JP2014005245A - Pharmaceutical composition containing bicyclic pyrimidine derivative - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a pharmaceutical composition containing a compound which has a MGAT inhibitory effect and is useful as a pharmaceutical or a physiologically acceptable salt of the compound.SOLUTION: The pharmaceutical composition contains a bicyclic pyrimidine compound represented by the formula (I) or a physiologically acceptable salt of the compound (where Rrepresents an optionally substituted lower alkyl group or the like, Rrepresents a hydrogen atom or the like, Rrepresents a hydrogen atom or the like, Rand Reach independently represents a hydrogen atom or the like, X represents an oxygen atom or the like, Y represents -N(R)C(=Z)- (where Rrepresents a hydrogen atom or the like, Z represents an oxygen atom or the like) or the like, m represents 1, n represents 2).

Description

  The present invention relates to a pharmaceutical composition comprising a compound having a biacyl pyrimidine structure or a physiologically acceptable salt thereof, which has a monoacylglycerol acyltransferase (hereinafter also referred to as “MGAT”) inhibitory action.

  In recent years, so-called lifestyle-related diseases such as diabetes, hyperlipidemia, and hypertension have increased remarkably. In the modern society of overnutrition and lack of exercise, it is a big foundation that fat tissue is accumulated excessively, that is, obesity is increasing. It is therefore important to treat obesity. In Japan, guidelines for diagnosing and treating obesity as a disease called obesity have been published. BMI (body mass index) of 25 or more, caused by or related to obesity, and as a health disorder requiring weight loss, type 2 diabetes, impaired glucose tolerance, abnormal lipid metabolism, hypertension, hyperuricemia / gout, coronary artery disease, brain Obesity is caused by infarction, sleep apnea syndrome, fatty liver, orthopedic disease, menstrual abnormalities, or urine protein. Even in the absence of such a health disorder, obesity is considered to be a visceral fat type obesity.

  Diet and exercise therapy are used to treat obesity, but drug therapy is also used if there is not enough improvement. As anti-obesity drugs, fat absorption inhibitor orlistat, central appetite suppressants mazindol, sibutramine and the like are known, but none of them are sufficiently satisfactory in terms of medicinal effects and side effects. Therefore, the development of a drug that is superior in terms of both drug efficacy and side effects is desired.

  Neutral fat (triglycerol (TG)) ingested by meals is broken down into fatty acids and monoacylglycerol (MG) by pancreatic lipase in the digestive tract, forming micelles, and absorbed by small intestinal epithelial cells. The absorbed fatty acid becomes acyl-CoA by acyl-CoA synthase. Furthermore, diacylglycerol (DG) is synthesized from MG and acyl-CoA by monoacylglycerol acyltransferase (MGAT), and TG is re-synthesized from DG and acyl-CoA by diacylglycerol acyltransferase (DGAT). The synthesized TG associates with cholesterol ester and apoprotein by microsomal triglycerol transfer protein (MTP), becomes chylomicron, is secreted into the blood via lymphatic vessels, and is transported to peripheral tissues.

  As described above, MGAT catalyzes the reaction of synthesizing DG from MG and acyl-CoA, and plays an important role in the process of fat absorption from the small intestine. However, research has not progressed due to the difficulty of purification, and genes have recently been identified. Three molecular species (MGAT1, MGAT2, and MGAT3) have been cloned and reported so far (Proceedings of the Narional Academy of Sciences, 99, 8512-8517, 2002; Jounal of Biological Chemistry, 278, 18532-18537, 2003; Journal of Biological Chemistry, 278, 13860-13866, 2003; American Journal of Physiology, 285, E927-E937, 2003; Journal of Biological Chemistry, 278, 13611-13614, 2003). MGAT1 was expressed in the stomach and kidney and was not detected in the small intestine. On the other hand, MGAT2 was highly expressed in the small intestine. The gene of MGAT3 has been reported only in humans and was specifically expressed in the small intestine. Therefore, it is speculated that MGAT2 and MGAT3 are involved in fat absorption in the small intestine.

  In OLETF rats exhibiting obesity or hyperTG, increased MGAT activity in the small intestine has been reported, suggesting the involvement of MGAT in obesity or hyperTG (Diabetes Research and Clinical Practice, 57, 75-82, 2002). Further, in the small intestine of obese db / db mice and DIO (diet induced obesity) mice, an increase in the amount of MGAT2 protein and an increase in MGAT activity have been reported, suggesting an involvement in obesity (Journal of Biological Chemistry, 279, 18878-18886, 2004). Furthermore, it has been reported that MGAT2 gene-deficient mice are resistant to the induction of obesity and insulin resistance by a high fat diet (see Nature Medicine, 15, 442-446, 2009).

On the other hand, the compounds described in Patent Documents 1 and 2 have been reported as compounds having an MGAT inhibitory action and a bicyclic pyrimidine structure. In addition, compounds described in Patent Documents 3 and 4 have been reported as compounds having a GPR119 action and having a bicyclic pyrimidine structure.
However, specific compounds having an azetidine structure, which is one of the features of the present invention, are not described in these patent documents.

International Publication No. 2008/038768 International Publication No. 2010/095767 International Publication No. 2008/130581 International Publication No. 2008/130584

  The subject of this invention is providing the pharmaceutical composition containing the compound which has MGAT inhibitory effect useful as a pharmaceutical, or its physiologically acceptable salt.

  The inventors of the present invention have considered that if MGAT activity in the small intestine is inhibited, fat absorption from the small intestine is suppressed and effective against obesity, and as a result of intensive studies, the present inventors have expressed two formulas (I) below. A compound having a cyclic pyrimidine structure (hereinafter also referred to as “the compound of the present invention”) and physiologically acceptable salts thereof have an MGAT inhibitory action and a fat absorption inhibitory action, thereby completing the present invention. did. That is, the present invention is as follows.

［式中、
Ｒ^１は水素原子、置換されていてもよい低級アルキル基、置換されていてもよい低級アルケニル基、置換されていてもよい低級シクロアルキル基、置換されていてもよい低級シクロアルケニル基、置換されていてもよいフェニル基、置換されていてもよいナフチル基又は置換されていてもよい飽和若しくは不飽和のヘテロ環基を表し、
Ｒ^２は水素原子、置換されていてもよい低級アルキル基、置換されていてもよい低級アルケニル基、置換されていてもよい低級アルキニル基、置換されていてもよい低級シクロアルキル基、置換されていてもよい低級シクロアルケニル基、置換されていてもよい低級アルカノイル基、置換されていてもよいフェニルカルボニル基、置換されていてもよいフェニル基、置換されていてもよいナフチル基又は置換されていてもよい飽和若しくは不飽和のヘテロ環基を表し、
Ｒ^３は水素原子、置換されていてもよいアルキル基、置換されていてもよいアルケニル基、置換されていてもよいアルキニル基、置換されていてもよい低級シクロアルキル基、置換されていてもよい低級シクロアルケニル基、置換されていてもよいