.50 (1H, m), 3.73-3.83 (1H, m), 3.85-3.95 (1H, m), 3.98 (1H, d, J=13.5Hz), 6.57 (1H, s), 6.66 (1H, s), 6.69 (1H, s), 7.52 (1H, d, J=8.5Hz), 7.57 (1H, d, J=8.5Hz), 7.84 (1H, s).

実施例２６３

収率：quant. ％, 1H-NMR(CDCl3): δ1.11 (6H, d, J=6Hz), 2.28 (3H, s), 2.70-2.85 (2H, m), 2.95-3.10 (2H, m), 3.70-3.90 (4H, m), 6.53 (1H, s), 6.68 (1H, s), 6.72 (1H, s), 7.23 (1H, dd, J=8.5, 2Hz), 7.43 (1H, d, J=8.5Hz), 7.55 (1H, d, J=2Hz).

実施例２６４

収率：quant. ％, 1H-NMR(CDCl3): δ1.10 (6H, d, J=6Hz), 2.28 (3H, s), 2.70-2.85 (2H, m), 3.00-3.15 (2H, m), 3.75 (2H, s), 3.82-3.94 (2H, m), 5.53 (1H, brs), 6.52 (1H, s), 6.69 (1H, s), 6.72 (1H, s), 7.51 (1H, d, J=8.5Hz), 7.56 (1H, d, J=8.5Hz), 7.84 (1H, s).

実施例２６５

収率：quant. ％, 1H-NMR(CDCl3): δ1.42 (3H, d, J=7Hz), 2.20-2.28 (1H, m), 2.28 (3H, s), 2.30-2.45 (1H, m), 2.70-2.85 (1H, m), 2.90-3.00 (1H, m), 3.43 (1H, d, J=13.5Hz), 3.45-3.55 (1H, m), 3.58 (1H, d, J=13.5Hz), 3.80-3.90 (1H, m), 4.15-4.25 (1H, m), 6.60 (1H, s), 6.66 (1H, s), 6.77 (1H, s), 7.22 (1H, dd, J=8.5, 2Hz), 7.43 (1H, d, J=8.5Hz), 7.54 (1H, d, J=2Hz).

実施例２６６

収率：quant. ％, 1H-NMR(CDCl3): δ1.01 (3H, t, J=7.5Hz), 1.55-1.78 (2H, m), 2.29 (3H, s), 2.30-2.40 (1H, m), 2.48-2.56 (1H, m), 2.79-2.83 (1H, m), 3.18 (1H, d, J=13.5Hz), 3.37-3.56 (2H, m), 3.65-3.77 (1H, m), 3.82 (1H, dd, J=13, 3Hz), 3.93 (1H, d, J=13.5Hz), 6.57 (1H, s), 6.67 (1H, s), 6.70 (1H, s), 7.52 (1H, dd, J=8.5, 1.5Hz), 7.57 (1H, d, J=8.5Hz), 7.84 (1H, d, J=1.5Hz).

実施例２６７

収率：99 ％, 1H-NMR(CDCl3): δ2.27 (3H, s), 2.27-2.35 (1H, m), 2.77 (1H, d, J=13.5Hz), 3.02 (1H, d, J=11.5Hz), 3.28-3.50 (3H, m), 3.75 (1H, d, J=13.5Hz), 3.98 (1H, d, J=11Hz), 4.10-4.18 (1H, m), 5.61 (1H, brs), 6.54 (1H, s), 6.61 (1H, s), 6.64 (1H, s), 7.30-7.43 (3H, m), 7.45-7.60 (4H, m), 7.86 (1H, s).

実施例２６８

収率：96％, 1H-NMR(CDCl3): δ1.42 (3H, d, J=6.5Hz), 2.18 (1H, td, J=12, 3.5Hz), 2.29 (3H, s), 2.29-2.40 (1H, m), 2.74 (1H, d, J=11.5Hz), 2.89 (1H, d, J=11.5Hz), 3.39 (1H, d, J=13Hz), 3.47 (1H, d, J=13Hz), 3.55 (1H, td, J=12.5, 3.5Hz), 3.90 (1H, d, J=13Hz), 4.16-4.29 (1H, m), 6.58 (1H, s), 6.69 (1H, s), 6.70 (1H, s), 7.51 (1H, dd, J=8.5, 1.5Hz), 7.57 (1H, d, J=8.5Hz), 7.84 (1H, d, J=1.5Hz).

実施例２６９

収率：quant. ％, 1H-NMR(CDCl3): δ1.43 (3H, d, J=6.5Hz), 2.14-2.41 (5H, m), 2.71-2.80 (1H, m), 2.86-2.92 (1H, m), 3.35-3.59 (3H, m), 3.85-3.97 (1H, m), 4.17-4.29 (1H, m), 6.58 (1H, s), 6.69 (1H, s), 6.72 (1H, s), 7.48-7.60 (2H, m), 7.84 (1H, s).

実施例２７０

収率：96％, 1H-NMR(CDCl3): δ1.00 (3H, t, J=7.5Hz), 1.55-1.75 (2H, m), 2.29 (3H, s), 2.29-2.38 (1H, m), 2.47-2.57 (1H, m), 2.78-2.88 (1H, m), 3.17 (1H, d, J=13.5Hz), 3.37-3.55 (2H, m), 3.65-3.85 (2H, m), 3.93 (1H, d, J=13.5Hz), 6.57 (1H, s), 6.67 (1H, s), 6.69 (1H, s), 7.52 (1H, d, J=8.5Hz), 7.57 (1H, d, J=8.5Hz), 7.84 (1H, s).

実施例２７１

収率：92％, 1H-NMR(CDCl3): δ1.01 (3H, t, J=7.5Hz), 1.57-1.79 (2H, m), 2.29 (3H, s), 2.29-2.40 (1H, m), 2.46-2.58 (1H, m), 2.77-2.89 (1H, m), 3.18 (1H, d, J=13Hz), 3.32-3.58 (2H, m), 3.65-3.87 (2H, m), 3.93 (1H, d, J=13Hz), 6.57 (1H, s), 6.67 (1H, s), 6.69 (1H, s), 7.52 (1H, d, J=8.5Hz), 7.57 (1H, d, J=8.5Hz), 7.84 (1H, s).

実施例２７２

収率：95％, 1H-NMR(CDCl3): δ0.93 (3H, t, J=7.5Hz), 1.30-1.70 (4H, m), 2.29 (3H, s), 2.29-2.39 (1H, m), 2.55-2.65 (1H, m), 2.79-2.88 (1H, m), 3.19 (1H, d, J=13.5Hz), 3.41 (1H, dd, J=12.5, 8Hz), 3.48-3.58 (1H, m), 3.65-3.75 (1H, m), 3.82 (1H, dd, J=12.5, 2.5Hz), 3.92 (1H, d, J=13.5Hz), 6.57 (1H, s), 6.68 (1H, s), 6.70 (1H, s), 7.51 (1H, dd, J=8.5, 1.5Hz), 7.55 (1H, d, J=8.5Hz), 7.84 (1H, d, J=1.5Hz).

実施例２７３

収率：98％, 1H-NMR(CDCl3): δ0.93 (3 H, t, J = 7.5 Hz), 1.30-1.41 (1 H, m), 1.48-1.63 (3 H, m), 2.29 (3 H, s), 2.29-2.36 (1 H, m), 2.56-2.62 (1 H, m), 2.79-2.86 (1 H, m), 3.19 (1 H, d, J = 13.5 Hz), 3.41 (1 H, dd, J = 7.8, 12.9 Hz), 3.50-3.57 (1 H, m), 3.69-3.81 (2 H, m), 3.92 (1 H, d, J = 13.5 Hz), 6.67 (1 H, s), 6.68 (2 H, s), 7.50-7.59 (2 H, m), 7.84 (1 H, s)

実施例２７４

収率：98％, 1H-NMR(CDCl3): δ0.91 (3H, t, J=7Hz), 1.26-1.75 (6H, m), 2.30 (3H, s), 2.30-2.40 (1H, m), 2.52-2.63 (1H, m), 2.77-2.87 (1H, m), 3.19 (1H, d, J=13.5Hz), 3.35-3.45 (1H, m), 3.47-3.57 (1H, m), 3.65-3.75 (1H, m), 3.81 (1H, dd, J=12.5, 2.5Hz), 3.92 (1H, d, J=13.5Hz), 5.49 (1H, brs), 6.57 (1H, s), 6.67 (1H, s), 6.69 (1H, s), 7.52 (1H, dd, J=8.5, 1.5Hz), 7.57 (1H, d, J=8.5Hz), 7.84 (1H, d, J=1.5Hz)

実施例２７５

収率：96％, 1H-NMR(CDCl3): δ0.91 (3H, d, J=6.5Hz), 0.95 (3H, d, J=6.5Hz), 1.32-1.46 (1H, m), 1.47-1.59 (1H, m), 1.62-1.78 (1H, m), 2.29 (3H, s), 2.33-2.45 (1H, m), 2.62-2.74 (1H, m), 2.75-2.87 (1H, m), 3.27 (1H, d, J=13.5Hz), 3.36 (1H, dd, J=12.5, 7.5Hz), 3.55-3.65 (2H, m), 3.70-3.79 (1H, m), 3.86 (1H, d, J=13.5Hz), 6.56 (1H, s), 6.69 (2H, s), 7.22 (1H, dd, J=8.5, 2Hz), 7.43 (1H, d, J=8.5Hz), 7.54 (1H, d, J=2Hz).

実施例２７６

収率：quant.％, 1H-NMR(CDCl3): δ0.91 (3H, d, J=6.5Hz), 0.95 (3H, d, J=6.5Hz), 1.30-1.59 (2H, m), 1.62-1.79 (1H, m), 2.18 (1H, s), 2.29 (3H, s), 2.30-2.45 (1H, m), 2.60-2.72 (1H, m), 2.75-2.88 (1H, m), 3.27 (1H, d, J=13.5Hz), 3.29-3.42 (1H, m), 3.53-3.65 (2H, m), 3.74 (1H, dd, J=12.5, 3.5Hz), 3.86 (1H, d, J=13.5Hz), 6.56 (1H, s), 6.67 (1H, s), 6.70 (1H, s), 7.23 (1H, dd, J=8.5, 2.0Hz), 7.43 (1H, d, J=8.5Hz), 7.54 (1H, d, J=2.0Hz).

実施例２７７

収率：98％, 1H-NMR(CDCl3): δ0.91 (3H, d, J=6.5Hz), 0.95 (3H, d, J=6.5Hz), 1.37-1.45 (1H, m), 1.46-1.60 (1H, m), 1.64-1.77 (1H, m), 2.29 (3H, s), 2.36-2.47 (1H, m), 2.64-2.75 (1H, m), 2.78-2.90 (1H, m), 3.29 (1H, d, J=13.5Hz), 3.42 (1H, dd, J=12.5, 7.5Hz), 3.65 (2H, t, J=5Hz), 3.78 (1H, dd, J=13, 3Hz), 3.86 (1H, d, J=13.5Hz), 6.57 (1H, s), 6.70 (2H, s), 7.51 (1H, dd, J=8.5, 1.5Hz), 7.57 (1H, d, J=8.5Hz), 7.84 (1H, d, J=1.5Hz).

実施例２７８

収率：99％, 1H-NMR(CDCl3): δ1.21 (3H, d, J=6Hz), 2.22-2.28 (1H, m), 2.29 (3H, s), 2.59-2.70 (1H, m), 2.83 (1H, dt, J=12, 3.5Hz), 3.13 (1H, d, J=13.5Hz), 3.21 (1H, dd, J=11, 8.5Hz), 3.39-3.50 (1H, m), 3.72-3.83 (1H, m), 3.84-3.93 (1H, m), 3.97 (1H, d, J=13.5Hz), 6.56 (1H, s), 6.65 (1H, s), 6.70 (1H, s), 7.26 (1H, d, J=11.5Hz), 7.73 (1H, d, J=7Hz).

実施例２７９

収率：quant.％, 1H-NMR(CDCl3): δ2.00-2.14 (2H, m), 2.22 (3H, s), 2.68-2.93 (4H, m), 3.53-3.95 (6H, m), 6.60 (2H, s), 6.72(1H, s), 7.24 (1H, d, J=11.5Hz), 7.72 (1H, d, J=7.0Hz), 7.85 (1H, s).

実施例２８０

収率：89％, 1H-NMR(CDCl3): δ1.13 (6H, d, J=6.0Hz), 2.29 (3H, s), 2.72-2.88 (2H, m), 3.01-3.19 (2H, m), 3.77 (2H, s), 3.89 (2H, d, J=12.0Hz), 6.52 (1H, s), 6.70 (1H, s), 6.72 (1H, s), 7.27 (1H, d, J=11.5Hz), 7.75 (1H, d, J=6.5Hz).

実施例２８１

収率：95％, 1H-NMR(CDCl3): δ1.01 (3H, t, J=7.5Hz), 1.48-1.80 (2H, m), 2.25-2.40 (1H, m), 2.30 (3H, s), 2.46-2.58 (1H, m), 2.78-2.89 (1H, m), 3.19 (1H, d, J=13.5Hz), 3.32-3.57 (2H, m), 3.64-3.75 (1H, m), 3.76-3.87 (1H, m), 3.93 (1H, d, J=13.5Hz), 6.57 (1H, s), 6.67 (1H, s), 6.70 (1H, s), 7.27 (1H, d, J=11.5Hz), 7.74 (1H, d, J=7.0Hz).

実施例２８２

収率：quant％, 1H-NMR(CDCl3): δ2.23 (3H, s), 2.62-2.80 (4H, m), 3.52-3.73 (6H, m), 6.63 (1H, s), 6.65 (1H, s), 6.78 (1H, s), 7.20 (1H, t, J=7.5Hz), 7.31 (2H, t, J=7.5Hz), 7.35-7.44 (3H, m), 8.70 (1H, brs).

実施例２８３

収率：93％, 1H-NMR(CDCl3): δ1.13 (6H, d, J=6.0Hz), 2.29 (3H, s), 2.65-2.80 (2H, m), 2.90 (2H, t, J=11.5Hz), 3.76 (2H, s), 4.29 (2H, d, J=13.0Hz), 6.54 (1H, s), 6.70 (1H, s), 6.75 (1H, s), 7.34-7.43 (1H, m), 7.53-7.62 (1H, m), 7.69 (1H, d, J=8.0Hz), 7.88 (1H, d, J=8.0Hz), 8.55 (1H, s).

実施例２８４

収率：93％, 1H-NMR(CDCl3): δ1.25 (3H, d, J=5.5Hz), 2.21-2.34 (1H, m), 2.29 (3H, s), 2.54-2.70 (1H, m), 2.83-2.94 (1H, m), 3.07-3.22 (1H, m), 3.14 (1H, d, J=13.5Hz), 3.30-3.45 (1H, m), 4.02 (1H, d, J=13.5Hz), 4.06-4.17 (1H, m), 4.18-4.28 (1H, m), 6.58 (1H, s), 6.66-6.74 (2H, m), 7.34-7.43 (1H, m), 7.53-7.61 (1H, m), 7.68 (1H, dd, J=8.5, 1.0Hz), 7.88 (1H, dd, J=8.5, 1.0Hz), 8.55 (1H, s).

実施例２８５

収率：88％, 1H-NMR(CDCl3): δ1.16 (6H, d, J=6.0Hz), 2.29 (3H, s), 2.65-2.83 (2H, m) 2.94 (2H, t, J=11.5Hz), 3.77 (2H, s), 4.30 (2H, d, J=14.0Hz), 6.52 (1H, s), 6.72 (1H, s), 6.75 (1H, s), 7.50 (1H, dd, J=9.0, 2.5Hz), 7.60 (1H, d, J=9.0Hz), 7.85 (1H, d, J=2.5Hz), 8.54 (1H, s).

実施例２８６

収率：97％, 1H-NMR(CDCl3): δ1.17 (6H, d, J=6.0Hz), 2.28 (3H, s), 2.66-2.83 (2H, m), 2.90-3.06 (2H, m), 3.79 (2H, s), 4.34 (2H, d, J=13.0Hz), 6.55 (1H, s), 6.69 (1H, s), 6.75 (1H, s), 7.72 (2H, s), 8.14 (1H, s), 8.59 (1H, s). Thereafter, the compounds described in Examples 259 to 286 were obtained in the same manner as in Example 258.
Example 259

Yield: 85%, ¹ H-NMR (CDCl ₃ ); δ1.74 (1H, brs), 1.96-2.05 (2H, m), 2.26 (3H, s), 2.67 (2H, t, J = 5.1Hz ), 2.75-2.79 (2H, m), 3.52 (2H, s), 3.68-3.74 (4H, m), 6.55 (1H, s), 6.61 (1H, s), 6.65 (1H, s), 7.22 ( 1H, dd, J = 8.7, 2.1Hz), 7.43 (1H, d, J = 8.4Hz), 7.54 (1H, d, J = 2.1Hz).

Example 260

Yield: 100%, ¹ H-NMR (CDCl ₃ ); δ2.29 (3H, s), 2.61 (4H, t, J = 5Hz), 3.50 (2H, s), 3.71 (4H, t, J = 5Hz), 6.60 (1H, s), 6.69 (2H, s), 7.52 (1H, d, J = 7.5Hz), 7.58 (1H, d, J = 7.5Hz), 7.85 (1H, s).

Example 261

Yield: 71%, ¹ H-NMR (CDCl ₃ ); δ2.00-2.10 (2H, m), 2.28 (3H, s), 2.65-2.75 (2H, m), 2.80-2.90 (2H, m) , 3.57 (2H, s), 3.70-3.90 (4H, m), 6.56 (1H, s), 6.65-6.70 (2H, m), 7.45-7.60 (2H, m), 7.85 (1H, s).

Example 262

Yield: 99%, 1H-NMR (CDCl3): δ1.22 (3H, d, J = 6Hz), 1.64 (1H, brs), 2.25-2.29 (1H, m), 2.30 (3H, s), 2.60 -2.70 (1H, m), 2.80-2.83 (1H, m), 3.13 (1H, d, J = 13.5Hz), 3.17-3.25 (1H, m), 3.40-3.50 (1H, m), 3.73-3.83 (1H, m), 3.85-3.95 (1H, m), 3.98 (1H, d, J = 13.5Hz), 6.57 (1H, s), 6.66 (1H, s), 6.69 (1H, s), 7.52 ( 1H, d, J = 8.5Hz), 7.57 (1H, d, J = 8.5Hz), 7.84 (1H, s).

Example 263

Yield: quant.%, 1H-NMR (CDCl3): δ1.11 (6H, d, J = 6Hz), 2.28 (3H, s), 2.70-2.85 (2H, m), 2.95-3.10 (2H, m ), 3.70-3.90 (4H, m), 6.53 (1H, s), 6.68 (1H, s), 6.72 (1H, s), 7.23 (1H, dd, J = 8.5, 2Hz), 7.43 (1H, d , J = 8.5Hz), 7.55 (1H, d, J = 2Hz).

Example 264

Yield: quant.%, 1H-NMR (CDCl3): δ1.10 (6H, d, J = 6Hz), 2.28 (3H, s), 2.70-2.85 (2H, m), 3.00-3.15 (2H, m ), 3.75 (2H, s), 3.82-3.94 (2H, m), 5.53 (1H, brs), 6.52 (1H, s), 6.69 (1H, s), 6.72 (1H, s), 7.51 (1H, d, J = 8.5Hz), 7.56 (1H, d, J = 8.5Hz), 7.84 (1H, s).

Example 265

Yield: quant.%, 1H-NMR (CDCl3): δ1.42 (3H, d, J = 7Hz), 2.20-2.28 (1H, m), 2.28 (3H, s), 2.30-2.45 (1H, m ), 2.70-2.85 (1H, m), 2.90-3.00 (1H, m), 3.43 (1H, d, J = 13.5Hz), 3.45-3.55 (1H, m), 3.58 (1H, d, J = 13.5 Hz), 3.80-3.90 (1H, m), 4.15-4.25 (1H, m), 6.60 (1H, s), 6.66 (1H, s), 6.77 (1H, s), 7.22 (1H, dd, J = 8.5, 2Hz), 7.43 (1H, d, J = 8.5Hz), 7.54 (1H, d, J = 2Hz).

Example 266

Yield: quant.%, 1H-NMR (CDCl3): δ1.01 (3H, t, J = 7.5Hz), 1.55-1.78 (2H, m), 2.29 (3H, s), 2.30-2.40 (1H, m), 2.48-2.56 (1H, m), 2.79-2.83 (1H, m), 3.18 (1H, d, J = 13.5Hz), 3.37-3.56 (2H, m), 3.65-3.77 (1H, m) , 3.82 (1H, dd, J = 13, 3Hz), 3.93 (1H, d, J = 13.5Hz), 6.57 (1H, s), 6.67 (1H, s), 6.70 (1H, s), 7.52 (1H , dd, J = 8.5, 1.5Hz), 7.57 (1H, d, J = 8.5Hz), 7.84 (1H, d, J = 1.5Hz).

Example 267

Yield: 99%, 1H-NMR (CDCl3): δ2.27 (3H, s), 2.27-2.35 (1H, m), 2.77 (1H, d, J = 13.5Hz), 3.02 (1H, d, J = 11.5Hz), 3.28-3.50 (3H, m), 3.75 (1H, d, J = 13.5Hz), 3.98 (1H, d, J = 11Hz), 4.10-4.18 (1H, m), 5.61 (1H, brs), 6.54 (1H, s), 6.61 (1H, s), 6.64 (1H, s), 7.30-7.43 (3H, m), 7.45-7.60 (4H, m), 7.86 (1H, s).

Example 268

Yield: 96%, 1H-NMR (CDCl3): δ1.42 (3H, d, J = 6.5Hz), 2.18 (1H, td, J = 12, 3.5Hz), 2.29 (3H, s), 2.29- 2.40 (1H, m), 2.74 (1H, d, J = 11.5Hz), 2.89 (1H, d, J = 11.5Hz), 3.39 (1H, d, J = 13Hz), 3.47 (1H, d, J = 13Hz), 3.55 (1H, td, J = 12.5, 3.5Hz), 3.90 (1H, d, J = 13Hz), 4.16-4.29 (1H, m), 6.58 (1H, s), 6.69 (1H, s) , 6.70 (1H, s), 7.51 (1H, dd, J = 8.5, 1.5Hz), 7.57 (1H, d, J = 8.5Hz), 7.84 (1H, d, J = 1.5Hz).

Example 269

Yield: quant.%, 1H-NMR (CDCl3): δ1.43 (3H, d, J = 6.5Hz), 2.14-2.41 (5H, m), 2.71-2.80 (1H, m), 2.86-2.92 ( 1H, m), 3.35-3.59 (3H, m), 3.85-3.97 (1H, m), 4.17-4.29 (1H, m), 6.58 (1H, s), 6.69 (1H, s), 6.72 (1H, s), 7.48-7.60 (2H, m), 7.84 (1H, s).

Example 270

Yield: 96%, 1H-NMR (CDCl3): δ1.00 (3H, t, J = 7.5Hz), 1.55-1.75 (2H, m), 2.29 (3H, s), 2.29-2.38 (1H, m ), 2.47-2.57 (1H, m), 2.78-2.88 (1H, m), 3.17 (1H, d, J = 13.5Hz), 3.37-3.55 (2H, m), 3.65-3.85 (2H, m), 3.93 (1H, d, J = 13.5Hz), 6.57 (1H, s), 6.67 (1H, s), 6.69 (1H, s), 7.52 (1H, d, J = 8.5Hz), 7.57 (1H, d , J = 8.5Hz), 7.84 (1H, s).

Example 271

Yield: 92%, 1H-NMR (CDCl3): δ1.01 (3H, t, J = 7.5Hz), 1.57-1.79 (2H, m), 2.29 (3H, s), 2.29-2.40 (1H, m ), 2.46-2.58 (1H, m), 2.77-2.89 (1H, m), 3.18 (1H, d, J = 13Hz), 3.32-3.58 (2H, m), 3.65-3.87 (2H, m), 3.93 (1H, d, J = 13Hz), 6.57 (1H, s), 6.67 (1H, s), 6.69 (1H, s), 7.52 (1H, d, J = 8.5Hz), 7.57 (1H, d, J = 8.5Hz), 7.84 (1H, s).

Example 272

Yield: 95%, 1H-NMR (CDCl3): δ0.93 (3H, t, J = 7.5Hz), 1.30-1.70 (4H, m), 2.29 (3H, s), 2.29-2.39 (1H, m ), 2.55-2.65 (1H, m), 2.79-2.88 (1H, m), 3.19 (1H, d, J = 13.5Hz), 3.41 (1H, dd, J = 12.5, 8Hz), 3.48-3.58 (1H , m), 3.65-3.75 (1H, m), 3.82 (1H, dd, J = 12.5, 2.5Hz), 3.92 (1H, d, J = 13.5Hz), 6.57 (1H, s), 6.68 (1H, s), 6.70 (1H, s), 7.51 (1H, dd, J = 8.5, 1.5Hz), 7.55 (1H, d, J = 8.5Hz), 7.84 (1H, d, J = 1.5Hz).

Example 273

Yield: 98%, 1H-NMR (CDCl3): δ0.93 (3 H, t, J = 7.5 Hz), 1.30-1.41 (1 H, m), 1.48-1.63 (3 H, m), 2.29 ( 3 H, s), 2.29-2.36 (1 H, m), 2.56-2.62 (1 H, m), 2.79-2.86 (1 H, m), 3.19 (1 H, d, J = 13.5 Hz), 3.41 (1 H, dd, J = 7.8, 12.9 Hz), 3.50-3.57 (1 H, m), 3.69-3.81 (2 H, m), 3.92 (1 H, d, J = 13.5 Hz), 6.67 (1 H, s), 6.68 (2 H, s), 7.50-7.59 (2 H, m), 7.84 (1 H, s)

Example 274

Yield: 98%, 1H-NMR (CDCl3): δ0.91 (3H, t, J = 7Hz), 1.26-1.75 (6H, m), 2.30 (3H, s), 2.30-2.40 (1H, m) , 2.52-2.63 (1H, m), 2.77-2.87 (1H, m), 3.19 (1H, d, J = 13.5Hz), 3.35-3.45 (1H, m), 3.47-3.57 (1H, m), 3.65 -3.75 (1H, m), 3.81 (1H, dd, J = 12.5, 2.5Hz), 3.92 (1H, d, J = 13.5Hz), 5.49 (1H, brs), 6.57 (1H, s), 6.67 ( 1H, s), 6.69 (1H, s), 7.52 (1H, dd, J = 8.5, 1.5Hz), 7.57 (1H, d, J = 8.5Hz), 7.84 (1H, d, J = 1.5Hz)

Example 275

Yield: 96%, 1H-NMR (CDCl3): δ0.91 (3H, d, J = 6.5Hz), 0.95 (3H, d, J = 6.5Hz), 1.32-1.46 (1H, m), 1.47- 1.59 (1H, m), 1.62-1.78 (1H, m), 2.29 (3H, s), 2.33-2.45 (1H, m), 2.62-2.74 (1H, m), 2.75-2.87 (1H, m), 3.27 (1H, d, J = 13.5Hz), 3.36 (1H, dd, J = 12.5, 7.5Hz), 3.55-3.65 (2H, m), 3.70-3.79 (1H, m), 3.86 (1H, d, J = 13.5Hz), 6.56 (1H, s), 6.69 (2H, s), 7.22 (1H, dd, J = 8.5, 2Hz), 7.43 (1H, d, J = 8.5Hz), 7.54 (1H, d , J = 2Hz).

Example 276

Yield: quant.%, 1H-NMR (CDCl3): δ0.91 (3H, d, J = 6.5Hz), 0.95 (3H, d, J = 6.5Hz), 1.30-1.59 (2H, m), 1.62 -1.79 (1H, m), 2.18 (1H, s), 2.29 (3H, s), 2.30-2.45 (1H, m), 2.60-2.72 (1H, m), 2.75-2.88 (1H, m), 3.27 (1H, d, J = 13.5Hz), 3.29-3.42 (1H, m), 3.53-3.65 (2H, m), 3.74 (1H, dd, J = 12.5, 3.5Hz), 3.86 (1H, d, J = 13.5Hz), 6.56 (1H, s), 6.67 (1H, s), 6.70 (1H, s), 7.23 (1H, dd, J = 8.5, 2.0Hz), 7.43 (1H, d, J = 8.5Hz ), 7.54 (1H, d, J = 2.0Hz).

Example 277

Yield: 98%, 1H-NMR (CDCl3): δ 0.91 (3H, d, J = 6.5Hz), 0.95 (3H, d, J = 6.5Hz), 1.37-1.45 (1H, m), 1.46- 1.60 (1H, m), 1.64-1.77 (1H, m), 2.29 (3H, s), 2.36-2.47 (1H, m), 2.64-2.75 (1H, m), 2.78-2.90 (1H, m), 3.29 (1H, d, J = 13.5Hz), 3.42 (1H, dd, J = 12.5, 7.5Hz), 3.65 (2H, t, J = 5Hz), 3.78 (1H, dd, J = 13, 3Hz), 3.86 (1H, d, J = 13.5Hz), 6.57 (1H, s), 6.70 (2H, s), 7.51 (1H, dd, J = 8.5, 1.5Hz), 7.57 (1H, d, J = 8.5Hz ), 7.84 (1H, d, J = 1.5Hz).

Example 278

Yield: 99%, 1H-NMR (CDCl3): δ1.21 (3H, d, J = 6Hz), 2.22-2.28 (1H, m), 2.29 (3H, s), 2.59-2.70 (1H, m) , 2.83 (1H, dt, J = 12, 3.5Hz), 3.13 (1H, d, J = 13.5Hz), 3.21 (1H, dd, J = 11, 8.5Hz), 3.39-3.50 (1H, m), 3.72-3.83 (1H, m), 3.84-3.93 (1H, m), 3.97 (1H, d, J = 13.5Hz), 6.56 (1H, s), 6.65 (1H, s), 6.70 (1H, s) , 7.26 (1H, d, J = 11.5Hz), 7.73 (1H, d, J = 7Hz).

Example 279

Yield: quant.%, 1H-NMR (CDCl3): δ2.00-2.14 (2H, m), 2.22 (3H, s), 2.68-2.93 (4H, m), 3.53-3.95 (6H, m), 6.60 (2H, s), 6.72 (1H, s), 7.24 (1H, d, J = 11.5Hz), 7.72 (1H, d, J = 7.0Hz), 7.85 (1H, s).

Example 280

Yield: 89%, 1H-NMR (CDCl3): δ1.13 (6H, d, J = 6.0Hz), 2.29 (3H, s), 2.72-2.88 (2H, m), 3.01-3.19 (2H, m ), 3.77 (2H, s), 3.89 (2H, d, J = 12.0Hz), 6.52 (1H, s), 6.70 (1H, s), 6.72 (1H, s), 7.27 (1H, d, J = 11.5Hz), 7.75 (1H, d, J = 6.5Hz).

Example 281

Yield: 95%, 1H-NMR (CDCl3): δ1.01 (3H, t, J = 7.5Hz), 1.48-1.80 (2H, m), 2.25-2.40 (1H, m), 2.30 (3H, s ), 2.46-2.58 (1H, m), 2.78-2.89 (1H, m), 3.19 (1H, d, J = 13.5Hz), 3.32-3.57 (2H, m), 3.64-3.75 (1H, m), 3.76-3.87 (1H, m), 3.93 (1H, d, J = 13.5Hz), 6.57 (1H, s), 6.67 (1H, s), 6.70 (1H, s), 7.27 (1H, d, J = 11.5Hz), 7.74 (1H, d, J = 7.0Hz).

Example 282

Yield: quant%, 1H-NMR (CDCl3): δ2.23 (3H, s), 2.62-2.80 (4H, m), 3.52-3.73 (6H, m), 6.63 (1H, s), 6.65 (1H , s), 6.78 (1H, s), 7.20 (1H, t, J = 7.5Hz), 7.31 (2H, t, J = 7.5Hz), 7.35-7.44 (3H, m), 8.70 (1H, brs) .

Example 283

Yield: 93%, 1H-NMR (CDCl3): δ1.13 (6H, d, J = 6.0Hz), 2.29 (3H, s), 2.65-2.80 (2H, m), 2.90 (2H, t, J = 11.5Hz), 3.76 (2H, s), 4.29 (2H, d, J = 13.0Hz), 6.54 (1H, s), 6.70 (1H, s), 6.75 (1H, s), 7.34-7.43 (1H , m), 7.53-7.62 (1H, m), 7.69 (1H, d, J = 8.0Hz), 7.88 (1H, d, J = 8.0Hz), 8.55 (1H, s).

Example 284

Yield: 93%, 1H-NMR (CDCl3): δ1.25 (3H, d, J = 5.5Hz), 2.21-2.34 (1H, m), 2.29 (3H, s), 2.54-2.70 (1H, m ), 2.83-2.94 (1H, m), 3.07-3.22 (1H, m), 3.14 (1H, d, J = 13.5Hz), 3.30-3.45 (1H, m), 4.02 (1H, d, J = 13.5 Hz), 4.06-4.17 (1H, m), 4.18-4.28 (1H, m), 6.58 (1H, s), 6.66-6.74 (2H, m), 7.34-7.43 (1H, m), 7.53-7.61 ( 1H, m), 7.68 (1H, dd, J = 8.5, 1.0Hz), 7.88 (1H, dd, J = 8.5, 1.0Hz), 8.55 (1H, s).

Example 285

Yield: 88%, 1H-NMR (CDCl3): δ 1.16 (6H, d, J = 6.0Hz), 2.29 (3H, s), 2.65-2.83 (2H, m) 2.94 (2H, t, J = 11.5Hz), 3.77 (2H, s), 4.30 (2H, d, J = 14.0Hz), 6.52 (1H, s), 6.72 (1H, s), 6.75 (1H, s), 7.50 (1H, dd, J = 9.0, 2.5Hz), 7.60 (1H, d, J = 9.0Hz), 7.85 (1H, d, J = 2.5Hz), 8.54 (1H, s).

Example 286

Yield: 97%, 1H-NMR (CDCl3): δ 1.17 (6H, d, J = 6.0Hz), 2.28 (3H, s), 2.66-2.83 (2H, m), 2.90-3.06 (2H, m ), 3.79 (2H, s), 4.34 (2H, d, J = 13.0Hz), 6.55 (1H, s), 6.69 (1H, s), 6.75 (1H, s), 7.72 (2H, s), 8.14 (1H, s), 8.59 (1H, s).

6-クロロ-2-[4-(2-メトキシメトキシ-3-メチルベンジル)ピペラジン-1-イル]ベンゾチアゾール1.70g (4.067mmol)、4N 塩酸/ジオキサン溶液8.5mlの混合物を60℃で2時間撹拌した。空冷後、反応液を減圧下濃縮し、残渣に飽和炭酸水素ナトリウム水溶液を加えアルカリ性にした後、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄、無水硫酸ナトリウムで乾燥後、減圧下溶媒を留去した。結晶をジイソプロピルエーテルで洗浄し5-{[4-(6-クロロベンゾチアゾール-2-イル)ピペラジン-1-イル]メチル}-2-メチルフェノールを無色結晶として1.33ｇ（87％）得た。
¹H-NMR(CDCl₃): δ2.24 (3H, s), 2.55 (4H, t, J=5Hz), 3.46 (2H, s), 3.63 (4H, t, J=5Hz), 5.95 (1H, brs), 6.76 (1H, d, J=7.5Hz), 6.81 (1H, s), 7.07 (1H, d, J=7.5Hz), 7.23 (1H, dd, J=8, 2Hz), 7.45 (1H, d, J=8Hz), 7.55 (1H, d, J=2Hz). Example 287
Preparation of 5-{[4- (6-chlorobenzothiazol-2-yl) piperazin-1-yl] methyl} -2-methylphenol

A mixture of 1.70 g (4.067 mmol) of 6-chloro-2- [4- (2-methoxymethoxy-3-methylbenzyl) piperazin-1-yl] benzothiazole and 8.5 ml of 4N hydrochloric acid / dioxane solution at 60 ° C. for 2 hours. Stir. After cooling with air, the reaction mixture was concentrated under reduced pressure, and saturated aqueous sodium hydrogen carbonate solution was added to the residue to make it alkaline, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The crystals were washed with diisopropyl ether to obtain 1.33 g (87%) of 5-{[4- (6-chlorobenzothiazol-2-yl) piperazin-1-yl] methyl} -2-methylphenol as colorless crystals.
¹ H-NMR (CDCl ₃ ): δ2.24 (3H, s), 2.55 (4H, t, J = 5Hz), 3.46 (2H, s), 3.63 (4H, t, J = 5Hz), 5.95 (1H , brs), 6.76 (1H, d, J = 7.5Hz), 6.81 (1H, s), 7.07 (1H, d, J = 7.5Hz), 7.23 (1H, dd, J = 8, 2Hz), 7.45 ( 1H, d, J = 8Hz), 7.55 (1H, d, J = 2Hz).

収率：100％, ¹H-NMR(DMSO-d₆): δ2.12 (3H, s), 3.08-3.18 (2H, m), 3.39 (2H, d, J = 12.0 Hz), 3.65 (2H, t, J = 12.0 Hz), 4.13-4.21 (4H, m), 6.85 (1H, d, J = 8.4 Hz), 7.22 (1H, d, J = 8.4 Hz), 7.28 (1H, s), 7.28 (1H, m), 7.49 (1H, d, J = 8.7Hz), 7.99 (1H, d, J = 2.1Hz).

実施例２８９

収率：80％, ¹H-NMR(DMSO-d₆): δ2.12 (3H, s), 2.16-2.26 (2H, m), 3.03-3.15 (2H, m), 3.49-3.76 (4H, m), 4.02 (4H, s) 6.83 (1H, d, J = 8.1 Hz), 7.19 (1H, d, J = 8.1 Hz), 7.25 (1H, s),7.31 (1H, dd, J = 2.4, 8.7 Hz), 7.45 (1H, d, J = 9.7 Hz), 7.95 (1H, d, J = 2.4 Hz).

実施例２９０

収率：77％, 1H-NMR(DMSO-d6): δ1.59 (3 H, d, J = 6.3 Hz), 2.24 (3 H, s), 3.12 (2 H, br), 3.54 (1 H, br), 3.65 (2 H, br), 3.89-3.96 (1 H, m), 4.09 (1 H, d, J = 14.1 Hz), 4.21 (1 H, d, J = 12.9 Hz), 4.63 (1 H, d, J = 11.2 Hz), 6.68 (1 H, s), 6.81 (1 H, s), 6.88 (1 H, s), 7.34 (1 H, dd, J = 2.1, 8.7 Hz), 7.50 (1 H, d, J = 8.7 Hz), 8.00 (1 H, d, J = 2.1 Hz), 11.6 (1 H, s)

実施例２９１

収率：84％, 1H-NMR(DMSO-d6): δ1.58 (3 H, d, J = 6.0 Hz), 2.24 (3 H, s), 3.16 (2 H, br), 3.53 (1 H, br), 3.64 (1 H, br), 3.89-3.96 (2 H, m), 4.08 (1 H, d, J = 12.9 Hz), 4.21 (1 H, d, J = 12.9 Hz), 4.63 (1 H, d, J = 12.0 Hz), 6.68 (1 H, s), 6.81 (1 H, s), 6.87 (1 H, s), 7.34 (1 H, dd, J = 2.1, 8.7 Hz), 7.50 (1 H, d, J = 8.7 Hz), 8.00 (1 H, d, J = 2.1 Hz), 11.6 (1 H, br)

実施例２９２

収率：84％, 1H-NMR(CDCl3): δ1.21 (3H, d, J=6Hz), 2.24 (3H, s), 2.25-2.33 (1H, m), 2.59-2.70 (1H, m), 2.81 (1H, dt, J=12, 3Hz), 3.14 (1H, d, J=13.5Hz), 3.15-3.25 (1H, m), 3.39-3.50 (1H, m), 3.73-3.83 (1H, m), 3.84-3.94 (1H, m), 3.98 (1H, d, J=13.5Hz), 5.18 (1H, brs), 6.79 (1H, d, J=7.5Hz), 6.80 (1H, s), 7.07 (1H, d, J=7.5Hz), 7.51 (1H, d, J=8.5Hz), 7.57 (1H, d, J=8.5Hz), 7.84 (1H, s). Thereafter, the compounds described in Examples 288 to 292 were obtained in the same manner as in Example 287.
Example 288

Yield: 100%, ¹ H-NMR (DMSO-d ₆ ): δ2.12 (3H, s), 3.08-3.18 (2H, m), 3.39 (2H, d, J = 12.0 Hz), 3.65 (2H , t, J = 12.0 Hz), 4.13-4.21 (4H, m), 6.85 (1H, d, J = 8.4 Hz), 7.22 (1H, d, J = 8.4 Hz), 7.28 (1H, s), 7.28 (1H, m), 7.49 (1H, d, J = 8.7Hz), 7.99 (1H, d, J = 2.1Hz).

Example 289

Yield: 80%, ¹ H-NMR (DMSO-d ₆ ): δ2.12 (3H, s), 2.16-2.26 (2H, m), 3.03-3.15 (2H, m), 3.49-3.76 (4H, m), 4.02 (4H, s) 6.83 (1H, d, J = 8.1 Hz), 7.19 (1H, d, J = 8.1 Hz), 7.25 (1H, s), 7.31 (1H, dd, J = 2.4, 8.7 Hz), 7.45 (1H, d, J = 9.7 Hz), 7.95 (1H, d, J = 2.4 Hz).

Example 290

Yield: 77%, 1H-NMR (DMSO-d6): δ1.59 (3 H, d, J = 6.3 Hz), 2.24 (3 H, s), 3.12 (2 H, br), 3.54 (1 H , br), 3.65 (2 H, br), 3.89-3.96 (1 H, m), 4.09 (1 H, d, J = 14.1 Hz), 4.21 (1 H, d, J = 12.9 Hz), 4.63 ( 1 H, d, J = 11.2 Hz), 6.68 (1 H, s), 6.81 (1 H, s), 6.88 (1 H, s), 7.34 (1 H, dd, J = 2.1, 8.7 Hz), 7.50 (1 H, d, J = 8.7 Hz), 8.00 (1 H, d, J = 2.1 Hz), 11.6 (1 H, s)

Example 291

Yield: 84%, 1H-NMR (DMSO-d6): δ1.58 (3 H, d, J = 6.0 Hz), 2.24 (3 H, s), 3.16 (2 H, br), 3.53 (1 H , br), 3.64 (1 H, br), 3.89-3.96 (2 H, m), 4.08 (1 H, d, J = 12.9 Hz), 4.21 (1 H, d, J = 12.9 Hz), 4.63 ( 1 H, d, J = 12.0 Hz), 6.68 (1 H, s), 6.81 (1 H, s), 6.87 (1 H, s), 7.34 (1 H, dd, J = 2.1, 8.7 Hz), 7.50 (1 H, d, J = 8.7 Hz), 8.00 (1 H, d, J = 2.1 Hz), 11.6 (1 H, br)

Example 292

Yield: 84%, 1H-NMR (CDCl3): δ1.21 (3H, d, J = 6Hz), 2.24 (3H, s), 2.25-2.33 (1H, m), 2.59-2.70 (1H, m) , 2.81 (1H, dt, J = 12, 3Hz), 3.14 (1H, d, J = 13.5Hz), 3.15-3.25 (1H, m), 3.39-3.50 (1H, m), 3.73-3.83 (1H, m), 3.84-3.94 (1H, m), 3.98 (1H, d, J = 13.5Hz), 5.18 (1H, brs), 6.79 (1H, d, J = 7.5Hz), 6.80 (1H, s), 7.07 (1H, d, J = 7.5Hz), 7.51 (1H, d, J = 8.5Hz), 7.57 (1H, d, J = 8.5Hz), 7.84 (1H, s).

3-{[4-(6-クロロベンゾチアゾール-2-イル)ピペラジン1-イル]メチル}-5-メチルフェノール0.50g(1.34mmol)、ブロモ酢酸エチル0.22ml(2.01mmol)、炭酸セシウム0.65ｇ(2.01mmol)の無水N,N-ジメチルホルムアミド5mlの混合物を50℃で17時間撹拌した。反応液に水及び酢酸エチルを加え抽出した後、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。減圧下溶媒を留去した後、残渣をシリカゲルカラムクロマトグラフィー（ヘキサン：酢酸エチル＝2：1）で精製し、{ 3- [ [4-(6-クロロベンゾチアゾール-2-イル)ピペラジン-1-イル]メチル] -5-メチル}フェノキシ酢酸エチルを淡黄色油状物として0.48g（78％）得た。
¹H-NMR(CDCl₃): δ1.28 (3H, t, J=7Hz), 2.32 (3H, s), 2.56 (4H, t, J=5Hz), 3.49 (2H, s), 3.63 (4H, t, J=5Hz), 4.27 (2H, q, J=7Hz), 4.61 (2H, s), 6.64 (1H, s), 6.74 (1H, s), 6.78 (1H, s), 7.23 (1H, dd, J=8.5, 2Hz), 7.43 (1H, d, J=8.5Hz), 7.55 (1H, d, J=2Hz). Example 293
{3- [[4- (6-Chlorobenzothiazol-2-yl) piperazin-1-yl] methyl] -5-methyl} phenoxyacetate ethyl ester

3-{[4- (6-Chlorobenzothiazol-2-yl) piperazin-1-yl] methyl} -5-methylphenol 0.50 g (1.34 mmol), ethyl bromoacetate 0.22 ml (2.01 mmol), cesium carbonate 0.65 g A mixture of 5 ml of (2.01 mmol) anhydrous N, N-dimethylformamide was stirred at 50 ° C. for 17 hours. Water and ethyl acetate were added to the reaction solution for extraction, and the organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 2: 1) to give {3- [[4- (6-chlorobenzothiazol-2-yl) piperazine-1 0.48 g (78%) of ethyl -yl] methyl] -5-methyl} phenoxyacetate as a pale yellow oil.
¹ H-NMR (CDCl ₃ ): δ1.28 (3H, t, J = 7Hz), 2.32 (3H, s), 2.56 (4H, t, J = 5Hz), 3.49 (2H, s), 3.63 (4H , t, J = 5Hz), 4.27 (2H, q, J = 7Hz), 4.61 (2H, s), 6.64 (1H, s), 6.74 (1H, s), 6.78 (1H, s), 7.23 (1H , dd, J = 8.5, 2Hz), 7.43 (1H, d, J = 8.5Hz), 7.55 (1H, d, J = 2Hz).

収率：84％, ¹H-NMR(CDCl₃); δ1.27 (3H, t, J=7Hz), 1.59 (6H, s), 2.29 (3H, s), 2.55 (4H, t, J=5Hz), 3.46 (2H, s), 3.62 (4H, t, J=5Hz), 4.26 (2H, q, J=7Hz), 6.55 (1H, s), 6.60 (1H, s), 6.77 (1H, s), 7.23 (1H, dd, J=8.5, 2Hz), 7.42 (1H, d, J=8.5Hz), 7.55 (1H, d, J=2Hz).

実施例２９５

収率：78％, ¹H-NMR(CDCl₃); δ1.31 (3H, t, J=7Hz), 2.32 (3H, s), 2.58 (4H, t, J=5Hz), 3.50 (2H, s), 3.68 (4H, t, J=5Hz), 4.28 (2H, q, J=7Hz), 4.62 (2H, s), 6.65 (1H, s), 6.74 (1H, s), 6.78 (1H, s), 7.50-7.60 (2H, m), 7.85 (1H, s).

実施例２９６

収率：93％, ¹H-NMR(CDCl₃); δ1.30 (3H, t, J=6.9Hz), 1.98-2.05 (2H, m), 2.30 (3H, s), 2.67 (2H, t, J= 5.1Hz), 2.77-2.81(2H,m),3.57 (2H, s), 3.71-3.75 (4H, m), 4.27 (2H, q, J=7.2Hz), 4.60 (2H, s), 6.63 (1H, s), 6.73 (1H, s), 6.76 (1H, s), 7.23 (1H, dd, J=8.7, 2.4Hz), 7.42 (1H, d, J=8.4Hz), 7.55 (1H, d, J=2.1Hz).

実施例２９７

収率：66％, ¹H-NMR(CDCl₃); δ1.29 (3H, t, J=7Hz), 1.98-2.06 (2H, m), 2.30 (3H, s), 2.68 (2H, t, J=5.5Hz), 2.81 (2H, t, J=5.5Hz), 3.57 (2H, s), 3.70-3.85 (4H, m), 4.27 (2H, q, J=7Hz), 4.60 (2H, s), 6.63 (1H, s), 6.73 (1H, s), 6.76 (1H, s), 7.48-7.58 (2H, m), 7.84 (1H, s).

実施例２９８

収率：68％, ¹H-NMR(CDCl₃); δ1.29 (3H, t, J=7Hz), 2.28 (3H, s), 2.55 (4H, t, J=5Hz), 3.50 (2H, s), 3.62 (4H, t, J=5Hz), 4.26 (2H, q, J=7Hz), 4.65 (2H, s), 6.74 (1H, s), 6.84 (1H, d, J=7.5Hz), 7.10 (1H, d, J=7.5Hz), 7.23 (1H, dd, J=8.5, 2Hz), 7.43 (1H, d, J=8.5Hz), 7.55 (1H, d, J=2Hz).

実施例２９９

収率：84％, ¹H-NMR(CDCl₃); δ1.30 (3H, t, J = 7.2 Hz), 2.30 (3H, s), 2.55 (4H, t, J = 5.1 Hz), 3.46 (2H, s), 3.62 (4H, t, J = 5.1 Hz), 4.27 (2H, q, J = 7.2 Hz), 4.64 (2H, s), 6.66 (1H, dd, J = 8.1 Hz), 7.07 (1H, d, J = 8.1 Hz), 7.13 (1H, s), 7.23 (1H, dd, J = 8.4, 2.1Hz), 7.43 (1H, dd, J = 8.1 Hz), 7.55 (1H, d, J = 2.1Hz)

実施例３００

収率：90％, ¹H-NMR(CDCl₃); δ1.30 (3H, t, J = 7.2 Hz), 1.98-2.05 (2H, m), 2.28 (3H, s), 2.67 (2H, t, J = 5.1 Hz), 2.78 (2H, t, J = 5.1 Hz), 3.54 (2H, s), 3.71-3.78 (4H, m), 4.27 (2H, q, J = 7.2 Hz), 4.63 (2H, s), 6.64 (1H, d, J = 8.1 Hz), 7.05 (1H, d, J = 8.1 Hz), 7.11 (1H, s), 7.22 (1H, dd, J = 8.7, 2.1 Hz), 7.42 (1H, d, J = 8.7 Hz), 7.54 (1H, d, J= 2.1 Hz).

実施例３０１

収率：92％, 1H-NMR(CDCl3): δ1.21 (3H, d, J=6Hz), 1.31 (3H, t, J=7Hz), 2.20-2.32 (1H, m), 2.33 (3H, s), 2.60-2.70 (1H, m), 2.77-2.85 (1H, m), 3.05-3.25 (2H, m), 3.35-3.50 (1H, m), 3.70-3.80 (1H, m), 3.85-3.95 (1H, m), 3.98 (1H, d, J=13.5Hz), 4.28 (2H, q, J=7Hz), 4.61 (2H, s), 6.63 (1H, s), 6.75 (1H, s), 6.78 (1H, s), 7.53 (1H, d, J=8.5Hz), 7.56 (1H, d, J=8.5Hz), 7.84 (1H, s).

実施例３０２

収率：74％, 1H-NMR(CDCl3): δ1.10 (6H, d, J=6Hz), 1.30 (3H, t, J=7Hz), 2.31 (3H, s), 2.70-2.85 (2H, m), 3.01 (1H, d, J=10.5Hz), 3.05 (1H d, J=10.5Hz), 3.76 (2H, s), 3.80-3.90 (2H, m), 4.27 (2H, q, J=7Hz), 4.60 (2H, s), 6.57 (1H, s), 6.78 (1H, s), 6.83 (1H, s), 7.23 (1H, dd, J=8.5, 2Hz), 7.43 (1H, d, J=8.5Hz), 7.55 (1H, d, J=2Hz).

実施例３０３

収率：93％, 1H-NMR(CDCl3): δ1.12 (6H, d, J=6Hz), 1.30 (3H, t, J=7Hz), 2.31 (3H, s), 2.70-2.90 (2H, m), 3.00-3.15 (2H, m), 3.77 (2H, s), 3.85-3.95 (2H, m), 4.27 (2H, q, J=7Hz), 4.60 (2H, s), 6.57 (1H, s), 6.78 (1H, s), 6.84 (1H, s), 7.52 (1H, d, J=8.5Hz), 7.56 (1H, d, J=8.5Hz), 7.84 (1H, s).

実施例３０４

収率：95％, 1H-NMR(CDCl3): δ1.30 (3H, t, J=7Hz), 1.41 (3H, d, J=7Hz), 2.21 (1H, td, J=12, 3.5Hz), 2.25-2.35 (1H, m), 2.32 (3H, s), 2.73 (1H, d, J=11Hz), 2.90 (1H, d, J=11Hz), 3.38 (1H, d, J=13.5Hz), 3.48 (1H, td, J=12, 3.5Hz), 3.52 (1H, d, J=13.5Hz), 3.85 (1H, d, J=12Hz), 4.15-4.25 (1H, m), 4.27 (2H, q, J=7Hz), 4.61 (2H, s), 6.64 (1H, s), 6.76 (1H, s), 6.78 (1H, s), 7.22 (1H, dd, J=8, 2Hz), 7.42 (1H, d, J=8Hz), 7.54 (1H, d, J=2Hz).

実施例３０５

収率：43％, 1H-NMR(CDCl3): δ1.21 (3H, d, J=6Hz), 1.30 (3H, t, J=7Hz), 2.20-2.27 (1H, m), 2.28 (3H, s), 2.60-2.70 (1H, m), 2.75-2.85 (1H, m), 3.10-3.25 (2H, m), 3.35-3.50 (1H, m), 3.68-3.78 (1H, m), 3.85-3.95 (1H, m), 4.01 (1H, d, J=13Hz), 4.27 (2H, q, J=7Hz), 4.65 (2H, s), 6.74 (1H, s), 6.85 (1H, d, J=7.5Hz), 7.11 (1H, d, J=7.5Hz), 7.53 (1H, d, J=8.5Hz), 7.56 (1H, d, J=8.5Hz), 7.84 (1H, s).

実施例３０６

収率：79％, 1H-NMR(CDCl3): δ1.22 (3H, d, J=6.5Hz), 1.31 (3H, t, J=7Hz), 2.23-2.35 (1H, m), 2.60-2.73 (1H, m), 2.75-2.90 (1H, m), 3.15-3.25 (2H, m), 3.40-3.50 (1H, m), 3.70-3.82 (1H, m), 3.85-3.95 (1H, m), 4.03 (1H, d, J=13.5Hz), 4.28 (2H, q, J=7Hz), 4.63 (2H, s), 6.80 (1H, dd, J=8, 1.5Hz), 6.93-7.02 (2H, m), 7.25 (1H, t, J=8Hz), 7.53 (1H, d, J=8.5Hz), 7.56 (1H, d, J=8.5Hz), 7.84 (1H, s).

実施例３０７

収率：81％, 1H-NMR(CDCl3): δ1.02 (3H, t, J=7.5Hz), 1.31 (3H, t, J=7Hz), 1.58-1.79 (2H, m), 2.31 (3H, s), 2.31-2.38 (1H, m), 2.47-2.58 (1H, m), 2.78-2.88 (1H, m), 3.23 (1H, d, J=13.5Hz), 3.36-3.58 (2H, m), 3.64-3.75 (1H, m), 3.84 (1H, d, J=11Hz), 3.95 (1H, d, J=13.5Hz), 4.28 (2H, q, J=7Hz), 4.62 (2H, s), 6.63 (1H, s), 6.77 (1H, s), 6.78 (1H, s), 7.51 (1H, d, J=8.5Hz), 7.56 (1H, d, J=8.5Hz), 7.84 (1H, s)

実施例３０８

収率：91％, 1H-NMR(CDCl3): δ1.31 (3H, t, J=7Hz), 2.25-2.35 (4H, m), 2.82 (1H, d, J=13.5Hz), 3.01 (1H, d, J=11.5Hz), 3.25-3.50 (3H, m), 3.79 (1H, d, J=13.5Hz), 4.00-4.10 (2H, m), 4.28 (2H, q, J=7Hz), 4.60 (2H, s), 6.59 (1H, s), 6.70 (1H, s), 6.72 (1H, s), 7.30-7.45 (3H, m), 7.50-7.58 (4H, m), 7.84 (1H, s).

実施例３０９

収率：90％, 1H-NMR(CDCl3): δ1.21 (3 H, d, J = 6.3 Hz), 1.31 (3 H, t, J = 7.2 Hz), 2.22-2.31 (1 H, m), 2.32 (3 H, s), 2.58-2.68 (1 H, m), 2.83 (1 H, dt, J = 3.3, 12.3 Hz), 3.12-3.19 (2 H, m), 3.34-3.43 (1 H, m), 3.71 (1 H, d, J = 12.3 Hz), 3.86 (1 H, d, J = 10.5 Hz), 3.99 (1 H, d, J = 13.5 Hz), 4.28 (2 H, q, J = 7.2 Hz), 4.61 (2 H, s), 6.63 (1 H, s), 6.75 ( 1H, s), 6.78 (1 H, s), 7.23 (1 H, d, J = 2.4, 8.7 Hz), 7.43 (1 H, d, J = 8.7 Hz), 7.55 (1 H, d, J = 2.4 Hz)

実施例３１０

収率：70％, 1H-NMR(CDCl3): δ1.21 (3 H, d, J = 6.3 Hz),1.30 (3 H, t, J = 7.2 Hz), 2.23-2.32 (1 H, m), 2.32 (3 H, s), 2.58-2.67 (1 H, m), 2.80 (1 H, d,J = 3.3, 12.3 Hz), 3.12-3.19 (2 H, m), 3.35-3.42 (1H, m), 3.71 (1 H, dt, J = 12.0 Hz), 3.86 (1 H, dt, J = 12.0 Hz), 3.99 (1 H, d, J = 13.2 Hz), 4.28 (2 H, q, J = 7.2 Hz), 4.61 (2 H, s), 6.63 (1 H, s), 6.75 (1 H, s), 6.78 (1 H, s), 7.23 (1 H, dd, J = 2.1, 8.7 Hz), 7.43 (1 H, d, J = 8.7 Hz), 7.54 (1 H, d, J = 2.1 Hz)

実施例３１１

収率：89％, 1H-NMR(CDCl3): δ1.30 (3H, t, J=7Hz), 1.43 (3H, d, J=6.5Hz), 2.23 (1H, td, J=12, 3.5Hz), 2.31 (3H, s), 2.31-2.40 (1H, m), 2.73 (1H, d, J=11Hz), 2.91 (1H, d, J=11Hz), 3.40 (1H, d, J=13Hz), 3.46-3.51 (1H, m), 3.53 (1H, d, J=13Hz), 3.85-3.95 (1H, m), 4.20-4.27 (1H, m), 4.28 (2H, q, J=7Hz), 4.62 (2H, s), 6.65 (1H, s), 6.77 (1H, s), 6.79 (1H, s), 7.52 (1H, d, J=8.5Hz), 7.56 (1H, d, J=8.5Hz), 7.84 (1H, s).

実施例３１２

収率：84％, 1H-NMR(CDCl3): δ1.31 (3H, t, J=7.0Hz), 1.43 (3H, d, J=6.5Hz), 2.16-2.28 (1H, m), 2.30-2.39 (1H, m), 2.33 (3H, s), 2.70-2.78 (1H, m), 2.87-2.96 (1H, m), 3.40 (1H, d, J=13.5Hz), 3.45-3.58 (2H, m), 3.86-3.97 (1H, m), 4.18-4.30 (1H, m), 4.28 (2H, q, J=7.0Hz), 4.62 (2H, s), 6.65 (1H, s), 6.75-6.82 (2H, m), 7.48-7.60 (2H, m), 7.84 (1H, s).

実施例３１３

収率：86％, 1H-NMR(CDCl3): δ1.02 (3H, t, J=7.5Hz), 1.31 (3H, t, J=7Hz), 1.57-1.78 (2H, m), 2.30-2.33 (1H, m), 2.34 (3H, s), 2.48-2.60 (1H, m), 2.78-2.90 (1H, m), 3.17 (1H, d, J=13.5Hz), 3.37-3.58 (2H, m), 3.62-3.73 (1H, m), 3.79-3.88 (1H, m), 3.95 (1H, d, J=13.5Hz), 4.28 (2H, q, J=7Hz), 4.61 (2H, s), 6.63 (1H, s), 6.76 (1H, s), 6.78 (1H, s), 7.51 (1H, d, J=8.5Hz), 7.55 (1H, d, J=8.5Hz), 7.83 (1H, s).

実施例３１４

収率：85％, 1H-NMR(CDCl3): δ1.02 (3H, t, J=7.5Hz), 1.29 (3H, t, J=7Hz), 1.58-1.78 (2H, m), 2.04 (3H, s), 2.05-2.15 (1H, m), 2.48-2.58 (1H, m), 2.79-2.89 (1H, m), 3.23 (1H, d, J=13.5Hz), 3.42 (1H, dd, J=12.5, 8Hz), 3.47-3.56 (1H, m), 3.63-3.72 (1H, m), 3.80-3.90 (1H, m), 3.95 (1H, d, J=13.5Hz), 4.27 (2H, q, J=7Hz), 4.61 (2H, s), 6.63 (1H, s), 6.77 (1H, s), 6.78 (1H, s), 7.52 (1H, d, J=8.5Hz), 7.56 (1H, d, J=8.5Hz), 7.83 (1H, s).

実施例３１５

収率：60％, 1H-NMR(CDCl3): δ0.95 (3H, t, J=7.0Hz), 1.22-1.68 (4H, m), 1.31 (3H, t, J=7.0Hz), 2.27-2.40 (1H, m), 2.32 (3H, s), 2.54-2.65 (1H, m), 2.76-2.89 (1H, m), 3.25 (1H, d, J=13.5Hz), 3.41 (1H, dd, J=13.0, 7.5Hz), 3.48-3.59 (1H, m), 3.60-3.71 (1H, m), 3.83 (1H, dd, J=12.5, 3.5Hz), 3.93 (1H, d, J=13.5Hz), 4.28 (2H, q, J=7.0Hz), 4.61 (2H, s), 6.63 (1H, s), 6.76 (1H, s), 6.78 (1H, s), 7.52 (1H, d, J=8.5Hz), 7.56 (1H, d, J=8.5Hz), 7.83 (1H, s).

実施例３１６

収率：90％, 1H-NMR(CDCl3): δ0.95 (3 H, t, J = 7.2 Hz), 1.31 (3 H, t, J = 7.2 Hz), 1.33-1.62 (4 H, m), 2.32 (3 H, s), 2.32-2.38 (1 H, m), 2.57-2.62 (1 H, m), 2.79-2.86 (1 H, m), 3.24 (1 H, d, J = 13.5 Hz), 3.41 (1 H, dd, J = 7.8, 12.6 Hz), 3.38-3.44 (1 H, m), 3.64-3.69 (1 H, m), 3.83 (1 H, dd, J = 3.0, 12.6 Hz), 3.93 (1 H, d, J = 13.5 Hz), 4.28 (2 H, q, J = 7.2 Hz), 4.61 (2 H, s), 6.63 (1 H, s), 6.77 (2 H, d, J = 6.3 Hz), 7.53-7.55 (2 H, m), 7.83 (1 H, s)

実施例３１７

収率：64％, 1H-NMR(CDCl3): δ0.93 (3H, t, J=7.0Hz), 1.22-1.75 (6H, m), 1.31 (3H, t, J=7.0Hz), 2.27-2.39 (1H, m), 2.32 (3H, s), 2.51-2.64 (1H, m), 2.76-2.88 (1H, m), 3.24 (1H, d, J=13.0Hz), 3.41 (1H, dd, J=13.0, 7.5Hz), 3.47-3.59 (1H, m), 3.61-3.72 (1H, m), 3.84 (1H, dd, J=13.0, 3.0Hz), 3.94 (1H, d, J=13.0Hz), 4.28 (2H, q, J=7.0Hz), 4.61 (2H, s), 6.63 (1H, s), 6.76 (1H, s), 6.78 (1H, s), 7.51 (1H, d, J=8.5Hz), 7.56 (1H, d, J=8.5Hz), 7.84 (1H, s).

実施例３１８

収率：83％, 1H-NMR(CDCl3): δ0.91 (3H, d, J=6.5Hz), 0.95 (3H, d, J=6.5Hz), 1.30 (3H, t, J=7Hz), 1.35-1.45 (1H, m), 1.46-1.58 (1H, m), 1.65-1.80 (1H, m), 2.32 (3H, s), 2.33-2.44 (1H, m), 2.62-2.73 (1H, m), 2.75-2.86 (1H, m), 3.30 (1H, d, J=13.5Hz), 3.35 (1H, dd, J=13, 6.5Hz), 3.58 (2H, t, J=5Hz), 3.75 (1H, dd, J=13, 6.5Hz), 3.87 (1H, d, J=13.5Hz), 4.28 (2H, q, J=7Hz), 4.61 (2H, s), 6.62 (1H, s), 6.76 (1H, s), 6.78 (1H, s), 7.23 (1H, dd, J=8.5, 2Hz), 7.42 (1H, d, J=8.5Hz), 7.54 (1H, d, J=2Hz).

実施例３１９

収率：68％, 1H-NMR(CDCl3): δ0.92 (3H, d, J=6.5Hz), 0.95 (3H, d, J=7.0Hz), 1.20-1.44 (1H, m), 1.30 (3H, t, J=6.5Hz), 1.45-1.80 (2H, m), 2.27-2.47 (1H, m), 2.32 (3H, s), 2.61-2.72 (1H, m), 2.75-2.88 (1H, m), 3.25-3.41 (2H, m), 3.58 (2H, t, J=5.0Hz), 3.75 (1H, dd, J=12.5, 3.5Hz), 3.87 (1H, d, J=13.5Hz), 4.28 (2H, q, J=7.0Hz), 4.61 (2H, s), 6.62 (1H, s), 6.76 (1H, s), 6.78 (1H, s), 7.23 (1H, dd, J=8.0, 2.0Hz), 7.42 (1H, d, J=8.0Hz), 7.54 (1H, d, J=2.0Hz).

実施例３２０

収率：85％, 1H-NMR(CDCl3): δ0.92 (3H, d, J=6.5Hz), 0.95 (3H, d, J=6.5Hz), 1.31 (3H, t, J=7Hz), 1.34-1.45 (1H, m), 1.45-1.55 (1H, m), 1.65-1.80 (1H, m), 2.32 (3H, s), 2.35-2.46 (1H, m), 2.64-2.75 (1H, m), 2.78-2.88 (1H, m), 3.32 (1H, d, J=13.5Hz), 3.42 (1H, dd, J=13, 6.5Hz), 3.60-3.67 (2H, m), 3.79 (1H, dd, J=13, 3.5Hz), 3.87 (1H, d, J=13.5Hz), 4.28 (2H, q, J=7Hz), 4.61 (2H, s), 6.63 (1H, s), 6.77 (1H, s), 6.79 (1H, s), 7.51 (1H, d, J=8.5Hz), 7.56 (1H, d, J=8.5Hz), 7.83 (1H, s).

実施例３２１

収率：98％, 1H-NMR(CDCl3): δ1.21 (3H, d, J=6Hz), 1.31 (3H, t, J=7Hz), 2.20-2.32 (1H, m), 2.32 (3H, s), 2.59-2.70 (1H, m), 2.75-2.88 (1H, m), 3.16 (1H, d, J=13.5Hz), 3.17-3.25 (1H, m), 3.48-3.50 (1H, m), 3.69-3.80 (1H, m), 3.85-3.95 (1H, m), 3.98 (1H, d, J=13.5Hz), 4.28 (2H, q, J=7Hz), 4.62 (2H, s), 6.63 (1H, s), 6.75 (1H, s), 6.78 (1H, s), 7.26 (1H, d, J=12Hz), 7.74 (1H, d, J=7Hz).

実施例３２２

収率：69％, 1H-NMR(CDCl3): δ1.30 (3H, t, J=7.0Hz), 1.96-2.08 (2H, m), 2.30 (3H, s), 2.63-2.71 (2H, m), 2.74-2.84 (2H, m ), 3.57 (2H, s), 3.60-3.89 (4H, m), 4.27 (2H, q, J=7.0Hz), 4.60 (2H, s), 6.62 (1H, s), 6.73 (1H, s), 6.75 (1H, s), 7.27 (1H, d, J=7.0Hz), 7.75 (1H, d, J=11.5Hz).

実施例３２３

収率：75％, 1H-NMR(CDCl3): δ1.12 (6H, d, J=6.0Hz), 1.30 (3H, t, J=7.0Hz), 2.32 (3H, s), 2.72-2.86 (2H, m), 3.07 (1H, d, J=13.0Hz), 3.11 (1H, d, J=13.0Hz), 3.77 (2H, s), 3.89 (2H, d, J=11.0Hz), 4.28 (2H, q, J=7.0Hz), 4.60 (2H, s), 6.57 (1H, s), 6.78 (1H, s), 6.84 (1H, s), 7.27 (1H, d, J=11.5Hz), 7.75 (1H, d, J=6.0Hz).

実施例３２４

収率：79％, 1H-NMR(CDCl3): δ1.01 (3H, t, J=7.5Hz), 1.31 (3H, t, J=7.0Hz), 1.50-1.80 (2H, m), 2.26-2.39 (1H, m), 2.32 (3H, s), 2.47-2.58 (1H, m), 2.77-2.88 (1H, m), 3.24 (1H, d, J=13.5Hz), 3.36-3.57 (2H, m), 3.61-3.73 (1H, m), 3.77-3.88 (1H, m), 3.94 (1H, d, J=13.5Hz), 4.28 (2H, q, J=7.0Hz), 4.61 (2H, s), 6.62 (1H, s), 6.73-6.82 (2H, m), 7.26 (1H, d, J=11.5Hz), 7.74 (1H, d, J=7.0Hz)

実施例３２５

収率：71％, 1H-NMR(CDCl3): δ1.29 (3H, t, J=7.0Hz), 2.31 (3H, s), 2.54 (4H, t, J=5.0Hz), 3.47 (2H, s), 3.52 (4H, t, J=5.0Hz), 4.26 (2H, q, J=7.0Hz), 4.60 (2H, s), 6.64 (1H, s), 6.74 (1H, s), 6.78 (1H, s), 7.18 (1H, tt, J=7.5, 1.5Hz), 7.26-7.35 (2H, m), 7.37-7.44 (3H, m).

実施例３２６

収率：74％, 1H-NMR(CDCl3): δ1.15 (6H, d, J=7.0Hz), 1.30 (3H, t, J=7.0Hz), 2.32 (3H, s), 2.68-2.83 (2H, m), 2.93 (1H, d, J=13.0Hz), 2.96 (1H, d, J=13.0Hz), 3.78 (2H, s), 4.26-4.38 (2H, m), 4.27 (2H, q, J=7.0Hz), 4.61 (2H, s), 6.57 (1H, s), 6.80 (1H, s), 6.86 (1H, s), 7.34-7.43 (1H, m), 7.52-7.62 (1H, m), 7.67 (1H, dd, J=8.5, 1.5Hz), 7.87 (1H, dd, J=8.5, 1.5Hz), 8.56 (1H, s).

実施例３２７

収率：79％, 1H-NMR(CDCl3): δ1.25 (3H, d, J=6.0Hz), 1.31 (3H, t, J=7.0Hz), 2.20-2.32 (1H, m), 2.33 (3H, s), 2.55-2.68 (1H, m), 2.85 (1H, dt, J=12.0, 3.5Hz), 3.14 (1H, d, J=13.0Hz), 3.16 (1H, d, J=13.5Hz), 3.30-3.43 (1H, m), 4.02 (1H, d, J=13.0Hz), 4.04-4.15 (1H, m), 4.17-4.26 (1H, m), 4.28 (2H, q, J=7.0Hz), 4.62 (2H, s), 6.63 (1H, s), 6.77 (1H, s), 6.80 (1H, s), 7.34-7.42 (1H, m), 7.52-7.61 (1H, m), 7.67 (1H, dd, J=8.5, 1.5Hz), 7.87 (1H, dd, J=8.5, 1.5Hz), 8.55 (1H, s).

実施例３２８

収率：74％, 1H-NMR(CDCl3): δ1.15 (6H, d, J=6.0Hz), 1.30 (3H, t, J=7.0Hz), 2.32 (3H, s), 2.67-2.81 (2H, m), 2.93 (1H, d, J=13.0Hz), 2.97 (1H, d, J=13.0Hz), 3.78 (2H, s), 4.24-4.35 (2H, m), 4.27 (2H, q, J=7.0Hz), 4.61 (2H, s), 6.66 (1H, s), 6.79 (1H, s), 6.86 (1H, s), 7.50 (1H, dd, J=9.5, 2.0Hz), 7.59 (1H, d, J=9.5Hz), 7.85 (1H, d, J=2.0Hz), 8.54 (1H, s).

実施例３２９

収率：51％, 1H-NMR(CDCl3): δ1.15 (6H, d, J=6.0Hz), 1.29 (3H, t, J=7.0Hz), 2.31 (3H, s), 2.65-2.79 (2H, m), 2.95 (1H, d, J=13.0Hz), 2.99 (1H, d, J=13.0Hz), 3.76 (2H, s), 4.26 (2H, q, J=7.0Hz), 4.35 (2H, d, J=12.0Hz), 4.62 (2H, s), 6.58 (1H, s), 6.79 (1H, s), 6.86 (1H, s), 7.69 (1H, s), 7.70 (1H, s), 8.13 (1H, s), 8.59 (1H, s). Thereafter, the compounds described in Examples 294 to 329 were obtained in the same manner as in Example 293.
Example 294

Yield: 84%, ¹ H-NMR (CDCl ₃ ); δ 1.27 (3H, t, J = 7Hz), 1.59 (6H, s), 2.29 (3H, s), 2.55 (4H, t, J = 5Hz), 3.46 (2H, s), 3.62 (4H, t, J = 5Hz), 4.26 (2H, q, J = 7Hz), 6.55 (1H, s), 6.60 (1H, s), 6.77 (1H, s), 7.23 (1H, dd, J = 8.5, 2Hz), 7.42 (1H, d, J = 8.5Hz), 7.55 (1H, d, J = 2Hz).

Example 295

Yield: 78%, ¹ H-NMR (CDCl ₃ ); δ1.31 (3H, t, J = 7Hz), 2.32 (3H, s), 2.58 (4H, t, J = 5Hz), 3.50 (2H, s), 3.68 (4H, t, J = 5Hz), 4.28 (2H, q, J = 7Hz), 4.62 (2H, s), 6.65 (1H, s), 6.74 (1H, s), 6.78 (1H, s), 7.50-7.60 (2H, m), 7.85 (1H, s).

Example 296

Yield: 93%, ¹ H-NMR (CDCl ₃ ); δ1.30 (3H, t, J = 6.9Hz), 1.98-2.05 (2H, m), 2.30 (3H, s), 2.67 (2H, t , J = 5.1Hz), 2.77-2.81 (2H, m), 3.57 (2H, s), 3.71-3.75 (4H, m), 4.27 (2H, q, J = 7.2Hz), 4.60 (2H, s) , 6.63 (1H, s), 6.73 (1H, s), 6.76 (1H, s), 7.23 (1H, dd, J = 8.7, 2.4Hz), 7.42 (1H, d, J = 8.4Hz), 7.55 ( (1H, d, J = 2.1Hz).

Example 297

Yield: 66%, ¹ H-NMR (CDCl ₃ ); δ 1.29 (3H, t, J = 7Hz), 1.98-2.06 (2H, m), 2.30 (3H, s), 2.68 (2H, t, J = 5.5Hz), 2.81 (2H, t, J = 5.5Hz), 3.57 (2H, s), 3.70-3.85 (4H, m), 4.27 (2H, q, J = 7Hz), 4.60 (2H, s ), 6.63 (1H, s), 6.73 (1H, s), 6.76 (1H, s), 7.48-7.58 (2H, m), 7.84 (1H, s).

Example 298

Yield: 68%, ¹ H-NMR (CDCl ₃ ); δ 1.29 (3H, t, J = 7Hz), 2.28 (3H, s), 2.55 (4H, t, J = 5Hz), 3.50 (2H, s), 3.62 (4H, t, J = 5Hz), 4.26 (2H, q, J = 7Hz), 4.65 (2H, s), 6.74 (1H, s), 6.84 (1H, d, J = 7.5Hz) , 7.10 (1H, d, J = 7.5Hz), 7.23 (1H, dd, J = 8.5, 2Hz), 7.43 (1H, d, J = 8.5Hz), 7.55 (1H, d, J = 2Hz).

Example 299

Yield: 84%, ¹ H-NMR (CDCl ₃ ); δ1.30 (3H, t, J = 7.2 Hz), 2.30 (3H, s), 2.55 (4H, t, J = 5.1 Hz), 3.46 ( 2H, s), 3.62 (4H, t, J = 5.1 Hz), 4.27 (2H, q, J = 7.2 Hz), 4.64 (2H, s), 6.66 (1H, dd, J = 8.1 Hz), 7.07 ( 1H, d, J = 8.1 Hz), 7.13 (1H, s), 7.23 (1H, dd, J = 8.4, 2.1 Hz), 7.43 (1H, dd, J = 8.1 Hz), 7.55 (1H, d, J = 2.1Hz)

Example 300

Yield: 90%, ¹ H-NMR (CDCl ₃ ); δ1.30 (3H, t, J = 7.2 Hz), 1.98-2.05 (2H, m), 2.28 (3H, s), 2.67 (2H, t , J = 5.1 Hz), 2.78 (2H, t, J = 5.1 Hz), 3.54 (2H, s), 3.71-3.78 (4H, m), 4.27 (2H, q, J = 7.2 Hz), 4.63 (2H , s), 6.64 (1H, d, J = 8.1 Hz), 7.05 (1H, d, J = 8.1 Hz), 7.11 (1H, s), 7.22 (1H, dd, J = 8.7, 2.1 Hz), 7.42 (1H, d, J = 8.7 Hz), 7.54 (1H, d, J = 2.1 Hz).

Example 301

Yield: 92%, 1H-NMR (CDCl3): δ1.21 (3H, d, J = 6Hz), 1.31 (3H, t, J = 7Hz), 2.20-2.32 (1H, m), 2.33 (3H, s), 2.60-2.70 (1H, m), 2.77-2.85 (1H, m), 3.05-3.25 (2H, m), 3.35-3.50 (1H, m), 3.70-3.80 (1H, m), 3.85- 3.95 (1H, m), 3.98 (1H, d, J = 13.5Hz), 4.28 (2H, q, J = 7Hz), 4.61 (2H, s), 6.63 (1H, s), 6.75 (1H, s) , 6.78 (1H, s), 7.53 (1H, d, J = 8.5Hz), 7.56 (1H, d, J = 8.5Hz), 7.84 (1H, s).

Example 302

Yield: 74%, 1H-NMR (CDCl3): δ1.10 (6H, d, J = 6Hz), 1.30 (3H, t, J = 7Hz), 2.31 (3H, s), 2.70-2.85 (2H, m), 3.01 (1H, d, J = 10.5Hz), 3.05 (1H d, J = 10.5Hz), 3.76 (2H, s), 3.80-3.90 (2H, m), 4.27 (2H, q, J = 7Hz), 4.60 (2H, s), 6.57 (1H, s), 6.78 (1H, s), 6.83 (1H, s), 7.23 (1H, dd, J = 8.5, 2Hz), 7.43 (1H, d, J = 8.5Hz), 7.55 (1H, d, J = 2Hz).

Example 303

Yield: 93%, 1H-NMR (CDCl3): δ1.12 (6H, d, J = 6Hz), 1.30 (3H, t, J = 7Hz), 2.31 (3H, s), 2.70-2.90 (2H, m), 3.00-3.15 (2H, m), 3.77 (2H, s), 3.85-3.95 (2H, m), 4.27 (2H, q, J = 7Hz), 4.60 (2H, s), 6.57 (1H, s), 6.78 (1H, s), 6.84 (1H, s), 7.52 (1H, d, J = 8.5Hz), 7.56 (1H, d, J = 8.5Hz), 7.84 (1H, s).

Example 304

Yield: 95%, 1H-NMR (CDCl3): δ1.30 (3H, t, J = 7Hz), 1.41 (3H, d, J = 7Hz), 2.21 (1H, td, J = 12, 3.5Hz) , 2.25-2.35 (1H, m), 2.32 (3H, s), 2.73 (1H, d, J = 11Hz), 2.90 (1H, d, J = 11Hz), 3.38 (1H, d, J = 13.5Hz) , 3.48 (1H, td, J = 12, 3.5Hz), 3.52 (1H, d, J = 13.5Hz), 3.85 (1H, d, J = 12Hz), 4.15-4.25 (1H, m), 4.27 (2H , q, J = 7Hz), 4.61 (2H, s), 6.64 (1H, s), 6.76 (1H, s), 6.78 (1H, s), 7.22 (1H, dd, J = 8, 2Hz), 7.42 (1H, d, J = 8Hz), 7.54 (1H, d, J = 2Hz).

Example 305

Yield: 43%, 1H-NMR (CDCl3): δ1.21 (3H, d, J = 6Hz), 1.30 (3H, t, J = 7Hz), 2.20-2.27 (1H, m), 2.28 (3H, s), 2.60-2.70 (1H, m), 2.75-2.85 (1H, m), 3.10-3.25 (2H, m), 3.35-3.50 (1H, m), 3.68-3.78 (1H, m), 3.85- 3.95 (1H, m), 4.01 (1H, d, J = 13Hz), 4.27 (2H, q, J = 7Hz), 4.65 (2H, s), 6.74 (1H, s), 6.85 (1H, d, J = 7.5Hz), 7.11 (1H, d, J = 7.5Hz), 7.53 (1H, d, J = 8.5Hz), 7.56 (1H, d, J = 8.5Hz), 7.84 (1H, s).

Example 306

Yield: 79%, 1H-NMR (CDCl3): δ1.22 (3H, d, J = 6.5Hz), 1.31 (3H, t, J = 7Hz), 2.23-2.35 (1H, m), 2.60-2.73 (1H, m), 2.75-2.90 (1H, m), 3.15-3.25 (2H, m), 3.40-3.50 (1H, m), 3.70-3.82 (1H, m), 3.85-3.95 (1H, m) , 4.03 (1H, d, J = 13.5Hz), 4.28 (2H, q, J = 7Hz), 4.63 (2H, s), 6.80 (1H, dd, J = 8, 1.5Hz), 6.93-7.02 (2H , m), 7.25 (1H, t, J = 8Hz), 7.53 (1H, d, J = 8.5Hz), 7.56 (1H, d, J = 8.5Hz), 7.84 (1H, s).

Example 307

Yield: 81%, 1H-NMR (CDCl3): δ1.02 (3H, t, J = 7.5Hz), 1.31 (3H, t, J = 7Hz), 1.58-1.79 (2H, m), 2.31 (3H , s), 2.31-2.38 (1H, m), 2.47-2.58 (1H, m), 2.78-2.88 (1H, m), 3.23 (1H, d, J = 13.5Hz), 3.36-3.58 (2H, m ), 3.64-3.75 (1H, m), 3.84 (1H, d, J = 11Hz), 3.95 (1H, d, J = 13.5Hz), 4.28 (2H, q, J = 7Hz), 4.62 (2H, s ), 6.63 (1H, s), 6.77 (1H, s), 6.78 (1H, s), 7.51 (1H, d, J = 8.5Hz), 7.56 (1H, d, J = 8.5Hz), 7.84 (1H , s)

Example 308

Yield: 91%, 1H-NMR (CDCl3): δ1.31 (3H, t, J = 7Hz), 2.25-2.35 (4H, m), 2.82 (1H, d, J = 13.5Hz), 3.01 (1H , d, J = 11.5Hz), 3.25-3.50 (3H, m), 3.79 (1H, d, J = 13.5Hz), 4.00-4.10 (2H, m), 4.28 (2H, q, J = 7Hz), 4.60 (2H, s), 6.59 (1H, s), 6.70 (1H, s), 6.72 (1H, s), 7.30-7.45 (3H, m), 7.50-7.58 (4H, m), 7.84 (1H, s).

Example 309

Yield: 90%, 1H-NMR (CDCl3): δ1.21 (3 H, d, J = 6.3 Hz), 1.31 (3 H, t, J = 7.2 Hz), 2.22-2.31 (1 H, m) , 2.32 (3 H, s), 2.58-2.68 (1 H, m), 2.83 (1 H, dt, J = 3.3, 12.3 Hz), 3.12-3.19 (2 H, m), 3.34-3.43 (1 H , m), 3.71 (1 H, d, J = 12.3 Hz), 3.86 (1 H, d, J = 10.5 Hz), 3.99 (1 H, d, J = 13.5 Hz), 4.28 (2 H, q, J = 7.2 Hz), 4.61 (2 H, s), 6.63 (1 H, s), 6.75 (1H, s), 6.78 (1 H, s), 7.23 (1 H, d, J = 2.4, 8.7 Hz ), 7.43 (1 H, d, J = 8.7 Hz), 7.55 (1 H, d, J = 2.4 Hz)

Example 310

Yield: 70%, 1H-NMR (CDCl3): δ1.21 (3 H, d, J = 6.3 Hz), 1.30 (3 H, t, J = 7.2 Hz), 2.23-2.32 (1 H, m) , 2.32 (3 H, s), 2.58-2.67 (1 H, m), 2.80 (1 H, d, J = 3.3, 12.3 Hz), 3.12-3.19 (2 H, m), 3.35-3.42 (1H, m), 3.71 (1 H, dt, J = 12.0 Hz), 3.86 (1 H, dt, J = 12.0 Hz), 3.99 (1 H, d, J = 13.2 Hz), 4.28 (2 H, q, J = 7.2 Hz), 4.61 (2 H, s), 6.63 (1 H, s), 6.75 (1 H, s), 6.78 (1 H, s), 7.23 (1 H, dd, J = 2.1, 8.7 Hz ), 7.43 (1 H, d, J = 8.7 Hz), 7.54 (1 H, d, J = 2.1 Hz)

Example 311

Yield: 89%, 1H-NMR (CDCl3): δ1.30 (3H, t, J = 7Hz), 1.43 (3H, d, J = 6.5Hz), 2.23 (1H, td, J = 12, 3.5Hz ), 2.31 (3H, s), 2.31-2.40 (1H, m), 2.73 (1H, d, J = 11Hz), 2.91 (1H, d, J = 11Hz), 3.40 (1H, d, J = 13Hz) , 3.46-3.51 (1H, m), 3.53 (1H, d, J = 13Hz), 3.85-3.95 (1H, m), 4.20-4.27 (1H, m), 4.28 (2H, q, J = 7Hz), 4.62 (2H, s), 6.65 (1H, s), 6.77 (1H, s), 6.79 (1H, s), 7.52 (1H, d, J = 8.5Hz), 7.56 (1H, d, J = 8.5Hz ), 7.84 (1H, s).

Example 312

Yield: 84%, 1H-NMR (CDCl3): δ1.31 (3H, t, J = 7.0Hz), 1.43 (3H, d, J = 6.5Hz), 2.16-2.28 (1H, m), 2.30- 2.39 (1H, m), 2.33 (3H, s), 2.70-2.78 (1H, m), 2.87-2.96 (1H, m), 3.40 (1H, d, J = 13.5Hz), 3.45-3.58 (2H, m), 3.86-3.97 (1H, m), 4.18-4.30 (1H, m), 4.28 (2H, q, J = 7.0Hz), 4.62 (2H, s), 6.65 (1H, s), 6.75-6.82 (2H, m), 7.48-7.60 (2H, m), 7.84 (1H, s).

Example 313

Yield: 86%, 1H-NMR (CDCl3): δ1.02 (3H, t, J = 7.5Hz), 1.31 (3H, t, J = 7Hz), 1.57-1.78 (2H, m), 2.30-2.33 (1H, m), 2.34 (3H, s), 2.48-2.60 (1H, m), 2.78-2.90 (1H, m), 3.17 (1H, d, J = 13.5Hz), 3.37-3.58 (2H, m ), 3.62-3.73 (1H, m), 3.79-3.88 (1H, m), 3.95 (1H, d, J = 13.5Hz), 4.28 (2H, q, J = 7Hz), 4.61 (2H, s), 6.63 (1H, s), 6.76 (1H, s), 6.78 (1H, s), 7.51 (1H, d, J = 8.5Hz), 7.55 (1H, d, J = 8.5Hz), 7.83 (1H, s ).

Example 314

Yield: 85%, 1H-NMR (CDCl3): δ1.02 (3H, t, J = 7.5Hz), 1.29 (3H, t, J = 7Hz), 1.58-1.78 (2H, m), 2.04 (3H , s), 2.05-2.15 (1H, m), 2.48-2.58 (1H, m), 2.79-2.89 (1H, m), 3.23 (1H, d, J = 13.5Hz), 3.42 (1H, dd, J = 12.5, 8Hz), 3.47-3.56 (1H, m), 3.63-3.72 (1H, m), 3.80-3.90 (1H, m), 3.95 (1H, d, J = 13.5Hz), 4.27 (2H, q , J = 7Hz), 4.61 (2H, s), 6.63 (1H, s), 6.77 (1H, s), 6.78 (1H, s), 7.52 (1H, d, J = 8.5Hz), 7.56 (1H, d, J = 8.5Hz), 7.83 (1H, s).

Example 315

Yield: 60%, 1H-NMR (CDCl3): δ0.95 (3H, t, J = 7.0Hz), 1.22-1.68 (4H, m), 1.31 (3H, t, J = 7.0Hz), 2.27- 2.40 (1H, m), 2.32 (3H, s), 2.54-2.65 (1H, m), 2.76-2.89 (1H, m), 3.25 (1H, d, J = 13.5Hz), 3.41 (1H, dd, J = 13.0, 7.5Hz), 3.48-3.59 (1H, m), 3.60-3.71 (1H, m), 3.83 (1H, dd, J = 12.5, 3.5Hz), 3.93 (1H, d, J = 13.5Hz ), 4.28 (2H, q, J = 7.0Hz), 4.61 (2H, s), 6.63 (1H, s), 6.76 (1H, s), 6.78 (1H, s), 7.52 (1H, d, J = 8.5Hz), 7.56 (1H, d, J = 8.5Hz), 7.83 (1H, s).

Example 316

Yield: 90%, 1H-NMR (CDCl3): δ 0.95 (3 H, t, J = 7.2 Hz), 1.31 (3 H, t, J = 7.2 Hz), 1.33-1.62 (4 H, m) , 2.32 (3 H, s), 2.32-2.38 (1 H, m), 2.57-2.62 (1 H, m), 2.79-2.86 (1 H, m), 3.24 (1 H, d, J = 13.5 Hz ), 3.41 (1 H, dd, J = 7.8, 12.6 Hz), 3.38-3.44 (1 H, m), 3.64-3.69 (1 H, m), 3.83 (1 H, dd, J = 3.0, 12.6 Hz) ), 3.93 (1 H, d, J = 13.5 Hz), 4.28 (2 H, q, J = 7.2 Hz), 4.61 (2 H, s), 6.63 (1 H, s), 6.77 (2 H, d , J = 6.3 Hz), 7.53-7.55 (2 H, m), 7.83 (1 H, s)

Example 317

Yield: 64%, 1H-NMR (CDCl3): δ0.93 (3H, t, J = 7.0Hz), 1.22-1.75 (6H, m), 1.31 (3H, t, J = 7.0Hz), 2.27- 2.39 (1H, m), 2.32 (3H, s), 2.51-2.64 (1H, m), 2.76-2.88 (1H, m), 3.24 (1H, d, J = 13.0Hz), 3.41 (1H, dd, J = 13.0, 7.5Hz), 3.47-3.59 (1H, m), 3.61-3.72 (1H, m), 3.84 (1H, dd, J = 13.0, 3.0Hz), 3.94 (1H, d, J = 13.0Hz ), 4.28 (2H, q, J = 7.0Hz), 4.61 (2H, s), 6.63 (1H, s), 6.76 (1H, s), 6.78 (1H, s), 7.51 (1H, d, J = 8.5Hz), 7.56 (1H, d, J = 8.5Hz), 7.84 (1H, s).

Example 318

Yield: 83%, 1H-NMR (CDCl3): δ0.91 (3H, d, J = 6.5Hz), 0.95 (3H, d, J = 6.5Hz), 1.30 (3H, t, J = 7Hz), 1.35-1.45 (1H, m), 1.46-1.58 (1H, m), 1.65-1.80 (1H, m), 2.32 (3H, s), 2.33-2.44 (1H, m), 2.62-2.73 (1H, m ), 2.75-2.86 (1H, m), 3.30 (1H, d, J = 13.5Hz), 3.35 (1H, dd, J = 13, 6.5Hz), 3.58 (2H, t, J = 5Hz), 3.75 ( 1H, dd, J = 13, 6.5Hz), 3.87 (1H, d, J = 13.5Hz), 4.28 (2H, q, J = 7Hz), 4.61 (2H, s), 6.62 (1H, s), 6.76 (1H, s), 6.78 (1H, s), 7.23 (1H, dd, J = 8.5, 2Hz), 7.42 (1H, d, J = 8.5Hz), 7.54 (1H, d, J = 2Hz).

Example 319

Yield: 68%, 1H-NMR (CDCl3): δ0.92 (3H, d, J = 6.5Hz), 0.95 (3H, d, J = 7.0Hz), 1.20-1.44 (1H, m), 1.30 ( 3H, t, J = 6.5Hz), 1.45-1.80 (2H, m), 2.27-2.47 (1H, m), 2.32 (3H, s), 2.61-2.72 (1H, m), 2.75-2.88 (1H, m), 3.25-3.41 (2H, m), 3.58 (2H, t, J = 5.0Hz), 3.75 (1H, dd, J = 12.5, 3.5Hz), 3.87 (1H, d, J = 13.5Hz), 4.28 (2H, q, J = 7.0Hz), 4.61 (2H, s), 6.62 (1H, s), 6.76 (1H, s), 6.78 (1H, s), 7.23 (1H, dd, J = 8.0, 2.0Hz), 7.42 (1H, d, J = 8.0Hz), 7.54 (1H, d, J = 2.0Hz).

Example 320

Yield: 85%, 1H-NMR (CDCl3): δ 0.92 (3H, d, J = 6.5Hz), 0.95 (3H, d, J = 6.5Hz), 1.31 (3H, t, J = 7Hz), 1.34-1.45 (1H, m), 1.45-1.55 (1H, m), 1.65-1.80 (1H, m), 2.32 (3H, s), 2.35-2.46 (1H, m), 2.64-2.75 (1H, m ), 2.78-2.88 (1H, m), 3.32 (1H, d, J = 13.5Hz), 3.42 (1H, dd, J = 13, 6.5Hz), 3.60-3.67 (2H, m), 3.79 (1H, dd, J = 13, 3.5Hz), 3.87 (1H, d, J = 13.5Hz), 4.28 (2H, q, J = 7Hz), 4.61 (2H, s), 6.63 (1H, s), 6.77 (1H , s), 6.79 (1H, s), 7.51 (1H, d, J = 8.5Hz), 7.56 (1H, d, J = 8.5Hz), 7.83 (1H, s).

Example 321

Yield: 98%, 1H-NMR (CDCl3): δ1.21 (3H, d, J = 6Hz), 1.31 (3H, t, J = 7Hz), 2.20-2.32 (1H, m), 2.32 (3H, s), 2.59-2.70 (1H, m), 2.75-2.88 (1H, m), 3.16 (1H, d, J = 13.5Hz), 3.17-3.25 (1H, m), 3.48-3.50 (1H, m) , 3.69-3.80 (1H, m), 3.85-3.95 (1H, m), 3.98 (1H, d, J = 13.5Hz), 4.28 (2H, q, J = 7Hz), 4.62 (2H, s), 6.63 (1H, s), 6.75 (1H, s), 6.78 (1H, s), 7.26 (1H, d, J = 12Hz), 7.74 (1H, d, J = 7Hz).

Example 322

Yield: 69%, 1H-NMR (CDCl3): δ1.30 (3H, t, J = 7.0Hz), 1.96-2.08 (2H, m), 2.30 (3H, s), 2.63-2.71 (2H, m ), 2.74-2.84 (2H, m), 3.57 (2H, s), 3.60-3.89 (4H, m), 4.27 (2H, q, J = 7.0Hz), 4.60 (2H, s), 6.62 (1H, s), 6.73 (1H, s), 6.75 (1H, s), 7.27 (1H, d, J = 7.0Hz), 7.75 (1H, d, J = 11.5Hz).

Example 323

Yield: 75%, 1H-NMR (CDCl3): δ1.12 (6H, d, J = 6.0Hz), 1.30 (3H, t, J = 7.0Hz), 2.32 (3H, s), 2.72-2.86 ( 2H, m), 3.07 (1H, d, J = 13.0Hz), 3.11 (1H, d, J = 13.0Hz), 3.77 (2H, s), 3.89 (2H, d, J = 11.0Hz), 4.28 ( 2H, q, J = 7.0Hz), 4.60 (2H, s), 6.57 (1H, s), 6.78 (1H, s), 6.84 (1H, s), 7.27 (1H, d, J = 11.5Hz), 7.75 (1H, d, J = 6.0Hz).

Example 324

Yield: 79%, 1H-NMR (CDCl3): δ1.01 (3H, t, J = 7.5Hz), 1.31 (3H, t, J = 7.0Hz), 1.50-1.80 (2H, m), 2.26- 2.39 (1H, m), 2.32 (3H, s), 2.47-2.58 (1H, m), 2.77-2.88 (1H, m), 3.24 (1H, d, J = 13.5Hz), 3.36-3.57 (2H, m), 3.61-3.73 (1H, m), 3.77-3.88 (1H, m), 3.94 (1H, d, J = 13.5Hz), 4.28 (2H, q, J = 7.0Hz), 4.61 (2H, s ), 6.62 (1H, s), 6.73-6.82 (2H, m), 7.26 (1H, d, J = 11.5Hz), 7.74 (1H, d, J = 7.0Hz)

Example 325

Yield: 71%, 1H-NMR (CDCl3): δ 1.29 (3H, t, J = 7.0Hz), 2.31 (3H, s), 2.54 (4H, t, J = 5.0Hz), 3.47 (2H, s), 3.52 (4H, t, J = 5.0Hz), 4.26 (2H, q, J = 7.0Hz), 4.60 (2H, s), 6.64 (1H, s), 6.74 (1H, s), 6.78 ( 1H, s), 7.18 (1H, tt, J = 7.5, 1.5Hz), 7.26-7.35 (2H, m), 7.37-7.44 (3H, m).

Example 326

Yield: 74%, 1H-NMR (CDCl3): δ 1.15 (6H, d, J = 7.0Hz), 1.30 (3H, t, J = 7.0Hz), 2.32 (3H, s), 2.68-2.83 ( 2H, m), 2.93 (1H, d, J = 13.0Hz), 2.96 (1H, d, J = 13.0Hz), 3.78 (2H, s), 4.26-4.38 (2H, m), 4.27 (2H, q , J = 7.0Hz), 4.61 (2H, s), 6.57 (1H, s), 6.80 (1H, s), 6.86 (1H, s), 7.34-7.43 (1H, m), 7.52-7.62 (1H, m), 7.67 (1H, dd, J = 8.5, 1.5Hz), 7.87 (1H, dd, J = 8.5, 1.5Hz), 8.56 (1H, s).

Example 327

Yield: 79%, 1H-NMR (CDCl3): δ1.25 (3H, d, J = 6.0Hz), 1.31 (3H, t, J = 7.0Hz), 2.20-2.32 (1H, m), 2.33 ( 3H, s), 2.55-2.68 (1H, m), 2.85 (1H, dt, J = 12.0, 3.5Hz), 3.14 (1H, d, J = 13.0Hz), 3.16 (1H, d, J = 13.5Hz ), 3.30-3.43 (1H, m), 4.02 (1H, d, J = 13.0Hz), 4.04-4.15 (1H, m), 4.17-4.26 (1H, m), 4.28 (2H, q, J = 7.0 Hz), 4.62 (2H, s), 6.63 (1H, s), 6.77 (1H, s), 6.80 (1H, s), 7.34-7.42 (1H, m), 7.52-7.61 (1H, m), 7.67 (1H, dd, J = 8.5, 1.5Hz), 7.87 (1H, dd, J = 8.5, 1.5Hz), 8.55 (1H, s).

Example 328

Yield: 74%, 1H-NMR (CDCl3): δ 1.15 (6H, d, J = 6.0Hz), 1.30 (3H, t, J = 7.0Hz), 2.32 (3H, s), 2.67-2.81 ( 2H, m), 2.93 (1H, d, J = 13.0Hz), 2.97 (1H, d, J = 13.0Hz), 3.78 (2H, s), 4.24-4.35 (2H, m), 4.27 (2H, q , J = 7.0Hz), 4.61 (2H, s), 6.66 (1H, s), 6.79 (1H, s), 6.86 (1H, s), 7.50 (1H, dd, J = 9.5, 2.0Hz), 7.59 (1H, d, J = 9.5Hz), 7.85 (1H, d, J = 2.0Hz), 8.54 (1H, s).

Example 329

Yield: 51%, 1H-NMR (CDCl3): δ 1.15 (6H, d, J = 6.0Hz), 1.29 (3H, t, J = 7.0Hz), 2.31 (3H, s), 2.65-2.79 ( 2H, m), 2.95 (1H, d, J = 13.0Hz), 2.99 (1H, d, J = 13.0Hz), 3.76 (2H, s), 4.26 (2H, q, J = 7.0Hz), 4.35 ( 2H, d, J = 12.0Hz), 4.62 (2H, s), 6.58 (1H, s), 6.79 (1H, s), 6.86 (1H, s), 7.69 (1H, s), 7.70 (1H, s ), 8.13 (1H, s), 8.59 (1H, s).

酢酸4-{[4-（6-クロロベンゾチアゾール-2-イル）ピペラジン-1-イル]メチル}フェニルエステル0.33ｇ(0.834mmol)、水酸化リチウム0.04ｇ(0.831mmol)及びTHF8mlの混合物を室温下で5時間撹拌した。反応液を減圧下、溶媒を留去した後、残渣にブロモ酢酸エチル0.14ml(1.26mmol)、 炭酸セシウム0.41ｇ(1.26mmol)及び無水N,N-ジメチルホルムアミド4mlを加え、室温下17時間撹拌した。反応液に水及び酢酸エチルを加え抽出した後、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。減圧下溶媒を留去した後、残渣をシリカゲルカラムクロマトグラフィー（ヘキサン：酢酸エチル＝2：1）で精製し、4-{[4-(6-クロロベンゾチアゾール-2-イル)ピペラジン-1-イル]メチル}フェノキシ酢酸エチルを無色油状物として0.35ｇ（93％）得た。
¹H-NMR(CDCl₃): δ1.31 (3H, t, J = 7.2 Hz), 2.55 (4H, t, J = 5.1 Hz), 3.50 (2H, s), 3.62 (4H, t, J = 5.1 Hz), 4.28 (2H, q, J = 7.2 Hz), 4.66 (2H, s), 6.88 (1H, d, J = 8.1 Hz), 7.22-7.26 (4H, m), 7.43 (1H, d, J = 8.1 Hz), 7.55 (1H, d, J = 2.1 Hz).

実施例３３１
3-クロロ-5-{[4-(6-クロロベンゾチアゾール-2-イル)ピペラジン-1-イル]メチル}フェノキシ酢酸エチルの製造

3-クロロ-5-[4-(2-メトキシメトキシ-3-メチルベンジル)ピペラジン-1-イル]ベンゾチアゾール0.15g (0.346mmol)、4N 塩酸/ジオキサン溶液8.5mlの混合物を60℃で2時間撹拌した。空冷後、反応液を減圧下濃縮した。残渣にブロモ酢酸エチル0.05ml(0.451mmol)、炭酸セシウム0.50g(1.56mmol)及び無水N,N-ジメチルホルムアミド3mlを加え、室温下17時間撹拌した。反応液に水及び酢酸エチルを加え抽出した後、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。減圧下溶媒を留去した後、残渣をシリカゲルカラムクロマトグラフィー（ヘキサン：酢酸エチル＝2：1）で精製し、3-クロロ-5-{[4-(6-クロロベンゾチアゾール-2-イル)ピペラジン-1-イル]メチル}フェノキシ酢酸エチルを無色油状物として0.13g（77％）得た。
¹H-NMR(CDCl₃): δ1.31 (3H, t, J = 6.9 Hz), 2.56 (4H, t, J = 5.1 Hz), 3.49 (2H, s), 3.63 (4H, t, J = 5.1 Hz), 4.28 (2H, q, J = 6.9 Hz), 4.61 (2H, s), 6.87 (1H, t, J = 1.5 Hz), 6.84 (1H, s), 6.99 (1H, t, J = 1.5 Hz), 7.24 (1H, dd, J = 2.1, 8.7 Hz), 7.44 (1H, d, J = 8.7 Hz), 7.55 (1H, dd, J = 2.1 Hz) Example 330
Preparation of 4-{[4- (6-Chlorobenzothiazol-2-yl) piperazin-1-yl] methyl} phenoxyacetate

Acetic acid 4-{[4- (6-chlorobenzothiazol-2-yl) piperazin-1-yl] methyl} phenyl ester 0.33 g (0.834 mmol), lithium hydroxide 0.04 g (0.831 mmol) and THF 8 ml were mixed at room temperature. Stirred under for 5 hours. After the solvent was distilled off under reduced pressure, 0.14 ml (1.26 mmol) of ethyl bromoacetate, 0.41 g (1.26 mmol) of cesium carbonate and 4 ml of anhydrous N, N-dimethylformamide were added to the residue, followed by stirring at room temperature for 17 hours. did. Water and ethyl acetate were added to the reaction solution for extraction, and the organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 2: 1) to give 4-{[4- (6-chlorobenzothiazol-2-yl) piperazine-1- Obtained 0.35 g (93%) of ethyl [yl] methyl} phenoxyacetate as a colorless oil.
¹ H-NMR (CDCl ₃ ): δ1.31 (3H, t, J = 7.2 Hz), 2.55 (4H, t, J = 5.1 Hz), 3.50 (2H, s), 3.62 (4H, t, J = 5.1 Hz), 4.28 (2H, q, J = 7.2 Hz), 4.66 (2H, s), 6.88 (1H, d, J = 8.1 Hz), 7.22-7.26 (4H, m), 7.43 (1H, d, J = 8.1 Hz), 7.55 (1H, d, J = 2.1 Hz).

Example 331
Preparation of ethyl 3-chloro-5-{[4- (6-chlorobenzothiazol-2-yl) piperazin-1-yl] methyl} phenoxyacetate

A mixture of 0.15 g (0.346 mmol) of 3-chloro-5- [4- (2-methoxymethoxy-3-methylbenzyl) piperazin-1-yl] benzothiazole and 8.5 ml of 4N hydrochloric acid / dioxane solution at 60 ° C. for 2 hours Stir. After air cooling, the reaction solution was concentrated under reduced pressure. To the residue were added 0.05 ml (0.451 mmol) of ethyl bromoacetate, 0.50 g (1.56 mmol) of cesium carbonate and 3 ml of anhydrous N, N-dimethylformamide, and the mixture was stirred at room temperature for 17 hours. Water and ethyl acetate were added to the reaction solution for extraction, and the organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 2: 1) to give 3-chloro-5-{[4- (6-chlorobenzothiazol-2-yl) 0.13 g (77%) of piperazin-1-yl] methyl} phenoxyacetate was obtained as a colorless oil.
¹ H-NMR (CDCl ₃ ): δ1.31 (3H, t, J = 6.9 Hz), 2.56 (4H, t, J = 5.1 Hz), 3.49 (2H, s), 3.63 (4H, t, J = 5.1 Hz), 4.28 (2H, q, J = 6.9 Hz), 4.61 (2H, s), 6.87 (1H, t, J = 1.5 Hz), 6.84 (1H, s), 6.99 (1H, t, J = 1.5 Hz), 7.24 (1H, dd, J = 2.1, 8.7 Hz), 7.44 (1H, d, J = 8.7 Hz), 7.55 (1H, dd, J = 2.1 Hz)

収率：84％, ¹H-NMR(CDCl₃); δ1.31-1.50 (2H, m), 1.65 (1H, s), 1.74-1.96 (5H, m), 2.21 (3H, s), 3.07-3.20 (2H, m), 4.02-4.18 (4H, m), 4.65 (2H, d, J=5.5Hz), 6.83 (1H, d, J=7.5Hz), 6.86 (1H, s), 7.12 (1H, d,J=7.5Hz), 7.22 (1H, dd, J=8.5, 2.0Hz), 7.42 (1H, d, J=8.5Hz), 7.54 (1H, d, J=2.0Hz).

実施例３３３
実施例３３２を原料に、実施例１５４と同様の方法により、以下の化合物を得た。

収率：79％, ¹H-NMR(CDCl₃); δ1.33-1.52 (2H, m), 1.78-1.98 (5H, m), 2.21 (3H, s), 3.08-3.21 (2H, m), 4.03-4.17 (4H, m), 4.50 (2H, s), 6.82-6.90 (2H, m), 7.11 (1H, d, J=7.5Hz), 7.22 (1H, dd, J=8.5, 2.0Hz), 7.42 (1H, d, J=8.5Hz), 7.55 (1H, d, J=2.0Hz).

実施例３３４
実施例３３３を原料に、実施例１７９と同様の方法により、以下の化合物を得た。

収率：96％, ¹H-NMR(CDCl₃); δ1.34-1.52 (2H, m), 1.77-1.97 (5H, m), 2.21 (3H, s), 3.08-3.22 (2H, m), 3.72 (2H, s), 4.01-4.19 (4H, m), 6.75-6.81 (2H, m), 7.13 (1H, d, J=7.5Hz), 7.23 (1H, dd, J=8.5, 2.0Hz), 7.42 (1H, d, J=8.5Hz), 7.55 (1H, d, J=2.0Hz). Example 332
The following compounds were obtained in the same manner as in Example 129 using Example 217 as a raw material.

Yield: 84%, ¹ H-NMR (CDCl ₃ ); δ1.31-1.50 (2H, m), 1.65 (1H, s), 1.74-1.96 (5H, m), 2.21 (3H, s), 3.07 -3.20 (2H, m), 4.02-4.18 (4H, m), 4.65 (2H, d, J = 5.5Hz), 6.83 (1H, d, J = 7.5Hz), 6.86 (1H, s), 7.12 ( 1H, d, J = 7.5Hz), 7.22 (1H, dd, J = 8.5, 2.0Hz), 7.42 (1H, d, J = 8.5Hz), 7.54 (1H, d, J = 2.0Hz).

Example 333
The following compounds were obtained in the same manner as in Example 154 using Example 332 as a starting material.

Yield: 79%, ¹ H-NMR (CDCl ₃ ); δ1.33-1.52 (2H, m), 1.78-1.98 (5H, m), 2.21 (3H, s), 3.08-3.21 (2H, m) , 4.03-4.17 (4H, m), 4.50 (2H, s), 6.82-6.90 (2H, m), 7.11 (1H, d, J = 7.5Hz), 7.22 (1H, dd, J = 8.5, 2.0Hz ), 7.42 (1H, d, J = 8.5Hz), 7.55 (1H, d, J = 2.0Hz).

Example 334
The following compounds were obtained in the same manner as in Example 179 using Example 333 as a raw material.

Yield: 96%, ¹ H-NMR (CDCl ₃ ); δ1.34-1.52 (2H, m), 1.77-1.97 (5H, m), 2.21 (3H, s), 3.08-3.22 (2H, m) , 3.72 (2H, s), 4.01-4.19 (4H, m), 6.75-6.81 (2H, m), 7.13 (1H, d, J = 7.5Hz), 7.23 (1H, dd, J = 8.5, 2.0Hz ), 7.42 (1H, d, J = 8.5Hz), 7.55 (1H, d, J = 2.0Hz).

3-{2-[1-(6-クロロベンゾチアゾール-2-イル)ピペリジン-4-イル]エトキシ}安息香酸エチル0.30g(6.671mmol)、2N-水酸化ナトリウム水溶液1.5ml及びメタノール3mlの混合物を60℃で1時間撹拌した。反応液を減圧下濃縮し、残渣に水及び2N塩酸水溶液を加え、中性とした。析出結晶を濾取し、水及びジイソプロピルエーテルで洗浄後3-｛2-[1-(6-クロロベンゾチアゾール-2-イル)ピペリジン-4-イル]エトキシ｝安息香酸を無色結晶として0.26g（93％）得た。
¹H-NMR(DMSO-d₆): δ1.20-1.39 (2H, m), 1.66-1.93 (5H, m), 3.10-3.26 (2H, m), 3.94-4.16 (4H, m), 7.20 (1H, dd, J=8.5, 2.5Hz), 7.27 (1H, d, J=8.5, 2.0Hz), 7.36-7.47 (3H, m), 7.52 (1H, d, J=7.5Hz), 7.89 (1H, d, J=2.0Hz). Example 335
Preparation of 3- {2- [1- (6-chlorobenzothiazol-2-yl) piperidin-4-yl] ethoxy} benzoic acid

3- {2- [1- (6-chlorobenzothiazol-2-yl) piperidin-4-yl] ethoxy} ethyl benzoate 0.30 g (6.671 mmol), 2N sodium hydroxide aqueous solution 1.5 ml and methanol 3 ml mixture Was stirred at 60 ° C. for 1 hour. The reaction mixture was concentrated under reduced pressure, and neutralized with water and 2N aqueous hydrochloric acid solution. The precipitated crystals were collected by filtration, washed with water and diisopropyl ether, and then 0.26 g of 3- {2- [1- (6-chlorobenzothiazol-2-yl) piperidin-4-yl] ethoxy} benzoic acid as colorless crystals ( 93%).
¹ H-NMR (DMSO-d ₆ ): δ1.20-1.39 (2H, m), 1.66-1.93 (5H, m), 3.10-3.26 (2H, m), 3.94-4.16 (4H, m), 7.20 (1H, dd, J = 8.5, 2.5Hz), 7.27 (1H, d, J = 8.5, 2.0Hz), 7.36-7.47 (3H, m), 7.52 (1H, d, J = 7.5Hz), 7.89 ( (1H, d, J = 2.0Hz).

収率：18％, ¹H-NMR(DMSO-d₆): δ1.68-1.84 (2H, m), 2.00-2.15 (2H, m), 3.50-3.64 (2H, m), 3.78-3.92 (2H, m), 4.68-4.81 (1H, m), 7.12-7.18 (1H, m), 7.26-7.39 (2H, m), 7.43 (1H, d, J=8.5Hz), 7.48-7.55 (2H, m), 7.91 (1H, d, J=2.0Hz).

実施例３３７

収率：27％, ¹H-NMR(DMSO-d₆): δ1.66-1.83 (2H, m), 2.00-2.15 (2H, m), 3.48-3.64 (4H, m), 3.78-3.93 (2H, m), 4.62-4.75 (1H, m), 6.80-6.98 (3H, m), 7.19-7.28 (1H, m), 7.29 (1H,dd,J=8.5,2.5Hz),7.44(1H, d, J=8.5Hz), 7.90 (1H, d, J=2.5Hz), 12.29 (1H, s).

実施例３３８

収率：84％, ¹H-NMR(DMSO-d₆): δ1.35-1.55 (2H, m), 1.85-2.00 (2H, m), 2.00-2.20 (1H, m), 3.10-3.30 (2H, m), 3.94 (2H, d, J=6Hz), 4.00-4.15 (2H, m), 6.98 (1H, t, J=7.5Hz), 7.10 (1H, d, J=7.5Hz), 7.27 (1H, dd, J=8.5, 2Hz), 7.41 (1H, d, J=8.5Hz), 7.47 (1H, t, J=7.5Hz), 7.61 (1H, d, J=7.5Hz), 7.89 (1H, d, J=2Hz), 12.50 (1H, brs).

実施例３３９

収率：84％, ¹H-NMR(DMSO-d₆): δ1.30-1.50 (2H, m), 1.80-1.95 (2H, m), 2.00-2.15 (1H, m), 3.15-3.30 (2H, m), 3.93 (2H, d, J=6Hz), 4.00-4.15 (2H, m), 7.20 (1H, dd, J=8, 2.5Hz), 7.27 (1H, dd, J=8.5, 2Hz), 7.35-7.45 (3H, m), 7.52 (1H, d, J=8Hz), 7.88 (1H, d, J=2Hz), 13.0 (1H, brs).

実施例３４０

収率：59％, ¹H-NMR(DMSO-d₆): δ1.30-1.50 (2H, m), 1.85-1.95 (2H, m), 2.00-2.20 (1H, m), 3.00-3.20 (2H, m), 3.96 (2H, d, J=6.5Hz), 4.04-4.14 (2H, m), 7.00 (2H, d, J=8Hz), 7.28 (1H, dd, J=8.5, 1.5Hz), 7.41 (1H, d, J=8.5Hz), 7.87 (2H, d, J=8Hz), 7.89 (1H, d, J=1.5Hz).

実施例３４１

収率：88％, ¹H-NMR(DMSO-d₆): δ1.20-1.45 (2H, m), 1.70-1.90 (1H, m), 1.90-2.05 (2H, m), 3.02 (2H, d, J=7Hz), 3.10-3.25 (2H, m), 3.95-4.10 (2H, m), 7.70 (1H, dd, J=8.5, 2Hz), 7.40 (1H, d, J=8.5Hz), 7.44 (1H, t, J=7.5Hz), 7.59 (1H, d, J=7.5Hz), 7.73 (1H, d, J=7.5Hz), 7.83 (1H, s), 7.88 (1H, d, J=2Hz), 13.40 (1H, brs).

実施例３４２

収率：32％, ¹H-NMR(CDCl₃); δ1.30-1.48 (2H, m), 1.70-1.90 (1H, m), 1.85-2.05 (2H, m), 2.88 (2H, d, J=7Hz), 3.02-3.15 (2H, m), 3.63 (2H, s), 4.05-4.18 (2H, m), 7.05-7.15 (1H, m), 7.24 (1H, dd, J=8.5, 2Hz), 7.25-7.30 (3H, m), 7.42 (1H, d, J=8.5Hz), 7.53 (1H, d, J=2Hz).

実施例３４３

収率：88％, ¹H-NMR(DMSO-d₆): δ1.20-1.38 (2H, m), 1.71 (2H, q, J=6.0Hz), 1.78-1.94 (3H, m), 3.09-3.23 (2H, m), 3.95-4.07 (2H, m), 4.10 (2H, t, J=6.0Hz), 6.99 (1H, td, J=7.5, 1.5Hz), 7.14 (1H, d, J=7.5Hz), 7.27 (1H, dd, J=8.5, 2.0Hz), 7.40 (1H, d, J=8.5Hz), 7.48 (1H, td, J=1.5, 7.5Hz), 7.60 (1H, dd, J=7.5, 1.5Hz), 7.88 (1H, d, J=2.0Hz), 12.55 (1H, br).

実施例３４４

収率：82％,¹H-NMR(DMSO-d₆): δ1.20-1.39 (2H, m), 1.68-1.92 (5H, m), 3.10-3.26 (2H,m), 3.08-4.08 (2H, m), 4.12 (2H, t, J=6.0Hz), 7.03 (2H, d, J=9.0Hz), 7.27 (1H, dd, J=8.5, 2.0Hz), 7.40 (1H, d, J=8.5Hz), 7.88 (1H, d, J=2.0Hz), 7.88 (2H, d, J=9.0Hz), 12.62 (1H, br).

実施例３４５

収率：75％, ¹H-NMR(DMSO-d₆): δ1.22-1.40 (2H,m), 1.70-1.92 (5H, m), 2.21 (3H, s), 3.12-3.24 (2H, m), 3.96-4.08 (2H, m), 4.09 (2H, t, J=6.0Hz), 7.25 (1H, d, J=8.0Hz), 7.27 (1H, dd, J=8.5, 2.0Hz), 7.40 (1H, d, J=8.5Hz),7.43(2H,m),7.88(1H,d, J=2.0Hz).

実施例３４６

収率：78％, ¹H-NMR(DMSO-d₆): δ1.18-1.38 (2H, m), 1.64-1.91 (5H, m), 3.11-3.24 (2H, m), 3.52 (2H, s), 3.96-4.07 (4H, m), 6.78-6.87 (3H, m), 7.21 (1H, t, J=7.5Hz), 7.27 (1H,dd,J=8.5,2.0Hz),7.40(1H, d, J=8.5Hz), 7.88 (1H, d, J=2.0Hz), 12.31 (1H, brs).

実施例３４７

収率：84％,¹H-NMR(DMSO-d₆): δ1.19-1.39(2H, m), 1.64-1.92(5H,m), 3.09-3.28 (2H, m), 3.47 (2H, s), 3.95-4.10 (4H, m), 6.80 (2H, d, J=8.5Hz), 7.15 (2H, d, J=8.5Hz) ,7.27 (1H, dd, J=8.5, 2.0Hz), 7.40 (1H, d, J=8.5Hz), 7.88 (1H, d, J=2.0Hz).

実施例３４８

収率：35％, ¹H-NMR(CDCl₃); δ1.18-1.37 (2H,m), 1.68-1.91 (5H,m),2.77 (2H,t,J=7.5Hz), 3.09-3.43(4H, m), 3.94-4.06 (4H, m), 6.71-6.83 (3H, m), 7.16 (1H, t, J=8.0Hz), 7.27 (1H, dd, J=8.5, 2.0Hz), 7.40 (1H, d, J=8.5Hz), 7.88 (1H, d, J=2.0Hz).

実施例３４９

収率：27％, ¹H-NMR(DMSO-d₆): δ1.18-1.42 (2H, m), 1.68-1.94 (5H, m), 2.47 (2H, t, J=7.5Hz), 2.80 (2H, t, J=7.5Hz), 3.10-3.23 (2H, m), 3.96-4.10 (4H, m), 6.84 (1H, t, J=7.5Hz), 6.96 (1H, d, J=7.5Hz), 7.12-7.21 (2H, m), 7.27 (1H, dd, J=8.5, 2.0Hz), 7.40 (1H, d, J=8.5Hz), 7.88 (1H, d, J=2.0Hz), 12.09 (1H, s).

実施例３５０

収率：27％, ¹H-NMR(DMSO-d₆): δ1.14-1.31 (2H, m),1.50-1.61(2H,m),1.64-1.86(3H, m), 2.96-3.22 (4H, m), 3.93-4.03 (2H, m), 7.23-7.36 (3H, m), 7.39 (1H, d, J=8.5Hz), 7.67 (1H, d, J=7.0Hz), 7.81 (1H, s), 7.88 (1H, d, J=2.0Hz).

実施例３５１

収率：72％, ¹H-NMR(DMSO-d₆): δ1.12-1.32 (2H, m), 1.50-1.63 (2H, m), 1.64-1.87 (3H, m), 2.95-3.06 (2H, m), 3.07-3.22 (2H, m), 3.55 (2H, s), 3.92-4.08 (2H, m), 4.05 (1H, d, J=2.0Hz), 7.17-7.31 (4H, m), 7.39 (1H,d,J=8.5Hz), 7.87 (1H, d, J=7.5Hz), 12.36 (1H, brs).

実施例３５２

収率：65％, ¹H-NMR(CDCl₃); δ1.33 (2H, m), 1.73-1.90 (5H, m), 2.31 (3H, s), 3.14 (2H, t, J=12.6Hz), 3.58 (2H, s), 4.01 (2H, t, J=5.7 Hz),4.11(2H,d,J =14.1Hz), 6.65 (2H, s), 6.70 (1H, s), 7.23 (1H, dd, J=8.4, 2.1Hz), 7.43 (1H, d, J=8.4Hz), 7.54 (1H, d, J=2.1Hz)

実施例３５３

収率：90％, ¹H-NMR(DMSO-d₆): δ1.23-1.36 (2H, m), 1.72-1.87 (5H, m), 2.07 (3H, s), 3.15-3.23 (2H, m), 3.56 (2H, s), 4.01 (4H, t, J=5.7Hz), 6.77 (1H, d, J=8.1Hz), 6.87 (1H, d, J=8.1Hz), 7.07 (1H, t, J=8.1Hz), 7.28 (1H, dd, J=8.7, 2.1Hz), 7.40 (1H, d, J=8.7 Hz), 7.89 (1H, d, J=2.1Hz).

実施例３５４

収率：65％, ¹H-NMR(DMSO-d₆): δ1.20-1.35 (1H, m), 1.65-1.90 (6H, m), 3.10-3.25 (2H, m), 3.54 (2H, s), 3.95-4.15 (4H, m), 6.75-6.85 (1H, m), 7.10 (1H, dd, J=8, 3.5Hz), 7.14 (1H, d, J=8Hz), 7.24 (1H, dd, J=8.5, 2Hz), 7.40 (1H, d, J=8.5Hz), 7.88 (1H, d, J=2Hz), 12.34 (1H, brs).

実施例３５５

収率：36％, ¹H-NMR(DMSO-d₆): δ1.20-1.39 (2H,m),1.66-1.93(5H,m),3.08-3.23 (2H, m), 3.40 (2H, s), 3.94-4.13 (4H, m), 6.76-6.84 (1H, m), 7.06 (1H, s), 7.23-7.32 (2H, m), 7.36-7.43 (1H, m), 7.87 (1H, d, J=2.0Hz).

実施例３５６

収率：59％, ¹H-NMR(DMSO-d₆): δ1.17-1.37 (2H, m), 1.62-1.91 (5H, m), 3.09-3.25 (2H, m), 3.34(2H, s), 3.92-4.07 (4H, m), 6.75 (1H, dd, J=8.5, 3.0Hz), 6.92 (1H, d, J=3.0Hz), 7.21 (1H, d, J=8.5Hz), 7.27 (1H, dd, J=8.5, 2.0Hz), 7.40 (1H, d, J=8.5Hz), 7.88 (1H, d, J=2.0Hz).

実施例３５７

収率：63％, ¹H-NMR(DMSO-d₆): δ2.69 (4H, t, J=4.5Hz), 2.80 (2H, t, J=5.5Hz), 3.56 (4H, t, J=4.5Hz), 4.22 (2H,t,J=5.5Hz),7.01(1H, t, J=7.5Hz), 7.16 (1H, d, J=7.5Hz), 7.29 (1H, dd, J=8.5, 2.0Hz), 7.43 (1H, d, J=8.5Hz), 7.48 (1H, t, J=7.5Hz), 7.61 (1H, d, J=7.5Hz), 7.91 (1H, d, J=2.0Hz).

実施例３５８

収率：31％, ¹H-NMR(DMSO-d₆): δ2.65 (4H, t, J=5.0Hz), 2.80 (2H, t, J=5.5Hz), 3.57 (4H, t, J=5.0Hz), 4.15(2H, t, J=5.5Hz), 7.10 (1H, d, J=8.0Hz), 7.27-7.36 (2H, m), 7.41-7.52 (3H, m), 7.91 (1H, d, J=2.2Hz).

実施例３５９

収率：50％, ¹H-NMR(DMSO-d₆):δ2.64 (4H, t, J=5.0Hz), 2.80 (2H, t, J=5.5Hz), 3.57 (4H, t, J=5.0Hz), 4.20 (2H, t, J=5.5Hz), 7.03 (2H,d,J=9Hz), 7.29 (1H, dd, J=8.5, 2.0Hz), 7.42 ( 1H, d, J=8.5Hz), 7.87 (2H, d, J=9.0Hz), 7.91 (1H, d, J=2.0Hz).

実施例３６０

収率：29％, ¹H-NMR(DMSO-d₆): δ1.18-1.36 (2H, m),1.68-1.88 (5H, m), 3.00-3.25 (2H, m), 3.94-4.07 (2H,m ), 4.20 (2H, t, J=6.0Hz), 6.41(1H, d, J=4.0Hz), 7.27(1H, dd, J=8.5, 2.0Hz), 7.40 (1H, d, J=8.5Hz), 7.44 (1H, d, J=4.0Hz), 7.88 (1H, d, J=2.0Hz).

実施例３６１

収率：64％, ¹H-NMR(DMSO-d₆): δ2.13 (3H, s), 2.68 (4H, t, J=5Hz), 2.82 (2H, t, J=5.5Hz), 3.47 (2H, s), 3.63 (4H, t, J=5Hz), 4.10(2H, t, J=5.5Hz), 6.72 (1H, d, J=8Hz), 6.86 (1H, s), 7.05(1H, d, J=7.5Hz), 7.57 (2H, s), 8.25 (1H, s), 12.50 (1H, brs).

実施例３６２

収率：25％, ¹H-NMR(DMSO-d₆): δ1.88-1.94 (2H, m), 2.73-2.75(2H,m),2.87 (2H, t, J=5.1Hz), 2.92-2.95 (2H, m), 3.25 (2H, s), 3.67-3.72 (4H, m), 4.01 (2H, t, J=5.7Hz), 6.68-6.82 (3H, m), 7.10 (1H, t, J=7.5Hz), 7.26 (1H, dd, J= 8.7, 2.1Hz), 7.40 (1H, d, J=8.7Hz), 7.88 (1H, d, J=2.1Hz).

実施例３６３

収率：68％, ¹H-NMR(DMSO-d₆): δ1.85-1.95 (2H, m), 2.09 (3H, s), 2.75-2.82 (2H, m), 2.92 (2H, t, J=5.5Hz), 2.95-3.02 (2H, m), 3.49 (2H, s), 3.60-3.75 (4H, m), 4.03 (2H, t, J=5.5Hz), 6.71 (1H, d, J=7.5Hz), 6.83 (1H, s), 7.03 (1H, d, J=7.5Hz), 7.26 (1H, dd, J=8.5, 2Hz), 7.39 (1H, d, J=8.5Hz), 7.87 (1H, d, J=2Hz), 12.37 (1H, brs).

実施例３６４

収率：67％, ¹H-NMR(DMSO-d₆): δ1.85-1.95 (2H, m), 2.75-2.85 (2H, m), 2.93 (2H, t, J=5.5Hz), 2.95-3.05 (2H, m), 3.55 (2H, s), 3.60-3.80 (4H, m), 4.12 (2H, t, J=5.5Hz), , 6.83 (1H, dd, J=8, 1.5Hz), 7.07(1H, d, J=1.5Hz), 7.25 (1H, dd, J=8.5, 2Hz), 7.33 (1H, d, J=8Hz), 7.39 (1H, d, J=8.5Hz), 7.87 (1H, d, J=2Hz), 12.37 (1H, brs).

実施例３６５

収率：45％, ¹H-NMR(DMSO-d₆): δ1.20-1.39 (2H, m), 1.65-1.94 (5H, m), 3.17-3.32 (2H, m), 3.99-4.12 (4H, m), 6.92-6.99 (1H, m), 7.23 (1H, t, J=7.5Hz), 7.40-7.48 (2H, m), 7.51-7.59 (2H, m), 8.21 (1H, s).

実施例３６６

収率：48％, ¹H-NMR(DMSO-d₆): δ1.18-1.38 (2H, m), 1.63-1.94 (5H, m), 3.13-3.30 (2H, m), 3.32 (2H, s), 3.93-4.13 (4H,m), 6.70-6.85 (3H, m), 7.13 (1H, t, J=8.0Hz), 7.49-7.60 (2H, m), 8.21 (1H, s).

実施例３６７

収率：82％, ¹H-NMR(DMSO-d₆): δ1.17-1.42 (2H,m), 1.68-1.96 (5H, m), 3.13-3.30 (2H, m), 3.43(2H, s), 3.95-4.19 (4H, m), 6.81 (1H, d, J=7.5Hz), 7.07 (1H, s), 7.28 (1H, d, J=7.5Hz), 7.49-7.61 (2H, m), 8.21 (1H, s).

実施例３６８

収率：77％, ¹H-NMR(DMSO-d₆): δ1.85-2.00 (2H, m), 2.68-2.81 (2H, m), 2.82-3.03 (4H, m), 3.51 (2H, s), 3.60-3.89 (4H, m), 3.97-4.09 (2H, m), 6.75-6.90 (3H, m), 7.19 (1H, t, J=8.0Hz), 7.50-7.60 (2H, m), 8.22 (1H, s), 12.26 (1H, br).

実施例３６９

収率：78％, ¹H-NMR(DMSO-d₆): δ1.84-1.98 (2H, m), 2.74-2.85 (2H, m), 2.86-3.07 (4H, m), 3.56 (2H, s), 3.60-3.85 (4H, m), 4.06-4.18 (2H, m), 6.83 (1H, dd, J=8.0, 2.0Hz), 7.07 (1H, d, J=2.0Hz), 7.33 (1H, d, J=8.0Hz), 7.51-7.57 (2H, m), 8.22 (1H, s), 12.35 (1H, br).

実施例３７０

収率：68％, ¹H-NMR(CDCl₃); δ1.19-1.39 (2H,m),1.64-1.92(5H,m),3.12-3.27 (2H, m), 3.96-4.08(4H,m),6.80-6.87(1H,m),7.06(1H, dd, J=8.0, 2.0Hz), 7.15 (1H, t, J=8.0Hz), 7.38-7.47 (3H, m), 7.76 (1H, d, J=8.0Hz).

実施例３７１

収率：87％, ¹H-NMR(DMSO-d₆): δ1.19-1.40 (2H,m),1.63-1.92(5H,m),3.10-3.27 (2H, m), 3.51 (2H, s), 3.94-4.10 (4H, m), 6.77-6.86 (3H, m), 7.07 (1H, dd, J=8.5, 2.0Hz), 7.20 (1H, t, J=7.5Hz), 7.44 (1H, d, J=2.0Hz), 7.76 (1H, d, J=8.5Hz), 12.33 (1H, br).

実施例３７２

収率：36％, ¹H-NMR(DMSO-d₆): δ1.20-1.39 (2H, m), 1.63-1.93 (5H, m), 3.12-3.28 (2H, m),3.53 (2H,s),3.95-4.12 (4H, m), 6.78-6.88 (3H, m), 7.13 (1H, dd, J=8.0, 1.0Hz), 7.20 (1H, t, J=7.5Hz), 7.31 (1H, d, J=8.0Hz), 7.39 (1H, dd, J=8.0, 1.0Hz), 12.31 (1H, s).

実施例３７３

収率：89％, ¹H-NMR(DMSO-d₆): δ1.19-1.39 (2H, m), 1.65-1.93 (5H, m), 3.10-3.25 (2H, m), 3.96-4.09 (4H, m), 6.87-6.94 (1H, m), 7.20 (1H, t, J=8.0Hz), 7.31-7.48 (4H, m), 8.00 (1H, d, J=2.0Hz).

実施例３７４

収率：58％, ¹H-NMR(DMSO-d₆): δ1.18-1.37 (2H, m), 1.63-1.91 (5H, m), 3.10-3.26 (4H, m), 3.92-4.07 (4H, m), 6.63-6.84 (3H, m), 7.08 (1H, t, J=8.0Hz), 7.31-7.42 (2H, m), 7.99 (1H, d, J=2.0Hz).

実施例３７５

収率：46％, ¹H-NMR(DMSO-d₆): δ1.18-1.36 (2H, m), 1.61-1.90 (5H, m), 2.32 (3H, s), 3.04-3.19 (2H, m), 3.39 (2H, s), 3.91-4.07 (4H, m), 6.72-6.86 (3H, m), 7.06 (1H, d, J=8.5Hz), 7.16 (1H, t, J=8.0Hz), 7.31 (1H, d, J=8.5Hz), 7.53 (1H, s).

実施例３７６

収率：83％, ¹H-NMR(DMSO-d₆): δ1.18-1.39 (2H,m),1.63-1.92(5H,m),3.07-3.24 (2H, m), 3.52 (2H, s), 3.93-4.09 (4H, m), 6.77-6.78 (3H,m),7.10(1H,td,J=9.0, 2.5Hz), 7.21 (1H, t, J=8.0Hz), 7.41 (1H, dd, J=9.0, 4.5Hz), 7.69 (1H, dd, J=9.0, 2.5Hz), 12.34 (1H, br).

実施例３７７

収率：51％, ¹H-NMR(DMSO-d₆): δ1.18-1.35 (2H, m), 1.63-1.93 (5H, m), 3.09-3.26 (2H, m), 3.52 (2H,s), 3.95-4.13 (4H, m), 6.77-6.90 (3H, m), 7.20 (1H, t, J=8.0Hz), 7.31 (1H,t,J=8.0Hz),7.43 (2H, t, J=8.0Hz), 7.48 (1H, d, J=8.5Hz),7.57 (1H,d,J=8.5Hz), 7.66 (2H,d,J=8.0Hz), 8.07 (1H, s),12.31(1H,br).

実施例３７８

収率：77％, ¹H-NMR(DMSO-d₆): δ1.19-1.40 (2H,m),1.64-1.91(5H,m),2.98-3.14 (2H, m), 3.53 (2H, s), 3.86-4.10 (4H, m), 6.78-6.90 (3H, m), 7.16-7.26 (2H, m), 7.31-7.34 (2H, m), 7.44-7.50 (2H, m),7.58 (1H, s), 12.30 (1H, s).

実施例３７９

収率：76％, ¹H-NMR(DMSO-d₆): δ1.22-1.41 (2H,m),1.68-1.90(5H,m),2.97-3.13 (2H, m), 3.56(2H,s),3.86-3.99(2H,m), 4.06-4.16 (2H, m), 6.84 (1H, dd, J=8.0, 1.5Hz), 7.09 (1H, d,J=1.5Hz),7.20(1H, t, J=7.5Hz), 7.31-7.41 (3H, m), 7.43-7.51 (2H, m), 7.58 (1H, s).

実施例３８０

収率：69％, 1H-NMR(DMSO-d6): δ1.83-1.95 (2H, m), 2.73-2.83 (2H, m), 2.87-3.00 (4H, m), 3.52-3.71 (6H, m), 4.12 (2H, m), 6.83 (1H, d, J=7.0Hz), 7.08 (1H, s), 7.18 (1H, t, J=7.5Hz), 7.28-7.38 (3H, m), 7.40-7.47 (2H, m), 7.56 (1H, s).

実施例３８１

収率：79％, 1H-NMR(DMSO-d6): δ1.20-1.41 (2H, m),1.65-1.93 (5H, m), 3.05 (2H, m), 3.53 (2H, s), 3.90-4.10 (4H, m), 6.76-6.87 (3H, m), 7.16-7.32 (3H, m), 7.38 (2H, t, J=7.5Hz), 7.85 (2H, d, J=7.5Hz), 12.29 (1H, s).

実施例３８２

収率：54％, 1H-NMR(CDCl3): 1.88-2.03 (2H, m), 2.73-3.04 (6H, m), 3.30 (2H, s), 3.47-3.84 (4H, m), 3.86-4.02 (2H, m), 6.59 (1H, d, J=8.0Hz), 6.68 (1H, s), 7.07 (1H, d, J=8.0Hz), 7.20 (1H, d, J=11.5Hz), 7.68 (1H, d, J=7.0Hz).

実施例３８３

収率12％, ¹H-NMR(DMSO-d₆): δ2.25 (3H, s), 2.45-2.55 (4H, m), 3.44 (2H, s), 3.50-3.60 (4H, m), 4.47 (2H, s), 6.59 (1H, s), 6.65 (1H, s),7.00(1H,s),7.28(1H,dd, J=8.5, 2Hz), 7.42 (1H, d, J=8.5Hz), 7.90 (1H, d, J=2Hz).

実施例３８４

収率68％, ¹H-NMR(CDCl₃); δ1.60 (6H, s), 2.23 (3H, s), 2.65 (4H, t, J=5Hz), 3.57 (2H, s),3.62(4H, t, J=5Hz), 6.19 (1H, brs), 6.70-6.88 (3H, m), 7.24 (1H, dd, J=8.5, 2Hz), 7.42 (1H, d, J=8.5Hz), 7.54 (1H, d, J=2Hz).

実施例３８５

収率64％, ¹H-NMR(DMSO-d₆): δ2.24 (3H, s), 2.51 (4H, t, J=5.5Hz), 3.43 (2H, s), 3.62 (4H,t,J=5.5Hz),4.10(2H,s),6.53(1H,s), 6.61 (1H,s),6.64(1H,s),7.57 (2H, s), 8.24 (1H, s).

実施例３８６

収率96％, ¹H-NMR(DMSO-d₆): δ1.89-1.97 (2H, m), 2.23 (3H, s), 2.60 (2H, t, J=4.2Hz), 2.74-2.77 (2H, m), 3.55 (2H, s), 3.68-3.70 (4H, m), 4.56 (2H, s), 6.58 (1H, s), 6.65 (1H, s), 6.70 (1H, s), 7.26 (1H, dd, J=9.0, 2.1Hz), 7.39 (1H, d, J=8.7Hz), 7.86 (1H, d, J=2.4Hz).

実施例３８７

収率98％, ¹H-NMR(DMSO-d₆): δ1.85-2.00 (2H, m), 2.20 (3H, s), 2.55-2.65 (2H, m), 2.70-2.83 (2H, m), 3.52 (2H, s), 3.55-3.85 (4H, m), 4.14 (2H, s), 6.52 (1H, s), 6.58-6.65 (2H, m), 7.55 (2H, s), 8.22 (1H, s).

実施例３８８

収率59％, 1H-NMR(CD3OD): δ2.29 (3H, s), 2.60 (4H, t, J=5.0Hz), 3.46-3.57 (6H, m), 4.36 (2H, s), 6.69 (1H, s), 6.75 (2H, s), 7.21 (1H, t, J=7.5Hz), 7.33 (2H, t, J=7.5Hz), 7.41 (1H, s), 7.45 (2H, d, J=7.5Hz).

実施例３８９

収率67％, 1H-NMR(CD3OD): δ1.98-2.12 (2H, m), 2.27 (3H, s), 2.70-2.81 (2H, m), 2.84-2.94 (2H, m), 3.65 (2H, s), 3.67-3.93 (4H, m), 4.39 (2H, s), 6.67 (1H, s), 6.73 (1H, s), 6.74 (1H, s), 7.27 (1H, d, J=12.0Hz), 7.96 (1H, d, J=7.0Hz).

実施例３９０

収率97％, 1H-NMR(DMSO-d6): δ1.15 (3H, d, J=6Hz), 2.18-2.33 (1H, m), 2.58-2.70 (1H, m), 2.70-2.83 (1H, m), 3.15-3.30 (2H, m), 3.35-3.50 (1H, m), 3.65-3.80 (1H, m), 3.83 (1H, d, J=11Hz), 3.93 (1H, d, J=14Hz), 4.65 (2H, s), 6.78 (1H, d, J=8Hz), 6.90-6.95 (2H, m), 7.24 (1H, t, J=8Hz), 7.56 (2H, s), 8.24 (1H, s), 13.0 (1H, brs).

実施例３９１

収率86％, 1H-NMR(DMSO-d6): δ1.13 (3H, d, J=6Hz), 2.17 (3H, s), 2.20-2.30 (1H, m), 2.55-2.65 (1H, m), 2.68-2.80 (1H, m), 3.15-3.50 (3H, m), 3.65-3.75 (1H, m), 3.82 (1H, d, J=9Hz), 3.88 (1H, d, J=13.5Hz), 4.68 (2H, s), 6.80 (1H, s), 6.83 (1H, d, J=7.5Hz), 7.09 (1H, d, J=7.5Hz), 7.56 (2H, s), 8.23 (1H, s), 12.30 (1H, brs).

実施例３９２

収率86％, 1H-NMR(DMSO-d6): δ1.14 (3H, d, J=6Hz), 2.20-2.25 (1H, m), 2.26 (3H, s), 2.55-2.65 (1H, m), 2.70-2.80 (1H, m), 3.10-3.50 (3H, m), 3.70-3.82 (3H, m), 4.63 (2H, s), 6.61 (1H, s), 6.70 (1H, s), 6.75 (1H, s), 7.55-7.59 (2H, m), 8.24 (1H, s), 12.9 (1H, brs).

実施例３９３

収率73％, 1H-NMR(DMSO-d6): δ1.03 (6H, d, J=6Hz), 2.25 (3H, s), 2.60-2.80 (2H, m), 2.95-3.10 (2H, m), 3.71 (2H, s), 3.80-3.85 (2H, m), 4.61 (2H, s), 6.55 (1H, s), 6.76 (2H, s), 7.28 (1H, dd, J=8.5, 2Hz), 7.42 (1H, d, J=8.5Hz), 7.90 (1H, d, J=2Hz), 12.95 (1H, s).

実施例３９４

収率82％, 1H-NMR(DMSO-d6): δ1.04 (6H, d, J=6Hz), 2.25 (3H, s), 2.70-2.80 (2H, m), 2.95-3.15 (2H, m), 3.71 (2H, s), 3.80-3.95 (2H, m), 4.61 (2H, s), 6.55 (1H, s), 6.76 (2H, s), 7.57 (2H, s), 8.24 (1H, s), 12.94 (1H, brs).

実施例３９５

収率72％, 1H-NMR(DMSO-d6): δ1.31 (3H, d, J=6.5Hz), 2.02-2.24 (2H, m), 2.25 (3H, s), 2.70 (1H, d, J=11Hz), 2.88 (1H, d, J=12Hz), 3.20-3.35 (1H, m), 3.37 (1H, d, J=13.5Hz), 3.51 (1H, d, J=13.5Hz), 3.77 (1H, d, J=13Hz), 4.10-4.25 (1H, m), 4.60 (2H, s), 6.61 (1H, s), 6.70 (1H, s), 6.73 (1H, s), 7.26 (1H, dd, J=8.5, 2Hz), 7.40 (1H, d, J=8.5Hz), 7.88 (1H, d, J=2Hz), 13.00 (1H, brs).

実施例３９６

収率76％, 1H-NMR(DMSO-d6): δ1.34 (3H, d, J=6.5Hz), 2.06-2.30 (5H, m), 2.73 (1H, d, J=10.5Hz), 2.90 (1H, d, J=10.5Hz), 3.30-3.56 (3H, m), 3.84 (1H, d, J=11.5Hz), 4.19-4.32 (1H, m), 4.38 (2H, s), 6.58 (1H, s), 6.67 (1H, s), 6.70 (1H, s), 7.56 (2H, s), 8.24 (1H, s).

実施例３９７

収率82％, 1H-NMR(CDCl3): δ0.97 (3H, t, J=7.5Hz), 1.62-1.85 (2H, m), 2.28 (3H, s), 2.80-3.00 (3H, m), 3.55 (1H, d, J=13Hz), 3.65-3.77 (1H, m), 3.77-3.90 (3H, m), 4.23 (1H, d, J=13Hz), 4.65 (2H, s), 6.63 (1H, s), 6.80 (1H, s), 7.01 (1H, s), 7.53 (1H, d, J=8.5Hz), 7.56 (1H, d, J=8.5Hz), 7.84 (1H, s).

実施例３９８

収率92％, 1H-NMR(CDCl3): δ2.27 (3H, s), 2.27-2.40 (1H, m), 2.90 (1H, d, J=13.5Hz), 3.06 (1H, d, J=11.5Hz), 3.32-3.55 (3H, m), 3.80 (1H, d, J=13.5Hz), 3.95-4.10 (2H, m), 5.30 (2H, s), 6.63 (1H, s), 6.66 (1H, s), 6.72 (1H, s), 7.30-7.45 (3H, m), 7.45-7.60 (4H, m), 7.82 (1H, s).

実施例３９９

収率81％, 1H-NMR(CDCl3): δ1.32 (3 H, d, J = 6.6 Hz), 2.26 (3 H, s), 2.76 (1 H, s), 2.93-3.02 (2 H, m), 3.37 (1 H, d, J = 12.9 Hz), 3.49-3.56 (1 H, m), 3.70 (2 H s), 3.87 (1 H, d, J = 10.8 Hz), 4.25 (1 H, d, J = 12.9 Hz), 4.63 (2 H, s), 6.62 (1 H, s), 6.77 (1 H, s), 6.99 (1 H, s), 7.24 (1 H, dd, J = 2.1, 8.7 Hz), 7.42 (1 H, d, J = 8.7 Hz), 7.54 (1 H, d, J = 2.1 Hz)

実施例４００

収率80％, 1H-NMR(CDCl3): δ1.33 (3 H, d, J = 6.0 Hz), 2.27 (3 H, s), 2.76 (1 H, br), 2.93-3.02 (2 H, m), 3.38 (1 H, d, J = 12.6 Hz), 3.49-3.56 (1 H, m), 3.71 (2 H, s), 3.87 (1 H, d, J = 11.1 Hz), 4.25 (1 H, d, J = 12.6 Hz), 4.63 (2 H, s), 6.62 (1 H, s), 6.77 (1 H, s), 6.99 (1 H, s), 7.24 (1 H, dd, J = 1.8, 8.7 Hz), 7.42 (1 H, d, J = 8.7 Hz), 7.54 (1 H, d, J = 1.8 Hz)

実施例４０１

収率88％, 1H-NMR(CDCl3): δ1.41 (3H, d, J=6.5Hz), 2.29 (3H, s), 2.35 (1H, td, J=12, 3.5Hz), 2.48 (1H, dd, J=12, 4Hz), 2.91 (1H, d, J=12Hz), 3.26 (1H, d, J=11.5Hz), 3.52 (1H, d, J=13Hz), 3.54-3.65 (1H, m), 3.80 (1H, d, J=13Hz), 3.89 (1H, d, J=13Hz), 4.25-4.36 (1H, m), 4.62 (2H, s), 6.69 (1H, s), 6.75 (1H, s), 6.86 (1H, s), 7.52 (1H, d, J=8.5Hz), 7.56 (1H, d, J=8.5Hz), 7.83 (1H, s).

実施例４０２

収率94％, 1H-NMR(CDCl3): δ0.96 (3H, t, J=7Hz), 1.60-1.86 (2H, m), 2.29 (3H, s), 2.75-2.86 (1H, m), 2.87-3.00 (1H, m), 3.00-3.10 (1H, m), 3.51 (1H, d, J=13Hz), 3.65-3.80 (1H, m), 3.80-3.93 (3H, m), 4.28 (1H, d, J=13Hz), 4.63 (1H, d, J=16.5Hz), 4.71 (1H, d, J=16.5Hz) 6.63 (1H, s), 6.81 (1H, s), 7.02 (1H, s), 7.53 (1H, d, J=8.5Hz), 7.57 (1H, d, J=8.5Hz), 7.84 (1H, s).

実施例４０３

収率86％, 1H-NMR(CDCl3): δ0.96 (3H, t, J=7.5Hz), 1.62-1.86 (2H, m), 2.28 (3H, s), 2.76-2.88 (1H, m), 2.89-3.00 (1H, m), 3.01-3.13 (1H, m), 3.52 (1H, d, J=13Hz), 3.65-3.93 (4H, m), 4.30 (1H, d, J=13Hz), 4.63 (1H, d, J=16.5Hz), 4.72 (1H, d, J=16.5Hz), 6.63 (1H, s), 6.82 (1H, s), 7.03 (1H, s), 7.49-7.60 (2H, m), 7.84 (1H, s).

実施例４０４

収率68％, 1H-NMR(DMSO-d6): δ0.89 (3H, t, J=7.0Hz), 1.22-1.69 (4H, m), 2.22-2.37 (1H, m), 2.24 (3H, s), 2.49-2.62 (1H, m), 2.68-2.82 (1H, m), 3.28 (1H, d, J=13.5Hz), 3.38-3.68 (3H, m), 3.69-3.80 (1H, m), 3.83 (1H, d, J=13.5Hz), 4.28 (2H, s), 6.53 (1H, s), 6.64 (1H, s), 6.67 (1H, s), 7.53 (1H, d, J=8.5Hz), 7.57 (1H, d, J=8.5Hz), 8.22 (1H, s).

実施例４０５

収率87％, 1H-NMR(CDCl3): δ0.90 (3 H, t, J = 7.2 Hz), 1.19-1.28 (1 H, m), 1.45-1.52 (1 H, m), 1.65 (2 H, br), 2.78 (3 H, s), 2.93 (2 H, br), 3.05 (1 H, br), 3.52 (1 H, d, J = 12.6 Hz), 3.67-3.74 (1 H, m), 3.81-3.91 (3 H, m), 4.30 (1 H, d), 4.66 (2 H, q, J = 11.1 Hz), 6.62 (1 H, s), 6.81 (1 H, s), 7.03 (1 H, s), 7.52-7.61 (2 H, m), 7.84 (1 H, s)

実施例４０６

収率82％, 1H-NMR(DMSO-d6): δ0.88 (3H, t, J=6.5Hz), 1.18-1.70 (6H, m), 2.23 (3H, s), 2.24-2.37 (1H, m), 2.48-2.60 (1H, m), 2.67-2.80 (1H, m), 3.27 (1H, d, J=13.5Hz), 3.36-3.82 (4H, m), 3.83 (1H, d, J=13.5Hz), 4.31 (2H, s), 6.54 (1H, s), 6.65 (1H, s), 6.67 (1H, s), 7.53 (1H, d, J=9.0Hz), 7.56 (1H, d, J=9.0Hz), 8.22 (1H, s).

実施例４０７

収率70％, 1H-NMR(DMSO-d6): δ0.88 (6H, t, J=6.5Hz), 1.21-1.35 (1H, m), 1.45-1.58 (1H, m), 1.58-1.73 (1H, m), 2.23 (3H, s), 2.32-2.43 (1H, m), 2.59-2.80 (2H, m), 3.35 (1H, d, J=13.5Hz), 3.37-3.45 (1H, m), 3.45-3.60 (2H, m), 3.60-3.71 (1H, m), 3.77 (1H, d, J=13.5Hz), 4.19 (2H, s), 6.51 (1H, s), 6.63 (1H, s), 6.66 (1H, s), 7.27 (1H, dd, J=8.5, 2Hz), 7.40 (1H, d, J=8.5Hz), 7.88 (1H, d, J=2Hz).

実施例４０８

収率77％, 1H-NMR(DMSO-d6): δ0.87 (3H, d, J=6.5Hz), 0.89 (3H, d, J=6.5Hz), 1.21-1.36 (1H, m), 1.43-1.57 (1H, m), 1.58-1.73 (1H, m), 2.23 (3H, s), 2.30-2.43 (1H, m), 2.60-2.79 (2H, m), 3.34 (1H, d, J=13.5Hz), 3.35-3.72 (4H, m), 3.77 (1H, d, J=13.5Hz), 4.25 (2H, s), 6.53 (1H, s), 6.64 (1H, s), 6.70 (1H, s), 7.27 (1H, dd, J=8.5, 2.0Hz), 7.40 (1H, d, J=8.5Hz), 7.88 (1H, d, J=2.0Hz).

実施例４０９

収率76％, 1H-NMR(CDCl3): δ0.77 (3H, d, J=6.5Hz), 0.92 (3H, d, J=6.5Hz), 1.40-1.75 (3H, m), 2.25 (3H, s), 2.80-3.05 (3H, m), 3.46 (1H, d, J=13Hz), 3.60-3.95 (4H, m), 4.22 (1H, d, J=13Hz), 4.56 (1H, d, J=16Hz), 4.65 (1H, d, J=16Hz), 6.63 (1H, s), 6.77 (1H, s), 7.01 (1H, s), 7.52 (1H, d, J=8.5Hz), 7.59 (1H, d, J=8.5Hz), 7.83 (1H, s).

実施例４１０

収率79％, 1H-NMR(CDCl3): δ1.33 (3H, d, J=6.5Hz), 2.28 (3H, s), 2.70-2.83 (1H, m), 2.92-3.08 (2H, m), 3.38 (1H, d, J=13Hz), 3.54-3.65 (1H, m), 3.70-3.82 (2H, m), 3.87-3.97 (1H, m), 4.25 (1H, d, J=13Hz), 4.60 (1H, d, J=16.5Hz), 4.67 (1H, d, J=16.5Hz), 6.64 (1H, s), 6.78 (1H, s), 6.99 (1H, s), 7.26 (1H, d, J=11.5Hz), 7.74 (1H, d, J=7Hz).

実施例４１１

収率93％, 1H-NMR(CDCl3): δ0.92 (3H, t, J=7.0Hz), 1.42-1.74 (2H, m), 2.13 (3H, s), 2.27-2.57 (2H, m), 2.62-2.82 (1H, m), 3.08-3.24 (1H, m), 3.35-3.77 (4H, m), 3.80-3.97 (1H, m), 4.37 (2H, s), 6.58 (1H, s), 6.63 (1H, s), 6.74 (1H, s), 7.20 (1H, d, J=11.5Hz), 7.66 (1H, d, J=7.0Hz).

実施例４１２

収率80％, 1H-NMR(CDCl3): δ1.18 (6H, d, J=6.0Hz), 2.25 (3H, s), 2.78-2.94 (2H, m), 3.13-3.29 (2H, m), 3.78-3.94 (4H, m), 4.54 (2H, s), 6.61 (1H, s), 6.74 (1H, s), 6.80 (1H, s), 7.24 (1H, d, J=11.5Hz), 7.72 (1H, d, J=7.0Hz).

実施例４１３

収率82％, ¹H-NMR(DMSO-d₆): δ3.52 (2H, s), 3.57 (8H, s), 4.65 (2H, s), 6.87 (2H, s), 6.98(1H,s), 7.29 (1H,d,J = 8.7,2.4 Hz), 7.42 (1H,dd,J = 8.7 Hz),7.91 (1H, d, J = 2.4 Hz)

実施例４１４

収率83％, ¹H-NMR(DMSO-d₆): δ2.40-2.55 (4H, m), 3.46 (2H, s), 3.53-3.56 (4H, m), 4.55 (2H, s), 6.85 (2H, d, J = 8.4 Hz), 7.22 (2H, d, J = 8.4 Hz), 7.28 (1H, dd, J = 8.4, 2.4 Hz), 7.42 (1H, d, J = 8.4 Hz), 7.90 (1H, d, J = 2.4 Hz).

実施例４１５

収率51％, ¹H-NMR(DMSO-d₆): δ2.16 (3H, s), 2.40-2.55 (4H, m), 3.47 (2H, s), 3.50-3.60 (4H, m), 4.67 (2H, s), 6.75-6.85 (2H, m), 7.08 (1H, d, J=7.5Hz), 7.27 (1H, dd, J=8.5, 1Hz), 7.41 (1H, d, J=8Hz), 7.88 (1H, d, J=2Hz), 12.9 (1H, brs).

実施例４１６

収率92％, ¹H-NMR(DMSO-d₆): δ2.19 (3H, s), 2.50-2.55 (4H, m), 3.52 (4H, s), 3.55-3.58 (4H, m), 6.76 (1H, d, J = 8.4 Hz), 7.07 (1H, d, J = 8.4 Hz), 7.11 (1H, s), 7.28 (1H, dd, 8.7, 1.5Hz), 7.42 (1H, d, J = 8.7 Hz), 7.90 (1H, d, J = 1.5 Hz).

実施例４１７

収率91％, ¹H-NMR(DMSO-d₆): δ1.90 (2H, m), 2.14 (3H, s), 2.58 (2H, m), 2.73 (2H, m), 3.50 (2H, s), 3.65-3.70 (4H, m), 4.49 (2H, s), 6.68 (1H, d, J = 8.4 Hz), 7.01 (1H, d, J = 8.4 Hz), 705 (1H,s), 7.26 (1H, dd, J=8.7, 2.1Hz),7.40(1H,d,J =8.7Hz),7.88(1H,d,J = 2.1Hz).

実施例４１８

収率28％, 1H-NMR(CDCl3): δ1.33 (6H, d, J=6.0Hz), 2.27 (3H, s), 2.87-3.04 (2H, m), 3.12-3.29 (2H, m), 4.02 (2H, s), 4.30 (2H, d, J=13.0Hz), 4.59 (2H, s), 6.70 (2H, s), 6.83 (1H, s), 7.35-7.44 (1H, m), 7.52-7.61 (1H, m), 7.65 (1H, d, J=7.0Hz), 7.86 (1H, d, J=7.0Hz), 8.51 (1H, s).

実施例４１９

収率37％, 1H-NMR(CDCl3): δ1.37 (3H, d, J=6.5Hz), 2.26 (3H, s), 2.84-3.23 (3H, m), 3.45 (1H, d, J=13.0Hz), 3.71-4.14 (4H, m), 4.34 (1H, d, J=13.0Hz), 4.62 (1H, d, J=16.0Hz), 4.69 (1H, d, J=16.0Hz), 6.60 (1H, s), 6.81 (1H, s), 7.12 (1H, s), 7.37-7.47 (1H, m), 7.53-7.63 (1H, m), 7.67 (1H, d, J=8.0Hz), 7.89 (1H, d, J=8.0Hz), 8.52 (1H, s).

実施例４２０

収率55％, 1H-NMR(CDCl3): δ1.24 (6H, d, J=6.0Hz), 2.20 (3H, s), 2.77-2.92 (2H, m), 3.03-3.18 (2H, m), 3.89 (2H, s), 4.23 (2H, d, J=11.5Hz), 4.48 (2H, s), 6.61 (1H, s), 6.69 (1H, s), 6.78 (1H, s), 7.46 (1H, dd, J=9.0, 2.0Hz), 7.54 (1H, d, J=9.0Hz), 7.81 (1H, d, J=2.0Hz), 8.47 (1H, s).

実施例４２１

収率60％, 1H-NMR(CDCl3): δ1.32 (6H, d, J=6.0Hz), 2.27 (3H, s), 2.85-3.00 (2H, m), 3.16-3.30 (2H, m), 3.98 (2H, s), 4.29-4.41 (2H, m), 4.60 (2H, s), 6.67 (1H, s), 6.73 (1H, s), 6.83 (1H, s), 7.65-7.75 (2H, m), 8.12 (1H, s), 8.57 (1H, s).

実施例４２２

収率46％, ¹H-NMR(DMSO-d₆): δ3.53 (2H, s), 3.54-3.74 (8H, m), 4.87 (2H, s), 6.79-6.90 (3H, m), 7.22 (1H, t, J=7.5Hz), 7.32 (1H, dd, J=8.5, 2.0Hz), 7.46 (1H, d, J=8.5Hz), 7.94 (1H, d, J=2.0Hz), 12.31 (1H, br).

実施例４２３

収率21％, ¹H-NMR(DMSO-d₆): δ2.45-2.55 (4H, m), 3.33 (2H, s), 3.55-3.60 (4H, m), 6.50-6.60 (1H, m), 7.15-7.20 (1H, m), 7.29 (1H, dd, J=8.5, 2Hz), 7.43 (1H, d, J=8.5Hz), 7.92 (1H, d, J=2.5Hz).

実施例４２４

収率76％, ¹H-NMR(DMSO-d₆): δ2.58 (4H, s), 3.35 (2H, s), 3.59 (2H, s), 3.81 (2H, s), 7.06 (1H, d, J=3.6Hz), 7.29 (1H, dd, J=8.7, 2.1Hz), 7.43 (1H, d, J=8.4Hz), 7.60 (1H, d, J=3.3Hz), 7.91 (1H, d, J=2.1Hz), 12.99 (1H, brs).

実施例４２５

収率76％, ¹H-NMR(DMSO-d₆): δ1.25 (2H, m), 3.30 (2H, m), 3.62 (2H, m), 4.20 (2H, m), 4.45 (2H, brs), 7.33 (1H, dd, J=8.4,1.8Hz), 7.49 (1H, d, J=8.7Hz), 7.69-7.71 (2H, m), 7.98 (1H, d, J=1.8Hz), 8.02 (2H, d, J=8.1Hz).

実施例４２６

収率81％, ¹H-NMR(DMSO-d₆): δ2.45-2.50 (4H, m), 3.45-3.60 (8H, m), 7.15-7.35 (5H, m), 7.42 (1H, d, J=8.5Hz), 7.91 (1H, d, J=2Hz), 12.31 (1H, brs).

実施例４２７

収率94％, ¹H-NMR(DMS-d₆): δ2.50-2.55 (4H, m), 3.52 (4H, s), 3.57 (4H, s), 7.17 (1H, s), 7.24 (2H, s), 7.29 (1H, dd, J=2.1, 8.4Hz), 7.42 (1H, d, J = 8.4Hz), 7.91 (1H, d, J = 2.1 Hz)

実施例４２８

収率86％, ¹H-NMR(DMS-d₆): δ1.92 (2H, s), 2.61 (2H, s), 2.77 (2H, s), 3.53 (2H, s), 3.61 (2H, s), 3.60-3.65 (4H, m), 7.15 (1H, s), 7.21 (1H, s), 7.22 (1H, s), 7.26 (1H, dd, J = 8.4, 2.1Hz), 7.40 (1H, d, J = 8.4 Hz), 7.88 (1H, d, J = 2.1Hz).

実施例４２９

収率18％, 1H-NMR(DMSO-d6): δ1.85-2.00 (2H, m), 2.57-2.68 (2H, m), 2.74-2.85 (2H, m), 3.52 (2H, s), 3.61 (2H, s), 3.62-3.85 (4H, m), 7.09-7.31 (4H, m), 7.52-7.58 (2H, m), 8.22 (1H, s).

実施例４３０

収率95％, 1H-NMR(DMSO-d6): δ1.05 (6H, d, J=6.5Hz), 2.65-2.80 (2H, m), 3.04-3.15 (2H, m), 3.55 (2H, s), 3.79 (2H, s), 3.83-3.95 (2H, m), 7.05-7.15 (1H, m), 7.20-7.30 (3H, m), 7.57 (2H, s), 8.24 (1H, s), 12.27 (1H, brs).

実施例４３１

収率61％, 1H-NMR(CDCl3): δ1.08 (6H, d, J=6.5Hz), 2.74-2.86 (2H, m), 3.08 (1H, d, J=13Hz), 3.12 (1H, d, J=13Hz), 3.62 (2H, s), 3.78 (2H, s), 3.86-3.95 (2H, m), 7.16-7.18 (2H, m), 7.34 (1H, s), 7.52 (1H, d, J=8.5Hz), 7.57 (1H, d, J=8.5Hz), 7.84 (1H, s).

実施例４３２

収率87％, 1H-NMR(DMSO-d6): δ1.01 (3H, d, J=6.5Hz), 1.33 (3H, d, J=6.5Hz), 2.25-2.35 (1H, m), 2.75-2.85 (1H, m), 3.08-3.20 (1H, m), 3.49 (1H, d, J=14Hz), 3.56 (2H, s), 3.63-3.75 (3H, m), 4.23-4.35 (1H, m), 7.10-7.20 (1H, m), 7.20-7.35 (3H, m), 7.50-7.60 (2H, m), 8.21 (1H, s), 12.23 (1H, brs).

実施例４３３

収率87％, 1H-NMR(DMSO-d6): δ1.33 (3H, d, J=6.5Hz), 2.10-2.30 (2H, m), 2.72 (1H, d, J=11.5Hz), 2.94 (1H, d, J=12Hz), 3.35-3.50 (2H, m), 3.57 (2H, s), 3.60 (1H, d, J=13.5Hz), 3.75-3.90 (1H, m), 4.20-4.30 (1H, m), 7.15-7.32 (4H, m), 7.56 (2H, s), 8.22 (1H, s), 12.28 (1H, brs).

実施例４３４

収率82％, 1H-NMR(DMSO-d6): δ1.16 (3H, d, J=6Hz), 2.15-2.35 (1H, m), 2.55-2.68 (1H, m), 2.70-2.80 (1H, m), 3.15-3.30 (2H, m), 3.35-3.50 (1H, m), 3.56 (2H, s), 3.70-3.80 (1H, m), 3.80-3.90 (1H, m), 3.97 (1H, d, J=13.5Hz), 7.10-7.35 (4H, m), 7.56 (2H, s), 8.23 (1H, s), 12.29 (1H, brs).

実施例４３５

収率98％, 1H-NMR(CDCl3): δ1.00 (3 H, t, J = 7.5 Hz), 1.59-1.69 (1 H, m), 1.73-1.80 (1 H, m), 2.37-2.45 (1 H, m), 2.54-2.59 (1 H, m), 2.80-2.86 (1 H, m), 3.34-3.54 (3 H, m), 3.59-3.63 (1 H, m), 3.63 (2 H, s), 3.79 (1 H, dd, J = 2.7, 13.2 Hz), 4.04 (1 H, d, J = 13.2 Hz), 7.20-7.29 (5 H, m), 7.42 (1 H, d, J = 8.7 Hz), 7.53 (1 H, d, J = 2.1 Hz)

実施例４３６

収率96％, 1H-NMR(CDCl3): δ0.92 (6 H, dd, J = 6.3, 16.2 Hz), 1.38-1.47 (1 H, m), 1.51-1.59 (1 H, m), 1.64-1.75 (1 H, m), 2.43-2.51 (1 H, m), 2.71-2.76 (1 H, m), 2.79-2.87 (1 H, m), 3.40 (2 H, dt, J = 3.0, 13.2 Hz), 3.57-3.64 (2 H, m), 3.63 (2 H, s), 3.76 (1 H, dd, J = 3.0, 12.9 Hz), 3.99 (1 H, d, J = 13.2 Hz), 7.21-7.31 (5 H, m), 7.43 (1 H, d, J = 8.4 Hz), 7.53 (1 H, d, J = 2.4 Hz)

実施例４３７

収率89％, 1H-NMR(CDCl3): δ1.25 (3 H, d, J = 6.0 Hz), 2.30-2.38 (1 H, m), 2.68-2.74 (1 H, m), 2.83 (1 H, dt, J = 3.9, 12.0 Hz), 3.18-3.28 (2 H, m), 3.39-3.49 (1 H, m), 3.63 (2 H, s), 3.63-3.70 (1 H, m), 3.86 (1 H, dd, J = 2.4, 12.0 Hz), 4.10 (1 H, d, J = 13.2 Hz), 7.19-7.30 (5 H, m), 7.43 (1 H, d, J = 8.4 Hz), 7.53 (1 H, d, J = 2.4 Hz)

実施例４３８

収率91％, 1H-NMR(CDCl3): δ1.30 (3 H, d, J = 6.0 Hz), 2.40 (1 H, t, J = 9.6 Hz), 2.78 (1 H, br), 2.88 (1 H, br), 3.33 (2 H, d, J = 12.6 Hz), 3.48-3.54 (1 H, m), 3.64 (2 H, s), 3.72 (1 H, d, J = 13.2 Hz), 3.89 (1 H, d, J = 10.2 Hz), 4.16 (1 H, d, J = 13.2 Hz), 7.22-7.33 (5 H, m), 7.43 (1 H, d, J = 8.7 Hz), 7.54 (1 H, d, J = 2.1 Hz)

実施例４３９

収率96％, 1H-NMR(CDCl3): δ1.26 (3H, d, J=6Hz), 2.25-2.40 (4H, m), 2.65-2.75 (1H, m), 2.80-2.90 (1H, m), 3.20 (1H, d, J=13Hz), 3.25-3.30 (1H, m), 3.45-3.53 (1H, m), 3.61 (2H, s), 3.68-3.80 (1H, m), 3.84-3.95 (1H, m), 4.07 (1H, d, J=13Hz), 7.03 (2H, s), 7.10 (1H, s), 7.51 (1H, d, J=8.5Hz), 7.53 (1H, d, J=8.5Hz), 7.83 (1H, s)

実施例４４０

収率67％, 1H-NMR(DMSO-d6): δ1.31 (3H, d, J=6.5Hz), 2.03-2.25 (2H, m), 2.70 (1H, d, J=11.5Hz), 2.91 (1H, d, J=12Hz), 3.35-3.43 (2H, m), 3.56 (2H, s), 3.56-3.65 (1H, m), 3.79 (1H, d, J=11Hz), 4.15-4.25 (1H, m), 7.15 (1H, d, J=7Hz), 7.20-7.33 (4H, m), 7.41 (1H, d, J=8.5Hz), 7.89 (1H, d, J=1.5Hz), 12.30 (1H, brs).

実施例４４１

収率86％, 1H-NMR(CDCl3): δ1.37 (3H, d, J=7.0Hz), 2.23 (1H, td, J=11.0, 3.5Hz), 2.31 (1H, dd, J=11.0, 3.5Hz), 2.71 (1H, d, J=11.0Hz), 2.91 (1H, d, J=11.0Hz), 3.44 (1H, d, J=13.5Hz), 3.47 (1H, td, J=12.5, 3.5Hz), 3.60 (1H, d, J=11.0Hz), 3.64 (2H, s), 3.83 (1H, d, J=12.5Hz), 4.09-4.21 (1H, m), 7.14-7.33 (5H, m), 7.42 (1H, d, J=8.5Hz), 7.53 (1H, d, J=2.0Hz).

実施例４４２

収率94％, 1H-NMR(CDCl3): δ1.37 (3H, d, J=6.5Hz), 2.23 (1H, td, J=11.5, 3.5Hz), 2.25-2.30 (1H, m), 2.32 (3H, s), 2.71 (1H, d, J=11.5Hz), 2.91 (1H, d, J=11Hz), 3.39 (1H, d, J=13.5Hz), 3.45-3.54 (1H, m), 3.55 (1H, d, J=13.5Hz), 3.60 (2H, s), 3.83 (1H, d, J=11.5Hz), 4.10-4.20 (1H, m), 7.01 (1H, s), 7.06 (1H, s), 7.09 (1H, s), 7.23 (1H, dd, J=8.5, 2Hz), 7.42 (1H, d, J=8.5Hz), 7.54 (1H, d, J=2Hz).

実施例４４３

収率82％, 1H-NMR(CDCl3): δ1.37 (3H, d, J=6.5Hz), 2.13-2.36 (5H, m), 2.70 (1H, d, J=11.5Hz), 2.89 (1H, d, J=11.5Hz), 3.32-3.62 (5H, m), 3.76-3.87 (1H, m), 4.07-4.22 (1H, m), 6.99 (1H, s), 7.05 (1H, s), 7.07 (1H, s), 7.22 (1H, dd, J=8.5, 2.0Hz), 7.42 (1H, d, J=8.5Hz), 7.53 (1H, d, J=2.0Hz).

実施例４４４

収率87％, 1H-NMR(DMSO-d6): δ1.33 (3H, d, J=6.5Hz), 2.10-2.30 (2H, m), 2.72 (1H, d, J=11.5Hz), 2.93 (1H, d, J=11.5Hz), 3.30-3.50 (2H, m), 3.56 (2H, s), 3.59 (1H, d, J=13.5Hz), 3.86 (1H, d, J=12.5Hz), 4.20-4.30 (1H, m), 7.10-7.35 (4H, m), 7.56 (2H, s), 8.24 (1H, s), 12.43 (1H, brs).

実施例４４５

収率96％, 1H-NMR(CDCl3): δ1.34 (3H, d, J=6.5Hz), 2.14 (1H, td, J=11.5, 3.5Hz), 2.25 (1H, dd, J=11.5, 3.5Hz), 2.66 (1H, d, J=11.5Hz), 2.83 (1H, d, J=11.5Hz), 3.37 (1H, d,J=13.5Hz), 3.38-3.55 (4H, m), 3.82 (1H, d, J=11.5Hz), 4.08-4.22 (1H, m), 7.10 (1H, s), 7.14-7.23 (3H, m), 7.45-7.56 (2H, m), 7.81 (1H, s).

実施例４４６

収率98％, 1H-NMR(CDCl3): δ1.39 (3H, d, J=6.5Hz), 2.23 (1H, td, J=12, 3.5Hz), 2.25-2.31 (1H, m), 2.32 (3H, s), 2.73 (1H, d, J=11.5Hz), 2.92 (1H, d, J=12Hz), 3.41 (1H, d, J=13Hz), 3.45-3.55 (1H, m), 3.56 (1H, d, J=13Hz), 3.59 (2H, s), 3.88 (1H, d, J=12Hz), 4.17-4.28 (1H, m), 7.01 (1H, s), 7.06 (1H, s), 7.09 (1H, s), 7.51 (1H, d, J=8.5Hz), 7.55 (1H, d, J=8.5Hz), 7.83 (1H, s).

実施例４４７

収率72％, 1H-NMR(CDCl3): δ1.39 (3H, d, J=6.5Hz), 2.13-2.34 (5H, m), 2.71 (1H, d, J=11.5Hz), 2.90 (1H, d, J=11.5Hz), 3.39 (1H, d, J=13.0Hz), 3.43-3.60 (4H, m), 3.87 (1H, d, J=12.5Hz), 4.13-4.26 (1H, m), 6.99 (1H, s), 7.05 (2H, s), 7.46-7.58 (2H, m), 7.83 (1H, s).

実施例４４８

収率90％, 1H-NMR(CDCl3): δ1.40 (3H, d, J=6.5Hz), 2.26 (1H, td, J=12, 3.5Hz), 2.35 (1H, dd, J=11.5, 3.5Hz), 2.72 (1H, d, J=11.5Hz), 2.91 (1H, d, J=12Hz), 3.43 (1H, d, J=13.5Hz), 3.52 (1H, td, J=12.5, 3.5Hz), 3.57 (1H, d, J=13.5Hz), 3.64 (2H, s), 3.85-3.95 (1H, m), 4.19-4.30 (1H, m), 7.18 (1H, s), 7.21 (1H, s), 7.29 (1H, s), 7.51 (1H, d, J=8.5Hz), 7.57 (1H, d, J=8.5Hz), 7.84 (1H, s).

実施例４４９

収率68％, 1H-NMR(CDCl3): δ0.85 (3H, t, J=7.5Hz), 1.82-1.99 (2H, m), 2.17-2.29 (2H, m), 2.78-2.92 (2H, m), 3.37-3.51 (1H, m), 3.42 (1H, d, J=13.0Hz), 3.59 (1H, d, J=13.0Hz), 3.65 (2H, s), 3.76-3.87 (1H, m), 3.93-4.04 (1H, m), 7.16-7.34 (5H, m), 7.39 (1H, d, J=8.5Hz), 7.52 (1H, d, J=2.0Hz).

実施例４５０

収率95％, 1H-NMR(DMSO-d6): δ0.79 (3H, t, J=7.5Hz), 1.72-1.95 (2H, m), 2.07-2.20 (2H, m), 2.81 (1H, d, J=11Hz), 2.89 (1H, d, J=11Hz), 3.25-3.39 (2H, m), 3.40 (1H, d, J=13.5Hz), 3.55 (2H, s), 3.59 (1H, d, J=13.5Hz), 3.80-3.95 (1H, m), 7.13-7.34 (5H, m), 7.38 (1H, d, J=8.5Hz), 7.87 (1H, d, J=2Hz), 12.45 (1H, brs).

実施例４５１

収率96％, 1H-NMR(CDCl3): δ0.86 (3H, t, J=7.5Hz), 1.80-2.00 (2H, m), 2.16-2.29 (2H, m), 2.33 (3H, s), 2.79-2.94 (2H, m), 3.38 (1H, d, J=13.5Hz), 3.50 (1H, td, J=12.5, 3.5Hz), 3.57 (1H, d, J=13.5Hz), 3.61 (2H, s), 3.75-3.87 (1H, m), 3.93-4.03 (1H, m), 7.02 (1H, s), 7.06 (1H, s), 7.08 (1H, s), 7.21 (1H, dd, J=8.5, 2Hz), 7.39 (1H, d, J=8.5Hz), 7.52 (1H, d, J=2Hz).

実施例４５２

収率77％, 1H-NMR(DMSO-d6): δ0.80 (3H, t, J=7.5Hz), 1.67-1.97 (2H, m), 2.03-2.19 (2H, m), 2.28 (3H, s), 2.81 (1H, d, J=11.5Hz), 2.89 (1H, d, J=11.0Hz), 3.27-3.44 (2H, m), 3.48 (2H, s), 3.55 (1H, d, J=13.5Hz), 3.81-3.95 (2H, m), 6.96 (1H, s), 7.02 (2H, s), 7.26 (1H, dd, J=8.5, 2.0Hz), 7.38 (1H, d, J=8.5Hz), 7.87 (1H, d, J=2.0Hz).

実施例４５３

収率96％, 1H-NMR(DMSO-d6): δ0.80 (3H, t, J=7.5Hz), 1.76-1.96 (2H, m), 2.09-2.20 (2H, m), 2.82 (1H, d, J=11.5Hz), 2.89 (1H, d, J=11.5Hz), 3.30-3.42 (2H, m), 3.43 (1H, d, J=13.5Hz), 3.56 (2H, s), 3.60 (1H, d, J=13.5Hz), 3.88-4.00 (1H, m), 7.12-7.32 (4H, m), 7.51 (1H, d, J=8.5Hz), 7.56 (1H, d, J=8.5Hz), 8.21 (1H, s), 12.3 (1H, brs).

実施例４５４

収率89％, 1H-NMR(CDCl3): δ0.87 (3H, t, J=7.5Hz), 1.85-2.00 (2H, m), 2.23 (2H, td, J=12.5, 3.5Hz), 2.34 (3H, s), 2.81-2.96 (2H, m), 3.38 (1H, d, J=13.5Hz), 3.49 (1H, td, J=12.5, 3.5Hz), 3.58 (1H, d, J=13.5Hz), 3.62 (2H, s), 3.80-3.95 (1H, m), 3.97-4.10 (1H, m), 7.02 (1H, s), 7.06 (1H, s), 7.08 (1H, s), 7.46-7.50 (2H, m), 7.81 (1H, s).

実施例４５５

収率89％, 1H-NMR(CDCl3): δ0.88 (3H, t, J=7.5Hz), 1.93 (2H, quant, J=7.5Hz), 2.19-2.32 (2H, m), 2.78-2.93 (2H, m), 3.40 (1H, d, J=13.5Hz), 3.49 (1H, td, J=12.5, 3.5Hz), 3.57 (1H, d, J=13.5Hz), 3.64 (2H, s), 3.84-3.95 (1H, m), 3.96-4.10 (1H, m), 7.16 (1H, s), 7.22 (1H, s), 7.28 (1H, s), 7.45-7.57 (2H, m), 7.82 (1H, s).

実施例４５６

収率93％, 1H-NMR(CDCl3): δ0.86 (3H, t, J=7.5Hz), 1.92 (2H, quant, J=7.5Hz), 2.15-2.31 (2H, m), 2.80-2.96 (2H, m), 3.42 (1H, d, J=13Hz), 3.48 (1H, td, J=12.5, 3Hz), 3.61 (1H, d, J=13Hz), 3.66 (2H, s), 3.80-3.95 (1H, m), 3.96-4.10 (1H, m), 7.15-7.33 (4H, m), 7.49 (1H, d, J=8.5Hz), 7.50 (1H, d, J=8.5Hz) 7.81 (1H, s).

実施例４５７

収率96％, 1H-NMR(CDCl3): δ0.87 (3H, t, J=7.5Hz), 1.85-2.00 (2H, m), 2.15-2.28 (2H, m), 2.34 (3H, s), 2.80-2.95 (2H, m), 3.39 (1H, d, J=13Hz), 3.51 (1H, td, J=13, 3.5Hz), 3.58 (1H, d, J=13Hz), 3.62 (2H, s), 3.80-3.95 (1H, m), 3.96-4.10 (1H, m), 7.02 (1H, s), 7.06 (1H, s), 7.08 (1H, s), 7.50 (1H, d, J=8.5Hz), 7.53 (1H, d, J=8.5Hz) 7.81 (1H, s).

実施例４５８

収率98％, 1H-NMR(CDCl3): δ0.87 (3H, t, J=7.5Hz), 1.11-1.28 (2H, m), 1.68-1.88 (2H, m), 2.20-2.18 (2H, m), 2.64-2.79 (2H, m), 3.23-3.48 (5H, m), 3.74-3.96 (2H, m), 6.98-7.23 (5H, m), 7.35 (1H, d, J=8.5Hz), 7.49 (1H, d, J=2.0Hz).

実施例４５９

収率98％, 1H-NMR(CDCl3): δ0.91 (3 H, t, J = 7.2 Hz), 1.19-1.29 (2 H, m), 1.77-1.94 (2 H, m), 2.18-2.28 (2 H, m), 2.81(1 H, d, J = 11.1 Hz), 2.89 (1 H, d, J = 11.1 Hz), 3.40-3.47 (2 H, m), 3.61 (1 H, d, J = 13.2 Hz), 3.66 (2 H, s), 3.90 (1 H, s), 3.99 (1 H, d, J = 12.0 Hz), 7.20-7.31 (5 H, m), 7.39 (1 H, d, J = 8.7 Hz), 7.52 (1 H, d, J = 2.1Hz)

実施例４６０

収率69％, 1H-NMR(CDCl3): δ0.92 (3H, t, J=7.0Hz), 1.16-1.34 (2H, m), 1.68-2.00 (2H, m), 2.12-2.27 (2H, m), 2.32 (3H, s), 2.79 (1H, d, J=11.5Hz), 2.86 (1H, d, J=11.5Hz), 3.35 (1H, d, J=13.5Hz), 3.39-3.62 (2H, m), 3.58 (2H, s), 3.82-4.03 (2H, m), 6.99 (1H, s), 7.03 (1H, s), 7.06 (1H, s), 7.21 (1H, dd, J=8.5, 2.0Hz), 7.39 (1H, d, J=8.5Hz), 7.52 (1H, d, J=2.0Hz).

実施例４６１

収率91％, 1H-NMR(CDCl3): δ0.92 (3 H, t, J = 7.2 Hz), 1.20-1.30 (2 H, m), 1.75-1.84 (1 H, m), 1.87-1.97 (1 H, m), 2.18-2.28 (2 H, m), 2.34 (3 H, s), 2.86 (2 H, dd, J = 11.1 Hz), 3.37 (1 H, d, J = 13.2 Hz), 3.48 (1 H, dt, J = 3.3, 12.6 Hz), 3.61 (1H, d, J = 12.1 Hz), 3.62 (2 H, s), 3.90 (1 H, s), 3.99 (1 H, d, J = 11.1 Hz), 7.02 (1H, s), 7.07 (2 H, s), 7.22 (1 H, dd, J = 2.1, 8.7 Hz), 7.40 (1 H, d, J = 8.7 Hz), 7.52 (1 H, d, J = 2.1 Hz)

実施例４６２

収率70％, 1H-NMR(CDCl3): δ0.92 (3H, t, J=7.0Hz), 1.18-1.35 (2H, m), 1.75-1.98 (2H, m), 2.15-2.29 (2H, m), 2.81 (1H, d, J=11.5Hz), 2.88 (1H, d, J=11.5Hz), 3.41 (1H, d, J=13.0Hz), 3.48 (1H, td, J=12.5, 3.0Hz), 3.58 (1H, d, J=13.0Hz), 3.62 (2H, s), 3.89-4.09 (2H, m), 7.14-7.32 (4H, m), 7.49 (1H, d, J=8.5Hz), 7.53 (1H, d, J=8.5Hz), 7.81 (1H, s).

実施例４６３

収率81％, 1H-NMR(CDCl3): δ0.92 (3 H, t, J = 7.2 Hz), 1.21-1.31 (2 H, m), 1.80-1.94 (2 H, m), 2.20-2.29 (2 H, m), 2.82 (1 H, d, J = 11.4 Hz), 2.91 (1 H, d, J = 11.1 Hz), 3.43 (1 H, d, J = 13.2 Hz), 3.50 (1 H, dt, J = 3.0, 12.6 Hz), 3.61 (1 H, d, J = 13.2 Hz), 3.67 (2 H, s), 3.99 (1 H, d, J = 14.1 Hz), 4.06 (1 H, s), 7.20-7.34 (4 H, m), 7.52 (2 H, s), 7.82 (1 H, s)

実施例４６４

収率81％, 1H-NMR(CDCl3): δ0.86 (3H, t, J=7.5Hz), 1.14-1.38 (4H, m), 1.74-1.99 (2H, m), 2.16-2.30 (2H, m), 2.81 (1H, d, J=11.5Hz), 2.89 (1H, d, J=11.5Hz), 3.42 (1H, d, J=13Hz), 3.46 (1H, td, J=13.5, 3.5Hz), 3.60 (1H, d, J=13Hz), 3.66 (2H, s), 3.80-3.93 (1H, m), 3.95-4.06 (1H, m), 7.15-7.35 (5H, m), 7.40 (1H, d, J=8.5Hz), 7.52 (1H, d, J=2.5Hz).

実施例４６５

収率91％, 1H-NMR(CDCl3): δ0.86 (3H, t, J=7.5Hz), 1.13-1.40 (4H, m), 1.74-2.00 (2H, m), 2.16-2.30 (2H, m), 2.82 (1H, d, J=12Hz), 2.88 (1H, d, J=11.5Hz), 3.41 (1H, d, J=13.5Hz), 3.41-3.51 (1H, m), 3.60 (1H, d, J=13.5Hz), 3.66 (2H, s), 3.80-3.92 (1H, m), 3.94-4.05 (1H, m), 7.16-7.34 (5H, m), 7.39 (1H, d, J=8.5Hz), 7.52 (1H, d, J=2Hz).

実施例４６６

収率81％, 1H-NMR(CDCl3): δ0.87 (3H, t, J=7.5Hz), 1.17-1.39 (4H, m), 1.75-2.03 (2H, m), 2.17-2.30 (2H, m), 2.34 (3H, s), 2.83 (1H, d, J=11.5Hz), 2.91 (1H, d, J=10.5Hz), 3.38 (1H, d, J=13.5Hz), 3.44-3.55 (1H, m), 3.58 (1H, d, J=13.5Hz), 3.62 (2H, s), 3.85-3.97 (1H, m), 4.00-4.10 (1H, m), 7.02 (1H, s), 7.06 (1H, s), 7.07 (1H, s), 7.51 (2H, s), 7.82 (1H, s).

実施例４６７

収率53％, 1H-NMR(DMSO-d6): δ0.87 (3H, d, J=6.5Hz), 0.89 (3H, d, J=6.5Hz), 2.02-2.25 (2H, m), 2.29 (3H, s), 2.45-3.05 (4H, m), 3.10 (1H, d, J=13.0Hz), 3.35-3.58 (2H, m), 3.53 (2H, s), 4.01-4.22 (1H, m), 6.96 (1H, s), 7.00 (1H, s), 7.03 (1H, s), 7.49 (2H, s), 7.78 (1H, s).

実施例４６８

収率70％, 1H-NMR(DMSO-d6): δ0.85 (6H, t, J=7.5Hz), 2.00 (1H, d, J=11.5Hz), 2.14 (1H, t, J=11.5Hz), 2.28 (3H, s), 2.50-2.57 (1H, m), 2.93 (2H, t, J=11.5Hz), 3.32 (1H, d, J=13.5Hz), 3.32-3.48 (1H, m), 3.49 (2H, s), 3.57 (1H, d, J=13.5Hz), 3.58-3.65 (1H, m), 3.95-4.10 (1H, m), 6.97 (1H, s), 7.02 (2H, s), 7.49 (1H, d, J=8.5Hz), 7.55 (1H, d, J=8.5Hz), 8.18 (1H, s), 12.4 (1H, brs).

実施例４６９

収率67％, 1H-NMR(DMSO-d6): δ0.88 (3H, d, J=6.5Hz), 0.90 (3H, d, J=6.5Hz), 1.32-1.58 (2H, m), 1.80-1.96 (1H, m), 2.05-2.23 (2H, m), 2.75 (1H, d, J=10.5Hz), 2.89 (1H, d, J=11.5Hz), 3.30-3.53 (2H, m), 3.48 (2H, s), 3.59 (1H, d, J=13.5Hz), 3.80-4.08 (2H, m), 7.10-7.30 (5H, m), 7.38 (1H, d, J=8.5Hz), 7.87 (1H, d, J=2.0Hz).

実施例４７０

収率88％, 1H-NMR(CDCl3): δ0.90 (6H, dd, J=6, 2Hz), 1.30-1.59 (2H, m), 1.80-1.95 (1H, m), 2.08-2.24 (2H, m), 2.75 (1H, d, J=11.5Hz), 2.91 (1H, d, J=11.5Hz), 3.20-3.37 (1H, m), 3.38 (1H, d, J=13.5Hz), 3.55 (2H, s), 3.62 (1H, d, J=13.5Hz), 3.80-3.96 (1H, m), 3.97-4.10 (1H, m), 7.10-7.32 (5H, m), 7.38 (1H, d, J=8.5Hz), 7.89 (1H, d, J=2Hz), 12.43 (1H, brs).

実施例４７１

収率62％, 1H-NMR(CDCl3): δ0.91 (3H, d, J=6.5Hz), 0.93 (3H, d, J=6.5Hz), 1.34-1.64 (2H, m), 1.85-2.00 (1H, m), 2.11-2.38 (2H, m), 2.31 (3H, s), 2.77 (1H, d, J=11.0Hz), 2.86 (1H, d, J=10.5Hz), 3.32 (1H, d, J=13.0Hz), 3.38-3.64 (2H, m), 3.56 (2H, s), 3.83-4.07 (2H, m), 6.98 (1H, s), 7.01 (1H, s), 7.05 (1H, s), 7.21 (1H, dd, J=8.5, 2.0Hz), 7.39 (1H, d, J=8.5Hz), 7.52 (1H, d, J=2.0Hz).

実施例４７２

収率92％, 1H-NMR(CDCl3): δ0.90 (6H, t, J=6Hz), 1.42-1.53 (2H, m), 1.93-2.01 (1H, m), 2.02-2.12 (2H, m), 2.29 (3H, s), 2.75 (1H, d, J=11.5Hz), 2.91 (1H, d, J=11.5Hz), 3.31 (1H, d, J=13.5Hz), 3.32-3.50 (1H, m), 3.51 (2H, s), 3.61 (1H, d, J=13.5Hz), 3.87-4.04 (2H, m), 6.97 (1H, s), 7.02 (1H, s), 7.04 (1H, s), 7.27 (1H, dd, J=8.5, 2Hz), 7.38 (1H, d, J=8.5Hz), 7.89 (1H, d, J=2Hz), 12.28 (1H, brs).

実施例４７３

収率99％, 1H-NMR(CDCl3): δ0.90 (3H, d, J=6.0Hz), 0.92 (3H, d, J=6.0Hz), 1.34-1.64 (2H, m), 1.84-1.98 (1H, m), 2.07-2.30 (2H, m), 2.26 (3H, s), 2.74 (1H, d, J=11.0Hz), 2.82 (1H, d, J=10.5Hz), 3.28 (1H, d, J=13.5Hz), 3.35-3.54 (4H, m), 3.87-4.07 (2H, m), 6.91 (1H, s), 6.93 (1H, s), 7.02 (1H, s), 7.50 (2H, s), 7.81 (1H, s).

実施例４７４

収率98％, 1H-NMR(CDCl3): δ0.93 (6 H, dd, J = 3.6, 6.3 Hz), 1.42-1.50 (1 H, m), 1.55-1.64 (1 H, m), 1.90-1.99 (1 H, m), 2.23 (2 H, td, J = 3.6, 11.4 Hz), 2.34 (3 H, s), 2.81 (1 H, d, J = 11.4 Hz), 2.92 (1 H, d, J = 10.2 Hz), 3.37 (1 H, d, J = 13.2 Hz), 3.52 (1 H, td, J = 3.3, 12.9 Hz), 3.62 (1 H, d, J = 13.2 Hz), 3.62 (2 H, s), 4.04 (2 H, br), 7.02 (1 H, s), 7.07 (2 H, s), 7.52 (2 H, s), 7.82(1 H, s)

実施例４７５

収率62％, 1H-NMR(CDCl3): δ1.23 (3H, d, J=6.5Hz), 1.38 (3H, d, J=6.5Hz), 2.11-2.26 (1H, m), 2.65-2.89 (2H, m), 2.98-3.15 (1H, m), 3.35-3.52 (1H, m), 3.67 (2H, s), 3.68-3.82 (1H, m), 4.03-4.22 (2H, m), 7.17-7.36 (4H, m), 7.48-7.60 (2H, m), 7.83 (1H, s).

実施例４７６

収率80％, 1H-NMR(DMSO-d6): δ2.43-2.58 (4H, m), 3.54 (2H, s), 3.57 (2H, s), 3.58-3.70 (4H, m), 7.13-7.34 (4H, m), 7.47 (1H, d, J=12.5Hz), 8.27 (1H, d, J=7.5Hz), 12.28 (1H, s).

実施例４７７

収率92％, 1H-NMR(CDCl3): δ2.28 (3H, s), 2.50-2.62 (4H, m), 3.47 (2H, s), 3.52 (2H, s), 3.58-3.68 (4H, m), 6.97 (2H, s), 7.04 (1H, s), 7.25 (1H, d, J=11.5Hz), 7.73 (1H, d, J=7.0Hz).

実施例４７８

収率59％, 1H-NMR(CD3OD): δ2.06-2.18 (2H, m), 2.31 (3H, s), 2.87-2.97 (2H, m), 2.99-3.08 (2H, m), 3.52 (2H, s), 3.70-3.98 (4H, m), 3.82 (2H, s), 7.07 (2H, s), 7.11 (1H, s), 7.29 (1H, d, J=12.0Hz), 7.98 (1H, d, J=7.0Hz).

実施例４７９

収率85％, 1H-NMR(DMSO-d6): δ1.15 (3H, d, J=6Hz), 2.16-2.27 (1H, m), 2.28 (3H, s), 2.55-2.68 (1H, m), 2.69-2.80 (1H, m), 3.17 (1H, d, J=13.5Hz), 3.18-3.26 (1H, m), 3.35-3.48 (1H, m), 3.49 (2H, s), 3.65-3.79 (1H, m), 3.80-3.90 (1H, m), 3.92 (1H, d, J=13.5Hz), 6.96 (1H, s), 7.00 (1H, s), 7.01 (1H, s), 7.45 (1H, d, J=12Hz), 8.25 (1H, d, J=8Hz), 12.40 (1H, brs).

実施例４８０

収率67％, 1H-NMR(CDCl3): δ1.39 (3H, d, J=7.0Hz), 2.14-2.35 (2H, m), 2.32 (3H, s), 2.72 (1H, d, J=11.0Hz), 2.91 (1H, d, J=11.0Hz), 3.40 (1H, d, J=14.0Hz), 3.43-3.62 (2H, m), 3.58 (2H, s), 3.86 (1H, d, J=12.5Hz), 4.12-4.28 (1H, m), 6.99 (1H, s), 7.02-7.10 (2H, m), 7.25 (1H, d, J=11.5Hz), 7.73 (1H, d, J=7.0Hz).

実施例４８１

収率78％, 1H-NMR(CDCl3): δ1.38 (3H, d, J=7.0Hz), 2.12-2.35 (2H, m), 2.30 (3H, s), 2.70 (1H, d, J=11.5Hz), 2.88 (1H, d, J=11.5Hz), 3.32-3.60 (5H, m), 3.84 (1H, d, J=11.5Hz), 4.10-4.25 (1H, m), 6.97 (1H, s), 7.04 (2H, s), 7.24 (1H, d, J=12.0Hz), 7.73 (1H, d, J=7.0Hz).

実施例４８２

収率82％, 1H-NMR(DMSO-d6): δ2.45-2.60 (4H, m), 3.48-3.63 (8H, m), 7.06 (1H, td, J=7.5, 1.0Hz), 7.13-7.33 (5H, m), 7.45 (1H, d, J=7.5Hz), 7.76 (1H, d, J=7.5Hz), 12.32 (1H, brs).

実施例４８３

収率60％, 1H-NMR(CDCl3): δ0.85 (3H, t, J=7.5Hz), 1.80-2.00 (2H, m), 2.12-2.26 (2H, m), 2.31 (3H, s), 2.77-2.91 (2H, m), 3.36 (1H, d, J=13.5Hz), 3.36-3.62 (2H, m), 3.57 (2H, s), 3.75-3.87 (1H, m), 3.88-4.02 (1H, m), 6.98 (1H, s), 7.04 (2H, s), 7.24 (1H, d, J=10.5Hz), 7.51 (1H, d, J=7.0Hz).

実施例４８４

収率67％, 1H-NMR(CDCl3): δ2.75 (4H, t, J=5.0Hz), 3.68 (4H, s), 3.85 (4H, t, J=5.0Hz), 7.13-7.21 (1H, m), 7.22-7.34 (2H, m), 7.37-7.46 (2H, m), 7.54-7.64 (1H, m), 7.69 (1H, dd, J=8.0, 1.0Hz), 7.89 (1H, dd, J=8.0, 1.0Hz), 8.56 (1H, s).

実施例４８５

収率57％, 1H-NMR(CDCl3): δ2.82 (4H, t, J=4.5Hz), 3.66 (2H, s), 3.74 (2H, s), 3.83 (4H, t, J=4.5Hz), 6.93 (1H, d, J=9.0Hz), 7.07-7.15 (1H, m), 7.20-7.31 (3H, m), 7.47 (1H, s), 7.54 (1H, td, J=8.0, 1.5Hz), 7.60 (1H, d, J=8.0), 7.70 (1H, d, J=8.0Hz), 7.89 (1H, d, J=9.0Hz).

実施例４８６

収率42％, 1H-NMR(CDCl3): δ2.65-2.77 (4H, m), 3.64 (4H, s), 3.76-3.88 (4H, m), 7.13-7.32 (3H, m), 7.38 (1H, s), 7.50 (1H, dd, J=9.0, 2.0Hz), 7.59 (1H, d, J=9.0Hz), 7.86 (1H, d, J=2.0Hz), 8.53 (1H, s).

実施例４８７

収率81％, 1H-NMR(CDCl3): δ2.60-2.74 (4H, m), 2.63 (3H, s), 3.35-3.49 (4H, m), 3.52 (2H, s), 3.54 (2H, s), 7.05-7.23 (3H, m), 7.29 (1H, s), 7.69 (1H, d, J=9.0Hz), 7.80 (1H, d, J=9.0Hz), 8.14 (1H, s).

実施例４８８

収率79％, 1H-NMR(CDCl3): δ1.35 (3H, d, J=6.5Hz), 2.12-2.35 (5H, m), 2.79 (1H, d, J=11.5Hz), 2.99 (1H, d, J=11.5Hz), 3.27-3.43 (2H, m), 3.50-3.62 (3H, m), 4.35 (1H, d, J=12.5Hz), 4.59-4.72 (1H, m), 6.98 (1H, s), 7.05 (1H, s), 7.08 (1H, s), 7.70 (2H, s), 8.13 (1H, s), 8.56 (1H, s).

実施例４８９

収率76％, 1H-NMR(CD3OD): δ2.69-2.78 (4H, m), 3.52-3.60 (4H, m), 3.61 (2H, s), 3.71 (2H, s), 7.18-7.39 (7H, m), 7.42-7.50 (3H, m). The compounds described in Examples 336 to 489 were obtained in the same manner as in Example 335.
Example 336

Yield: 18%, ¹ H-NMR (DMSO-d ₆ ): δ1.68-1.84 (2H, m), 2.00-2.15 (2H, m), 3.50-3.64 (2H, m), 3.78-3.92 ( 2H, m), 4.68-4.81 (1H, m), 7.12-7.18 (1H, m), 7.26-7.39 (2H, m), 7.43 (1H, d, J = 8.5Hz), 7.48-7.55 (2H, m), 7.91 (1H, d, J = 2.0Hz).

Example 337

Yield: 27%, ¹ H-NMR (DMSO-d ₆ ): δ1.66-1.83 (2H, m), 2.00-2.15 (2H, m), 3.48-3.64 (4H, m), 3.78-3.93 ( 2H, m), 4.62-4.75 (1H, m), 6.80-6.98 (3H, m), 7.19-7.28 (1H, m), 7.29 (1H, dd, J = 8.5,2.5Hz), 7.44 (1H, d, J = 8.5Hz), 7.90 (1H, d, J = 2.5Hz), 12.29 (1H, s).

Example 338

Yield: 84%, ¹ H-NMR (DMSO-d ₆ ): δ1.35-1.55 (2H, m), 1.85-2.00 (2H, m), 2.00-2.20 (1H, m), 3.10-3.30 ( 2H, m), 3.94 (2H, d, J = 6Hz), 4.00-4.15 (2H, m), 6.98 (1H, t, J = 7.5Hz), 7.10 (1H, d, J = 7.5Hz), 7.27 (1H, dd, J = 8.5, 2Hz), 7.41 (1H, d, J = 8.5Hz), 7.47 (1H, t, J = 7.5Hz), 7.61 (1H, d, J = 7.5Hz), 7.89 ( 1H, d, J = 2Hz), 12.50 (1H, brs).

Example 339

Yield: 84%, ¹ H-NMR (DMSO-d ₆ ): δ 1.30-1.50 (2H, m), 1.80-1.95 (2H, m), 2.00-2.15 (1H, m), 3.15-3.30 ( 2H, m), 3.93 (2H, d, J = 6Hz), 4.00-4.15 (2H, m), 7.20 (1H, dd, J = 8, 2.5Hz), 7.27 (1H, dd, J = 8.5, 2Hz ), 7.35-7.45 (3H, m), 7.52 (1H, d, J = 8Hz), 7.88 (1H, d, J = 2Hz), 13.0 (1H, brs).

Example 340

Yield: 59%, ¹ H-NMR (DMSO-d ₆ ): δ 1.30-1.50 (2H, m), 1.85-1.95 (2H, m), 2.00-2.20 (1H, m), 3.00-3.20 ( 2H, m), 3.96 (2H, d, J = 6.5Hz), 4.04-4.14 (2H, m), 7.00 (2H, d, J = 8Hz), 7.28 (1H, dd, J = 8.5, 1.5Hz) , 7.41 (1H, d, J = 8.5Hz), 7.87 (2H, d, J = 8Hz), 7.89 (1H, d, J = 1.5Hz).

Example 341

Yield: 88%, ¹ H-NMR (DMSO-d ₆ ): δ1.20-1.45 (2H, m), 1.70-1.90 (1H, m), 1.90-2.05 (2H, m), 3.02 (2H, d, J = 7Hz), 3.10-3.25 (2H, m), 3.95-4.10 (2H, m), 7.70 (1H, dd, J = 8.5, 2Hz), 7.40 (1H, d, J = 8.5Hz), 7.44 (1H, t, J = 7.5Hz), 7.59 (1H, d, J = 7.5Hz), 7.73 (1H, d, J = 7.5Hz), 7.83 (1H, s), 7.88 (1H, d, J = 2Hz), 13.40 (1H, brs).

Example 342

Yield: 32%, ¹ H-NMR (CDCl ₃ ); δ1.30-1.48 (2H, m), 1.70-1.90 (1H, m), 1.85-2.05 (2H, m), 2.88 (2H, d, J = 7Hz), 3.02-3.15 (2H, m), 3.63 (2H, s), 4.05-4.18 (2H, m), 7.05-7.15 (1H, m), 7.24 (1H, dd, J = 8.5, 2Hz ), 7.25-7.30 (3H, m), 7.42 (1H, d, J = 8.5Hz), 7.53 (1H, d, J = 2Hz).

Example 343

Yield: 88%, ¹ H-NMR (DMSO-d ₆ ): δ1.20-1.38 (2H, m), 1.71 (2H, q, J = 6.0Hz), 1.78-1.94 (3H, m), 3.09 -3.23 (2H, m), 3.95-4.07 (2H, m), 4.10 (2H, t, J = 6.0Hz), 6.99 (1H, td, J = 7.5, 1.5Hz), 7.14 (1H, d, J = 7.5Hz), 7.27 (1H, dd, J = 8.5, 2.0Hz), 7.40 (1H, d, J = 8.5Hz), 7.48 (1H, td, J = 1.5, 7.5Hz), 7.60 (1H, dd , J = 7.5, 1.5Hz), 7.88 (1H, d, J = 2.0Hz), 12.55 (1H, br).

Example 344

Yield: 82%, ¹ H-NMR (DMSO-d ₆ ): δ1.20-1.39 (2H, m), 1.68-1.92 (5H, m), 3.10-3.26 (2H, m), 3.08-4.08 ( 2H, m), 4.12 (2H, t, J = 6.0Hz), 7.03 (2H, d, J = 9.0Hz), 7.27 (1H, dd, J = 8.5, 2.0Hz), 7.40 (1H, d, J = 8.5Hz), 7.88 (1H, d, J = 2.0Hz), 7.88 (2H, d, J = 9.0Hz), 12.62 (1H, br).

Example 345

Yield: 75%, ¹ H-NMR (DMSO-d ₆ ): δ1.22-1.40 (2H, m), 1.70-1.92 (5H, m), 2.21 (3H, s), 3.12-3.24 (2H, m), 3.96-4.08 (2H, m), 4.09 (2H, t, J = 6.0Hz), 7.25 (1H, d, J = 8.0Hz), 7.27 (1H, dd, J = 8.5, 2.0Hz), 7.40 (1H, d, J = 8.5Hz), 7.43 (2H, m), 7.88 (1H, d, J = 2.0Hz).

Example 346

Yield: 78%, ¹ H-NMR (DMSO-d ₆ ): δ1.18-1.38 (2H, m), 1.64-1.91 (5H, m), 3.11-3.24 (2H, m), 3.52 (2H, s), 3.96-4.07 (4H, m), 6.78-6.87 (3H, m), 7.21 (1H, t, J = 7.5Hz), 7.27 (1H, dd, J = 8.5,2.0Hz), 7.40 (1H , d, J = 8.5Hz), 7.88 (1H, d, J = 2.0Hz), 12.31 (1H, brs).

Example 347

Yield: 84%, ¹ H-NMR (DMSO-d ₆ ): δ1.19-1.39 (2H, m), 1.64-1.92 (5H, m), 3.09-3.28 (2H, m), 3.47 (2H, s), 3.95-4.10 (4H, m), 6.80 (2H, d, J = 8.5Hz), 7.15 (2H, d, J = 8.5Hz), 7.27 (1H, dd, J = 8.5, 2.0Hz), 7.40 (1H, d, J = 8.5Hz), 7.88 (1H, d, J = 2.0Hz).

Example 348

Yield: 35%, ¹ H-NMR (CDCl ₃ ); δ1.18-1.37 (2H, m), 1.68-1.91 (5H, m), 2.77 (2H, t, J = 7.5Hz), 3.09-3.43 (4H, m), 3.94-4.06 (4H, m), 6.71-6.83 (3H, m), 7.16 (1H, t, J = 8.0Hz), 7.27 (1H, dd, J = 8.5, 2.0Hz), 7.40 (1H, d, J = 8.5Hz), 7.88 (1H, d, J = 2.0Hz).

Example 349

Yield: 27%, ¹ H-NMR (DMSO-d ₆ ): δ1.18-1.42 (2H, m), 1.68-1.94 (5H, m), 2.47 (2H, t, J = 7.5Hz), 2.80 (2H, t, J = 7.5Hz), 3.10-3.23 (2H, m), 3.96-4.10 (4H, m), 6.84 (1H, t, J = 7.5Hz), 6.96 (1H, d, J = 7.5 Hz), 7.12-7.21 (2H, m), 7.27 (1H, dd, J = 8.5, 2.0Hz), 7.40 (1H, d, J = 8.5Hz), 7.88 (1H, d, J = 2.0Hz), 12.09 (1H, s).

Example 350

Yield: 27%, ¹ H-NMR (DMSO-d ₆ ): δ1.14-1.31 (2H, m), 1.50-1.61 (2H, m), 1.64-1.86 (3H, m), 2.96-3.22 ( 4H, m), 3.93-4.03 (2H, m), 7.23-7.36 (3H, m), 7.39 (1H, d, J = 8.5Hz), 7.67 (1H, d, J = 7.0Hz), 7.81 (1H , s), 7.88 (1H, d, J = 2.0Hz).

Example 351

Yield: 72%, ¹ H-NMR (DMSO-d ₆ ): δ1.12-1.32 (2H, m), 1.50-1.63 (2H, m), 1.64-1.87 (3H, m), 2.95-3.06 ( 2H, m), 3.07-3.22 (2H, m), 3.55 (2H, s), 3.92-4.08 (2H, m), 4.05 (1H, d, J = 2.0Hz), 7.17-7.31 (4H, m) , 7.39 (1H, d, J = 8.5Hz), 7.87 (1H, d, J = 7.5Hz), 12.36 (1H, brs).

Example 352

Yield: 65%, ¹ H-NMR (CDCl ₃ ); δ1.33 (2H, m), 1.73-1.90 (5H, m), 2.31 (3H, s), 3.14 (2H, t, J = 12.6Hz ), 3.58 (2H, s), 4.01 (2H, t, J = 5.7 Hz), 4.11 (2H, d, J = 14.1Hz), 6.65 (2H, s), 6.70 (1H, s), 7.23 (1H , dd, J = 8.4, 2.1Hz), 7.43 (1H, d, J = 8.4Hz), 7.54 (1H, d, J = 2.1Hz)

Example 353

Yield: 90%, ¹ H-NMR (DMSO-d ₆ ): δ1.23-1.36 (2H, m), 1.72-1.87 (5H, m), 2.07 (3H, s), 3.15-3.23 (2H, m), 3.56 (2H, s), 4.01 (4H, t, J = 5.7Hz), 6.77 (1H, d, J = 8.1Hz), 6.87 (1H, d, J = 8.1Hz), 7.07 (1H, t, J = 8.1Hz), 7.28 (1H, dd, J = 8.7, 2.1Hz), 7.40 (1H, d, J = 8.7 Hz), 7.89 (1H, d, J = 2.1Hz).

Example 354

Yield: 65%, ¹ H-NMR (DMSO-d ₆ ): δ1.20-1.35 (1H, m), 1.65-1.90 (6H, m), 3.10-3.25 (2H, m), 3.54 (2H, s), 3.95-4.15 (4H, m), 6.75-6.85 (1H, m), 7.10 (1H, dd, J = 8, 3.5Hz), 7.14 (1H, d, J = 8Hz), 7.24 (1H, dd, J = 8.5, 2Hz), 7.40 (1H, d, J = 8.5Hz), 7.88 (1H, d, J = 2Hz), 12.34 (1H, brs).

Example 355

Yield: 36%, ¹ H-NMR (DMSO-d ₆ ): δ 1.20-1.39 (2H, m), 1.66-1.93 (5H, m), 3.08-3.23 (2H, m), 3.40 (2H, s), 3.94-4.13 (4H, m), 6.76-6.84 (1H, m), 7.06 (1H, s), 7.23-7.32 (2H, m), 7.36-7.43 (1H, m), 7.87 (1H, d, J = 2.0Hz).

Example 356

Yield: 59%, ¹ H-NMR (DMSO-d ₆ ): δ1.17-1.37 (2H, m), 1.62-1.91 (5H, m), 3.09-3.25 (2H, m), 3.34 (2H, s), 3.92-4.07 (4H, m), 6.75 (1H, dd, J = 8.5, 3.0Hz), 6.92 (1H, d, J = 3.0Hz), 7.21 (1H, d, J = 8.5Hz), 7.27 (1H, dd, J = 8.5, 2.0Hz), 7.40 (1H, d, J = 8.5Hz), 7.88 (1H, d, J = 2.0Hz).

Example 357

Yield: 63%, ¹ H-NMR (DMSO-d ₆ ): δ 2.69 (4H, t, J = 4.5Hz), 2.80 (2H, t, J = 5.5Hz), 3.56 (4H, t, J = 4.5Hz), 4.22 (2H, t, J = 5.5Hz), 7.01 (1H, t, J = 7.5Hz), 7.16 (1H, d, J = 7.5Hz), 7.29 (1H, dd, J = 8.5 , 2.0Hz), 7.43 (1H, d, J = 8.5Hz), 7.48 (1H, t, J = 7.5Hz), 7.61 (1H, d, J = 7.5Hz), 7.91 (1H, d, J = 2.0 Hz).

Example 358

Yield: 31%, ¹ H-NMR (DMSO-d ₆ ): δ 2.65 (4H, t, J = 5.0Hz), 2.80 (2H, t, J = 5.5Hz), 3.57 (4H, t, J = 5.0Hz), 4.15 (2H, t, J = 5.5Hz), 7.10 (1H, d, J = 8.0Hz), 7.27-7.36 (2H, m), 7.41-7.52 (3H, m), 7.91 (1H , d, J = 2.2Hz).

Example 359

Yield: 50%, ¹ H-NMR (DMSO-d ₆ ): δ 2.64 (4H, t, J = 5.0Hz), 2.80 (2H, t, J = 5.5Hz), 3.57 (4H, t, J = 5.0Hz), 4.20 (2H, t, J = 5.5Hz), 7.03 (2H, d, J = 9Hz), 7.29 (1H, dd, J = 8.5, 2.0Hz), 7.42 (1H, d, J = 8.5Hz), 7.87 (2H, d, J = 9.0Hz), 7.91 (1H, d, J = 2.0Hz).

Example 360

Yield: 29%, ¹ H-NMR (DMSO-d ₆ ): δ1.18-1.36 (2H, m), 1.68-1.88 (5H, m), 3.00-3.25 (2H, m), 3.94-4.07 ( 2H, m), 4.20 (2H, t, J = 6.0Hz), 6.41 (1H, d, J = 4.0Hz), 7.27 (1H, dd, J = 8.5, 2.0Hz), 7.40 (1H, d, J = 8.5Hz), 7.44 (1H, d, J = 4.0Hz), 7.88 (1H, d, J = 2.0Hz).

Example 361

Yield: 64%, ¹ H-NMR (DMSO-d ₆ ): δ2.13 (3H, s), 2.68 (4H, t, J = 5Hz), 2.82 (2H, t, J = 5.5Hz), 3.47 (2H, s), 3.63 (4H, t, J = 5Hz), 4.10 (2H, t, J = 5.5Hz), 6.72 (1H, d, J = 8Hz), 6.86 (1H, s), 7.05 (1H , d, J = 7.5Hz), 7.57 (2H, s), 8.25 (1H, s), 12.50 (1H, brs).

Example 362

Yield: 25%, ¹ H-NMR (DMSO-d ₆ ): δ1.88-1.94 (2H, m), 2.73-2.75 (2H, m), 2.87 (2H, t, J = 5.1Hz), 2.92 -2.95 (2H, m), 3.25 (2H, s), 3.67-3.72 (4H, m), 4.01 (2H, t, J = 5.7Hz), 6.68-6.82 (3H, m), 7.10 (1H, t , J = 7.5Hz), 7.26 (1H, dd, J = 8.7, 2.1Hz), 7.40 (1H, d, J = 8.7Hz), 7.88 (1H, d, J = 2.1Hz).

Example 363

Yield: 68%, ¹ H-NMR (DMSO-d ₆ ): δ1.85-1.95 (2H, m), 2.09 (3H, s), 2.75-2.82 (2H, m), 2.92 (2H, t, J = 5.5Hz), 2.95-3.02 (2H, m), 3.49 (2H, s), 3.60-3.75 (4H, m), 4.03 (2H, t, J = 5.5Hz), 6.71 (1H, d, J = 7.5Hz), 6.83 (1H, s), 7.03 (1H, d, J = 7.5Hz), 7.26 (1H, dd, J = 8.5, 2Hz), 7.39 (1H, d, J = 8.5Hz), 7.87 (1H, d, J = 2Hz), 12.37 (1H, brs).

Example 364

Yield: 67%, ¹ H-NMR (DMSO-d ₆ ): δ1.85-1.95 (2H, m), 2.75-2.85 (2H, m), 2.93 (2H, t, J = 5.5Hz), 2.95 -3.05 (2H, m), 3.55 (2H, s), 3.60-3.80 (4H, m), 4.12 (2H, t, J = 5.5Hz),, 6.83 (1H, dd, J = 8, 1.5Hz) , 7.07 (1H, d, J = 1.5Hz), 7.25 (1H, dd, J = 8.5, 2Hz), 7.33 (1H, d, J = 8Hz), 7.39 (1H, d, J = 8.5Hz), 7.87 (1H, d, J = 2Hz), 12.37 (1H, brs).

Example 365

Yield: 45%, ¹ H-NMR (DMSO-d ₆ ): δ1.20-1.39 (2H, m), 1.65-1.94 (5H, m), 3.17-3.32 (2H, m), 3.99-4.12 ( 4H, m), 6.92-6.99 (1H, m), 7.23 (1H, t, J = 7.5Hz), 7.40-7.48 (2H, m), 7.51-7.59 (2H, m), 8.21 (1H, s) .

Example 366

Yield: 48%, ¹ H-NMR (DMSO-d ₆ ): δ1.18-1.38 (2H, m), 1.63-1.94 (5H, m), 3.13-3.30 (2H, m), 3.32 (2H, s), 3.93-4.13 (4H, m), 6.70-6.85 (3H, m), 7.13 (1H, t, J = 8.0Hz), 7.49-7.60 (2H, m), 8.21 (1H, s).

Example 367

Yield: 82%, ¹ H-NMR (DMSO-d ₆ ): δ1.17-1.42 (2H, m), 1.68-1.96 (5H, m), 3.13-3.30 (2H, m), 3.43 (2H, s), 3.95-4.19 (4H, m), 6.81 (1H, d, J = 7.5Hz), 7.07 (1H, s), 7.28 (1H, d, J = 7.5Hz), 7.49-7.61 (2H, m ), 8.21 (1H, s).

Example 368

Yield: 77%, ¹ H-NMR (DMSO-d ₆ ): δ1.85-2.00 (2H, m), 2.68-2.81 (2H, m), 2.82-3.03 (4H, m), 3.51 (2H, s), 3.60-3.89 (4H, m), 3.97-4.09 (2H, m), 6.75-6.90 (3H, m), 7.19 (1H, t, J = 8.0Hz), 7.50-7.60 (2H, m) , 8.22 (1H, s), 12.26 (1H, br).

Example 369

Yield: 78%, ¹ H-NMR (DMSO-d ₆ ): δ1.84-1.98 (2H, m), 2.74-2.85 (2H, m), 2.86-3.07 (4H, m), 3.56 (2H, s), 3.60-3.85 (4H, m), 4.06-4.18 (2H, m), 6.83 (1H, dd, J = 8.0, 2.0Hz), 7.07 (1H, d, J = 2.0Hz), 7.33 (1H , d, J = 8.0Hz), 7.51-7.57 (2H, m), 8.22 (1H, s), 12.35 (1H, br).

Example 370

Yield: 68%, ¹ H-NMR (CDCl ₃ ); δ1.19-1.39 (2H, m), 1.64-1.92 (5H, m), 3.12-3.27 (2H, m), 3.96-4.08 (4H, m), 6.80-6.87 (1H, m), 7.06 (1H, dd, J = 8.0, 2.0Hz), 7.15 (1H, t, J = 8.0Hz), 7.38-7.47 (3H, m), 7.76 (1H , d, J = 8.0Hz).

Example 371

Yield: 87%, ¹ H-NMR (DMSO-d ₆ ): δ1.19-1.40 (2H, m), 1.63-1.92 (5H, m), 3.10-3.27 (2H, m), 3.51 (2H, s), 3.94-4.10 (4H, m), 6.77-6.86 (3H, m), 7.07 (1H, dd, J = 8.5, 2.0Hz), 7.20 (1H, t, J = 7.5Hz), 7.44 (1H , d, J = 2.0Hz), 7.76 (1H, d, J = 8.5Hz), 12.33 (1H, br).

Example 372

Yield: 36%, ¹ H-NMR (DMSO-d ₆ ): δ1.20-1.39 (2H, m), 1.63-1.93 (5H, m), 3.12-3.28 (2H, m), 3.53 (2H, s), 3.95-4.12 (4H, m), 6.78-6.88 (3H, m), 7.13 (1H, dd, J = 8.0, 1.0Hz), 7.20 (1H, t, J = 7.5Hz), 7.31 (1H , d, J = 8.0Hz), 7.39 (1H, dd, J = 8.0, 1.0Hz), 12.31 (1H, s).

Example 373

Yield: 89%, ¹ H-NMR (DMSO-d ₆ ): δ1.19-1.39 (2H, m), 1.65-1.93 (5H, m), 3.10-3.25 (2H, m), 3.96-4.09 ( 4H, m), 6.87-6.94 (1H, m), 7.20 (1H, t, J = 8.0Hz), 7.31-7.48 (4H, m), 8.00 (1H, d, J = 2.0Hz).

Example 374

Yield: 58%, ¹ H-NMR (DMSO-d ₆ ): δ1.18-1.37 (2H, m), 1.63-1.91 (5H, m), 3.10-3.26 (4H, m), 3.92-4.07 ( 4H, m), 6.63-6.84 (3H, m), 7.08 (1H, t, J = 8.0Hz), 7.31-7.42 (2H, m), 7.99 (1H, d, J = 2.0Hz).

Example 375

Yield: 46%, ¹ H-NMR (DMSO-d ₆ ): δ1.18-1.36 (2H, m), 1.61-1.90 (5H, m), 2.32 (3H, s), 3.04-3.19 (2H, m), 3.39 (2H, s), 3.91-4.07 (4H, m), 6.72-6.86 (3H, m), 7.06 (1H, d, J = 8.5Hz), 7.16 (1H, t, J = 8.0Hz ), 7.31 (1H, d, J = 8.5Hz), 7.53 (1H, s).

Example 376

Yield: 83%, ¹ H-NMR (DMSO-d ₆ ): δ1.18-1.39 (2H, m), 1.63-1.92 (5H, m), 3.07-3.24 (2H, m), 3.52 (2H, s), 3.93-4.09 (4H, m), 6.77-6.78 (3H, m), 7.10 (1H, td, J = 9.0, 2.5Hz), 7.21 (1H, t, J = 8.0Hz), 7.41 (1H , dd, J = 9.0, 4.5Hz), 7.69 (1H, dd, J = 9.0, 2.5Hz), 12.34 (1H, br).

Example 377

Yield: 51%, ¹ H-NMR (DMSO-d ₆ ): δ1.18-1.35 (2H, m), 1.63-1.93 (5H, m), 3.09-3.26 (2H, m), 3.52 (2H, s), 3.95-4.13 (4H, m), 6.77-6.90 (3H, m), 7.20 (1H, t, J = 8.0Hz), 7.31 (1H, t, J = 8.0Hz), 7.43 (2H, t , J = 8.0Hz), 7.48 (1H, d, J = 8.5Hz), 7.57 (1H, d, J = 8.5Hz), 7.66 (2H, d, J = 8.0Hz), 8.07 (1H, s), 12.31 (1H, br).

Example 378

Yield: 77%, ¹ H-NMR (DMSO-d ₆ ): δ1.19-1.40 (2H, m), 1.64-1.91 (5H, m), 2.98-3.14 (2H, m), 3.53 (2H, s), 3.86-4.10 (4H, m), 6.78-6.90 (3H, m), 7.16-7.26 (2H, m), 7.31-7.34 (2H, m), 7.44-7.50 (2H, m), 7.58 ( 1H, s), 12.30 (1H, s).

Example 379

Yield: 76%, ¹ H-NMR (DMSO-d ₆ ): δ1.22-1.41 (2H, m), 1.68-1.90 (5H, m), 2.97-3.13 (2H, m), 3.56 (2H, s), 3.86-3.99 (2H, m), 4.06-4.16 (2H, m), 6.84 (1H, dd, J = 8.0, 1.5Hz), 7.09 (1H, d, J = 1.5Hz), 7.20 (1H , t, J = 7.5Hz), 7.31-7.41 (3H, m), 7.43-7.51 (2H, m), 7.58 (1H, s).

Example 380

Yield: 69%, 1H-NMR (DMSO-d6): δ1.83-1.95 (2H, m), 2.73-2.83 (2H, m), 2.87-3.00 (4H, m), 3.52-3.71 (6H, m), 4.12 (2H, m), 6.83 (1H, d, J = 7.0Hz), 7.08 (1H, s), 7.18 (1H, t, J = 7.5Hz), 7.28-7.38 (3H, m), 7.40-7.47 (2H, m), 7.56 (1H, s).

Example 381

Yield: 79%, 1H-NMR (DMSO-d6): δ 1.20-1.41 (2H, m), 1.65-1.93 (5H, m), 3.05 (2H, m), 3.53 (2H, s), 3.90 -4.10 (4H, m), 6.76-6.87 (3H, m), 7.16-7.32 (3H, m), 7.38 (2H, t, J = 7.5Hz), 7.85 (2H, d, J = 7.5Hz), 12.29 (1H, s).

Example 382

Yield: 54%, 1H-NMR (CDCl3): 1.88-2.03 (2H, m), 2.73-3.04 (6H, m), 3.30 (2H, s), 3.47-3.84 (4H, m), 3.86-4.02 (2H, m), 6.59 (1H, d, J = 8.0Hz), 6.68 (1H, s), 7.07 (1H, d, J = 8.0Hz), 7.20 (1H, d, J = 11.5Hz), 7.68 (1H, d, J = 7.0Hz).

Example 383

Yield 12%, ¹ H-NMR (DMSO-d ₆ ): δ 2.25 (3H, s), 2.45-2.55 (4H, m), 3.44 (2H, s), 3.50-3.60 (4H, m), 4.47 (2H, s), 6.59 (1H, s), 6.65 (1H, s), 7.00 (1H, s), 7.28 (1H, dd, J = 8.5, 2Hz), 7.42 (1H, d, J = 8.5 Hz), 7.90 (1H, d, J = 2Hz).

Example 384

Yield 68%, ¹ H-NMR (CDCl ₃ ); δ1.60 (6H, s), 2.23 (3H, s), 2.65 (4H, t, J = 5Hz), 3.57 (2H, s), 3.62 ( 4H, t, J = 5Hz), 6.19 (1H, brs), 6.70-6.88 (3H, m), 7.24 (1H, dd, J = 8.5, 2Hz), 7.42 (1H, d, J = 8.5Hz), 7.54 (1H, d, J = 2Hz).

Example 385

Yield 64%, ¹ H-NMR (DMSO-d ₆ ): δ2.24 (3H, s), 2.51 (4H, t, J = 5.5Hz), 3.43 (2H, s), 3.62 (4H, t, J = 5.5Hz), 4.10 (2H, s), 6.53 (1H, s), 6.61 (1H, s), 6.64 (1H, s), 7.57 (2H, s), 8.24 (1H, s).

Example 386

Yield 96%, ¹ H-NMR (DMSO-d ₆ ): δ1.89-1.97 (2H, m), 2.23 (3H, s), 2.60 (2H, t, J = 4.2Hz), 2.74-2.77 ( 2H, m), 3.55 (2H, s), 3.68-3.70 (4H, m), 4.56 (2H, s), 6.58 (1H, s), 6.65 (1H, s), 6.70 (1H, s), 7.26 (1H, dd, J = 9.0, 2.1Hz), 7.39 (1H, d, J = 8.7Hz), 7.86 (1H, d, J = 2.4Hz).

Example 387

Yield 98%, ¹ H-NMR (DMSO-d ₆ ): δ1.85-2.00 (2H, m), 2.20 (3H, s), 2.55-2.65 (2H, m), 2.70-2.83 (2H, m ), 3.52 (2H, s), 3.55-3.85 (4H, m), 4.14 (2H, s), 6.52 (1H, s), 6.58-6.65 (2H, m), 7.55 (2H, s), 8.22 ( 1H, s).

Example 388

Yield 59%, 1H-NMR (CD3OD): δ 2.29 (3H, s), 2.60 (4H, t, J = 5.0Hz), 3.46-3.57 (6H, m), 4.36 (2H, s), 6.69 (1H, s), 6.75 (2H, s), 7.21 (1H, t, J = 7.5Hz), 7.33 (2H, t, J = 7.5Hz), 7.41 (1H, s), 7.45 (2H, d, J = 7.5Hz).

Example 389

Yield 67%, 1H-NMR (CD3OD): δ1.98-2.12 (2H, m), 2.27 (3H, s), 2.70-2.81 (2H, m), 2.84-2.94 (2H, m), 3.65 ( 2H, s), 3.67-3.93 (4H, m), 4.39 (2H, s), 6.67 (1H, s), 6.73 (1H, s), 6.74 (1H, s), 7.27 (1H, d, J = 12.0Hz), 7.96 (1H, d, J = 7.0Hz).

Example 390

Yield 97%, 1H-NMR (DMSO-d6): δ1.15 (3H, d, J = 6Hz), 2.18-2.33 (1H, m), 2.58-2.70 (1H, m), 2.70-2.83 (1H , m), 3.15-3.30 (2H, m), 3.35-3.50 (1H, m), 3.65-3.80 (1H, m), 3.83 (1H, d, J = 11Hz), 3.93 (1H, d, J = 14Hz), 4.65 (2H, s), 6.78 (1H, d, J = 8Hz), 6.90-6.95 (2H, m), 7.24 (1H, t, J = 8Hz), 7.56 (2H, s), 8.24 ( 1H, s), 13.0 (1H, brs).

Example 391

Yield 86%, 1H-NMR (DMSO-d6): δ1.13 (3H, d, J = 6Hz), 2.17 (3H, s), 2.20-2.30 (1H, m), 2.55-2.65 (1H, m ), 2.68-2.80 (1H, m), 3.15-3.50 (3H, m), 3.65-3.75 (1H, m), 3.82 (1H, d, J = 9Hz), 3.88 (1H, d, J = 13.5Hz ), 4.68 (2H, s), 6.80 (1H, s), 6.83 (1H, d, J = 7.5Hz), 7.09 (1H, d, J = 7.5Hz), 7.56 (2H, s), 8.23 (1H , s), 12.30 (1H, brs).

Example 392

Yield 86%, 1H-NMR (DMSO-d6): δ1.14 (3H, d, J = 6Hz), 2.20-2.25 (1H, m), 2.26 (3H, s), 2.55-2.65 (1H, m ), 2.70-2.80 (1H, m), 3.10-3.50 (3H, m), 3.70-3.82 (3H, m), 4.63 (2H, s), 6.61 (1H, s), 6.70 (1H, s), 6.75 (1H, s), 7.55-7.59 (2H, m), 8.24 (1H, s), 12.9 (1H, brs).

Example 393

Yield 73%, 1H-NMR (DMSO-d6): δ1.03 (6H, d, J = 6Hz), 2.25 (3H, s), 2.60-2.80 (2H, m), 2.95-3.10 (2H, m ), 3.71 (2H, s), 3.80-3.85 (2H, m), 4.61 (2H, s), 6.55 (1H, s), 6.76 (2H, s), 7.28 (1H, dd, J = 8.5, 2Hz ), 7.42 (1H, d, J = 8.5Hz), 7.90 (1H, d, J = 2Hz), 12.95 (1H, s).

Example 394

Yield 82%, 1H-NMR (DMSO-d6): δ1.04 (6H, d, J = 6Hz), 2.25 (3H, s), 2.70-2.80 (2H, m), 2.95-3.15 (2H, m ), 3.71 (2H, s), 3.80-3.95 (2H, m), 4.61 (2H, s), 6.55 (1H, s), 6.76 (2H, s), 7.57 (2H, s), 8.24 (1H, s), 12.94 (1H, brs).

Example 395

Yield 72%, 1H-NMR (DMSO-d6): δ1.31 (3H, d, J = 6.5Hz), 2.02-2.24 (2H, m), 2.25 (3H, s), 2.70 (1H, d, J = 11Hz), 2.88 (1H, d, J = 12Hz), 3.20-3.35 (1H, m), 3.37 (1H, d, J = 13.5Hz), 3.51 (1H, d, J = 13.5Hz), 3.77 (1H, d, J = 13Hz), 4.10-4.25 (1H, m), 4.60 (2H, s), 6.61 (1H, s), 6.70 (1H, s), 6.73 (1H, s), 7.26 (1H , dd, J = 8.5, 2Hz), 7.40 (1H, d, J = 8.5Hz), 7.88 (1H, d, J = 2Hz), 13.00 (1H, brs).

Example 396

Yield 76%, 1H-NMR (DMSO-d6): δ1.34 (3H, d, J = 6.5Hz), 2.06-2.30 (5H, m), 2.73 (1H, d, J = 10.5Hz), 2.90 (1H, d, J = 10.5Hz), 3.30-3.56 (3H, m), 3.84 (1H, d, J = 11.5Hz), 4.19-4.32 (1H, m), 4.38 (2H, s), 6.58 ( 1H, s), 6.67 (1H, s), 6.70 (1H, s), 7.56 (2H, s), 8.24 (1H, s).

Example 397

Yield 82%, 1H-NMR (CDCl3): δ0.97 (3H, t, J = 7.5Hz), 1.62-1.85 (2H, m), 2.28 (3H, s), 2.80-3.00 (3H, m) , 3.55 (1H, d, J = 13Hz), 3.65-3.77 (1H, m), 3.77-3.90 (3H, m), 4.23 (1H, d, J = 13Hz), 4.65 (2H, s), 6.63 ( 1H, s), 6.80 (1H, s), 7.01 (1H, s), 7.53 (1H, d, J = 8.5Hz), 7.56 (1H, d, J = 8.5Hz), 7.84 (1H, s).

Example 398

Yield 92%, 1H-NMR (CDCl3): δ 2.27 (3H, s), 2.27-2.40 (1H, m), 2.90 (1H, d, J = 13.5Hz), 3.06 (1H, d, J = 11.5Hz), 3.32-3.55 (3H, m), 3.80 (1H, d, J = 13.5Hz), 3.95-4.10 (2H, m), 5.30 (2H, s), 6.63 (1H, s), 6.66 ( 1H, s), 6.72 (1H, s), 7.30-7.45 (3H, m), 7.45-7.60 (4H, m), 7.82 (1H, s).

Example 399

Yield 81%, 1H-NMR (CDCl3): δ1.32 (3 H, d, J = 6.6 Hz), 2.26 (3 H, s), 2.76 (1 H, s), 2.93-3.02 (2 H, m), 3.37 (1 H, d, J = 12.9 Hz), 3.49-3.56 (1 H, m), 3.70 (2 H s), 3.87 (1 H, d, J = 10.8 Hz), 4.25 (1 H , d, J = 12.9 Hz), 4.63 (2 H, s), 6.62 (1 H, s), 6.77 (1 H, s), 6.99 (1 H, s), 7.24 (1 H, dd, J = 2.1, 8.7 Hz), 7.42 (1 H, d, J = 8.7 Hz), 7.54 (1 H, d, J = 2.1 Hz)

Example 400

Yield 80%, 1H-NMR (CDCl3): δ1.33 (3 H, d, J = 6.0 Hz), 2.27 (3 H, s), 2.76 (1 H, br), 2.93-3.02 (2 H, m), 3.38 (1 H, d, J = 12.6 Hz), 3.49-3.56 (1 H, m), 3.71 (2 H, s), 3.87 (1 H, d, J = 11.1 Hz), 4.25 (1 H, d, J = 12.6 Hz), 4.63 (2 H, s), 6.62 (1 H, s), 6.77 (1 H, s), 6.99 (1 H, s), 7.24 (1 H, dd, J = 1.8, 8.7 Hz), 7.42 (1 H, d, J = 8.7 Hz), 7.54 (1 H, d, J = 1.8 Hz)

Example 401

Yield 88%, 1H-NMR (CDCl3): δ1.41 (3H, d, J = 6.5Hz), 2.29 (3H, s), 2.35 (1H, td, J = 12, 3.5Hz), 2.48 (1H , dd, J = 12, 4Hz), 2.91 (1H, d, J = 12Hz), 3.26 (1H, d, J = 11.5Hz), 3.52 (1H, d, J = 13Hz), 3.54-3.65 (1H, m), 3.80 (1H, d, J = 13Hz), 3.89 (1H, d, J = 13Hz), 4.25-4.36 (1H, m), 4.62 (2H, s), 6.69 (1H, s), 6.75 ( 1H, s), 6.86 (1H, s), 7.52 (1H, d, J = 8.5Hz), 7.56 (1H, d, J = 8.5Hz), 7.83 (1H, s).

Example 402

Yield 94%, 1H-NMR (CDCl3): δ0.96 (3H, t, J = 7Hz), 1.60-1.86 (2H, m), 2.29 (3H, s), 2.75-2.86 (1H, m), 2.87-3.00 (1H, m), 3.00-3.10 (1H, m), 3.51 (1H, d, J = 13Hz), 3.65-3.80 (1H, m), 3.80-3.93 (3H, m), 4.28 (1H , d, J = 13Hz), 4.63 (1H, d, J = 16.5Hz), 4.71 (1H, d, J = 16.5Hz) 6.63 (1H, s), 6.81 (1H, s), 7.02 (1H, s ), 7.53 (1H, d, J = 8.5Hz), 7.57 (1H, d, J = 8.5Hz), 7.84 (1H, s).

Example 403

Yield 86%, 1H-NMR (CDCl3): δ0.96 (3H, t, J = 7.5Hz), 1.62-1.86 (2H, m), 2.28 (3H, s), 2.76-2.88 (1H, m) , 2.89-3.00 (1H, m), 3.01-3.13 (1H, m), 3.52 (1H, d, J = 13Hz), 3.65-3.93 (4H, m), 4.30 (1H, d, J = 13Hz), 4.63 (1H, d, J = 16.5Hz), 4.72 (1H, d, J = 16.5Hz), 6.63 (1H, s), 6.82 (1H, s), 7.03 (1H, s), 7.49-7.60 (2H m), 7.84 (1H, s).

Example 404

Yield 68%, 1H-NMR (DMSO-d6): δ0.89 (3H, t, J = 7.0Hz), 1.22-1.69 (4H, m), 2.22-2.37 (1H, m), 2.24 (3H, s), 2.49-2.62 (1H, m), 2.68-2.82 (1H, m), 3.28 (1H, d, J = 13.5Hz), 3.38-3.68 (3H, m), 3.69-3.80 (1H, m) , 3.83 (1H, d, J = 13.5Hz), 4.28 (2H, s), 6.53 (1H, s), 6.64 (1H, s), 6.67 (1H, s), 7.53 (1H, d, J = 8.5 Hz), 7.57 (1H, d, J = 8.5Hz), 8.22 (1H, s).

Example 405

Yield 87%, 1H-NMR (CDCl3): δ0.90 (3 H, t, J = 7.2 Hz), 1.19-1.28 (1 H, m), 1.45-1.52 (1 H, m), 1.65 (2 H, br), 2.78 (3 H, s), 2.93 (2 H, br), 3.05 (1 H, br), 3.52 (1 H, d, J = 12.6 Hz), 3.67-3.74 (1 H, m ), 3.81-3.91 (3 H, m), 4.30 (1 H, d), 4.66 (2 H, q, J = 11.1 Hz), 6.62 (1 H, s), 6.81 (1 H, s), 7.03 (1 H, s), 7.52-7.61 (2 H, m), 7.84 (1 H, s)

Example 406

Yield 82%, 1H-NMR (DMSO-d6): δ0.88 (3H, t, J = 6.5Hz), 1.18-1.70 (6H, m), 2.23 (3H, s), 2.24-2.37 (1H, m), 2.48-2.60 (1H, m), 2.67-2.80 (1H, m), 3.27 (1H, d, J = 13.5Hz), 3.36-3.82 (4H, m), 3.83 (1H, d, J = 13.5Hz), 4.31 (2H, s), 6.54 (1H, s), 6.65 (1H, s), 6.67 (1H, s), 7.53 (1H, d, J = 9.0Hz), 7.56 (1H, d, J = 9.0Hz), 8.22 (1H, s).

Example 407

Yield 70%, 1H-NMR (DMSO-d6): δ0.88 (6H, t, J = 6.5Hz), 1.21-1.35 (1H, m), 1.45-1.58 (1H, m), 1.58-1.73 ( 1H, m), 2.23 (3H, s), 2.32-2.43 (1H, m), 2.59-2.80 (2H, m), 3.35 (1H, d, J = 13.5Hz), 3.37-3.45 (1H, m) , 3.45-3.60 (2H, m), 3.60-3.71 (1H, m), 3.77 (1H, d, J = 13.5Hz), 4.19 (2H, s), 6.51 (1H, s), 6.63 (1H, s ), 6.66 (1H, s), 7.27 (1H, dd, J = 8.5, 2Hz), 7.40 (1H, d, J = 8.5Hz), 7.88 (1H, d, J = 2Hz).

Example 408

Yield 77%, 1H-NMR (DMSO-d6): δ0.87 (3H, d, J = 6.5Hz), 0.89 (3H, d, J = 6.5Hz), 1.21-1.36 (1H, m), 1.43 -1.57 (1H, m), 1.58-1.73 (1H, m), 2.23 (3H, s), 2.30-2.43 (1H, m), 2.60-2.79 (2H, m), 3.34 (1H, d, J = 13.5Hz), 3.35-3.72 (4H, m), 3.77 (1H, d, J = 13.5Hz), 4.25 (2H, s), 6.53 (1H, s), 6.64 (1H, s), 6.70 (1H, s), 7.27 (1H, dd, J = 8.5, 2.0Hz), 7.40 (1H, d, J = 8.5Hz), 7.88 (1H, d, J = 2.0Hz).

Example 409

Yield 76%, 1H-NMR (CDCl3): δ0.77 (3H, d, J = 6.5Hz), 0.92 (3H, d, J = 6.5Hz), 1.40-1.75 (3H, m), 2.25 (3H , s), 2.80-3.05 (3H, m), 3.46 (1H, d, J = 13Hz), 3.60-3.95 (4H, m), 4.22 (1H, d, J = 13Hz), 4.56 (1H, d, J = 16Hz), 4.65 (1H, d, J = 16Hz), 6.63 (1H, s), 6.77 (1H, s), 7.01 (1H, s), 7.52 (1H, d, J = 8.5Hz), 7.59 (1H, d, J = 8.5Hz), 7.83 (1H, s).

Example 410

Yield 79%, 1H-NMR (CDCl3): δ1.33 (3H, d, J = 6.5Hz), 2.28 (3H, s), 2.70-2.83 (1H, m), 2.92-3.08 (2H, m) , 3.38 (1H, d, J = 13Hz), 3.54-3.65 (1H, m), 3.70-3.82 (2H, m), 3.87-3.97 (1H, m), 4.25 (1H, d, J = 13Hz), 4.60 (1H, d, J = 16.5Hz), 4.67 (1H, d, J = 16.5Hz), 6.64 (1H, s), 6.78 (1H, s), 6.99 (1H, s), 7.26 (1H, d , J = 11.5Hz), 7.74 (1H, d, J = 7Hz).

Example 411

Yield 93%, 1H-NMR (CDCl3): δ0.92 (3H, t, J = 7.0Hz), 1.42-1.74 (2H, m), 2.13 (3H, s), 2.27-2.57 (2H, m) , 2.62-2.82 (1H, m), 3.08-3.24 (1H, m), 3.35-3.77 (4H, m), 3.80-3.97 (1H, m), 4.37 (2H, s), 6.58 (1H, s) , 6.63 (1H, s), 6.74 (1H, s), 7.20 (1H, d, J = 11.5Hz), 7.66 (1H, d, J = 7.0Hz).

Example 412

Yield 80%, 1H-NMR (CDCl3): δ 1.18 (6H, d, J = 6.0Hz), 2.25 (3H, s), 2.78-2.94 (2H, m), 3.13-3.29 (2H, m) , 3.78-3.94 (4H, m), 4.54 (2H, s), 6.61 (1H, s), 6.74 (1H, s), 6.80 (1H, s), 7.24 (1H, d, J = 11.5Hz), 7.72 (1H, d, J = 7.0Hz).

Example 413

Yield 82%, ¹ H-NMR (DMSO-d ₆ ): δ3.52 (2H, s), 3.57 (8H, s), 4.65 (2H, s), 6.87 (2H, s), 6.98 (1H, s), 7.29 (1H, d, J = 8.7,2.4 Hz), 7.42 (1H, dd, J = 8.7 Hz), 7.91 (1H, d, J = 2.4 Hz)

Example 414

Yield 83%, ¹ H-NMR (DMSO-d ₆ ): δ2.40-2.55 (4H, m), 3.46 (2H, s), 3.53-3.56 (4H, m), 4.55 (2H, s), 6.85 (2H, d, J = 8.4 Hz), 7.22 (2H, d, J = 8.4 Hz), 7.28 (1H, dd, J = 8.4, 2.4 Hz), 7.42 (1H, d, J = 8.4 Hz), 7.90 (1H, d, J = 2.4 Hz).

Example 415

Yield 51%, ¹ H-NMR (DMSO-d ₆ ): δ 2.16 (3H, s), 2.40-2.55 (4H, m), 3.47 (2H, s), 3.50-3.60 (4H, m), 4.67 (2H, s), 6.75-6.85 (2H, m), 7.08 (1H, d, J = 7.5Hz), 7.27 (1H, dd, J = 8.5, 1Hz), 7.41 (1H, d, J = 8Hz ), 7.88 (1H, d, J = 2Hz), 12.9 (1H, brs).

Example 416

Yield 92%, ¹ H-NMR (DMSO-d ₆ ): δ2.19 (3H, s), 2.50-2.55 (4H, m), 3.52 (4H, s), 3.55-3.58 (4H, m), 6.76 (1H, d, J = 8.4 Hz), 7.07 (1H, d, J = 8.4 Hz), 7.11 (1H, s), 7.28 (1H, dd, 8.7, 1.5Hz), 7.42 (1H, d, J = 8.7 Hz), 7.90 (1H, d, J = 1.5 Hz).

Example 417

Yield 91%, ¹ H-NMR (DMSO-d ₆ ): δ 1.90 (2H, m), 2.14 (3H, s), 2.58 (2H, m), 2.73 (2H, m), 3.50 (2H, s), 3.65-3.70 (4H, m), 4.49 (2H, s), 6.68 (1H, d, J = 8.4 Hz), 7.01 (1H, d, J = 8.4 Hz), 705 (1H, s), 7.26 (1H, dd, J = 8.7, 2.1Hz), 7.40 (1H, d, J = 8.7Hz), 7.88 (1H, d, J = 2.1Hz).

Example 418

Yield 28%, 1H-NMR (CDCl3): δ1.33 (6H, d, J = 6.0Hz), 2.27 (3H, s), 2.87-3.04 (2H, m), 3.12-3.29 (2H, m) , 4.02 (2H, s), 4.30 (2H, d, J = 13.0Hz), 4.59 (2H, s), 6.70 (2H, s), 6.83 (1H, s), 7.35-7.44 (1H, m), 7.52-7.61 (1H, m), 7.65 (1H, d, J = 7.0Hz), 7.86 (1H, d, J = 7.0Hz), 8.51 (1H, s).

Example 419

Yield 37%, 1H-NMR (CDCl3): δ1.37 (3H, d, J = 6.5Hz), 2.26 (3H, s), 2.84-3.23 (3H, m), 3.45 (1H, d, J = 13.0Hz), 3.71-4.14 (4H, m), 4.34 (1H, d, J = 13.0Hz), 4.62 (1H, d, J = 16.0Hz), 4.69 (1H, d, J = 16.0Hz), 6.60 (1H, s), 6.81 (1H, s), 7.12 (1H, s), 7.37-7.47 (1H, m), 7.53-7.63 (1H, m), 7.67 (1H, d, J = 8.0Hz), 7.89 (1H, d, J = 8.0Hz), 8.52 (1H, s).

Example 420

Yield 55%, 1H-NMR (CDCl3): δ1.24 (6H, d, J = 6.0Hz), 2.20 (3H, s), 2.77-2.92 (2H, m), 3.03-3.18 (2H, m) , 3.89 (2H, s), 4.23 (2H, d, J = 11.5Hz), 4.48 (2H, s), 6.61 (1H, s), 6.69 (1H, s), 6.78 (1H, s), 7.46 ( 1H, dd, J = 9.0, 2.0Hz), 7.54 (1H, d, J = 9.0Hz), 7.81 (1H, d, J = 2.0Hz), 8.47 (1H, s).

Example 421

Yield 60%, 1H-NMR (CDCl3): δ1.32 (6H, d, J = 6.0Hz), 2.27 (3H, s), 2.85-3.00 (2H, m), 3.16-3.30 (2H, m) , 3.98 (2H, s), 4.29-4.41 (2H, m), 4.60 (2H, s), 6.67 (1H, s), 6.73 (1H, s), 6.83 (1H, s), 7.65-7.75 (2H , m), 8.12 (1H, s), 8.57 (1H, s).

Example 422

Yield 46%, ¹ H-NMR (DMSO-d ₆ ): δ3.53 (2H, s), 3.54-3.74 (8H, m), 4.87 (2H, s), 6.79-6.90 (3H, m), 7.22 (1H, t, J = 7.5Hz), 7.32 (1H, dd, J = 8.5, 2.0Hz), 7.46 (1H, d, J = 8.5Hz), 7.94 (1H, d, J = 2.0Hz), 12.31 (1H, br).

Example 423

Yield 21%, ¹ H-NMR (DMSO-d ₆ ): δ2.45-2.55 (4H, m), 3.33 (2H, s), 3.55-3.60 (4H, m), 6.50-6.60 (1H, m ), 7.15-7.20 (1H, m), 7.29 (1H, dd, J = 8.5, 2Hz), 7.43 (1H, d, J = 8.5Hz), 7.92 (1H, d, J = 2.5Hz).

Example 424

Yield 76%, ¹ H-NMR (DMSO-d ₆ ): δ2.58 (4H, s), 3.35 (2H, s), 3.59 (2H, s), 3.81 (2H, s), 7.06 (1H, d, J = 3.6Hz), 7.29 (1H, dd, J = 8.7, 2.1Hz), 7.43 (1H, d, J = 8.4Hz), 7.60 (1H, d, J = 3.3Hz), 7.91 (1H, d, J = 2.1Hz), 12.99 (1H, brs).

Example 425

Yield 76%, ¹ H-NMR (DMSO-d ₆ ): δ1.25 (2H, m), 3.30 (2H, m), 3.62 (2H, m), 4.20 (2H, m), 4.45 (2H, brs), 7.33 (1H, dd, J = 8.4, 1.8Hz), 7.49 (1H, d, J = 8.7Hz), 7.69-7.71 (2H, m), 7.98 (1H, d, J = 1.8Hz), 8.02 (2H, d, J = 8.1Hz).

Example 426

Yield 81%, ¹ H-NMR (DMSO-d ₆ ): δ2.45-2.50 (4H, m), 3.45-3.60 (8H, m), 7.15-7.35 (5H, m), 7.42 (1H, d , J = 8.5Hz), 7.91 (1H, d, J = 2Hz), 12.31 (1H, brs).

Example 427

Yield 94%, ¹ H-NMR (DMS-d ₆ ): δ2.50-2.55 (4H, m), 3.52 (4H, s), 3.57 (4H, s), 7.17 (1H, s), 7.24 ( 2H, s), 7.29 (1H, dd, J = 2.1, 8.4Hz), 7.42 (1H, d, J = 8.4Hz), 7.91 (1H, d, J = 2.1 Hz)

Example 428

Yield 86%, ¹ H-NMR (DMS-d ₆ ): δ1.92 (2H, s), 2.61 (2H, s), 2.77 (2H, s), 3.53 (2H, s), 3.61 (2H, s), 3.60-3.65 (4H, m), 7.15 (1H, s), 7.21 (1H, s), 7.22 (1H, s), 7.26 (1H, dd, J = 8.4, 2.1Hz), 7.40 (1H , d, J = 8.4 Hz), 7.88 (1H, d, J = 2.1 Hz).

Example 429

Yield 18%, 1H-NMR (DMSO-d6): δ1.85-2.00 (2H, m), 2.57-2.68 (2H, m), 2.74-2.85 (2H, m), 3.52 (2H, s), 3.61 (2H, s), 3.62-3.85 (4H, m), 7.09-7.31 (4H, m), 7.52-7.58 (2H, m), 8.22 (1H, s).

Example 430

Yield 95%, 1H-NMR (DMSO-d6): δ1.05 (6H, d, J = 6.5Hz), 2.65-2.80 (2H, m), 3.04-3.15 (2H, m), 3.55 (2H, s), 3.79 (2H, s), 3.83-3.95 (2H, m), 7.05-7.15 (1H, m), 7.20-7.30 (3H, m), 7.57 (2H, s), 8.24 (1H, s) , 12.27 (1H, brs).

Example 431

Yield 61%, 1H-NMR (CDCl3): δ1.08 (6H, d, J = 6.5Hz), 2.74-2.86 (2H, m), 3.08 (1H, d, J = 13Hz), 3.12 (1H, d, J = 13Hz), 3.62 (2H, s), 3.78 (2H, s), 3.86-3.95 (2H, m), 7.16-7.18 (2H, m), 7.34 (1H, s), 7.52 (1H, d, J = 8.5Hz), 7.57 (1H, d, J = 8.5Hz), 7.84 (1H, s).

Example 432

Yield 87%, 1H-NMR (DMSO-d6): δ1.01 (3H, d, J = 6.5Hz), 1.33 (3H, d, J = 6.5Hz), 2.25-2.35 (1H, m), 2.75 -2.85 (1H, m), 3.08-3.20 (1H, m), 3.49 (1H, d, J = 14Hz), 3.56 (2H, s), 3.63-3.75 (3H, m), 4.23-4.35 (1H, m), 7.10-7.20 (1H, m), 7.20-7.35 (3H, m), 7.50-7.60 (2H, m), 8.21 (1H, s), 12.23 (1H, brs).

Example 433

Yield 87%, 1H-NMR (DMSO-d6): δ1.33 (3H, d, J = 6.5Hz), 2.10-2.30 (2H, m), 2.72 (1H, d, J = 11.5Hz), 2.94 (1H, d, J = 12Hz), 3.35-3.50 (2H, m), 3.57 (2H, s), 3.60 (1H, d, J = 13.5Hz), 3.75-3.90 (1H, m), 4.20-4.30 (1H, m), 7.15-7.32 (4H, m), 7.56 (2H, s), 8.22 (1H, s), 12.28 (1H, brs).

Example 434

Yield 82%, 1H-NMR (DMSO-d6): δ1.16 (3H, d, J = 6Hz), 2.15-2.35 (1H, m), 2.55-2.68 (1H, m), 2.70-2.80 (1H , m), 3.15-3.30 (2H, m), 3.35-3.50 (1H, m), 3.56 (2H, s), 3.70-3.80 (1H, m), 3.80-3.90 (1H, m), 3.97 (1H , d, J = 13.5Hz), 7.10-7.35 (4H, m), 7.56 (2H, s), 8.23 (1H, s), 12.29 (1H, brs).

Example 435

Yield 98%, 1H-NMR (CDCl3): δ1.00 (3 H, t, J = 7.5 Hz), 1.59-1.69 (1 H, m), 1.73-1.80 (1 H, m), 2.37-2.45 (1 H, m), 2.54-2.59 (1 H, m), 2.80-2.86 (1 H, m), 3.34-3.54 (3 H, m), 3.59-3.63 (1 H, m), 3.63 (2 H, s), 3.79 (1 H, dd, J = 2.7, 13.2 Hz), 4.04 (1 H, d, J = 13.2 Hz), 7.20-7.29 (5 H, m), 7.42 (1 H, d, J = 8.7 Hz), 7.53 (1 H, d, J = 2.1 Hz)

Example 436

Yield 96%, 1H-NMR (CDCl3): δ 0.92 (6 H, dd, J = 6.3, 16.2 Hz), 1.38-1.47 (1 H, m), 1.51-1.59 (1 H, m), 1.64 -1.75 (1 H, m), 2.43-2.51 (1 H, m), 2.71-2.76 (1 H, m), 2.79-2.87 (1 H, m), 3.40 (2 H, dt, J = 3.0, 13.2 Hz), 3.57-3.64 (2 H, m), 3.63 (2 H, s), 3.76 (1 H, dd, J = 3.0, 12.9 Hz), 3.99 (1 H, d, J = 13.2 Hz), 7.21-7.31 (5 H, m), 7.43 (1 H, d, J = 8.4 Hz), 7.53 (1 H, d, J = 2.4 Hz)

Example 437

Yield 89%, 1H-NMR (CDCl3): δ1.25 (3 H, d, J = 6.0 Hz), 2.30-2.38 (1 H, m), 2.68-2.74 (1 H, m), 2.83 (1 H, dt, J = 3.9, 12.0 Hz), 3.18-3.28 (2 H, m), 3.39-3.49 (1 H, m), 3.63 (2 H, s), 3.63-3.70 (1 H, m), 3.86 (1 H, dd, J = 2.4, 12.0 Hz), 4.10 (1 H, d, J = 13.2 Hz), 7.19-7.30 (5 H, m), 7.43 (1 H, d, J = 8.4 Hz) , 7.53 (1 H, d, J = 2.4 Hz)

Example 438

Yield 91%, 1H-NMR (CDCl3): δ1.30 (3 H, d, J = 6.0 Hz), 2.40 (1 H, t, J = 9.6 Hz), 2.78 (1 H, br), 2.88 ( 1 H, br), 3.33 (2 H, d, J = 12.6 Hz), 3.48-3.54 (1 H, m), 3.64 (2 H, s), 3.72 (1 H, d, J = 13.2 Hz), 3.89 (1 H, d, J = 10.2 Hz), 4.16 (1 H, d, J = 13.2 Hz), 7.22-7.33 (5 H, m), 7.43 (1 H, d, J = 8.7 Hz), 7.54 (1 H, d, J = 2.1 Hz)

Example 439

Yield 96%, 1H-NMR (CDCl3): δ1.26 (3H, d, J = 6Hz), 2.25-2.40 (4H, m), 2.65-2.75 (1H, m), 2.80-2.90 (1H, m ), 3.20 (1H, d, J = 13Hz), 3.25-3.30 (1H, m), 3.45-3.53 (1H, m), 3.61 (2H, s), 3.68-3.80 (1H, m), 3.84-3.95 (1H, m), 4.07 (1H, d, J = 13Hz), 7.03 (2H, s), 7.10 (1H, s), 7.51 (1H, d, J = 8.5Hz), 7.53 (1H, d, J = 8.5Hz), 7.83 (1H, s)

Example 440

Yield 67%, 1H-NMR (DMSO-d6): δ1.31 (3H, d, J = 6.5Hz), 2.03-2.25 (2H, m), 2.70 (1H, d, J = 11.5Hz), 2.91 (1H, d, J = 12Hz), 3.35-3.43 (2H, m), 3.56 (2H, s), 3.56-3.65 (1H, m), 3.79 (1H, d, J = 11Hz), 4.15-4.25 ( 1H, m), 7.15 (1H, d, J = 7Hz), 7.20-7.33 (4H, m), 7.41 (1H, d, J = 8.5Hz), 7.89 (1H, d, J = 1.5Hz), 12.30 (1H, brs).

Example 441

Yield 86%, 1H-NMR (CDCl3): δ1.37 (3H, d, J = 7.0Hz), 2.23 (1H, td, J = 11.0, 3.5Hz), 2.31 (1H, dd, J = 11.0, 3.5Hz), 2.71 (1H, d, J = 11.0Hz), 2.91 (1H, d, J = 11.0Hz), 3.44 (1H, d, J = 13.5Hz), 3.47 (1H, td, J = 12.5, 3.5Hz), 3.60 (1H, d, J = 11.0Hz), 3.64 (2H, s), 3.83 (1H, d, J = 12.5Hz), 4.09-4.21 (1H, m), 7.14-7.33 (5H, m), 7.42 (1H, d, J = 8.5Hz), 7.53 (1H, d, J = 2.0Hz).

Example 442

Yield 94%, 1H-NMR (CDCl3): δ1.37 (3H, d, J = 6.5Hz), 2.23 (1H, td, J = 11.5, 3.5Hz), 2.25-2.30 (1H, m), 2.32 (3H, s), 2.71 (1H, d, J = 11.5Hz), 2.91 (1H, d, J = 11Hz), 3.39 (1H, d, J = 13.5Hz), 3.45-3.54 (1H, m), 3.55 (1H, d, J = 13.5Hz), 3.60 (2H, s), 3.83 (1H, d, J = 11.5Hz), 4.10-4.20 (1H, m), 7.01 (1H, s), 7.06 (1H , s), 7.09 (1H, s), 7.23 (1H, dd, J = 8.5, 2Hz), 7.42 (1H, d, J = 8.5Hz), 7.54 (1H, d, J = 2Hz).

Example 443

Yield 82%, 1H-NMR (CDCl3): δ1.37 (3H, d, J = 6.5Hz), 2.13-2.36 (5H, m), 2.70 (1H, d, J = 11.5Hz), 2.89 (1H , d, J = 11.5Hz), 3.32-3.62 (5H, m), 3.76-3.87 (1H, m), 4.07-4.22 (1H, m), 6.99 (1H, s), 7.05 (1H, s), 7.07 (1H, s), 7.22 (1H, dd, J = 8.5, 2.0Hz), 7.42 (1H, d, J = 8.5Hz), 7.53 (1H, d, J = 2.0Hz).

Example 444

Yield 87%, 1H-NMR (DMSO-d6): δ1.33 (3H, d, J = 6.5Hz), 2.10-2.30 (2H, m), 2.72 (1H, d, J = 11.5Hz), 2.93 (1H, d, J = 11.5Hz), 3.30-3.50 (2H, m), 3.56 (2H, s), 3.59 (1H, d, J = 13.5Hz), 3.86 (1H, d, J = 12.5Hz) , 4.20-4.30 (1H, m), 7.10-7.35 (4H, m), 7.56 (2H, s), 8.24 (1H, s), 12.43 (1H, brs).

Example 445

Yield 96%, 1H-NMR (CDCl3): δ1.34 (3H, d, J = 6.5Hz), 2.14 (1H, td, J = 11.5, 3.5Hz), 2.25 (1H, dd, J = 11.5, 3.5Hz), 2.66 (1H, d, J = 11.5Hz), 2.83 (1H, d, J = 11.5Hz), 3.37 (1H, d, J = 13.5Hz), 3.38-3.55 (4H, m), 3.82 (1H, d, J = 11.5Hz), 4.08-4.22 (1H, m), 7.10 (1H, s), 7.14-7.23 (3H, m), 7.45-7.56 (2H, m), 7.81 (1H, s ).

Example 446

Yield 98%, 1H-NMR (CDCl3): δ 1.39 (3H, d, J = 6.5Hz), 2.23 (1H, td, J = 12, 3.5Hz), 2.25-2.31 (1H, m), 2.32 (3H, s), 2.73 (1H, d, J = 11.5Hz), 2.92 (1H, d, J = 12Hz), 3.41 (1H, d, J = 13Hz), 3.45-3.55 (1H, m), 3.56 (1H, d, J = 13Hz), 3.59 (2H, s), 3.88 (1H, d, J = 12Hz), 4.17-4.28 (1H, m), 7.01 (1H, s), 7.06 (1H, s) , 7.09 (1H, s), 7.51 (1H, d, J = 8.5Hz), 7.55 (1H, d, J = 8.5Hz), 7.83 (1H, s).

Example 447

Yield 72%, 1H-NMR (CDCl3): δ1.39 (3H, d, J = 6.5Hz), 2.13-2.34 (5H, m), 2.71 (1H, d, J = 11.5Hz), 2.90 (1H , d, J = 11.5Hz), 3.39 (1H, d, J = 13.0Hz), 3.43-3.60 (4H, m), 3.87 (1H, d, J = 12.5Hz), 4.13-4.26 (1H, m) , 6.99 (1H, s), 7.05 (2H, s), 7.46-7.58 (2H, m), 7.83 (1H, s).

Example 448

Yield 90%, 1H-NMR (CDCl3): δ1.40 (3H, d, J = 6.5Hz), 2.26 (1H, td, J = 12, 3.5Hz), 2.35 (1H, dd, J = 11.5, 3.5Hz), 2.72 (1H, d, J = 11.5Hz), 2.91 (1H, d, J = 12Hz), 3.43 (1H, d, J = 13.5Hz), 3.52 (1H, td, J = 12.5, 3.5 Hz), 3.57 (1H, d, J = 13.5Hz), 3.64 (2H, s), 3.85-3.95 (1H, m), 4.19-4.30 (1H, m), 7.18 (1H, s), 7.21 (1H , s), 7.29 (1H, s), 7.51 (1H, d, J = 8.5Hz), 7.57 (1H, d, J = 8.5Hz), 7.84 (1H, s).

Example 449

Yield 68%, 1H-NMR (CDCl3): δ0.85 (3H, t, J = 7.5Hz), 1.82-1.99 (2H, m), 2.17-2.29 (2H, m), 2.78-2.92 (2H, m), 3.37-3.51 (1H, m), 3.42 (1H, d, J = 13.0Hz), 3.59 (1H, d, J = 13.0Hz), 3.65 (2H, s), 3.76-3.87 (1H, m ), 3.93-4.04 (1H, m), 7.16-7.34 (5H, m), 7.39 (1H, d, J = 8.5Hz), 7.52 (1H, d, J = 2.0Hz).

Example 450

Yield 95%, 1H-NMR (DMSO-d6): δ0.79 (3H, t, J = 7.5Hz), 1.72-1.95 (2H, m), 2.07-2.20 (2H, m), 2.81 (1H, d, J = 11Hz), 2.89 (1H, d, J = 11Hz), 3.25-3.39 (2H, m), 3.40 (1H, d, J = 13.5Hz), 3.55 (2H, s), 3.59 (1H, d, J = 13.5Hz), 3.80-3.95 (1H, m), 7.13-7.34 (5H, m), 7.38 (1H, d, J = 8.5Hz), 7.87 (1H, d, J = 2Hz), 12.45 (1H, brs).

Example 451

Yield 96%, 1H-NMR (CDCl3): δ0.86 (3H, t, J = 7.5Hz), 1.80-2.00 (2H, m), 2.16-2.29 (2H, m), 2.33 (3H, s) , 2.79-2.94 (2H, m), 3.38 (1H, d, J = 13.5Hz), 3.50 (1H, td, J = 12.5, 3.5Hz), 3.57 (1H, d, J = 13.5Hz), 3.61 ( 2H, s), 3.75-3.87 (1H, m), 3.93-4.03 (1H, m), 7.02 (1H, s), 7.06 (1H, s), 7.08 (1H, s), 7.21 (1H, dd, J = 8.5, 2Hz), 7.39 (1H, d, J = 8.5Hz), 7.52 (1H, d, J = 2Hz).

Example 452

Yield 77%, 1H-NMR (DMSO-d6): δ0.80 (3H, t, J = 7.5Hz), 1.67-1.97 (2H, m), 2.03-2.19 (2H, m), 2.28 (3H, s), 2.81 (1H, d, J = 11.5Hz), 2.89 (1H, d, J = 11.0Hz), 3.27-3.44 (2H, m), 3.48 (2H, s), 3.55 (1H, d, J = 13.5Hz), 3.81-3.95 (2H, m), 6.96 (1H, s), 7.02 (2H, s), 7.26 (1H, dd, J = 8.5, 2.0Hz), 7.38 (1H, d, J = 8.5Hz), 7.87 (1H, d, J = 2.0Hz).

Example 453

Yield 96%, 1H-NMR (DMSO-d6): δ0.80 (3H, t, J = 7.5Hz), 1.76-1.96 (2H, m), 2.09-2.20 (2H, m), 2.82 (1H, d, J = 11.5Hz), 2.89 (1H, d, J = 11.5Hz), 3.30-3.42 (2H, m), 3.43 (1H, d, J = 13.5Hz), 3.56 (2H, s), 3.60 ( 1H, d, J = 13.5Hz), 3.88-4.00 (1H, m), 7.12-7.32 (4H, m), 7.51 (1H, d, J = 8.5Hz), 7.56 (1H, d, J = 8.5Hz ), 8.21 (1H, s), 12.3 (1H, brs).

Example 454

Yield 89%, 1H-NMR (CDCl3): δ0.87 (3H, t, J = 7.5Hz), 1.85-2.00 (2H, m), 2.23 (2H, td, J = 12.5, 3.5Hz), 2.34 (3H, s), 2.81-2.96 (2H, m), 3.38 (1H, d, J = 13.5Hz), 3.49 (1H, td, J = 12.5, 3.5Hz), 3.58 (1H, d, J = 13.5 Hz), 3.62 (2H, s), 3.80-3.95 (1H, m), 3.97-4.10 (1H, m), 7.02 (1H, s), 7.06 (1H, s), 7.08 (1H, s), 7.46 -7.50 (2H, m), 7.81 (1H, s).

Example 455

Yield 89%, 1H-NMR (CDCl3): δ0.88 (3H, t, J = 7.5Hz), 1.93 (2H, quant, J = 7.5Hz), 2.19-2.32 (2H, m), 2.78-2.93 (2H, m), 3.40 (1H, d, J = 13.5Hz), 3.49 (1H, td, J = 12.5, 3.5Hz), 3.57 (1H, d, J = 13.5Hz), 3.64 (2H, s) , 3.84-3.95 (1H, m), 3.96-4.10 (1H, m), 7.16 (1H, s), 7.22 (1H, s), 7.28 (1H, s), 7.45-7.57 (2H, m), 7.82 (1H, s).

Example 456

Yield 93%, 1H-NMR (CDCl3): δ0.86 (3H, t, J = 7.5Hz), 1.92 (2H, quant, J = 7.5Hz), 2.15-2.31 (2H, m), 2.80-2.96 (2H, m), 3.42 (1H, d, J = 13Hz), 3.48 (1H, td, J = 12.5, 3Hz), 3.61 (1H, d, J = 13Hz), 3.66 (2H, s), 3.80- 3.95 (1H, m), 3.96-4.10 (1H, m), 7.15-7.33 (4H, m), 7.49 (1H, d, J = 8.5Hz), 7.50 (1H, d, J = 8.5Hz) 7.81 ( 1H, s).

Example 457

Yield 96%, 1H-NMR (CDCl3): δ0.87 (3H, t, J = 7.5Hz), 1.85-2.00 (2H, m), 2.15-2.28 (2H, m), 2.34 (3H, s) , 2.80-2.95 (2H, m), 3.39 (1H, d, J = 13Hz), 3.51 (1H, td, J = 13, 3.5Hz), 3.58 (1H, d, J = 13Hz), 3.62 (2H, s), 3.80-3.95 (1H, m), 3.96-4.10 (1H, m), 7.02 (1H, s), 7.06 (1H, s), 7.08 (1H, s), 7.50 (1H, d, J = 8.5Hz), 7.53 (1H, d, J = 8.5Hz) 7.81 (1H, s).

Example 458

Yield 98%, 1H-NMR (CDCl3): δ0.87 (3H, t, J = 7.5Hz), 1.11-1.28 (2H, m), 1.68-1.88 (2H, m), 2.20-2.18 (2H, m), 2.64-2.79 (2H, m), 3.23-3.48 (5H, m), 3.74-3.96 (2H, m), 6.98-7.23 (5H, m), 7.35 (1H, d, J = 8.5Hz) , 7.49 (1H, d, J = 2.0Hz).

Example 459

Yield 98%, 1H-NMR (CDCl3): δ 0.91 (3 H, t, J = 7.2 Hz), 1.19-1.29 (2 H, m), 1.77-1.94 (2 H, m), 2.18-2.28 (2 H, m), 2.81 (1 H, d, J = 11.1 Hz), 2.89 (1 H, d, J = 11.1 Hz), 3.40-3.47 (2 H, m), 3.61 (1 H, d, J = 13.2 Hz), 3.66 (2 H, s), 3.90 (1 H, s), 3.99 (1 H, d, J = 12.0 Hz), 7.20-7.31 (5 H, m), 7.39 (1 H, d, J = 8.7 Hz), 7.52 (1 H, d, J = 2.1 Hz)

Example 460

Yield 69%, 1H-NMR (CDCl3): δ 0.92 (3H, t, J = 7.0Hz), 1.16-1.34 (2H, m), 1.68-2.00 (2H, m), 2.12-2.27 (2H, m), 2.32 (3H, s), 2.79 (1H, d, J = 11.5Hz), 2.86 (1H, d, J = 11.5Hz), 3.35 (1H, d, J = 13.5Hz), 3.39-3.62 ( 2H, m), 3.58 (2H, s), 3.82-4.03 (2H, m), 6.99 (1H, s), 7.03 (1H, s), 7.06 (1H, s), 7.21 (1H, dd, J = 8.5, 2.0Hz), 7.39 (1H, d, J = 8.5Hz), 7.52 (1H, d, J = 2.0Hz).

Example 461

Yield 91%, 1H-NMR (CDCl3): δ 0.92 (3 H, t, J = 7.2 Hz), 1.20-1.30 (2 H, m), 1.75-1.84 (1 H, m), 1.87-1.97 (1 H, m), 2.18-2.28 (2 H, m), 2.34 (3 H, s), 2.86 (2 H, dd, J = 11.1 Hz), 3.37 (1 H, d, J = 13.2 Hz) , 3.48 (1 H, dt, J = 3.3, 12.6 Hz), 3.61 (1H, d, J = 12.1 Hz), 3.62 (2 H, s), 3.90 (1 H, s), 3.99 (1 H, d , J = 11.1 Hz), 7.02 (1H, s), 7.07 (2 H, s), 7.22 (1 H, dd, J = 2.1, 8.7 Hz), 7.40 (1 H, d, J = 8.7 Hz), 7.52 (1 H, d, J = 2.1 Hz)

Example 462

Yield 70%, 1H-NMR (CDCl3): δ0.92 (3H, t, J = 7.0Hz), 1.18-1.35 (2H, m), 1.75-1.98 (2H, m), 2.15-2.29 (2H, m), 2.81 (1H, d, J = 11.5Hz), 2.88 (1H, d, J = 11.5Hz), 3.41 (1H, d, J = 13.0Hz), 3.48 (1H, td, J = 12.5, 3.0 Hz), 3.58 (1H, d, J = 13.0Hz), 3.62 (2H, s), 3.89-4.09 (2H, m), 7.14-7.32 (4H, m), 7.49 (1H, d, J = 8.5Hz ), 7.53 (1H, d, J = 8.5Hz), 7.81 (1H, s).

Example 463

Yield 81%, 1H-NMR (CDCl3): δ 0.92 (3 H, t, J = 7.2 Hz), 1.21-1.31 (2 H, m), 1.80-1.94 (2 H, m), 2.20-2.29 (2 H, m), 2.82 (1 H, d, J = 11.4 Hz), 2.91 (1 H, d, J = 11.1 Hz), 3.43 (1 H, d, J = 13.2 Hz), 3.50 (1 H , dt, J = 3.0, 12.6 Hz), 3.61 (1 H, d, J = 13.2 Hz), 3.67 (2 H, s), 3.99 (1 H, d, J = 14.1 Hz), 4.06 (1 H, s), 7.20-7.34 (4 H, m), 7.52 (2 H, s), 7.82 (1 H, s)

Example 464

Yield 81%, 1H-NMR (CDCl3): δ0.86 (3H, t, J = 7.5Hz), 1.14-1.38 (4H, m), 1.74-1.99 (2H, m), 2.16-2.30 (2H, m), 2.81 (1H, d, J = 11.5Hz), 2.89 (1H, d, J = 11.5Hz), 3.42 (1H, d, J = 13Hz), 3.46 (1H, td, J = 13.5, 3.5Hz ), 3.60 (1H, d, J = 13Hz), 3.66 (2H, s), 3.80-3.93 (1H, m), 3.95-4.06 (1H, m), 7.15-7.35 (5H, m), 7.40 (1H , d, J = 8.5Hz), 7.52 (1H, d, J = 2.5Hz).

Example 465

Yield 91%, 1H-NMR (CDCl3): δ0.86 (3H, t, J = 7.5Hz), 1.13-1.40 (4H, m), 1.74-2.00 (2H, m), 2.16-2.30 (2H, m), 2.82 (1H, d, J = 12Hz), 2.88 (1H, d, J = 11.5Hz), 3.41 (1H, d, J = 13.5Hz), 3.41-3.51 (1H, m), 3.60 (1H , d, J = 13.5Hz), 3.66 (2H, s), 3.80-3.92 (1H, m), 3.94-4.05 (1H, m), 7.16-7.34 (5H, m), 7.39 (1H, d, J = 8.5Hz), 7.52 (1H, d, J = 2Hz).

Example 466

Yield 81%, 1H-NMR (CDCl3): δ0.87 (3H, t, J = 7.5Hz), 1.17-1.39 (4H, m), 1.75-2.03 (2H, m), 2.17-2.30 (2H, m), 2.34 (3H, s), 2.83 (1H, d, J = 11.5Hz), 2.91 (1H, d, J = 10.5Hz), 3.38 (1H, d, J = 13.5Hz), 3.44-3.55 ( 1H, m), 3.58 (1H, d, J = 13.5Hz), 3.62 (2H, s), 3.85-3.97 (1H, m), 4.00-4.10 (1H, m), 7.02 (1H, s), 7.06 (1H, s), 7.07 (1H, s), 7.51 (2H, s), 7.82 (1H, s).

Example 467

Yield 53%, 1H-NMR (DMSO-d6): δ0.87 (3H, d, J = 6.5Hz), 0.89 (3H, d, J = 6.5Hz), 2.02-2.25 (2H, m), 2.29 (3H, s), 2.45-3.05 (4H, m), 3.10 (1H, d, J = 13.0Hz), 3.35-3.58 (2H, m), 3.53 (2H, s), 4.01-4.22 (1H, m ), 6.96 (1H, s), 7.00 (1H, s), 7.03 (1H, s), 7.49 (2H, s), 7.78 (1H, s).

Example 468

Yield 70%, 1H-NMR (DMSO-d6): δ0.85 (6H, t, J = 7.5Hz), 2.00 (1H, d, J = 11.5Hz), 2.14 (1H, t, J = 11.5Hz ), 2.28 (3H, s), 2.50-2.57 (1H, m), 2.93 (2H, t, J = 11.5Hz), 3.32 (1H, d, J = 13.5Hz), 3.32-3.48 (1H, m) , 3.49 (2H, s), 3.57 (1H, d, J = 13.5Hz), 3.58-3.65 (1H, m), 3.95-4.10 (1H, m), 6.97 (1H, s), 7.02 (2H, s ), 7.49 (1H, d, J = 8.5Hz), 7.55 (1H, d, J = 8.5Hz), 8.18 (1H, s), 12.4 (1H, brs).

Example 469

Yield 67%, 1H-NMR (DMSO-d6): δ0.88 (3H, d, J = 6.5Hz), 0.90 (3H, d, J = 6.5Hz), 1.32-1.58 (2H, m), 1.80 -1.96 (1H, m), 2.05-2.23 (2H, m), 2.75 (1H, d, J = 10.5Hz), 2.89 (1H, d, J = 11.5Hz), 3.30-3.53 (2H, m), 3.48 (2H, s), 3.59 (1H, d, J = 13.5Hz), 3.80-4.08 (2H, m), 7.10-7.30 (5H, m), 7.38 (1H, d, J = 8.5Hz), 7.87 (1H, d, J = 2.0Hz).

Example 470

Yield 88%, 1H-NMR (CDCl3): δ0.90 (6H, dd, J = 6, 2Hz), 1.30-1.59 (2H, m), 1.80-1.95 (1H, m), 2.08-2.24 (2H , m), 2.75 (1H, d, J = 11.5Hz), 2.91 (1H, d, J = 11.5Hz), 3.20-3.37 (1H, m), 3.38 (1H, d, J = 13.5Hz), 3.55 (2H, s), 3.62 (1H, d, J = 13.5Hz), 3.80-3.96 (1H, m), 3.97-4.10 (1H, m), 7.10-7.32 (5H, m), 7.38 (1H, d , J = 8.5Hz), 7.89 (1H, d, J = 2Hz), 12.43 (1H, brs).

Example 471

Yield 62%, 1H-NMR (CDCl3): δ 0.91 (3H, d, J = 6.5Hz), 0.93 (3H, d, J = 6.5Hz), 1.34-1.64 (2H, m), 1.85-2.00 (1H, m), 2.11-2.38 (2H, m), 2.31 (3H, s), 2.77 (1H, d, J = 11.0Hz), 2.86 (1H, d, J = 10.5Hz), 3.32 (1H, d, J = 13.0Hz), 3.38-3.64 (2H, m), 3.56 (2H, s), 3.83-4.07 (2H, m), 6.98 (1H, s), 7.01 (1H, s), 7.05 (1H , s), 7.21 (1H, dd, J = 8.5, 2.0Hz), 7.39 (1H, d, J = 8.5Hz), 7.52 (1H, d, J = 2.0Hz).

Example 472

Yield 92%, 1H-NMR (CDCl3): δ0.90 (6H, t, J = 6Hz), 1.42-1.53 (2H, m), 1.93-2.01 (1H, m), 2.02-2.12 (2H, m ), 2.29 (3H, s), 2.75 (1H, d, J = 11.5Hz), 2.91 (1H, d, J = 11.5Hz), 3.31 (1H, d, J = 13.5Hz), 3.32-3.50 (1H , m), 3.51 (2H, s), 3.61 (1H, d, J = 13.5Hz), 3.87-4.04 (2H, m), 6.97 (1H, s), 7.02 (1H, s), 7.04 (1H, s), 7.27 (1H, dd, J = 8.5, 2Hz), 7.38 (1H, d, J = 8.5Hz), 7.89 (1H, d, J = 2Hz), 12.28 (1H, brs).

Example 473

Yield 99%, 1H-NMR (CDCl3): δ0.90 (3H, d, J = 6.0Hz), 0.92 (3H, d, J = 6.0Hz), 1.34-1.64 (2H, m), 1.84-1.98 (1H, m), 2.07-2.30 (2H, m), 2.26 (3H, s), 2.74 (1H, d, J = 11.0Hz), 2.82 (1H, d, J = 10.5Hz), 3.28 (1H, d, J = 13.5Hz), 3.35-3.54 (4H, m), 3.87-4.07 (2H, m), 6.91 (1H, s), 6.93 (1H, s), 7.02 (1H, s), 7.50 (2H , s), 7.81 (1H, s).

Example 474

Yield 98%, 1H-NMR (CDCl3): δ 0.93 (6 H, dd, J = 3.6, 6.3 Hz), 1.42-1.50 (1 H, m), 1.55-1.64 (1 H, m), 1.90 -1.99 (1 H, m), 2.23 (2 H, td, J = 3.6, 11.4 Hz), 2.34 (3 H, s), 2.81 (1 H, d, J = 11.4 Hz), 2.92 (1 H, d, J = 10.2 Hz), 3.37 (1 H, d, J = 13.2 Hz), 3.52 (1 H, td, J = 3.3, 12.9 Hz), 3.62 (1 H, d, J = 13.2 Hz), 3.62 (2 H, s), 4.04 (2 H, br), 7.02 (1 H, s), 7.07 (2 H, s), 7.52 (2 H, s), 7.82 (1 H, s)

Example 475

Yield 62%, 1H-NMR (CDCl3): δ1.23 (3H, d, J = 6.5Hz), 1.38 (3H, d, J = 6.5Hz), 2.11-2.26 (1H, m), 2.65-2.89 (2H, m), 2.98-3.15 (1H, m), 3.35-3.52 (1H, m), 3.67 (2H, s), 3.68-3.82 (1H, m), 4.03-4.22 (2H, m), 7.17 -7.36 (4H, m), 7.48-7.60 (2H, m), 7.83 (1H, s).

Example 476

Yield 80%, 1H-NMR (DMSO-d6): δ2.43-2.58 (4H, m), 3.54 (2H, s), 3.57 (2H, s), 3.58-3.70 (4H, m), 7.13- 7.34 (4H, m), 7.47 (1H, d, J = 12.5Hz), 8.27 (1H, d, J = 7.5Hz), 12.28 (1H, s).

Example 477

Yield 92%, 1H-NMR (CDCl3): δ 2.28 (3H, s), 2.50-2.62 (4H, m), 3.47 (2H, s), 3.52 (2H, s), 3.58-3.68 (4H, m), 6.97 (2H, s), 7.04 (1H, s), 7.25 (1H, d, J = 11.5Hz), 7.73 (1H, d, J = 7.0Hz).

Example 478

Yield 59%, 1H-NMR (CD3OD): δ2.06-2.18 (2H, m), 2.31 (3H, s), 2.87-2.97 (2H, m), 2.99-3.08 (2H, m), 3.52 ( 2H, s), 3.70-3.98 (4H, m), 3.82 (2H, s), 7.07 (2H, s), 7.11 (1H, s), 7.29 (1H, d, J = 12.0Hz), 7.98 (1H , d, J = 7.0Hz).

Example 479

Yield 85%, 1H-NMR (DMSO-d6): δ1.15 (3H, d, J = 6Hz), 2.16-2.27 (1H, m), 2.28 (3H, s), 2.55-2.68 (1H, m ), 2.69-2.80 (1H, m), 3.17 (1H, d, J = 13.5Hz), 3.18-3.26 (1H, m), 3.35-3.48 (1H, m), 3.49 (2H, s), 3.65- 3.79 (1H, m), 3.80-3.90 (1H, m), 3.92 (1H, d, J = 13.5Hz), 6.96 (1H, s), 7.00 (1H, s), 7.01 (1H, s), 7.45 (1H, d, J = 12Hz), 8.25 (1H, d, J = 8Hz), 12.40 (1H, brs).

Example 480

Yield 67%, 1H-NMR (CDCl3): δ1.39 (3H, d, J = 7.0Hz), 2.14-2.35 (2H, m), 2.32 (3H, s), 2.72 (1H, d, J = 11.0Hz), 2.91 (1H, d, J = 11.0Hz), 3.40 (1H, d, J = 14.0Hz), 3.43-3.62 (2H, m), 3.58 (2H, s), 3.86 (1H, d, J = 12.5Hz), 4.12-4.28 (1H, m), 6.99 (1H, s), 7.02-7.10 (2H, m), 7.25 (1H, d, J = 11.5Hz), 7.73 (1H, d, J = 7.0Hz).

Example 481

Yield 78%, 1H-NMR (CDCl3): δ1.38 (3H, d, J = 7.0Hz), 2.12-2.35 (2H, m), 2.30 (3H, s), 2.70 (1H, d, J = 11.5Hz), 2.88 (1H, d, J = 11.5Hz), 3.32-3.60 (5H, m), 3.84 (1H, d, J = 11.5Hz), 4.10-4.25 (1H, m), 6.97 (1H, s), 7.04 (2H, s), 7.24 (1H, d, J = 12.0Hz), 7.73 (1H, d, J = 7.0Hz).

Example 482

Yield 82%, 1H-NMR (DMSO-d6): δ2.45-2.60 (4H, m), 3.48-3.63 (8H, m), 7.06 (1H, td, J = 7.5, 1.0Hz), 7.13- 7.33 (5H, m), 7.45 (1H, d, J = 7.5Hz), 7.76 (1H, d, J = 7.5Hz), 12.32 (1H, brs).

Example 483

Yield 60%, 1H-NMR (CDCl3): δ0.85 (3H, t, J = 7.5Hz), 1.80-2.00 (2H, m), 2.12-2.26 (2H, m), 2.31 (3H, s) , 2.77-2.91 (2H, m), 3.36 (1H, d, J = 13.5Hz), 3.36-3.62 (2H, m), 3.57 (2H, s), 3.75-3.87 (1H, m), 3.88-4.02 (1H, m), 6.98 (1H, s), 7.04 (2H, s), 7.24 (1H, d, J = 10.5Hz), 7.51 (1H, d, J = 7.0Hz).

Example 484

Yield 67%, 1H-NMR (CDCl3): δ 2.75 (4H, t, J = 5.0Hz), 3.68 (4H, s), 3.85 (4H, t, J = 5.0Hz), 7.13-7.21 (1H , m), 7.22-7.34 (2H, m), 7.37-7.46 (2H, m), 7.54-7.64 (1H, m), 7.69 (1H, dd, J = 8.0, 1.0Hz), 7.89 (1H, dd , J = 8.0, 1.0Hz), 8.56 (1H, s).

Example 485

Yield 57%, 1H-NMR (CDCl3): δ2.82 (4H, t, J = 4.5Hz), 3.66 (2H, s), 3.74 (2H, s), 3.83 (4H, t, J = 4.5Hz ), 6.93 (1H, d, J = 9.0Hz), 7.07-7.15 (1H, m), 7.20-7.31 (3H, m), 7.47 (1H, s), 7.54 (1H, td, J = 8.0, 1.5 Hz), 7.60 (1H, d, J = 8.0), 7.70 (1H, d, J = 8.0Hz), 7.89 (1H, d, J = 9.0Hz).

Example 486

Yield 42%, 1H-NMR (CDCl3): δ2.65-2.77 (4H, m), 3.64 (4H, s), 3.76-3.88 (4H, m), 7.13-7.32 (3H, m), 7.38 ( 1H, s), 7.50 (1H, dd, J = 9.0, 2.0Hz), 7.59 (1H, d, J = 9.0Hz), 7.86 (1H, d, J = 2.0Hz), 8.53 (1H, s).

Example 487

Yield 81%, 1H-NMR (CDCl3): δ 2.60-2.74 (4H, m), 2.63 (3H, s), 3.35-3.49 (4H, m), 3.52 (2H, s), 3.54 (2H, s), 7.05-7.23 (3H, m), 7.29 (1H, s), 7.69 (1H, d, J = 9.0Hz), 7.80 (1H, d, J = 9.0Hz), 8.14 (1H, s).

Example 488

Yield 79%, 1H-NMR (CDCl3): δ1.35 (3H, d, J = 6.5Hz), 2.12-2.35 (5H, m), 2.79 (1H, d, J = 11.5Hz), 2.99 (1H , d, J = 11.5Hz), 3.27-3.43 (2H, m), 3.50-3.62 (3H, m), 4.35 (1H, d, J = 12.5Hz), 4.59-4.72 (1H, m), 6.98 ( 1H, s), 7.05 (1H, s), 7.08 (1H, s), 7.70 (2H, s), 8.13 (1H, s), 8.56 (1H, s).

Example 489

Yield 76%, 1H-NMR (CD3OD): δ 2.69-2.78 (4H, m), 3.52-3.60 (4H, m), 3.61 (2H, s), 3.71 (2H, s), 7.18-7.39 ( 7H, m), 7.42-7.50 (3H, m).

{3-[[4-(6-クロロベンゾチアゾール-2-イル)ピペラジン-1-イル]メチル]フェニル}アセトニトリル0.35g（0.914mmol）、濃硫酸2ml及び水2mlの混合物を80℃で2時間撹拌した。空冷後、5N-水酸化ナトリウム水溶液でアルカリ性とした後、酢酸エチルを加え逆抽出した。水層を2N-塩酸水溶液で中性とした後、 酢酸エチルで抽出した。有機層を飽和食塩水で洗浄、無水硫酸ナトリウムで乾燥した後、減圧下溶媒を留去し、3-[[4-(6-クロロベンゾチアゾール-2-イル)ピペラジン-1-イル]メチル]フェニル酢酸を無色無晶型固体として0.08g（22％）を得た。
¹H-NMR(DMSO-d₆): δ2.45-2.50 (4H, m), 3.53 (2H, s), 3.53-3.65 (6H, m), 7.10-7.35 (5H, m), 7.42 (1H, d, J=8.5Hz), 7.91 (1H, d, J=2Hz), 12.28 (1H, brs). Example 490
3-[[4- (6-Chlorobenzothiazol-2-yl) piperazin-1-yl] methyl] phenylacetic acid

{3-[[4- (6-Chlorobenzothiazol-2-yl) piperazin-1-yl] methyl] phenyl} acetonitrile 0.35 g (0.914 mmol), 2 ml of concentrated sulfuric acid and 2 ml of water were mixed at 80 ° C. for 2 hours. Stir. After air cooling, the mixture was alkalified with 5N aqueous sodium hydroxide solution and then back-extracted with ethyl acetate. The aqueous layer was neutralized with 2N-hydrochloric acid aqueous solution, and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give 3-[[4- (6-chlorobenzothiazol-2-yl) piperazin-1-yl] methyl] 0.08 g (22%) of phenylacetic acid was obtained as a colorless amorphous solid.
¹ H-NMR (DMSO-d ₆ ): δ2.45-2.50 (4H, m), 3.53 (2H, s), 3.53-3.65 (6H, m), 7.10-7.35 (5H, m), 7.42 (1H , d, J = 8.5Hz), 7.91 (1H, d, J = 2Hz), 12.28 (1H, brs).

収率：43％, ¹H-NMR(DMSO-d₆): δ1.90-1.96 (2H,m),2.61(2H,t, J=4.8Hz), 2.77-2.80 (2H, m), 3.57-3.62 (4H, m), 3.62-3.71 (4H, m), 7.12-7.16 (2H, m), 7.21-7.28 (3H, m), 7.40 (1H, d, J=8.5Hz), 7.88 (1H, d, J=2.4Hz).

実施例４９２

収率：78％, ¹H-NMR(DMSO-d₆): δ2.52 (4H, t, J=5Hz), 3.54 (2H, s), 3.57 (2H, s), 3.63 (4H, t, J=5Hz), 7.10-7.35 (4H, m), 7.57 (2H, s), 8.24 (1H, s), 12.31 (1H, s).

実施例４９３

収率：18％,¹H-NMR(DMSO-d₆): δ1.85-2.00 (2H, m),2.57-2.68 (2H, m), 2.74-2.85 (2H, m), 3.52 (2H, s),3.61(2H, s),3.62-3.85(4H, m), 7.09-7.31 (4H, m), 7.52-7.58 (2H, m), 8.22 (2H, s).

実施例４９４

収率：79％, ¹H-NMR(DMSO-d₆): δ1.31 (3H, d, J=6.5Hz), 2.15 (1H, td, J=12, 3.5Hz), 2.22 (1H, dd, J=11.5, 3.5Hz), 2.70 (1H, d, J=11.5Hz), 2.91 (1H, d, J=12Hz), 3.41 (1H, td, J=12, 3.5Hz), 3.44 (1H, d, J=13.5Hz), 3.56 (2H, s), 3.59 (1H, d, J=13.5Hz), 3.80 (1H, d, J=12Hz), 4.10-4.30 (1H, m), 7.10-7.35 (5H, m), 7.41 (1H, d, J=8.5Hz), 7.90 (1H, d, J=2Hz), 12.40 (1H, brs).

実施例４９５

収率：69％,¹H-NMR(DMSO-d₆): δ1.05-1.25 (3H,m),2.15-2.30(1H, s), 2.50-2.65 (1H, m), 2.65-2.80 (1H, m), 3.05-3.40 (3H, m), 3.57 (2H,s),3.60-3.70(1H,m), 3.70-3.85 (1H, m), 3.90-4.00 (1H, m),7.05-7.35 (5H, m), 7.41 (1H, d, J=8.5Hz),7.90(1H, s), 12.29 (1H, s).

実施例４９６

収率：92％, ¹H-NMR(DMSO-d₆): δ1.04 (6H, d, J=6Hz), 2.60-2.80 (2H, m), 2.95-3.10 (2H, m), 3.53 (2H, s), 3.77 (2H, s), 3.77-3.87 (2H, m), 7.00-7.10 (1H, m), 7.20-7.30 (4H, m), 7.42 (1H, d, J=8.5Hz), 7.90 (1H, d, J=2Hz), 12.5 (1H, brs).

実施例４９７

収率：76％, ¹H-NMR(DMSO-d₆): δ1.00 (3H, d, J=6Hz), 1.30 (3H, d, J=6Hz), 2.30 (1H, d, J=9.5Hz), 2.70-2.85 (1H, m), 3.05-3.15 (1H,m),3.40-3.45(1H, m), 3.49 (2H, s), 3.62 (2H, s), 3.63-3.70 (1H, m), 4.10-4.30 (1H, m), 7.05-7.10 (1H, m), 7.20-7.35 (4H, m), 7.38 (1H, d, J=9Hz), 7.87 (1H, d, J=2Hz).

実施例４９８

収率：42％,¹H-NMR(DMSO-d₆):2.31(3H, s), 2.50 (4H, t, J=5Hz), 3.47 (2H, s), 3.52 (2H, s), 3.55 (4H, t, J=5Hz), 7.00-7.18 (3H, m), 7.28(1H,dd,J=8.5,2Hz),7.42(1H,d, J= 8.5Hz), 7.91(1H, d, J=2Hz), 12.25 (1H, brs).

実施例４９９

収率：39％, ¹H-NMR(DMSO-d₆): δ2.58 (4H, t,J=5Hz), 3.58 (4H, t, J=5Hz), 3.61 (2H, s), 3.62 (2H, s), 7.19 (1H, dd, J=8, 2Hz), 7.29 (1H,dd,J=8.5,1.5Hz),7.39(1H, d, J=8.5Hz), 7.42 (1H, d, J=8Hz),7.43 (1H, d, J=1.5Hz), 7.91 (1H, d, J=2Hz), 12.41 (1H, brs).

実施例５００

収率：68％, ¹H-NMR(CDCl₃); δ2.32 (3H, s), 2.67 (4H, t, J=5Hz), 3.59 (2H, s), 3.61 (2H, s), 3.67 (4H, t, J=5Hz), 6.99 (1H, s), 7.04 (1H, s), 7.14 (1H, s), 7.24 (1H, dd, J=8.5, 2Hz), 7.43 (1H, d, J=8.5Hz), 7.55 (1H, d, J=2Hz).

実施例５０１

収率：73％, ¹H-NMR(DMSO-d₆): δ1.88-1.94 (2H, m), 2.25 (3H, s), 2.60 (2H, t, J=4.5Hz), 2.74-2.78 (2H, m), 3.48 (2H, s), 3.56 (2H, s), 3.66-3.73 (4H, m), 6.94-6.98 (3H, m), 7.26 (1H, dd, J=8.7, 2.1Hz ), 7.40 (1H, d, J=8.4Hz), 7.88 (1H, d, J =2.1Hz).

実施例５０２

収率：67％, ¹H-NMR(CDCl₃); δ2.71 (4H, t, J=5Hz), 3.67 (4H, t, J=5Hz), 3.78 (2H, s), 3.81 (2H, s), 6.78 (2H, s), 7.24 (1H, dd, J=8.5, 2Hz), 7.43 (1H, d, J=8.5Hz), 7.56 (1H, d, J=2Hz).

実施例５０３

収率：46％, ¹H-NMR(CDCl₃); δ2.16-2.20 (2H, m), 2.91-2.95 (2H, m), 3.03-3.06 (2H, m), 3.68 (2H, t, J=6.0Hz), 3.79 (2H, s), 3.90-3.91 (2H, m), 3.97 (2H, s), 6.75 (1H, d, J=3.6Hz), 6.77 (1H, d, J=3.3Hz), 7.24 (1H, dd, J=9.0, 2.4Hz), 7.43 (1H, d, J=9.0Hz), 7.55 (1H, d, J=2.1Hz).

実施例５０４

収率：2％, ¹H-NMR(DMSO-d₆): δ2.40-2.50 (4H, m), 2.53 (2H, t, J=7.5Hz), 2.81 (2H, t, J=7.5Hz), 3.50 (2H, s), 3.55 (4H, t, J=5Hz), 7.19 (2H, d, J=8Hz), 7.23 (2H, d, J=8Hz), 7.29 (1H, dd, J=8.5, 2Hz), 7.41 (1H, d, J=8.5Hz), 7.90 (1H, d, J=2Hz), 12.05 (1H, brs).

実施例５０５

収率：70％,¹H-NMR(DMSO-d₆): δ2.28(3H, s), 2.45-2.55(4H, m), 3.49 (2H, s), 3.51 (2H, s), 3.60-3.65 (4H, m), 6.97 (1H, s), 7.02 (2H, s), 7.57 (2H, s), 8.25 (1H, s), 12.4 (1H, brs).

実施例５０６

収率：55％, ¹H-NMR(DMSO-d₆): δ1.85-2.00 (2H, m), 2.25 (3H, s), 2.55-2.70 (2H, m), 2.70-2.85(2H, m), 3.49 (2H, s), 3.57 (2H, s), 3.60-3.85 (4H, m), 6.94 (1H, s), 6.99 (2H, s), 7.55 (2H, s), 8.22 (1H, s), 12.4 (1H, brs).

実施例５０７

収率99％, 1H-NMR(CDCl3): δ1.24 (3 H, d, J = 6.0 Hz), 2.26-2.33 (1 H, m), 2.33 (3 H, s), 2.64-2.71 (1 H, m), 2.82 (1 H, dt, J = 3.6, 12.0 Hz), 3.19 (2 H, d, J = 12.9 Hz), 3.38-3.45 (1 H, m), 3.61 (2 H, s), 3.70 (1 H, dt, J = 3.6, 12.9 Hz), 3.86 (1 H, dd, J = 2.1, 11.7 Hz), 4.05 (1 H, d, J = 12.9 Hz), 7.03 (2 H, d, J = 4.5 Hz), 7.09 (1 H, s), 7.23 (1 H, dd, J = 2.1, 8.7 Hz), 7.43 (1 H, d, J = 8.7 Hz), 7.54 (1 H, d, J = 2.1 Hz)

実施例５０８

収率93％, 1H-NMR(CDCl3): δ1.24 (3 H, d, J = 6.3 Hz), 2.27-2.37 (1 H, m), 2.33 (3 H, s), 2.56-2.71 (1 H, m), 2.83 (1 H, dt, J = 3.3, 12.0 Hz), 3.19 (2 H, d, J = 13.2 Hz), 3.38-3.47 (1 H, m), 3.60 (2 H, s), 3.70 (1 H, dt, J = 4.8, 12.6 Hz), 3.86 (1 H, dd, J = 2.7, 12.6 Hz), 4.06 (1 H, d, J = 13.2 Hz), 7.03 (2 H, s), 7.09 (1 H, s), 7.23 (1 H, dd, J = 2.1, 8.7 Hz), 7.43 (1 H, d, J = 8.7 Hz), 7.54 (1 H, d, J = 2.1 Hz)

実施例５０９

収率95％, 1H-NMR(DMSO-d6): δ1.04 (6H, d, J=6Hz), 2.26 (3H, s), 2.60-2.80 (2H, m), 3.07 (1H, d, J=13Hz), 3.09 (1H, d, J=13Hz), 3.48 (2H, s), 3.73 (2H, s), 3.80-3.90 (2H, m), 6.88 (1H, s), 7.05 (2H, s), 7.55 (2H, s), 8.22 (1H, s), 12.21 (1H, brs).

実施例５１０

収率82％, 1H-NMR(DMSO-d6): δ1.15 (3H, d, J=6.5Hz), 2.18-2.25 (1H, m), 2.28 (3H, s), 2.55-2.68 (1H, m), 2.68-2.80 (1H, m), 3.15-3.48 (3H, m), 3.50 (2H, s), 3.70-3.76 (1H, m), 3.80-3.90 (1H, m), 3.93 (1H, d, J=13.5Hz), 6.96 (1H, s), 7.02 (2H, s), 7.56 (2H, s), 8.23 (1H, s), 12.43 (1H, brs).

実施例５１１

収率64％, 1H-NMR(CDCl3): δ1.23 (3H, d, J=6.5Hz), 2.22-2.40 (4H, m), 2.60-2.74 (1H, m), 2.76-2.89 (1H, m), 3.10-3.31 (2H, m), 3.38-3.52 (1H, m), 3.59 (2H, s), 3.67-3.80 (1H, m), 3.84-3.96 (1H, m), 4.04 (1H, d, J=13.0Hz), 6.97-7.12 (3H, m), 7.47-7.60 (2H, m), 7.83 (1H, s).

実施例５１２

収率93％, 1H-NMR(DMSO-d6): δ1.33 (3H, d, J=6.5Hz), 2.05-2.28 (2H, m), 2.29 (3H, s), 2.72 (1H, d, J=11Hz), 2.93 (1H, d, J=11Hz), 3.25-3.50 (2H, m), 3.51 (2H, s), 3.51-3.60 (1H, m), 3.86 (1H, d, J=11Hz), 4.20-4.35 (1H, m), 6.97 (1H, s), 7.05 (2H, s), 7.56 (2H, s), 8.24 (1H, s), 12.43 (1H, brs). The compounds described in Examples 491 to 512 were obtained in the same manner as in Example 490.
Example 491

Yield: 43%, ¹ H-NMR (DMSO-d ₆ ): δ1.90-1.96 (2H, m), 2.61 (2H, t, J = 4.8Hz), 2.77-2.80 (2H, m), 3.57 -3.62 (4H, m), 3.62-3.71 (4H, m), 7.12-7.16 (2H, m), 7.21-7.28 (3H, m), 7.40 (1H, d, J = 8.5Hz), 7.88 (1H , d, J = 2.4Hz).

Example 492

Yield: 78%, ¹ H-NMR (DMSO-d ₆ ): δ2.52 (4H, t, J = 5Hz), 3.54 (2H, s), 3.57 (2H, s), 3.63 (4H, t, J = 5Hz), 7.10-7.35 (4H, m), 7.57 (2H, s), 8.24 (1H, s), 12.31 (1H, s).

Example 493

Yield: 18%, ¹ H-NMR (DMSO-d ₆ ): δ1.85-2.00 (2H, m), 2.57-2.68 (2H, m), 2.74-2.85 (2H, m), 3.52 (2H, s), 3.61 (2H, s), 3.62-3.85 (4H, m), 7.09-7.31 (4H, m), 7.52-7.58 (2H, m), 8.22 (2H, s).

Example 494

Yield: 79%, ¹ H-NMR (DMSO-d ₆ ): δ1.31 (3H, d, J = 6.5Hz), 2.15 (1H, td, J = 12, 3.5Hz), 2.22 (1H, dd , J = 11.5, 3.5Hz), 2.70 (1H, d, J = 11.5Hz), 2.91 (1H, d, J = 12Hz), 3.41 (1H, td, J = 12, 3.5Hz), 3.44 (1H, d, J = 13.5Hz), 3.56 (2H, s), 3.59 (1H, d, J = 13.5Hz), 3.80 (1H, d, J = 12Hz), 4.10-4.30 (1H, m), 7.10-7.35 (5H, m), 7.41 (1H, d, J = 8.5Hz), 7.90 (1H, d, J = 2Hz), 12.40 (1H, brs).

Example 495

Yield: 69%, ¹ H-NMR (DMSO-d ₆ ): δ1.05-1.25 (3H, m), 2.15-2.30 (1H, s), 2.50-2.65 (1H, m), 2.65-2.80 ( 1H, m), 3.05-3.40 (3H, m), 3.57 (2H, s), 3.60-3.70 (1H, m), 3.70-3.85 (1H, m), 3.90-4.00 (1H, m), 7.05- 7.35 (5H, m), 7.41 (1H, d, J = 8.5Hz), 7.90 (1H, s), 12.29 (1H, s).

Example 496

Yield: 92%, ¹ H-NMR (DMSO-d ₆ ): δ1.04 (6H, d, J = 6Hz), 2.60-2.80 (2H, m), 2.95-3.10 (2H, m), 3.53 ( 2H, s), 3.77 (2H, s), 3.77-3.87 (2H, m), 7.00-7.10 (1H, m), 7.20-7.30 (4H, m), 7.42 (1H, d, J = 8.5Hz) , 7.90 (1H, d, J = 2Hz), 12.5 (1H, brs).

Example 497

Yield: 76%, ¹ H-NMR (DMSO-d ₆ ): δ1.00 (3H, d, J = 6Hz), 1.30 (3H, d, J = 6Hz), 2.30 (1H, d, J = 9.5 Hz), 2.70-2.85 (1H, m), 3.05-3.15 (1H, m), 3.40-3.45 (1H, m), 3.49 (2H, s), 3.62 (2H, s), 3.63-3.70 (1H, m), 4.10-4.30 (1H, m), 7.05-7.10 (1H, m), 7.20-7.35 (4H, m), 7.38 (1H, d, J = 9Hz), 7.87 (1H, d, J = 2Hz ).

Example 498

Yield: 42%, ¹ H-NMR (DMSO-d ₆ ): 2.31 (3H, s), 2.50 (4H, t, J = 5Hz), 3.47 (2H, s), 3.52 (2H, s), 3.55 (4H, t, J = 5Hz), 7.00-7.18 (3H, m), 7.28 (1H, dd, J = 8.5,2Hz), 7.42 (1H, d, J = 8.5Hz), 7.91 (1H, d, J = 2Hz), 12.25 (1H, brs).

Example 499

Yield: 39%, ¹ H-NMR (DMSO-d ₆ ): δ2.58 (4H, t, J = 5Hz), 3.58 (4H, t, J = 5Hz), 3.61 (2H, s), 3.62 ( 2H, s), 7.19 (1H, dd, J = 8, 2Hz), 7.29 (1H, dd, J = 8.5, 1.5Hz), 7.39 (1H, d, J = 8.5Hz), 7.42 (1H, d, J = 8Hz), 7.43 (1H, d, J = 1.5Hz), 7.91 (1H, d, J = 2Hz), 12.41 (1H, brs).

Example 500

Yield: 68%, ¹ H-NMR (CDCl ₃ ); δ2.32 (3H, s), 2.67 (4H, t, J = 5Hz), 3.59 (2H, s), 3.61 (2H, s), 3.67 (4H, t, J = 5Hz), 6.99 (1H, s), 7.04 (1H, s), 7.14 (1H, s), 7.24 (1H, dd, J = 8.5, 2Hz), 7.43 (1H, d, J = 8.5Hz), 7.55 (1H, d, J = 2Hz).

Example 501

Yield: 73%, ¹ H-NMR (DMSO-d ₆ ): δ1.88-1.94 (2H, m), 2.25 (3H, s), 2.60 (2H, t, J = 4.5Hz), 2.74-2.78 (2H, m), 3.48 (2H, s), 3.56 (2H, s), 3.66-3.73 (4H, m), 6.94-6.98 (3H, m), 7.26 (1H, dd, J = 8.7, 2.1Hz ), 7.40 (1H, d, J = 8.4Hz), 7.88 (1H, d, J = 2.1Hz).

Example 502

Yield: 67%, ¹ H-NMR (CDCl ₃ ); δ2.71 (4H, t, J = 5Hz), 3.67 (4H, t, J = 5Hz), 3.78 (2H, s), 3.81 (2H, s), 6.78 (2H, s), 7.24 (1H, dd, J = 8.5, 2Hz), 7.43 (1H, d, J = 8.5Hz), 7.56 (1H, d, J = 2Hz).

Example 503

Yield: 46%, ¹ H-NMR (CDCl ₃ ); δ2.16-2.20 (2H, m), 2.91-2.95 (2H, m), 3.03-3.06 (2H, m), 3.68 (2H, t, J = 6.0Hz), 3.79 (2H, s), 3.90-3.91 (2H, m), 3.97 (2H, s), 6.75 (1H, d, J = 3.6Hz), 6.77 (1H, d, J = 3.3 Hz), 7.24 (1H, dd, J = 9.0, 2.4Hz), 7.43 (1H, d, J = 9.0Hz), 7.55 (1H, d, J = 2.1Hz).

Example 504

Yield: 2%, ¹ H-NMR (DMSO-d ₆ ): δ 2.40-2.50 (4H, m), 2.53 (2H, t, J = 7.5Hz), 2.81 (2H, t, J = 7.5Hz ), 3.50 (2H, s), 3.55 (4H, t, J = 5Hz), 7.19 (2H, d, J = 8Hz), 7.23 (2H, d, J = 8Hz), 7.29 (1H, dd, J = 8.5, 2Hz), 7.41 (1H, d, J = 8.5Hz), 7.90 (1H, d, J = 2Hz), 12.05 (1H, brs).

Example 505

Yield: 70%, ¹ H-NMR (DMSO-d ₆ ): δ 2.28 (3H, s), 2.45-2.55 (4H, m), 3.49 (2H, s), 3.51 (2H, s), 3.60 -3.65 (4H, m), 6.97 (1H, s), 7.02 (2H, s), 7.57 (2H, s), 8.25 (1H, s), 12.4 (1H, brs).

Example 506

Yield: 55%, ¹ H-NMR (DMSO-d ₆ ): δ1.85-2.00 (2H, m), 2.25 (3H, s), 2.55-2.70 (2H, m), 2.70-2.85 (2H, m), 3.49 (2H, s), 3.57 (2H, s), 3.60-3.85 (4H, m), 6.94 (1H, s), 6.99 (2H, s), 7.55 (2H, s), 8.22 (1H , s), 12.4 (1H, brs).

Example 507

Yield 99%, 1H-NMR (CDCl3): δ1.24 (3 H, d, J = 6.0 Hz), 2.26-2.33 (1 H, m), 2.33 (3 H, s), 2.64-2.71 (1 H, m), 2.82 (1 H, dt, J = 3.6, 12.0 Hz), 3.19 (2 H, d, J = 12.9 Hz), 3.38-3.45 (1 H, m), 3.61 (2 H, s) , 3.70 (1 H, dt, J = 3.6, 12.9 Hz), 3.86 (1 H, dd, J = 2.1, 11.7 Hz), 4.05 (1 H, d, J = 12.9 Hz), 7.03 (2 H, d , J = 4.5 Hz), 7.09 (1 H, s), 7.23 (1 H, dd, J = 2.1, 8.7 Hz), 7.43 (1 H, d, J = 8.7 Hz), 7.54 (1 H, d, (J = 2.1 Hz)

Example 508

Yield 93%, 1H-NMR (CDCl3): δ1.24 (3 H, d, J = 6.3 Hz), 2.27-2.37 (1 H, m), 2.33 (3 H, s), 2.56-2.71 (1 H, m), 2.83 (1 H, dt, J = 3.3, 12.0 Hz), 3.19 (2 H, d, J = 13.2 Hz), 3.38-3.47 (1 H, m), 3.60 (2 H, s) , 3.70 (1 H, dt, J = 4.8, 12.6 Hz), 3.86 (1 H, dd, J = 2.7, 12.6 Hz), 4.06 (1 H, d, J = 13.2 Hz), 7.03 (2 H, s ), 7.09 (1 H, s), 7.23 (1 H, dd, J = 2.1, 8.7 Hz), 7.43 (1 H, d, J = 8.7 Hz), 7.54 (1 H, d, J = 2.1 Hz)

Example 509

Yield 95%, 1H-NMR (DMSO-d6): δ1.04 (6H, d, J = 6Hz), 2.26 (3H, s), 2.60-2.80 (2H, m), 3.07 (1H, d, J = 13Hz), 3.09 (1H, d, J = 13Hz), 3.48 (2H, s), 3.73 (2H, s), 3.80-3.90 (2H, m), 6.88 (1H, s), 7.05 (2H, s ), 7.55 (2H, s), 8.22 (1H, s), 12.21 (1H, brs).

Example 510

Yield 82%, 1H-NMR (DMSO-d6): δ1.15 (3H, d, J = 6.5Hz), 2.18-2.25 (1H, m), 2.28 (3H, s), 2.55-2.68 (1H, m), 2.68-2.80 (1H, m), 3.15-3.48 (3H, m), 3.50 (2H, s), 3.70-3.76 (1H, m), 3.80-3.90 (1H, m), 3.93 (1H, d, J = 13.5Hz), 6.96 (1H, s), 7.02 (2H, s), 7.56 (2H, s), 8.23 (1H, s), 12.43 (1H, brs).

Example 511

Yield 64%, 1H-NMR (CDCl3): δ1.23 (3H, d, J = 6.5Hz), 2.22-2.40 (4H, m), 2.60-2.74 (1H, m), 2.76-2.89 (1H, m), 3.10-3.31 (2H, m), 3.38-3.52 (1H, m), 3.59 (2H, s), 3.67-3.80 (1H, m), 3.84-3.96 (1H, m), 4.04 (1H, d, J = 13.0Hz), 6.97-7.12 (3H, m), 7.47-7.60 (2H, m), 7.83 (1H, s).

Example 512

Yield 93%, 1H-NMR (DMSO-d6): δ1.33 (3H, d, J = 6.5Hz), 2.05-2.28 (2H, m), 2.29 (3H, s), 2.72 (1H, d, J = 11Hz), 2.93 (1H, d, J = 11Hz), 3.25-3.50 (2H, m), 3.51 (2H, s), 3.51-3.60 (1H, m), 3.86 (1H, d, J = 11Hz ), 4.20-4.35 (1H, m), 6.97 (1H, s), 7.05 (2H, s), 7.56 (2H, s), 8.24 (1H, s), 12.43 (1H, brs).

2-{3-[4-(6-クロロベンゾチアゾール-2-イル)ピペラジン-1-イルメチル]ベンジル}マロン酸ジエチル0.38ｇ（0.736mmol）に6N-塩酸水溶液を加え2時間加熱還流した。空冷後、飽和炭酸水素ナトリウム水溶液を加え中性とした後、酢酸エチルを加え抽出した。有機層を飽和食塩水で洗浄、無水硫酸ナトリウムで乾燥した後、減圧下溶媒を留去した。残渣をジイソプロピルエーテルで洗浄し、3-{3-[4-(6-クロロベンゾチアゾール-2-イル)ピペラジン-1-イル]メチル}フェニルプロピオン酸を無色結晶として0.08ｇ（22％）を得た。
¹H-NMR(DMSO-d₆): δ2.50-2.52 (4H, m), 2.53 (2H, t, J=7.5Hz), 2.82 (2H, t, J=7.5Hz), 3.51 (2H, s), 3.57 (4H, t, J=5Hz), 7.10-7.20 (3H, m), 7.24 (1H, d, J=7.5Hz), 7.28 (1H, dd, J=8.5, 2Hz), 7.42 (1H, d, J=8.5Hz), 7.91 (1H, d, J=2Hz), 12.15 (1H, brs). Example 513
Preparation of 3- {3- [4- (6-chlorobenzothiazol-2-yl) piperazin-1-yl] methyl} phenylpropionic acid

6-N hydrochloric acid aqueous solution was added to 0.38 g (0.736 mmol) of diethyl 2- {3- [4- (6-chlorobenzothiazol-2-yl) piperazin-1-ylmethyl] benzyl} malonate, and the mixture was heated to reflux for 2 hours. After air cooling, the mixture was neutralized with a saturated aqueous sodium hydrogen carbonate solution, and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was washed with diisopropyl ether to give 0.08 g (22%) of 3- {3- [4- (6-chlorobenzothiazol-2-yl) piperazin-1-yl] methyl} phenylpropionic acid as colorless crystals. It was.
¹ H-NMR (DMSO-d ₆ ): δ2.50-2.52 (4H, m), 2.53 (2H, t, J = 7.5Hz), 2.82 (2H, t, J = 7.5Hz), 3.51 (2H, s), 3.57 (4H, t, J = 5Hz), 7.10-7.20 (3H, m), 7.24 (1H, d, J = 7.5Hz), 7.28 (1H, dd, J = 8.5, 2Hz), 7.42 ( 1H, d, J = 8.5Hz), 7.91 (1H, d, J = 2Hz), 12.15 (1H, brs).

収率：55％, ¹H-NMR(CDCl₃): δ2.63 (4H, t, J=5Hz), 2.72 (2H, t, J=7.5Hz), 3.13 (2H, t, J=7.5Hz), 3.64 (4H, t, J=5Hz), 3.72 (2H, s), 6.68 (1H, d, J=3.5Hz), 6.73 (1H, d, J=3.5Hz), 7.24 (1H, dd, J=8.5, 2Hz), 7.43 (1H, d, J=8.5Hz), 7.55 (1H, d, J=2Hz). Thereafter, the compound described in Example 514 was obtained in the same manner as in Example 513.
Example 514

Yield: 55%, ¹ H-NMR (CDCl ₃ ): δ2.63 (4H, t, J = 5Hz), 2.72 (2H, t, J = 7.5Hz), 3.13 (2H, t, J = 7.5Hz ), 3.64 (4H, t, J = 5Hz), 3.72 (2H, s), 6.68 (1H, d, J = 3.5Hz), 6.73 (1H, d, J = 3.5Hz), 7.24 (1H, dd, J = 8.5, 2Hz), 7.43 (1H, d, J = 8.5Hz), 7.55 (1H, d, J = 2Hz).

Example 515
Preparation of 3- {3- [4- (6-chlorobenzothiazol-2-yl) piperazin-1-yl] methyl} phenoxyacetic acid

収率：55％, ¹H-NMR(DMSO-d₆): δ2.50-2.55 (4H, m), 3.51 (2H, s), 3.55-3.65 (4H, m), 4.61 (2H, s), 6.75-7.00 (3H, m), 7.20-7.35 (2H, m), 7.42 (1H, d, J=8Hz), 7.90 (1H, d, J=2Hz). The following compound was obtained in the same manner as in Reference Example 155.

Yield: 55%, ¹ H-NMR (DMSO-d ₆ ): δ2.50-2.55 (4H, m), 3.51 (2H, s), 3.55-3.65 (4H, m), 4.61 (2H, s) , 6.75-7.00 (3H, m), 7.20-7.35 (2H, m), 7.42 (1H, d, J = 8Hz), 7.90 (1H, d, J = 2Hz).

[3-{2-[1-(6-クロロベンゾチアゾール-2-イル)ピペリジン-4-イル]エトキシ}-4メチルフェニル]アセトニトリル1.14g (2.68mmol)、水酸化ナトリウム0.54g(13.5mmol)、水1.6ml及びエタノール21mlの混合物を80℃で6時間撹拌した。反応液を減圧下濃縮し、2N-塩酸水溶液でpH＝7とした後、析出結晶を濾取し、3-{2-[1-(6-クロロベンゾチアゾール-2-イル)ピペリジン-4-イル]エトキシ}-4-メチルフェニル酢酸を無色結晶として0.63ｇ（53％）を得た。
¹H-NMR(DMSO-d₆): δ1.20-1.38 (2H, m), 1.67-1.91 (5H, m), 2.09 (3H, s), 3.10-3.25 (4H, m), 3.93-4.06 (4H, m), 6.54 (1H, d, J=7.5Hz), 6.82 (1H, s), 6.92 (1H, d, J=7.5Hz), 7.27 (1H, dd, J=8.5, 2.0Hz), 7.40 (1H, d, J=8.5Hz), 7.88 (1H, d, J=2.0Hz). Example 516
Preparation of 3- {2- [1- (6-chlorobenzothiazol-2-yl) piperidin-4-yl] ethoxy} -4-methylphenylacetic acid

[3- {2- [1- (6-Chlorobenzothiazol-2-yl) piperidin-4-yl] ethoxy} -4methylphenyl] acetonitrile 1.14 g (2.68 mmol), sodium hydroxide 0.54 g (13.5 mmol) A mixture of 1.6 ml of water and 21 ml of ethanol was stirred at 80 ° C. for 6 hours. The reaction mixture was concentrated under reduced pressure, adjusted to pH = 7 with 2N-hydrochloric acid aqueous solution, and the precipitated crystals were collected by filtration to give 3- {2- [1- (6-chlorobenzothiazol-2-yl) piperidin-4- 0.63 g (53%) of yl] ethoxy} -4-methylphenylacetic acid as colorless crystals was obtained.
¹ H-NMR (DMSO-d ₆ ): δ1.20-1.38 (2H, m), 1.67-1.91 (5H, m), 2.09 (3H, s), 3.10-3.25 (4H, m), 3.93-4.06 (4H, m), 6.54 (1H, d, J = 7.5Hz), 6.82 (1H, s), 6.92 (1H, d, J = 7.5Hz), 7.27 (1H, dd, J = 8.5, 2.0Hz) , 7.40 (1H, d, J = 8.5Hz), 7.88 (1H, d, J = 2.0Hz).

m/z=461(M+H)+

実施例５１８

m/z=431(M+H)+

実施例５１９

m/z=447(M+H)+

実施例５２０

m/z=435(M+H)+

実施例５２１

Rf=0.49(AcOEt)

実施例５２２

1H NMR(DMSO-d6): d 12,9(br, 1H), 7.86(s, 1H), 7.39(d, 1H, J = 6.3Hz), 7.25(d, 1H, J = 6.3Hz), 6.88(s, 1H), 6.87(d, 1H, J = 6.0Hz), 6.77(d, 1H, J = 6.0Hz), 4.01(m, 2H), 3.72(s, 3H), 3.67(br, 4H), 3.46(s, 2H), 2.94(s, 2H), 2.87(t, 2H, J = 4.2Hz), 2.75(br, 2H), 1.90(s, 2H).

実施例５２３

m/z=461(M+H)+

実施例５２４

m/z=475(M+H)+

実施例５２５

m/z=505(M+H)+

実施例５２６

m/z=493(M+H)+

実施例５２７

MS (ESI) m/e calcd. for C24H25ClFN2O3S2 (MH)+ 507.1, found 507

実施例５２８

MS (ESI) m/e calcd. for C24H26ClN2O2S2 (MH)+ 473.1, found 473

実施例５２９

MS (ESI) m/e calcd. for C23H23Cl2N2O2S2 (MH)+ 493.1, found 493

実施例５３０

MS (ESI) m/e calcd. for C₂₅H₂₆ClN₂O₃S₂ (MH⁺) 501.1, found 501.4

実施例５３１

MS (ESI) m/e calcd. for C₂₅H₂₆ClN₂O₂S₃ (MH⁺) 517.1, found 517.4

実施例５３２

MS (ESI) m/e calcd. for C₂₄H₂₅ClN₃O₂S₂ (MH⁺) 486.1, found 486.4

実施例５３３

m/z=489(M+H)+

実施例５３４

m/z=445(M+H)+

実施例５３５

MS (ESI) m/e calcd. for C₂₄H₂₉ClN₃O₃S (MH⁺) 474.2, found 474.4

実施例５３６

MS (ESI) m/e calcd. for C26H29ClN3O3S (MH)+ 498.2, found 498

実施例５３７

m/z=460(M+H)+

実施例５３８

m/z=461(M+H)+

実施例５３９

MS (ESI) m/e calcd. for C₂₅H₂₆ClN₂O₄S (MH⁺) 485.1, found 485.2

実施例５４０

MS (ESI) m/e calcd. for C₂₄H₂₈ClN₂O₃S (MH⁺) 459.2, found 459.4

実施例５４１

m/z=479(M+H)+

実施例５４２

m/z=493(M+H)+

実施例５４３

MS (ESI) ｍ/z 438 [M+H]+

実施例５４４

MS (ESI) m/z 438 [M+H]+

実施例５４５

m/z=446(M+H)+

実施例５４６

m/z=466(M+H)+

実施例５４７

m/z=482(M+H)+

実施例５４８

m/z=430(M+H)+

実施例５４９

m/z=444(M+H)+

実施例５５０

m/z=494(M+H)+

実施例５５１

m/z=474(M+H)+

実施例５５２

m/z=402(M+H)+

実施例５５３

m/z=431(M+H)+

実施例５５４

m/z=451(M+H)+

実施例５５５

m/z=462(M+H)+

実施例５５６

m/z=478(M+H)+

実施例５５７

m/z=478(M+H)+
The following compounds synthesized in the same manner are also included in the present invention.
Example 517

m / z = 461 (M + H) +

Example 518

m / z = 431 (M + H) +

Example 519

m / z = 447 (M + H) +

Example 520

m / z = 435 (M + H) +

Example 521

Rf = 0.49 (AcOEt)

Example 522

1H NMR (DMSO-d6): d 12,9 (br, 1H), 7.86 (s, 1H), 7.39 (d, 1H, J = 6.3Hz), 7.25 (d, 1H, J = 6.3Hz), 6.88 (s, 1H), 6.87 (d, 1H, J = 6.0Hz), 6.77 (d, 1H, J = 6.0Hz), 4.01 (m, 2H), 3.72 (s, 3H), 3.67 (br, 4H) , 3.46 (s, 2H), 2.94 (s, 2H), 2.87 (t, 2H, J = 4.2Hz), 2.75 (br, 2H), 1.90 (s, 2H).

Example 523

m / z = 461 (M + H) +

Example 524

m / z = 475 (M + H) +

Example 525

m / z = 505 (M + H) +

Example 526

m / z = 493 (M + H) +

Example 527

MS (ESI) m / e calcd.for C24H25ClFN2O3S2 (MH) + 507.1, found 507

Example 528

MS (ESI) m / e calcd.for C24H26ClN2O2S2 (MH) + 473.1, found 473

Example 529

MS (ESI) m / e calcd.for C23H23Cl2N2O2S2 (MH) + 493.1, found 493

Example 530

MS (ESI) m / e calcd.for C ₂₅ H ₂₆ ClN ₂ O ₃ S ₂ (MH ⁺ ) 501.1, found 501.4

Example 531

MS (ESI) m / e calcd.for C ₂₅ H ₂₆ ClN ₂ O ₂ S ₃ (MH ⁺ ) 517.1, found 517.4

Example 532

MS (ESI) m / e calcd.for C ₂₄ H ₂₅ ClN ₃ O ₂ S ₂ (MH ⁺ ) 486.1, found 486.4

Example 533

m / z = 489 (M + H) +

Example 534

m / z = 445 (M + H) +

Example 535

MS (ESI) m / e calcd.for C ₂₄ H ₂₉ ClN ₃ O ₃ S (MH ⁺ ) 474.2, found 474.4

Example 536

MS (ESI) m / e calcd.for C26H29ClN3O3S (MH) + 498.2, found 498

Example 537

m / z = 460 (M + H) +

Example 538

m / z = 461 (M + H) +

Example 539

MS (ESI) m / e calcd.for C ₂₅ H ₂₆ ClN ₂ O ₄ S (MH ⁺ ) 485.1, found 485.2

Example 540

MS (ESI) m / e calcd.for C ₂₄ H ₂₈ ClN ₂ O ₃ S (MH ⁺ ) 459.2, found 459.4

Example 541

m / z = 479 (M + H) +

Example 542

m / z = 493 (M + H) +

Example 543

MS (ESI) m / z 438 [M + H] +

Example 544

MS (ESI) m / z 438 [M + H] +

Example 545

m / z = 446 (M + H) +

Example 546

m / z = 466 (M + H) +

Example 547

m / z = 482 (M + H) +

Example 548

m / z = 430 (M + H) +

Example 549

m / z = 444 (M + H) +

Example 550

m / z = 494 (M + H) +

Example 551

m / z = 474 (M + H) +

Example 552

m / z = 402 (M + H) +

Example 553

m / z = 431 (M + H) +

Example 554

m / z = 451 (M + H) +

Example 555

m / z = 462 (M + H) +

Example 556

m / z = 478 (M + H) +

Example 557

m / z = 478 (M + H) +

2,5-ジブロモチアゾール(29.5g)、2,6-ジメチルピペラジン(13.8g)、炭酸カリウム(20.1g)、ジメチルホルムアミド(150mL)の混合物を60℃で6時間攪拌した。反応液に水を加えた後、酢酸エチルで抽出した。有機層を水、飽和食塩水で洗浄後、硫酸ナトリウムで乾燥した。減圧下溶媒を留去し、表記化合物(21.5g)を得た。収率64%。
¹H-NMR (CDCl₃) δ: 1.14 (6H, d, J = 6.3 Hz), 2.05(1H, br), 2.59-2.63 (2H, m), 2.98-3.02 (2H, m), 3.70-3.74 (2H, m), 7.06 (1H, s).

参考例２２９
[4-(5-ブロモチアゾール-2-イル)-2,6-ジメチルピペラジン-1-イル]酢酸メチルエステルの製造

1-(5-ブロモチアゾール-2-イル)-3,5-ジメチルピペラジン(21.5g)、ブロモ酢酸メチル(8.8mL)、炭酸カリウム(12.9g)、ジメチルホルムアミド(150mL)の混合物を60℃で2.5時間攪拌した。反応液に水を加え、酢酸エチルで抽出した。有機層を水、飽和食塩水で洗浄後、硫酸マグネシウムで乾燥した。減圧下溶媒を留去し、残渣をカラムクロマトで精製し、表記化合物(20.1g)を得た。収率74%。
¹H-NMR (CDCl₃) δ: 1.17 (6H, d, J = 6.0 Hz), 2.80-2.84 (2H, m), 3.13-3.16 (2H, m), 3.65 (2H, s), 3.65-3.68 (2H, m), 3.73 (3H, s), 7.08 (1H, s).

参考例２３０
2-[4-(5-ブロモチアゾール-2-イル)-2,6-ジメチルピペラジン-1-イル]エタノールの製造

[4-(5-ブロモチアゾール-2-イル)-2,6-ジメチルピペラジン-1-イル]酢酸 メチルエステル(20.1g)のテトラヒドロフラン(300mL)溶液に、-78℃で水素化ジイソブチルアルミニウム(1Mトルエン溶液、200mL)を滴下した。-78℃で3.5時間攪拌後、反応液に塩化アンモニウム水溶液(150mL)、ジエチルエーテル(45mL)を加え、不溶物をろ過した。母液をジエチルエーテルで抽出した。有機層を水、飽和食塩水で洗浄後、硫酸マグネシウムで洗浄した。減圧下溶媒を留去し、残渣をカラムクロマトで精製して表記化合物(13.2g)を得た。収率71%。
¹H-NMR (CDCl₃) δ: 1.17 (6H, d, J = 5.8 Hz), 2.44(1H, br), 2.84 (6H, dd, J = 16.9, 11.1 Hz), 3.60-3.64 (4H, m), 7.06 (1H, s).

参考例２３１
[3-[2-[4-(5-ブロモチアゾール-2-イル)-2,6-ジメチルピペラジン-1-イル]エトキシ]-4-メチルフェニル]酢酸メチルエステルの製造

2-[4-(5-ブロモチアゾール-2-イル)-2,6-ジメチルピペラジン-1-イル]エタノール(9.87g)、トリエチルアミン(8.6mL)、塩化メチレン(100mL)の混合物に、0℃でメタンスルホニルクロリド(2.9mL)を滴下した。0℃で0.5時間攪拌後、反応液に水を加えクロロホルムで抽出した。有機層を水、飽和食塩水で洗浄し、硫酸マグネシウムで乾燥、減圧下溶媒を留去した。得られた残渣をアセトニトリル(100mL)に溶解し、(3-ヒドロキシ-4-メチルフェニル)酢酸メチルエステル(5.0g)、炭酸セシウム(12.0g)を加え60℃で1時間攪拌した。反応液を酢酸エチルで希釈した後、不溶物をろ過し、母液を減圧下留去した。残渣をカラムクロマトで精製し表記化合物(8.49g)を得た。収率57%。
¹H-NMR (CDCl₃) δ: 1.27 (6H, d, J = 6.6 Hz), 2.20 (3H, s), 2.87-2.91 (4H, m), 3.25-3.27 (2H, m), 3.60 (2H, s), 3.68(2H, brm), 3.71 (3H, s), 4.03-4.05 (2H, m), 6.75 (1H, d, J = 1.4 Hz), 6.79 (1H, dd, J = 7.7, 1.4 Hz), 7.07 (1H, s), 7.10 (1H, d, J = 7.7 Hz).

参考例２３２
[3-[2-[4-(5-ブロモチアゾール-2-イル)-2,6-ジメチルピペラジン-1-イル]エトキシ]-4-メチルフェニル]酢酸の製造

[3-[2-[4-(5-ブロモチアゾール-2-イル)-2,6-ジメチルピペラジン-1-イル]エトキシ]-4-メチルフェニル]酢酸メチルエステル(8.49g)、2N水酸化ナトリウム水溶液(22mL)、メタノール(50mL)、テトラヒドロフラン(50mL)の混合物を室温で1.5時間攪拌した。反応液に水、飽和食塩水を加え、酢酸エチルで洗浄した。水層を2N塩酸で中和した後、クロロホルムで抽出した。有機層を水、飽和食塩水で洗浄後、硫酸マグネシウムで洗浄した。減圧下溶媒を留去し、残渣をジイソプロピルエーテルで洗浄し、表記化合物(5.81g)を得た。収率71%。
¹H-NMR (DMSO-d₆) δ: 1.16 (6H, d, J = 5.5 Hz), 2.13 (3H, s), 2.71-2.83 (4H, m), 3.12-3.14 (2H, m), 3.52 (2H, s), 3.65-3.68 (2H, m), 3.99-4.01 (2H, m), 6.74 (1H, d, J = 7.4 Hz), 6.87 (1H, s), 7.07 (1H, d, J = 7.4 Hz), 8.34 (1H, s). Reference Example 228
Production of 1- (5-bromothiazol-2-yl) -3,5-dimethylpiperazine

A mixture of 2,5-dibromothiazole (29.5 g), 2,6-dimethylpiperazine (13.8 g), potassium carbonate (20.1 g), and dimethylformamide (150 mL) was stirred at 60 ° C. for 6 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and then dried over sodium sulfate. The solvent was distilled off under reduced pressure to obtain the title compound (21.5 g). Yield 64%.
¹ H-NMR (CDCl ₃ ) δ: 1.14 (6H, d, J = 6.3 Hz), 2.05 (1H, br), 2.59-2.63 (2H, m), 2.98-3.02 (2H, m), 3.70-3.74 (2H, m), 7.06 (1H, s).

Reference Example 229
Preparation of [4- (5-bromothiazol-2-yl) -2,6-dimethylpiperazin-1-yl] acetic acid methyl ester

A mixture of 1- (5-bromothiazol-2-yl) -3,5-dimethylpiperazine (21.5 g), methyl bromoacetate (8.8 mL), potassium carbonate (12.9 g), dimethylformamide (150 mL) at 60 ° C. Stir for 2.5 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by column chromatography to obtain the title compound (20.1 g). Yield 74%.
¹ H-NMR (CDCl ₃ ) δ: 1.17 (6H, d, J = 6.0 Hz), 2.80-2.84 (2H, m), 3.13-3.16 (2H, m), 3.65 (2H, s), 3.65-3.68 (2H, m), 3.73 (3H, s), 7.08 (1H, s).

Reference Example 230
Preparation of 2- [4- (5-bromothiazol-2-yl) -2,6-dimethylpiperazin-1-yl] ethanol

[4- (5-Bromothiazol-2-yl) -2,6-dimethylpiperazin-1-yl] acetic acid methyl ester (20.1 g) in tetrahydrofuran (300 mL) at −78 ° C. with diisobutylaluminum hydride (1M Toluene solution, 200 mL) was added dropwise. After stirring at −78 ° C. for 3.5 hours, an aqueous ammonium chloride solution (150 mL) and diethyl ether (45 mL) were added to the reaction solution, and the insoluble material was filtered off. The mother liquor was extracted with diethyl ether. The organic layer was washed with water and saturated brine, and then washed with magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by column chromatography to obtain the title compound (13.2 g). Yield 71%.
¹ H-NMR (CDCl ₃ ) δ: 1.17 (6H, d, J = 5.8 Hz), 2.44 (1H, br), 2.84 (6H, dd, J = 16.9, 11.1 Hz), 3.60-3.64 (4H, m ), 7.06 (1H, s).

Reference Example 231
Preparation of [3- [2- [4- (5-Bromothiazol-2-yl) -2,6-dimethylpiperazin-1-yl] ethoxy] -4-methylphenyl] acetic acid methyl ester

To a mixture of 2- [4- (5-bromothiazol-2-yl) -2,6-dimethylpiperazin-1-yl] ethanol (9.87 g), triethylamine (8.6 mL) and methylene chloride (100 mL) was added at 0 ° C. Methanesulfonyl chloride (2.9 mL) was added dropwise. After stirring at 0 ° C. for 0.5 hour, water was added to the reaction mixture and the mixture was extracted with chloroform. The organic layer was washed with water and saturated brine, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was dissolved in acetonitrile (100 mL), (3-hydroxy-4-methylphenyl) acetic acid methyl ester (5.0 g) and cesium carbonate (12.0 g) were added, and the mixture was stirred at 60 ° C. for 1 hr. The reaction solution was diluted with ethyl acetate, insolubles were filtered off, and the mother liquor was evaporated under reduced pressure. The residue was purified by column chromatography to obtain the title compound (8.49 g). Yield 57%.
¹ H-NMR (CDCl ₃ ) δ: 1.27 (6H, d, J = 6.6 Hz), 2.20 (3H, s), 2.87-2.91 (4H, m), 3.25-3.27 (2H, m), 3.60 (2H , s), 3.68 (2H, brm), 3.71 (3H, s), 4.03-4.05 (2H, m), 6.75 (1H, d, J = 1.4 Hz), 6.79 (1H, dd, J = 7.7, 1.4 Hz), 7.07 (1H, s), 7.10 (1H, d, J = 7.7 Hz).

Reference Example 232
Preparation of [3- [2- [4- (5-Bromothiazol-2-yl) -2,6-dimethylpiperazin-1-yl] ethoxy] -4-methylphenyl] acetic acid

[3- [2- [4- (5-Bromothiazol-2-yl) -2,6-dimethylpiperazin-1-yl] ethoxy] -4-methylphenyl] acetic acid methyl ester (8.49 g), 2N hydroxylation A mixture of an aqueous sodium solution (22 mL), methanol (50 mL), and tetrahydrofuran (50 mL) was stirred at room temperature for 1.5 hours. Water and saturated brine were added to the reaction mixture, and the mixture was washed with ethyl acetate. The aqueous layer was neutralized with 2N hydrochloric acid and extracted with chloroform. The organic layer was washed with water and saturated brine, and then washed with magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was washed with diisopropyl ether to obtain the title compound (5.81 g). Yield 71%.
¹ H-NMR (DMSO-d ₆ ) δ: 1.16 (6H, d, J = 5.5 Hz), 2.13 (3H, s), 2.71-2.83 (4H, m), 3.12-3.14 (2H, m), 3.52 (2H, s), 3.65-3.68 (2H, m), 3.99-4.01 (2H, m), 6.74 (1H, d, J = 7.4 Hz), 6.87 (1H, s), 7.07 (1H, d, J = 7.4 Hz), 8.34 (1H, s).

[3-[2-[4-(5-ブロモチアゾール-2-イル)-2,6-ジメチルピペラジン-1-イル]エトキシ]-4-メチルフェニル]酢酸(400mg)、2,5-ジフルオロフェニルボロン酸(270mg)、テトラキス(トリフェニルホスフィン)パラジウム(100mg)、1M炭酸ナトリウム(4.3mL)、ジメチルホルムアミド(8mL) の混合物をマイクロウェーブ反応装置を用いて180℃で5分間反応した。反応液に水を加え、クロロホルムで抽出した。有機層を水、飽和食塩水で洗浄後、硫酸マグネシウムで乾燥した。減圧下溶媒を留去し、残渣をカラムクロマトで精製し、表記化合物(369mg)を得た。収率87%。
MS(ESI) m/z 502[M+H] Example 558
Preparation of [3- [2- [4- [5- (2,5-difluorophenyl) thiazol-2-yl] -2,6-dimethylpiperazin-1-yl] ethoxy] -4-methylphenyl] acetic acid

[3- [2- [4- (5-Bromothiazol-2-yl) -2,6-dimethylpiperazin-1-yl] ethoxy] -4-methylphenyl] acetic acid (400 mg), 2,5-difluorophenyl A mixture of boronic acid (270 mg), tetrakis (triphenylphosphine) palladium (100 mg), 1M sodium carbonate (4.3 mL) and dimethylformamide (8 mL) was reacted at 180 ° C. for 5 minutes using a microwave reactor. Water was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was washed with water and saturated brine, and dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by column chromatography to obtain the title compound (369 mg). Yield 87%.
MS (ESI) m / z 502 [M + H]

MS(ESI) m/z 508[M+]

実施例５６０

MS(ESI) m/z 508[M+]

実施例５６１

MS(ESI) m/z 515, 517 [M+H]+

実施例５６２

MS(ESI) m/z 501, 503 [M+H]+

実施例５６３

MS(ESI) m/z 579, 581 [M+H]+

実施例５６４

MS(ESI) m/z 529, 531 [M+H]+

実施例５６５

1H-NMR (DMSO-d6) δ: 1.11 (6H, d, J = 5.1 Hz), 2.60-2.70 (2H, m), 3.00-3.05 (2H, m), 3.55 (2H, s), 3.96-4.05 (2H, m), 4.32-4.45 (2H, m), 6.80-6.96 (3H, m), 8.44 (2H, s).

実施例５６６

1H-NMR (DMSO-d6) δ: 1.17 (6H, d, J = 4.9 Hz), 2.64-2.74 (4H, m), 3.09-3.18 (2H, m), 3.55 (2H, s), 4.03-4.10 (2H, m), 4.48-4.60 (2H, m), 6.83 (1H, dd, J = 8.0, 0.8 Hz), 7.09 (1H, d, J = 1.1 Hz), 7.33 (1H, d, J = 8.0 Hz), 7.47-7.83 (3H, m), 8.71 (2H, s).

実施例５６７

1H-NMR (DMSO-d6) δ: 1.17 (6H, d, J = 4.4 Hz), 2.64-2.76 (4H, m), 3.10-3.18 (2H, m), 3.56 (2H, s), 4.04-4.11 (2H, m), 4.49-4.60 (2H, m), 6.83 (1H, d, J = 8.0 Hz), 7.07-7.59 (5H, m), 8.59 (2H, s).

実施例５６８

1H-NMR (CDCl3) δ: 1.31 (6H, d, J = 5.8 Hz), 2.40 (3H, s), 2.90-3.08 (4H, m), 3.35-3.42 (2H, m), 3.54 (2H, s), 4.08-4.16 (2H, m), 4.52-4.67 (2H, m), 6.79-7.34 (7H, m), 8.52 (2H, s).

実施例５６９

1H-NMR (Acetone) δ: 8.62 (2.0H, s), 7.61-7.59 (2.0H, m), 7.45 (2.0H, dd, J = 7.55, 7.55 Hz), 7.37-7.28 (2.0H, m), 7.14 (1.0H, d, J = 1.89 Hz), 6.89 (1.0H, dd, J = 8.10, 1.89 Hz), 4.64 (2.0H, d, J = 11.81 Hz), 4.16 (2.0H, dd, J = 6.11, 6.11 Hz), 3.59 (2.0H, s), 3.24 (2.0H, dd, J = 6.11, 6.11 Hz), 2.93-2.64 (4.0H, m), 1.25 (6.0H, d, J = 6.04 Hz).

実施例５７０

MS(ESI) m/z 508[M+H]+

実施例５７１

1H-NMR(DMSO-d6)) d:7.81(1H, s),7.67(1H, s), 7.32-7.29(2H, m), 7.07(1H ,s), 6.81(1H, d, J=8.8Hz), 6.75(1H, s), 4.06-4.03(2H, m), 3.67(2H, d, J=10.8Hz), 3.52(2H, s), 3.12-3.09(2H, m), 2.82-2.69(4H, m), 1.13(6H, d, J=5.7Hz).

実施例５７２

MS(ESI) m/z 525[M+H]+

実施例５７３

1H-NMR (DMSO-d6) δ: 7.79 (1.0H, s), 7.70-7.64 (4.0H, m), 7.03 (1.0H, d, J = 7.56 Hz), 6.85 (1.0H, s), 6.71 (1.0H, d, J = 7.56 Hz), 3.99 (2.0H, dd, J = 5.49, 5.49 Hz), 3.79 (2.0H, d, J = 9.06 Hz), 3.47 (2.0H, s), 3.15-3.11 (2.0H, m), 2.89-2.78 (4.0H, m), 2.11 (3.0H, s), 1.17 (6.0H, d, J = 5.22 Hz).

実施例５７４

1H-NMR (DMSO-d6) δ: 7.83-7.70 (3.0H, m), 7.63-7.50 (2.0H, m), 7.03 (1.0H, d, J = 7.69 Hz), 6.85 (1.0H, s), 6.70 (1.0H, d, J = 7.69 Hz), 4.02-3.96 (2.0H, m), 3.79 (2.0H, d, J = 9.06 Hz), 3.47 (2.0H, s), 3.17-3.10 (2.0H, m), 2.91-2.76 (4.0H, m), 2.12 (3.0H, s), 1.26-1.11 (6.0H, d, J = 6.0 Hz).

実施例５７５

1H-NMR (DMSO-d6) δ: 7.58 (1.0H, s), 7.46 (2.0H, d, J = 7.42 Hz), 7.35 (2.0H, dd, J = 7.42, 7.42 Hz), 7.21 (1.0H, dd, J = 7.42, 7.42 Hz), 7.03 (1.0H, d, J = 7.80 Hz), 6.85 (1.0H, s), 6.70 (1.0H, d, J = 7.80 Hz), 4.01-3.97 (2.0H, m), 3.76 (2.0H, d, J = 10.99 Hz), 3.45 (2.0H, s), 3.14-3.11 (2.0H, m), 2.89-2.74 (4.0H, m), 2.11 (3.0H, s), 1.17 (6.0H, d, J = 5.49 Hz).

実施例５７６

1H-NMR(CDCl3) δ 1.17(6H, m), 2.12(3H, s), 2.82(4H, m), 2.13(2H, br), 3.30(3H, d, J=2.1Hz), 3.49(2H, s), 3.77(2H, d, J=10.2Hz), 3.99(2H, br), 4.41(2H, s), 6.71(1H, brd), 6.85(1H, brd), 7.04(1H, brd), 7.15(1H, brd), 7.30-7.41(3H, m), 7.60(1H, d, 1.8Hz)

実施例５７７

1H-NMR(DMSO-d6) δ 1.16(6H, d, J=6.0Hz), 1.33(3H, t, J=6.9Hz), 2.12(3H, s), 2.74-2.90(4H, m), 3.13(2H, t, J=5.1Hz), 3.49(2H, s), 3.76(2H, d, J=10.5Hz), 3.97-4.08(4H, m), 6.72(1H, d, J=7.8Hz), 6.78(1H, dd, J=8.4Hz, 2.4Hz), 6.85(1H, s), 6.98-7.06(3H, m), 7.24(1H, t, J=8.1Hz), 7.61(1H, s)

実施例５７８

1H-NMR(DMSO-d6) δ 1.16(6H, d, J=5.7Hz), 2.12(3H, s), 2.72-2.91(4H, m), 2.91(6H, s), 3.12(2H, brs), 3.49(2H, s), 3.76(2H, d, J=10.5Hz), 3.99(2H, brs), 6.57-6.61(1H, m), 6.70-6.77(3H, m), 6.85(1H, s), 7.05(1H, d, J=7.5Hz), 7.15(1H, t, J=7.8Hz), 7.54(1H, s)

実施例５７９

1H-NMR (Acetone) δ: 8.62 (2.0H, s), 7.61-7.59 (2.0H, m), 7.45 (2.0H, dd, J = 7.55, 7.55 Hz), 7.37-7.28 (2.0H, m), 7.14 (1.0H, d, J = 1.89 Hz), 6.89 (1.0H, dd, J = 8.10, 1.89 Hz), 4.64 (2.0H, d, J = 11.81 Hz), 4.16 (2.0H, dd, J = 6.11, 6.11 Hz), 3.59 (2.0H, s), 3.24 (2.0H, dd, J = 6.11, 6.11 Hz), 2.93-2.64 (4.0H, m), 1.25 (6.0H, d, J = 6.04 Hz).

実施例５８０

1H-NMR (DMSO-d6) δ: 8.69 (2.0H, s), 7.63 (2.0H, d, J = 7.42 Hz), 7.45 (2.0H, dd, J = 7.42, 7.42 Hz), 7.35 (1.0H, d, J = 7.42 Hz), 6.62 (3.0H, s), 4.53 (2.0H, d, J = 8.79 Hz), 3.96 (2.0H, dd, J = 6.48, 6.48 Hz), 3.45 (2.0H, s), 3.03 (2.0H, dd, J = 6.48, 6.48 Hz), 2.67 (4.0H, d, J = 7.97 Hz), 2.23 (3.0H, s), 1.14 (6.0H, d, J = 4.94 Hz).

実施例５８１

1H-NMR (DMSO-d6) δ: 8.65 (2.0H, s), 7.32 (1.0H, d, J = 8.23 Hz), 7.23 (1.0H, dd, J = 8.10, 8.10 Hz), 7.09 (1.0H, d, J = 1.65 Hz), 6.87-6.81 (3.0H, m), 6.72-6.67 (1.0H, m), 4.52 (2.0H, d, J = 9.61 Hz), 4.07 (2.0H, dd, J = 5.40, 5.40 Hz), 3.55 (2.0H, s), 3.13 (2.0H, dd, J = 5.40, 5.40 Hz), 2.93 (6.0H, s), 2.73-2.62 (4.0H, m), 1.18 (6.0H, d, J = 6.04 Hz). In the same manner, the following compound was obtained.
Example 559

MS (ESI) m / z 508 [M +]

Example 560

MS (ESI) m / z 508 [M +]

Example 561

MS (ESI) m / z 515, 517 [M + H] +

Example 562

MS (ESI) m / z 501, 503 [M + H] +

Example 563

MS (ESI) m / z 579, 581 [M + H] +

Example 564

MS (ESI) m / z 529, 531 [M + H] +

Example 565

1H-NMR (DMSO-d6) δ: 1.11 (6H, d, J = 5.1 Hz), 2.60-2.70 (2H, m), 3.00-3.05 (2H, m), 3.55 (2H, s), 3.96-4.05 (2H, m), 4.32-4.45 (2H, m), 6.80-6.96 (3H, m), 8.44 (2H, s).

Example 566

1H-NMR (DMSO-d6) δ: 1.17 (6H, d, J = 4.9 Hz), 2.64-2.74 (4H, m), 3.09-3.18 (2H, m), 3.55 (2H, s), 4.03-4.10 (2H, m), 4.48-4.60 (2H, m), 6.83 (1H, dd, J = 8.0, 0.8 Hz), 7.09 (1H, d, J = 1.1 Hz), 7.33 (1H, d, J = 8.0 Hz), 7.47-7.83 (3H, m), 8.71 (2H, s).

Example 567

1H-NMR (DMSO-d6) δ: 1.17 (6H, d, J = 4.4 Hz), 2.64-2.76 (4H, m), 3.10-3.18 (2H, m), 3.56 (2H, s), 4.04-4.11 (2H, m), 4.49-4.60 (2H, m), 6.83 (1H, d, J = 8.0 Hz), 7.07-7.59 (5H, m), 8.59 (2H, s).

Example 568

1H-NMR (CDCl3) δ: 1.31 (6H, d, J = 5.8 Hz), 2.40 (3H, s), 2.90-3.08 (4H, m), 3.35-3.42 (2H, m), 3.54 (2H, s ), 4.08-4.16 (2H, m), 4.52-4.67 (2H, m), 6.79-7.34 (7H, m), 8.52 (2H, s).

Example 569

1H-NMR (Acetone) δ: 8.62 (2.0H, s), 7.61-7.59 (2.0H, m), 7.45 (2.0H, dd, J = 7.55, 7.55 Hz), 7.37-7.28 (2.0H, m) , 7.14 (1.0H, d, J = 1.89 Hz), 6.89 (1.0H, dd, J = 8.10, 1.89 Hz), 4.64 (2.0H, d, J = 11.81 Hz), 4.16 (2.0H, dd, J = 6.11, 6.11 Hz), 3.59 (2.0H, s), 3.24 (2.0H, dd, J = 6.11, 6.11 Hz), 2.93-2.64 (4.0H, m), 1.25 (6.0H, d, J = 6.04 Hz).

Example 570

MS (ESI) m / z 508 [M + H] +

Example 571

1H-NMR (DMSO-d6)) d: 7.81 (1H, s), 7.67 (1H, s), 7.32-7.29 (2H, m), 7.07 (1H, s), 6.81 (1H, d, J = 8.8 Hz), 6.75 (1H, s), 4.06-4.03 (2H, m), 3.67 (2H, d, J = 10.8Hz), 3.52 (2H, s), 3.12-3.09 (2H, m), 2.82-2.69 (4H, m), 1.13 (6H, d, J = 5.7Hz).

Example 572

MS (ESI) m / z 525 [M + H] +

Example 573

1H-NMR (DMSO-d6) δ: 7.79 (1.0H, s), 7.70-7.64 (4.0H, m), 7.03 (1.0H, d, J = 7.56 Hz), 6.85 (1.0H, s), 6.71 (1.0H, d, J = 7.56 Hz), 3.99 (2.0H, dd, J = 5.49, 5.49 Hz), 3.79 (2.0H, d, J = 9.06 Hz), 3.47 (2.0H, s), 3.15- 3.11 (2.0H, m), 2.89-2.78 (4.0H, m), 2.11 (3.0H, s), 1.17 (6.0H, d, J = 5.22 Hz).

Example 574

1H-NMR (DMSO-d6) δ: 7.83-7.70 (3.0H, m), 7.63-7.50 (2.0H, m), 7.03 (1.0H, d, J = 7.69 Hz), 6.85 (1.0H, s) , 6.70 (1.0H, d, J = 7.69 Hz), 4.02-3.96 (2.0H, m), 3.79 (2.0H, d, J = 9.06 Hz), 3.47 (2.0H, s), 3.17-3.10 (2.0 H, m), 2.91-2.76 (4.0H, m), 2.12 (3.0H, s), 1.26-1.11 (6.0H, d, J = 6.0 Hz).

Example 575

1H-NMR (DMSO-d6) δ: 7.58 (1.0H, s), 7.46 (2.0H, d, J = 7.42 Hz), 7.35 (2.0H, dd, J = 7.42, 7.42 Hz), 7.21 (1.0H , dd, J = 7.42, 7.42 Hz), 7.03 (1.0H, d, J = 7.80 Hz), 6.85 (1.0H, s), 6.70 (1.0H, d, J = 7.80 Hz), 4.01-3.97 (2.0 H, m), 3.76 (2.0H, d, J = 10.99 Hz), 3.45 (2.0H, s), 3.14-3.11 (2.0H, m), 2.89-2.74 (4.0H, m), 2.11 (3.0H , s), 1.17 (6.0H, d, J = 5.49 Hz).

Example 576

1H-NMR (CDCl3) δ 1.17 (6H, m), 2.12 (3H, s), 2.82 (4H, m), 2.13 (2H, br), 3.30 (3H, d, J = 2.1Hz), 3.49 (2H , s), 3.77 (2H, d, J = 10.2Hz), 3.99 (2H, br), 4.41 (2H, s), 6.71 (1H, brd), 6.85 (1H, brd), 7.04 (1H, brd) , 7.15 (1H, brd), 7.30-7.41 (3H, m), 7.60 (1H, d, 1.8Hz)

Example 577

1H-NMR (DMSO-d6) δ 1.16 (6H, d, J = 6.0Hz), 1.33 (3H, t, J = 6.9Hz), 2.12 (3H, s), 2.74-2.90 (4H, m), 3.13 (2H, t, J = 5.1Hz), 3.49 (2H, s), 3.76 (2H, d, J = 10.5Hz), 3.97-4.08 (4H, m), 6.72 (1H, d, J = 7.8Hz) , 6.78 (1H, dd, J = 8.4Hz, 2.4Hz), 6.85 (1H, s), 6.98-7.06 (3H, m), 7.24 (1H, t, J = 8.1Hz), 7.61 (1H, s)

Example 578

1H-NMR (DMSO-d6) δ 1.16 (6H, d, J = 5.7Hz), 2.12 (3H, s), 2.72-2.91 (4H, m), 2.91 (6H, s), 3.12 (2H, brs) , 3.49 (2H, s), 3.76 (2H, d, J = 10.5Hz), 3.99 (2H, brs), 6.57-6.61 (1H, m), 6.70-6.77 (3H, m), 6.85 (1H, s ), 7.05 (1H, d, J = 7.5Hz), 7.15 (1H, t, J = 7.8Hz), 7.54 (1H, s)

Example 579

1H-NMR (Acetone) δ: 8.62 (2.0H, s), 7.61-7.59 (2.0H, m), 7.45 (2.0H, dd, J = 7.55, 7.55 Hz), 7.37-7.28 (2.0H, m) , 7.14 (1.0H, d, J = 1.89 Hz), 6.89 (1.0H, dd, J = 8.10, 1.89 Hz), 4.64 (2.0H, d, J = 11.81 Hz), 4.16 (2.0H, dd, J = 6.11, 6.11 Hz), 3.59 (2.0H, s), 3.24 (2.0H, dd, J = 6.11, 6.11 Hz), 2.93-2.64 (4.0H, m), 1.25 (6.0H, d, J = 6.04 Hz).

Example 580

1H-NMR (DMSO-d6) δ: 8.69 (2.0H, s), 7.63 (2.0H, d, J = 7.42 Hz), 7.45 (2.0H, dd, J = 7.42, 7.42 Hz), 7.35 (1.0H , d, J = 7.42 Hz), 6.62 (3.0H, s), 4.53 (2.0H, d, J = 8.79 Hz), 3.96 (2.0H, dd, J = 6.48, 6.48 Hz), 3.45 (2.0H, s), 3.03 (2.0H, dd, J = 6.48, 6.48 Hz), 2.67 (4.0H, d, J = 7.97 Hz), 2.23 (3.0H, s), 1.14 (6.0H, d, J = 4.94 Hz) ).

Example 581

1H-NMR (DMSO-d6) δ: 8.65 (2.0H, s), 7.32 (1.0H, d, J = 8.23 Hz), 7.23 (1.0H, dd, J = 8.10, 8.10 Hz), 7.09 (1.0H , d, J = 1.65 Hz), 6.87-6.81 (3.0H, m), 6.72-6.67 (1.0H, m), 4.52 (2.0H, d, J = 9.61 Hz), 4.07 (2.0H, dd, J = 5.40, 5.40 Hz), 3.55 (2.0H, s), 3.13 (2.0H, dd, J = 5.40, 5.40 Hz), 2.93 (6.0H, s), 2.73-2.62 (4.0H, m), 1.18 ( 6.0H, d, J = 6.04 Hz).

２，６−ジメチルピペラジン（１０．０ｇ）の塩化メチレン（２００ｍL）の混合物に、ジ-t-ブチルジカルボナート（１９．１ｇ）を氷冷下加えた。室温で17時間攪拌したのち、反応液に水を加え塩化メチレンで抽出した。有機層を飽和食塩水で洗浄後、硫酸マグネシウムで乾燥した。溶媒を減圧下留去し、表記化合物１８．７ｇを得た。収率１００％。
１H-NMR(CDCl3) δ 1.15(6H, d, J=6.3), 1.32 (2H, m), 1.49 (9H, s), 2.43 (1H, m), 2.85(2H, m), 3.99(1H, m).

参考例２３４
4-メトキシカルボニルメチル-3,5-ジメチルピペラジン-1-カルボン酸 t-ブチルエステルの製造

3,5-ジメチルカルボニルピペラジン-1-カルボン酸 t-ブチルエステル(18.7g)、炭酸カリウム(14.5g)、ブロモ酢酸メチル(14.7g)、DMF(90mL)の混合物を60℃で3時間攪拌した。反応液に水を加え、酢酸エチルで抽出した。有機層を水、飽和食塩水で洗浄後、硫酸マグネシウムで乾燥した。減圧下溶媒を留去し表記化合物を得た。このものはさらに精製をせず次の反応に付した。

参考例２３５
4-(2-ヒドロキシエチル)-3,5-ジメチルピペラジン-1-カルボン酸 t-ブチルエステルの製造

上記反応で得た3,5-ジメチルカルボニルピペラジン-1-カルボン酸 t-ブチルエステルをTHF(300mL)に溶解した後、氷冷下、水素化リチウムアルミニウム(3.31g)を加えた。0℃で1時間攪拌後、水、2N 水酸化ナトリウム水溶液を順次加えた。不溶物をろ過後、母液を減圧下の濃縮し、表記化合物(20.3g)を得た。収率90%。

参考例２３６
4-[2-(5-カルボニルメチル-2-クロロフェノキシ)エチル]-3,5-ジメチルピペラジン1-1カルボン酸 t-ブチルエステルの製造

4-(2-ヒドロキシエチル)-3,5-ジメチルピペラジン-1-カルボン酸 t-ブチルエステル（3.0g）、トリエチルアミン(1.76g)、メシルクロリド(1.60g)、塩化メチレン(60mL) の混合物を氷冷下1.5時間攪拌した。反応液に水を加えた後、酢酸エチルで抽出した。有機層を水、飽和食塩水で洗浄、硫酸マグネシウムで乾燥後、減圧下溶媒を留去した。得られた残渣をアセトニトリル(60mL)に溶解後、(4-クロロ-3-ヒドロキシフェニル)酢酸メチルエステル(2.33g)、炭酸セシウム(4.54g)を加え、60℃で5時間攪拌した。不溶物をろ過した後、母液を濃縮し、得られた残渣をカラムクロマトで精製し、表記化合物(3.58g)を得た。収率70%。
1H-NMR (DMSO-d6) δ: 1.09(6H, d, J=6.0), 1.40(9H, s), 2,40-2.50(2H, m), 2.52-2,61(2H, m), 3.08-3.12(2H, m), 3.64(3H, s), 3.71(2H, 2), 3.77(2H, m), 4.02-4.09(2H, m), 6.87(1H, d, J=8.0), 7.13(1H, s), 7.37(1H, d, J=8.0)

参考例２３７
[4-クロロ-3-[2-(2,6-ジメチルピペラジン-1-イル)エトキシ]フェニル]酢酸 メチルエステルの製造

4-[2-(5-カルボニルメチル-2-クロロフェノキシ)エチル]-3,5-ジメチルピペラジン1-1カルボン酸 t-ブチルエステル（400mg）、4N塩酸-ジオキサン溶液(4mL)を室温下2時間攪拌した。反応液に水、酢酸エチルを加えた後、炭酸ナトリウムで中和した。混合物を酢酸エチルで抽出後、有機層を飽和食塩水で洗浄した。減圧下溶媒を留去し、表記化合物(291mg)を得た。収率94％。
1H-NMR (DMSO-d6) δ:1.02(3H, d, J=6.3), 2.22-2.29(2H, m), 2.50-2.54(2H, m), 2.72-2.76(2H, m), 3.03-3.07(2H, m), 4.03-4.07(2H, m), 6.87(1H, d, J=8.2), 7.13(1H, s), 7.37(1H, d, J=8.2) Reference Example 233
Production of 3,5-dimethylcarbonylpiperazine-1-carboxylic acid t-butyl ester

Di-t-butyl dicarbonate (19.1 g) was added to a mixture of 2,6-dimethylpiperazine (10.0 g) in methylene chloride (200 mL) under ice cooling. After stirring at room temperature for 17 hours, water was added to the reaction mixture, and the mixture was extracted with methylene chloride. The organic layer was washed with saturated brine and dried over magnesium sulfate. The solvent was distilled off under reduced pressure to obtain 18.7 g of the title compound. Yield 100%.
1H-NMR (CDCl3) δ 1.15 (6H, d, J = 6.3), 1.32 (2H, m), 1.49 (9H, s), 2.43 (1H, m), 2.85 (2H, m), 3.99 (1H, m).

Reference Example 234
Preparation of 4-methoxycarbonylmethyl-3,5-dimethylpiperazine-1-carboxylic acid t-butyl ester

A mixture of 3,5-dimethylcarbonylpiperazine-1-carboxylic acid t-butyl ester (18.7 g), potassium carbonate (14.5 g), methyl bromoacetate (14.7 g) and DMF (90 mL) was stirred at 60 ° C. for 3 hours. . Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over magnesium sulfate. The title compound was obtained by distilling off the solvent under reduced pressure. This was subjected to the next reaction without further purification.

Reference Example 235
Preparation of 4- (2-hydroxyethyl) -3,5-dimethylpiperazine-1-carboxylic acid t-butyl ester

3,5-Dimethylcarbonylpiperazine-1-carboxylic acid t-butyl ester obtained in the above reaction was dissolved in THF (300 mL), and then lithium aluminum hydride (3.31 g) was added under ice cooling. After stirring at 0 ° C. for 1 hour, water and 2N aqueous sodium hydroxide solution were sequentially added. The insoluble material was filtered off, and the mother liquor was concentrated under reduced pressure to obtain the title compound (20.3 g). Yield 90%.

Reference Example 236
Preparation of 4- [2- (5-carbonylmethyl-2-chlorophenoxy) ethyl] -3,5-dimethylpiperazine 1-1 carboxylic acid t-butyl ester

A mixture of 4- (2-hydroxyethyl) -3,5-dimethylpiperazine-1-carboxylic acid t-butyl ester (3.0 g), triethylamine (1.76 g), mesyl chloride (1.60 g), and methylene chloride (60 mL) The mixture was stirred for 1.5 hours under ice cooling. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was dissolved in acetonitrile (60 mL), methyl (4-chloro-3-hydroxyphenyl) acetic acid (2.33 g) and cesium carbonate (4.54 g) were added, and the mixture was stirred at 60 ° C. for 5 hr. The insoluble material was filtered off, the mother liquor was concentrated, and the resulting residue was purified by column chromatography to obtain the title compound (3.58 g). Yield 70%.
1H-NMR (DMSO-d6) δ: 1.09 (6H, d, J = 6.0), 1.40 (9H, s), 2,40-2.50 (2H, m), 2.52-2,61 (2H, m), 3.08-3.12 (2H, m), 3.64 (3H, s), 3.71 (2H, 2), 3.77 (2H, m), 4.02-4.09 (2H, m), 6.87 (1H, d, J = 8.0), 7.13 (1H, s), 7.37 (1H, d, J = 8.0)

Reference Example 237
Preparation of methyl ester of [4-chloro-3- [2- (2,6-dimethylpiperazin-1-yl) ethoxy] phenyl] acetic acid

4- [2- (5-carbonylmethyl-2-chlorophenoxy) ethyl] -3,5-dimethylpiperazine 1-1carboxylic acid t-butyl ester (400 mg), 4N hydrochloric acid-dioxane solution (4 mL) at room temperature 2 Stir for hours. Water and ethyl acetate were added to the reaction solution, and then neutralized with sodium carbonate. The mixture was extracted with ethyl acetate, and the organic layer was washed with saturated brine. The solvent was distilled off under reduced pressure to obtain the title compound (291 mg). Yield 94%.
1H-NMR (DMSO-d6) δ: 1.02 (3H, d, J = 6.3), 2.22-2.29 (2H, m), 2.50-2.54 (2H, m), 2.72-2.76 (2H, m), 3.03- 3.07 (2H, m), 4.03-4.07 (2H, m), 6.87 (1H, d, J = 8.2), 7.13 (1H, s), 7.37 (1H, d, J = 8.2)

[4-クロロ-3-[2-(2,6-ジメチルピペラジン-1-イル)エトキシ]フェニル]酢酸 メチルエステル(50mg)、フェニルイソシアナート(19mg)、炭酸カリウム(41mg)、塩化メチレン(2mL)の混合物を室温で3時間攪拌した。不溶物をろ過後、母液を減圧下濃縮し、残渣をカラムクロマトで精製し、表記化合物(52m)を得た。収率77%。
1H-NMR (DMSO-d6) δ: 1.15(6H, d, J=5.8), 2.11(2H, brm), 2.57(2H, brm), 2.67(2H, brm), 3.13(2H, brm), 3.64(3H, s), 3.71(2H, s), 4.04-4.09(2H, m), 6.86-6.97(2H, m), 7.14(1H, s), 7.22-7.25(2H, m), 7.36-7.47(3H, m), 8.48(1H, s).

実施例５８３
[4-クロロ-3-[2-(2,6-ジメチル-4-フェニルカルバモイルピペラジン-1-イル)エトキシ]フェニル]酢酸の製造

[4-クロロ-3-[2-(2,6-ジメチル-4-フェニルカルバモイルピペラジン-1-イル)エトキシ]フェニル]酢酸 メチルエステル(50mg)、2N水酸化ナトリウム(0.1mL)、テトラヒドロフラン(1mL) の混合物を室温で4時間攪拌した。2N塩酸で中和した後。酢酸エチルで抽出した。有機層を飽和食塩水で洗浄後、硫酸マグネシウムで乾燥した。減圧下溶媒を留去し、残渣をカラクロマトで精製して、表記化合物(18mg)を得た。収率37%。
1H-NMR (DMSO-d6) δ: 1.12 (6H, d, J = 5.8 Hz), 2.42-2.70 (4H, m), 3.06-3.16 (2H, m), 3.56 (2H, s), 3.93-4.11 (4H, m), 6.81-7.47 (6H, m), 8.46 (1H, s). Example 582
Preparation of [4-chloro-3- [2- (2,6-dimethyl-4-phenylcarbamoylpiperazin-1-yl) ethoxy] phenyl] acetic acid methyl ester

[4-Chloro-3- [2- (2,6-dimethylpiperazin-1-yl) ethoxy] phenyl] acetic acid methyl ester (50 mg), phenyl isocyanate (19 mg), potassium carbonate (41 mg), methylene chloride (2 mL ) Was stirred at room temperature for 3 hours. The insoluble material was filtered off, the mother liquor was concentrated under reduced pressure, and the residue was purified by column chromatography to obtain the title compound (52m). Yield 77%.
1H-NMR (DMSO-d6) δ: 1.15 (6H, d, J = 5.8), 2.11 (2H, brm), 2.57 (2H, brm), 2.67 (2H, brm), 3.13 (2H, brm), 3.64 (3H, s), 3.71 (2H, s), 4.04-4.09 (2H, m), 6.86-6.97 (2H, m), 7.14 (1H, s), 7.22-7.25 (2H, m), 7.36-7.47 (3H, m), 8.48 (1H, s).

Example 583
Preparation of [4-chloro-3- [2- (2,6-dimethyl-4-phenylcarbamoylpiperazin-1-yl) ethoxy] phenyl] acetic acid

[4-Chloro-3- [2- (2,6-dimethyl-4-phenylcarbamoylpiperazin-1-yl) ethoxy] phenyl] acetic acid methyl ester (50 mg), 2N sodium hydroxide (0.1 mL), tetrahydrofuran (1 mL ) Was stirred at room temperature for 4 hours. After neutralization with 2N hydrochloric acid. Extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by color chromatography to obtain the title compound (18 mg). Yield 37%.
1H-NMR (DMSO-d6) δ: 1.12 (6H, d, J = 5.8 Hz), 2.42-2.70 (4H, m), 3.06-3.16 (2H, m), 3.56 (2H, s), 3.93-4.11 (4H, m), 6.81-7.47 (6H, m), 8.46 (1H, s).

1H-NMR (DMSO-d6) δ: 1.10-1.29 (2H, m), 1.70-1.83 (4H, m), 2.73-2.87 (2H, m), 3.59 (2H, s), 4.07-4.20 (4H, m), 6.83-7.51 (6H, m), 8.46 (1H, s). In the same manner, the following compound was obtained.
Example 584

1H-NMR (DMSO-d6) δ: 1.10-1.29 (2H, m), 1.70-1.83 (4H, m), 2.73-2.87 (2H, m), 3.59 (2H, s), 4.07-4.20 (4H, m), 6.83-7.51 (6H, m), 8.46 (1H, s).

cis-2,6-ジメチルピペラジン(247mg)のテトラヒドロフラン(5mL) 溶液に、-78℃で n-BuLi(2.67 Mヘキサン溶液、1.62mL)を加えた。室温で30分攪拌後、トリメチルシリルクロリド(0.27mL)を加えた。40分間攪拌後、2-クロロ-6-トリフルオロメチルベンゾチアゾール(500mg)のテトラヒドロフラン(2mL) 溶液を加え、さらに2時間攪拌した。反応液に水を加え、酢酸エチルで抽出した。有機層を水洗後、炭酸ナトリウムで乾燥した。残渣をカラムクロマトで精製し、表記化合物(367mg)を得た。収率54%。
¹H-NMR (CDCl₃) δ: 1.47 (6H, d, J = 6.87 Hz), 2.13 (2H, s), 2.91-3.10 (4H, m), 4.14-4.23 (2H, m), 7.51-7.59 (2H, m), 7.85 (1H, s).

参考例２３９
2-[3,5-ジメチル-4-(6-トルフルオロメチルベンゾチアゾール-2-イル)ピペラジン-1-イル]エタノールの製造

2-(2,6-ジメチルピペラジン-1-イル)-6-トリフルオロメチルベンゾチアゾール(360mg)、(2-ブロモエトキシ)-t-ブチルジメチルシラン(257uL)、炭酸カリウム(157mg)、ジメチルホルムアミド(2mL)の混合物を、60℃で20時間攪拌した。反応液に水を加え酢酸エチルで抽出した。有機層を水洗後、炭酸ナトリウムで乾燥した。溶媒を留去後、残渣をカラムクロマトで精製し、表記化合物(265mg)を得た。収率65%。
¹H-NMR (CDCl₃) δ: 1.53 (6H, d, J = 6.59 Hz), 2.54-2.57 (2H, br m), 2.67-2.70 (2H, br m), 2.80-2.90 (2H, br m), 3.74-3.77 (2H, br m), 4.29-4.32 (2H, br m), 7.52-7.61 (2H, m), 7.87 (1H, s). Reference Example 238
Preparation of 2- (2,6-dimethylpiperazin-1-yl) -6-trifluoromethylbenzothiazole

n-BuLi (2.67 M hexane solution, 1.62 mL) was added to a solution of cis-2,6-dimethylpiperazine (247 mg) in tetrahydrofuran (5 mL) at −78 ° C. After stirring at room temperature for 30 minutes, trimethylsilyl chloride (0.27 mL) was added. After stirring for 40 minutes, a solution of 2-chloro-6-trifluoromethylbenzothiazole (500 mg) in tetrahydrofuran (2 mL) was added, and the mixture was further stirred for 2 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and dried over sodium carbonate. The residue was purified by column chromatography to obtain the title compound (367 mg). Yield 54%.
¹ H-NMR (CDCl ₃ ) δ: 1.47 (6H, d, J = 6.87 Hz), 2.13 (2H, s), 2.91-3.10 (4H, m), 4.14-4.23 (2H, m), 7.51-7.59 (2H, m), 7.85 (1H, s).

Reference Example 239
Preparation of 2- [3,5-dimethyl-4- (6-trifluoromethylbenzothiazol-2-yl) piperazin-1-yl] ethanol

2- (2,6-dimethylpiperazin-1-yl) -6-trifluoromethylbenzothiazole (360 mg), (2-bromoethoxy) -t-butyldimethylsilane (257 uL), potassium carbonate (157 mg), dimethylformamide A mixture of (2 mL) was stirred at 60 ° C. for 20 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and dried over sodium carbonate. After the solvent was distilled off, the residue was purified by column chromatography to obtain the title compound (265 mg). Yield 65%.
¹ H-NMR (CDCl ₃ ) δ: 1.53 (6H, d, J = 6.59 Hz), 2.54-2.57 (2H, br m), 2.67-2.70 (2H, br m), 2.80-2.90 (2H, br m ), 3.74-3.77 (2H, br m), 4.29-4.32 (2H, br m), 7.52-7.61 (2H, m), 7.87 (1H, s).

2-[3,5-ジメチル-4-(6-トルフルオロメチルベンゾチアゾール-2-イル)ピペラジン-1-イル]エタノール(138mg)の塩化メチレン(3mL)溶液に、メタンスルホニルクロリド(45μL)、トリエチルアミン(107μL)を加え、室温で1時間攪拌した。反応液に水を加えクロロホルムで抽出した。有機層は水、飽和食塩水で洗浄後、硫酸ナトリウムで乾燥した。減圧下溶媒を留去した。得られた残渣にジメチルホルムアミド(2mL)、炭酸セシウム(248mg)、(4-クロロ-3-ヒドロキシフェニル)酢酸メチルエステル(92mg)を加え、60℃で2時間攪拌した。反応液に2N塩酸を加え中和した後、酢酸エチルで抽出した。有機層を水洗後、硫酸マグネシウムで乾燥した。残渣をカラムクロマトで精製し、表記化合物(178mg)を得た。収率89％。

実施例５８６
[4-クロロ-3-[2-[3,5-ジメチル-4-(6-トリフルオロメチルベンゾチアゾール-2-イル)ピペラジン-1-イル]エトキシ]フェニル]酢酸の製造

[4-クロロ-3-[2-[3,5-ジメチル-4-(6-トリフルオロメチルベンゾチアゾール-2-イル)ピペラジン-1-イル]エトキシ]フェニル]酢酸 メチルエステル(178mg)、2N水酸化ナトリウム水溶液(0.66mL)、テトラヒドロフラン(2mL)、メタノール(2mL)の混合物を室温で2時間攪拌した。2N 塩酸で中和した後、酢酸エチルで抽出した。有機層を水洗後、硫酸ナトリウムで乾燥した。減圧下溶媒を留去した後、残渣をカラムクロマトで精製し、表記化合物(83mg)を得た。収率48%。
MS(ESI) m/z 528 [M+H]+ Example 585
Preparation of [4-chloro-3- [2- [3,5-dimethyl-4- (6-trifluoromethylbenzothiazol-2-yl) piperazin-1-yl] ethoxy] phenyl] acetic acid methyl ester

To a solution of 2- [3,5-dimethyl-4- (6-trifluoromethylbenzothiazol-2-yl) piperazin-1-yl] ethanol (138 mg) in methylene chloride (3 mL), methanesulfonyl chloride (45 μL), Triethylamine (107 μL) was added and stirred at room temperature for 1 hour. Water was added to the reaction solution and extracted with chloroform. The organic layer was washed with water and saturated brine, and then dried over sodium sulfate. The solvent was distilled off under reduced pressure. Dimethylformamide (2 mL), cesium carbonate (248 mg), (4-chloro-3-hydroxyphenyl) acetic acid methyl ester (92 mg) were added to the resulting residue, and the mixture was stirred at 60 ° C. for 2 hr. The reaction mixture was neutralized with 2N hydrochloric acid, and extracted with ethyl acetate. The organic layer was washed with water and dried over magnesium sulfate. The residue was purified by column chromatography to obtain the title compound (178 mg). Yield 89%.

Example 586
Preparation of [4-Chloro-3- [2- [3,5-dimethyl-4- (6-trifluoromethylbenzothiazol-2-yl) piperazin-1-yl] ethoxy] phenyl] acetic acid

[4-Chloro-3- [2- [3,5-dimethyl-4- (6-trifluoromethylbenzothiazol-2-yl) piperazin-1-yl] ethoxy] phenyl] acetic acid methyl ester (178 mg), 2N A mixture of an aqueous sodium hydroxide solution (0.66 mL), tetrahydrofuran (2 mL), and methanol (2 mL) was stirred at room temperature for 2 hours. The mixture was neutralized with 2N hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with water and dried over sodium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by column chromatography to obtain the title compound (83 mg). Yield 48%.
MS (ESI) m / z 528 [M + H] +

MS(ESI) m/z 508 [M+H]+ In the same manner, the following compound was obtained.
Example 587

MS (ESI) m / z 508 [M + H] +

2-(2,6-ジメチルピペラジン-1-イル)-6-トリフルオロメチルベンゾチアゾール(163mg)、(3-ブロモメチルフェニル)酢酸メチルエステル(126mg)、炭酸カリウム(75mg)、ジメチルホルムアミド(4mL)の混合物を、室温で18時間攪拌した。反応液に水を加え、酢酸エチルで抽出した。有機層を水洗後、硫酸ナトリウムで乾燥し、減圧下溶媒を留去した。残渣をカラムクロマトで精製し、表記化合物(171mg)を得た。収率65%。

実施例５８９
[3-[3,5-ジメチル-4-(6-トリフルオロメチルベンゾチアゾール-2-イル)ピペラジン-1-イルメチル]フェニル]酢酸の製造

[3-[3,5-ジメチル-4-(6-トリフルオロメチルベンゾチアゾール-2-イル)ピペラジン-1-イルメチル]フェニル]酢酸 メチルエステル(171mg)、2N 水酸化ナトリウム(1mL)、メタノール(2mL)の混合物を室温で1時間攪拌した。2N 塩酸で中和した後、酢酸エチルで抽出し、減圧下溶媒を留去した。残渣をカラムクロマトで精製し、表記化合物(82mg)を得た。収率52%。
MS(ESI) m/z 464 [M+H]+ Example 588
Preparation of [3- [3,5-dimethyl-4- (6-trifluoromethylbenzothiazol-2-yl) piperazin-1-ylmethyl] phenyl] acetic acid methyl ester

2- (2,6-dimethylpiperazin-1-yl) -6-trifluoromethylbenzothiazole (163 mg), (3-bromomethylphenyl) acetic acid methyl ester (126 mg), potassium carbonate (75 mg), dimethylformamide (4 mL ) Was stirred at room temperature for 18 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and dried over sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by column chromatography to obtain the title compound (171 mg). Yield 65%.

Example 589
Preparation of [3- [3,5-Dimethyl-4- (6-trifluoromethylbenzothiazol-2-yl) piperazin-1-ylmethyl] phenyl] acetic acid

[3- [3,5-Dimethyl-4- (6-trifluoromethylbenzothiazol-2-yl) piperazin-1-ylmethyl] phenyl] acetic acid methyl ester (171 mg), 2N sodium hydroxide (1 mL), methanol ( 2 mL) was stirred at room temperature for 1 hour. The mixture was neutralized with 2N hydrochloric acid, extracted with ethyl acetate, and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography to obtain the title compound (82 mg). Yield 52%.
MS (ESI) m / z 464 [M + H] +

MS(ESI) m/z 494 [M+H]+

実施例５９１

MS(ESI) m/z 475 [M+H]+

実施例５９２

MS(ESI) m/z 478 [M+H]+ In the same manner, the following compound was obtained.
Example 590

MS (ESI) m / z 494 [M + H] +

Example 591

MS (ESI) m / z 475 [M + H] +

Example 592

MS (ESI) m / z 478 [M + H] +

水素化ナトリウム(4.02g)をテトラヒドロフラン(300mL)の懸濁液に、0℃でホスホノ酢酸トリメチルを加えた。0℃で1時間攪拌後、1-Boc-4-ピペリドン(20g)のテトラヒドロフラン(150mL)溶液を加えた。50℃で1.5時間攪拌後、反応液に水を加え、酢酸エチルで抽出した。有機層を水、飽和食塩水で洗浄後、硫酸ナトリウムで乾燥した。減圧下溶媒を留去した後、残渣をカラムクロマトで精製し、表記化合物(27.0g)を得た。収率100%。
¹H-NMR (CDCl₃) δ: 1.47 (9H, s), 2.27-2.29 (2H, m), 2.93-2.94 (2H, m), 3.47-3.51 (4H, m), 3.70 (3H, s), 5.72 (1H, s).

参考例２４１
[1-(6-クロロベンゾチアゾール-2-イル)ピペリジン-4-イリデン]酢酸メチルエステルの製造

4-カルボキシルメチレンピペリジン-1-カルボン酸 t-ブチルエステル(8.00g)、４N塩酸/ジオキサン溶液(80mL)を室温で1時間攪拌した。減圧下溶媒を留去した後、残渣をジメチルホルムアミド(60mL)に溶解し、0℃で炭酸カリウム(8.65g)、2,6-ジクロロベンゾチアゾール(6.39g)を加えた。50℃で1時間、60℃で3時間攪拌した後、水を加え、酢酸エチルで抽出した。有機層を水、飽和食塩水で洗浄後、硫酸ナトリウムで乾燥した。減圧下溶媒を留去し、残渣をカラムクロマトで精製し、表記化合物(9.48g)を得た。収率94%。
¹H-NMR (CDCl₃) δ: 2.47-2.49 (2H, m), 3.14-3.19 (2H, m), 3.72 (3H, s), 3.70-3.77 (4H, m), 5.81 (1H, s), 7.25 (1H, dd, J = 8.5, 2.2 Hz), 7.46 (1H, d, J = 8.8 Hz), 7.57 (1H, d, J = 2.2 Hz).

参考例２４２
[1-(6-クロロベンゾチアゾール-2-イル)-4-エチルピペリジン-4-イル]酢酸メチルエステルの製造

ヨウ化銅(1.77g)をテトラヒドロフラン(18mL)に懸濁し、-30℃でエチルマグネシウムブロミド(1.0M テトラヒドロフラン溶液、18.6mL)を加えた。-25℃で0.5時間攪拌した後、反応液を-78℃に冷却した。[1-(6-クロロベンゾチアゾール-2-イル)ピペリジン-4-イリデン]酢酸メチルエステル(1.00g)のテトラヒドロフラン(10mL)溶液を滴下後、トリメチルシリル トリフルオロメタンスルホナート(1.12mL)を加えた。-78℃で2時間攪拌後、炭酸水素ナトリウム水溶液を加えた。不溶物をろ過後、母液を酢酸エチルで抽出した。有機層を水、飽和食塩水で洗浄後、硫酸マグネシウムで洗浄した。減圧下溶媒を留去し、残渣をカラムクロマトで精製して、表記化合物(979mg)を得た。収率90%。
¹H-NMR (CDCl₃) δ: 0.93 (3H, t, J = 7.6 Hz), 1.67-1.75 (6H, m), 2.42 (2H, s), 3.57-3.68 (4H, m), 3.70 (3H, s), 7.26 (1H, dd, J = 8.5, 2.2 Hz), 7.47 (1H, d, J = 8.5 Hz), 7.58 (1H, d, J = 2.2 Hz).

参考例２４３
2-[1-(6-クロロベンゾチアゾール-2-イル)-4-エチルピペリジン-4-イル]エタノールの製造

水素化リチウムアルミニウム(202mg)をテトラヒドロフラン(10mL)に懸濁し、0℃で[1-(6-クロロベンゾチアゾール-2-イル)-4-エチルピペリジン-4-イル]酢酸メチルエステル(940mg)のテトラヒドロフラン(10mL)溶液を加えた。0℃で1時間攪拌後、反応液に水(0.2mL)、10%水酸化ナトリウム(0.2mL)、水(0.6mL)を順次加え、不溶物を濾取した。母液を酢酸エチルで抽出後、有機層を水、飽和食塩水で洗浄し、硫酸ナトリウムで乾燥した。減圧下溶媒を留去し、残渣をカラムクロマトで精製し、表記化合物(790mg)を得た。収率91%。
¹H-NMR (CDCl₃) δ: 0.87 (3H, t, J = 7.5 Hz), 1.44 (2H, q, J = 7.5 Hz), 1.58-1.60 (4H, m), 1.68 (2H, t, J = 7.5 Hz), 1.81 (1H, br), 3.60-3.62 (4H, m), 3.71-3.74 (2H, m), 7.23 (1H, dd, J = 8.8, 2.2 Hz), 7.44 (1H, d, J = 8.8 Hz), 7.55 (1H, d, J = 2.2 Hz).

参考例２４４
6-クロロ-2-[4-(2-クロロエチル)-4-エチルピペリジン-1-イル]ベンゾチアゾールの製造の製造

2-[1-(6-クロロベンゾチアゾール-2-イル)-4-エチルピペリジン-4-イル]エタノール(764mg)、塩化チオニル(4mL)の混合物を60℃で1.5時間攪拌した。反応液に氷を加え、酢酸エチルで抽出した。有機層を炭酸水素ナトリウム、飽和食塩水で洗浄後、硫酸ナトリウムで乾燥した。減圧下溶媒を留去した後、残渣をカラムクロマトで精製し、表記化合物(739mg)を得た。収率92%。
¹H-NMR (CDCl₃) δ: 0.91 (3H, t, J = 7.6 Hz), 1.47 (2H, q, J = 7.6 Hz), 1.60-1.63 (4H, m), 1.92-1.94 (2H, m), 3.53-3.56 (2H, m), 3.62-3.65 (4H, m), 7.26 (1H, dd, J = 8.5, 2.2 Hz), 7.47 (1H, d, J = 8.5 Hz), 7.58 (1H, d, J = 2.2 Hz). Reference Example 240
Preparation of 4-methoxycarboxylmethylenepiperidine-1-carboxylic acid t-butyl ester

Trimethylphosphonoacetate was added to a suspension of sodium hydride (4.02 g) in tetrahydrofuran (300 mL) at 0 ° C. After stirring at 0 ° C. for 1 hour, a solution of 1-Boc-4-piperidone (20 g) in tetrahydrofuran (150 mL) was added. After stirring at 50 ° C. for 1.5 hours, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and then dried over sodium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by column chromatography to obtain the title compound (27.0 g). Yield 100%.
¹ H-NMR (CDCl ₃ ) δ: 1.47 (9H, s), 2.27-2.29 (2H, m), 2.93-2.94 (2H, m), 3.47-3.51 (4H, m), 3.70 (3H, s) , 5.72 (1H, s).

Reference Example 241
Preparation of [1- (6-chlorobenzothiazol-2-yl) piperidin-4-ylidene] acetic acid methyl ester

4-Carboxylmethylenepiperidine-1-carboxylic acid t-butyl ester (8.00 g), 4N hydrochloric acid / dioxane solution (80 mL) were stirred at room temperature for 1 hour. After evaporating the solvent under reduced pressure, the residue was dissolved in dimethylformamide (60 mL), and potassium carbonate (8.65 g) and 2,6-dichlorobenzothiazole (6.39 g) were added at 0 ° C. After stirring at 50 ° C. for 1 hour and at 60 ° C. for 3 hours, water was added and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and then dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by column chromatography to obtain the title compound (9.48 g). Yield 94%.
¹ H-NMR (CDCl ₃ ) δ: 2.47-2.49 (2H, m), 3.14-3.19 (2H, m), 3.72 (3H, s), 3.70-3.77 (4H, m), 5.81 (1H, s) , 7.25 (1H, dd, J = 8.5, 2.2 Hz), 7.46 (1H, d, J = 8.8 Hz), 7.57 (1H, d, J = 2.2 Hz).

Reference Example 242
Preparation of [1- (6-chlorobenzothiazol-2-yl) -4-ethylpiperidin-4-yl] acetic acid methyl ester

Copper iodide (1.77 g) was suspended in tetrahydrofuran (18 mL), and ethylmagnesium bromide (1.0 M tetrahydrofuran solution, 18.6 mL) was added at −30 ° C. After stirring at -25 ° C for 0.5 hour, the reaction solution was cooled to -78 ° C. A solution of [1- (6-chlorobenzothiazol-2-yl) piperidin-4-ylidene] acetic acid methyl ester (1.00 g) in tetrahydrofuran (10 mL) was added dropwise, and then trimethylsilyl trifluoromethanesulfonate (1.12 mL) was added. After stirring at -78 ° C for 2 hours, an aqueous sodium hydrogen carbonate solution was added. The insoluble material was filtered off, and the mother liquor was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and then washed with magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by column chromatography to obtain the title compound (979 mg). Yield 90%.
¹ H-NMR (CDCl ₃ ) δ: 0.93 (3H, t, J = 7.6 Hz), 1.67-1.75 (6H, m), 2.42 (2H, s), 3.57-3.68 (4H, m), 3.70 (3H , s), 7.26 (1H, dd, J = 8.5, 2.2 Hz), 7.47 (1H, d, J = 8.5 Hz), 7.58 (1H, d, J = 2.2 Hz).

Reference Example 243
Preparation of 2- [1- (6-chlorobenzothiazol-2-yl) -4-ethylpiperidin-4-yl] ethanol

Lithium aluminum hydride (202 mg) was suspended in tetrahydrofuran (10 mL), and [1- (6-chlorobenzothiazol-2-yl) -4-ethylpiperidin-4-yl] acetic acid methyl ester (940 mg) was suspended at 0 ° C. Tetrahydrofuran (10 mL) solution was added. After stirring at 0 ° C. for 1 hour, water (0.2 mL), 10% sodium hydroxide (0.2 mL), and water (0.6 mL) were successively added to the reaction solution, and insoluble matters were collected by filtration. The mother liquor was extracted with ethyl acetate, and the organic layer was washed with water and saturated brine, and dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by column chromatography to obtain the title compound (790 mg). Yield 91%.
¹ H-NMR (CDCl ₃ ) δ: 0.87 (3H, t, J = 7.5 Hz), 1.44 (2H, q, J = 7.5 Hz), 1.58-1.60 (4H, m), 1.68 (2H, t, J = 7.5 Hz), 1.81 (1H, br), 3.60-3.62 (4H, m), 3.71-3.74 (2H, m), 7.23 (1H, dd, J = 8.8, 2.2 Hz), 7.44 (1H, d, J = 8.8 Hz), 7.55 (1H, d, J = 2.2 Hz).

Reference Example 244
Production of 6-chloro-2- [4- (2-chloroethyl) -4-ethylpiperidin-1-yl] benzothiazole

A mixture of 2- [1- (6-chlorobenzothiazol-2-yl) -4-ethylpiperidin-4-yl] ethanol (764 mg) and thionyl chloride (4 mL) was stirred at 60 ° C. for 1.5 hours. Ice was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with sodium hydrogen carbonate and saturated brine, and then dried over sodium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by column chromatography to obtain the title compound (739 mg). Yield 92%.
¹ H-NMR (CDCl ₃ ) δ: 0.91 (3H, t, J = 7.6 Hz), 1.47 (2H, q, J = 7.6 Hz), 1.60-1.63 (4H, m), 1.92-1.94 (2H, m ), 3.53-3.56 (2H, m), 3.62-3.65 (4H, m), 7.26 (1H, dd, J = 8.5, 2.2 Hz), 7.47 (1H, d, J = 8.5 Hz), 7.58 (1H, d, J = 2.2 Hz).

6-クロロ-2-[4-(2-クロロエチル)-4-エチルピペリジン-1-イル]ベンゾチアゾール(150mg)、(4-クロロ-3-ヒドロキシフェニル)酢酸 メチルエステル(176mg)、炭酸セシウム(285mg)、ジメチルホルムアミド(2mL)の混合物を75℃で24時間攪拌した。反応液に水を加え、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄後、硫酸ナトリウムで乾燥した。減圧下溶媒を留去した後、残渣をカラムクロマトで精製し、表記化合物(174mg)を得た。収率79%。
¹H-NMR (CDCl₃) δ: 0.94 (3H, t, J = 7.6 Hz), 1.52-1.78 (8H, m), 3.59 (2H, s), 3.60-3.63 (2H, m), 3.68-3.70 (2H, m), 3.72 (3H, s), 4.09-4.18 (2H, m), 6.80-6.88 (2H, m), 6.98-6.98 (1H, m), 7.27-7.32 (1H, m), 7.48 (1H, d, J = 8.5 Hz), 7.57 (1H, d, J = 1.9 Hz).

実施例５９４
[4-クロロ-3-[2-[1-(6-クロロベンゾチアゾール-2-イル)-4-エチルピペリジン-4-イル]エトキシ]フェニル]酢酸の製造

[4-クロロ-3-[2-[1-(6-クロロベンゾチアゾール-2-イル)-4-エチルピペリジン-4-イル]エトキシ]フェニル]酢酸 メチルエステル(152mg)、2N 水酸化ナトリウム水溶液(0.45mL)、テトラヒドロフラン(1mL)、メタノール(1mL)の混合物を、室温で2時間攪拌した。反応液を2N塩酸で中和後、酢酸エチルで抽出した。有機層を水、飽和食塩水で洗浄後、硫酸ナトリウムで乾燥した。減圧下溶媒を留去し、残渣をカラムクロマトで精製し、表記化合物(53mg)を得た。収率36%。
MS (ESI) m/z 493 [M+H]⁺ Example 593
Preparation of methyl ester of [4-chloro-3- [2- [1- (6-chlorobenzothiazol-2-yl) -4-ethylpiperidin-4-yl] ethoxy] phenyl] acetic acid

6-chloro-2- [4- (2-chloroethyl) -4-ethylpiperidin-1-yl] benzothiazole (150 mg), (4-chloro-3-hydroxyphenyl) acetic acid methyl ester (176 mg), cesium carbonate ( 285 mg) and dimethylformamide (2 mL) were stirred at 75 ° C. for 24 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over sodium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by column chromatography to obtain the title compound (174 mg). Yield 79%.
¹ H-NMR (CDCl ₃ ) δ: 0.94 (3H, t, J = 7.6 Hz), 1.52-1.78 (8H, m), 3.59 (2H, s), 3.60-3.63 (2H, m), 3.68-3.70 (2H, m), 3.72 (3H, s), 4.09-4.18 (2H, m), 6.80-6.88 (2H, m), 6.98-6.98 (1H, m), 7.27-7.32 (1H, m), 7.48 (1H, d, J = 8.5 Hz), 7.57 (1H, d, J = 1.9 Hz).

Example 594
Preparation of [4-chloro-3- [2- [1- (6-chlorobenzothiazol-2-yl) -4-ethylpiperidin-4-yl] ethoxy] phenyl] acetic acid

[4-Chloro-3- [2- [1- (6-chlorobenzothiazol-2-yl) -4-ethylpiperidin-4-yl] ethoxy] phenyl] acetic acid methyl ester (152 mg), 2N aqueous sodium hydroxide solution A mixture of (0.45 mL), tetrahydrofuran (1 mL), and methanol (1 mL) was stirred at room temperature for 2 hours. The reaction mixture was neutralized with 2N hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and then dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by column chromatography to obtain the title compound (53 mg). Yield 36%.
MS (ESI) m / z 493 [M + H] ⁺

MS (ESI) m/z 479 [M+H]⁺

実施例５９６

MS (ESI) m/z 459 [M+H]⁺

実施例５９７

MS (ESI) m/z 507 [M+H]⁺

実施例５９８

MS (ESI) m/z 547 [M+H]⁺

実施例５９９

MS (ESI) m/z 564 [M+H]+

実施例６００

1H-NMR (Acetone-d6) δ: 8.65 (1H, s), 7.60-7.63 (2H, m), 7.48 (2H, t, J = 7.55 Hz), 7.36 (1H, t, J = 7.55 Hz), 7.20-7.25 (1H, m), 6.97 (1H, s), 6.84-6.87 (2H, m), 4.19-4.27 (2H, m), 4.14 (2H, t, J = 7.42 Hz), 3.65-3.72 (2H, m), 3.62 (2H, s), 2.05-2.10 (2H, m), 1.57-1.79 (7H, m), 0.96-1.00 (6H, m).

実施例６０１

1H-NMR (Acetone-d6) δ: 8.65 (1H, s), 7.62-7.65 (2H, m), 7.48 (2H, t, J = 7.55 Hz), 7.36 (1H, t, J = 7.55 Hz), 6.76 (1H, s), 6.72 (2H, s), 4.19-4.27 (2H, m), 4.14 (2H, t, J = 7.42 Hz), 3.65-3.72 (2H, m), 3.62 (2H, s), 2.25(3H, s), 2.05-2.10 (2H, m), 1.57-1.79 (7H, m), 0.96-1.00 (6H, m).

実施例６０２

1H-NMR (Acetone) δ: 8.65 (1H, s), 7.62-7.65 (2H, m), 7.48 (2H, t, J = 7.55 Hz), 7.36 (1H, t, J = 7.55 Hz), 6.76 (1H, s), 6.72 (2H, s), 4.19-4.27 (2H, m), 4.14 (2H, t, J = 7.42 Hz), 3.65-3.72 (2H, m), 3.62 (2H, s), 2.05-2.10 (2H, m), 1.57-1.79 (7H, m), 0.96-1.00 (6H, m).

実施例６０３

MS(ESI) m/z 547 [M+H]+

実施例６０４

1H-NMR (CDCl3) δ: 0.87-1.98 (15H, m), 3.44-3.78 (6H, m), 4.03 (3H, t, J = 7.1 Hz), 6.78-7.45 (7H, m), 7.54 (1H, d, J = 1.9 Hz).

実施例６０５

1H-NMR (CDCl3) δ: 0.83-1.99 (15H, m), 2.30 (3H, s), 3.47-3.79 (6H, m), 4.02 (2H, t, J = 7.1 Hz), 6.62 (2H, s), 6.69 (1H, s), 7.22-7.26 (1H, m), 7.46 (1H, d, J = 9.1 Hz), 7.54 (1H, d, J = 2.2 Hz).

実施例６０６

1H-NMR (CDCl3) δ: 7.42 (1.0H, s), 7.29-7.24 (1.0H, m), 7.17 (1.0H, ddd, J = 7.97, 1.30, 1.30 Hz), 7.10 (1.0H, ddd, J = 9.89, 2.13, 2.13 Hz), 6.93-6.85 (2.0H, m), 6.80 (1.0H, dd, J = 1.92, 1.92 Hz), 6.72 (1.0H, dd, J = 1.79, 1.79 Hz), 4.03 (2.0H, dd, J = 7.14, 7.14 Hz), 3.67-3.57 (4.0H, m), 3.47-3.39 (2.0H, m), 1.93 (2.0H, dd, J = 7.14, 7.14 Hz), 1.82-1.77 (2.0H, m), 1.67-1.54 (4.0H, m), 1.50-1.42 (1.0H, m), 0.98-0.90 (6.0H, m).

実施例６０７

1H-NMR (CDCl3) δ: 7.42 (1.0H, s), 7.30 (1.0H, dd, J = 5.63, 2.06 Hz), 7.17 (1.0H, d, J = 8.79 Hz), 7.12-7.07 (1.0H, m), 6.92-6.85 (1.0H, m), 6.69 (1.0H, s), 6.63 (2.0H, d, J = 4.67 Hz), 4.04 (2.0H, dd, J = 7.00, 7.00 Hz), 3.68-3.57 (4.0H, m), 3.47-3.39 (2.0H, m), 2.31 (3.0H, s), 1.95-1.54 (8.0H, m), 1.49-1.42 (1.0H, m), 0.97-0.90 (6.0H, m).

実施例６０８

1H-NMR (Acetone) δ: 7.60 (1.0H, d, J = 1.65 Hz), 7.42-7.33 (1.0H, m), 7.30-7.18 (3.0H, m), 6.99-6.92 (2.0H, m), 6.89-6.83 (2.0H, m), 4.15-4.09 (2.0H, m), 3.72-3.47 (6.0H, m), 1.85-1.56 (6.0H, m), 1.31-1.27 (3.0H, m), 0.99-0.92 (6.0H, m).

実施例６０９

1H-NMR(DMSO-d6) δ 1.25(2H, br), 1.46-1.64(10H, m), 1.94(2H, t, J=6.9Hz), 2.12(1H, m), 3.43-3.52(2H, m), 3.56(2H, s), 3.70-3.80(2H, br), 4.02(3H, 2H, J=6.9Hz), 6.83(1H, s), 6.90(1H, s), 6.96(1H, s), 7.25-7.29(1H, m), 7.40(1H, d, J=8.7Hz), 7.89(1H, d, J=2.4Hz) In the same manner, the following compound was obtained.
Example 595

MS (ESI) m / z 479 [M + H] ⁺

Example 596

MS (ESI) m / z 459 [M + H] ⁺

Example 597

MS (ESI) m / z 507 [M + H] ⁺

Example 598

MS (ESI) m / z 547 [M + H] ⁺

Example 599

MS (ESI) m / z 564 [M + H] +

Example 600

1H-NMR (Acetone-d6) δ: 8.65 (1H, s), 7.60-7.63 (2H, m), 7.48 (2H, t, J = 7.55 Hz), 7.36 (1H, t, J = 7.55 Hz), 7.20-7.25 (1H, m), 6.97 (1H, s), 6.84-6.87 (2H, m), 4.19-4.27 (2H, m), 4.14 (2H, t, J = 7.42 Hz), 3.65-3.72 ( 2H, m), 3.62 (2H, s), 2.05-2.10 (2H, m), 1.57-1.79 (7H, m), 0.96-1.00 (6H, m).

Example 601

1H-NMR (Acetone-d6) δ: 8.65 (1H, s), 7.62-7.65 (2H, m), 7.48 (2H, t, J = 7.55 Hz), 7.36 (1H, t, J = 7.55 Hz), 6.76 (1H, s), 6.72 (2H, s), 4.19-4.27 (2H, m), 4.14 (2H, t, J = 7.42 Hz), 3.65-3.72 (2H, m), 3.62 (2H, s) , 2.25 (3H, s), 2.05-2.10 (2H, m), 1.57-1.79 (7H, m), 0.96-1.00 (6H, m).

Example 602

1H-NMR (Acetone) δ: 8.65 (1H, s), 7.62-7.65 (2H, m), 7.48 (2H, t, J = 7.55 Hz), 7.36 (1H, t, J = 7.55 Hz), 6.76 ( 1H, s), 6.72 (2H, s), 4.19-4.27 (2H, m), 4.14 (2H, t, J = 7.42 Hz), 3.65-3.72 (2H, m), 3.62 (2H, s), 2.05 -2.10 (2H, m), 1.57-1.79 (7H, m), 0.96-1.00 (6H, m).

Example 603

MS (ESI) m / z 547 [M + H] +

Example 604

1H-NMR (CDCl3) δ: 0.87-1.98 (15H, m), 3.44-3.78 (6H, m), 4.03 (3H, t, J = 7.1 Hz), 6.78-7.45 (7H, m), 7.54 (1H , d, J = 1.9 Hz).

Example 605

1H-NMR (CDCl3) δ: 0.83-1.99 (15H, m), 2.30 (3H, s), 3.47-3.79 (6H, m), 4.02 (2H, t, J = 7.1 Hz), 6.62 (2H, s ), 6.69 (1H, s), 7.22-7.26 (1H, m), 7.46 (1H, d, J = 9.1 Hz), 7.54 (1H, d, J = 2.2 Hz).

Example 606

1H-NMR (CDCl3) δ: 7.42 (1.0H, s), 7.29-7.24 (1.0H, m), 7.17 (1.0H, ddd, J = 7.97, 1.30, 1.30 Hz), 7.10 (1.0H, ddd, J = 9.89, 2.13, 2.13 Hz), 6.93-6.85 (2.0H, m), 6.80 (1.0H, dd, J = 1.92, 1.92 Hz), 6.72 (1.0H, dd, J = 1.79, 1.79 Hz), 4.03 (2.0H, dd, J = 7.14, 7.14 Hz), 3.67-3.57 (4.0H, m), 3.47-3.39 (2.0H, m), 1.93 (2.0H, dd, J = 7.14, 7.14 Hz), 1.82-1.77 (2.0H, m), 1.67-1.54 (4.0H, m), 1.50-1.42 (1.0H, m), 0.98-0.90 (6.0H, m).

Example 607

1H-NMR (CDCl3) δ: 7.42 (1.0H, s), 7.30 (1.0H, dd, J = 5.63, 2.06 Hz), 7.17 (1.0H, d, J = 8.79 Hz), 7.12-7.07 (1.0H , m), 6.92-6.85 (1.0H, m), 6.69 (1.0H, s), 6.63 (2.0H, d, J = 4.67 Hz), 4.04 (2.0H, dd, J = 7.00, 7.00 Hz), 3.68-3.57 (4.0H, m), 3.47-3.39 (2.0H, m), 2.31 (3.0H, s), 1.95-1.54 (8.0H, m), 1.49-1.42 (1.0H, m), 0.97- 0.90 (6.0H, m).

Example 608

1H-NMR (Acetone) δ: 7.60 (1.0H, d, J = 1.65 Hz), 7.42-7.33 (1.0H, m), 7.30-7.18 (3.0H, m), 6.99-6.92 (2.0H, m) , 6.89-6.83 (2.0H, m), 4.15-4.09 (2.0H, m), 3.72-3.47 (6.0H, m), 1.85-1.56 (6.0H, m), 1.31-1.27 (3.0H, m) , 0.99-0.92 (6.0H, m).

Example 609

1H-NMR (DMSO-d6) δ 1.25 (2H, br), 1.46-1.64 (10H, m), 1.94 (2H, t, J = 6.9Hz), 2.12 (1H, m), 3.43-3.52 (2H, m), 3.56 (2H, s), 3.70-3.80 (2H, br), 4.02 (3H, 2H, J = 6.9Hz), 6.83 (1H, s), 6.90 (1H, s), 6.96 (1H, s ), 7.25-7.29 (1H, m), 7.40 (1H, d, J = 8.7Hz), 7.89 (1H, d, J = 2.4Hz)

2,6-ジクロロベンゾチアゾール(2.00g)、3-(トリフルオロアセトアミド)ピロリジン塩酸塩(2.14g)、炭酸カリウム(4.06g)、ジメチルホルムアミド(15mL)の混合物を60℃で2時間攪拌した。反応液に水を加え、酢酸エチルで抽出した。有機層を水、飽和食塩水で洗浄後、硫酸マグネシウムで乾燥した。減圧下溶媒を留去したのち、残渣をn-ヘキサンで洗浄した。得られた精製物をテトラヒドロフラン(20mL)、メタノール(10mL)に溶解し、2N水酸化ナトリウムを加えて2.5時間攪拌した。減圧下溶媒を留去後、水を加え、酢酸エチルで抽出した。有機層を水、飽和食塩水で洗浄後、硫酸ナトリウムで乾燥した。減圧下、溶媒を留去し、表記化合物(2.49g)を得た。収率100％。
1H-NMR (DMSO-d6) δ: 1.72-1.80(2H, m), 3.45-3.63(5H, m), 7.26(1H, dd, H=2.0, 8.0), 7.41(1H, d, J=8.5), 7.88(1H, d, J=2.0)

参考例２４６
N-[1(6-クロロベンゾチアゾール-2-イル)ピロリジン-3-イル]-2-ニトロベンゼンスルホンアミドの製造

1-(6-クロロベンゾチアゾール-2-イル)ピロリジン-3-イルアミン(2.49g)、2-ニトロベンゼンスルホニルクロリド(2.40g)、トリエチルアミン(3.02mL)、ジメチルホルムアミド(15mL)の混合物を60℃で3時間攪拌した。反応液に水を加えた後、酢酸エチルで抽出した。有機層を水、飽和食塩水で洗浄後、硫酸ナトリウムで乾燥した。減圧下溶媒を留去し、残渣をカラムクロマトで精製し表記化合物(2.01g)を得た。収率47％。
¹H-NMR (DMSO-d₆) δ: 1.99-2.03 (1H, m), 2.19-2.23 (1H, m), 3.55-3.63 (4H, m), 4.07-4.09 (1H, m), 7.30 (1H, dd, J = 8.5, 2.2 Hz), 7.45 (1H, d, J = 8.8 Hz), 7.90-7.94 (3H, m), 8.01-8.10 (2H, m).

参考例２４７
[3-[[[1-(6-クロロベンゾチアゾール-2-イル)ピロリジン-3-イル]-(2-ニトロベンゼンスルホニル)アミノ]メチル]フェニル]酢酸 メチルエステルの製造

N-[1(6-クロロベンゾチアゾール-2-イル)ピロリジン-3-イル]-2-ニトロベンゼンスルホンアミド(500mg)をジメチルホルムアミド(5mL)に溶解した後、水素化ナトリウム(60％、油性、50mg)を加え、室温で1時間攪拌した。(3-ブロモメチルフェニル)酢酸 メチルエステル(305mg)を加えた後、さらに16時間攪拌した。反応液に水を加え、酢酸エチルで抽出した。有機層を水、飽和食塩水で洗浄後、硫酸マグネシウムで乾燥した。減圧下溶媒を留去下した後、残渣をカラムクロマトで精製し、表記化合物(412mg)を得た。収率60%。
¹H-NMR (CDCl₃) δ: 2.11-2.19 (1H, m), 2.34-2.37 (1H, m), 3.53-3.59 (6H, m), 3.69 (3H, s), 3.78-3.81 (1H, m), 4.53-4.63 (2H, m), 7.07-7.19 (4H, m), 7.25-7.32 (1H, m), 7.50-7.58 (3H, m), 7.65-7.67 (2H, m), 7.85 (1H, d, J = 7.7 Hz). Reference Example 245
Preparation of 1- (6-chlorobenzothiazol-2-yl) pyrrolidin-3-ylamine

A mixture of 2,6-dichlorobenzothiazole (2.00 g), 3- (trifluoroacetamido) pyrrolidine hydrochloride (2.14 g), potassium carbonate (4.06 g) and dimethylformamide (15 mL) was stirred at 60 ° C. for 2 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over magnesium sulfate. After evaporating the solvent under reduced pressure, the residue was washed with n-hexane. The obtained purified product was dissolved in tetrahydrofuran (20 mL) and methanol (10 mL), 2N sodium hydroxide was added, and the mixture was stirred for 2.5 hours. After evaporating the solvent under reduced pressure, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and then dried over sodium sulfate. The solvent was distilled off under reduced pressure to obtain the title compound (2.49 g). Yield 100%.
1H-NMR (DMSO-d6) δ: 1.72-1.80 (2H, m), 3.45-3.63 (5H, m), 7.26 (1H, dd, H = 2.0, 8.0), 7.41 (1H, d, J = 8.5 ), 7.88 (1H, d, J = 2.0)

Reference Example 246
Preparation of N- [1 (6-chlorobenzothiazol-2-yl) pyrrolidin-3-yl] -2-nitrobenzenesulfonamide

A mixture of 1- (6-chlorobenzothiazol-2-yl) pyrrolidin-3-ylamine (2.49 g), 2-nitrobenzenesulfonyl chloride (2.40 g), triethylamine (3.02 mL), dimethylformamide (15 mL) at 60 ° C. Stir for 3 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and then dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by column chromatography to obtain the title compound (2.01 g). Yield 47%.
¹ H-NMR (DMSO-d ₆ ) δ: 1.99-2.03 (1H, m), 2.19-2.23 (1H, m), 3.55-3.63 (4H, m), 4.07-4.09 (1H, m), 7.30 ( 1H, dd, J = 8.5, 2.2 Hz), 7.45 (1H, d, J = 8.8 Hz), 7.90-7.94 (3H, m), 8.01-8.10 (2H, m).

Reference Example 247
Preparation of [3-[[[1- (6-Chlorobenzothiazol-2-yl) pyrrolidin-3-yl]-(2-nitrobenzenesulfonyl) amino] methyl] phenyl] acetic acid methyl ester

N- [1 (6-chlorobenzothiazol-2-yl) pyrrolidin-3-yl] -2-nitrobenzenesulfonamide (500 mg) was dissolved in dimethylformamide (5 mL) and then sodium hydride (60%, oily, 50 mg) was added and stirred at room temperature for 1 hour. After adding (3-bromomethylphenyl) acetic acid methyl ester (305 mg), the mixture was further stirred for 16 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over magnesium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by column chromatography to obtain the title compound (412 mg). Yield 60%.
¹ H-NMR (CDCl ₃ ) δ: 2.11-2.19 (1H, m), 2.34-2.37 (1H, m), 3.53-3.59 (6H, m), 3.69 (3H, s), 3.78-3.81 (1H, m), 4.53-4.63 (2H, m), 7.07-7.19 (4H, m), 7.25-7.32 (1H, m), 7.50-7.58 (3H, m), 7.65-7.67 (2H, m), 7.85 ( (1H, d, J = 7.7 Hz).

[3-[[[1-(6-クロロベンゾチアゾール-2-イル)ピロリジン-3-イル]-(2-ニトロベンゼンスルホニル)アミノ]メチル]フェニル]酢酸 メチルエステル(412mg)、メルカプト酢酸(95μL)、1,8-ジアザビシクロ[5,4,0]-7-ウンデセン(4mL)、ジメチルホルムアミド(4mL)の混合物を室温で1時間攪拌した。反応液に水を加えた後、酢酸エチルで抽出した。有機層を水、飽和食塩水で洗浄後、硫酸ナトリウムで乾燥した。減圧下溶媒を留去した後、カラムクロマトで精製し、表記化合物(204mg)を得た。収率71%。
¹H-NMR (CDCl₃) δ: 2.11-2.14 (1H, m), 2.27-2.32 (1H, m), 3.49-3.59 (2H, m), 3.63 (2H, s), 3.70 (3H, s), 3.74-3.82 (2H, m), 3.89 (2H, s), 7.23 (2H, dd, J = 8.5, 2.2 Hz), 7.31-7.33 (3H, m), 7.45 (1H, d, J = 8.5 Hz), 7.46 (1H, s), 7.54 (1H, d, J = 2.2 Hz), 8.02(1H, brs).

実施例６１１
[3-[[ブチル-[1-(6-クロロベンゾチアゾール-2-イル)ピロリジン-3-イル]アミノ]メチル]フェニル]酢酸 メチルエステルの製造

[3-[[1-(6-クロロベンゾチアゾール-2-イル)ピロリジン-3-イルアミノ]メチル]フェニル]酢酸 メチルエステル(68mg)、1-ヨードブタン(37μL)、炭酸カリウム(45mg)、ジメチルホルムアミド(1mL)の混合物を80℃で3.5時間攪拌した。反応液に水を加え、酢酸エチルで抽出した。有機層を水、飽和食塩水で洗浄後、硫酸ナトリウムで乾燥した。残渣をカラムクロマトで精製し、表記化合物(28mg)を得た。収率36%。
¹H-NMR (CDCl₃) δ: 0.90 (3H, t, J = 7.3 Hz), 1.24-1.36 (2H, m), 1.47-1.50 (2H, m), 2.54-2.56 (2H, m), 3.51-3.71 (14H, m), 7.21-7.29 (5H, m), 7.50 (1H, d, J = 8.8 Hz), 7.58 (1H, d, J = 2.2 Hz).

実施例６１２
[3-[[ブチル-[1-(6-クロロベンゾチアゾール-2-イル)ピロリジン-3-イル]アミノ]メチル]フェニル]酢酸の製造

[3-[[ブチル-[1-(6-クロロベンゾチアゾール-2-イル)ピロリジン-3-イル]アミノ]メチル]フェニル]酢酸 メチルエステル(28mg)、2N水酸化ナトリウム(0.15mL)、テトラヒドロフラン(1mL)、メタノール(0.5mL)の混合物を室温で1時間攪拌した。2N 塩酸で中和後、減圧下濃縮した。酢酸エチルで抽出後、有機層を水、飽和食塩水で洗浄、硫酸ナトリウムで乾燥し、表記化合物(19mg)を得た。収率68%。
MS (ESI) m/z 458 [M+H]+ Example 610
Preparation of [3-[[1- (6-Chlorobenzothiazol-2-yl) pyrrolidin-3-ylamino] methyl] phenyl] acetic acid methyl ester

[3-[[[1- (6-Chlorobenzothiazol-2-yl) pyrrolidin-3-yl]-(2-nitrobenzenesulfonyl) amino] methyl] phenyl] acetic acid methyl ester (412 mg), mercaptoacetic acid (95 μL) , 1,8-diazabicyclo [5,4,0] -7-undecene (4 mL) and dimethylformamide (4 mL) were stirred at room temperature for 1 hour. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and then dried over sodium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by column chromatography to obtain the title compound (204 mg). Yield 71%.
¹ H-NMR (CDCl ₃ ) δ: 2.11-2.14 (1H, m), 2.27-2.32 (1H, m), 3.49-3.59 (2H, m), 3.63 (2H, s), 3.70 (3H, s) , 3.74-3.82 (2H, m), 3.89 (2H, s), 7.23 (2H, dd, J = 8.5, 2.2 Hz), 7.31-7.33 (3H, m), 7.45 (1H, d, J = 8.5 Hz ), 7.46 (1H, s), 7.54 (1H, d, J = 2.2 Hz), 8.02 (1H, brs).

Example 611
Preparation of [3-[[butyl- [1- (6-chlorobenzothiazol-2-yl) pyrrolidin-3-yl] amino] methyl] phenyl] acetic acid methyl ester

[3-[[1- (6-Chlorobenzothiazol-2-yl) pyrrolidin-3-ylamino] methyl] phenyl] acetic acid methyl ester (68 mg), 1-iodobutane (37 μL), potassium carbonate (45 mg), dimethylformamide (1 mL) was stirred at 80 ° C. for 3.5 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and then dried over sodium sulfate. The residue was purified by column chromatography to obtain the title compound (28 mg). Yield 36%.
¹ H-NMR (CDCl ₃ ) δ: 0.90 (3H, t, J = 7.3 Hz), 1.24-1.36 (2H, m), 1.47-1.50 (2H, m), 2.54-2.56 (2H, m), 3.51 -3.71 (14H, m), 7.21-7.29 (5H, m), 7.50 (1H, d, J = 8.8 Hz), 7.58 (1H, d, J = 2.2 Hz).

Example 612
Preparation of [3-[[butyl- [1- (6-chlorobenzothiazol-2-yl) pyrrolidin-3-yl] amino] methyl] phenyl] acetic acid

[3-[[Butyl- [1- (6-chlorobenzothiazol-2-yl) pyrrolidin-3-yl] amino] methyl] phenyl] acetic acid methyl ester (28 mg), 2N sodium hydroxide (0.15 mL), tetrahydrofuran A mixture of (1 mL) and methanol (0.5 mL) was stirred at room temperature for 1 hour. The mixture was neutralized with 2N hydrochloric acid and concentrated under reduced pressure. After extraction with ethyl acetate, the organic layer was washed with water and saturated brine, and dried over sodium sulfate to obtain the title compound (19 mg). Yield 68%.
MS (ESI) m / z 458 [M + H] +

MS (ESI) m/z 430 [M+H]+

実施例６１４

MS (ESI) m/z 416 [M+H]+

実施例６１５

MS (ESI) m/z 480 [M+H]+

実施例６１６

MS (ESI) m/z 402 [M+H]+
In the same manner, the following compound was obtained.
Example 613

MS (ESI) m / z 430 [M + H] +

Example 614

MS (ESI) m / z 416 [M + H] +

Example 615

MS (ESI) m / z 480 [M + H] +

Example 616

MS (ESI) m / z 402 [M + H] +

4-Boc-アミノピペリジン(3.23g)、2,6-ジクロロベンゾチアゾール(3.29g)、炭酸カリウム(6.68g)、ジメチルホルムアミド(20mL)の混合物を60℃で16時間攪拌した。反応液に水を加えた後、晶析物を濾取した。得られた表記化合物は精製せず、そのまま次の反応に付した。

参考例２４９
1-(6-クロロベンゾチアゾール-2-イル)ピペリジン-4-イルアミンの合成

上記反応で得られた[1-(6-クロロベンゾチアゾール-2-イル)ピペリジン-4-イル]カルバミド酸 tert-ブチルエステルをクロロホルムに溶解した後、4N塩酸/ジオキサン溶液を加え、室温で16時間攪拌した。減圧下溶媒を濃縮後、水を加え、酢酸エチルで洗浄した。水層を2N水酸化ナトリウムで中和した後、酢酸エチルで抽出した。有機層を硫酸マグネシウムで洗浄後、減圧下溶媒を留去し、表記化合物(3.31g)を得た。収率77%。
¹H-NMR (DMSO-d₆) δ: 1.24-1.33 (4H, m), 3.20-3.30 (3H, m), 3.90-3.95 (2H, m), 7.27 (1H, dd, J = 8.5, 2.2 Hz), 7.40 (1H, d, J = 8.8 Hz), 7.88 (1H, d, J = 2.2 Hz). Reference Example 248
Production of [1- (6-chlorobenzothiazol-2-yl) piperidin-4-yl] carbamic acid tert-butyl ester

A mixture of 4-Boc-aminopiperidine (3.23 g), 2,6-dichlorobenzothiazole (3.29 g), potassium carbonate (6.68 g), and dimethylformamide (20 mL) was stirred at 60 ° C. for 16 hours. After adding water to the reaction solution, the crystallized product was collected by filtration. The obtained title compound was subjected to the next reaction without purification.

Reference Example 249
Synthesis of 1- (6-chlorobenzothiazol-2-yl) piperidin-4-ylamine

[1- (6-Chlorobenzothiazol-2-yl) piperidin-4-yl] carbamic acid tert-butyl ester obtained in the above reaction was dissolved in chloroform, 4N hydrochloric acid / dioxane solution was added, and the mixture was stirred at room temperature. Stir for hours. The solvent was concentrated under reduced pressure, water was added, and the mixture was washed with ethyl acetate. The aqueous layer was neutralized with 2N sodium hydroxide and extracted with ethyl acetate. The organic layer was washed with magnesium sulfate, and the solvent was evaporated under reduced pressure to obtain the title compound (3.31 g). Yield 77%.
¹ H-NMR (DMSO-d ₆ ) δ: 1.24-1.33 (4H, m), 3.20-3.30 (3H, m), 3.90-3.95 (2H, m), 7.27 (1H, dd, J = 8.5, 2.2 Hz), 7.40 (1H, d, J = 8.8 Hz), 7.88 (1H, d, J = 2.2 Hz).

1-(6-クロロベンゾチアゾール-2-イル)ピペリジン-4-イルアミン(500mg)、(3-ブロモメチルフェニル)酢酸 メチルエステル(454mg)、炭酸カリウム(284mg)、ジメチルホルムアミド(6mL)の混合物を室温で1時間攪拌した。反応液に水を加え酢酸エチルで抽出した。有機層を水、飽和食塩水で洗浄し、硫酸ナトリウムで乾燥した。減圧下溶媒を留去したのち、カラムクロマトに付し、表記化合物(434mg)を得た。収率55%。

実施例６１８
[3-[[[1-(6-クロロベンゾチアゾール-2-イル)ピペリジン-4-イル]エチルアミノ]メチル]フェニル]酢酸 メチルエステルの製造

[3-[[1-(6-クロロベンゾチアゾール-2-イル)ピペリジン-4-イルアミノ]メチル]フェニル]酢酸 メチルエステル(110mg)、ヨウ化メチル(800mg)、炭酸カリウム(71mg)、ジメチルホルムアミド(2mL)の混合物を80℃で5時間攪拌した。反応液に水を加え、酢酸エチルで抽出した。有機層を水、飽和食塩水で洗浄後、硫酸ナトリウムで乾燥した。減圧下、溶媒を留去した後、カラムクロマトに付し、表記化合物(65mg)を得た。収率56%。
¹H-NMR (CDCl₃) δ: 1.03-1.07 (3H, br m), 1.63-1.66 (2H, br m), 1.89-1.92 (2H, br m), 2.58-2.62 (1H, br m), 2.91(2H, s), 2.98 (2H, s), 3.09-3.13 (2H, m), 3.64-3.67 (2H, br m), 3.71 (3H, s), 4.20-4.23 (2H, br m), 7.25-7.28 (5H, m), 7.44 (1H, d, J = 8.5 Hz), 7.57 (1H, d, J = 10.0 Hz).

実施例６１９
[3-[[[1-(6-クロロベンゾチアゾール-2-イル)ピペリジン-4-イル]エチルアミノ]メチル]フェニル]酢酸 の製造

[3-[[[1-(6-クロロベンゾチアゾール-2-イル)ピペリジン-4-イル]エチルアミノ]メチル]フェニル]酢酸 メチルエステル(65mg)、2N水酸化ナトリウム(0.36mL)、テトラヒドロフラン(1mL) 、メタノール(1mL)の混合物を室温で1時間攪拌した。2N塩酸で中和した後、酢酸エチルで抽出した。有機層を水、飽和食塩水で洗浄後、硫酸ナトリウムで乾燥した。減圧下、溶媒を留去し、得られた残渣を酢酸エチル／n−ヘキサンの混合溶媒で洗浄し、表記化合物(19mg)を得た。収率30%。
MS (ESI) m/z 444 [M+H]+ Example 617
Preparation of [3-[[1- (6-Chlorobenzothiazol-2-yl) piperidin-4-ylamino] methyl] phenyl] acetic acid methyl ester

A mixture of 1- (6-chlorobenzothiazol-2-yl) piperidin-4-ylamine (500 mg), (3-bromomethylphenyl) acetic acid methyl ester (454 mg), potassium carbonate (284 mg), dimethylformamide (6 mL) Stir at room temperature for 1 hour. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over sodium sulfate. After evaporating the solvent under reduced pressure, the residue was subjected to column chromatography to obtain the title compound (434 mg). Yield 55%.

Example 618
Preparation of [3-[[[1- (6-Chlorobenzothiazol-2-yl) piperidin-4-yl] ethylamino] methyl] phenyl] acetic acid methyl ester

[3-[[1- (6-Chlorobenzothiazol-2-yl) piperidin-4-ylamino] methyl] phenyl] acetic acid methyl ester (110 mg), methyl iodide (800 mg), potassium carbonate (71 mg), dimethylformamide (2 mL) was stirred at 80 ° C. for 5 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and then dried over sodium sulfate. The solvent was distilled off under reduced pressure, followed by column chromatography to obtain the title compound (65 mg). Yield 56%.
¹ H-NMR (CDCl ₃ ) δ: 1.03-1.07 (3H, br m), 1.63-1.66 (2H, br m), 1.89-1.92 (2H, br m), 2.58-2.62 (1H, br m), 2.91 (2H, s), 2.98 (2H, s), 3.09-3.13 (2H, m), 3.64-3.67 (2H, br m), 3.71 (3H, s), 4.20-4.23 (2H, br m), 7.25-7.28 (5H, m), 7.44 (1H, d, J = 8.5 Hz), 7.57 (1H, d, J = 10.0 Hz).

Example 619
Preparation of [3-[[[1- (6-Chlorobenzothiazol-2-yl) piperidin-4-yl] ethylamino] methyl] phenyl] acetic acid

[3-[[[1- (6-Chlorobenzothiazol-2-yl) piperidin-4-yl] ethylamino] methyl] phenyl] acetic acid methyl ester (65 mg), 2N sodium hydroxide (0.36 mL), tetrahydrofuran ( 1 mL) and methanol (1 mL) were stirred at room temperature for 1 hour. The mixture was neutralized with 2N hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and then dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was washed with a mixed solvent of ethyl acetate / n-hexane to obtain the title compound (19 mg). Yield 30%.
MS (ESI) m / z 444 [M + H] +

MS (ESI) m/z 472 [M+H]+

実施例６２１

MS (ESI) m/z 472 [M+H]+

実施例６２２

MS (ESI) m/z 494 [M+H]+ In the same manner, the following compound was obtained.
Example 620

MS (ESI) m / z 472 [M + H] +

Example 621

MS (ESI) m / z 472 [M + H] +

Example 622

MS (ESI) m / z 494 [M + H] +

1-(6-クロロベンゾチアゾール-2-イル)ピペリジン-4-イルアミン(335mg)、アセトン(92ul)、酢酸(0.1mL)、メタノール(3mL)の混合物を室温下5分攪拌した。反応液にトリアセトキシ水素化ほう素ナトリウム(332mg)を加え、室温下16時間攪拌した。減圧下反応液を濃縮した後、炭酸水素ナトリウム水溶液を加え酢酸エチルで抽出した。有機層を水、飽和食塩水で洗浄後、硫酸ナトリウムで乾燥し、減圧下溶媒を留去した。残渣をカラムクロマトで精製し、表記化合物(160mg)を得た。収率41%。
¹H-NMR (CDCl₃) δ: 1.11 (6H, d, J = 6.3 Hz), 1.48-1.51 (2H, m), 2.01-2.05 (2H, m), 2.84-2.91 (1H, m), 3.00-3.08 (1H, m), 3.14-3.24 (2H, m), 4.08-4.16 (2H, m), 7.23 (1H, dd, J = 8.5, 2.2 Hz), 7.42 (1H, d, J = 8.5 Hz), 7.55 (1H, d, J = 2.2 Hz). Reference Example 250
Preparation of [1- (6-chlorobenzothiazol-2-yl) piperidin-4-yl] isopropylamine

A mixture of 1- (6-chlorobenzothiazol-2-yl) piperidin-4-ylamine (335 mg), acetone (92 ul), acetic acid (0.1 mL), and methanol (3 mL) was stirred at room temperature for 5 minutes. Sodium triacetoxyborohydride (332 mg) was added to the reaction mixture, and the mixture was stirred at room temperature for 16 hr. The reaction mixture was concentrated under reduced pressure, an aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography to obtain the title compound (160 mg). Yield 41%.
¹ H-NMR (CDCl ₃ ) δ: 1.11 (6H, d, J = 6.3 Hz), 1.48-1.51 (2H, m), 2.01-2.05 (2H, m), 2.84-2.91 (1H, m), 3.00 -3.08 (1H, m), 3.14-3.24 (2H, m), 4.08-4.16 (2H, m), 7.23 (1H, dd, J = 8.5, 2.2 Hz), 7.42 (1H, d, J = 8.5 Hz ), 7.55 (1H, d, J = 2.2 Hz).

[1-(6-クロロベンゾチアゾール-2-イル)ピペリジン-4-イル]イソプロピルアミン(159mg)、(3-ブロモメチルフェニル)酢酸 メチルエステル(138mg)、炭酸カリウム(107mg)、ジメチルホルムアミド(2mL)の混合物を80℃で8時間攪拌した。反応液に水を加え、酢酸エチルで抽出した。有機層を水、飽和食塩水で洗浄後、硫酸マグネシウムで乾燥し、減圧下溶媒を留去した。残渣をカラムクロマトで精製し、表記化合物(90mg)を得た。収率37%。

実施例６２４
[3-[[[1-(6-クロロベンゾチアゾール-2-イル)ピペリジン-4-イル]イソプロピルアミノ]メチル]フェニル]酢酸の製造

[3-[[[1-(6-クロロベンゾチアゾール-2-イル)ピペリジン-4-イル]イソプロピルアミノ]メチル]フェニル]酢酸 メチルエステル(90mg)、2N 水酸化ナトリウム(0.5mL)、テトラヒドロフラン(2mL)、メタノール(1mL)の混合物を室温で1時間攪拌した。2N塩酸で中和後、反応液を減圧下濃縮し、酢酸エチルで抽出した。有機層を水、飽和食塩水で洗浄後、硫酸マグネシウムで乾燥し、減圧下溶媒を留去した。残渣をカラムクロマトで精製し、表記化合物(28mg)を得た。収率32%。
MS (ESI) m/z 458 [M+H]+

実施例６２５
[3-[2-[1-(6-クロロベンゾチアゾール-2-イル)ピロリジン-3-イルアミノ]エトキシ]フェニル]酢酸 メチルエステルの製造

1-(6-クロロベンゾチアゾール-2-イル)ピロリジン-3-イルアミン(190mg)、 [3-(2-ブロモエトキシ)フェニル]酢酸 メチルエステル(205mg)、炭酸カリウム(114mg)の混合物を80℃で2時間攪拌した。反応液に水を加え、酢酸エチルで抽出した。有機層を水、飽和食塩水で洗浄後、硫酸ナトリウムで乾燥し、減圧下溶媒を留去した。残渣をカラムクロマトで精製し、表記化合物(174mg)を得た。収率52%。
¹H-NMR (CDCl₃) δ: 2.01-2.06 (1H, m), 2.31-2.36 (1H, m), 3.09 (2H, t, J = 4.9 Hz), 3.48-3.50 (1H, m), 3.62 (2H, s), 3.64-3.80 (4H, m), 3.72 (3H, s), 4.12 (2H, t, J = 4.9 Hz), 6.83-6.91 (3H, m), 7.24-7.28 (3H, m), 7.50 (1H, d, J = 8.5 Hz), 7.59 (1H, d, J = 1.9 Hz).

実施例６２６
[3-[2-[[1-(6-クロロベンゾチアゾール-2-イル)ピロリジン-3-イル]エチルアミノ]エトキシ]フェニル]酢酸 メチルエステルの製造

[3-[2-[1-(6-クロロベンゾチアゾール-2-イル)ピロリジン-3-イルアミノ]エトキシ]フェニル]酢酸 メチルエステル(174mg)、ヨウ化エチル(68uL)、炭酸カリウム(81mg)、ジメチルホルムアミド(2mL)の混合物を80℃で6.5時間攪拌した。反応液に水を加え、酢酸エチルで抽出した。有機層を水、飽和食塩水で洗浄後、硫酸ナトリウムで乾燥し、減圧下溶媒を留去した。残渣をカラムクロマトで精製し、表記化合物(101mg)を得た。収率55%。
¹H-NMR (CDCl₃) δ: 1.14 (3H, t, J = 6.7 Hz), 2.08-2.11 (1H, m), 2.29-2.32 (1H, m), 2.79-2.81 (2H, m), 2.98-3.03 (2H, m), 3.46-3.86 (5H, m), 3.62 (2H, s), 3.71 (3H, s), 4.05-4.08 (2H, m), 6.82-6.90 (3H, m), 7.23-7.29 (2H, m), 7.50 (1H, d, J = 8.8 Hz), 7.59 (1H, d, J = 1.9 Hz).

実施例６２７
[3-[2-[[1-(6-クロロベンゾチアゾール-2-イル)ピロリジン-3-イル]エチルアミノ]エトキシ]フェニル]酢酸の製造

[3-[2-[[1-(6-クロロベンゾチアゾール-2-イル)ピロリジン-3-イル]エチルアミノ]エトキシ]フェニル]酢酸 メチルエステル（101mg）、2N水酸化ナトリウム水溶液(0.535mL)、テトラヒドロフラン(1mL)、メタノール(0.5mL)の混合物を室温で1時間攪拌した。減圧下反応液を濃縮後、酢酸エチルで抽出した。有機層を水、飽和食塩水で洗浄後、硫酸ナトリウムで乾燥し、減圧下溶媒を留去した。残渣を酢酸エチル/n-ヘキサンで洗浄し、表記化合物(13mg)を得た。収率14%。
MS (ESI) m/z 459 [M+H]+ Example 623
Preparation of [3-[[[1- (6-Chlorobenzothiazol-2-yl) piperidin-4-yl] isopropylamino] methyl] phenyl] acetic acid methyl ester

[1- (6-Chlorobenzothiazol-2-yl) piperidin-4-yl] isopropylamine (159 mg), (3-bromomethylphenyl) acetic acid methyl ester (138 mg), potassium carbonate (107 mg), dimethylformamide (2 mL ) Was stirred at 80 ° C. for 8 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography to obtain the title compound (90 mg). Yield 37%.

Example 624
Preparation of [3-[[[1- (6-Chlorobenzothiazol-2-yl) piperidin-4-yl] isopropylamino] methyl] phenyl] acetic acid

[3-[[[1- (6-Chlorobenzothiazol-2-yl) piperidin-4-yl] isopropylamino] methyl] phenyl] acetic acid methyl ester (90 mg), 2N sodium hydroxide (0.5 mL), tetrahydrofuran ( 2 mL) and methanol (1 mL) were stirred at room temperature for 1 hour. After neutralizing with 2N hydrochloric acid, the reaction mixture was concentrated under reduced pressure and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography to obtain the title compound (28 mg). Yield 32%.
MS (ESI) m / z 458 [M + H] +

Example 625
Preparation of [3- [2- [1- (6-Chlorobenzothiazol-2-yl) pyrrolidin-3-ylamino] ethoxy] phenyl] acetic acid methyl ester

A mixture of 1- (6-chlorobenzothiazol-2-yl) pyrrolidin-3-ylamine (190 mg), [3- (2-bromoethoxy) phenyl] acetic acid methyl ester (205 mg) and potassium carbonate (114 mg) For 2 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography to obtain the title compound (174 mg). Yield 52%.
¹ H-NMR (CDCl ₃ ) δ: 2.01-2.06 (1H, m), 2.31-2.36 (1H, m), 3.09 (2H, t, J = 4.9 Hz), 3.48-3.50 (1H, m), 3.62 (2H, s), 3.64-3.80 (4H, m), 3.72 (3H, s), 4.12 (2H, t, J = 4.9 Hz), 6.83-6.91 (3H, m), 7.24-7.28 (3H, m ), 7.50 (1H, d, J = 8.5 Hz), 7.59 (1H, d, J = 1.9 Hz).

Example 626
Preparation of [3- [2-[[1- (6-Chlorobenzothiazol-2-yl) pyrrolidin-3-yl] ethylamino] ethoxy] phenyl] acetic acid methyl ester

[3- [2- [1- (6-Chlorobenzothiazol-2-yl) pyrrolidin-3-ylamino] ethoxy] phenyl] acetic acid methyl ester (174 mg), ethyl iodide (68 uL), potassium carbonate (81 mg), A mixture of dimethylformamide (2 mL) was stirred at 80 ° C. for 6.5 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography to obtain the title compound (101 mg). Yield 55%.
¹ H-NMR (CDCl ₃ ) δ: 1.14 (3H, t, J = 6.7 Hz), 2.08-2.11 (1H, m), 2.29-2.32 (1H, m), 2.79-2.81 (2H, m), 2.98 -3.03 (2H, m), 3.46-3.86 (5H, m), 3.62 (2H, s), 3.71 (3H, s), 4.05-4.08 (2H, m), 6.82-6.90 (3H, m), 7.23 -7.29 (2H, m), 7.50 (1H, d, J = 8.8 Hz), 7.59 (1H, d, J = 1.9 Hz).

Example 627
Preparation of [3- [2-[[1- (6-Chlorobenzothiazol-2-yl) pyrrolidin-3-yl] ethylamino] ethoxy] phenyl] acetic acid

[3- [2-[[1- (6-Chlorobenzothiazol-2-yl) pyrrolidin-3-yl] ethylamino] ethoxy] phenyl] acetic acid methyl ester (101 mg), 2N aqueous sodium hydroxide solution (0.535 mL) , Tetrahydrofuran (1 mL) and methanol (0.5 mL) were stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was washed with ethyl acetate / n-hexane to obtain the title compound (13 mg). Yield 14%.
MS (ESI) m / z 459 [M + H] +

MS (ESI) m/z 487 [M+H]+

実施例６２９

MS (ESI) m/z 473 [M+H]+

実施例６３０

MS (ESI) m/z 516 [M+H]+

実施例６３１

MS (ESI) m/z 548 [M+H]+

実施例６３２

MS (ESI) m/z 528 [M+H]+

実施例６３３

MS (ESI) m/z 508 [M+H]+ In the same manner, the following compound was obtained.
Example 628

MS (ESI) m / z 487 [M + H] +

Example 629

MS (ESI) m / z 473 [M + H] +

Example 630

MS (ESI) m / z 516 [M + H] +

Example 631

MS (ESI) m / z 548 [M + H] +

Example 632

MS (ESI) m / z 528 [M + H] +

Example 633

MS (ESI) m / z 508 [M + H] +

1-ベンジル-4-ピペリドン(3mL)、ピロリジン(6.95mL)、トルエン(30mL)の混合物を1時間還流した。減圧下溶媒を留去した後、残渣に酢酸(0.96mL)を加え室温で5分攪拌した。反応液に亜鉛(1.37g)、ブロモ酢酸メチル(2.17mL)を加え、室温で2時間攪拌した。反応液に炭酸ナトリウム水溶液(20mL)を加えた後、酢酸エチルで抽出した。有機層を水、飽和食塩水で洗浄後、硫酸ナトリウムで乾燥した。減圧下溶媒を留去した後、残渣をカラムクロマトで精製し、表記化合物(2.77g)を得た。収率52%。
¹H-NMR (CDCl₃) δ: 1.71-1.73 (4H, m), 1.81-1.84 (4H, m), 2.45-2.56 (10H, m), 3.55-3.58 (2H, m), 3.69 (3H, s), 7.26-7.36 (5H, m).

参考例２５２
2-(1-ベンジル-4-ピロリジン-1-イルピペリジン-4-イル)エタノールの製造

水素化リチウムアルミニウム(324mg)をテトラヒドロフラン(25mL)に懸濁し、0℃で(1-ベンジル-4ピロリジン-1-イルピペリジン-4-イル)酢酸メチルエステル(2.70g)のテトラヒドロフラン(25mL)溶液を加えた。0℃で1時間攪拌後、反応液に水(0.35mL)、10%水酸化ナトリウム水溶液(0.35mL)、水(1.05mL)を順次加えた。不溶物をろ過後、母液を酢酸エチルで抽出した。有機層を水、飽和食塩水で洗浄後、硫酸ナトリウムで乾燥した。減圧下溶媒を留去し、表記化合物を得た。得られた目的物はさらなる精製をせずに、そのまま次の反応に用いた。
¹H-NMR (CDCl₃) δ: 1.74-1.76 (6H, m), 1.89-1.94 (4H, m), 2.06-2.17 (2H, m), 2.80-2.83 (6H, m), 3.54 (3H, s), 3.85-3.87 (2H, m), 7.33 (5H, t, J = 3.6 Hz).

参考例２５３
2-[1-(6-クロロベンゾチアゾール-2-イル)-4-ピロリジン-1-イルピペリジン-4-イル]エタノールの製造

上記で得た2-(1-ベンジル-4-ピロリジン-1-イルピペリジン-4-イル)エタノールをメタノール(60mL)に溶解した後、Pd/C(600mg)を加え、水素雰囲気下19時間攪拌した。不溶物をろ過後、母液を減圧下濃縮した。得られた残渣にジメチルホルムアミド(30mL)、炭酸カリウム(1.24g)、2,6-ジクロロベンゾチアゾール(1.83g)を加え、60℃で21時間攪拌した。反応液に水を加え、酢酸エチルで抽出した。有機層を水、飽和食塩水で洗浄後、硫酸ナトリウムで乾燥した。減圧下溶媒を留去した後、残渣をカラムクロマトで精製し、表記化合物(2.58g)を得た。収率83%。
¹H-NMR (CDCl₃) δ: 1.83-1.86 (4H, m), 2.00-2.01 (6H, m), 2.91-2.98 (4H, m), 3.29-3.38 (2H, m), 3.92-4.05 (4H, m), 7.26 (1H, d, J = 2.2 Hz), 7.45 (1H, t, J = 7.8 Hz), 7.59 (1H, d, J = 2.2 Hz). Reference Example 251
Preparation of (1-benzyl-4pyrrolidin-1-ylpiperidin-4-yl) acetic acid methyl ester

A mixture of 1-benzyl-4-piperidone (3 mL), pyrrolidine (6.95 mL) and toluene (30 mL) was refluxed for 1 hour. After evaporating the solvent under reduced pressure, acetic acid (0.96 mL) was added to the residue, and the mixture was stirred at room temperature for 5 minutes. To the reaction solution were added zinc (1.37 g) and methyl bromoacetate (2.17 mL), and the mixture was stirred at room temperature for 2 hours. A sodium carbonate aqueous solution (20 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and then dried over sodium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by column chromatography to obtain the title compound (2.77 g). Yield 52%.
¹ H-NMR (CDCl ₃ ) δ: 1.71-1.73 (4H, m), 1.81-1.84 (4H, m), 2.45-2.56 (10H, m), 3.55-3.58 (2H, m), 3.69 (3H, s), 7.26-7.36 (5H, m).

Reference Example 252
Preparation of 2- (1-benzyl-4-pyrrolidin-1-ylpiperidin-4-yl) ethanol

Lithium aluminum hydride (324 mg) was suspended in tetrahydrofuran (25 mL), and a solution of (1-benzyl-4pyrrolidin-1-ylpiperidin-4-yl) acetic acid methyl ester (2.70 g) in tetrahydrofuran (25 mL) was added at 0 ° C. added. After stirring at 0 ° C. for 1 hour, water (0.35 mL), 10% aqueous sodium hydroxide solution (0.35 mL), and water (1.05 mL) were sequentially added to the reaction solution. The insoluble material was filtered off, and the mother liquor was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and then dried over sodium sulfate. The solvent was distilled off under reduced pressure to obtain the title compound. The obtained target product was directly used in the next reaction without further purification.
¹ H-NMR (CDCl ₃ ) δ: 1.74-1.76 (6H, m), 1.89-1.94 (4H, m), 2.06-2.17 (2H, m), 2.80-2.83 (6H, m), 3.54 (3H, s), 3.85-3.87 (2H, m), 7.33 (5H, t, J = 3.6 Hz).

Reference Example 253
Preparation of 2- [1- (6-chlorobenzothiazol-2-yl) -4-pyrrolidin-1-ylpiperidin-4-yl] ethanol

After 2- (1-benzyl-4-pyrrolidin-1-ylpiperidin-4-yl) ethanol obtained above was dissolved in methanol (60 mL), Pd / C (600 mg) was added, and the mixture was stirred for 19 hours under a hydrogen atmosphere. did. The insoluble material was filtered off, and the mother liquor was concentrated under reduced pressure. Dimethylformamide (30 mL), potassium carbonate (1.24 g) and 2,6-dichlorobenzothiazole (1.83 g) were added to the resulting residue, and the mixture was stirred at 60 ° C. for 21 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and then dried over sodium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by column chromatography to obtain the title compound (2.58 g). Yield 83%.
¹ H-NMR (CDCl ₃ ) δ: 1.83-1.86 (4H, m), 2.00-2.01 (6H, m), 2.91-2.98 (4H, m), 3.29-3.38 (2H, m), 3.92-4.05 ( 4H, m), 7.26 (1H, d, J = 2.2 Hz), 7.45 (1H, t, J = 7.8 Hz), 7.59 (1H, d, J = 2.2 Hz).

2-[1-(6-クロロベンゾチアゾール-2-イル)-4-ピロリジン-1-イルピペリジン-4-イル]エタノール(1.60g)、トリ-n-ブチルホスフィン(1.15mL)、1,1’-(アゾジカルボニル)ジピペリジン(1.16g)、テトラヒドロフラン(25mL)の混合物を、室温で１時間攪拌した。不溶物をろ過した後、母液に炭酸水素ナトリウム水溶液を加え、酢酸エチルで抽出した。有機層を水、飽和食塩水で洗浄後、硫酸ナトリウムで乾燥した。減圧下溶媒を留去し、残渣をカラムクロマトで精製し、表記化合物(874mg)を得た。収率36%。
¹H-NMR (CDCl₃) δ: 1.77-1.81 (6H, m), 1.94-2.03 (4H, m), 2.69-2.72 (4H, m), 3.53-3.77 (4H, m), 3.56 (2H, s), 3.72 (3H, s), 4.01 (2H, m), 6.75-6.84 (3H, m), 7.25 (1H, dd, J = 8.7, 2.1 Hz), 7.44 (1H, d, J = 8.8 Hz), 7.57 (1H, d, J = 2.2 Hz).

実施例６３５
[3-クロロ-5-[2-[1-(6-クロロベンゾチアゾール-2-イル)-4-ピロリジン-1-イルピペリジン-4-イル]エタノール]フェニル]酢酸の製造

[3-クロロ-5-[2-[1-(6-クロロベンゾチアゾール-2-イル)-4-ピロリジン-1-イルピペリジン-4-イル]エタノール]フェニル]酢酸メチルエステル(851mg)、2N 水酸化ナトリウム(2.33mL)、テトラヒドロフラン(5mL)、メタノール(5mL) の混合物を室塩で0.5時間攪拌した。2N 塩酸で中和した後、酢酸エチルで抽出した。有機層を水、飽和食塩水で洗浄後、硫酸マグネシウムで乾燥した。減圧下、溶媒を留去した後、残渣をヘキサンで洗浄し、表記化合物(725mg)を得た。収率88%。
MS (ESI) m/z 534 [M+H]⁺ Example 634
Preparation of [3-chloro-5- [2- [1- (6-chlorobenzothiazol-2-yl) -4-pyrrolidin-1-ylpiperidin-4-yl] ethanol] phenyl] acetic acid methyl ester

2- [1- (6-Chlorobenzothiazol-2-yl) -4-pyrrolidin-1-ylpiperidin-4-yl] ethanol (1.60 g), tri-n-butylphosphine (1.15 mL), 1,1 A mixture of '-(azodicarbonyl) dipiperidine (1.16 g) and tetrahydrofuran (25 mL) was stirred at room temperature for 1 hour. The insoluble material was filtered off, an aqueous sodium hydrogen carbonate solution was added to the mother liquor, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and then dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by column chromatography to obtain the title compound (874 mg). Yield 36%.
¹ H-NMR (CDCl ₃ ) δ: 1.77-1.81 (6H, m), 1.94-2.03 (4H, m), 2.69-2.72 (4H, m), 3.53-3.77 (4H, m), 3.56 (2H, s), 3.72 (3H, s), 4.01 (2H, m), 6.75-6.84 (3H, m), 7.25 (1H, dd, J = 8.7, 2.1 Hz), 7.44 (1H, d, J = 8.8 Hz ), 7.57 (1H, d, J = 2.2 Hz).

Example 635
Preparation of [3-chloro-5- [2- [1- (6-chlorobenzothiazol-2-yl) -4-pyrrolidin-1-ylpiperidin-4-yl] ethanol] phenyl] acetic acid

[3-Chloro-5- [2- [1- (6-chlorobenzothiazol-2-yl) -4-pyrrolidin-1-ylpiperidin-4-yl] ethanol] phenyl] acetic acid methyl ester (851 mg), 2N A mixture of sodium hydroxide (2.33 mL), tetrahydrofuran (5 mL) and methanol (5 mL) was stirred with Muro salt for 0.5 hours. The mixture was neutralized with 2N hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over magnesium sulfate. After evaporating the solvent under reduced pressure, the residue was washed with hexane to obtain the title compound (725 mg). Yield 88%.
MS (ESI) m / z 534 [M + H] ⁺

MS (ESI) m/z 568 [M+H]⁺

実施例６３７

MS (ESI) m/z 534 [M+H]⁺


実施例６３８

MS (ESI) m/z 568 [M+H]⁺

実施例６３９

MS(ESI) m/z 520[M+H]+

実施例６４０

MS (ESI) m/z 548 [M+H]⁺

実施例６４１

MS (ESI) m/z 582 [M+H]⁺

実施例６４２

MS (ESI) m/z 582 [M+H]⁺

実施例６４３

MS (ESI) m/z 514 [M+H]⁺

実施例６４４

MS (ESI) m/z 514 [M+H]⁺

実施例６４５

MS (ESI) m/z 584 [M+H]⁺

実施例６４６

MS (ESI) m/z 584 [M+H]⁺

実施例６４７

MS (ESI) m/z 550 [M+H]⁺

実施例６４８

MS (ESI) m/z 612 [M+H]⁺

実施例６４９

MS (ESI) m/z 612 [M+H]⁺

実施例６５０

MS (ESI) m/z 612 [M+H]⁺

実施例６５１

MS (ESI) m/z 612 [M+H]⁺

実施例６５２

MS (ESI) m/z 578 [M+H]⁺

実施例６５３

MS (ESI) m/z 578 [M+H]⁺

実施例６５４

1H-NMR (CDCl3) δ: 1.08 (6H, t, J = 7.1 Hz), 1.65-1.77 (2H, m), 1.92-2.05 (4H, m), 2.65 (4H, q, J = 7.1 Hz), 3.54-3.77 (6H, m), 4.01 (2H, t, J = 6.6 Hz), 6.70 (1H, s), 6.78 (1H, s), 6.87 (1H, s), 7.22 (1H, dd, J = 8.5, 2.2 Hz), 7.43 (1H, d, J = 8.5 Hz), 7.54 (1H, d, J = 2.2 Hz).

実施例６５５

1H-NMR (CDCl3) δ: 1.07 (6H, t, J = 7.0 Hz), 1.70-2.10 (6H, m), 2.66 (4H, q, J = 7.0 Hz), 3.56-3.79 (6H, m), 4.05-4.13 (2H, m), 6.76-6.85 (2H, m), 7.19-7.30 (2H, m), 7.42 (1H, d, J = 8.5 Hz), 7.53 (1H, d, J = 1.6 Hz).

実施例６５６

1H-NMR (CDCl3) δ: 1.08 (3H, t, J = 6.9 Hz), 1.64-2.03 (6H, m), 2.26 (3H, s), 2.53 (2H, q, J = 6.9 Hz), 3.52-3.68 (6H, m), 3.96-4.03 (2H, m), 6.68-6.88 (3H, m), 7.22 (1H, dd, J = 8.5, 2.2 Hz), 7.43 (1H, d, J = 8.8 Hz), 7.54 (1H, d, J = 2.2 Hz).

実施例６５７

1H-NMR (CDCl3) δ: 1.05 (3H, t, J = 7.1 Hz), 1.64-2.03 (6H, m), 2.23 (3H, s), 2.44-2.56 (2H, m), 3.45-3.68 (6H, m), 3.98-4.08 (2H, m), 6.68-6.85 (2H, m), 7.18-7.25 (2H, m), 7.41 (1H, d, J = 8.8 Hz), 7.52 (1H, d, J = 1.4 Hz).

実施例６５８

1H-NMR (CDCl3) δ: 1.08 (3H, t, J = 7.1 Hz), 1.64-2.06 (6H, m), 2.26 (3H, s), 2.52 (2H, q, J = 7.1 Hz), 3.56 (2H, s), 3.60-3.80 (4H, m), 4.00 (2H, t, J = 6.7 Hz), 6.68-6.89 (3H, m), 7.49-7.58 (2H, m), 7.83 (1H, s).

実施例６５９

1H-NMR (CDCl3) δ: 1.07 (3H, t, J = 6.9 Hz), 1.70-2.07 (6H, m), 2.25 (3H, s), 2.52 (2H, q, J = 6.9 Hz), 3.53 (2H, s), 3.59-3.76 (5H, m), 4.03-4.10 (2H, m), 6.74-6.84 (2H, m), 7.23-7.28 (1H, m), 7.47-7.57 (2H, m), 7.82 (1H, s).

実施例６６０

1H-NMR (CDCl3) δ: 7.54 (1.0H, d, J = 1.92 Hz), 7.42 (1.0H, d, J = 8.79 Hz), 7.31-7.29 (1.0H, m), 7.24-7.21 (1.0H, m), 6.85-6.79 (2.0H, m), 4.09 (2.0H, dd, J = 7.14, 7.14 Hz), 3.78-3.58 (6.0H, m), 2.79-2.73 (4.0H, br m), 2.10-1.52 (14.0H, m).

実施例６６１

1H-NMR (CDCl3) δ: 7.54 (1.0H, d, J = 2.20 Hz), 7.43 (1.0H, d, J = 8.24 Hz), 7.25-7.20 (1.0H, m), 6.87 (1.0H, s), 6.78 (1.0H, s), 6.70 (1.0H, s), 3.99 (2.0H, dd, J = 7.00, 7.00 Hz), 3.77-3.56 (6.0H, m), 2.76-2.72 (4.0H, m), 2.13-1.91 (10.0H, m), 1.73-1.56 (4.0H, m).

実施例６６２

1H-NMR (CDCl3) δ: 7.53 (1.0H, d, J = 1.92 Hz), 7.41 (1.0H, d, J = 8.79 Hz), 7.26-7.20 (2.0H, m), 6.86 (1.0H, s), 6.76 (1.0H, d, J = 8.52 Hz), 4.17-4.10 (2.0H, m), 3.92-3.84 (1.0H, m), 3.81-3.40 (4.0H, m), 3.33-3.24 (2.0H, m), 2.97-2.89 (1.0H, m), 2.76-2.66 (1.0H, m), 2.19-1.61 (8.0H, m), 1.54-1.42 (2.0H, m), 1.04 (3.0H, d, J = 6.30 Hz).

実施例６６３

MS(ESI) m/z 548 [M+H]+

実施例６６４

MS(ESI) m/z 525[M+H]+

実施例６６５

1H-NMR (CDCl3) δ: 7.83 (1.0H, d, J = 1.24 Hz), 7.55 (1.0H, d, J = 8.51 Hz), 7.50 (1.0H, dd, J = 8.78, 1.24 Hz), 7.30 (1.0H, d, J = 8.10 Hz), 6.85 (1.0H, d, J = 1.78 Hz), 6.80 (1.0H, dd, J = 8.10, 1.78 Hz), 4.15-4.10 (2.0H, m), 3.79-3.61 (6.0H, m), 3.47 (2.0H, t, J = 6.45 Hz), 3.36 (3.0H, s), 2.71 (4.0H, t, J = 6.45 Hz), 2.07-1.98 (4.0H, m), 1.82-1.71 (2.0H, m).

実施例６６６

1H-NMR (CDCl3) δ: 7.83 (1.0H, d, J = 0.89 Hz), 7.56 (1.0H, d, J = 8.85 Hz), 7.51 (1.0H, dd, J = 8.85, 0.89 Hz), 6.88-6.87 (1.0H, m), 6.79 (1.0H, dd, J = 1.92, 0.96 Hz), 6.71-6.69 (1.0H, m), 4.02 (2.0H, t, J = 6.31 Hz), 3.79-3.63 (4.0H, m), 3.57 (2.0H, s), 3.46 (2.0H, t, J = 6.24 Hz), 3.35 (3.0H, s), 2.68 (3.0H, t, J = 6.24 Hz), 2.31 (3.0H, s), 2.07-1.91 (4.0H, m), 1.77-1.64 (2.0H, m). In the same manner, the following compound was obtained.
Example 636

MS (ESI) m / z 568 [M + H] ⁺

Example 637

MS (ESI) m / z 534 [M + H] ⁺


Example 638

MS (ESI) m / z 568 [M + H] ⁺

Example 639

MS (ESI) m / z 520 [M + H] +

Example 640

MS (ESI) m / z 548 [M + H] ⁺

Example 641

MS (ESI) m / z 582 [M + H] ⁺

Example 642

MS (ESI) m / z 582 [M + H] ⁺

Example 643

MS (ESI) m / z 514 [M + H] ⁺

Example 644

MS (ESI) m / z 514 [M + H] ⁺

Example 645

MS (ESI) m / z 584 [M + H] ⁺

Example 646

MS (ESI) m / z 584 [M + H] ⁺

Example 647

MS (ESI) m / z 550 [M + H] ⁺

Example 648

MS (ESI) m / z 612 [M + H] ⁺

Example 649

MS (ESI) m / z 612 [M + H] ⁺

Example 650

MS (ESI) m / z 612 [M + H] ⁺

Example 651

MS (ESI) m / z 612 [M + H] ⁺

Example 652

MS (ESI) m / z 578 [M + H] ⁺

Example 653

MS (ESI) m / z 578 [M + H] ⁺

Example 654

1H-NMR (CDCl3) δ: 1.08 (6H, t, J = 7.1 Hz), 1.65-1.77 (2H, m), 1.92-2.05 (4H, m), 2.65 (4H, q, J = 7.1 Hz), 3.54-3.77 (6H, m), 4.01 (2H, t, J = 6.6 Hz), 6.70 (1H, s), 6.78 (1H, s), 6.87 (1H, s), 7.22 (1H, dd, J = 8.5, 2.2 Hz), 7.43 (1H, d, J = 8.5 Hz), 7.54 (1H, d, J = 2.2 Hz).

Example 655

1H-NMR (CDCl3) δ: 1.07 (6H, t, J = 7.0 Hz), 1.70-2.10 (6H, m), 2.66 (4H, q, J = 7.0 Hz), 3.56-3.79 (6H, m), 4.05-4.13 (2H, m), 6.76-6.85 (2H, m), 7.19-7.30 (2H, m), 7.42 (1H, d, J = 8.5 Hz), 7.53 (1H, d, J = 1.6 Hz) .

Example 656

1H-NMR (CDCl3) δ: 1.08 (3H, t, J = 6.9 Hz), 1.64-2.03 (6H, m), 2.26 (3H, s), 2.53 (2H, q, J = 6.9 Hz), 3.52- 3.68 (6H, m), 3.96-4.03 (2H, m), 6.68-6.88 (3H, m), 7.22 (1H, dd, J = 8.5, 2.2 Hz), 7.43 (1H, d, J = 8.8 Hz) , 7.54 (1H, d, J = 2.2 Hz).

Example 657

1H-NMR (CDCl3) δ: 1.05 (3H, t, J = 7.1 Hz), 1.64-2.03 (6H, m), 2.23 (3H, s), 2.44-2.56 (2H, m), 3.45-3.68 (6H , m), 3.98-4.08 (2H, m), 6.68-6.85 (2H, m), 7.18-7.25 (2H, m), 7.41 (1H, d, J = 8.8 Hz), 7.52 (1H, d, J = 1.4 Hz).

Example 658

1H-NMR (CDCl3) δ: 1.08 (3H, t, J = 7.1 Hz), 1.64-2.06 (6H, m), 2.26 (3H, s), 2.52 (2H, q, J = 7.1 Hz), 3.56 ( 2H, s), 3.60-3.80 (4H, m), 4.00 (2H, t, J = 6.7 Hz), 6.68-6.89 (3H, m), 7.49-7.58 (2H, m), 7.83 (1H, s) .

Example 659

1H-NMR (CDCl3) δ: 1.07 (3H, t, J = 6.9 Hz), 1.70-2.07 (6H, m), 2.25 (3H, s), 2.52 (2H, q, J = 6.9 Hz), 3.53 ( 2H, s), 3.59-3.76 (5H, m), 4.03-4.10 (2H, m), 6.74-6.84 (2H, m), 7.23-7.28 (1H, m), 7.47-7.57 (2H, m), 7.82 (1H, s).

Example 660

1H-NMR (CDCl3) δ: 7.54 (1.0H, d, J = 1.92 Hz), 7.42 (1.0H, d, J = 8.79 Hz), 7.31-7.29 (1.0H, m), 7.24-7.21 (1.0H , m), 6.85-6.79 (2.0H, m), 4.09 (2.0H, dd, J = 7.14, 7.14 Hz), 3.78-3.58 (6.0H, m), 2.79-2.73 (4.0H, br m), 2.10-1.52 (14.0H, m).

Example 661

1H-NMR (CDCl3) δ: 7.54 (1.0H, d, J = 2.20 Hz), 7.43 (1.0H, d, J = 8.24 Hz), 7.25-7.20 (1.0H, m), 6.87 (1.0H, s ), 6.78 (1.0H, s), 6.70 (1.0H, s), 3.99 (2.0H, dd, J = 7.00, 7.00 Hz), 3.77-3.56 (6.0H, m), 2.76-2.72 (4.0H, m), 2.13-1.91 (10.0H, m), 1.73-1.56 (4.0H, m).

Example 662

1H-NMR (CDCl3) δ: 7.53 (1.0H, d, J = 1.92 Hz), 7.41 (1.0H, d, J = 8.79 Hz), 7.26-7.20 (2.0H, m), 6.86 (1.0H, s ), 6.76 (1.0H, d, J = 8.52 Hz), 4.17-4.10 (2.0H, m), 3.92-3.84 (1.0H, m), 3.81-3.40 (4.0H, m), 3.33-3.24 (2.0 H, m), 2.97-2.89 (1.0H, m), 2.76-2.66 (1.0H, m), 2.19-1.61 (8.0H, m), 1.54-1.42 (2.0H, m), 1.04 (3.0H, d, J = 6.30 Hz).

Example 663

MS (ESI) m / z 548 [M + H] +

Example 664

MS (ESI) m / z 525 [M + H] +

Example 665

1H-NMR (CDCl3) δ: 7.83 (1.0H, d, J = 1.24 Hz), 7.55 (1.0H, d, J = 8.51 Hz), 7.50 (1.0H, dd, J = 8.78, 1.24 Hz), 7.30 (1.0H, d, J = 8.10 Hz), 6.85 (1.0H, d, J = 1.78 Hz), 6.80 (1.0H, dd, J = 8.10, 1.78 Hz), 4.15-4.10 (2.0H, m), 3.79-3.61 (6.0H, m), 3.47 (2.0H, t, J = 6.45 Hz), 3.36 (3.0H, s), 2.71 (4.0H, t, J = 6.45 Hz), 2.07-1.98 (4.0H , m), 1.82-1.71 (2.0H, m).

Example 666

1H-NMR (CDCl3) δ: 7.83 (1.0H, d, J = 0.89 Hz), 7.56 (1.0H, d, J = 8.85 Hz), 7.51 (1.0H, dd, J = 8.85, 0.89 Hz), 6.88 -6.87 (1.0H, m), 6.79 (1.0H, dd, J = 1.92, 0.96 Hz), 6.71-6.69 (1.0H, m), 4.02 (2.0H, t, J = 6.31 Hz), 3.79-3.63 (4.0H, m), 3.57 (2.0H, s), 3.46 (2.0H, t, J = 6.24 Hz), 3.35 (3.0H, s), 2.68 (3.0H, t, J = 6.24 Hz), 2.31 (3.0H, s), 2.07-1.91 (4.0H, m), 1.77-1.64 (2.0H, m).

2-(1-ベンジル-4-ピロリジン-1-イルピペリジン-4-イル)エタノール(9.28g)、10%Pd/C(1.86g)、メタノール(100mL)の混合物を4気圧の水素雰囲気下3日間攪拌した。不溶物をろ過した後、母液を濃縮し、表記化合物(6.30g)を得た。収率99%。
¹H-NMR (DMSO-d₆) δ: 1.76-1.79 (6H, m), 1.88-1.91 (4H, m), 2.77-2.80 (4H, m), 3.02-3.05 (2H, br m), 3.15-3.18 (2H, br m), 3.53-3.55 (2H, br m).

参考例２５５
2-[1-(5-ブロモチアゾール-2-イル)-4-ピロリジン-1-イル-ピペリジン-4-イル]エタノールの製造

2-(4-ピロリジン-1-イルピペリジン-4-イル)エタノール(4.11g)、2,5-ジブロモチアゾール(5.03g)、炭酸カリウム(3.43g)、ジメチルホルムアミド(75mL)の混合物を60℃で16時間攪拌した。反応液に水を加え、酢酸エチルで抽出した。有機層を水、飽和食塩水で洗浄し、硫酸マグネシウムで洗浄した。減圧下溶媒を留去し、残渣をカラムクロマトで精製して、表記化合物(3.88g)を得た。収率52%。

実施例６６７
[3-[2-[1-(5-ブロモチアゾール-2-イル)-4-ピロリジン-1-イル-ピペリジン-4-イル]エトキシ]-5-クロロフェニル]酢酸メチルエステルの製造

2-[1-(5-ブロモチアゾール-2-イル)-4-ピロリジン-1-イル-ピペリジン-4-イル]エタノール(1.30g)、(3-クロロ-5-ヒドロキシフェニル)酢酸(796mg)、トリ-n-ブチルホスフィン(0.99mL)、1,1’-(アゾジカルボニル)ジピペリジン(1.00g)、テトラヒドロフラン(20mL)の混合物を室温で4時間攪拌した。反応液に水を加え、酢酸エチルで抽出した。有機層を水、飽和食塩水で洗浄し、硫酸マグネシウムで乾燥した。減圧下溶媒を留去した後、残渣をカラムクロマトで精製し、表記化合物(1.45g)を得た。収率74％。
¹H-NMR (CDCl₃) δ: 1.71-1.85 (8H, m), 2.09-2.10 (2H, m), 2.69-2.71 (4H, br m), 3.48-3.53 (4H, m), 3.61 (2H, s), 3.71 (3H, s), 4.12-4.16 (2H, m), 6.83 (2H, dd, J = 8.0, 2.2 Hz), 7.07 (1H, d, J = 2.2 Hz), 7.31 (1H, d, J = 8.0 Hz).
実施例６６８
[3-[2-[1-(5-ブロモチアゾール-2-イル)-4-ピロリジン-1-イル-ピペリジン-4-イル]エトキシ]-5-クロロフェニル]酢酸の製造

[3-[2-[1-(5-ブロモチアゾール-2-イル)-4-ピロリジン-1-イル-ピペリジン-4-イル]エトキシ]-5-クロロフェニル]酢酸メチルエステル(1.45g)、2N水酸化ナトリウム(3.3mL)、テトラヒドロフラン(15mL)、メタノール(15mL)の混合物を室温で3時間攪拌した。反応液に水を加え、クロロホルムで洗浄した。水層を2N塩酸で中和した後、クロロホルムで抽出した。有機層を水、飽和食塩水で洗浄後、硫酸マグネシウムで乾燥した。減圧下溶媒を留去し、残渣をカラムクロマトで精製して、表記化合物(916mg)を得た。収率65%。
¹H-NMR (DMSO-d₆) δ: 1.75-1.89 (10H, m), 2.64-2.67 (4H, m), 3.33-3.36 (2H, m), 3.34 (2H, s) 3.51-3.55 (2H, m), 4.11-4.14 (2H, m), 6.85 (1H, dd, J = 7.8, 2.1 Hz), 7.10 (1H, d, J = 2.1 Hz), 7.19 (1H, s), 7.34 (1H, d, J = 7.8 Hz).

実施例６６９
[3-クロロ-5-[2-[1-[5-(3-フルオロフェニル)チアゾール-2-イル]-4-ピロリジン-1-イル-ピペリジン-4-イル]エトキシ]フェニル]酢酸の製造

[3-[2-[1-(5-ブロモチアゾール-2-イル)-4-ピロリジン-1-イル-ピペリジン-4-イル]エトキシ]-5-クロロフェニル]酢酸(60mg)、3-フルオロフェニルボロン酸(32mg)、テトラキス（トリフェニルホスフィン）パラジウム(13mg)、1M炭酸ナトリウム(0.55mL)、ジメチルホルムアミド(1mL)の混合物を、マイクロウェーブ反応装置を用いて、180℃で5分間反応させた。不溶物をろ過後、母液に蟻酸を加え、減圧下溶媒を留去した。残渣を高速液体クロマトグラフィーで精製し、表記化合物(14.4mg)を得た。収率24%。
1H-NMR(DMSO-d6)) δ:8.18(1H, s),7.69(1H, s), 7.39-7.26(3H, m), 7.01(1H ,m), 6.90(1H, d, J=10.8Hz), 6.82(1H, s), 4.53(2H, m), 3.58-3.54(4H, m), 2.64(2H,s), 1.94-1.69(8H,m) Reference Example 254
Production of 2- (4-pyrrolidin-1-ylpiperidin-4-yl) ethanol

A mixture of 2- (1-benzyl-4-pyrrolidin-1-ylpiperidin-4-yl) ethanol (9.28 g), 10% Pd / C (1.86 g), methanol (100 mL) under a hydrogen atmosphere of 4 atm 3 Stir for days. The insoluble material was filtered off, and the mother liquor was concentrated to obtain the title compound (6.30 g). Yield 99%.
¹ H-NMR (DMSO-d ₆ ) δ: 1.76-1.79 (6H, m), 1.88-1.91 (4H, m), 2.77-2.80 (4H, m), 3.02-3.05 (2H, br m), 3.15 -3.18 (2H, br m), 3.53-3.55 (2H, br m).

Reference Example 255
Preparation of 2- [1- (5-bromothiazol-2-yl) -4-pyrrolidin-1-yl-piperidin-4-yl] ethanol

A mixture of 2- (4-pyrrolidin-1-ylpiperidin-4-yl) ethanol (4.11 g), 2,5-dibromothiazole (5.03 g), potassium carbonate (3.43 g), dimethylformamide (75 mL) was added at 60 ° C. For 16 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and washed with magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by column chromatography to obtain the title compound (3.88 g). Yield 52%.

Example 667
Preparation of [3- [2- [1- (5-Bromothiazol-2-yl) -4-pyrrolidin-1-yl-piperidin-4-yl] ethoxy] -5-chlorophenyl] acetic acid methyl ester

2- [1- (5-Bromothiazol-2-yl) -4-pyrrolidin-1-yl-piperidin-4-yl] ethanol (1.30 g), (3-chloro-5-hydroxyphenyl) acetic acid (796 mg) , Tri-n-butylphosphine (0.99 mL), 1,1 ′-(azodicarbonyl) dipiperidine (1.00 g), and tetrahydrofuran (20 mL) were stirred at room temperature for 4 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over magnesium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by column chromatography to obtain the title compound (1.45 g). Yield 74%.
¹ H-NMR (CDCl ₃ ) δ: 1.71-1.85 (8H, m), 2.09-2.10 (2H, m), 2.69-2.71 (4H, br m), 3.48-3.53 (4H, m), 3.61 (2H , s), 3.71 (3H, s), 4.12-4.16 (2H, m), 6.83 (2H, dd, J = 8.0, 2.2 Hz), 7.07 (1H, d, J = 2.2 Hz), 7.31 (1H, d, J = 8.0 Hz).
Example 668
Preparation of [3- [2- [1- (5-Bromothiazol-2-yl) -4-pyrrolidin-1-yl-piperidin-4-yl] ethoxy] -5-chlorophenyl] acetic acid

[3- [2- [1- (5-Bromothiazol-2-yl) -4-pyrrolidin-1-yl-piperidin-4-yl] ethoxy] -5-chlorophenyl] acetic acid methyl ester (1.45 g), 2N A mixture of sodium hydroxide (3.3 mL), tetrahydrofuran (15 mL), and methanol (15 mL) was stirred at room temperature for 3 hours. Water was added to the reaction solution and washed with chloroform. The aqueous layer was neutralized with 2N hydrochloric acid and extracted with chloroform. The organic layer was washed with water and saturated brine, and dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by column chromatography to obtain the title compound (916 mg). Yield 65%.
¹ H-NMR (DMSO-d ₆ ) δ: 1.75-1.89 (10H, m), 2.64-2.67 (4H, m), 3.33-3.36 (2H, m), 3.34 (2H, s) 3.51-3.55 (2H , m), 4.11-4.14 (2H, m), 6.85 (1H, dd, J = 7.8, 2.1 Hz), 7.10 (1H, d, J = 2.1 Hz), 7.19 (1H, s), 7.34 (1H, d, J = 7.8 Hz).

Example 669
Preparation of [3-chloro-5- [2- [1- [5- (3-fluorophenyl) thiazol-2-yl] -4-pyrrolidin-1-yl-piperidin-4-yl] ethoxy] phenyl] acetic acid

[3- [2- [1- (5-Bromothiazol-2-yl) -4-pyrrolidin-1-yl-piperidin-4-yl] ethoxy] -5-chlorophenyl] acetic acid (60 mg), 3-fluorophenyl A mixture of boronic acid (32 mg), tetrakis (triphenylphosphine) palladium (13 mg), 1M sodium carbonate (0.55 mL), dimethylformamide (1 mL) was reacted at 180 ° C. for 5 minutes using a microwave reactor. . After filtering the insoluble material, formic acid was added to the mother liquor, and the solvent was distilled off under reduced pressure. The residue was purified by high performance liquid chromatography to obtain the title compound (14.4 mg). Yield 24%.
1H-NMR (DMSO-d6)) δ: 8.18 (1H, s), 7.69 (1H, s), 7.39-7.26 (3H, m), 7.01 (1H, m), 6.90 (1H, d, J = 10.8 Hz), 6.82 (1H, s), 4.53 (2H, m), 3.58-3.54 (4H, m), 2.64 (2H, s), 1.94-1.69 (8H, m)

MS(ESI) m/z 584[M+]

実施例６７１

MS(ESI) m/z 586[M+]

実施例６７２

MS(ESI) m/z 569[M+]

実施例６７３

MS(ESI) m/z 584[M+]

実施例６７４

MS(ESI) m/z 586[M+]

実施例６７５

MS(ESI) m/z 569[M+]

実施例６７６

MS(ESI) m/z 546[M+H]+

実施例６７７

1H-NMR(DMSO-d6)) d:8.18(1H, s),7.69(1H, s), 7.39-7.26(3H, m), 7.01(1H ,m), 6.90(1H, d, J=10.8Hz), 6.82(1H, s), 4.53(2H, m), 3.58-3.54(4H, m), 2.64(2H,s), 1.94-1.69(8H,m).

実施例６７８

MS(ESI) m/z 540[M+H]+ In the same manner, the following compound was obtained.
Example 670

MS (ESI) m / z 584 [M +]

Example 671

MS (ESI) m / z 586 [M +]

Example 672

MS (ESI) m / z 569 [M +]

Example 673

MS (ESI) m / z 584 [M +]

Example 674

MS (ESI) m / z 586 [M +]

Example 675

MS (ESI) m / z 569 [M +]

Example 676

MS (ESI) m / z 546 [M + H] +

Example 677

1H-NMR (DMSO-d6)) d: 8.18 (1H, s), 7.69 (1H, s), 7.39-7.26 (3H, m), 7.01 (1H, m), 6.90 (1H, d, J = 10.8 Hz), 6.82 (1H, s), 4.53 (2H, m), 3.58-3.54 (4H, m), 2.64 (2H, s), 1.94-1.69 (8H, m).

Example 678

MS (ESI) m / z 540 [M + H] +

1H-NMR(CDCl3) δ 2.93-3.18(4H, m), 3.29(1H, td, J=12.0, 3.2Hz), 3.35-3.42(1H, m), 3.39(3H, s), 3.48(1H, dd, J=9.2, 3.6Hz), 3.91(1H, d, J=12.0Hz), 3.99(1H, d, J=12.0Hz), 7.24(1H, dd, J=8.8, 2.4Hz), 7.44(1H, d, J=8.8Hz), 7.56(1H, d, J=2.4Hz).

参考例２５７

1H-NMR(CDCl3) δ 1.22(3H, t, J=7.2Hz), 2.92-3.02(2H, m), 3.04-3.11(1H, m), 3.12-3.17(1H, m), 3.26(1H, td, J=12.0, 3.2Hz), 3.39(1H, dd, J=9.2, 7.2Hz), 3.48-3.59(3H, m), 3.91(1H, brd, J=12.0Hz), 3.98(1H, brd, J=12.0Hz), 7.24(1H, dd, J=8.8, 2.0Hz), 7.44(1H, d, J=8.8Hz), 7.56(1H, d, J=2.0Hz). Reference Example 256

1H-NMR (CDCl3) δ 2.93-3.18 (4H, m), 3.29 (1H, td, J = 12.0, 3.2Hz), 3.35-3.42 (1H, m), 3.39 (3H, s), 3.48 (1H, dd, J = 9.2, 3.6Hz), 3.91 (1H, d, J = 12.0Hz), 3.99 (1H, d, J = 12.0Hz), 7.24 (1H, dd, J = 8.8, 2.4Hz), 7.44 ( 1H, d, J = 8.8Hz), 7.56 (1H, d, J = 2.4Hz).

Reference Example 257

1H-NMR (CDCl3) δ 1.22 (3H, t, J = 7.2Hz), 2.92-3.02 (2H, m), 3.04-3.11 (1H, m), 3.12-3.17 (1H, m), 3.26 (1H, td, J = 12.0, 3.2Hz), 3.39 (1H, dd, J = 9.2, 7.2Hz), 3.48-3.59 (3H, m), 3.91 (1H, brd, J = 12.0Hz), 3.98 (1H, brd , J = 12.0Hz), 7.24 (1H, dd, J = 8.8, 2.0Hz), 7.44 (1H, d, J = 8.8Hz), 7.56 (1H, d, J = 2.0Hz).

TLC Rf 0.13 (MeOH-CHCl3, 1:10)

実施例６８０

mp 109-112

実施例６８１

mp 92-98

実施例６８２

TLC Rf 0.15 (MeOH-CHCl3, 1:10)

実施例６８３

TLC Rf 0.23(MeOH-CHCl3, 1:10)

実施例６８４

Rf 0.12(MeOH-CHCl3, 1:10)

実施例６８５

Rf 0.24(MeOH-CHCl3, 1:10)

実施例６８６

MS (ESI) m/z 480 [M+H]+

実施例６８７

MS (ESI) m/z 480 [M+H]+

実施例６８８

MS (ESI) m/z 479 [M+H]+

実施例６８９

MS(ESI) m/z 514, 516 [M+H]+

実施例６９０

MS(ESI) m/z 514, 516 [M+H]+

実施例６９１

MS(ESI) m/z 494 [M+H]+

実施例６９２

MS(ESI) m/z 494 [M+H]+

実施例６９３

MS(ESI) m/z 528, 530 [M+H]+
1H-NMR (DMSO-d6) δ: 0.93(3H, t, J=7.5 Hz), 1.46-1.69(2H, m), 2.64-2.71(2H, m), 2.86-2.91(1H, m), 3.05-3.09(2H, m), 3.50-3.53(2H, m), 3/57(2H, s), 3.68-3.77(2H, m), 4.15(2H, t, J=5.7 Hz), 6.84(1H, dd, J=1.8, 8.1 Hz), 7.10(1H, d, J=1.8 Hz), 7.34(1H, d, J=8.1 Hz), 7.56-7.57(2H, m), 8.23(1H, s)
アモルファス

実施例６９４

MS(ESI) m/z 528, 530 [M+H]+

実施例６９５

MS(ESI) m/z 508 [M+H]+

実施例６９６

MS(ESI) m/z 508 [M+H]+

実施例６９７

MS(ESI) m/z 480 [M+H]+

実施例６９８

1H-NMR (300MHz, CDCl3)：1.46 (3H, d, J=6.9 Hz), 2.53-2.60 (1H, m), 2.73-2.77 (1H, m), 3.06 (2H, s), 3.16-3.20 (1H, m), 3.27-3.31 (1H, m), 3.55-3.60 (1H, m), 3.60 (2H, s), 3.89-3.94 (1H, m), 4.29 (3H, m), 6.84 (1H, d, J=8.1 Hz), 6.87 (1H, s), 7.25 (1H, dd, J=8.7 Hz, 2.1 Hz), 7.31 (1H, d, J=8.1 Hz), 7.44 (1H, d, J=8.7 Hz), 7.56 (1H, d,J=2.1 Hz)

実施例６９９

MS (ESI) m/z 494 [M+H]+

実施例７００

MS(ESI) m/z 528[M+H]+

実施例７０１

MS(ESI) m/z 508[M+H]+

実施例７０２

MS(ESI) m/z 528[M+H]+

実施例７０３

MS(ESI) m/z 474, 476, 478 [M+H]+

実施例７０４

1H-NMR (DMSO-d6) δ: 1.18 (6H, d, J = 4.7 Hz), 2.80-2.95 (4H, m), 3.10-3.19 (2H, m), 3.55 (2H, s), 3.85 (2H, d, J = 9.9 Hz), 4.03-4.11 (2H, m), 6.83 (1H, d, J = 8.2 Hz), 7.02-7.11 (2H, m), 7.22-7.48 (3H, m), 7.75 (1H, d, J = 8.0 Hz).

実施例７０５

1H-NMR (DMSO-d6) δ: 1.16 (6H, d, J = 5.8 Hz), 2.61-2.85 (5H, m), 3.07-3.16 (3H, m), 3.55 (2H, s), 3.89-4.11 (5H, m), 6.79-7.36 (8H, m).

実施例７０６

1H-NMR (DMSO-d6) δ: 1.22 (6H, d, J = 6.0 Hz), 2.58-2.84 (4H, m), 3.09-3.19 (2H, m), 3.52 (2H, s), 4.06-4.14 (2H, m), 4.34-4.46 (2H, m), 6.84 (1H, d, J = 8.2 Hz), 7.09-7.74 (7H, m), 8.03 (1H, d, J = 9.1 Hz).

実施例７０７

1H-NMR (Acetone) δ: 8.38-8.35 (1.0H, m), 7.71 (1.0H, dd, J = 9.34, 2.20 Hz), 7.31 (1.0H, dd, J = 7.97, 1.65 Hz), 7.13 (1.0H, d, J = 1.92 Hz), 6.97-6.87 (2.0H, m), 4.33 (2.0H, d, J = 12.64 Hz), 4.17 (2.0H, dd, J = 5.91, 5.91 Hz), 3.61 (2.0H, s), 3.25-3.23 (2.0H, m), 2.83-2.67 (4.0H, m), 1.24 (6.0H, d, J = 6.00 Hz).

実施例７０８

1H-NMR (DMSO-d6) δ: 8.66 (1.0H, d, J = 4.94 Hz), 7.31 (1.0H, d, J = 8.10 Hz), 7.08 (1.0H, s), 6.99 (1.0H, d, J = 4.94 Hz), 6.82 (1.0H, d, J = 8.10 Hz), 4.45 (2.0H, d, J = 8.24 Hz), 4.08-3.99 (3.0H, m), 3.53 (2.0H, s), 3.13 (2.0H, dd, J = 5.63, 5.63 Hz), 2.76-2.65 (4.0H, m), 1.16 (6.0H, d, J = 6.32 Hz).

実施例７０９

1H-NMR (Acetone) δ: 8.14 (1.0H, d, J = 2.54 Hz), 7.60 (1.0H, dd, J = 9.13, 2.54 Hz), 7.40 (1.0H, s), 7.34 (1.0H, d, J = 7.69 Hz), 7.25 (1.0H, dd, J = 7.69, 7.69 Hz), 7.15 (1.0H, d, J = 7.69 Hz), 6.81 (1.0H, d, J = 9.13 Hz), 4.13 (2.0H, d, J = 11.54 Hz), 3.81 (2.0H, s), 3.62 (2.0H, s), 2.76-2.62 (4.0H, m), 1.07 (6.0H, d, J = 5.77 Hz).

実施例７１０

1H-NMR (DMSO-d6) δ: 1.14 (6H, d, J = 5.1 Hz), 2.60-2.76 (2H, m), 3.00-3.10 (2H, m), 3.55 (2H, s), 3.97-4.06 (2H, m), 4.46-4.60 (2H, m), 6.80-6.96 (3H, m), 7.30-7.67 (3H, m), 8.69 (2H, s).

実施例７１１

1H-NMR (DMSO-d6) δ: 7.18-7.18 (1.0H, m), 7.04 (1.0H, d, J = 7.28 Hz), 6.84 (1.0H, s), 6.71 (1.0H, d, J = 7.28 Hz), 3.98 (2.0H, dd, J = 5.10, 5.10 Hz), 3.64 (2.0H, d, J = 10.99 Hz), 3.48 (2.0H, s), 3.10 (2.0H, dd, J = 5.10, 5.10 Hz), 2.84-2.69 (4.0H, m), 2.11 (3.0H, s), 1.14 (6.0H, d, J = 5.77 Hz).

実施例７１２

1H-NMR (Acetone) δ: 8.12 (1.0H, d, J = 2.68 Hz), 7.59 (1.0H, dd, J = 9.13, 2.68 Hz), 7.32 (1.0H, d, J = 8.11 Hz), 7.13 (1.0H, d, J = 1.92 Hz), 6.90 (1.0H, dd, J = 8.11, 1.92 Hz), 6.80 (1.0H, d, J = 9.13 Hz), 4.18-4.13 (4.0H, m), 3.63 (2.0H, s), 3.22 (2.0H, dd, J = 6.04, 6.04 Hz), 2.85-2.78 (2.0H, m), 2.62-2.53 (2.0H, m), 1.23 (6.0H, d, J = 6.04 Hz).

実施例７１３

1H-NMR (Acetone) δ: 8.34 (2.0H, s), 7.30 (1.0H, d, J = 8.04 Hz), 7.13 (1.0H, d, J = 1.65 Hz), 6.90 (1.0H, dd, J = 8.04, 1.65 Hz), 4.49 (2.0H, d, J = 12.36 Hz), 4.15 (2.0H, dd, J = 5.91, 5.91 Hz), 3.60 (2.0H, s), 3.23 (2.0H, dd, J = 6.04, 6.04 Hz), 2.82-2.60 (4.0H, m), 1.22 (6.0H, d, J = 6.04 Hz).

実施例７１４

1H-NMR (DMSO-d6) δ: 8.44 (2.0H, s), 6.61 (3.0H, s), 4.43-4.33 (2.0H, m), 3.95 (2.0H, dd, J = 6.59, 6.59 Hz), 3.43 (2.0H, s), 3.03 (2.0H, dd, J = 6.00, 6.00 Hz), 2.63 (4.0H, d, J = 6.90 Hz), 2.23 (3.0H, s), 1.12 (6.0H, d, J = 5.22 Hz).

実施例７１５

1H-NMR (DMSO-d6) δ: 1.23-1.41 (2H, m), 1.70-1.92 (5H, m), 3.09-3.23 (2H, m), 3.57 (2H, s), 3.98-4.15 (4H, m), 6.81-7.46 (6H, m), 7.74 (1H, d, J = 8.0 Hz).

実施例７１６

1H-NMR (Acetone) δ: 8.37 (1.0H, s), 7.71 (1.0H, dd, J = 9.06, 2.47 Hz), 7.33 (1.0H, d, J = 7.97 Hz), 7.12 (1.0H, d, J = 1.65 Hz), 6.93-6.89 (2.0H, m), 4.55-4.50 (2.0H, m), 4.19 (2.0H, dd, J = 6.32, 6.32 Hz), 3.62 (2.0H, s), 2.96-2.92 (3.0H, m), 1.96-1.79 (4.0H, m), 1.37-1.24 (2.0H, m).

実施例７１７

1H-NMR (DMSO-d6) δ: 8.65 (1.0H, d, J = 4.67 Hz), 7.33 (1.0H, d, J = 8.11 Hz), 7.08 (1.0H, s), 6.95 (1.0H, d, J = 4.67 Hz), 6.83 (1.0H, d, J = 8.11 Hz), 4.64 (2.0H, d, J = 12.42 Hz), 4.10 (2.0H, dd, J = 6.59, 6.59 Hz), 3.55 (2.0H, s), 3.40-3.25 (1.0H, m), 2.96 (2.0H, dd, J = 12.42, 12.42 Hz), 1.91-1.72 (4.0H, m), 1.24-1.15 (2.0H, m).

実施例７１８

1H-NMR (DMSO-d6) δ: 1.13-1.36 (2H, m), 1.67-1.87 (5H, m), 2.86-3.00 (2H, m), 3.56 (2H, s), 4.05-4.16 (5H, m), 6.80-7.36 (7H, m).

実施例７１９

1H-NMR (300MHz, CDCl3)：1.40 (6H, m), 3.27-3.44 (6H, m), 3.93-3.98 (2H, m), 4.14 (2H, m), 4.53 (2H, s), 6.47-6.55 (3H, m), 7.13-7.26 (2H, m), 7.43 (1H, d, J=8.1 Hz), 7.55 (1H, s).

実施例７２０

1H-NMR (300MHz, CDCl3)：1.98-2.17 (5H, m), 3.21-3.29 (2H, m), 3.84 (2H, d, J=6.0 Hz), 4.23 (2H, m), 4.65 (2H, s), 6.49-6.56 (3H, m), 7.20 (1H, t, J=8.1 Hz), 7.26-7.29 (2H, m), 7.55 (1H, d, J=2.1 Hz)

実施例７２１

1H-NMR (300MHz, CDCl3)：1.28 (6H, m), 2.64 (2H, t, J=7.5 Hz), 2.91 (2H, t, J=7.5 Hz), 2.99 (4H, m), 3.24 (2H, m), 3.87-3.91 (2H, m), 4.05 (2H, m), 6.70-6.73 (2H, m), 6.80 (1H, d, J=7.5 Hz), 7.19 (1H, t, J=7.5 Hz), 7.22-7.25 (1H, m), 7.43 (1H, d, J=8.4 Hz), 7.54 (1H, d, J=2.1 Hz).

実施例７２２

1H-NMR (300MHz, CDCl3)：1.27 (6H, m), 2.99 (4H, m), 3.23 (2H, m), 3.89-3.93 (2H, m), 4.09 (2H, m), 6.43 (1H, d, J=15.9 Hz), 6.92 (1H, dd, J=8.1 Hz, 2.1 Hz), 7.04 (1H, s), 7.14 (1H, d, J=8.1 Hz), 7.24 (1H, dd, J=8.7 Hz, 2.1 Hz), 7.31 (1H, t, J=8,1 Hz), 7.44 (1H, d, J=8.7 Hz), 7.56 (1H, d, J=2.1 Hz), 7.71 (1H, d, J=15.9 Hz).

実施例７２３

1H-NMR (300MHz, CDCl3)：1.35 (6H, m), 2.53 (4H, m), 3.15 (2H, m), 3.71 (3H, s), 3.90-3.94 (2H，m), 4.14 (2H, m), 6.81 (1H, dd, J=8.7 Hz, 2.1 Hz), 7.01-7.02 (2H, m), 7.14 (1H, d, J=8.7 Hz), 7.24 (1H, dd, J=8.7 Hz), 7.44 (1H, d, J=8.7 Hz), 7.54 (1H, d, J=2.1 Hz).

実施例７２４

TLC Rf 0.13(MeOH-CHCl3, 1:10)

実施例７２５

TLC Rf 0.20(MeOH-CHCl3, 1:10)

実施例７２６

TLC Rf 0.30(MeOH-CHCl3, 1:10)

実施例７２７

TLC Rf 0.31(MeOH-CHCl3, 1:10)

実施例７２８

TLC Rf 0.23(MeOH-CHCl3, 1:5)

実施例７２９

MS (ESI) m/z 495 [M+H]+

実施例７３０

MS (ESI) m/z 564 [M+H]+

実施例７３１

MS (ESI) m/z 564 [M+H]+

実施例７３２

MS (ESI) m/z 602 [M+H]+

実施例７３３

MS (ESI) m/z 585 [M+H]+

実施例７３４

MS (ESI) m/z 600 [M+H]+
1H-NMR (DMSO-d6) δ: 1.76(2H, br), 1.99 (4H, br), 2.63(4H, br), 3.55-3.70 (8H, m), 3.70(2H, s), 4.00 (2H, brm), 6.69-6.91 (3H, m), 7.16 (1H, d, J=9.0 Hz), 7.47-7.52 (2H, m).
アモルファス

実施例７３５

MS (ESI) m/z 534 [M+H]+
1H-NMR (DMSO-d6) δ: 1.63-1.70(2H, m), 1.88-1.99(4H, m), 2.55(4H, br), 3.47-3.60(6H, m), 3.54(2H, s), 3.76-3.80(2H, m), 4.02(2H, t, J=7.2Hz), 6.81-6.93(3H, m), 7.17(1H, dd, J=2.1, 8.4 Hz), 7.24(1H, d, J=8.4 Hz), 7.55 (1H, d, J=2.1 Hz)
アモルファス
実施例７３６

MS (ESI) m/z 539 [M+H]+

実施例７３７

MS (ESI) m/z 555 [M+H]+

実施例７３８

MS (ESI) m/z 544 [M+H]+

実施例７３９

MS (ESI) m/z 537 [M+H]+

実施例７４０

MS (ESI) m/z 527 [M+H]+

実施例７４１

MS (ESI) m/z 560 [M+H]+

実施例７４２

MS (ESI) m/z 542 [M+H]+

実施例７４３

MS (ESI) m/z 532 [M+H]+

実施例７４４

MS (ESI) m/z 528 [M+H]+
1H-NMR (DMSO-d6) δ: 1.55-1.62(2H, m), 1.90(4H, br), 2.56(4H, br), 3.55(2H, s), 3.58(6H, br), 3.89-3.93(2H, m), 4.03(2H, d, J=7.2 Hz), 6.82-6.94(4H, m), 7.73-7,77(1H, m), 8.38(1H, brm)
アモルファス

実施例７４５

MS (ESI) m/z 578 [M+H]+

実施例７４６

MS (ESI) m/z 584 [M+H]+

実施例７４７

MS (ESI) m/z 512 [M+H]+

実施例７４８

MS (ESI) m/z 512 [M+H]+

実施例７４９

MS (ESI) m/z 569 [M+H]+
1H-NMR (DMSO-d6) δ: 1.71(6H, br), 1.85-1.98(4H, m), 2.65(4H, br), 3.54(2H, s), 3.54-3.61(2H, m), 3.81(2H, br), 4.04(2H, t, J=7.2 Hz), 6.81-6.91(3H, m), 7.75(1H, d, J=8.4 Hz), 7.85(1H, d, J=8.4 Hz).
アモルファス

実施例７５０

MS (ESI) m/z 569 [M+H]+

実施例７５１

TLC:(SiO2) CHCl3-MeOH(10:1)Rf=0.1

実施例７５２

1H-NMR (DMSO-d6) δ: 7.56 (1.0H, d, J = 1.92 Hz), 7.26 (1.0H, d, J = 8.51 Hz), 7.19 (1.0H, dd, J = 8.51, 4.25 Hz), 7.04 (1.0H, d, J = 7.41 Hz), 6.86 (1.0H, s), 6.71 (1.0H, d, J = 7.41 Hz), 4.06-4.03 (2.0H, m), 3.84-3.80 (2.0H, m), 3.65-3.48 (2.0H, m), 2.68 (4.0H, br s), 2.10 (2.0H, s), 2.03-1.67 (6.0H, m), 1.06 (3.0H, d, J = 6.04 Hz).

実施例７５３

1H-NMR (CDCl3) δ: 7.84-7.82 (1.0H, m), 7.64-7.49 (2.0H, m), 6.93-6.76 (3.0H, m), 4.22-4.11 (1.0H, m), 3.99-3.37 (9.0H, m), 3.31 (3.0H, s), 3.09-2.95 (1.0H, m), 2.89-2.64 (3.0H, m), 2.31-1.12 (8.0H, m).

実施例７５４

1H-NMR (CDCl3) δ: 7.86-7.82 (1.0H, m), 7.59-7.48 (2.0H, m), 6.89-6.85 (1.0H, m), 6.80-6.77 (1.0H, m), 6.73-6.69 (1.0H, m), 4.05 (2.0H, dd, J = 6.59, 6.59 Hz), 3.95-3.87 (1.0H, m), 3.79-3.60 (4.0H, m), 3.56 (2.0H, s), 3.31 (3.0H, s), 3.01 (1.0H, dd, J = 7.68, 5.49 Hz), 2.83-2.69 (3.0H, m), 2.07-1.68 (8.0H, m).

実施例７５５

1H-NMR (CDCl3) δ: 7.83 (1.0H, s), 7.58-7.48 (2.0H, m), 7.07 (1.0H, d, J = 7.41 Hz), 6.79-6.70 (2.0H, m), 4.04 (2.0H, dd, J = 6.59, 6.59 Hz), 3.83-3.56 (6.0H, m), 3.47 (2.0H, dd, J = 6.59, 6.59 Hz), 3.36 (3.0H, s), 2.70 (2.0H, dd, J = 6.59, 6.59 Hz), 2.33 (3.0H, s), 2.17 (3.0H, s), 2.06-1.95 (4.0H, m), 1.84-1.70 (2.0H, m).

実施例７５６

1H-NMR (CDCl3) δ: 7.83 (1.0H, br s), 7.57-7.48 (2.0H, m), 6.68 (1.0H, s), 6.62-6.58 (2.0H, m), 4.00 (2.0H, dd, J = 6.59, 6.59 Hz), 3.82-3.61 (4.0H, m), 3.55 (2.0H, s), 3.47 (2.0H, dd, J = 6.31, 6.31 Hz), 3.35 (3.0H, s), 2.68 (2.0H, dd, J = 6.31, 6.31 Hz), 2.31 (3.0H, s), 2.29 (3.0H, s), 2.04-1.91 (4.0H, m), 1.80-1.66 (2.0H, m).

実施例７５７

1H-NMR (CDCl3) δ: 7.31 (1.0H, d, J = 8.23 Hz), 7.08 (1.0H, s), 6.93-6.87 (1.0H, m), 6.83 (1.0H, dd, J = 8.23, 1.65 Hz), 4.30-4.07 (2.0H, m), 3.89-3.66 (4.0H, m), 3.65-3.55 (4.0H, m), 3.53-3.34 (4.0H, m), 2.87-2.52 (4.0H, m), 2.32-1.62 (6.0H, m).

実施例７５８

1H-NMR (CDCl3) δ: 7.55-7.44 (2.0H, m), 7.31 (1.0H, d, J = 8.23 Hz), 7.19-7.13 (1.0H, m), 6.93-6.80 (2.0H, m), 4.32-4.08 (2.0H, m), 3.91-3.57 (10.0H, m), 2.91-2.51 (4.0H, m), 2.33-1.61 (6.0H, m).

実施例７５９

1H-NMR (DMSO-d6) δ: 8.22 (1.0H, s), 7.59-7.52 (2.0H, m), 7.13 (1.0H, dd, J = 8.51, 8.51 Hz), 6.54-6.49 (1.0H, m), 6.46-6.41 (3.0H, m), 4.57-4.47 (2.0H, m), 4.00 (2.0H, dd, J = 7.14, 7.14 Hz), 3.82-3.67 (2.0H, m), 3.63-3.44 (6.0H, m), 2.60-2.53 (4.0H, m), 2.01 (2.0H, d, J = 12.90 Hz), 1.90 (2.0H, dd, J = 7.14, 7.14 Hz), 1.77-1.63 (2.0H, m).

実施例７６０

1H-NMR (DMSO-d6) δ: 7.55 (1.0H, d, J = 2.20 Hz), 7.30 (1.0H, d, J = 8.23 Hz), 7.24 (1.0H, d, J = 8.23 Hz), 7.20-7.14 (1.0H, m), 7.07 (1.0H, s), 6.82 (1.0H, d, J = 9.61 Hz), 4.12-4.00 (2.0H, m), 3.83-3.71 (2.0H, m), 3.63-3.51 (8.0H, m), 2.58-2.53 (4.0H, m), 2.03-1.89 (4.0H, m), 1.77-1.65 (2.0H, m).

実施例７６１

1H-NMR (DMSO-d6) δ: 12.36 (1.0H, br s), 7.59 (1.0H, s), 7.46 (2.0H, d, J = 7.41 Hz), 7.38-7.31 (3.0H, m), 7.20 (1.0H, dd, J = 7.41, 7.41 Hz), 7.10 (1.0H, d, J = 1.65 Hz), 6.83 (1.0H, dd, J = 7.41, 1.65 Hz), 4.11 (2.0H, dd, J = 6.59, 6.59 Hz), 3.63-3.53 (8.0H, m), 3.47-3.39 (2.0H, m), 2.60-2.53 (4.0H, m), 2.05-1.90 (4.0H, m), 1.80-1.66 (2.0H, m).

実施例７６２

1H-NMR (DMSO-d6) δ: 7.70 (1.0H, s), 7.42-7.30 (3.0H, m), 7.25 (1.0H, d, J = 8.23 Hz), 7.10 (1.0H, d, J = 1.92 Hz), 7.06-6.97 (1.0H, m), 6.83 (1.0H, dd, J = 8.23, 1.92 Hz), 4.11 (2.0H, dd, J = 6.59, 6.59 Hz), 3.63-3.54 (8.0H, m), 3.47-3.40 (2.0H, m), 2.60-2.53 (4.0H, m), 2.06-1.90 (4.0H, m), 1.80-1.66 (2.0H, m).

実施例７６３

1H-NMR (CDCl3) δ: 8.29 (2.0H, s), 7.31 (1.0H, d, J = 8.23 Hz), 6.91 (1.0H, s), 6.85-6.82 (1.0H, m), 4.31-4.16 (2.0H, m), 4.00-3.70 (6.0H, m), 3.69-3.60 (4.0H, m), 2.98-2.69 (4.0H, m), 2.29-1.60 (6.0H, m).

実施例７６４

1H-NMR (DMSO-d6) δ: 8.23 (1.0H, d, J = 7.41 Hz), 7.44 (1.0H, d, J = 12.35 Hz), 7.31 (1.0H, d, J = 8.23 Hz), 7.08 (1.0H, d, J = 2.20 Hz), 6.82 (1.0H, dd, J = 8.23, 2.20 Hz), 4.10 (2.0H, dd, J = 7.14, 7.14 Hz), 3.65-3.50 (6.0H, m), 3.49-3.12 (4.0H, m), 2.60-2.53 (4.0H, m), 2.10-1.89 (4.0H, m), 1.82-1.68 (2.0H, m).

実施例７６５

1H-NMR (DMSO-d6) δ: 7.86 (1.0H, d, J = 8.51 Hz), 7.76 (1.0H, d, J = 8.51 Hz), 7.31 (1.0H, d, J = 7.96 Hz), 7.08 (1.0H, d, J = 1.92 Hz), 6.83 (1.0H, dd, J = 7.96, 1.92 Hz), 4.10 (2.0H, dd, J = 6.86, 6.86 Hz), 3.67-3.52 (6.0H, m), 3.44-3.22 (4.0H, m), 2.62-2.54 (4.0H, m), 2.10-1.92 (4.0H, m), 1.83-1.68 (2.0H, m).

実施例７６６

1H-NMR (DMSO-d6) δ: 7.83 (1.0H, s), 7.71-7.67 (1.0H, m), 7.33-7.31 (2.0H, m), 7.09 (1.0H, s), 6.83 (1.0H, d, J = 7.96 Hz), 6.78 (1.0H, s), 4.10 (2.0H, dd, J = 6.86, 6.86 Hz), 3.63-3.46 (6.0H, m), 3.45-3.24 (4.0H, m), 2.61-2.52 (4.0H, m), 2.03-1.89 (4.0H, m), 1.78-1.65 (2.0H, m), 1.04 (2.7H, d, J = 6.04 Hz).

実施例７６７

1H-NMR (DMSO-d6) δ: 12.37 (1.0H, br s), 8.61 (2.0H, s), 8.10 (1.0H, s), 7.75-7.72 (1.0H, m), 7.32 (1.0H, d, J = 8.23 Hz), 7.08 (1.0H, s), 6.93 (1.0H, s), 6.82 (1.0H, d, J = 8.23 Hz), 4.16-3.96 (4.0H, m), 3.64-3.47 (8.0H, m), 2.62-2.53 (4.0H, m), 2.00-1.86 (4.0H, m), 1.67-1.52 (2.0H, m).

実施例７６８

1H-NMR (DMSO-d6) δ: 12.40 (1.0H, br s), 8.69 (2.0H, s), 7.63 (2.0H, d, J = 7.72 Hz), 7.43 (2.0H, dd, J = 7.72, 7.72 Hz), 7.34-7.31 (2.0H, m), 7.08 (1.0H, d, J = 1.85 Hz), 6.82 (1.0H, dd, J = 8.23, 1.85 Hz), 4.20-4.06 (4.0H, m), 3.63-3.52 (8.0H, m), 2.62-2.54 (4.0H, m), 2.02-1.87 (4.0H, m), 1.68-1.54 (2.0H, m).

実施例７６９

1H-NMR (DMSO-d6) δ: 8.73 (2.0H, s), 7.57-7.42 (3.0H, m), 7.31 (1.0H, d, J = 8.23 Hz), 7.19-7.07 (2.0H, m), 6.82 (1.0H, d, J = 8.23 Hz), 4.20-4.06 (4.0H, m), 3.63-3.51 (8.0H, m), 2.63-2.55 (4.0H, m), 2.01-1.87 (4.0H, m), 1.67-1.54 (2.0H, m).

実施例７７０

1H-NMR (DMSO-d6) δ: 8.21 (1.0H, s), 7.58-7.51 (2.0H, m), 7.12 (1.0H, dd, J = 8.56, 8.56 Hz), 6.54-6.40 (2.0H, m), 4.56-4.41 (1.0H, m), 4.08-3.97 (3.0H, m), 3.84-3.69 (2.0H, m), 3.59-3.46 (2.0H, m), 2.71-2.60 (4.0H, m), 2.00-1.81 (4.0H, m), 1.79-1.65 (6.0H, m).

実施例７７１

1H-NMR (CDCl3) δ: 7.85 (1.0H, s), 7.62-7.49 (2.0H, m), 7.31-7.20 (1.0H, m), 6.94-6.76 (3.0H, m), 4.14-3.95 (2.0H, m), 3.84-3.58 (8.0H, m), 2.72-2.55 (4.0H, m), 2.12-1.90 (4.0H, m), 1.88-1.69 (2.0H, m). Example 679

TLC Rf 0.13 (MeOH-CHCl3, 1:10)

Example 680

mp 109-112

Example 681

mp 92-98

Example 682

TLC Rf 0.15 (MeOH-CHCl3, 1:10)

Example 683

TLC Rf 0.23 (MeOH-CHCl3, 1:10)

Example 684

Rf 0.12 (MeOH-CHCl3, 1:10)

Example 685

Rf 0.24 (MeOH-CHCl3, 1:10)

Example 686

MS (ESI) m / z 480 [M + H] +

Example 687

MS (ESI) m / z 480 [M + H] +

Example 688

MS (ESI) m / z 479 [M + H] +

Example 689

MS (ESI) m / z 514, 516 [M + H] +

Example 690

MS (ESI) m / z 514, 516 [M + H] +

Example 691

MS (ESI) m / z 494 [M + H] +

Example 692

MS (ESI) m / z 494 [M + H] +

Example 693

MS (ESI) m / z 528, 530 [M + H] +
1H-NMR (DMSO-d6) δ: 0.93 (3H, t, J = 7.5 Hz), 1.46-1.69 (2H, m), 2.64-2.71 (2H, m), 2.86-2.91 (1H, m), 3.05 -3.09 (2H, m), 3.50-3.53 (2H, m), 3/57 (2H, s), 3.68-3.77 (2H, m), 4.15 (2H, t, J = 5.7 Hz), 6.84 (1H , dd, J = 1.8, 8.1 Hz), 7.10 (1H, d, J = 1.8 Hz), 7.34 (1H, d, J = 8.1 Hz), 7.56-7.57 (2H, m), 8.23 (1H, s)
amorphous

Example 694

MS (ESI) m / z 528, 530 [M + H] +

Example 695

MS (ESI) m / z 508 [M + H] +

Example 696

MS (ESI) m / z 508 [M + H] +

Example 697

MS (ESI) m / z 480 [M + H] +

Example 698

1H-NMR (300MHz, CDCl3): 1.46 (3H, d, J = 6.9 Hz), 2.53-2.60 (1H, m), 2.73-2.77 (1H, m), 3.06 (2H, s), 3.16-3.20 ( 1H, m), 3.27-3.31 (1H, m), 3.55-3.60 (1H, m), 3.60 (2H, s), 3.89-3.94 (1H, m), 4.29 (3H, m), 6.84 (1H, d, J = 8.1 Hz), 6.87 (1H, s), 7.25 (1H, dd, J = 8.7 Hz, 2.1 Hz), 7.31 (1H, d, J = 8.1 Hz), 7.44 (1H, d, J = 8.7 Hz), 7.56 (1H, d, J = 2.1 Hz)

Example 699

MS (ESI) m / z 494 [M + H] +

Example 700

MS (ESI) m / z 528 [M + H] +

Example 701

MS (ESI) m / z 508 [M + H] +

Example 702

MS (ESI) m / z 528 [M + H] +

Example 703

MS (ESI) m / z 474, 476, 478 [M + H] +

Example 704

1H-NMR (DMSO-d6) δ: 1.18 (6H, d, J = 4.7 Hz), 2.80-2.95 (4H, m), 3.10-3.19 (2H, m), 3.55 (2H, s), 3.85 (2H , d, J = 9.9 Hz), 4.03-4.11 (2H, m), 6.83 (1H, d, J = 8.2 Hz), 7.02-7.11 (2H, m), 7.22-7.48 (3H, m), 7.75 ( 1H, d, J = 8.0 Hz).

Example 705

1H-NMR (DMSO-d6) δ: 1.16 (6H, d, J = 5.8 Hz), 2.61-2.85 (5H, m), 3.07-3.16 (3H, m), 3.55 (2H, s), 3.89-4.11 (5H, m), 6.79-7.36 (8H, m).

Example 706

1H-NMR (DMSO-d6) δ: 1.22 (6H, d, J = 6.0 Hz), 2.58-2.84 (4H, m), 3.09-3.19 (2H, m), 3.52 (2H, s), 4.06-4.14 (2H, m), 4.34-4.46 (2H, m), 6.84 (1H, d, J = 8.2 Hz), 7.09-7.74 (7H, m), 8.03 (1H, d, J = 9.1 Hz).

Example 707

1H-NMR (Acetone) δ: 8.38-8.35 (1.0H, m), 7.71 (1.0H, dd, J = 9.34, 2.20 Hz), 7.31 (1.0H, dd, J = 7.97, 1.65 Hz), 7.13 ( 1.0H, d, J = 1.92 Hz), 6.97-6.87 (2.0H, m), 4.33 (2.0H, d, J = 12.64 Hz), 4.17 (2.0H, dd, J = 5.91, 5.91 Hz), 3.61 (2.0H, s), 3.25-3.23 (2.0H, m), 2.83-2.67 (4.0H, m), 1.24 (6.0H, d, J = 6.00 Hz).

Example 708

1H-NMR (DMSO-d6) δ: 8.66 (1.0H, d, J = 4.94 Hz), 7.31 (1.0H, d, J = 8.10 Hz), 7.08 (1.0H, s), 6.99 (1.0H, d , J = 4.94 Hz), 6.82 (1.0H, d, J = 8.10 Hz), 4.45 (2.0H, d, J = 8.24 Hz), 4.08-3.99 (3.0H, m), 3.53 (2.0H, s) , 3.13 (2.0H, dd, J = 5.63, 5.63 Hz), 2.76-2.65 (4.0H, m), 1.16 (6.0H, d, J = 6.32 Hz).

Example 709

1H-NMR (Acetone) δ: 8.14 (1.0H, d, J = 2.54 Hz), 7.60 (1.0H, dd, J = 9.13, 2.54 Hz), 7.40 (1.0H, s), 7.34 (1.0H, d , J = 7.69 Hz), 7.25 (1.0H, dd, J = 7.69, 7.69 Hz), 7.15 (1.0H, d, J = 7.69 Hz), 6.81 (1.0H, d, J = 9.13 Hz), 4.13 ( 2.0H, d, J = 11.54 Hz), 3.81 (2.0H, s), 3.62 (2.0H, s), 2.76-2.62 (4.0H, m), 1.07 (6.0H, d, J = 5.77 Hz).

Example 710

1H-NMR (DMSO-d6) δ: 1.14 (6H, d, J = 5.1 Hz), 2.60-2.76 (2H, m), 3.00-3.10 (2H, m), 3.55 (2H, s), 3.97-4.06 (2H, m), 4.46-4.60 (2H, m), 6.80-6.96 (3H, m), 7.30-7.67 (3H, m), 8.69 (2H, s).

Example 711

1H-NMR (DMSO-d6) δ: 7.18-7.18 (1.0H, m), 7.04 (1.0H, d, J = 7.28 Hz), 6.84 (1.0H, s), 6.71 (1.0H, d, J = 7.28 Hz), 3.98 (2.0H, dd, J = 5.10, 5.10 Hz), 3.64 (2.0H, d, J = 10.99 Hz), 3.48 (2.0H, s), 3.10 (2.0H, dd, J = 5.10 , 5.10 Hz), 2.84-2.69 (4.0H, m), 2.11 (3.0H, s), 1.14 (6.0H, d, J = 5.77 Hz).

Example 712

1H-NMR (Acetone) δ: 8.12 (1.0H, d, J = 2.68 Hz), 7.59 (1.0H, dd, J = 9.13, 2.68 Hz), 7.32 (1.0H, d, J = 8.11 Hz), 7.13 (1.0H, d, J = 1.92 Hz), 6.90 (1.0H, dd, J = 8.11, 1.92 Hz), 6.80 (1.0H, d, J = 9.13 Hz), 4.18-4.13 (4.0H, m), 3.63 (2.0H, s), 3.22 (2.0H, dd, J = 6.04, 6.04 Hz), 2.85-2.78 (2.0H, m), 2.62-2.53 (2.0H, m), 1.23 (6.0H, d, J = 6.04 Hz).

Example 713

1H-NMR (Acetone) δ: 8.34 (2.0H, s), 7.30 (1.0H, d, J = 8.04 Hz), 7.13 (1.0H, d, J = 1.65 Hz), 6.90 (1.0H, dd, J = 8.04, 1.65 Hz), 4.49 (2.0H, d, J = 12.36 Hz), 4.15 (2.0H, dd, J = 5.91, 5.91 Hz), 3.60 (2.0H, s), 3.23 (2.0H, dd, J = 6.04, 6.04 Hz), 2.82-2.60 (4.0H, m), 1.22 (6.0H, d, J = 6.04 Hz).

Example 714

1H-NMR (DMSO-d6) δ: 8.44 (2.0H, s), 6.61 (3.0H, s), 4.43-4.33 (2.0H, m), 3.95 (2.0H, dd, J = 6.59, 6.59 Hz) , 3.43 (2.0H, s), 3.03 (2.0H, dd, J = 6.00, 6.00 Hz), 2.63 (4.0H, d, J = 6.90 Hz), 2.23 (3.0H, s), 1.12 (6.0H, d, J = 5.22 Hz).

Example 715

1H-NMR (DMSO-d6) δ: 1.23-1.41 (2H, m), 1.70-1.92 (5H, m), 3.09-3.23 (2H, m), 3.57 (2H, s), 3.98-4.15 (4H, m), 6.81-7.46 (6H, m), 7.74 (1H, d, J = 8.0 Hz).

Example 716

1H-NMR (Acetone) δ: 8.37 (1.0H, s), 7.71 (1.0H, dd, J = 9.06, 2.47 Hz), 7.33 (1.0H, d, J = 7.97 Hz), 7.12 (1.0H, d , J = 1.65 Hz), 6.93-6.89 (2.0H, m), 4.55-4.50 (2.0H, m), 4.19 (2.0H, dd, J = 6.32, 6.32 Hz), 3.62 (2.0H, s), 2.96-2.92 (3.0H, m), 1.96-1.79 (4.0H, m), 1.37-1.24 (2.0H, m).

Example 717

1H-NMR (DMSO-d6) δ: 8.65 (1.0H, d, J = 4.67 Hz), 7.33 (1.0H, d, J = 8.11 Hz), 7.08 (1.0H, s), 6.95 (1.0H, d , J = 4.67 Hz), 6.83 (1.0H, d, J = 8.11 Hz), 4.64 (2.0H, d, J = 12.42 Hz), 4.10 (2.0H, dd, J = 6.59, 6.59 Hz), 3.55 ( 2.0H, s), 3.40-3.25 (1.0H, m), 2.96 (2.0H, dd, J = 12.42, 12.42 Hz), 1.91-1.72 (4.0H, m), 1.24-1.15 (2.0H, m) .

Example 718

1H-NMR (DMSO-d6) δ: 1.13-1.36 (2H, m), 1.67-1.87 (5H, m), 2.86-3.00 (2H, m), 3.56 (2H, s), 4.05-4.16 (5H, m), 6.80-7.36 (7H, m).

Example 719

1H-NMR (300MHz, CDCl3): 1.40 (6H, m), 3.27-3.44 (6H, m), 3.93-3.98 (2H, m), 4.14 (2H, m), 4.53 (2H, s), 6.47- 6.55 (3H, m), 7.13-7.26 (2H, m), 7.43 (1H, d, J = 8.1 Hz), 7.55 (1H, s).

Example 720

1H-NMR (300MHz, CDCl3): 1.98-2.17 (5H, m), 3.21-3.29 (2H, m), 3.84 (2H, d, J = 6.0 Hz), 4.23 (2H, m), 4.65 (2H, s), 6.49-6.56 (3H, m), 7.20 (1H, t, J = 8.1 Hz), 7.26-7.29 (2H, m), 7.55 (1H, d, J = 2.1 Hz)

Example 721

1H-NMR (300MHz, CDCl3): 1.28 (6H, m), 2.64 (2H, t, J = 7.5 Hz), 2.91 (2H, t, J = 7.5 Hz), 2.99 (4H, m), 3.24 (2H , m), 3.87-3.91 (2H, m), 4.05 (2H, m), 6.70-6.73 (2H, m), 6.80 (1H, d, J = 7.5 Hz), 7.19 (1H, t, J = 7.5 Hz), 7.22-7.25 (1H, m), 7.43 (1H, d, J = 8.4 Hz), 7.54 (1H, d, J = 2.1 Hz).

Example 722

1H-NMR (300MHz, CDCl3): 1.27 (6H, m), 2.99 (4H, m), 3.23 (2H, m), 3.89-3.93 (2H, m), 4.09 (2H, m), 6.43 (1H, d, J = 15.9 Hz), 6.92 (1H, dd, J = 8.1 Hz, 2.1 Hz), 7.04 (1H, s), 7.14 (1H, d, J = 8.1 Hz), 7.24 (1H, dd, J = 8.7 Hz, 2.1 Hz), 7.31 (1H, t, J = 8,1 Hz), 7.44 (1H, d, J = 8.7 Hz), 7.56 (1H, d, J = 2.1 Hz), 7.71 (1H, d , J = 15.9 Hz).

Example 723

1H-NMR (300MHz, CDCl3): 1.35 (6H, m), 2.53 (4H, m), 3.15 (2H, m), 3.71 (3H, s), 3.90-3.94 (2H, m), 4.14 (2H, m), 6.81 (1H, dd, J = 8.7 Hz, 2.1 Hz), 7.01-7.02 (2H, m), 7.14 (1H, d, J = 8.7 Hz), 7.24 (1H, dd, J = 8.7 Hz) , 7.44 (1H, d, J = 8.7 Hz), 7.54 (1H, d, J = 2.1 Hz).

Example 724

TLC Rf 0.13 (MeOH-CHCl3, 1:10)

Example 725

TLC Rf 0.20 (MeOH-CHCl3, 1:10)

Example 726

TLC Rf 0.30 (MeOH-CHCl3, 1:10)

Example 727

TLC Rf 0.31 (MeOH-CHCl3, 1:10)

Example 728

TLC Rf 0.23 (MeOH-CHCl3, 1: 5)

Example 729

MS (ESI) m / z 495 [M + H] +

Example 730

MS (ESI) m / z 564 [M + H] +

Example 731

MS (ESI) m / z 564 [M + H] +

Example 732

MS (ESI) m / z 602 [M + H] +

Example 733

MS (ESI) m / z 585 [M + H] +

Example 734

MS (ESI) m / z 600 [M + H] +
1H-NMR (DMSO-d6) δ: 1.76 (2H, br), 1.99 (4H, br), 2.63 (4H, br), 3.55-3.70 (8H, m), 3.70 (2H, s), 4.00 (2H , brm), 6.69-6.91 (3H, m), 7.16 (1H, d, J = 9.0 Hz), 7.47-7.52 (2H, m).
amorphous

Example 735

MS (ESI) m / z 534 [M + H] +
1H-NMR (DMSO-d6) δ: 1.63-1.70 (2H, m), 1.88-1.99 (4H, m), 2.55 (4H, br), 3.47-3.60 (6H, m), 3.54 (2H, s) , 3.76-3.80 (2H, m), 4.02 (2H, t, J = 7.2Hz), 6.81-6.93 (3H, m), 7.17 (1H, dd, J = 2.1, 8.4 Hz), 7.24 (1H, d , J = 8.4 Hz), 7.55 (1H, d, J = 2.1 Hz)
Amorphous Example 736

MS (ESI) m / z 539 [M + H] +

Example 737

MS (ESI) m / z 555 [M + H] +

Example 738

MS (ESI) m / z 544 [M + H] +

Example 739

MS (ESI) m / z 537 [M + H] +

Example 740

MS (ESI) m / z 527 [M + H] +

Example 741

MS (ESI) m / z 560 [M + H] +

Example 742

MS (ESI) m / z 542 [M + H] +

Example 743

MS (ESI) m / z 532 [M + H] +

Example 744

MS (ESI) m / z 528 [M + H] +
1H-NMR (DMSO-d6) δ: 1.55-1.62 (2H, m), 1.90 (4H, br), 2.56 (4H, br), 3.55 (2H, s), 3.58 (6H, br), 3.89-3.93 (2H, m), 4.03 (2H, d, J = 7.2 Hz), 6.82-6.94 (4H, m), 7.73-7,77 (1H, m), 8.38 (1H, brm)
amorphous

Example 745

MS (ESI) m / z 578 [M + H] +

Example 746

MS (ESI) m / z 584 [M + H] +

Example 747

MS (ESI) m / z 512 [M + H] +

Example 748

MS (ESI) m / z 512 [M + H] +

Example 749

MS (ESI) m / z 569 [M + H] +
1H-NMR (DMSO-d6) δ: 1.71 (6H, br), 1.85-1.98 (4H, m), 2.65 (4H, br), 3.54 (2H, s), 3.54-3.61 (2H, m), 3.81 (2H, br), 4.04 (2H, t, J = 7.2 Hz), 6.81-6.91 (3H, m), 7.75 (1H, d, J = 8.4 Hz), 7.85 (1H, d, J = 8.4 Hz) .
amorphous

Example 750

MS (ESI) m / z 569 [M + H] +

Example 751

TLC: (SiO2) CHCl3-MeOH (10: 1) Rf = 0.1

Example 752

1H-NMR (DMSO-d6) δ: 7.56 (1.0H, d, J = 1.92 Hz), 7.26 (1.0H, d, J = 8.51 Hz), 7.19 (1.0H, dd, J = 8.51, 4.25 Hz) , 7.04 (1.0H, d, J = 7.41 Hz), 6.86 (1.0H, s), 6.71 (1.0H, d, J = 7.41 Hz), 4.06-4.03 (2.0H, m), 3.84-3.80 (2.0 H, m), 3.65-3.48 (2.0H, m), 2.68 (4.0H, br s), 2.10 (2.0H, s), 2.03-1.67 (6.0H, m), 1.06 (3.0H, d, J = 6.04 Hz).

Example 753

1H-NMR (CDCl3) δ: 7.84-7.82 (1.0H, m), 7.64-7.49 (2.0H, m), 6.93-6.76 (3.0H, m), 4.22-4.11 (1.0H, m), 3.99- 3.37 (9.0H, m), 3.31 (3.0H, s), 3.09-2.95 (1.0H, m), 2.89-2.64 (3.0H, m), 2.31-1.12 (8.0H, m).

Example 754

1H-NMR (CDCl3) δ: 7.86-7.82 (1.0H, m), 7.59-7.48 (2.0H, m), 6.89-6.85 (1.0H, m), 6.80-6.77 (1.0H, m), 6.73- 6.69 (1.0H, m), 4.05 (2.0H, dd, J = 6.59, 6.59 Hz), 3.95-3.87 (1.0H, m), 3.79-3.60 (4.0H, m), 3.56 (2.0H, s) , 3.31 (3.0H, s), 3.01 (1.0H, dd, J = 7.68, 5.49 Hz), 2.83-2.69 (3.0H, m), 2.07-1.68 (8.0H, m).

Example 755

1H-NMR (CDCl3) δ: 7.83 (1.0H, s), 7.58-7.48 (2.0H, m), 7.07 (1.0H, d, J = 7.41 Hz), 6.79-6.70 (2.0H, m), 4.04 (2.0H, dd, J = 6.59, 6.59 Hz), 3.83-3.56 (6.0H, m), 3.47 (2.0H, dd, J = 6.59, 6.59 Hz), 3.36 (3.0H, s), 2.70 (2.0 H, dd, J = 6.59, 6.59 Hz), 2.33 (3.0H, s), 2.17 (3.0H, s), 2.06-1.95 (4.0H, m), 1.84-1.70 (2.0H, m).

Example 756

1H-NMR (CDCl3) δ: 7.83 (1.0H, br s), 7.57-7.48 (2.0H, m), 6.68 (1.0H, s), 6.62-6.58 (2.0H, m), 4.00 (2.0H, dd, J = 6.59, 6.59 Hz), 3.82-3.61 (4.0H, m), 3.55 (2.0H, s), 3.47 (2.0H, dd, J = 6.31, 6.31 Hz), 3.35 (3.0H, s) , 2.68 (2.0H, dd, J = 6.31, 6.31 Hz), 2.31 (3.0H, s), 2.29 (3.0H, s), 2.04-1.91 (4.0H, m), 1.80-1.66 (2.0H, m ).

Example 757

1H-NMR (CDCl3) δ: 7.31 (1.0H, d, J = 8.23 Hz), 7.08 (1.0H, s), 6.93-6.87 (1.0H, m), 6.83 (1.0H, dd, J = 8.23, 1.65 Hz), 4.30-4.07 (2.0H, m), 3.89-3.66 (4.0H, m), 3.65-3.55 (4.0H, m), 3.53-3.34 (4.0H, m), 2.87-2.52 (4.0H , m), 2.32-1.62 (6.0H, m).

Example 758

1H-NMR (CDCl3) δ: 7.55-7.44 (2.0H, m), 7.31 (1.0H, d, J = 8.23 Hz), 7.19-7.13 (1.0H, m), 6.93-6.80 (2.0H, m) , 4.32-4.08 (2.0H, m), 3.91-3.57 (10.0H, m), 2.91-2.51 (4.0H, m), 2.33-1.61 (6.0H, m).

Example 759

1H-NMR (DMSO-d6) δ: 8.22 (1.0H, s), 7.59-7.52 (2.0H, m), 7.13 (1.0H, dd, J = 8.51, 8.51 Hz), 6.54-6.49 (1.0H, m), 6.46-6.41 (3.0H, m), 4.57-4.47 (2.0H, m), 4.00 (2.0H, dd, J = 7.14, 7.14 Hz), 3.82-3.67 (2.0H, m), 3.63- 3.44 (6.0H, m), 2.60-2.53 (4.0H, m), 2.01 (2.0H, d, J = 12.90 Hz), 1.90 (2.0H, dd, J = 7.14, 7.14 Hz), 1.77-1.63 ( 2.0H, m).

Example 760

1H-NMR (DMSO-d6) δ: 7.55 (1.0H, d, J = 2.20 Hz), 7.30 (1.0H, d, J = 8.23 Hz), 7.24 (1.0H, d, J = 8.23 Hz), 7.20 -7.14 (1.0H, m), 7.07 (1.0H, s), 6.82 (1.0H, d, J = 9.61 Hz), 4.12-4.00 (2.0H, m), 3.83-3.71 (2.0H, m), 3.63-3.51 (8.0H, m), 2.58-2.53 (4.0H, m), 2.03-1.89 (4.0H, m), 1.77-1.65 (2.0H, m).

Example 761

1H-NMR (DMSO-d6) δ: 12.36 (1.0H, br s), 7.59 (1.0H, s), 7.46 (2.0H, d, J = 7.41 Hz), 7.38-7.31 (3.0H, m), 7.20 (1.0H, dd, J = 7.41, 7.41 Hz), 7.10 (1.0H, d, J = 1.65 Hz), 6.83 (1.0H, dd, J = 7.41, 1.65 Hz), 4.11 (2.0H, dd, J = 6.59, 6.59 Hz), 3.63-3.53 (8.0H, m), 3.47-3.39 (2.0H, m), 2.60-2.53 (4.0H, m), 2.05-1.90 (4.0H, m), 1.80- 1.66 (2.0H, m).

Example 762

1H-NMR (DMSO-d6) δ: 7.70 (1.0H, s), 7.42-7.30 (3.0H, m), 7.25 (1.0H, d, J = 8.23 Hz), 7.10 (1.0H, d, J = 1.92 Hz), 7.06-6.97 (1.0H, m), 6.83 (1.0H, dd, J = 8.23, 1.92 Hz), 4.11 (2.0H, dd, J = 6.59, 6.59 Hz), 3.63-3.54 (8.0H , m), 3.47-3.40 (2.0H, m), 2.60-2.53 (4.0H, m), 2.06-1.90 (4.0H, m), 1.80-1.66 (2.0H, m).

Example 763

1H-NMR (CDCl3) δ: 8.29 (2.0H, s), 7.31 (1.0H, d, J = 8.23 Hz), 6.91 (1.0H, s), 6.85-6.82 (1.0H, m), 4.31-4.16 (2.0H, m), 4.00-3.70 (6.0H, m), 3.69-3.60 (4.0H, m), 2.98-2.69 (4.0H, m), 2.29-1.60 (6.0H, m).

Example 764

1H-NMR (DMSO-d6) δ: 8.23 (1.0H, d, J = 7.41 Hz), 7.44 (1.0H, d, J = 12.35 Hz), 7.31 (1.0H, d, J = 8.23 Hz), 7.08 (1.0H, d, J = 2.20 Hz), 6.82 (1.0H, dd, J = 8.23, 2.20 Hz), 4.10 (2.0H, dd, J = 7.14, 7.14 Hz), 3.65-3.50 (6.0H, m ), 3.49-3.12 (4.0H, m), 2.60-2.53 (4.0H, m), 2.10-1.89 (4.0H, m), 1.82-1.68 (2.0H, m).

Example 765

1H-NMR (DMSO-d6) δ: 7.86 (1.0H, d, J = 8.51 Hz), 7.76 (1.0H, d, J = 8.51 Hz), 7.31 (1.0H, d, J = 7.96 Hz), 7.08 (1.0H, d, J = 1.92 Hz), 6.83 (1.0H, dd, J = 7.96, 1.92 Hz), 4.10 (2.0H, dd, J = 6.86, 6.86 Hz), 3.67-3.52 (6.0H, m ), 3.44-3.22 (4.0H, m), 2.62-2.54 (4.0H, m), 2.10-1.92 (4.0H, m), 1.83-1.68 (2.0H, m).

Example 766

1H-NMR (DMSO-d6) δ: 7.83 (1.0H, s), 7.71-7.67 (1.0H, m), 7.33-7.31 (2.0H, m), 7.09 (1.0H, s), 6.83 (1.0H , d, J = 7.96 Hz), 6.78 (1.0H, s), 4.10 (2.0H, dd, J = 6.86, 6.86 Hz), 3.63-3.46 (6.0H, m), 3.45-3.24 (4.0H, m ), 2.61-2.52 (4.0H, m), 2.03-1.89 (4.0H, m), 1.78-1.65 (2.0H, m), 1.04 (2.7H, d, J = 6.04 Hz).

Example 767

1H-NMR (DMSO-d6) δ: 12.37 (1.0H, br s), 8.61 (2.0H, s), 8.10 (1.0H, s), 7.75-7.72 (1.0H, m), 7.32 (1.0H, d, J = 8.23 Hz), 7.08 (1.0H, s), 6.93 (1.0H, s), 6.82 (1.0H, d, J = 8.23 Hz), 4.16-3.96 (4.0H, m), 3.64-3.47 (8.0H, m), 2.62-2.53 (4.0H, m), 2.00-1.86 (4.0H, m), 1.67-1.52 (2.0H, m).

Example 768

1H-NMR (DMSO-d6) δ: 12.40 (1.0H, br s), 8.69 (2.0H, s), 7.63 (2.0H, d, J = 7.72 Hz), 7.43 (2.0H, dd, J = 7.72 , 7.72 Hz), 7.34-7.31 (2.0H, m), 7.08 (1.0H, d, J = 1.85 Hz), 6.82 (1.0H, dd, J = 8.23, 1.85 Hz), 4.20-4.06 (4.0H, m), 3.63-3.52 (8.0H, m), 2.62-2.54 (4.0H, m), 2.02-1.87 (4.0H, m), 1.68-1.54 (2.0H, m).

Example 769

1H-NMR (DMSO-d6) δ: 8.73 (2.0H, s), 7.57-7.42 (3.0H, m), 7.31 (1.0H, d, J = 8.23 Hz), 7.19-7.07 (2.0H, m) , 6.82 (1.0H, d, J = 8.23 Hz), 4.20-4.06 (4.0H, m), 3.63-3.51 (8.0H, m), 2.63-2.55 (4.0H, m), 2.01-1.87 (4.0H , m), 1.67-1.54 (2.0H, m).

Example 770

1H-NMR (DMSO-d6) δ: 8.21 (1.0H, s), 7.58-7.51 (2.0H, m), 7.12 (1.0H, dd, J = 8.56, 8.56 Hz), 6.54-6.40 (2.0H, m), 4.56-4.41 (1.0H, m), 4.08-3.97 (3.0H, m), 3.84-3.69 (2.0H, m), 3.59-3.46 (2.0H, m), 2.71-2.60 (4.0H, m), 2.00-1.81 (4.0H, m), 1.79-1.65 (6.0H, m).

Example 771

1H-NMR (CDCl3) δ: 7.85 (1.0H, s), 7.62-7.49 (2.0H, m), 7.31-7.20 (1.0H, m), 6.94-6.76 (3.0H, m), 4.14-3.95 ( 2.0H, m), 3.84-3.58 (8.0H, m), 2.72-2.55 (4.0H, m), 2.12-1.90 (4.0H, m), 1.88-1.69 (2.0H, m).

4-シアノピペリジン-1-カルボン酸t-ブチルエステル(5.35g)をトリフルオロ酢酸(20mL)に加え、室温で10分間攪拌した。減圧下トリフルオロ酢酸を留去し、無色結晶として表記化合物（5.62g）を得た。収率99%。
¹H-NMR (DMSO-d₆) δ: 1.83-1.96 (2H, m), 2.08-2.14 (2H, m), 3.00-3.08 (2H, m), 3.14-3.26 (2H, m), 3.41 (1H, br s). Reference Example 258
Production of piperidine-4-carbonitrile trifluoroacetate

4-Cyanopiperidine-1-carboxylic acid t-butyl ester (5.35 g) was added to trifluoroacetic acid (20 mL), and the mixture was stirred at room temperature for 10 minutes. Trifluoroacetic acid was distilled off under reduced pressure to obtain the title compound (5.62 g) as colorless crystals. Yield 99%.
¹ H-NMR (DMSO-d ₆ ) δ: 1.83-1.96 (2H, m), 2.08-2.14 (2H, m), 3.00-3.08 (2H, m), 3.14-3.26 (2H, m), 3.41 ( 1H, br s).

2-クロロ-6-トリフルオロベンゾチアゾール(5.84g)、ピペリジン-4-カルボニトリル トリフルオロ酢酸塩(5.62g)、炭酸カリウム(10.39g)、ジメチルスルホキシド(50mL)を60℃で6時間攪拌した。反応液に水を加え、酢酸エチルで抽出した。有機層を水、飽和食塩水で洗浄後、硫酸マグネシウムで乾燥した。減圧下溶媒を留去し、残渣をイソプロピルエーテルで洗浄し、無色結晶の表記化合物(6.84g)を得た。収率89%。
¹H-NMR (CDCl₃) δ: 1.99-2.17 (4H, m), 2.97-3.05 (1H, m), 3.68-3.76 (2H, m), 3.87-3.95 (2H, m), 7.55-7.63 (2H, m), 7.89-7.90 (1H, m). Reference Example 259
Preparation of 1- (6-trifluoromethylbenzothiazol-2-yl) piperidine-4-carbonitrile

2-Chloro-6-trifluorobenzothiazole (5.84 g), piperidine-4-carbonitrile trifluoroacetate (5.62 g), potassium carbonate (10.39 g), dimethyl sulfoxide (50 mL) were stirred at 60 ° C. for 6 hours. . Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was washed with isopropyl ether to obtain the title compound (6.84 g) as colorless crystals. Yield 89%.
¹ H-NMR (CDCl ₃ ) δ: 1.99-2.17 (4H, m), 2.97-3.05 (1H, m), 3.68-3.76 (2H, m), 3.87-3.95 (2H, m), 7.55-7.63 ( 2H, m), 7.89-7.90 (1H, m).

1-(6-トリフルオロメチルベンゾチアゾール-2-イル)ピペリジン-4-カルボニトリル(1.00g)のテトラヒドロフラン(10mL)溶液に、-15℃でリチウムビス（トリメチルシリル）アミド(3.21mL)を加えた。反応液に (2-ブロモエトキシ)-t-ブチルジメチルシラン(689μL)を加え0℃で3時間攪拌した。反応液に飽和食塩水を加え、酢酸エチルで抽出した。有機層を水、飽和食塩水で洗浄後、硫酸マグネシウムで乾燥した。減圧下溶媒を留去し、得られた残渣をカラムクロマトで精製し、表記化合物(1.23g)を得た。収率82%。
¹H-NMR (CDCl₃) δ: 0.10 (6H, s), 0.93 (9H, s), 1.71-1.81 (2H, m), 1.88 (2H, t, J = 6.0 Hz), 2.17-2.21 (2H, m), 3.49-3.59 (2H, m), 3.94 (2H, t, J = 6.0 Hz), 4.11-4.23 (2H, m), 7.55-7.62 (2H, m), 7.89-7.89 (1H, m). Reference Example 260
Preparation of 4- [2- (t-butyldimethylsilyloxy) ethyl] -1- (6-trifluoromethylbenzothiazol-2-yl) piperidine-4-carbonitrile

To a solution of 1- (6-trifluoromethylbenzothiazol-2-yl) piperidine-4-carbonitrile (1.00 g) in tetrahydrofuran (10 mL) was added lithium bis (trimethylsilyl) amide (3.21 mL) at −15 ° C. . (2-Bromoethoxy) -t-butyldimethylsilane (689 μL) was added to the reaction solution, and the mixture was stirred at 0 ° C. for 3 hours. Saturated brine was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified by column chromatography to obtain the title compound (1.23 g). Yield 82%.
¹ H-NMR (CDCl ₃ ) δ: 0.10 (6H, s), 0.93 (9H, s), 1.71-1.81 (2H, m), 1.88 (2H, t, J = 6.0 Hz), 2.17-2.21 (2H , m), 3.49-3.59 (2H, m), 3.94 (2H, t, J = 6.0 Hz), 4.11-4.23 (2H, m), 7.55-7.62 (2H, m), 7.89-7.89 (1H, m ).

4-[2-(t-ブチルジメチルシリルオキシ)エチル]-1-(6-トリフルオロメチルベンゾチアゾール-2-イル)ピペリジン-4-カルボニトリル(510mg)にテトラブチルアンモニウムフルオリド(1Mテトラヒドロフラン溶液、1.63mL)を加え、0℃で0.5時間攪拌した。反応液にクエン酸水溶液を加え、酢酸エチルで抽出した。有機層を水、飽和食塩水で洗浄後、硫酸ナトリウムで乾燥した。減圧下溶媒を留去し、残渣をカラムクロマトで精製して表記化合物(366mg)を得た。収率95%。
¹H-NMR (Acetone) δ: 1.82-1.99 (4H, m), 2.20-2.25 (2H, m), 3.44-3.54 (2H, m), 3.89 (2H, t, J = 5.9 Hz), 4.25-4.29 (2H, m), 7.62-7.63 (2H, m), 8.13-8.16 (1H, br m). Reference Example 261
Preparation of 4- (2-hydroxyethyl) -1- (6-trifluoromethylbenzothiazol-2-yl) piperidine-4-carbonitrile

4- [2- (t-Butyldimethylsilyloxy) ethyl] -1- (6-trifluoromethylbenzothiazol-2-yl) piperidine-4-carbonitrile (510 mg) in tetrabutylammonium fluoride (1M tetrahydrofuran solution) 1.63 mL) and stirred at 0 ° C. for 0.5 hour. To the reaction solution was added an aqueous citric acid solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and then dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by column chromatography to obtain the title compound (366 mg). Yield 95%.
¹ H-NMR (Acetone) δ: 1.82-1.99 (4H, m), 2.20-2.25 (2H, m), 3.44-3.54 (2H, m), 3.89 (2H, t, J = 5.9 Hz), 4.25- 4.29 (2H, m), 7.62-7.63 (2H, m), 8.13-8.16 (1H, br m).

4-(2-ヒドロキシエチル)-1-(6-トリフルオロメチルベンゾチアゾール-2-イル)ピペリジン-4-カルボニトリルから、実施例５８５、実施例５８６の方法に従って合成した。
MS (ESI) m/z 524 [M+H]+ Example 772
Preparation of [3-Chloro-5- [2- [4-cyano-1- (6-trifluoromethylbenzothiazol-2-yl) piperidin-4-yl] ethoxy] phenyl] acetic acid

Synthesized from 4- (2-hydroxyethyl) -1- (6-trifluoromethylbenzothiazol-2-yl) piperidine-4-carbonitrile according to the methods of Example 585 and Example 586.
MS (ESI) m / z 524 [M + H] +

MS (ESI) m/z 524 [M+H]+
In the same manner, the following compound was obtained.
Example 773

MS (ESI) m / z 524 [M + H] +

4-[2-(t-ブチルジメチルシリルオキシ)エチル]-1-(6-トリフルオロメチルベンゾチアゾール-2-イル)ピペリジン-4-カルボニトリル(600mg)の1,2-ジメトキシエタン(12mL)溶液に、0℃でジイソブチルアルミニウムヒドリド(1.0M トルエン溶液、6.39mL)を加え、4時間攪拌した。反応液にクエン酸水溶液を加えた後、酢酸エチルで抽出した。有機層をクエン酸水溶液、水、飽和食塩水で順次洗浄後、硫酸マグネシウムで乾燥した。減圧下溶媒を留去した後、残渣をカラムクロマトで精製して表記化合物(526mg)を得た。収率87%。
¹H-NMR (CDCl₃) δ: 0.05 (6H, s), 0.90 (9H, s), 1.64-1.74 (2H, m), 1.85 (2H, t, J = 5.8 Hz), 2.13-2.19 (2H, m), 3.40-3.50 (2H, m), 3.68 (2H, t, J = 5.8 Hz), 3.93-4.00 (2H, m), 7.52-7.59 (2H, m), 7.85-7.88 (1H, br m), 9.57-9.60 (1H, br m).
Reference Example 262
Preparation of 4- [2- (t-butyldimethylsilanyloxy) ethyl] -1- (6-trifluoromethylbenzothiazol-2-yl) piperidine-4-carbaldehyde

4- [2- (t-Butyldimethylsilyloxy) ethyl] -1- (6-trifluoromethylbenzothiazol-2-yl) piperidine-4-carbonitrile (600 mg) 1,2-dimethoxyethane (12 mL) Diisobutylaluminum hydride (1.0 M toluene solution, 6.39 mL) was added to the solution at 0 ° C., and the mixture was stirred for 4 hours. A citric acid aqueous solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with aqueous citric acid solution, water and saturated brine, and dried over magnesium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by column chromatography to obtain the title compound (526 mg). Yield 87%.
¹ H-NMR (CDCl ₃ ) δ: 0.05 (6H, s), 0.90 (9H, s), 1.64-1.74 (2H, m), 1.85 (2H, t, J = 5.8 Hz), 2.13-2.19 (2H , m), 3.40-3.50 (2H, m), 3.68 (2H, t, J = 5.8 Hz), 3.93-4.00 (2H, m), 7.52-7.59 (2H, m), 7.85-7.88 (1H, br m), 9.57-9.60 (1H, br m).

4-[2-(t-ブチルジメチルシラニルオキシ)エチル]-1-(6-トリフルオロメチルベンゾチアゾール-2-イル)ピペリジン-4-カルボアルデヒド(500mg)のテトラヒドロフラン(20mL)溶液に、エトキシアミン塩酸塩(124mg)を加え60℃で4時間攪拌した。減圧下溶媒を留去した後、残渣にテトラブチルアンモニウムフルオリド(1Mテトラヒドロフラン溶液、1.59m)を加えて0℃で0.5時間、室温で1時間、40℃で2時間攪拌した。反応液にクエン酸水溶液を加え、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄後、硫酸マグネシウムで乾燥した。減圧下溶媒を留去し、残渣をカラムクロマトで精製して、表記化合物(394mg)を得た。収率93％。
¹H-NMR (CDCl₃) δ: 1.28 (3H, t, J = 7.0 Hz), 1.68-1.77 (2H, m), 1.80 (2H, t, J = 6.7 Hz), 2.03-2.10 (2H, m), 3.47-3.56 (2H, m), 3.74-3.80 (2H, m), 3.92-3.99 (2H, m), 4.13 (2H, q, J = 7.0 Hz), 7.33-7.36 (1H, br m), 7.52-7.59 (2H, m), 7.84-7.88 (1H, br m). Reference Example 263
Preparation of N- [4- (2-hydroxyethyl) -1- (6-trifluoromethylbenzothiazol-2-yl) piperidin-4-yl] formimidic acid ethyl ester

To a solution of 4- [2- (t-butyldimethylsilanyloxy) ethyl] -1- (6-trifluoromethylbenzothiazol-2-yl) piperidine-4-carbaldehyde (500 mg) in tetrahydrofuran (20 mL) was added ethoxy Amine hydrochloride (124 mg) was added and stirred at 60 ° C. for 4 hours. After evaporating the solvent under reduced pressure, tetrabutylammonium fluoride (1M tetrahydrofuran solution, 1.59 m) was added to the residue, and the mixture was stirred at 0 ° C for 0.5 hour, at room temperature for 1 hour, and at 40 ° C for 2 hours. To the reaction solution was added an aqueous citric acid solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by column chromatography to obtain the title compound (394 mg). Yield 93%.
¹ H-NMR (CDCl ₃ ) δ: 1.28 (3H, t, J = 7.0 Hz), 1.68-1.77 (2H, m), 1.80 (2H, t, J = 6.7 Hz), 2.03-2.10 (2H, m ), 3.47-3.56 (2H, m), 3.74-3.80 (2H, m), 3.92-3.99 (2H, m), 4.13 (2H, q, J = 7.0 Hz), 7.33-7.36 (1H, br m) , 7.52-7.59 (2H, m), 7.84-7.88 (1H, br m).

N-[4-(2-ヒドロキシエチル)-1-(6-トリフルオロメチルベンゾチアゾール-2-イル)ピペリジン-4-イル]ホルムイミド酸エチルエステルから、実施例５８５、実施例５８６の方法に従って合成した。
MS (ESI) m/z 570 [M+H]+ Example 774
Preparation of [3-Chloro-5- [2- [4-ethoxymethyleneamino-1- (6-trifluoromethylbenzothiazol-2-yl) piperidin-4-yl] ethoxy] phenyl] acetic acid

Synthesis from N- [4- (2-hydroxyethyl) -1- (6-trifluoromethylbenzothiazol-2-yl) piperidin-4-yl] formimidic acid ethyl ester according to the methods of Example 585 and Example 586 did.
MS (ESI) m / z 570 [M + H] +

MS (ESI) m/z 570 [M+H]+

実施例７７６

MS (FABMS) m/z 582 [M+H]+

実施例７７７

TLC_Rf = 0.61 (MeOH:CHCl3 = 1:15)

実施例７７８

TLC_Rf = 0.63 (MeOH:CHCl3 = 1:15)

実施例７７９

MS (ESI) m/z 547 [M+H]⁺

実施例７８０

MS (ESI) m/z 521 [M+H]⁺

実施例７８１

MS (ESI) m/z 507 [M+H]⁺

実施例７８２

MS (ESI) m/z 521 [M+H]⁺

実施例７８３

MS (ESI) m/z 521 [M+H]⁺

実施例７８４

MS (ESI) m/z 555 [M+H]⁺

実施例７８５

MS(ESI) m/z 508[M+H]+

実施例７８６

MS (ESI) m/z 493 [M+H]+

実施例７８７

MS (ESI) m/z 479 [M+H]+

実施例７８８

1H-NMR (DMSO-d6) δ: 7.88 (1.0H, d, J = 8.51 Hz), 7.78 (1.0H, d, J = 8.51 Hz), 7.05 (2.0H, d, J = 5.21 Hz), 7.00 (1.0H, s), 4.22-3.91 (1.0H, m), 3.65-3.36 (4.0H, m), 2.97 (1.0H, d, J = 11.53 Hz), 2.83 (1.0H, d, J = 11.53 Hz), 2.31 (3.0H, s), 2.21-2.16 (3.0H, m), 2.02-1.93 (1.0H, m), 1.83-1.78 (1.0H, m), 1.38-1.16 (4.0H, m), 0.86 (3.0H, t, J = 7.27 Hz).

実施例７８９

1H-NMR (DMSO-d6) δ: 7.88 (1.0H, d, J = 8.23 Hz), 7.78 (1.0H, d, J = 8.23 Hz), 7.34-7.18 (4.0H, m), 4.06 (1.0H, br s), 3.61-3.41 (5.0H, m), 2.96 (1.0H, d, J = 11.80 Hz), 2.84 (1.0H, d, J = 11.80 Hz), 2.19-2.17 (2.0H, m), 1.92-1.84 (2.0H, m), 1.32-1.21 (4.0H, m), 0.86 (3.0H, t, J = 7.27 Hz).

実施例７９０

1H-NMR (DMSO-d6) δ: 12.32 (1.0H, br s), 8.26 (1.0H, d, J = 7.41 Hz), 7.46 (1.0H, d, J = 12.08 Hz), 7.05 (2.0H, d, J = 5.76 Hz), 7.00 (1.0H, s), 4.07-4.04 (1.0H, m), 3.58-3.40 (5.0H, m), 2.95 (1.0H, d, J = 12.08 Hz), 2.82 (1.0H, d, J = 12.08 Hz), 2.31 (3.0H, s), 2.22-2.11 (2.0H, m), 2.02-1.92 (1.0H, m), 1.78-1.74 (1.0H, m), 1.30-1.22 (4.0H, m), 0.86 (3.0H, t, J = 7.27 Hz).

実施例７９１

¹H-NMR (300 MHz, DMSO-d₆)：d 0.83 (3H, t, J=7.2 Hz), 1.13-1.20 (2H, m), 1.27-1.34 (2H, m), 1.71-1.94 (2H, m), 2.09-2.19 (2H, m), 2.28 (3H, s), 2.78-2.94 (2H, m), 3.32-3.61 (5H, m), 3.99 (2H, m), 6.97-7.02 (3H, m), 7.50-7.57 (2H, m), 8.22 (1H, s)

実施例７９２

¹H-NMR (300 MHz, DMSO-d₆)：δ 0.83 (3H, t, J=7.2 Hz), 1.13-1.20 (2H, m), 1.27-1.36 (2H, m), 1.72-1.94 (2H, m), 2.12-2.15 (2H, m), 2.78-2.92 (2H, m), 3.37-3.61 (5H, m), 3.99 (2H, m), 7.16-7.29 (4H, m), 7.50-7.57 (2H, m), 8.21 (1H, s)

実施例７９３

¹H-NMR (300 MHz, DMSO-d₆)：d 0.81 (3H, t, J=7.2 Hz), 1.07-1.17 (2H, m), 1.25-1.32 (2H, m), 1.68-1.77 (2H, m), 2.09-2.18 (2H, m), 2.26 (3H, s), 2.75-2.93 (2H, m), 3.26-3.42 (3H, m), 3.48 (2H, s), 3.57 (1H, d, J=13.5 Hz), 3.97 (1H, m), 6.95-7.02 (3H, m), 7.41 (1H, d, J=12.3 Hz), 8.22 (1H, d, J=6.6 Hz), 12.24 (1H, br)

実施例７９４

¹H-NMR (300 MHz, DMSO-d₆)：d 0.81 (3H, t, J=7.2 Hz), 1.13-1.31 (4H, m), 1.75-1.95 (2H, m), 2.10-2.13 (2H, m), 2.76-2.90 (1H, m), 3.21-4.37 (8H, m), 7.15-7.59 (5H, m), 8.21-8.30 (1H, m), 12.34 (1H, br)

実施例７９５

¹H-NMR (300 MHz, CDCl₃)：d 0.88 (3H, t, J=7.2 Hz), 1.21-1.39 (4H, m), 1.94 (2H, m), 2.27 (2H, m), 2.36 (3H, s), 2.91 (2H, m), 3.45 (3H, m), 3.64 (2H, s). 4.11 (2H, m), 7.06-7.11 (3H, m), 7.58 (1H, d, J=8.4 Hz), 7.71 (1H, d, J=8.4 Hz)

実施例７９６

1H-NMR (DMSO-d6) δ: 8.24 (1H, s), 7.58-7.55 (2H, m), 7.06 (2H, s), 7.00 (1H, s), 4.09-3.95 (2H, m), 3.64-3.32 (2H, m), 3.53 (2H, s), 2.94 (1H, d, J = 11.2 Hz), 2.82 (1H, d, J = 11.4 Hz), 2.31 (3H, s), 2.19-2.14 (2H, m), 1.98-1.89 (1H, m), 1.80-1.71 (1H, m), 1.27-1.19 (2H, m), 0.92 (3H, t, J = 7.3 Hz).

実施例７９７

¹H-NMR (300 MHz, CDCl₃)：d 0.87 (3H, t, J=7.2 Hz), 1.20-1.38 (4H, m), 1.92 (2H, m), 2.27 (2H, m), 2.89 (2H, m), 3.50 (3H, m), 3.67 (2H, s). 4.11 (2H, m), 7.31 (4H, m), 7.57 (1H, d, J=8.4 Hz), 7.70 (1H, d, J=8.4 Hz)

実施例７９８

1H-NMR (DMSO-d6) δ: 7.55 (1H, d, J = 2.0 Hz), 7.26-7.17 (2H, m), 7.04 (1H, s), 7.02 (1H, s), 6.97 (1H, s), 4.13 (1H, s), 3.95 (1H, d, J = 12.3 Hz), 3.50 (2H, s), 3.48 (2H, dd, J = 58.3, 14.7 Hz), 2.90 (1H, d, J = 12.1 Hz), 2.76 (1H, d, J = 12.1 Hz), 2.28 (3H, s), 2.15-2.09 (2H, m), 1.92-1.83 (1H, m), 1.79-1.70 (1H, m), 1.31-1.26 (2H, m), 1.16-1.10 (2H, m), 0.83 (3H, t, J = 7.3 Hz).

実施例７９９

1H-NMR (DMSO-d6) δ: 7.88 (1H, s), 7.45 (1H, d, J = 8.8 Hz), 7.24 (1H, d, J = 9.1 Hz), 7.03 (1H, s), 7.01 (1H, s), 6.97 (1H, s), 3.99-3.90 (2H, m), 3.50 (2H, s), 3.49 (2H, dd, J = 58.4, 12.7 Hz), 2.91 (1H, d, J = 11.5 Hz), 2.79 (1H, d, J = 11.5 Hz), 2.28 (3H, s), 2.15-2.09 (2H, m), 1.97-1.91 (1H, m), 1.73-1.67 (1H, m), 1.32-1.26 (2H, m), 1.19-1.13 (2H, m), 0.84 (3H, t, J = 7.1 Hz).

実施例８００

1H-NMR (DMSO-d6) δ: 8.40 (1H, s), 7.77 (1H, dd, J = 9.3, 2.6 Hz), 7.05 (2H, d, J = 6.2 Hz), 6.99 (1H, s), 6.88 (1H, d, J = 9.1 Hz), 4.41 (1H, s), 4.25 (1H, d, J = 10.0 Hz), 3.63-3.29 (2H, m), 3.51 (2H, s), 3.14 (1H, t, J = 11.3 Hz), 2.93 (1H, d, J = 10.2 Hz), 2.81 (1H, d, J = 11.8 Hz), 2.30 (3H, s), 2.11-1.88 (3H, m), 1.53-1.48 (1H, m), 1.32-1.23 (2H, m), 1.16-1.06 (2H, m), 0.84 (3H, t, J = 7.3 Hz).

実施例８０１

1H-NMR (DMSO-d6) δ: 8.37 (1H, s), 7.74 (1H, dd, J = 9.1, 2.5 Hz), 7.03 (2H, d, J = 6.6 Hz), 6.97 (1H, s), 6.85 (1H, d, J = 9.3 Hz), 4.38 (1H, s), 4.22 (1H, d, J = 11.6 Hz), 3.50 (2H, s), 3.44 (2H, dd, J = 87.8, 13.2 Hz), 3.12 (1H, t, J = 11.3 Hz), 2.91 (1H, d, J = 11.0 Hz), 2.79 (1H, d, J = 11.3 Hz), 2.28 (3H, s), 1.51-1.45 (1H, m), 1.28-1.21 (2H, m), 1.13-1.06 (2H, m), 0.81 (3H, t, J = 7.3 Hz).

実施例８０２

1H-NMR (DMSO-d6) δ: 7.87 (1H, d, J = 8.6 Hz), 7.78 (1H, d, J = 8.6 Hz), 7.05 (2H, s), 7.00 (1H, s), 4.13-4.02 (2H, m), 3.63-3.34 (2H, m), 3.51 (2H, s), 2.96 (1H, d, J = 11.4 Hz), 2.83 (1H, d, J = 11.9 Hz), 2.31 (3H, s), 2.21-2.15 (2H, m), 1.95-1.87 (1H, m), 1.84-1.76 (1H, m), 1.27-1.18 (2H, m), 0.92 (3H, t, J = 7.3 Hz).

実施例８０３

1H-NMR (CDCl3) δ: 7.71 (1.0H, d, J = 8.23 Hz), 7.58 (1.0H, d, J = 8.23 Hz), 7.17-7.00 (3.0H, m), 4.22-4.01 (2.0H, m), 3.67-3.29 (5.0H, m), 3.07-2.72 (2.0H, m), 2.38-2.19 (5.0H, m), 2.03-1.90 (1.0H, m), 1.75-1.56 (2.0H, m), 1.55-1.40 (1.0H, m), 1.02-0.88 (6.0H, m).

実施例８０４

1H-NMR (CDCl3) δ: 7.70 (1.0H, d, J = 8.51 Hz), 7.57 (1.0H, d, J = 8.51 Hz), 7.37-7.20 (4.0H, m), 4.22-4.03 (2.0H, m), 3.74-3.38 (5.0H, m), 3.13-2.74 (2.0H, m), 2.43-2.18 (2.0H, m), 2.00-1.85 (1.0H, m), 1.80-1.58 (1.0H, m), 1.50-1.41 (1.0H, m), 0.98-0.89 (6.0H, m).

実施例８０５

1H-NMR (DMSO-d6) δ: 8.25 (1.0H, d, J = 7.41 Hz), 7.42 (1.0H, d, J = 12.90 Hz), 7.05-6.95 (3.0H, m), 4.17-3.88 (2.0H, m), 3.59 (2.0H, d, J = 14.00 Hz), 3.49 (2.0H, s), 3.45-3.19 (2.0H, m), 2.93 (1.0H, d, J = 11.53 Hz), 2.76 (1.0H, d, J = 11.53 Hz), 2.28 (3.0H, s), 2.23-2.07 (2.0H, m), 1.98-1.87 (1.0H, m), 1.59-1.34 (1.6H, m), 0.93-0.87 (6.0H, m).

実施例８０６

1H-NMR (DMSO-d6) δ: 8.24 (1.0H, d, J = 7.41 Hz), 7.42 (1.0H, d, J = 12.62 Hz), 7.32-7.13 (4.0H, m), 4.24-3.82 (2.0H, m), 3.63 (1.0H, d, J = 13.72 Hz), 3.56 (2.0H, s), 3.53-3.36 (3.0H, m), 2.93 (1.0H, d, J = 11.53 Hz), 2.77 (1.0H, d, J = 11.53 Hz), 2.23-2.11 (2.0H, m), 1.95-1.80 (1.0H, m), 1.64-1.50 (1.0H, m), 1.48-1.32 (1.0H, m), 0.94-0.86 (6.0H, m).

実施例８０７

1H-NMR (CDCl3) δ: 7.29-7.19 (3.0H, m), 7.17-7.02 (3.0H, m), 4.43-4.25 (1.0H, m), 4.16-4.01 (1.0H, m), 3.67-3.35 (4.0H, m), 3.11-2.69 (2.0H, m), 2.41-2.16 (5.0H, m), 1.85-1.70 (2.0H, m), 1.53-1.39 (1.0H, m), 0.98-0.86 (6.0H, m).

実施例８０８

1H-NMR (CDCl3) δ: 7.40-7.19 (6.0H, m), 7.14 (1.0H, dd, J = 8.51, 1.92 Hz), 4.49-4.24 (1.0H, m), 4.22-4.01 (1.0H, m), 3.71-3.39 (4.0H, m), 2.99-2.71 (2.0H, m), 2.53-1.69 (4.0H, m), 1.55-1.39 (1.0H, m), 0.96-0.89 (6.0H, m).

実施例８０９

TLC_Rf = 0.55 (MeOH:CHCl3 = 1:10)
The following compounds were synthesized by the same method.
Example 775

MS (ESI) m / z 570 [M + H] +

Example 776

MS (FABMS) m / z 582 [M + H] +

Example 777

TLC_Rf = 0.61 (MeOH: CHCl3 = 1:15)

Example 778

TLC_Rf = 0.63 (MeOH: CHCl3 = 1:15)

Example 779

MS (ESI) m / z 547 [M + H] ⁺

Example 780

MS (ESI) m / z 521 [M + H] ⁺

Example 781

MS (ESI) m / z 507 [M + H] ⁺

Example 782

MS (ESI) m / z 521 [M + H] ⁺

Example 783

MS (ESI) m / z 521 [M + H] ⁺

Example 784

MS (ESI) m / z 555 [M + H] ⁺

Example 785

MS (ESI) m / z 508 [M + H] +

Example 786

MS (ESI) m / z 493 [M + H] +

Example 787

MS (ESI) m / z 479 [M + H] +

Example 788

1H-NMR (DMSO-d6) δ: 7.88 (1.0H, d, J = 8.51 Hz), 7.78 (1.0H, d, J = 8.51 Hz), 7.05 (2.0H, d, J = 5.21 Hz), 7.00 (1.0H, s), 4.22-3.91 (1.0H, m), 3.65-3.36 (4.0H, m), 2.97 (1.0H, d, J = 11.53 Hz), 2.83 (1.0H, d, J = 11.53 Hz), 2.31 (3.0H, s), 2.21-2.16 (3.0H, m), 2.02-1.93 (1.0H, m), 1.83-1.78 (1.0H, m), 1.38-1.16 (4.0H, m) , 0.86 (3.0H, t, J = 7.27 Hz).

Example 789

1H-NMR (DMSO-d6) δ: 7.88 (1.0H, d, J = 8.23 Hz), 7.78 (1.0H, d, J = 8.23 Hz), 7.34-7.18 (4.0H, m), 4.06 (1.0H , br s), 3.61-3.41 (5.0H, m), 2.96 (1.0H, d, J = 11.80 Hz), 2.84 (1.0H, d, J = 11.80 Hz), 2.19-2.17 (2.0H, m) , 1.92-1.84 (2.0H, m), 1.32-1.21 (4.0H, m), 0.86 (3.0H, t, J = 7.27 Hz).

Example 790

1H-NMR (DMSO-d6) δ: 12.32 (1.0H, br s), 8.26 (1.0H, d, J = 7.41 Hz), 7.46 (1.0H, d, J = 12.08 Hz), 7.05 (2.0H, d, J = 5.76 Hz), 7.00 (1.0H, s), 4.07-4.04 (1.0H, m), 3.58-3.40 (5.0H, m), 2.95 (1.0H, d, J = 12.08 Hz), 2.82 (1.0H, d, J = 12.08 Hz), 2.31 (3.0H, s), 2.22-2.11 (2.0H, m), 2.02-1.92 (1.0H, m), 1.78-1.74 (1.0H, m), 1.30-1.22 (4.0H, m), 0.86 (3.0H, t, J = 7.27 Hz).

Example 791

¹ H-NMR (300 MHz, DMSO-d ₆ ): d 0.83 (3H, t, J = 7.2 Hz), 1.13-1.20 (2H, m), 1.27-1.34 (2H, m), 1.71-1.94 (2H , m), 2.09-2.19 (2H, m), 2.28 (3H, s), 2.78-2.94 (2H, m), 3.32-3.61 (5H, m), 3.99 (2H, m), 6.97-7.02 (3H , m), 7.50-7.57 (2H, m), 8.22 (1H, s)

Example 792

¹ H-NMR (300 MHz, DMSO-d ₆ ): δ 0.83 (3H, t, J = 7.2 Hz), 1.13-1.20 (2H, m), 1.27-1.36 (2H, m), 1.72-1.94 (2H , m), 2.12-2.15 (2H, m), 2.78-2.92 (2H, m), 3.37-3.61 (5H, m), 3.99 (2H, m), 7.16-7.29 (4H, m), 7.50-7.57 (2H, m), 8.21 (1H, s)

Example 793

¹ H-NMR (300 MHz, DMSO-d ₆ ): d 0.81 (3H, t, J = 7.2 Hz), 1.07-1.17 (2H, m), 1.25-1.32 (2H, m), 1.68-1.77 (2H , m), 2.09-2.18 (2H, m), 2.26 (3H, s), 2.75-2.93 (2H, m), 3.26-3.42 (3H, m), 3.48 (2H, s), 3.57 (1H, d , J = 13.5 Hz), 3.97 (1H, m), 6.95-7.02 (3H, m), 7.41 (1H, d, J = 12.3 Hz), 8.22 (1H, d, J = 6.6 Hz), 12.24 (1H , br)

Example 794

¹ H-NMR (300 MHz, DMSO-d ₆ ): d 0.81 (3H, t, J = 7.2 Hz), 1.13-1.31 (4H, m), 1.75-1.95 (2H, m), 2.10-2.13 (2H , m), 2.76-2.90 (1H, m), 3.21-4.37 (8H, m), 7.15-7.59 (5H, m), 8.21-8.30 (1H, m), 12.34 (1H, br)

Example 795

¹ H-NMR (300 MHz, CDCl ₃ ): d 0.88 (3H, t, J = 7.2 Hz), 1.21-1.39 (4H, m), 1.94 (2H, m), 2.27 (2H, m), 2.36 ( 3H, s), 2.91 (2H, m), 3.45 (3H, m), 3.64 (2H, s) .4.11 (2H, m), 7.06-7.11 (3H, m), 7.58 (1H, d, J = 8.4 Hz), 7.71 (1H, d, J = 8.4 Hz)

Example 796

1H-NMR (DMSO-d6) δ: 8.24 (1H, s), 7.58-7.55 (2H, m), 7.06 (2H, s), 7.00 (1H, s), 4.09-3.95 (2H, m), 3.64 -3.32 (2H, m), 3.53 (2H, s), 2.94 (1H, d, J = 11.2 Hz), 2.82 (1H, d, J = 11.4 Hz), 2.31 (3H, s), 2.19-2.14 ( 2H, m), 1.98-1.89 (1H, m), 1.80-1.71 (1H, m), 1.27-1.19 (2H, m), 0.92 (3H, t, J = 7.3 Hz).

Example 797

¹ H-NMR (300 MHz, CDCl ₃ ): d 0.87 (3H, t, J = 7.2 Hz), 1.20-1.38 (4H, m), 1.92 (2H, m), 2.27 (2H, m), 2.89 ( 2H, m), 3.50 (3H, m), 3.67 (2H, s) .4.11 (2H, m), 7.31 (4H, m), 7.57 (1H, d, J = 8.4 Hz), 7.70 (1H, d , J = 8.4 Hz)

Example 798

1H-NMR (DMSO-d6) δ: 7.55 (1H, d, J = 2.0 Hz), 7.26-7.17 (2H, m), 7.04 (1H, s), 7.02 (1H, s), 6.97 (1H, s ), 4.13 (1H, s), 3.95 (1H, d, J = 12.3 Hz), 3.50 (2H, s), 3.48 (2H, dd, J = 58.3, 14.7 Hz), 2.90 (1H, d, J = 12.1 Hz), 2.76 (1H, d, J = 12.1 Hz), 2.28 (3H, s), 2.15-2.09 (2H, m), 1.92-1.83 (1H, m), 1.79-1.70 (1H, m), 1.31-1.26 (2H, m), 1.16-1.10 (2H, m), 0.83 (3H, t, J = 7.3 Hz).

Example 799

1H-NMR (DMSO-d6) δ: 7.88 (1H, s), 7.45 (1H, d, J = 8.8 Hz), 7.24 (1H, d, J = 9.1 Hz), 7.03 (1H, s), 7.01 ( 1H, s), 6.97 (1H, s), 3.99-3.90 (2H, m), 3.50 (2H, s), 3.49 (2H, dd, J = 58.4, 12.7 Hz), 2.91 (1H, d, J = 11.5 Hz), 2.79 (1H, d, J = 11.5 Hz), 2.28 (3H, s), 2.15-2.09 (2H, m), 1.97-1.91 (1H, m), 1.73-1.67 (1H, m), 1.32-1.26 (2H, m), 1.19-1.13 (2H, m), 0.84 (3H, t, J = 7.1 Hz).

Example 800

1H-NMR (DMSO-d6) δ: 8.40 (1H, s), 7.77 (1H, dd, J = 9.3, 2.6 Hz), 7.05 (2H, d, J = 6.2 Hz), 6.99 (1H, s), 6.88 (1H, d, J = 9.1 Hz), 4.41 (1H, s), 4.25 (1H, d, J = 10.0 Hz), 3.63-3.29 (2H, m), 3.51 (2H, s), 3.14 (1H , t, J = 11.3 Hz), 2.93 (1H, d, J = 10.2 Hz), 2.81 (1H, d, J = 11.8 Hz), 2.30 (3H, s), 2.11-1.88 (3H, m), 1.53 -1.48 (1H, m), 1.32-1.23 (2H, m), 1.16-1.06 (2H, m), 0.84 (3H, t, J = 7.3 Hz).

Example 801

1H-NMR (DMSO-d6) δ: 8.37 (1H, s), 7.74 (1H, dd, J = 9.1, 2.5 Hz), 7.03 (2H, d, J = 6.6 Hz), 6.97 (1H, s), 6.85 (1H, d, J = 9.3 Hz), 4.38 (1H, s), 4.22 (1H, d, J = 11.6 Hz), 3.50 (2H, s), 3.44 (2H, dd, J = 87.8, 13.2 Hz ), 3.12 (1H, t, J = 11.3 Hz), 2.91 (1H, d, J = 11.0 Hz), 2.79 (1H, d, J = 11.3 Hz), 2.28 (3H, s), 1.51-1.45 (1H , m), 1.28-1.21 (2H, m), 1.13-1.06 (2H, m), 0.81 (3H, t, J = 7.3 Hz).

Example 802

1H-NMR (DMSO-d6) δ: 7.87 (1H, d, J = 8.6 Hz), 7.78 (1H, d, J = 8.6 Hz), 7.05 (2H, s), 7.00 (1H, s), 4.13- 4.02 (2H, m), 3.63-3.34 (2H, m), 3.51 (2H, s), 2.96 (1H, d, J = 11.4 Hz), 2.83 (1H, d, J = 11.9 Hz), 2.31 (3H , s), 2.21-2.15 (2H, m), 1.95-1.87 (1H, m), 1.84-1.76 (1H, m), 1.27-1.18 (2H, m), 0.92 (3H, t, J = 7.3 Hz ).

Example 803

1H-NMR (CDCl3) δ: 7.71 (1.0H, d, J = 8.23 Hz), 7.58 (1.0H, d, J = 8.23 Hz), 7.17-7.00 (3.0H, m), 4.22-4.01 (2.0H , m), 3.67-3.29 (5.0H, m), 3.07-2.72 (2.0H, m), 2.38-2.19 (5.0H, m), 2.03-1.90 (1.0H, m), 1.75-1.56 (2.0H , m), 1.55-1.40 (1.0H, m), 1.02-0.88 (6.0H, m).

Example 804

1H-NMR (CDCl3) δ: 7.70 (1.0H, d, J = 8.51 Hz), 7.57 (1.0H, d, J = 8.51 Hz), 7.37-7.20 (4.0H, m), 4.22-4.03 (2.0H , m), 3.74-3.38 (5.0H, m), 3.13-2.74 (2.0H, m), 2.43-2.18 (2.0H, m), 2.00-1.85 (1.0H, m), 1.80-1.58 (1.0H , m), 1.50-1.41 (1.0H, m), 0.98-0.89 (6.0H, m).

Example 805

1H-NMR (DMSO-d6) δ: 8.25 (1.0H, d, J = 7.41 Hz), 7.42 (1.0H, d, J = 12.90 Hz), 7.05-6.95 (3.0H, m), 4.17-3.88 ( 2.0H, m), 3.59 (2.0H, d, J = 14.00 Hz), 3.49 (2.0H, s), 3.45-3.19 (2.0H, m), 2.93 (1.0H, d, J = 11.53 Hz), 2.76 (1.0H, d, J = 11.53 Hz), 2.28 (3.0H, s), 2.23-2.07 (2.0H, m), 1.98-1.87 (1.0H, m), 1.59-1.34 (1.6H, m) , 0.93-0.87 (6.0H, m).

Example 806

1H-NMR (DMSO-d6) δ: 8.24 (1.0H, d, J = 7.41 Hz), 7.42 (1.0H, d, J = 12.62 Hz), 7.32-7.13 (4.0H, m), 4.24-3.82 ( 2.0H, m), 3.63 (1.0H, d, J = 13.72 Hz), 3.56 (2.0H, s), 3.53-3.36 (3.0H, m), 2.93 (1.0H, d, J = 11.53 Hz), 2.77 (1.0H, d, J = 11.53 Hz), 2.23-2.11 (2.0H, m), 1.95-1.80 (1.0H, m), 1.64-1.50 (1.0H, m), 1.48-1.32 (1.0H, m), 0.94-0.86 (6.0H, m).

Example 807

1H-NMR (CDCl3) δ: 7.29-7.19 (3.0H, m), 7.17-7.02 (3.0H, m), 4.43-4.25 (1.0H, m), 4.16-4.01 (1.0H, m), 3.67- 3.35 (4.0H, m), 3.11-2.69 (2.0H, m), 2.41-2.16 (5.0H, m), 1.85-1.70 (2.0H, m), 1.53-1.39 (1.0H, m), 0.98- 0.86 (6.0H, m).

Example 808

1H-NMR (CDCl3) δ: 7.40-7.19 (6.0H, m), 7.14 (1.0H, dd, J = 8.51, 1.92 Hz), 4.49-4.24 (1.0H, m), 4.22-4.01 (1.0H, m), 3.71-3.39 (4.0H, m), 2.99-2.71 (2.0H, m), 2.53-1.69 (4.0H, m), 1.55-1.39 (1.0H, m), 0.96-0.89 (6.0H, m).

Example 809

TLC_Rf = 0.55 (MeOH: CHCl3 = 1:10)

2-クロロ-6-トリフルオロメチルベンゾチアゾール(2.79g)、（S)-4-N-Boc-ピペラジンカルボン酸メチルエステル(3.10g)、炭酸カリウム(1.95g)、ジメチルホルムアミド(20mL)を55℃で16時間、90℃で7時間攪拌した。反応液に水を加え、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄後、硫酸マグネシウムで乾燥した。減圧下溶媒を留去した後、残渣をカラムクロマトで精製し、表記化合物(1.40g)を得た。収率27％。
1H-NMR (CDCl3) δ: 1.47(9H, s), 2.97-3.18(1H, m), 3.20-3.38(1H, m), 3.58-3.81(2H, m), 3.76(3H, s), 4.09-4.37(1H, m), 4.61-4.77(1H, m), 5.06(1H, brs), 7.55(1H, d, J=8.4, 1.2 Hz), 7.61(1H, d, J=8.4Hz), 7.90(1H, d, J=1.2 Hz). Reference Example 264
(S) -4- (6-Trifluoromethylbenzothiazol-2-yl) piperazine-1,3-dicarboxylic acid 1-t-butyl ester 3-methyl ester

2-Chloro-6-trifluoromethylbenzothiazole (2.79 g), (S) -4-N-Boc-piperazinecarboxylic acid methyl ester (3.10 g), potassium carbonate (1.95 g), dimethylformamide (20 mL) The mixture was stirred for 16 hours at 90 ° C. and 7 hours at 90 ° C. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over magnesium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by column chromatography to obtain the title compound (1.40 g). Yield 27%.
1H-NMR (CDCl3) δ: 1.47 (9H, s), 2.97-3.18 (1H, m), 3.20-3.38 (1H, m), 3.58-3.81 (2H, m), 3.76 (3H, s), 4.09 -4.37 (1H, m), 4.61-4.77 (1H, m), 5.06 (1H, brs), 7.55 (1H, d, J = 8.4, 1.2 Hz), 7.61 (1H, d, J = 8.4Hz), 7.90 (1H, d, J = 1.2 Hz).

（S）-4-(6-トリフルオロメチルベンゾチアゾール-2-イル)ピペラジン-1,3-ジカルボン酸 1-t-ブチルエステル 3-メチルエステル(1.18g)のテトラヒドロフラン(10mL)溶液に、水素化ホウ素リチウム(65.7mg)を加え、20時間攪拌した。反応液に塩化アンモニウム水溶液を加え、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄後、硫酸マグネシウムで乾燥した。減圧下溶媒を留去した後、残渣をカラムクロマトで精製して、表記化合物(840mg)を得た。収率76％。
1H-NMR (CDCl3) δ: 1.50(9H, s), 3.03-3.30(2H, m), 3.35-3.55(1H, m), 3.68-4.00(3H, m), 4.00-4.43(3H, m), 7.51-7.59(2H, m), 7.87(1H, d, J=0.8 Hz). Reference Example 265
Preparation of (S) -3-hydroxymethyl-4- (6-trifluoromethylbenzothiazol-2-yl) piperazine-1-carboxylic acid t-butyl ester

To a solution of (S) -4- (6-trifluoromethylbenzothiazol-2-yl) piperazine-1,3-dicarboxylic acid 1-t-butyl ester 3-methyl ester (1.18 g) in tetrahydrofuran (10 mL), hydrogen Lithium borohydride (65.7 mg) was added and stirred for 20 hours. Aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over magnesium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by column chromatography to obtain the title compound (840 mg). Yield 76%.
1H-NMR (CDCl3) δ: 1.50 (9H, s), 3.03-3.30 (2H, m), 3.35-3.55 (1H, m), 3.68-4.00 (3H, m), 4.00-4.43 (3H, m) , 7.51-7.59 (2H, m), 7.87 (1H, d, J = 0.8 Hz).

(S)-3-ヒドロキシメチル-4-(6-トリフルオロメチルベンゾチアゾール-2-イル)ピペラジン-1-カルボン酸 t-ブチルエステル(209mg)のジメチルホルムアミド(2mL)溶液に、ヨウ化メチル(0.5mL)、水素化ナトリウム(62.4mg)を順次加え、室温で24時間攪拌した。反応液に氷水を加え、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄後、硫酸マグネシウムで乾燥した。減圧下溶媒を留去し、残渣をカラムクロマトで精製して表記化合物(167mg)を得た。収率77％。
1H-NMR (CDCl3) δ: 1.50(9H, s), 2.96-3.19(2H, m), 3.34-3.45(1H, m), 3.38(3H, s), 3.57(2H, d, J=6.9 Hz), 3.94-4.06(1H, m), 4.20-4.33(3H, m), 7.53(1H, dd, J=8.7, 1.5 Hz), 7.58(1H, d, J=8.7 Hz), 7.86(1H, d, J=1.5Hz). Reference Example 266
Preparation of (S) -3-methoxymethyl-4- (6-trifluoromethylbenzothiazol-2-yl) piperazine-1-carboxylic acid t-butyl ester

To a solution of (S) -3-hydroxymethyl-4- (6-trifluoromethylbenzothiazol-2-yl) piperazine-1-carboxylic acid t-butyl ester (209 mg) in dimethylformamide (2 mL) was added methyl iodide ( 0.5 mL) and sodium hydride (62.4 mg) were sequentially added, and the mixture was stirred at room temperature for 24 hours. Ice water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by column chromatography to obtain the title compound (167 mg). Yield 77%.
1H-NMR (CDCl3) δ: 1.50 (9H, s), 2.96-3.19 (2H, m), 3.34-3.45 (1H, m), 3.38 (3H, s), 3.57 (2H, d, J = 6.9 Hz ), 3.94-4.06 (1H, m), 4.20-4.33 (3H, m), 7.53 (1H, dd, J = 8.7, 1.5 Hz), 7.58 (1H, d, J = 8.7 Hz), 7.86 (1H, d, J = 1.5Hz).

(S)-3-メトキシメチル-4-(6-トリフルオロメチルベンゾチアゾール-2-イル)ピペラジン-1-カルボン酸 t-ブチルエステル(167mg)の塩化メチレン(1.5mL)溶液に、トリフルオロ酢酸(0.3mL)を加え、室温で20時間攪拌した。減圧下、反応液を濃縮した後、飽和炭酸水素ナトリウム水溶液を加え、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄後、硫酸マグネシウムで乾燥した。減圧下、溶媒を留去し表記化合物(123mg)を得た。収率96％。
1H-NMR (CDCl3) δ: 2.84-2.96(3H, m), 3.01(1H, dd, J=12.0, 3.9 Hz), 3.06-3.16(1H, m), 3.26(1H, d, J=12.9 Hz), 3.39(1H, s), 3.46(1H, dd, J=12.0, 3.3 Hz), 3.66(1H, dd, J=12.4, 5.1 Hz), 3.91(1H, dd, J=12.4, 7.2 Hz), 3.90-3.96(1H, m), 4.12-4.21(1H, m), 7.52(1H, dd, J=8.4, 2.1 Hz), 7.56(1H, d, J=8.4 Hz), 7.85(1H, d, J=2.1 Hz). Reference Example 267
Preparation of 2-((S) -2-methoxymethylpiperazin-1-yl) -6-trifluoromethylbenzothiazole

To a solution of (S) -3-methoxymethyl-4- (6-trifluoromethylbenzothiazol-2-yl) piperazine-1-carboxylic acid t-butyl ester (167 mg) in methylene chloride (1.5 mL) was added trifluoroacetic acid. (0.3 mL) was added and stirred at room temperature for 20 hours. The reaction mixture was concentrated under reduced pressure, saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over magnesium sulfate. The solvent was distilled off under reduced pressure to obtain the title compound (123 mg). Yield 96%.
1H-NMR (CDCl3) δ: 2.84-2.96 (3H, m), 3.01 (1H, dd, J = 12.0, 3.9 Hz), 3.06-3.16 (1H, m), 3.26 (1H, d, J = 12.9 Hz ), 3.39 (1H, s), 3.46 (1H, dd, J = 12.0, 3.3 Hz), 3.66 (1H, dd, J = 12.4, 5.1 Hz), 3.91 (1H, dd, J = 12.4, 7.2 Hz) , 3.90-3.96 (1H, m), 4.12-4.21 (1H, m), 7.52 (1H, dd, J = 8.4, 2.1 Hz), 7.56 (1H, d, J = 8.4 Hz), 7.85 (1H, d , J = 2.1 Hz).

2-((S)-2-メトキシメチルピペラジン-1-イル)-6-トリフルオロメチルベンゾチアゾール(123mg)、(3-ブロモメチルフェニル)酢酸エチルエステル(104mg)、炭酸カリウム(259mg)、ジメチルホルムアミド(1.5mL)の混合物を室温で2時間攪拌した。反応液に水を加え、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄後、硫酸マグネシウムで乾燥した。減圧下溶媒を留去した後、残渣をカラムクロマトで精製し、表記化合物(169mg)を得た。収率90％。
1H-NMR (CDCl3) δ: 1.26(3H, t, J=7.2 Hz), 2.20-2.32(2H, m), 2.90(1H, brd, J=10.8 Hz), 3.04(1H, d, J=11.7 Hz), 3.36(3H, s), 3.39-3.64(3H, m), 3.62(2H, s), 3.70(1H, dd, J=9.0, 6.0 Hz), 3.83(1H, t, J=9.0 Hz), 4.03(1H, brd, J=12.6 Hz), 4.16(2H, q, J=7.2 Hz), 4.13-4.24(1H, m), 7.18-7.33(4H, m), 7.51(1H, dd, J=8.4, 1.8 Hz), 7.56(1H, d, J=8.4 Hz), 7.83(1H, d, J=1.8 Hz). Reference Example 268
Preparation of [3-[(S) -3-methoxymethyl-4- (6-trifluoromethylbenzothiazol-2-yl) piperazin-1-ylmethyl] phenyl] acetic acid ethyl ester

2-((S) -2-methoxymethylpiperazin-1-yl) -6-trifluoromethylbenzothiazole (123 mg), (3-bromomethylphenyl) acetic acid ethyl ester (104 mg), potassium carbonate (259 mg), dimethyl A mixture of formamide (1.5 mL) was stirred at room temperature for 2 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over magnesium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by column chromatography to obtain the title compound (169 mg). Yield 90%.
1H-NMR (CDCl3) δ: 1.26 (3H, t, J = 7.2 Hz), 2.20-2.32 (2H, m), 2.90 (1H, brd, J = 10.8 Hz), 3.04 (1H, d, J = 11.7 Hz), 3.36 (3H, s), 3.39-3.64 (3H, m), 3.62 (2H, s), 3.70 (1H, dd, J = 9.0, 6.0 Hz), 3.83 (1H, t, J = 9.0 Hz ), 4.03 (1H, brd, J = 12.6 Hz), 4.16 (2H, q, J = 7.2 Hz), 4.13-4.24 (1H, m), 7.18-7.33 (4H, m), 7.51 (1H, dd, J = 8.4, 1.8 Hz), 7.56 (1H, d, J = 8.4 Hz), 7.83 (1H, d, J = 1.8 Hz).

[3-[(S)-3-メトキシメチル-4-(6-トリフルオロメチルベンゾチアゾール-2-イル)ピペラジン-1-イルメチル]フェニル]酢酸エチルエステル(167mg)、2N水酸化ナトリウム水溶(0.8mL)、テトラヒドロフラン(1.2mL)、メタノール(1.2mL)の混合物を、室温で16時間攪拌した。減圧下反応液を濃縮し、残渣に2N塩酸を加え、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄後、硫酸マグネシウムで乾燥した。減圧下溶媒を留去し、表記化合物(153mg)を得た。収率97％。
TLC_Rf = 0.40 (MeOH:CHCl3 = 1:10) Example 810
Preparation of [3-[(S) -3-methoxymethyl-4- (6-trifluoromethylbenzothiazol-2-yl) piperazin-1-ylmethyl] phenyl] acetic acid

[3-[(S) -3-Methoxymethyl-4- (6-trifluoromethylbenzothiazol-2-yl) piperazin-1-ylmethyl] phenyl] acetic acid ethyl ester (167 mg), 2N aqueous sodium hydroxide (0.8 mL), tetrahydrofuran (1.2 mL), and methanol (1.2 mL) were stirred at room temperature for 16 hours. The reaction mixture was concentrated under reduced pressure, 2N hydrochloric acid was added to the residue, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over magnesium sulfate. The solvent was distilled off under reduced pressure to obtain the title compound (153 mg). Yield 97%.
TLC_Rf = 0.40 (MeOH: CHCl3 = 1:10)

TLC_Rf = 0.33 (MeOH:CHCl3 = 1:10)

実施例８１２

TLC_Rf = 0.52 (MeOH:CHCl3 = 1:15)

実施例８１３

TLC_Rf = 0.088 (MeOH:CHCl3 = 1:5)

実施例８１４

TLC_Rf = 0.17 (MeOH:CHCl3 = 1:15)

実施例８１５

TLC_Rf = 0.29 (MeOH:CHCl3 = 1:15)

実施例８１６

TLC_Rf = 0.23 (MeOH:CHCl3 = 1:15)

実施例８１７

TLC_Rf = 0.28 (MeOH:CHCl3 = 1:15)

実施例８１８

MS(ESI); m/z 463[M+H]+

実施例８１９

MS(ESI); m/z 445[M+H]+

実施例８２０

MS(ESI); m/z 449[M+H]+

実施例８２１

MS(ESI); m/z 431[M+H]+

実施例８２２

TLC:(SiO2)AcOEt-Hexane(3:1) Rf=0.21

実施例８２３

TLC:(SiO2)AcOEt Rf=0.46

実施例８２４

TLC:(SiO2)AcOEt Rf=0.45

実施例８２５

TLC:(SiO2)AcOEt Rf=0.67

実施例８２６

TLC:(SiO2)AcOEt Rf=0.60

実施例８２７

TLC:(SiO2)AcOEt-Hexane(1:1) Rf=0.18

実施例８２８

TLC:(SiO2)AcOEt-Hexane(1:1) Rf=0.25

実施例８２９

TLC:(SiO2)AcOEt-Hexane(1:1) Rf=0.34

実施例８３０

TLC:(SiO2)AcOEt Rf=0.29

実施例８３１

TLC:(SiO2)AcOEt Rf=0.25

実施例８３２

MS (ESI) m/z 468[M+H]+

実施例８３３

MS (ESI) m/z 477[M+H]+

実施例８３４

MS (ESI) m/z 449[M+H]+

実施例８３５

MS (ESI) m/z 463[M+H]+

実施例８３６

MS (ESI) m/z 435[M+H]+

実施例８３７

MS (ESI) m/z 483[M+H]+

実施例８３８

MS (ESI) m/z 465[M+H]+

実施例８３９

1H-NMR (DMSO-d6) δ: 8.17 (1.0H, s), 7.78 (1.0H, d, J = 2.01 Hz), 7.33-7.17 (4.0H, m), 6.91 (1.0H, s), 6.83 (1.0H, d, J = 2.01 Hz), 4.06-0.29 (0.0H, m), 3.67-3.32 (4.0H, m), 3.19-3.16 (1.0H, m), 2.81 (1.0H, d, J = 11.58 Hz), 2.67 (1.0H, d, J = 11.58 Hz), 2.28-2.24 (2.0H, m), 1.95-1.92 (1.0H, br m), 1.45-1.42 (1.0H, br m), 1.28-1.08 (4.0H, m), 0.83 (3.0H, t, J = 7.22 Hz).

実施例８４０

¹H-NMR (300 MHz, DMSO-d₆)：δ 0.84 (3H, t, J=7.5 Hz), 1.12-1.34 (4H, m), 1.83-1.93 (2H, m), 2.34 (3H, s), 2.99-3.14 (2H, m), 3.14-3.57 (5H, m), 4.21-4.35 (2H, m), 4.81-4.86 (1H, m), 5.05-5.06 (1H, m), 7.15-7.63 (7H, m), 8.82 (2H, s), 10.52 (2H, br), 12.41 (1H, br)

実施例８４１

¹H-NMR (300 MHz, DMSO-d₆)：δ0.83 (3H, t, J=7.2 Hz), 1.12-1.32 (4H, m), 1.82-1.95 (2H, m), 3.00-3.15 (2H, m), 3.24-3.39 (3H, m), 3.62 (2H, s), 4.25-4.40 (2H, m), 4.81-4.86 (1H, m), 5.05 (1H, m), 7.18 (1H, m), 7.39-7.60 (7H, m), 8.82 (2H, s), 10.62 (2H, br), 12.45 (1H, br)

実施例８４２

1H-NMR (DMSO-d6) δ: 8.72 (2H, s), 7.52-7.48 (3H, m), 7.14-7.11 (1H, m), 7.03 (2H, s), 6.96 (1H, s), 4.73 (1H, s), 4.56 (1H, d, J = 12.3 Hz), 3.56-3.31 (2H, m), 3.51 (2H, s), 3.19-3.15 (1H, m), 2.90 (1H, d, J = 9.9 Hz), 2.79 (1H, d, J = 11.0 Hz), 2.29 (3H, s), 2.03 (2H, s), 1.86-1.83 (1H, m), 1.65-1.62 (1H, m), 1.18-1.15 (2H, m), 0.88 (3H, t, J = 7.1 Hz).

実施例８４３

1H-NMR (DMSO-d6) δ: 8.65 (2H, s), 7.23 (1H, t, J = 8.2 Hz), 7.03 (2H, s), 6.96 (1H, s), 6.88 (1H, s), 6.87 (1H, d, J = 7.8 Hz), 6.69 (1H, d, J = 9.3 Hz), 4.72 (1H, s), 4.54 (1H, d, J = 10.0 Hz), 3.59-3.32 (2H, m), 3.51 (2H, s), 3.15 (1H, t, J = 10.0 Hz), 2.94 (6H, s), 2.91-2.88 (1H, m), 2.77 (1H, t, J = 11.0 Hz), 2.29 (3H, s), 2.05-1.97 (2H, m), 1.89-1.81 (1H, m), 1.65-1.58 (1H, m), 1.18-1.14 (2H, m), 0.88 (3H, t, J = 7.3 Hz).

実施例８４４

1H-NMR (DMSO-d6) δ: 8.42 (1H, d, J = 2.7 Hz), 7.82 (1H, dd, J = 8.9, 2.6 Hz), 7.62 (1H, d, J = 1.4 Hz), 7.59 (1H, s), 7.42 (2H, t, J = 7.5 Hz), 7.29 (1H, d, J = 7.4 Hz), 7.04 (2H, d, J = 8.8 Hz), 6.97 (1H, s), 6.81 (1H, d, J = 9.1 Hz), 4.31 (1H, s), 4.14 (1H, d, J = 10.9 Hz), 3.62-3.33 (2H, m), 3.50 (2H, s), 3.14-3.06 (1H, m), 2.91 (1H, d, J = 10.0 Hz), 2.80 (1H, d, J = 10.0 Hz), 2.29 (3H, s), 2.09 (1H, t, J = 10.0 Hz), 2.01-1.92 (2H, m), 1.47-1.38 (1H, m), 1.29-1.23 (2H, m), 1.15-1.07 (2H, m), 0.82 (3H, t, J = 7.1 Hz).

実施例８４５

1H-NMR (DMSO-d6) δ: 8.47 (1H, d, J = 2.5 Hz), 7.87 (1H, dd, J = 8.9, 2.7 Hz), 7.46 (3H, t, J = 8.8 Hz), 7.05 (1H, s), 7.02 (1H, s), 6.97 (1H, s), 6.81 (1H, d, J = 9.1 Hz), 4.32 (1H, s), 4.16 (1H, d, J = 12.6 Hz), 3.63-3.28 (2H, m), 3.50 (2H, s), 3.10 (1H, t, J = 12.6 Hz), 2.92 (1H, d, J = 9.9 Hz), 2.80 (1H, d, J = 10.9 Hz), 2.29 (3H, s), 2.09 (1H, t, J = 9.4 Hz), 1.98-1.91 (2H, m), 1.44-1.39 (1H, m), 1.31-1.22 (2H, m), 1.15-1.06 (2H, m), 0.82 (3H, t, J = 7.2 Hz).

実施例８４６

MS(ESI); m/z 445[M+H]+

実施例８４７

MS(ESI) m/z 459 [M+H]+

実施例８４８

MS(ESI) m/z 426[M-H]-

実施例８４９

MS(ESI) m/z 440[M-H]-

実施例８５０

1H-NMR (DMSO-d6) δ: 1.03 (6H, d, J = 6.0 Hz), 2.27 (3H, s), 2.63-2.80 (2H, m), 2.85-2.97 (2H, m), 3.49 (2H, s), 3.69-3.78 (4H, m), 6.86-7.61 (9H, m).

実施例８５１

TLC R_f 0.64(hexane:AcOEt=1:1)

実施例８５２

TLC R_f 0.70(hexane:AcOEt=1:1)

実施例８５３

TLC:(SiO2)AcOEt-Hexane(1:1) Rf=0.34
The following compounds were synthesized by the same method.
Example 811

TLC_Rf = 0.33 (MeOH: CHCl3 = 1:10)

Example 812

TLC_Rf = 0.52 (MeOH: CHCl3 = 1:15)

Example 813

TLC_Rf = 0.088 (MeOH: CHCl3 = 1: 5)

Example 814

TLC_Rf = 0.17 (MeOH: CHCl3 = 1:15)

Example 815

TLC_Rf = 0.29 (MeOH: CHCl3 = 1:15)

Example 816

TLC_Rf = 0.23 (MeOH: CHCl3 = 1:15)

Example 817

TLC_Rf = 0.28 (MeOH: CHCl3 = 1:15)

Example 818

MS (ESI); m / z 463 [M + H] +

Example 819

MS (ESI); m / z 445 [M + H] +

Example 820

MS (ESI); m / z 449 [M + H] +

Example 821

MS (ESI); m / z 431 [M + H] +

Example 822

TLC: (SiO2) AcOEt-Hexane (3: 1) Rf = 0.21

Example 823

TLC: (SiO2) AcOEt Rf = 0.46

Example 824

TLC: (SiO2) AcOEt Rf = 0.45

Example 825

TLC: (SiO2) AcOEt Rf = 0.67

Example 826

TLC: (SiO2) AcOEt Rf = 0.60

Example 827

TLC: (SiO2) AcOEt-Hexane (1: 1) Rf = 0.18

Example 828

TLC: (SiO2) AcOEt-Hexane (1: 1) Rf = 0.25

Example 829

TLC: (SiO2) AcOEt-Hexane (1: 1) Rf = 0.34

Example 830

TLC: (SiO2) AcOEt Rf = 0.29

Example 831

TLC: (SiO2) AcOEt Rf = 0.25

Example 832

MS (ESI) m / z 468 [M + H] +

Example 833

MS (ESI) m / z 477 [M + H] +

Example 834

MS (ESI) m / z 449 [M + H] +

Example 835

MS (ESI) m / z 463 [M + H] +

Example 836

MS (ESI) m / z 435 [M + H] +

Example 837

MS (ESI) m / z 483 [M + H] +

Example 838

MS (ESI) m / z 465 [M + H] +

Example 839

1H-NMR (DMSO-d6) δ: 8.17 (1.0H, s), 7.78 (1.0H, d, J = 2.01 Hz), 7.33-7.17 (4.0H, m), 6.91 (1.0H, s), 6.83 (1.0H, d, J = 2.01 Hz), 4.06-0.29 (0.0H, m), 3.67-3.32 (4.0H, m), 3.19-3.16 (1.0H, m), 2.81 (1.0H, d, J = 11.58 Hz), 2.67 (1.0H, d, J = 11.58 Hz), 2.28-2.24 (2.0H, m), 1.95-1.92 (1.0H, br m), 1.45-1.42 (1.0H, br m), 1.28-1.08 (4.0H, m), 0.83 (3.0H, t, J = 7.22 Hz).

Example 840

¹ H-NMR (300 MHz, DMSO-d ₆ ): δ 0.84 (3H, t, J = 7.5 Hz), 1.12-1.34 (4H, m), 1.83-1.93 (2H, m), 2.34 (3H, s ), 2.99-3.14 (2H, m), 3.14-3.57 (5H, m), 4.21-4.35 (2H, m), 4.81-4.86 (1H, m), 5.05-5.06 (1H, m), 7.15-7.63 (7H, m), 8.82 (2H, s), 10.52 (2H, br), 12.41 (1H, br)

Example 841

¹ H-NMR (300 MHz, DMSO-d ₆ ): δ0.83 (3H, t, J = 7.2 Hz), 1.12-1.32 (4H, m), 1.82-1.95 (2H, m), 3.00-3.15 ( 2H, m), 3.24-3.39 (3H, m), 3.62 (2H, s), 4.25-4.40 (2H, m), 4.81-4.86 (1H, m), 5.05 (1H, m), 7.18 (1H, m), 7.39-7.60 (7H, m), 8.82 (2H, s), 10.62 (2H, br), 12.45 (1H, br)

Example 842

1H-NMR (DMSO-d6) δ: 8.72 (2H, s), 7.52-7.48 (3H, m), 7.14-7.11 (1H, m), 7.03 (2H, s), 6.96 (1H, s), 4.73 (1H, s), 4.56 (1H, d, J = 12.3 Hz), 3.56-3.31 (2H, m), 3.51 (2H, s), 3.19-3.15 (1H, m), 2.90 (1H, d, J = 9.9 Hz), 2.79 (1H, d, J = 11.0 Hz), 2.29 (3H, s), 2.03 (2H, s), 1.86-1.83 (1H, m), 1.65-1.62 (1H, m), 1.18 -1.15 (2H, m), 0.88 (3H, t, J = 7.1 Hz).

Example 843

1H-NMR (DMSO-d6) δ: 8.65 (2H, s), 7.23 (1H, t, J = 8.2 Hz), 7.03 (2H, s), 6.96 (1H, s), 6.88 (1H, s), 6.87 (1H, d, J = 7.8 Hz), 6.69 (1H, d, J = 9.3 Hz), 4.72 (1H, s), 4.54 (1H, d, J = 10.0 Hz), 3.59-3.32 (2H, m ), 3.51 (2H, s), 3.15 (1H, t, J = 10.0 Hz), 2.94 (6H, s), 2.91-2.88 (1H, m), 2.77 (1H, t, J = 11.0 Hz), 2.29 (3H, s), 2.05-1.97 (2H, m), 1.89-1.81 (1H, m), 1.65-1.58 (1H, m), 1.18-1.14 (2H, m), 0.88 (3H, t, J = (7.3 Hz).

Example 844

1H-NMR (DMSO-d6) δ: 8.42 (1H, d, J = 2.7 Hz), 7.82 (1H, dd, J = 8.9, 2.6 Hz), 7.62 (1H, d, J = 1.4 Hz), 7.59 ( 1H, s), 7.42 (2H, t, J = 7.5 Hz), 7.29 (1H, d, J = 7.4 Hz), 7.04 (2H, d, J = 8.8 Hz), 6.97 (1H, s), 6.81 ( 1H, d, J = 9.1 Hz), 4.31 (1H, s), 4.14 (1H, d, J = 10.9 Hz), 3.62-3.33 (2H, m), 3.50 (2H, s), 3.14-3.06 (1H , m), 2.91 (1H, d, J = 10.0 Hz), 2.80 (1H, d, J = 10.0 Hz), 2.29 (3H, s), 2.09 (1H, t, J = 10.0 Hz), 2.01-1.92 (2H, m), 1.47-1.38 (1H, m), 1.29-1.23 (2H, m), 1.15-1.07 (2H, m), 0.82 (3H, t, J = 7.1 Hz).

Example 845

1H-NMR (DMSO-d6) δ: 8.47 (1H, d, J = 2.5 Hz), 7.87 (1H, dd, J = 8.9, 2.7 Hz), 7.46 (3H, t, J = 8.8 Hz), 7.05 ( 1H, s), 7.02 (1H, s), 6.97 (1H, s), 6.81 (1H, d, J = 9.1 Hz), 4.32 (1H, s), 4.16 (1H, d, J = 12.6 Hz), 3.63-3.28 (2H, m), 3.50 (2H, s), 3.10 (1H, t, J = 12.6 Hz), 2.92 (1H, d, J = 9.9 Hz), 2.80 (1H, d, J = 10.9 Hz) ), 2.29 (3H, s), 2.09 (1H, t, J = 9.4 Hz), 1.98-1.91 (2H, m), 1.44-1.39 (1H, m), 1.31-1.22 (2H, m), 1.15- 1.06 (2H, m), 0.82 (3H, t, J = 7.2 Hz).

Example 846

MS (ESI); m / z 445 [M + H] +

Example 847

MS (ESI) m / z 459 [M + H] +

Example 848

MS (ESI) m / z 426 [MH]-

Example 849

MS (ESI) m / z 440 [MH]-

Example 850

1H-NMR (DMSO-d6) δ: 1.03 (6H, d, J = 6.0 Hz), 2.27 (3H, s), 2.63-2.80 (2H, m), 2.85-2.97 (2H, m), 3.49 (2H , s), 3.69-3.78 (4H, m), 6.86-7.61 (9H, m).

Example 851

TLC R _f 0.64 (hexane: AcOEt = 1: 1)

Example 852

TLC R _f 0.70 (hexane: AcOEt = 1: 1)

Example 853

TLC: (SiO2) AcOEt-Hexane (1: 1) Rf = 0.34

2-クロロ-6-トリフルオロメチルベンゾチアゾールとピペラジン-1-カルボン酸 t-ブチルエステルを出発原料として、参考例８４、１５５と同様の方法で合成した。
¹H-NMR (DMSO-d₆) δ: 0.90 (3H, t, J = 7.0 Hz), 1.31-1.37 (4H, m), 1.85-1.95 (2H, m), 3.03-3.18 (1H, m), 3.25-3.39 (3H, m), 3.42-3.55(1H, m), 4.13-4.33 (2H, m), 7.31 (1H, dd, J = 8.5, 1.8 Hz), 7.54 (1H, d, J = 8.5 Hz), 7.99 (1H, d, J = 1.8 Hz), 9.14 (1H, br s), 9.57 (1H, br s). Reference Example 269
Preparation of 2-((R) -2-butylpiperazin-1-yl) -6-trifluoromethoxybenzothiazole dihydrochloride

Synthesis was performed in the same manner as in Reference Examples 84 and 155 using 2-chloro-6-trifluoromethylbenzothiazole and piperazine-1-carboxylic acid t-butyl ester as starting materials.
¹ H-NMR (DMSO-d ₆ ) δ: 0.90 (3H, t, J = 7.0 Hz), 1.31-1.37 (4H, m), 1.85-1.95 (2H, m), 3.03-3.18 (1H, m) , 3.25-3.39 (3H, m), 3.42-3.55 (1H, m), 4.13-4.33 (2H, m), 7.31 (1H, dd, J = 8.5, 1.8 Hz), 7.54 (1H, d, J = 8.5 Hz), 7.99 (1H, d, J = 1.8 Hz), 9.14 (1H, br s), 9.57 (1H, br s).

2-((R)-2-ブチルピペラジン-1-イル)-6-トリフルオロメトキシベンゾチアゾール2塩酸塩(170mg)、(3-クロロメチル-5-メチルフェノキシ)酢酸メチルエステル(108mg)、炭酸カリウム(270mg)、ヨウ化カリウム(65mg)、ジメチルホルムアミド(4mL)の混合物を室温で24時間攪拌した。反応液に水を加えた後、酢酸エチルで抽出した。有機層を水、飽和食塩水で洗浄した後、硫酸マグネシウムで乾燥した。減圧下溶媒を留去し、残渣をカラムクロマトで精製して、表記化合物(203mg)を得た。収率94％。
TLC Rf 0.62 (AcOEt/n-hexane = 1/5). Reference Example 270

Preparation of [3-[(R) -3-butyl-4- (6-trifluoromethoxybenzothiazol-2-yl) -piperazin-1-ylmethyl] -5-methylphenoxy] acetic acid methyl ester

2-((R) -2-butylpiperazin-1-yl) -6-trifluoromethoxybenzothiazole dihydrochloride (170 mg), (3-chloromethyl-5-methylphenoxy) acetic acid methyl ester (108 mg), carbonic acid A mixture of potassium (270 mg), potassium iodide (65 mg) and dimethylformamide (4 mL) was stirred at room temperature for 24 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and then dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by column chromatography to obtain the title compound (203 mg). Yield 94%.
TLC Rf 0.62 (AcOEt / n-hexane = 1/5).

[3-[(R)-3-ブチル-4-(6-トリフルオロメトキシベンゾチアゾール-2-イル)-ピペラジン-1-イルメチル]-5-メチルフェノキシ]酢酸メチルエステル(203mg)、2N水酸化ナトリウム(0.46mL)、テトラヒドロフラン(2mL)、メタノール(2mL)の混合物を室温で16時間攪拌した。反応液に水、クロロホルムを加え、2N塩酸で中和した。反応液をクロロホルムで抽出した。有機層を飽和食塩水で洗浄後、硫酸マグネシウムで乾燥した。減圧下、溶媒を留去し、表記化合物(182mg)を得た。収率91％。
1H-NMR (DMSO-d6) δ: 7.90 (1.0H, d, J = 1.65 Hz), 7.48 (1.0H, d, J = 8.78 Hz), 7.25 (1.0H, dd, J = 8.78, 1.65 Hz), 6.74 (1.0H, s), 6.67 (1.0H, s), 6.61 (1.0H, s), 4.48 (2.0H, s), 4.06-3.80 (1.0H, m), 3.72-3.20 (3.0H, m), 2.90 (1.0H, d, J = 12.62 Hz), 2.81 Example 854
Preparation of [3-[(R) -3-butyl-4- (6-trifluoromethoxybenzothiazol-2-yl) -piperazin-1-ylmethyl] -5-methylphenoxy] acetic acid

[3-[(R) -3-Butyl-4- (6-trifluoromethoxybenzothiazol-2-yl) -piperazin-1-ylmethyl] -5-methylphenoxy] acetic acid methyl ester (203 mg), 2N hydroxylation A mixture of sodium (0.46 mL), tetrahydrofuran (2 mL) and methanol (2 mL) was stirred at room temperature for 16 hours. Water and chloroform were added to the reaction solution and neutralized with 2N hydrochloric acid. The reaction solution was extracted with chloroform. The organic layer was washed with saturated brine and dried over magnesium sulfate. The solvent was distilled off under reduced pressure to obtain the title compound (182 mg). Yield 91%.
1H-NMR (DMSO-d6) δ: 7.90 (1.0H, d, J = 1.65 Hz), 7.48 (1.0H, d, J = 8.78 Hz), 7.25 (1.0H, dd, J = 8.78, 1.65 Hz) , 6.74 (1.0H, s), 6.67 (1.0H, s), 6.61 (1.0H, s), 4.48 (2.0H, s), 4.06-3.80 (1.0H, m), 3.72-3.20 (3.0H, m), 2.90 (1.0H, d, J = 12.62 Hz), 2.81

MS(ESI) m/z 508 [M+H]+

実施例８５６

1H-NMR (DMSO-d6) δ: 8.23 (1.0H, s), 7.58-7.54 (2.0H, m), 6.74 (1.0H, s), 6.68 (1.0H, s), 6.62 (1.0H, s), 4.48 (2.0H, s), 4.11-3.87 (1.0H, m), 3.58-3.33 (3.0H, m), 2.94 (1.0H, d, J = 12.42 Hz), 2.83 (1.0H, d, J = 12.42 Hz), 2.27 (3.0H, s), 2.16-2.12 (2.0H, m), 2.01-1.92 (1.0H, m), 1.80-1.76 (1.0H, m), 1.34-1.21 (4.0H, m), 0.86 (3.0H, t, J = 7.22 Hz).

実施例８５７

1H-NMR (DMSO-d6) δ: 8.22 (1.0H, s), 7.59-7.49 (2.0H, m), 7.24 (1.0H, dd, J = 7.72, 7.72 Hz), 6.95-6.87 (2.0H, m), 6.82-6.76 (1.0H, m), 4.60 (2.0H, s), 4.20-3.89 (2.0H, m), 3.57 (1.0H, d, J = 13.76 Hz), 3.47-3.22 (2.0H, m), 2.96-2.70 (2.0H, m), 2.24-2.08 (2.0H, m), 1.93-1.79 (1.5H, br m), 1.70-1.56 (1.2H, br m), 1.52-1.37 (1.4H, br m), 0.92 (6.0H, d, J = 6.55 Hz).

実施例８５８

1H-NMR (DMSO-d6) δ: 8.22 (1.0H, s), 7.59-7.49 (2.0H, m), 6.75 (1.0H, s), 6.68 (1.0H, s), 6.64-6.61 (1.0H, m), 4.61 (2.0H, s), 4.18-3.89 (2.0H, m), 3.55 (1.0H, d, J = 13.26 Hz), 3.51-3.17 (2.0H, m), 2.90 (1.0H, d, J = 9.90 Hz), 2.83-2.71 (1.0H, m), 2.26 (3.0H, s), 2.22-2.09 (2.3H, m), 1.96-1.84 (1.0H, m), 1.65-1.52 (1.0H, m), 1.52-1.39 (1.0H, m), 0.98-0.88 (6.0H, m).

実施例８５９

MS(ESI) m/z 492 [M-H]-
1H-NMR (DMSO-d6) δ: 0.90(3H, t, J=7.5 Hz), 1.22-1.26(2H, m), 1.79-1.89(2H, m), 2.10-2.21(2H, m), 2.80-2.91(2H, m), 3.41-4.06(3H, m), 3.94-4.06(2H, brm), 4.65(2H, s), 6.78-6.82(1H, m), 6.90-6.94(2H, m), 7.22-7.28(1H, m), 7.53-7.58(2H, m), 8.20(1H, s).
アモルファス


実施例８６０

MS(ESI) m/z 506 [M-H]-

実施例８６１

1H-NMR (300MHz, DMSO-d6) δ 0.85 (3H, t, J=7.2 Hz), 1.16-1.36 (4H, m), 1.79-1.95 (2H, m), 2.15-2.19 (2H, m), 2.81-2.92 (2H, m), 3.34-3.60 (3H, m), 4.03 (2H, m), 4.66 (2H, s), 6.82 (1H, dd, J=7.8 Hz, 1.8Hz), 6.91 (1H, s), 6.94 (1H, d, J=7.8 Hz), 7.26 (1H, t, J=7.8 Hz), 7.51-7.58 (2H, m), 8.22 (1H, s), 13.00 (1H, br s)

実施例８６２

1H-NMR (300MHz, DMSO-d6) δ 0.84 (3H, t, J=7.2 Hz), 1.15-1.36 (4H, m), 1.73-1.97 (2H, m), 2.11-2.16 (2H, m), 2.27 (3H, s), 2.79-2.92 (2H, m), 3.33-3.57 (3H, m), 4.02 (2H, m), 4.62 (2H, s), 6.63 (1H, s), 6.69 (1H, s), 6.76 (1H, s), 7.51-7.58 (2H, m), 8.22 (1H, s), 12.98 (1H, br s)

実施例８６３

MS(ESI) 492[M-H]-

実施例８６４

MS(ESI) 506[M-H]-

実施例８６５

1H-NMR (300MHz, DMSO-d6) δ 0.84 (3H, t, J=7.2 Hz), 1.15-1.35 (4H, m), 1.77-1.95 (2H, m), 2.10-2.18 (2H, m), 2.80-2.92(2H, m), 3.25-3.59 (3H, m), 4.01 (2H, m), 4.61 (2H, s), 6.80 (1H, d, J=7.8 Hz), 6.89 (1H, s), 6.92 (1H, d, J=7.8 Hz), 7.25 (1H, t, J=7.8 Hz), 7.43 (1H, d, J=12.3 Hz), 8.23 (1H, d, J=7.5 Hz)

実施例８６６

1H-NMR (300MHz, DMSO-d6) δ 0.84 (3H, t, J=7.2 Hz), 1.15-1.35 (4H, m), 1.74-1.99 (2H, m), 2.11-2.14 (2H, m), 2.26 (3H, s), 2.79-2.92 (2H, m), 3.33-3.57 (3H, m), 3.99 (2H, m), 4.61 (2H, s), 6.63 (1H, s), 6.69 (1H, s), 6.75 (1H, s), 7.43 (1H, d, J=12.3 Hz), 8.23 (1H, d, J=7.5 Hz)

実施例８６７

1H-NMR (DMSO-d6) δ: 8.24 (1.0H, d, J = 7.72 Hz), 7.42 (1.0H, d, J = 12.59 Hz), 7.24 (1.0H, dd, J = 7.72, 7.72 Hz), 6.95-6.86 (2.0H, m), 6.82-6.75 (1.0H, m), 4.55 (2.0H, s), 4.11-3.86 (2.0H, m), 3.60-3.20 (3.0H, m), 2.90 (1.0H, d, J = 12.25 Hz), 2.77 (1.0H, d, J = 12.25 Hz), 2.25-2.06 (2.0H, m), 1.92-1.76 (1.0H, m), 1.70-1.54 (1.0H, m), 1.53-1.35 (1.0H, m), 0.95-0.88 (6.0H, m).

実施例８６８

1H-NMR (DMSO-d6) δ: 8.24 (1.0H, d, J = 7.39 Hz), 7.42 (1.0H, d, J = 12.59 Hz), 6.75 (1.0H, s), 6.68 (1.0H, s), 6.62 (1.0H, s), 4.61 (2.0H, s), 4.19-3.89 (2.0H, m), 3.59-3.21 (3.0H, m), 2.90 (1.0H, d, J = 10.74 Hz), 2.83-2.71 (1.0H, m), 2.26 (3.0H, s), 2.21-2.08 (2.0H, m), 1.96-1.83 (1.0H, m), 1.65-1.52 (1.0H, m), 1.51-1.36 (1.0H, m), 0.95-0.88 (6.0H, m).

実施例８６９

1H-NMR (DMSO-d6) δ: 8.23 (1.0H, d, J = 7.39 Hz), 7.43 (1.0H, d, J = 12.42 Hz), 7.25 (1.0H, dd, J = 7.72, 7.72 Hz), 6.96-6.88 (2.0H, m), 6.80 (1.0H, dd, J = 8.31, 2.27 Hz), 4.64 (2.0H, s), 4.15-3.89 (2.0H, m), 3.60-3.22 (3.0H, m), 2.89 (1.0H, d, J = 11.92 Hz), 2.82 (2.0H, d, J = 11.92 Hz), 2.23-2.07 (2.0H, m), 1.90-1.76 (2.0H, m), 1.31-1.14 (2.0H, m), 0.90 (3.0H, t, J = 7.30 Hz).

実施例８７０

1H-NMR (DMSO-d6) δ: 8.23 (1.0H, d, J = 7.22 Hz), 7.43 (1.0H, d, J = 12.42 Hz), 6.75 (1.0H, s), 6.69 (1.0H, s), 6.63 (1.0H, s), 4.62 (2.0H, s), 4.17-3.86 (2.0H, m), 3.57-3.22 (3.0H, m), 2.89 (1.0H, d, J = 11.58 Hz), 2.81 (1.0H, d, J = 11.58 Hz), 2.26 (3.0H, s), 2.19-2.07 (2.0H, m), 1.97-1.71 (2.0H, m), 1.31-1.15 (2.0H, m), 0.90 (3.0H, t, J = 7.30 Hz).

実施例８７１

1H-NMR (DMSO-d6) δ: 7.87 (1.0H, d, J = 8.73 Hz), 7.77 (1.0H, d, J = 8.39 Hz), 6.71 (1.0H, s), 6.64 (1.0H, s), 6.57 (1.0H, s), 4.28 (2.0H, s), 3.53-3.39 (6.0H, m), 3.00-2.71 (2.0H, m), 2.30-2.26 (3.0H, m), 2.18-2.15 (2.0H, m), 1.36-1.17 (4.0H, m), 0.87 (3.0H, t, J = 7.13 Hz).

実施例８７２

MS(ESI) 493[M-H]-

実施例８７３

MS(ESI) 507[M-H]-

実施例８７４

MS(ESI) m/z 493[M-H]-

実施例８７５

MS(ESI) m/z 507[M-H]-

実施例８７６

MS(ESI) m/z 524 [M+H]+

実施例８７７

1H-NMR (DMSO-d6) δ: 7.89 (1.0H, d, J = 2.18 Hz), 7.45 (1.0H, d, J = 8.73 Hz), 7.29-7.20 (2.0H, m), 6.95-6.88 (2.0H, m), 6.80 (1.0H, dd, J = 8.73, 2.18 Hz), 4.64 (2.0H, s), 4.11-4.01 (1.0H, m), 3.97-3.85 (1.0H, m), 3.56 (1.0H, d, J = 13.76 Hz), 3.44-3.29 (2.0H, m), 2.88 (1.0H, d, J = 10.74 Hz), 2.78 (1.0H, d, J = 10.74 Hz), 2.22-2.06 (2.0H, m), 1.90-1.76 (1.0H, m), 1.67-1.54 (1.0H, m), 1.50-1.37 (1.0H, m), 0.91 (6.0H, d, J = 6.55 Hz).

実施例８７８

1H-NMR (DMSO-d6) δ: 7.89 (1.0H, d, J = 2.18 Hz), 7.45 (1.0H, d, J = 8.73 Hz), 7.23 (1.0H, dd, J = 8.73, 2.18 Hz), 6.75 (1.0H, s), 6.68 (1.0H, s), 6.62 (1.0H, s), 4.61 (2.0H, s), 4.09-4.00 (1.0H, m), 3.96-3.86 (1.0H, m), 3.55 (2.0H, d, J = 13.26 Hz), 3.50-3.14 (1.0H, m), 2.89 (1.0H, d, J = 11.92 Hz), 2.77 (1.0H, d, J = 11.92 Hz), 2.26 (3.0H, s), 2.21-2.08 (2.0H, m), 1.96-1.83 (1.0H, m), 1.62-1.36 (2.0H, m), 0.94-0.88 (6.0H, m).

実施例８７９

1H-NMR (300MHz, DMSO-d6) δ0.90 (3H, t, J=7.2 Hz), 1.14-1.28 (2H, m), 1.72-1.90 (2H, m), 2.12-2.18 (2H, m), 2.79-2.89 (2H, m), 3.33-3.58 (3H, m), 3.89-4.00 (2H, m), 4.66 (2H, s), 6.80 (1H, dd, J=8.1 Hz, 1.8 Hz), 6.90-6.94 (2H, m), 7.22-7.28 (2H, m), 7.45 (1H, d, J=8.7 Hz), 7.88 (1H, s), 12.98 (1H, br s)

実施例８８０

1H-NMR (300MHz, DMSO-d6) δ0.88 (3H, t, J=7.5 Hz), 1.21 (2H, m), 1.71-1.91 (2H, m), 2.10-2.13 (2H, m), 2.24 (3H, s), 2.76-2.88 (2H, m), 3.30-3.53 (3H, m), 3.87-3.98 (2H, m), 4.60 (2H, s), 6.61 (1H, s), 6.67 (1H, s), 6.73 (1H, s), 7.21 (1H, d, J=8.7 Hz), 7.43 (1H, d, J=8.7 Hz), 7.85 (1H, s), 13.02 (1H, br s)

実施例８８１

1H-NMR (DMSO-d6) δ: 7.54 (1H, s), 7.28-7.15 (2H, m), 6.74 (1H, s), 6.94-6.89 (2H, m), 6.80 (1H, d, J = 7.8Hz), 4.64 (2H, s), 4.13 (1H, s), 3.95 (1H, m), 3.57-3.32 (3H, m), 2.90-2.76 (2H, m), 2.19-2.11 (2H, m), 1.85-1.80 (2.0H, m), 1.28 (2H, q, J = 7.2Hz), 1.13 (2H, q, J = 7.5 Hz), 0.83 (3H, t, J = 7.2Hz).

実施例８８２

1H-NMR (DMSO-d6) δ: 7.54 (1H, d, J = 1.85 Hz), 7.20 (2H, d, J = 8.4 Hz), 6.74 (1H, s), 6.68 (1H, s), 6.62 (1H, s), 4.62 (2H, s), 4.14-3.92 (2H, m), 3.52 (1H, d, J = 13.8 Hz), 2.90-2.75 2H, m), 2.26 (3H, s), 2.15-2.11 (2H, m), 1.80 (2.0H, m), 1.26 (2H, t, J = 7.2Hz), 0.85 (7.0H, t, J = 5.96 Hz).

実施例８８３

1H-NMR (DMSO-d6) δ: 7.54 (1.0H, d, J = 2.18 Hz), 7.28-7.21 (2.0H, m), 7.17 (1.0H, dd, J = 8.23, 2.18 Hz), 6.94-6.87 (2.0H, m), 6.79 (1.0H, dd, J = 8.23, 2.18 Hz), 4.63 (2.0H, s), 4.29-4.21 (1.0H, m), 3.94 (1.0H, d, J = 13.93 Hz), 3.54 (1.0H, d, J = 13.93 Hz), 3.45-3.24 (2.0H, m), 2.86 (1.0H, d, J = 10.74 Hz), 2.75 (1.3H, d, J = 10.74 Hz), 2.30-2.05 (2.0H, m), 1.81-1.62 (2.0H, m), 1.47-1.35 (1.0H, m), 0.93-0.86 (6.0H, m).

実施例８８４

1H-NMR (DMSO-d6) δ: 7.54 (1.0H, d, J = 1.85 Hz), 7.24 (1.0H, d, J = 8.56 Hz), 7.17 (1.0H, dd, J = 8.56, 1.85 Hz), 6.74 (1.0H, s), 6.68 (1.0H, s), 6.62 (1.0H, s), 4.62 (2.0H, s), 4.29-4.20 (1.0H, m), 3.94 (1.0H, d, J = 12.25 Hz), 3.52 (1.0H, d, J = 13.76 Hz), 3.45-3.36 (2.0H, m), 2.87 (1.0H, d, J = 10.58 Hz), 2.74 (1.0H, d, J = 10.58 Hz), 2.26 (3.0H, s), 2.20-2.05 (2.0H, m), 1.80-1.62 (2.0H, m), 1.49-1.34 (1.0H, m), 0.90 (7.0H, t, J = 5.96 Hz).

実施例８８５

MS(ESI) m/z 442 [M-H]-

実施例８８６

MS(ESI) m/z 456[M-H]-

実施例８８７

MS(ESI) m/z 442[M-H]-

実施例８８８

MS(ESI) m/z 456[M-H]-

実施例８８９

1H-NMR (DMSO-d6) δ: 8.74(2H, s), 7.55-7.45 (3H, m), 7.24(1H, t, J = 8.1 Hz), 7.14(1H, m), 6.95-6.90 (2H, m), 6.80 (1H, dd, J = 8.1, 2.4 Hz), 4.74 (1H, s), 4.64(2H, s), 4.55 (1H, m), 3.57-3.53 (2H, m),3.15 (1H, m), 2.89-2.79 (2H, m), 2.06-2.01 (2H, m), 1.84 (1H, m), 1.68 (1H, m), 127 (2H, q, J = 7.2 Hz), 117 (2H, q, J = 7.2 Hz), 0.82 (3H, t, J = 7.1 Hz).


実施例８９０

1H-NMR (DMSO-d6) δ: 8.74(2H, s), 7.55-7.45 (3H, m), 7.24(1H, t, J = 8.1 Hz), 6.75 (1H, s), 6.68 (1H, s), 6.62 (1H, s), 4.74 (1H, s), 4.64(2H, s), 4.55 (1H, m), 3.57-3.53 (2H, m),3.15 (1H, m), 2.89-2.79 (2H, m), 2.25(3H, s), 2.06-2.01 (2H, m), 1.84 (1H, m), 1.68 (1H, m), 127 (2H, q, J = 7.2 Hz), 117 (2H, q, J = 7.2 Hz), 0.82 (3H, t, J = 7.1 Hz).

実施例８９１

1H-NMR (DMSO-d6) δ: 8.73 (2.0H, s), 7.57-7.42 (3.0H, m), 7.25 (1.0H, dd, J = 7.89, 7.89 Hz), 7.18-7.09 (1.0H, m), 6.96-6.87 (2.0H, m), 6.80 (1.0H, dd, J = 7.89, 2.52 Hz), 4.92-4.83 (1.0H, m), 4.66-4.52 (3.0H, m), 3.53 (1.0H, d, J = 13.60 Hz), 3.48-3.07 (2.0H, m), 2.86 (1.0H, d, J = 11.25 Hz), 2.77 (1.0H, d, J = 11.25 Hz), 2.11-1.94 (2.0H, m), 1.74-1.61 (2.0H, m), 1.46-1.34 (1.0H, m), 0.93-0.86 (6.0H, m).

実施例８９２

1H-NMR (DMSO-d6) δ: 8.73 (2.0H, s), 7.58-7.42 (3.0H, m), 7.18-7.09 (1.0H, m), 6.76 (1.0H, s), 6.69 (1.0H, s), 6.62 (1.0H, s), 4.91-4.81 (1.0H, m), 4.64-4.52 (3.0H, m), 3.51 (1.0H, d, J = 13.60 Hz), 3.47-3.09 (2.0H, m), 2.92-2.82 (1.0H, m), 2.80-2.71 (1.0H, m), 2.26 (3.0H, s), 2.08-1.95 (2.0H, m), 1.81-1.69 (1.0H, m), 1.66-1.53 (1.0H, m), 1.49-1.35 (1.0H, m), 0.93-0.86 (6.0H, m).

実施例８９３

1H-NMR (DMSO-d6) δ: 8.74(2H, s), 7.55-7.45 (3H, m), 7.25(1H, t, J = 8.0 Hz), 7.14(1H, m), 6.94-6.90 (2H, m), 6.79 (1H, dd, J = 8.1, 2.4 Hz), 4.78 (1H, s), 4.64(2H, s), 4.59 (1H, m), 3.57-3.10 (3H, m), 2.89-2.79 (2H, m), 2.08-2.04 (2H, m), 1.77 (2H, m), 1.17 (2H, q, J = 7.2 Hz), 0.87 (3H, t, J = 7.1 Hz).

実施例８９４

1H-NMR (DMSO-d6) δ: 8.74(2H, s), 7.55-7.45 (3H, m), 7.25(1H, t, J = 8.0 Hz), 6.75 (1H, s), 6.68 (1H, s), 6.62 (1H, s), , 4.78 (1H, s), 4.64(2H, s), 4.59 (1H, m), 3.57-3.10 (3H, m), 2.89-2.79 (2H, m), 2.26 (3H, s), 2.08-2.04 (2H, m), 1.77 (2H, m), 1.17 (2H, q, J = 7.2 Hz), 0.87 (3H, t, J = 7.1 Hz).

実施例８９５

1H-NMR (300MHz, DMSO-d6) δ0.83 (3H, t, J=7.2 Hz), 1.13-1.33 (4H, m), 1.62-1.91 (2H, m), 1.98-2.04 (2H, m), 2.79-2.90 (2H, m), 3.12-3.56 (3H, m), 4.52-4.57 (3H, m), 4.74 (1H, m), 6.77 (1H, d, J=7.8 Hz), 6.88 (1H, s), 6.91 (1H, d, J=7.8 Hz), 7.11-7.16 (1H, m), 7.23 (1H, t, J=7.8 Hz), 7.43-7.55 (3H, m), 8.73 (2H, s)

実施例８９６

1H-NMR (300MHz, DMSO-d6) δ0.83 (3H, t, J=7.2 Hz), 1.06-1.33 (4H, m), 1.61-1.91 (2H, m), 1.98-2.05 (2H, m), 2.26 (3H, s), 2.78-2.90 (2H, m), 3.11-3.55 (3H, m), 4.55 (1H, d, =12.3 Hz), 4.61 (2H, s), 4.72 (1H, m), 6.62 (1H, s), 6.69 (1H, s), 6.76 (1H, s), 7.14 (1H, m), 7.45-7.55 (3H, m), 8.73 (2H, s), 12.94 (1H, br s)

実施例８９７

TLC:(SiO2)AcOEt Rf=0.29

実施例８９８

1H-NMR (DMSO-d6) δ: 8.42 (2.0H, s), 7.24 (1.0H, dd, J = 7.72, 7.72 Hz), 6.94-6.86 (2.0H, m), 6.79 (1.0H, dd, J = 8.56, 1.85 Hz), 4.76-4.67 (1.0H, m), 4.64 (2.0H, s), 4.40 (1.0H, d, J = 12.93 Hz), 3.51 (1.0H, d, J = 13.60 Hz), 3.42-3.21 (1.0H, m), 3.18-3.05 (1.0H, m), 2.83 (1.0H, d, J = 11.25 Hz), 2.74 (1.0H, d, J = 11.25 Hz), 2.09-1.90 (2.0H, m), 1.72-1.52 (2.0H, m), 1.41-1.30 (1.0H, m), 0.89-0.83 (6.0H, m).

実施例８９９

1H-NMR (DMSO-d6) δ: 8.42 (2.0H, s), 6.74 (1.0H, s), 6.67 (1.0H, s), 6.61 (1.0H, s), 4.76-4.66 (1.0H, br m), 4.60 (2.0H, s), 4.40 (1.0H, d, J = 13.26 Hz), 3.49 (1.0H, d, J = 13.93 Hz), 3.45-3.20 (1.0H, m), 3.18-3.05 (1.0H, m), 2.83 (1.0H, d, J = 12.09 Hz), 2.77-2.69 (1.0H, m), 2.25 (3.0H, s), 2.04-1.96 (2.0H, m), 1.77-1.65 (1.0H, m), 1.60-1.47 (1.0H, m), 1.44-1.28 (1.0H, m), 0.90-0.83 (6.0H, m).

実施例９００

1H-NMR (DMSO-d6) δ: 8.22 (1H, s), 7.59-7.53 (2H, m), 6.75 (1H, s), 6.68 (1H, s), 6.54(1H, s), 4.21-3.89 (2H, m), 3.55-3.30 (3H, m), 2.92-2.75 (2H, m), 2.24 (3H, s), 2.18-2.02 (2H, m), 1.83 (1H, m), 1.65-1.38 (2H, m), 1.51(6H, s), 0.93-0.91 (6H, m).

実施例９０１

MS(ESI) m/z 442 [M+H]+

実施例９０２

MS(ESI) m/z 462 [M+H]+

実施例９０３

MS(ESI) m/z 442 [M+H]+

実施例９０４

1H-NMR (DMSO-d6) δ: 1.01 (6H, d, J = 5.5 Hz), 2.70-2.87 (4H, m), 3.22 (3H, s), 3.47 (2H, d, J = 10.2 Hz), 3.55 (2H, s), 3.71-3.83 (4H, m), 4.15-4.24 (2H, m), 7.04-7.45 (8H, m).

実施例９０５

1H-NMR (DMSO-d6) δ: 1.03 (6H, d, J = 5.2 Hz), 2.70-2.88 (4H, m), 3.45 (2H, d, J = 11.0 Hz), 3.55 (2H, s), 3.60 (3H, s), 3.81 (2H, s), 7.04-7.42 (8H, m).

実施例９０６

1H-NMR (DMSO-d6) δ: 1.04 (6H, d, J = 6.0 Hz), 2.66-2.79 (2H, m), 3.01 (2H, t, J = 11.7 Hz), 3.54 (3H, s), 3.76-3.88 (4H, m), 7.02-7.31 (6H, m), 7.44 (1H, d, J = 8.0 Hz), 7.75 (1H, d, J = 7.7 Hz).

実施例９０７

1H-NMR (DMSO-d6) δ: 1.04 (6H, d, J = 6.0 Hz), 2.63-2.76 (2H, m), 2.93-3.04 (2H, m), 3.53 (2H, s), 3.78 (2H, s), 3.90-3.98 (2H, m), 6.98-7.41 (8H, m).

実施例９０８

1H-NMR (DMSO-d6) δ: 1.01 (6H, d, J = 6.0 Hz), 2.50-2.58 (2H, m), 2.80 (2H, dd, J = 12.6, 10.4 Hz), 3.52 (2H, s), 3.75 (2H, s), 4.34 (2H, dd, J = 12.6, 1.6 Hz), 7.05-7.27 (4H, m), 8.44 (2H, s).

実施例９０９

1H-NMR (DMSO-d6) δ: 1.02 (6H, d, J = 6.0 Hz), 2.47-2.55 (2H, m), 2.61-2.74 (2H, m), 3.52 (2H, s), 3.60-3.67 (2H, m), 3.76 (2H, s), 7.07-7.45 (6H, m), 8.07 (1H, d, J = 3.3 Hz).

実施例９１０

1H-NMR (Acetone) δ: 7.76 (1.0H, s), 7.50 (1.0H, d, J = 9.06 Hz), 7.41 (1.0H, s), 7.35 (1.0H, d, J = 7.42 Hz), 7.30-7.22 (2.0H, m), 7.16 (1.0H, d, J = 7.42 Hz), 3.94 (2.0H, dd, J = 12.71, 2.33 Hz), 3.86 (2.0H, s), 3.62 (2.0H, s), 3.10 (2.0H, dd, J = 12.71, 10.16 Hz), 2.87-2.77 (2.0H, m), 1.12 (6.0H, d, J = 6.00 Hz).

実施例９１１

1H-NMR (Acetone) δ: 8.27 (1.0H, d, J = 1.80 Hz), 7.82 (1.0H, dd, J = 8.46, 1.80 Hz), 7.58 (1.0H, d, J = 8.46 Hz), 7.41 (1.0H, s), 7.35 (1.0H, d, J = 7.42 Hz), 7.27 (1.0H, dd, J = 7.42, 7.42 Hz), 7.17 (1.0H, d, J = 7.42 Hz), 4.00 (2.0H, d, J = 12.64 Hz), 3.87 (2.0H, s), 3.63 (2.0H, s), 3.21-3.07 (5.0H, m), 2.89-2.78 (2.0H, m), 1.13 (6.0H, d, J = 6.32 Hz).

実施例９１２

1H-NMR (Acetone) δ: 7.81 (1.0H, s), 7.47-7.33 (4.0H, m), 7.26 (1.0H, dd, J = 7.54, 7.54 Hz), 7.16 (1.0H, d, J = 7.54 Hz), 3.96 (2.0H, d, J = 12.91 Hz), 3.86 (2.0H, s), 3.62 (2.0H, s), 3.15-3.01 (8.0H, m), 2.92-2.78 (2.0H, m), 1.12 (6.0H, d, J = 6.04 Hz).

実施例９１３

1H-NMR (Acetone) δ: 8.23 (1.0H, s), 7.82 (1.0H, d, J = 8.52 Hz), 7.64 (1.0H, br s), 7.48-7.23 (4.0H, m), 7.16 (1.0H, d, J = 7.14 Hz), 3.96 (2.0H, d, J = 12.64 Hz), 3.86 (2.0H, s), 3.62 (2.0H, s), 3.11 (2.0H, dd, J = 11.40, 11.40 Hz), 2.93-2.76 (5.0H, m), 1.12 (6.0H, d, J = 6.32 Hz).

実施例９１４

1H-NMR (Acetone) δ: 7.42-7.31 (4.0H, m), 7.26 (1.0H, dd, J = 7.42, 7.42 Hz), 7.16 (1.0H, d, J = 7.42 Hz), 6.90 (1.0H, dd, J = 8.79, 2.75 Hz), 3.90-3.84 (4.0H, m), 3.80 (3.0H, s), 3.60 (2.0H, s), 3.01 (2.0H, dd, J = 12.77, 10.30 Hz), 2.83-2.72 (2.0H, m), 1.11 (6.0H, d, J = 6.00 Hz).

実施例９１５

1H-NMR (Acetone) δ: 7.83 (1.0H, d, J = 8.24 Hz), 7.73 (1.0H, d, J = 8.24 Hz), 7.42 (1.0H, s), 7.36 (1.0H, d, J = 7.55 Hz), 7.27 (1.0H, dd, J = 7.55, 7.55 Hz), 7.17 (1.0H, d, J = 7.55 Hz), 4.05 (2.0H, d, J = 13.05 Hz), 3.88 (2.0H, s), 3.63 (2.0H, s), 3.21 (2.0H, dd, J = 13.05, 10.30 Hz), 1.14 (6.0H, d, J = 6.32 Hz).

実施例９１６

1H-NMR (DMSO-d6) δ: 7.70 (1.0H, dd, J = 8.52, 2.75 Hz), 7.43 (1.0H, dd, J = 9.06, 4.94 Hz), 7.28-7.20 (3.0H, m), 7.16-7.05 (2.0H, m), 3.83-3.78 (4.0H, m), 3.52 (2.0H, s), 3.01 (2.0H, dd, J = 11.54, 11.54 Hz), 2.77-2.69 (2.0H, m), 1.04 (6.0H, d, J = 6.04 Hz).

実施例９１７

1H-NMR (Acetone) δ: 8.30 (1.0H, d, J = 5.22 Hz), 7.31 (1.0H, d, J = 7.97 Hz), 7.13 (1.0H, d, J = 1.92 Hz), 7.05 (1.0H, s), 6.89 (1.0H, dd, J = 7.97, 1.92 Hz), 6.80 (1.0H, d, J = 5.22 Hz), 4.32 (2.0H, d, J = 13.73 Hz), 4.16 (2.0H, dd, J = 6.04, 6.04 Hz), 3.23 (2.0H, dd, J = 6.04, 6.04 Hz), 2.89-2.79 (2.0H, m), 2.70-2.61 (2.0H, m), 1.25 (6.0H, d, J = 6.04 Hz).

実施例９１８

1H-NMR (DMSO-d6) δ: 1.05 (7H, d, J = 6.0 Hz), 2.58-2.87 (4H, m), 3.54 (2H, s), 3.77 (2H, s), 4.23-4.34 (2H, m), 7.05-7.53 (8H, m), 7.90-8.06 (3H, m).

実施例９１９

1H-NMR (Acetone) δ: 7.50 (1.0H, dd, J = 7.97, 7.97 Hz), 7.40 (1.0H, s), 7.34 (1.0H, d, J = 7.42 Hz), 7.25 (1.0H, dd, J = 7.42, 7.42 Hz), 7.15 (1.0H, d, J = 7.42 Hz), 6.75 (1.0H, d, J = 7.97 Hz), 6.59 (1.0H, d, J = 7.97 Hz), 4.13 (2.0H, d, J = 11.54 Hz), 3.82 (2.0H, s), 3.61 (2.0H, s), 2.80-2.62 (4.0H, m), 1.08 (6.0H, d, J = 5.77 Hz).

実施例９２０

MS(ESI) m/z 428 [M+H]+

実施例９２１

1H-NMR (DMSO-d6) δ: 1.03 (6H, d, J = 6.0 Hz), 2.27 (3H, s), 2.63-2.80 (2H, m), 2.85-2.97 (2H, m), 3.49 (2H, s), 3.69-3.78 (4H, m), 6.86-7.61 (9H, m).

実施例９２２

1H-NMR (DMSO-d6) δ: 1.04 (6H, d, J = 6.0 Hz), 2.52-2.62 (2H, m), 2.84 (2H, dd, J = 12.9, 10.4 Hz), 3.54 (2H, s), 3.77 (2H, s), 4.44-4.52 (2H, m), 7.07-7.64 (9H, m), 8.69 (2H, s).

実施例９２３

1H-NMR(DMSO-d6)) δ:7.77(1H, s),7.59-7.53(1H, m), 7.37-7.29(1H, m), 7.14-7.06(3H ,m), 6.89(1H, s), 3.78-3.73(4H, m), 3.49(2H, s), 2.94(2H, t, J=12.6Hz), 2.74-2.68(2H, m), 2.27(3H, s), 1.03(6H, d, J=6.3Hz).

実施例９２４

1H-NMR(DMSO-d6)) δ:7.77(1H, s),7.59-7.53(1H, m), 7.37-7.29(1H, m), 7.14-7.06(3H ,m),6.76(2H, s), 6.54(1H, s),4.60(2H, s), 3.79-3.70(4H, m), 2.93(2H, t, J=10.5Hz), 2.70(2H,brs), 2.25(3H, s), 1.02(6H, d, J=6.0Hz).

実施例９２５

1H-NMR (Acetone) δ: 8.43 (1.0H, d, J = 2.54 Hz), 7.81 (1.0H, dd, J = 9.00, 2.54 Hz), 7.61-7.58 (2.0H, m), 7.45-7.24 (6.0H, m), 7.16 (1.0H, d, J = 7.69 Hz), 6.91 (1.0H, d, J = 9.00 Hz), 4.25 (2.0H, d, J = 11.81 Hz), 3.84 (2.0H, s), 3.63 (2.0H, s), 2.90-2.63 (4.0H, m), 1.10 (6.0H, d, J = 5.22 Hz).

実施例９２６

1H-NMR (Acetone) δ: 8.09-8.07 (2.0H, m), 7.60 (1.0H, dd, J = 7.76, 7.76 Hz), 7.48-7.34 (5.0H, m), 7.26 (1.0H, dd, J = 7.76, 7.76 Hz), 7.20-7.13 (2.0H, m), 6.79 (1.0H, d, J = 8.79 Hz), 4.32 (2.0H, d, J = 11.81 Hz), 3.83 (2.0H, s), 3.62 (2.0H, s), 2.93-2.67 (4.0H, m), 1.10 (2.0H, d, J = 5.70 Hz).

実施例９２７

1H-NMR (DMSO-d6) δ: 1.00 (6H, d, J = 6.0 Hz), 2.35 (3H, t, J = 10.7 Hz), 2.61-2.73 (2H, m), 3.53 (2H, s), 3.75 (2H, s), 5.90 (2H, s), 6.32 (1H, dd, J = 8.5, 1.6 Hz), 6.65-6.78 (2H, m), 7.05-7.28 (4H, m).

実施例９２８

1H-NMR (DMSO-d6) δ: 1.03 (7H, d, J = 6.0 Hz), 2.35-2.46 (2H, m), 2.68-2.81 (2H, m), 3.55 (2H, s), 3.72 (3H, s), 3.79 (2H, s), 6.27 (1H, d, J = 2.2 Hz), 6.90-7.31 (8H, m).

実施例９２９

1H-NMR (DMSO-d6) δ: 1.03 (6H, d, J = 5.2 Hz), 2.61-2.76 (4H, m), 2.92-3.00 (2H, m), 3.53 (2H, s), 3.75 (2H, s), 3.83 (2H, d, J = 10.7 Hz), 6.93-7.28 (6H, m), 7.42 (1H, d, J = 8.5 Hz).

実施例９３０

1H-NMR (DMSO-d6) δ: 1.04 (6H, d, J = 6.0 Hz), 2.50-2.58 (2H, m), 2.66-2.78 (2H, m), 3.54 (2H, s), 3.66 (2H, d, J = 11.5 Hz), 3.78 (2H, s), 7.06-7.31 (5H, m), 7.59 (1H, d, J = 2.2 Hz), 7.87 (1H, d, J = 9.1 Hz), 9.07 (1H, s).

実施例９３１

1H-NMR (DMSO-d6) δ: 1.04 (6H, d, J = 6.0 Hz), 2.45-2.75 (7H, m), 3.54 (2H, s), 3.61 (2H, d, J = 10.7 Hz), 3.78 (2H, s), 7.06-7.39 (6H, m), 7.78 (1H, d, J = 8.8 Hz).

実施例９３２

1H-NMR (Acetone) δ: 7.49 (2.0H, d, J = 8.66 Hz), 7.40 (1.0H, s), 7.35 (1.0H, d, J = 7.42 Hz), 7.26 (1.0H, dd, J = 7.42, 7.42 Hz), 7.16 (1.0H, d, J = 7.42 Hz), 7.08 (2.0H, d, J = 8.66 Hz), 3.83 (2.0H, s), 3.75 (2.0H, d, J = 10.71 Hz), 3.62 (2.0H, s), 2.84-2.66 (4.0H, m), 1.09 (6.0H, d, J = 5.77 Hz).

実施例９３３

1H-NMR (Acetone) δ: 7.53-7.49 (2.0H, m), 7.41 (1.0H, s), 7.37-7.32 (3.0H, m), 7.29 (1.0H, d, J = 4.39 Hz), 7.25 (1.0H, d, J = 7.42 Hz), 7.20-7.13 (3.0H, m), 6.17 (1.0H, d, J = 3.85 Hz), 3.85 (2.0H, s), 3.63 (2.0H, s), 3.43 (2.0H, d, J = 9.61 Hz), 2.86-2.83 (2.0H, m), 2.70-2.66 (2.0H, m), 1.09 (6.0H, d, J = 6.32 Hz).

実施例９３４

1H-NMR (DMSO-d6) δ: 8.72(2H, s), 7.59-7.40 (2H, m), 7.13(1H, t, J = 8.1Hz), 6.75 (1H, s), 6.66 (1H, s), 6.54(1H, s), 4.86(1H, br-s), 4.56(1H, d, J = 12.9Hz), 3.48-3.13 (3H, m), 2.86-2.72 (2H, m), 2.23 (3H, s), 2.10-1.90 (2H, m), 1.39 (1H, m), 0.91-0.87 (6H, m).

実施例９３５

1H-NMR (DMSO-d6) δ: 8.72(2H, s), 6.75 (1H, s), 6.66 (1H, s), 6.54(1H, s), 4.86(1H, br-s), 4.56(1H, d, J = 12.9Hz), 3.48-3.13 (3H, m), 2.86-2.72 (2H, m), 2.23 (3H, s), 2.10-1.90 (2H, m), 1.39 (1H, m), 0.91-0.87 (6H, m).

実施例９３６

1H-NMR (DMSO-d6) δ: 8.23 (1.0H, d, J = 7.22 Hz), 7.42 (1.0H, d, J = 12.42 Hz), 6.73 (1.0H, s), 6.65 (1.0H, s), 6.54 (1.0H, s), 4.15-3.86 (2.0H, m), 3.53-3.20 (3.0H, m), 2.92-2.75 (2.0H, m), 2.24 (3.0H, s), 2.20-2.05 (2.0H, m), 1.92-1.70 (2.0H, m), 1.52-1.48 (6.0H, m), 1.30-1.14 (2.0H, m), 0.90 (3.0H, t, J = 7.30 Hz).

実施例９３７

MS(ESI) 534[M-H]-

実施例９３８

MS(ESI) 494[M-H]-

実施例９３９

MS(ESI) 508[M-H]-

実施例９４０

MS(ESI) 536[M-H]-

実施例９４１

1H-NMR (300MHz, DMSO-d6) δ 0.85 (3H, t, J=7.2 Hz), 1.13-1.35 (4H, m), 1.50 (6H, s), 1.75-1.94 (2H, m), 2.12-2.17 (2H, m), 2.24 (3H, s), 2.78-2.90 (2H, m), 3.33-3.53 (3H, m), 4.02 (2H, m), 6.54 (1H, s), 6.65 (1H, s), 6.74 (1H, s), 7.43 (1H, d, J=12.0 Hz), 8.23 (1H, d, J=7.2 Hz), 12.97 (1H, br s)

実施例９４２

MS(ESI) m/z 428[M+H]+

実施例９４３

TLC_Rf = 0.55 (MeOH:CHCl3 = 1:10)

実施例９４４

1H-NMR (300MHz, DMSO-d6) d 0.83 (3H, t, J=7.2 Hz), 1.06-1.33 (4H, m), 1.51 (6H, s), 1.61-1.91 (2H, m), 1.98-2.05 (2H, m), 2.26 (3H, s), 2.78-2.90 (2H, m), 3.11-3.55 (3H, m), 4.55 (1H, d, =12.3 Hz), 4.72 (1H, m), 6.54 (1H, s), 6.66 (1H, s), 6.75 (1H, s), 7.14 (1H, m), 7.45-7.55 (3H, m), 8.72 (2H, s)
The following compounds were synthesized by the same method.
Example 855

MS (ESI) m / z 508 [M + H] +

Example 856

1H-NMR (DMSO-d6) δ: 8.23 (1.0H, s), 7.58-7.54 (2.0H, m), 6.74 (1.0H, s), 6.68 (1.0H, s), 6.62 (1.0H, s ), 4.48 (2.0H, s), 4.11-3.87 (1.0H, m), 3.58-3.33 (3.0H, m), 2.94 (1.0H, d, J = 12.42 Hz), 2.83 (1.0H, d, J = 12.42 Hz), 2.27 (3.0H, s), 2.16-2.12 (2.0H, m), 2.01-1.92 (1.0H, m), 1.80-1.76 (1.0H, m), 1.34-1.21 (4.0H , m), 0.86 (3.0H, t, J = 7.22 Hz).

Example 857

1H-NMR (DMSO-d6) δ: 8.22 (1.0H, s), 7.59-7.49 (2.0H, m), 7.24 (1.0H, dd, J = 7.72, 7.72 Hz), 6.95-6.87 (2.0H, m), 6.82-6.76 (1.0H, m), 4.60 (2.0H, s), 4.20-3.89 (2.0H, m), 3.57 (1.0H, d, J = 13.76 Hz), 3.47-3.22 (2.0H , m), 2.96-2.70 (2.0H, m), 2.24-2.08 (2.0H, m), 1.93-1.79 (1.5H, br m), 1.70-1.56 (1.2H, br m), 1.52-1.37 ( 1.4H, br m), 0.92 (6.0H, d, J = 6.55 Hz).

Example 858

1H-NMR (DMSO-d6) δ: 8.22 (1.0H, s), 7.59-7.49 (2.0H, m), 6.75 (1.0H, s), 6.68 (1.0H, s), 6.64-6.61 (1.0H , m), 4.61 (2.0H, s), 4.18-3.89 (2.0H, m), 3.55 (1.0H, d, J = 13.26 Hz), 3.51-3.17 (2.0H, m), 2.90 (1.0H, d, J = 9.90 Hz), 2.83-2.71 (1.0H, m), 2.26 (3.0H, s), 2.22-2.09 (2.3H, m), 1.96-1.84 (1.0H, m), 1.65-1.52 ( 1.0H, m), 1.52-1.39 (1.0H, m), 0.98-0.88 (6.0H, m).

Example 859

MS (ESI) m / z 492 [MH]-
1H-NMR (DMSO-d6) δ: 0.90 (3H, t, J = 7.5 Hz), 1.22-1.26 (2H, m), 1.79-1.89 (2H, m), 2.10-2.21 (2H, m), 2.80 -2.91 (2H, m), 3.41-4.06 (3H, m), 3.94-4.06 (2H, brm), 4.65 (2H, s), 6.78-6.82 (1H, m), 6.90-6.94 (2H, m) , 7.22-7.28 (1H, m), 7.53-7.58 (2H, m), 8.20 (1H, s).
amorphous


Example 860

MS (ESI) m / z 506 [MH]-

Example 861

1H-NMR (300MHz, DMSO-d6) δ 0.85 (3H, t, J = 7.2 Hz), 1.16-1.36 (4H, m), 1.79-1.95 (2H, m), 2.15-2.19 (2H, m), 2.81-2.92 (2H, m), 3.34-3.60 (3H, m), 4.03 (2H, m), 4.66 (2H, s), 6.82 (1H, dd, J = 7.8 Hz, 1.8Hz), 6.91 (1H , s), 6.94 (1H, d, J = 7.8 Hz), 7.26 (1H, t, J = 7.8 Hz), 7.51-7.58 (2H, m), 8.22 (1H, s), 13.00 (1H, br s )

Example 862

1H-NMR (300MHz, DMSO-d6) δ 0.84 (3H, t, J = 7.2 Hz), 1.15-1.36 (4H, m), 1.73-1.97 (2H, m), 2.11-2.16 (2H, m), 2.27 (3H, s), 2.79-2.92 (2H, m), 3.33-3.57 (3H, m), 4.02 (2H, m), 4.62 (2H, s), 6.63 (1H, s), 6.69 (1H, s), 6.76 (1H, s), 7.51-7.58 (2H, m), 8.22 (1H, s), 12.98 (1H, br s)

Example 863

MS (ESI) 492 [MH]-

Example 864

MS (ESI) 506 [MH]-

Example 865

1H-NMR (300MHz, DMSO-d6) δ 0.84 (3H, t, J = 7.2 Hz), 1.15-1.35 (4H, m), 1.77-1.95 (2H, m), 2.10-2.18 (2H, m), 2.80-2.92 (2H, m), 3.25-3.59 (3H, m), 4.01 (2H, m), 4.61 (2H, s), 6.80 (1H, d, J = 7.8 Hz), 6.89 (1H, s) , 6.92 (1H, d, J = 7.8 Hz), 7.25 (1H, t, J = 7.8 Hz), 7.43 (1H, d, J = 12.3 Hz), 8.23 (1H, d, J = 7.5 Hz)

Example 866

1H-NMR (300MHz, DMSO-d6) δ 0.84 (3H, t, J = 7.2 Hz), 1.15-1.35 (4H, m), 1.74-1.99 (2H, m), 2.11-2.14 (2H, m), 2.26 (3H, s), 2.79-2.92 (2H, m), 3.33-3.57 (3H, m), 3.99 (2H, m), 4.61 (2H, s), 6.63 (1H, s), 6.69 (1H, s), 6.75 (1H, s), 7.43 (1H, d, J = 12.3 Hz), 8.23 (1H, d, J = 7.5 Hz)

Example 867

1H-NMR (DMSO-d6) δ: 8.24 (1.0H, d, J = 7.72 Hz), 7.42 (1.0H, d, J = 12.59 Hz), 7.24 (1.0H, dd, J = 7.72, 7.72 Hz) , 6.95-6.86 (2.0H, m), 6.82-6.75 (1.0H, m), 4.55 (2.0H, s), 4.11-3.86 (2.0H, m), 3.60-3.20 (3.0H, m), 2.90 (1.0H, d, J = 12.25 Hz), 2.77 (1.0H, d, J = 12.25 Hz), 2.25-2.06 (2.0H, m), 1.92-1.76 (1.0H, m), 1.70-1.54 (1.0 H, m), 1.53-1.35 (1.0H, m), 0.95-0.88 (6.0H, m).

Example 868

1H-NMR (DMSO-d6) δ: 8.24 (1.0H, d, J = 7.39 Hz), 7.42 (1.0H, d, J = 12.59 Hz), 6.75 (1.0H, s), 6.68 (1.0H, s ), 6.62 (1.0H, s), 4.61 (2.0H, s), 4.19-3.89 (2.0H, m), 3.59-3.21 (3.0H, m), 2.90 (1.0H, d, J = 10.74 Hz) , 2.83-2.71 (1.0H, m), 2.26 (3.0H, s), 2.21-2.08 (2.0H, m), 1.96-1.83 (1.0H, m), 1.65-1.52 (1.0H, m), 1.51 -1.36 (1.0H, m), 0.95-0.88 (6.0H, m).

Example 869

1H-NMR (DMSO-d6) δ: 8.23 (1.0H, d, J = 7.39 Hz), 7.43 (1.0H, d, J = 12.42 Hz), 7.25 (1.0H, dd, J = 7.72, 7.72 Hz) , 6.96-6.88 (2.0H, m), 6.80 (1.0H, dd, J = 8.31, 2.27 Hz), 4.64 (2.0H, s), 4.15-3.89 (2.0H, m), 3.60-3.22 (3.0H , m), 2.89 (1.0H, d, J = 11.92 Hz), 2.82 (2.0H, d, J = 11.92 Hz), 2.23-2.07 (2.0H, m), 1.90-1.76 (2.0H, m), 1.31-1.14 (2.0H, m), 0.90 (3.0H, t, J = 7.30 Hz).

Example 870

1H-NMR (DMSO-d6) δ: 8.23 (1.0H, d, J = 7.22 Hz), 7.43 (1.0H, d, J = 12.42 Hz), 6.75 (1.0H, s), 6.69 (1.0H, s ), 6.63 (1.0H, s), 4.62 (2.0H, s), 4.17-3.86 (2.0H, m), 3.57-3.22 (3.0H, m), 2.89 (1.0H, d, J = 11.58 Hz) , 2.81 (1.0H, d, J = 11.58 Hz), 2.26 (3.0H, s), 2.19-2.07 (2.0H, m), 1.97-1.71 (2.0H, m), 1.31-1.15 (2.0H, m ), 0.90 (3.0H, t, J = 7.30 Hz).

Example 871

1H-NMR (DMSO-d6) δ: 7.87 (1.0H, d, J = 8.73 Hz), 7.77 (1.0H, d, J = 8.39 Hz), 6.71 (1.0H, s), 6.64 (1.0H, s ), 6.57 (1.0H, s), 4.28 (2.0H, s), 3.53-3.39 (6.0H, m), 3.00-2.71 (2.0H, m), 2.30-2.26 (3.0H, m), 2.18- 2.15 (2.0H, m), 1.36-1.17 (4.0H, m), 0.87 (3.0H, t, J = 7.13 Hz).

Example 872

MS (ESI) 493 [MH]-

Example 873

MS (ESI) 507 [MH]-

Example 874

MS (ESI) m / z 493 [MH]-

Example 875

MS (ESI) m / z 507 [MH]-

Example 876

MS (ESI) m / z 524 [M + H] +

Example 877

1H-NMR (DMSO-d6) δ: 7.89 (1.0H, d, J = 2.18 Hz), 7.45 (1.0H, d, J = 8.73 Hz), 7.29-7.20 (2.0H, m), 6.95-6.88 ( 2.0H, m), 6.80 (1.0H, dd, J = 8.73, 2.18 Hz), 4.64 (2.0H, s), 4.11-4.01 (1.0H, m), 3.97-3.85 (1.0H, m), 3.56 (1.0H, d, J = 13.76 Hz), 3.44-3.29 (2.0H, m), 2.88 (1.0H, d, J = 10.74 Hz), 2.78 (1.0H, d, J = 10.74 Hz), 2.22- 2.06 (2.0H, m), 1.90-1.76 (1.0H, m), 1.67-1.54 (1.0H, m), 1.50-1.37 (1.0H, m), 0.91 (6.0H, d, J = 6.55 Hz) .

Example 878

1H-NMR (DMSO-d6) δ: 7.89 (1.0H, d, J = 2.18 Hz), 7.45 (1.0H, d, J = 8.73 Hz), 7.23 (1.0H, dd, J = 8.73, 2.18 Hz) , 6.75 (1.0H, s), 6.68 (1.0H, s), 6.62 (1.0H, s), 4.61 (2.0H, s), 4.09-4.00 (1.0H, m), 3.96-3.86 (1.0H, m), 3.55 (2.0H, d, J = 13.26 Hz), 3.50-3.14 (1.0H, m), 2.89 (1.0H, d, J = 11.92 Hz), 2.77 (1.0H, d, J = 11.92 Hz ), 2.26 (3.0H, s), 2.21-2.08 (2.0H, m), 1.96-1.83 (1.0H, m), 1.62-1.36 (2.0H, m), 0.94-0.88 (6.0H, m).

Example 879

1H-NMR (300MHz, DMSO-d6) δ0.90 (3H, t, J = 7.2 Hz), 1.14-1.28 (2H, m), 1.72-1.90 (2H, m), 2.12-2.18 (2H, m) , 2.79-2.89 (2H, m), 3.33-3.58 (3H, m), 3.89-4.00 (2H, m), 4.66 (2H, s), 6.80 (1H, dd, J = 8.1 Hz, 1.8 Hz), 6.90-6.94 (2H, m), 7.22-7.28 (2H, m), 7.45 (1H, d, J = 8.7 Hz), 7.88 (1H, s), 12.98 (1H, br s)

Example 880

1H-NMR (300MHz, DMSO-d6) δ0.88 (3H, t, J = 7.5 Hz), 1.21 (2H, m), 1.71-1.91 (2H, m), 2.10-2.13 (2H, m), 2.24 (3H, s), 2.76-2.88 (2H, m), 3.30-3.53 (3H, m), 3.87-3.98 (2H, m), 4.60 (2H, s), 6.61 (1H, s), 6.67 (1H , s), 6.73 (1H, s), 7.21 (1H, d, J = 8.7 Hz), 7.43 (1H, d, J = 8.7 Hz), 7.85 (1H, s), 13.02 (1H, br s)

Example 881

1H-NMR (DMSO-d6) δ: 7.54 (1H, s), 7.28-7.15 (2H, m), 6.74 (1H, s), 6.94-6.89 (2H, m), 6.80 (1H, d, J = 7.8Hz), 4.64 (2H, s), 4.13 (1H, s), 3.95 (1H, m), 3.57-3.32 (3H, m), 2.90-2.76 (2H, m), 2.19-2.11 (2H, m ), 1.85-1.80 (2.0H, m), 1.28 (2H, q, J = 7.2Hz), 1.13 (2H, q, J = 7.5Hz), 0.83 (3H, t, J = 7.2Hz).

Example 882

1H-NMR (DMSO-d6) δ: 7.54 (1H, d, J = 1.85 Hz), 7.20 (2H, d, J = 8.4 Hz), 6.74 (1H, s), 6.68 (1H, s), 6.62 ( 1H, s), 4.62 (2H, s), 4.14-3.92 (2H, m), 3.52 (1H, d, J = 13.8 Hz), 2.90-2.75 2H, m), 2.26 (3H, s), 2.15- 2.11 (2H, m), 1.80 (2.0H, m), 1.26 (2H, t, J = 7.2Hz), 0.85 (7.0H, t, J = 5.96 Hz).

Example 883

1H-NMR (DMSO-d6) δ: 7.54 (1.0H, d, J = 2.18 Hz), 7.28-7.21 (2.0H, m), 7.17 (1.0H, dd, J = 8.23, 2.18 Hz), 6.94- 6.87 (2.0H, m), 6.79 (1.0H, dd, J = 8.23, 2.18 Hz), 4.63 (2.0H, s), 4.29-4.21 (1.0H, m), 3.94 (1.0H, d, J = 13.93 Hz), 3.54 (1.0H, d, J = 13.93 Hz), 3.45-3.24 (2.0H, m), 2.86 (1.0H, d, J = 10.74 Hz), 2.75 (1.3H, d, J = 10.74 Hz), 2.30-2.05 (2.0H, m), 1.81-1.62 (2.0H, m), 1.47-1.35 (1.0H, m), 0.93-0.86 (6.0H, m).

Example 884

1H-NMR (DMSO-d6) δ: 7.54 (1.0H, d, J = 1.85 Hz), 7.24 (1.0H, d, J = 8.56 Hz), 7.17 (1.0H, dd, J = 8.56, 1.85 Hz) , 6.74 (1.0H, s), 6.68 (1.0H, s), 6.62 (1.0H, s), 4.62 (2.0H, s), 4.29-4.20 (1.0H, m), 3.94 (1.0H, d, J = 12.25 Hz), 3.52 (1.0H, d, J = 13.76 Hz), 3.45-3.36 (2.0H, m), 2.87 (1.0H, d, J = 10.58 Hz), 2.74 (1.0H, d, J = 10.58 Hz), 2.26 (3.0H, s), 2.20-2.05 (2.0H, m), 1.80-1.62 (2.0H, m), 1.49-1.34 (1.0H, m), 0.90 (7.0H, t, J = 5.96 Hz).

Example 885

MS (ESI) m / z 442 [MH]-

Example 886

MS (ESI) m / z 456 [MH]-

Example 887

MS (ESI) m / z 442 [MH]-

Example 888

MS (ESI) m / z 456 [MH]-

Example 889

1H-NMR (DMSO-d6) δ: 8.74 (2H, s), 7.55-7.45 (3H, m), 7.24 (1H, t, J = 8.1 Hz), 7.14 (1H, m), 6.95-6.90 (2H , m), 6.80 (1H, dd, J = 8.1, 2.4 Hz), 4.74 (1H, s), 4.64 (2H, s), 4.55 (1H, m), 3.57-3.53 (2H, m), 3.15 ( 1H, m), 2.89-2.79 (2H, m), 2.06-2.01 (2H, m), 1.84 (1H, m), 1.68 (1H, m), 127 (2H, q, J = 7.2 Hz), 117 (2H, q, J = 7.2 Hz), 0.82 (3H, t, J = 7.1 Hz).


Example 890

1H-NMR (DMSO-d6) δ: 8.74 (2H, s), 7.55-7.45 (3H, m), 7.24 (1H, t, J = 8.1 Hz), 6.75 (1H, s), 6.68 (1H, s ), 6.62 (1H, s), 4.74 (1H, s), 4.64 (2H, s), 4.55 (1H, m), 3.57-3.53 (2H, m), 3.15 (1H, m), 2.89-2.79 ( 2H, m), 2.25 (3H, s), 2.06-2.01 (2H, m), 1.84 (1H, m), 1.68 (1H, m), 127 (2H, q, J = 7.2 Hz), 117 (2H , q, J = 7.2 Hz), 0.82 (3H, t, J = 7.1 Hz).

Example 891

1H-NMR (DMSO-d6) δ: 8.73 (2.0H, s), 7.57-7.42 (3.0H, m), 7.25 (1.0H, dd, J = 7.89, 7.89 Hz), 7.18-7.09 (1.0H, m), 6.96-6.87 (2.0H, m), 6.80 (1.0H, dd, J = 7.89, 2.52 Hz), 4.92-4.83 (1.0H, m), 4.66-4.52 (3.0H, m), 3.53 ( 1.0H, d, J = 13.60 Hz), 3.48-3.07 (2.0H, m), 2.86 (1.0H, d, J = 11.25 Hz), 2.77 (1.0H, d, J = 11.25 Hz), 2.11-1.94 (2.0H, m), 1.74-1.61 (2.0H, m), 1.46-1.34 (1.0H, m), 0.93-0.86 (6.0H, m).

Example 892

1H-NMR (DMSO-d6) δ: 8.73 (2.0H, s), 7.58-7.42 (3.0H, m), 7.18-7.09 (1.0H, m), 6.76 (1.0H, s), 6.69 (1.0H , s), 6.62 (1.0H, s), 4.91-4.81 (1.0H, m), 4.64-4.52 (3.0H, m), 3.51 (1.0H, d, J = 13.60 Hz), 3.47-3.09 (2.0 H, m), 2.92-2.82 (1.0H, m), 2.80-2.71 (1.0H, m), 2.26 (3.0H, s), 2.08-1.95 (2.0H, m), 1.81-1.69 (1.0H, m), 1.66-1.53 (1.0H, m), 1.49-1.35 (1.0H, m), 0.93-0.86 (6.0H, m).

Example 893

1H-NMR (DMSO-d6) δ: 8.74 (2H, s), 7.55-7.45 (3H, m), 7.25 (1H, t, J = 8.0 Hz), 7.14 (1H, m), 6.94-6.90 (2H , m), 6.79 (1H, dd, J = 8.1, 2.4 Hz), 4.78 (1H, s), 4.64 (2H, s), 4.59 (1H, m), 3.57-3.10 (3H, m), 2.89- 2.79 (2H, m), 2.08-2.04 (2H, m), 1.77 (2H, m), 1.17 (2H, q, J = 7.2 Hz), 0.87 (3H, t, J = 7.1 Hz).

Example 894

1H-NMR (DMSO-d6) δ: 8.74 (2H, s), 7.55-7.45 (3H, m), 7.25 (1H, t, J = 8.0 Hz), 6.75 (1H, s), 6.68 (1H, s ), 6.62 (1H, s),, 4.78 (1H, s), 4.64 (2H, s), 4.59 (1H, m), 3.57-3.10 (3H, m), 2.89-2.79 (2H, m), 2.26 (3H, s), 2.08-2.04 (2H, m), 1.77 (2H, m), 1.17 (2H, q, J = 7.2 Hz), 0.87 (3H, t, J = 7.1 Hz).

Example 895

1H-NMR (300MHz, DMSO-d6) δ0.83 (3H, t, J = 7.2 Hz), 1.13-1.33 (4H, m), 1.62-1.91 (2H, m), 1.98-2.04 (2H, m) , 2.79-2.90 (2H, m), 3.12-3.56 (3H, m), 4.52-4.57 (3H, m), 4.74 (1H, m), 6.77 (1H, d, J = 7.8 Hz), 6.88 (1H , s), 6.91 (1H, d, J = 7.8 Hz), 7.11-7.16 (1H, m), 7.23 (1H, t, J = 7.8 Hz), 7.43-7.55 (3H, m), 8.73 (2H, s)

Example 896

1H-NMR (300MHz, DMSO-d6) δ0.83 (3H, t, J = 7.2 Hz), 1.06-1.33 (4H, m), 1.61-1.91 (2H, m), 1.98-2.05 (2H, m) , 2.26 (3H, s), 2.78-2.90 (2H, m), 3.11-3.55 (3H, m), 4.55 (1H, d, = 12.3 Hz), 4.61 (2H, s), 4.72 (1H, m) , 6.62 (1H, s), 6.69 (1H, s), 6.76 (1H, s), 7.14 (1H, m), 7.45-7.55 (3H, m), 8.73 (2H, s), 12.94 (1H, br s)

Example 897

TLC: (SiO2) AcOEt Rf = 0.29

Example 898

1H-NMR (DMSO-d6) δ: 8.42 (2.0H, s), 7.24 (1.0H, dd, J = 7.72, 7.72 Hz), 6.94-6.86 (2.0H, m), 6.79 (1.0H, dd, J = 8.56, 1.85 Hz), 4.76-4.67 (1.0H, m), 4.64 (2.0H, s), 4.40 (1.0H, d, J = 12.93 Hz), 3.51 (1.0H, d, J = 13.60 Hz ), 3.42-3.21 (1.0H, m), 3.18-3.05 (1.0H, m), 2.83 (1.0H, d, J = 11.25 Hz), 2.74 (1.0H, d, J = 11.25 Hz), 2.09- 1.90 (2.0H, m), 1.72-1.52 (2.0H, m), 1.41-1.30 (1.0H, m), 0.89-0.83 (6.0H, m).

Example 899

1H-NMR (DMSO-d6) δ: 8.42 (2.0H, s), 6.74 (1.0H, s), 6.67 (1.0H, s), 6.61 (1.0H, s), 4.76-4.66 (1.0H, br m), 4.60 (2.0H, s), 4.40 (1.0H, d, J = 13.26 Hz), 3.49 (1.0H, d, J = 13.93 Hz), 3.45-3.20 (1.0H, m), 3.18-3.05 (1.0H, m), 2.83 (1.0H, d, J = 12.09 Hz), 2.77-2.69 (1.0H, m), 2.25 (3.0H, s), 2.04-1.96 (2.0H, m), 1.77- 1.65 (1.0H, m), 1.60-1.47 (1.0H, m), 1.44-1.28 (1.0H, m), 0.90-0.83 (6.0H, m).

Example 900

1H-NMR (DMSO-d6) δ: 8.22 (1H, s), 7.59-7.53 (2H, m), 6.75 (1H, s), 6.68 (1H, s), 6.54 (1H, s), 4.21-3.89 (2H, m), 3.55-3.30 (3H, m), 2.92-2.75 (2H, m), 2.24 (3H, s), 2.18-2.02 (2H, m), 1.83 (1H, m), 1.65-1.38 (2H, m), 1.51 (6H, s), 0.93-0.91 (6H, m).

Example 901

MS (ESI) m / z 442 [M + H] +

Example 902

MS (ESI) m / z 462 [M + H] +

Example 903

MS (ESI) m / z 442 [M + H] +

Example 904

1H-NMR (DMSO-d6) δ: 1.01 (6H, d, J = 5.5 Hz), 2.70-2.87 (4H, m), 3.22 (3H, s), 3.47 (2H, d, J = 10.2 Hz), 3.55 (2H, s), 3.71-3.83 (4H, m), 4.15-4.24 (2H, m), 7.04-7.45 (8H, m).

Example 905

1H-NMR (DMSO-d6) δ: 1.03 (6H, d, J = 5.2 Hz), 2.70-2.88 (4H, m), 3.45 (2H, d, J = 11.0 Hz), 3.55 (2H, s), 3.60 (3H, s), 3.81 (2H, s), 7.04-7.42 (8H, m).

Example 906

1H-NMR (DMSO-d6) δ: 1.04 (6H, d, J = 6.0 Hz), 2.66-2.79 (2H, m), 3.01 (2H, t, J = 11.7 Hz), 3.54 (3H, s), 3.76-3.88 (4H, m), 7.02-7.31 (6H, m), 7.44 (1H, d, J = 8.0 Hz), 7.75 (1H, d, J = 7.7 Hz).

Example 907

1H-NMR (DMSO-d6) δ: 1.04 (6H, d, J = 6.0 Hz), 2.63-2.76 (2H, m), 2.93-3.04 (2H, m), 3.53 (2H, s), 3.78 (2H , s), 3.90-3.98 (2H, m), 6.98-7.41 (8H, m).

Example 908

1H-NMR (DMSO-d6) δ: 1.01 (6H, d, J = 6.0 Hz), 2.50-2.58 (2H, m), 2.80 (2H, dd, J = 12.6, 10.4 Hz), 3.52 (2H, s ), 3.75 (2H, s), 4.34 (2H, dd, J = 12.6, 1.6 Hz), 7.05-7.27 (4H, m), 8.44 (2H, s).

Example 909

1H-NMR (DMSO-d6) δ: 1.02 (6H, d, J = 6.0 Hz), 2.47-2.55 (2H, m), 2.61-2.74 (2H, m), 3.52 (2H, s), 3.60-3.67 (2H, m), 3.76 (2H, s), 7.07-7.45 (6H, m), 8.07 (1H, d, J = 3.3 Hz).

Example 910

1H-NMR (Acetone) δ: 7.76 (1.0H, s), 7.50 (1.0H, d, J = 9.06 Hz), 7.41 (1.0H, s), 7.35 (1.0H, d, J = 7.42 Hz), 7.30-7.22 (2.0H, m), 7.16 (1.0H, d, J = 7.42 Hz), 3.94 (2.0H, dd, J = 12.71, 2.33 Hz), 3.86 (2.0H, s), 3.62 (2.0H , s), 3.10 (2.0H, dd, J = 12.71, 10.16 Hz), 2.87-2.77 (2.0H, m), 1.12 (6.0H, d, J = 6.00 Hz).

Example 911

1H-NMR (Acetone) δ: 8.27 (1.0H, d, J = 1.80 Hz), 7.82 (1.0H, dd, J = 8.46, 1.80 Hz), 7.58 (1.0H, d, J = 8.46 Hz), 7.41 (1.0H, s), 7.35 (1.0H, d, J = 7.42 Hz), 7.27 (1.0H, dd, J = 7.42, 7.42 Hz), 7.17 (1.0H, d, J = 7.42 Hz), 4.00 ( 2.0H, d, J = 12.64 Hz), 3.87 (2.0H, s), 3.63 (2.0H, s), 3.21-3.07 (5.0H, m), 2.89-2.78 (2.0H, m), 1.13 (6.0 H, d, J = 6.32 Hz).

Example 912

1H-NMR (Acetone) δ: 7.81 (1.0H, s), 7.47-7.33 (4.0H, m), 7.26 (1.0H, dd, J = 7.54, 7.54 Hz), 7.16 (1.0H, d, J = 7.54 Hz), 3.96 (2.0H, d, J = 12.91 Hz), 3.86 (2.0H, s), 3.62 (2.0H, s), 3.15-3.01 (8.0H, m), 2.92-2.78 (2.0H, m), 1.12 (6.0H, d, J = 6.04 Hz).

Example 913

1H-NMR (Acetone) δ: 8.23 (1.0H, s), 7.82 (1.0H, d, J = 8.52 Hz), 7.64 (1.0H, br s), 7.48-7.23 (4.0H, m), 7.16 ( 1.0H, d, J = 7.14 Hz), 3.96 (2.0H, d, J = 12.64 Hz), 3.86 (2.0H, s), 3.62 (2.0H, s), 3.11 (2.0H, dd, J = 11.40 , 11.40 Hz), 2.93-2.76 (5.0H, m), 1.12 (6.0H, d, J = 6.32 Hz).

Example 914

1H-NMR (Acetone) δ: 7.42-7.31 (4.0H, m), 7.26 (1.0H, dd, J = 7.42, 7.42 Hz), 7.16 (1.0H, d, J = 7.42 Hz), 6.90 (1.0H , dd, J = 8.79, 2.75 Hz), 3.90-3.84 (4.0H, m), 3.80 (3.0H, s), 3.60 (2.0H, s), 3.01 (2.0H, dd, J = 12.77, 10.30 Hz ), 2.83-2.72 (2.0H, m), 1.11 (6.0H, d, J = 6.00 Hz).

Example 915

1H-NMR (Acetone) δ: 7.83 (1.0H, d, J = 8.24 Hz), 7.73 (1.0H, d, J = 8.24 Hz), 7.42 (1.0H, s), 7.36 (1.0H, d, J = 7.55 Hz), 7.27 (1.0H, dd, J = 7.55, 7.55 Hz), 7.17 (1.0H, d, J = 7.55 Hz), 4.05 (2.0H, d, J = 13.05 Hz), 3.88 (2.0H , s), 3.63 (2.0H, s), 3.21 (2.0H, dd, J = 13.05, 10.30 Hz), 1.14 (6.0H, d, J = 6.32 Hz).

Example 916

1H-NMR (DMSO-d6) δ: 7.70 (1.0H, dd, J = 8.52, 2.75 Hz), 7.43 (1.0H, dd, J = 9.06, 4.94 Hz), 7.28-7.20 (3.0H, m), 7.16-7.05 (2.0H, m), 3.83-3.78 (4.0H, m), 3.52 (2.0H, s), 3.01 (2.0H, dd, J = 11.54, 11.54 Hz), 2.77-2.69 (2.0H, m), 1.04 (6.0H, d, J = 6.04 Hz).

Example 917

1H-NMR (Acetone) δ: 8.30 (1.0H, d, J = 5.22 Hz), 7.31 (1.0H, d, J = 7.97 Hz), 7.13 (1.0H, d, J = 1.92 Hz), 7.05 (1.0 H, s), 6.89 (1.0H, dd, J = 7.97, 1.92 Hz), 6.80 (1.0H, d, J = 5.22 Hz), 4.32 (2.0H, d, J = 13.73 Hz), 4.16 (2.0H , dd, J = 6.04, 6.04 Hz), 3.23 (2.0H, dd, J = 6.04, 6.04 Hz), 2.89-2.79 (2.0H, m), 2.70-2.61 (2.0H, m), 1.25 (6.0H , d, J = 6.04 Hz).

Example 918

1H-NMR (DMSO-d6) δ: 1.05 (7H, d, J = 6.0 Hz), 2.58-2.87 (4H, m), 3.54 (2H, s), 3.77 (2H, s), 4.23-4.34 (2H , m), 7.05-7.53 (8H, m), 7.90-8.06 (3H, m).

Example 919

1H-NMR (Acetone) δ: 7.50 (1.0H, dd, J = 7.97, 7.97 Hz), 7.40 (1.0H, s), 7.34 (1.0H, d, J = 7.42 Hz), 7.25 (1.0H, dd , J = 7.42, 7.42 Hz), 7.15 (1.0H, d, J = 7.42 Hz), 6.75 (1.0H, d, J = 7.97 Hz), 6.59 (1.0H, d, J = 7.97 Hz), 4.13 ( 2.0H, d, J = 11.54 Hz), 3.82 (2.0H, s), 3.61 (2.0H, s), 2.80-2.62 (4.0H, m), 1.08 (6.0H, d, J = 5.77 Hz).

Example 920

MS (ESI) m / z 428 [M + H] +

Example 921

1H-NMR (DMSO-d6) δ: 1.03 (6H, d, J = 6.0 Hz), 2.27 (3H, s), 2.63-2.80 (2H, m), 2.85-2.97 (2H, m), 3.49 (2H , s), 3.69-3.78 (4H, m), 6.86-7.61 (9H, m).

Example 922

1H-NMR (DMSO-d6) δ: 1.04 (6H, d, J = 6.0 Hz), 2.52-2.62 (2H, m), 2.84 (2H, dd, J = 12.9, 10.4 Hz), 3.54 (2H, s ), 3.77 (2H, s), 4.44-4.52 (2H, m), 7.07-7.64 (9H, m), 8.69 (2H, s).

Example 923

1H-NMR (DMSO-d6)) δ: 7.77 (1H, s), 7.59-7.53 (1H, m), 7.37-7.29 (1H, m), 7.14-7.06 (3H, m), 6.89 (1H, s ), 3.78-3.73 (4H, m), 3.49 (2H, s), 2.94 (2H, t, J = 12.6Hz), 2.74-2.68 (2H, m), 2.27 (3H, s), 1.03 (6H, d, J = 6.3Hz).

Example 924

1H-NMR (DMSO-d6)) δ: 7.77 (1H, s), 7.59-7.53 (1H, m), 7.37-7.29 (1H, m), 7.14-7.06 (3H, m), 6.76 (2H, s ), 6.54 (1H, s), 4.60 (2H, s), 3.79-3.70 (4H, m), 2.93 (2H, t, J = 10.5Hz), 2.70 (2H, brs), 2.25 (3H, s) , 1.02 (6H, d, J = 6.0Hz).

Example 925

1H-NMR (Acetone) δ: 8.43 (1.0H, d, J = 2.54 Hz), 7.81 (1.0H, dd, J = 9.00, 2.54 Hz), 7.61-7.58 (2.0H, m), 7.45-7.24 ( 6.0H, m), 7.16 (1.0H, d, J = 7.69 Hz), 6.91 (1.0H, d, J = 9.00 Hz), 4.25 (2.0H, d, J = 11.81 Hz), 3.84 (2.0H, s), 3.63 (2.0H, s), 2.90-2.63 (4.0H, m), 1.10 (6.0H, d, J = 5.22 Hz).

Example 926

1H-NMR (Acetone) δ: 8.09-8.07 (2.0H, m), 7.60 (1.0H, dd, J = 7.76, 7.76 Hz), 7.48-7.34 (5.0H, m), 7.26 (1.0H, dd, J = 7.76, 7.76 Hz), 7.20-7.13 (2.0H, m), 6.79 (1.0H, d, J = 8.79 Hz), 4.32 (2.0H, d, J = 11.81 Hz), 3.83 (2.0H, s ), 3.62 (2.0H, s), 2.93-2.67 (4.0H, m), 1.10 (2.0H, d, J = 5.70 Hz).

Example 927

1H-NMR (DMSO-d6) δ: 1.00 (6H, d, J = 6.0 Hz), 2.35 (3H, t, J = 10.7 Hz), 2.61-2.73 (2H, m), 3.53 (2H, s), 3.75 (2H, s), 5.90 (2H, s), 6.32 (1H, dd, J = 8.5, 1.6 Hz), 6.65-6.78 (2H, m), 7.05-7.28 (4H, m).

Example 928

1H-NMR (DMSO-d6) δ: 1.03 (7H, d, J = 6.0 Hz), 2.35-2.46 (2H, m), 2.68-2.81 (2H, m), 3.55 (2H, s), 3.72 (3H , s), 3.79 (2H, s), 6.27 (1H, d, J = 2.2 Hz), 6.90-7.31 (8H, m).

Example 929

1H-NMR (DMSO-d6) δ: 1.03 (6H, d, J = 5.2 Hz), 2.61-2.76 (4H, m), 2.92-3.00 (2H, m), 3.53 (2H, s), 3.75 (2H , s), 3.83 (2H, d, J = 10.7 Hz), 6.93-7.28 (6H, m), 7.42 (1H, d, J = 8.5 Hz).

Example 930

1H-NMR (DMSO-d6) δ: 1.04 (6H, d, J = 6.0 Hz), 2.50-2.58 (2H, m), 2.66-2.78 (2H, m), 3.54 (2H, s), 3.66 (2H , d, J = 11.5 Hz), 3.78 (2H, s), 7.06-7.31 (5H, m), 7.59 (1H, d, J = 2.2 Hz), 7.87 (1H, d, J = 9.1 Hz), 9.07 (1H, s).

Example 931

1H-NMR (DMSO-d6) δ: 1.04 (6H, d, J = 6.0 Hz), 2.45-2.75 (7H, m), 3.54 (2H, s), 3.61 (2H, d, J = 10.7 Hz), 3.78 (2H, s), 7.06-7.39 (6H, m), 7.78 (1H, d, J = 8.8 Hz).

Example 932

1H-NMR (Acetone) δ: 7.49 (2.0H, d, J = 8.66 Hz), 7.40 (1.0H, s), 7.35 (1.0H, d, J = 7.42 Hz), 7.26 (1.0H, dd, J = 7.42, 7.42 Hz), 7.16 (1.0H, d, J = 7.42 Hz), 7.08 (2.0H, d, J = 8.66 Hz), 3.83 (2.0H, s), 3.75 (2.0H, d, J = 10.71 Hz), 3.62 (2.0H, s), 2.84-2.66 (4.0H, m), 1.09 (6.0H, d, J = 5.77 Hz).

Example 933

1H-NMR (Acetone) δ: 7.53-7.49 (2.0H, m), 7.41 (1.0H, s), 7.37-7.32 (3.0H, m), 7.29 (1.0H, d, J = 4.39 Hz), 7.25 (1.0H, d, J = 7.42 Hz), 7.20-7.13 (3.0H, m), 6.17 (1.0H, d, J = 3.85 Hz), 3.85 (2.0H, s), 3.63 (2.0H, s) , 3.43 (2.0H, d, J = 9.61 Hz), 2.86-2.83 (2.0H, m), 2.70-2.66 (2.0H, m), 1.09 (6.0H, d, J = 6.32 Hz).

Example 934

1H-NMR (DMSO-d6) δ: 8.72 (2H, s), 7.59-7.40 (2H, m), 7.13 (1H, t, J = 8.1Hz), 6.75 (1H, s), 6.66 (1H, s ), 6.54 (1H, s), 4.86 (1H, br-s), 4.56 (1H, d, J = 12.9Hz), 3.48-3.13 (3H, m), 2.86-2.72 (2H, m), 2.23 ( 3H, s), 2.10-1.90 (2H, m), 1.39 (1H, m), 0.91-0.87 (6H, m).

Example 935

1H-NMR (DMSO-d6) δ: 8.72 (2H, s), 6.75 (1H, s), 6.66 (1H, s), 6.54 (1H, s), 4.86 (1H, br-s), 4.56 (1H , d, J = 12.9Hz), 3.48-3.13 (3H, m), 2.86-2.72 (2H, m), 2.23 (3H, s), 2.10-1.90 (2H, m), 1.39 (1H, m), 0.91-0.87 (6H, m).

Example 936

1H-NMR (DMSO-d6) δ: 8.23 (1.0H, d, J = 7.22 Hz), 7.42 (1.0H, d, J = 12.42 Hz), 6.73 (1.0H, s), 6.65 (1.0H, s ), 6.54 (1.0H, s), 4.15-3.86 (2.0H, m), 3.53-3.20 (3.0H, m), 2.92-2.75 (2.0H, m), 2.24 (3.0H, s), 2.20- 2.05 (2.0H, m), 1.92-1.70 (2.0H, m), 1.52-1.48 (6.0H, m), 1.30-1.14 (2.0H, m), 0.90 (3.0H, t, J = 7.30 Hz) .

Example 937

MS (ESI) 534 [MH]-

Example 938

MS (ESI) 494 [MH]-

Example 939

MS (ESI) 508 [MH]-

Example 940

MS (ESI) 536 [MH]-

Example 941

1H-NMR (300MHz, DMSO-d6) δ 0.85 (3H, t, J = 7.2 Hz), 1.13-1.35 (4H, m), 1.50 (6H, s), 1.75-1.94 (2H, m), 2.12- 2.17 (2H, m), 2.24 (3H, s), 2.78-2.90 (2H, m), 3.33-3.53 (3H, m), 4.02 (2H, m), 6.54 (1H, s), 6.65 (1H, s), 6.74 (1H, s), 7.43 (1H, d, J = 12.0 Hz), 8.23 (1H, d, J = 7.2 Hz), 12.97 (1H, br s)

Example 942

MS (ESI) m / z 428 [M + H] +

Example 943

TLC_Rf = 0.55 (MeOH: CHCl3 = 1:10)

Example 944

1H-NMR (300MHz, DMSO-d6) d 0.83 (3H, t, J = 7.2 Hz), 1.06-1.33 (4H, m), 1.51 (6H, s), 1.61-1.91 (2H, m), 1.98- 2.05 (2H, m), 2.26 (3H, s), 2.78-2.90 (2H, m), 3.11-3.55 (3H, m), 4.55 (1H, d, = 12.3 Hz), 4.72 (1H, m), 6.54 (1H, s), 6.66 (1H, s), 6.75 (1H, s), 7.14 (1H, m), 7.45-7.55 (3H, m), 8.72 (2H, s)

化合物Ｉ−２

化合物Ｉ−３

化合物Ｉ−４

化合物Ｉ−５

化合物Ｉ−６

化合物Ｉ−７

化合物Ｉ−８

化合物Ｉ−９

化合物Ｉ−１０

化合物Ｉ−１１

化合物Ｉ−１２

化合物Ｉ−１３

化合物Ｉ−１４

化合物Ｉ−１５

化合物Ｉ−１６

化合物Ｉ−１７

化合物Ｉ−１８

化合物Ｉ−１９

化合物Ｉ−２０

化合物Ｉ−２１

化合物Ｉ−２２

化合物Ｉ−２３

化合物Ｉ−２４

化合物Ｉ−２５

化合物Ｉ−２６

化合物Ｉ−２７

化合物Ｉ−２８

化合物Ｉ−２９

化合物Ｉ−３０

化合物Ｉ−３１

化合物Ｉ−３２

化合物Ｉ−３３

化合物Ｉ−３４

化合物Ｉ−３５

化合物Ｉ−３６

化合物Ｉ−３７

化合物Ｉ−３８

化合物Ｉ−３９

化合物Ｉ−４０

化合物Ｉ−４１

化合物Ｉ−４２

化合物Ｉ−４３

化合物Ｉ−４４

化合物Ｉ−４５

化合物Ｉ−４６

化合物Ｉ−４７

化合物Ｉ−４８

化合物Ｉ−４９

化合物Ｉ−５０

化合物Ｉ−５１

化合物Ｉ−５２

化合物Ｉ−５３

化合物Ｉ−５４

化合物Ｉ−５５

化合物Ｉ−５６

化合物Ｉ−５７

化合物Ｉ−５８

化合物Ｉ−５９

化合物Ｉ−６０

化合物Ｉ−６１

化合物Ｉ−６２

化合物Ｉ−６３

化合物Ｉ−６４

化合物Ｉ−６５

化合物Ｉ−６６

化合物Ｉ−６７

化合物Ｉ−６８

化合物Ｉ−６９

化合物Ｉ−７０

化合物Ｉ−７１

化合物Ｉ−７２

化合物Ｉ−７３

化合物Ｉ−７４

化合物Ｉ−７５

化合物Ｉ−７６

化合物Ｉ−７７

化合物Ｉ−７８

化合物Ｉ−７９

化合物Ｉ−８０

The following compounds synthesized in the same manner are also included in the present invention.
Compound I-1

Compound I-2

Compound I-3

Compound I-4

Compound I-5

Compound I-6

Compound I-7

Compound I-8

Compound I-9

Compound I-10

Compound I-11

Compound I-12

Compound I-13

Compound I-14

Compound I-15

Compound I-16

Compound I-17

Compound I-18

Compound I-19

Compound I-20

Compound I-21

Compound I-22

Compound I-23

Compound I-24

Compound I-25

Compound I-26

Compound I-27

Compound I-28

Compound I-29

Compound I-30

Compound I-31

Compound I-32

Compound I-33

Compound 1-34

Compound I-35

Compound 1-36

Compound I-37

Compound I-38

Compound I-39

Compound I-40

Compound I-41

Compound 1-42

Compound I-43

Compound I-44

Compound I-45

Compound I-46

Compound I-47

Compound I-48

Compound I-49

Compound I-50

Compound I-51

Compound I-52

Compound I-53

Compound I-54

Compound I-55

Compound I-56

Compound I-57

Compound I-58

Compound I-59

Compound I-60

Compound I-61

Compound I-62

Compound I-63

Compound I-64

Compound I-65

Compound I-66

Compound I-67

Compound I-68

Compound I-69

Compound I-70

Compound I-71

Compound I-72

Compound I-73

Compound I-74

Compound I-75

Compound I-76

Compound I-77

Compound I-78

Compound I-79

Compound I-80

Test Example 1 Pharmacological Test of HDL Elevating Action A pharmacological test example of serum HDL cholesterol increasing action using mice is given.
13 to 30-week-old human ApoB / human CETP transgenic mice were divided into groups of 6 to 7 mice, and the test compound (3 mg / kg / day) was orally administered for 8 days. The control group was orally administered with a 0.5% aqueous methylcellulose solution (10 mL / kg) for 8 days. Blood was collected under ether light anesthesia before the start of administration and 2 to 4 hours after the final administration, and serum HDL cholesterol concentration was measured using Cholestest N HDL (Daiichi Chemical Co., Ltd.). At the time of grouping, animals were distributed so that the average values of body weight and serum HDL cholesterol level were almost equal among the test groups. The effect of the test compound was expressed as the rate of change on the last administration day before the start of administration (HDL cholesterol increase rate;% Initial), and was tested for a significant difference from the control group.
"result"
HDL-C (3mg / kg, po,% control)

Compound 686: 122% * Compound 824: 144% *
Compound 842: 152% * Compound 847: 121% *
Compound 833: 124% * Compound 846: 128% *
Compound 798: 136% * Compound 854: 142% *
Compound 869: 142% * Compound 860: 138% *
Compound 870: 129% * Compound 878: 120% *
Compound 890: 122% * Compound 894: 126% *
Test Example 2 Transcriptional Activation Test for PPARδ and α The PPAR gene transcription activation assay used a detection system for nuclear receptor activity by a chimeric transcription factor. That is, two plasmids, a plasmid expressing a fusion protein of a DNA binding domain of GAL4 which is a transcription factor of yeast and a ligand binding domain of a receptor, and a reporter plasmid are transiently transfected into CHO cells and encoded by the reporter plasmid. The activation degree of the receptor is detected by using the activity of the promoter containing the recognition sequence of GAL4 as an index.

  Plasmid: Human PPARδ (hPPARδ) and α (hPPARα) ligand-binding regions (δ: aa 139 to C terminus; α: aa 167 to C terminus) were obtained by PCR amplification using Human Universal Quick-Clone cDNA (CLONTECH). Obtained. Each amplified cDNA was subcloned into the pCR2.1-TOPO vector (Invitrogen) and then sequenced to confirm the base sequence. Each obtained cDNA fragment was further subcloned into a pBIND vector (Promega) to construct a plasmid expressing a fusion protein with the DNA binding domain of the yeast transcription factor GAL4. The reporter plasmid used was pG51uc vector (Promega).

  Cell culture and transfection: CHO cells were cultured in 10% FBS-αMEM. Using a 96-well plate (Costar), 20000 CHO cells exfoliated by trypsin treatment per well and 25 ng of each of the two plasmids obtained by the above procedure per well according to the manufacturer's instructions. Transfection was performed using FuGene reagent (Roche).

Measurement of transcription activation ability: 100 μl of CHO cells transfected by the above procedure were dispensed into each well in which 0.5 μl of a test compound dissolved in DMSO was spotted in advance. Both the cells and the test compound were cultured in a CO ₂ incubator for 24 hours, and then luciferase activity was measured by adding 100 μl per well of luciferase luminescent substrate Picker Gene LT2.0 (Toyo Ink). For the measurement, LUMINUSCT-9000D (DIA-IATRON) was used.

For PPARδ, the concentration of the test compound showing 1/2 of the saturated luminescence amount was calculated from the obtained luminescence amount with Excel, and the EC ₅₀ value in the PPARδ activation action of the test compound was calculated. The results are shown in Table 9.

Test Example 3 CYP2C9 Enzyme Inhibition Test The CYP2C9 enzyme inhibition test was carried out using human liver microsomes, using as an index the 4-position hydroxylation activity of tolbutamide, which is a typical reaction of CYP2C9.
Reaction conditions are as follows: substrate, 5 μM tolbutamide ( ¹⁴ C-labeled compound); reaction time, 30 minutes; reaction temperature, 37 ° C .; protein concentration, 0.25 mg / mL (human liver microsome, 15 pol, Lot. 210296, USA XenoTech).
A protein (human liver microsome), a drug solution, and a substrate were added to HEPES Buffer (pH 7.4) with the above composition, and NADPH, a coenzyme for the reaction, was added to initiate the reaction. After the reaction for a predetermined time, the reaction was stopped by adding 2N hydrochloric acid solution to remove protein. The remaining substrate drug and produced metabolite were extracted with chloroform, and the solvent was distilled off and redissolved with methanol. This was spotted on TLC, developed with chloroform: methanol: acetic acid = 90: 10: 1, contacted with an imaging plate for about 14 to 20 hours, and then analyzed with BAS2000. With respect to the activity to produce the metabolite tolbutamide 4-position hydroxide, calculate the residual activity (%) of the drug solution added to the reaction system with the drug dissolved solvent added to the reaction system (100%). In addition, it was confirmed that the compound used in the present invention has little inhibition of the CYP2C9 enzyme.

Test example 4
Metabolic stability Evaluation of metabolic stability by liver microsomes: NADPH (final concentration 1 mM, in case of oxidative metabolism), liver microsomes (final concentration 0.5 mg protein / ml) and each compound (Tris-HCl buffer (pH 7.4)) (Final concentration 2 μM) was added and reacted at 37 ° C. for 0 and 30 minutes. In the case of glucuronidation, UDPGA (final concentration 5 mM) was added instead of NADPH. The reaction was stopped by adding acetonitrile / methanol = 1/1 (v / v) twice the amount of the reaction solution, and then the compound in the centrifugal supernatant was measured by HPLC. The amount of disappearance due to metabolic reaction was calculated from a comparison of values of 0 and 30 minutes, and the metabolic stability of the compound used in the present invention was confirmed.

Test Example 5
Solubility The compound used in the present invention and the measurement solvent (JP-2 solution, 20 mM sodium taurocholate-containing JP-2 solution) are stirred at 37 ° C. for 3 hours and then filtered through a 0.45 μm filter. The concentration of the filtrate is determined by HPLC. Measured by the method, the solubility of the compound used in the present invention was confirmed.

Test Example 6
Toxicity Rats are administered the compound used in the present invention (30-300 mg / kg / day). The number of deaths, status, food intake, and body weight of the rats after administration will be confirmed, and histopathological examinations will be conducted.
As a hematological test, blood is collected several days after administration, and PT, APTT, and Fbg are examined after blood treatment. The activities of extrinsic blood coagulation factors (F-II, FV, F-VII, FX) and endogenous blood coagulation factors (F-VIII, F-IX, F-XI, F-XII) are measured. Extrinsic blood coagulation factor and intrinsic blood coagulation factor were measured by adding PT-deficient plasma (Dade Behringmarburg) to rat plasma, preincubation, PT measurement method (exogenous system) and APTT measurement method ( The clotting time is measured by the intrinsic system. A standard curve was prepared by mixing the plasma of the control group rat plasma, and the plasma was serially diluted with Oren Veronal buffer. The clotting time and calibration curve measured by the clotting time method using factor-deficient plasma. The percent activity is calculated from and each clotting factor activity is assessed by the percent activity against the plasma of untreated rats.
From the above, the toxicity of the compound used in the present invention can be confirmed.

Claims (19)

Formula (I):

Ring Q is an optionally substituted monocyclic aryl, an optionally substituted monocyclic heteroaryl, an optionally substituted fused aryl or an optionally substituted heteroaryl (provided that ring Q is unsubstituted 11H-Dibenz [b, e] -azepin-6-yl)
Y ¹ is a single bond, —NR ⁶ — or —NR ⁶ —CO— (wherein R ⁶ is hydrogen or optionally substituted lower alkyl);
Provided that when ring Q is unsubstituted monocyclic aryl, Y ¹ is —NR ⁶ —CO—;
When ring Q is monocyclic aryl and Y ¹ is a single bond, ring Q is phenyl substituted with an alkyl halide;
Ring A is an optionally substituted non-aromatic heterocyclic diyl (provided that when Y ¹ is a single bond, ring Q is bonded to a nitrogen atom constituting ring A);
Formula: ^-Y 2 Z ¹ - is

(Wherein —Y ² Z ¹ — is not —SO ₂ —, and when ring Q is unsubstituted benzothiazol-2-yl or benzoxazol-2-yl, —Y ² Z ¹ — is — CH ₂ —CH ₂ —O— or not —O—),
Each R ⁷ is independently hydrogen, optionally substituted lower alkyl or optionally substituted cycloalkyl;
R ⁸ and R ⁹ are each independently hydrogen or optionally substituted lower alkyl,
n is an integer from 0 to 3,
Z ¹ is a single bond, —O—, —S— or —NR ⁹ — (wherein R ⁹ is hydrogen, optionally substituted lower alkyl, optionally substituted acyl, optionally substituted lower) Alkylsulfonyl or optionally substituted arylsulfonyl),
Ring B is an optionally substituted aromatic carbocyclic diyl or an optionally substituted aromatic heterocyclic diyl;
Y ³ is a single bond, which may be substituted, -O- may be interposed with lower alkylene, -O- may be interposed with cycloalkylene or optionally substituted lower alkenylene,
Z ² is COOR ³ , C (= NR ³ ) NR ¹⁴ OR ¹⁵ , CONHCN,

(Wherein R ³ , R ¹⁴ and R ¹⁵ are each independently hydrogen, optionally substituted lower alkyl, optionally substituted lower alkenyl, optionally substituted aryl, or optionally substituted. Is heteroaryl),
(However, the formula: ^-Y 2 Z ¹ - is

Except when n is 0 and Z ¹ is a single bond)
Or a pharmaceutically acceptable salt thereof, or a solvate thereof. Ring A is

[Wherein X ⁴ is N or CR ⁵ (where R ⁵ is hydrogen or optionally substituted lower alkyl) and X ⁵ is O, S, NR ¹⁶ or CR ¹⁷ R ¹⁸ (where R ⁵ is R ^{16 to} R ¹⁸ are each independently hydrogen, optionally substituted lower alkyl, cyano, optionally substituted non-aromatic heterocyclic group, optionally substituted heteroaryl, substituted It may be amino, optionally substituted lower alkoxy, aryl lower alkyl or optionally substituted cycloalkyl). However, the case where X ⁴ is CR ⁵ and X ⁵ is CR ¹⁷ R ¹⁸ is excluded. Each R ⁴ is independently halogen, optionally substituted lower alkyl, optionally substituted lower alkenyl, optionally substituted lower alkynyl, optionally substituted lower alkoxy, or substituted And m is an integer of 0-2. Bond from X ⁴ is bonded to Y ^1, the other bond is bound to Y ^2. When X ⁵ is NR ¹⁶ or CR ¹⁷ R ¹⁸ , the other bond may be bonded to X ⁵ . The HDL raising agent containing the compound of Claim 1 which is a group shown by this, its pharmaceutically acceptable salt, or those solvates. Ring A is

[Where X ⁴ is N or CR ⁵ (where R ⁵ is hydrogen or optionally substituted lower alkyl) and X ⁵ is NR ¹⁶ or CR ¹⁷ R ¹⁸ (where R ^{16 to} R ¹⁸ Are each independently hydrogen, optionally substituted lower alkyl, cyano, optionally substituted non-aromatic heterocyclic group, optionally substituted heteroaryl, optionally substituted amino, Optionally substituted lower alkoxy, aryl lower alkyl or optionally substituted cycloalkyl). Each R ⁴ is independently halogen, optionally substituted lower alkyl, optionally substituted lower alkenyl, optionally substituted lower alkynyl, optionally substituted lower alkoxy, or substituted And m is an integer of 0-2. Bond from X ⁴ is bonded to Y ^1, the other bond is bound to Y ^2. Bonds of the other side may be bonded to X ^5. The HDL raising agent containing the compound of Claim 1 which is a group shown by this, its pharmaceutically acceptable salt, or those solvates. Ring A is

(R ⁴ is each independently halogen, optionally substituted lower alkyl, optionally substituted lower alkenyl, optionally substituted lower alkynyl or optionally substituted lower alkoxy, m Is an integer of 1 or 2. An HDL-elevating agent containing the compound according to claim 1, a pharmaceutically acceptable salt thereof, or a solvate thereof. Ring A is

(R ¹⁷ is optionally substituted lower alkyl, cyano, optionally substituted non-aromatic heterocyclic group, optionally substituted heteroaryl, optionally substituted amino, substituted A lower alkoxy group, an aryl lower alkyl group, or an optionally substituted cycloalkyl group, a bond from N is bonded to Y ^1, and a bond from C is bonded to Y ² . The HDL raising agent containing the compound according to claim 1, a pharmaceutically acceptable salt thereof or a solvate thereof. Ring A is

[Where X ⁴ is N or CR ⁵ (where R ⁵ is hydrogen or optionally substituted lower alkyl) and X ⁵ is NR ¹⁶ or CR ¹⁷ R ¹⁸ (where R ^{16 to} R ¹⁸ Are each independently hydrogen, optionally substituted lower alkyl, cyano, optionally substituted non-aromatic heterocyclic group, optionally substituted heteroaryl, optionally substituted amino, Optionally substituted lower alkoxy, aryl lower alkyl or optionally substituted cycloalkyl). However, the case where X ⁴ is CR ⁵ and X ⁵ is CR ¹⁷ R ¹⁸ is excluded. Each R ⁴ is independently halogen, optionally substituted lower alkyl, optionally substituted lower alkenyl, optionally substituted lower alkynyl, optionally substituted lower alkoxy, or substituted And m is an integer of 0-2. Bond from X ⁴ is bonded to Y ^1, the other bond is bound to Y ^2. Bonds of the other side may be bonded to X ^5. The HDL raising agent containing the compound of Claim 1 which is a group shown by this, its pharmaceutically acceptable salt, or those solvates. The HDL raising agent containing the compound of Claim 1 or 2 whose ring Q is substituted substituted heteroaryl, its pharmaceutically acceptable salt, or those solvates. Ring Q substituted benzofuryl, substituted benzothienyl, substituted benzopyrrolyl, substituted benzoxazolyl, substituted benzoisoxazolyl, substituted benzothiazolyl, substituted benzoisothiazolyl, substituted A HDL-elevating agent containing the compound according to claim 1 or 2, a pharmaceutically acceptable salt thereof, or a solvate thereof, wherein the benzimidazolyl is substituted or substituted benzopyrazolyl. formula:

Is the formula:

[Where:
R ¹ is hydrogen, halogen, hydroxy, optionally substituted lower alkyl, optionally substituted lower alkenyl, optionally substituted lower alkynyl, optionally substituted lower alkoxy, or optionally substituted Good aryl,
R ² is halogen, optionally substituted alkyl, optionally substituted aryl, optionally substituted aryloxy, optionally substituted arylthio, or optionally substituted heteroaryl, or R ¹ and R ² may form a substituted fused heteroaryl together with a 5-membered ring containing adjacent carbon atoms, X ¹ and X ³ as constituent atoms,
X ¹ is N or CR ¹⁰ ,
X ³ is NR ¹¹ , O or S,
Wherein R ¹⁰ and R ¹¹ are each independently hydrogen or optionally substituted lower alkyl], or a pharmaceutically acceptable salt thereof. HDL elevating agent containing a salt or a solvate thereof. formula:

Is the formula:

[Where:
R ¹ is hydrogen, halogen, hydroxy, optionally substituted lower alkyl, optionally substituted lower alkenyl, optionally substituted lower alkynyl, or optionally substituted lower alkoxy,
R ² is halogen, optionally substituted alkyl, optionally substituted aryl, optionally substituted aryloxy, optionally substituted arylthio, or optionally substituted heteroaryl, or R ¹ and R ² may form a substituted fused heteroaryl together with a 5-membered ring containing adjacent carbon atoms, X ¹ and X ³ as constituent atoms,
X ¹ is N or CR ¹² ,
X ³ is NR ¹³ , O or S,
Wherein R ¹² and R ¹³ are each independently hydrogen or optionally substituted lower alkyl], or a pharmaceutically acceptable salt thereof. HDL elevating agent containing a salt or a solvate thereof. formula:

Is the formula:

[Where:
R ¹ is independently hydrogen, halogen, hydroxy, optionally substituted lower alkyl, optionally substituted lower alkenyl, optionally substituted lower alkynyl, or optionally substituted lower alkoxy. ,
R ² is halogen, optionally substituted alkyl, optionally substituted aryl, optionally substituted aryloxy, optionally substituted arylthio or optionally substituted heteroaryl;
X ¹ is N or CR ¹⁹ ,
X ³ is N or CR ²⁰
Wherein R ¹⁹ and R ²⁰ are each independently hydrogen or optionally substituted lower alkyl, provided that either X ¹ or X ³ is N. The HDL raising agent containing the compound according to claim 1 or 2, its pharmaceutically acceptable salt, or a solvate thereof. Formula: ^-Y 2 Z ¹ - is

A group represented by
R ⁸ and R ⁹ are each independently hydrogen or lower alkyl,
n is an integer from 0 to 2,
The HDL raising agent containing the compound according to claim 1 or 2, a pharmaceutically acceptable salt thereof, or a solvate thereof, wherein Z ¹ is a single bond, -O- or -S-. Ring B is optionally substituted phenylene, optionally substituted indolediyl, optionally substituted benzofurandiyl, optionally substituted benzothiophenediyl, optionally substituted furandyl, or substituted The HDL raising agent containing the compound, its pharmaceutically acceptable salt, or those solvates of Claim 1 or 2 which is the thiophene diyl which may be said. Y ³ is a single bond, an unsubstituted or substituted lower alkylene optionally, -O- optionally substituted lower alkylene or optionally substituted lower alkenylene, according to claim 1 or 2 A compound according, pharmaceutically HDL elevating agents containing acceptable salts or solvates thereof. The compound according to claim 1 or 2, a pharmaceutically acceptable salt thereof or a solvate thereof, wherein Z ² is COOR ³ (wherein R ³ is hydrogen or optionally substituted lower alkyl). Contains HDL raising agent. formula:

Is the formula:

[Where:
R ¹ is hydrogen;
R ² is an optionally substituted aryl, or R ¹ and R ² are fused heteroaryl substituted together with a 5-membered ring containing adjacent carbon atoms, X ¹ and X ³ as constituent atoms. May form,
X ¹ is N or CR ¹⁰ (where R ¹⁰ is hydrogen);
X ³ is O or S],
Y ¹ is a single bond,
Ring A is

[Wherein X ⁴ is N and X ⁵ is NR ¹⁶ or CR ¹⁷ R ¹⁸ (where R ^{16 to} R ¹⁸ are each independently hydrogen, optionally substituted lower alkyl, cyano, substituted May be a non-aromatic heterocyclic group, an optionally substituted heteroaryl, an optionally substituted amino, an optionally substituted lower alkoxy, an aryl lower alkyl or an optionally substituted cycloalkyl; Yes). Each R ⁴ is independently halogen, optionally substituted lower alkyl, optionally substituted lower alkenyl, optionally substituted lower alkynyl, optionally substituted lower alkoxy, or substituted And m is an integer of 0-2. Bond from X ⁴ is bonded to Y ^1, the other bond is bound to Y ^2. Bonds of the other side may be bonded to X ^5. Is a group represented by
Formula: ^-Y 2 Z ¹ - is

A group represented by
R ⁸ and R ⁹ are each independently hydrogen or lower alkyl,
n is an integer from 0 to 2,
Z ¹ is a single bond, —O— or —S—,
Ring B may be substituted phenylene (substituent is halogen, lower alkyl or lower alkoxy), may be substituted furanyl (substituent is halogen, lower alkyl or lower alkoxy) or substituted Optionally substituted thiophenediyl (as a substituent, halogen, lower alkyl or lower alkoxy),
Y ³ is a single bond, optionally substituted lower alkylene (substituent is halogen or lower alkylene), -O-optionally substituted lower alkylene (substituent is lower alkylene or halogen), substituted Lower alkenylene which may be substituted (as the substituent, lower alkylene or halogen),
The HDL raising agent containing the compound according to claim 1, a pharmaceutically acceptable salt thereof or a solvate thereof, wherein Z ² is COOR ³ (wherein R ³ is hydrogen or lower alkyl). formula:

Is the formula:

(Where
R ¹ is independently hydrogen, halogen, hydroxy, optionally substituted lower alkyl, optionally substituted lower alkenyl, optionally substituted lower alkynyl, or optionally substituted lower alkoxy. ,
R ² is alkyl which may be substituted or aryl which may be substituted, and X ¹ is N or CR ¹⁹ ,
X ³ is N or CR ²⁰
Wherein R ¹⁹ and R ²⁰ are each independently hydrogen or optionally substituted lower alkyl, provided that either X ¹ or X ³ is N. And
Y ¹ is a single bond,
Ring A is

[Wherein X ⁴ is N and X ⁵ is NR ¹⁶ or CR ¹⁷ R ¹⁸ (where R ^{16 to} R ¹⁸ are each independently hydrogen, optionally substituted lower alkyl, cyano, substituted May be a non-aromatic heterocyclic group, an optionally substituted heteroaryl, an optionally substituted amino, an optionally substituted lower alkoxy, an aryl lower alkyl or an optionally substituted cycloalkyl; Yes). Each R ⁴ is independently halogen, optionally substituted lower alkyl, optionally substituted lower alkenyl, optionally substituted lower alkynyl, optionally substituted lower alkoxy, or substituted And m is an integer of 0-2. Bond from X ⁴ is bonded to Y ^1, the other bond is bound to Y ^2. Bonds of the other side may be bonded to X ^5. Is a group represented by
Formula: ^-Y 2 Z ¹ - is

A group represented by
R ⁸ and R ⁹ are each independently hydrogen or lower alkyl,
n is an integer from 0 to 2,
Z ¹ is a single bond, —O— or —S—,
Ring B may be substituted phenylene (substituent is halogen, lower alkyl or lower alkoxy), may be substituted furanyl (substituent is halogen, lower alkyl or lower alkoxy) or substituted Optionally substituted thiophenediyl (as a substituent, halogen, lower alkyl or lower alkoxy),
Y ³ is a single bond, optionally substituted lower alkylene (substituent is halogen or lower alkylene), -O-optionally substituted lower alkylene (substituent is lower alkylene or halogen), substituted Lower alkenylene which may be substituted (as the substituent, lower alkylene or halogen),
The HDL raising agent containing the compound according to claim 1, a pharmaceutically acceptable salt thereof or a solvate thereof, wherein Z ² is COOR ³ (wherein R ³ is hydrogen or lower alkyl). Y ¹ is a single bond,
Ring A is

(R ⁴ is each independently halogen, optionally substituted lower alkyl, optionally substituted lower alkenyl, optionally substituted lower alkynyl or optionally substituted lower alkoxy, m Is an integer of 1 or 2.)
Formula: ^-Y 2 Z ¹ - is

A group represented by
R ⁸ and R ⁹ are each independently hydrogen or lower alkyl,
n is an integer of 1 to 2,
Z ¹ is a single bond or —O—,
Ring B is an optionally substituted phenylene,
Y ³ is optionally substituted lower alkylene (substituent is halogen or lower alkylene) or —O-substituted lower alkylene (substituent is lower alkylene or halogen);
The HDL raising agent containing the compound according to claim 1, a pharmaceutically acceptable salt thereof or a solvate thereof, wherein Z ² is COOR ³ (wherein R ³ is hydrogen or lower alkyl). Y ¹ is a single bond,
Ring A is

(R ¹⁷ is optionally substituted lower alkyl, cyano, optionally substituted non-aromatic heterocyclic group, optionally substituted heteroaryl, optionally substituted amino, substituted A lower alkoxy group which may be substituted, an aryl lower alkyl group or an optionally substituted cycloalkyl group, a bond from N is bonded to Y ^1, and a bond from C is bonded to Y ² . And
Formula: ^-Y 2 Z ¹ - is

A group represented by
R ⁸ and R ⁹ are each independently hydrogen or lower alkyl,
n is 2,
Z ¹ is —O—,
Ring B is an optionally substituted phenylene,
Y ³ is optionally substituted lower alkylene (substituent is halogen or lower alkylene) or —O-substituted lower alkylene (substituent is lower alkylene or halogen);
The HDL raising agent containing the compound according to claim 1, a pharmaceutically acceptable salt thereof or a solvate thereof, wherein Z ² is COOR ³ (wherein R ³ is hydrogen or lower alkyl).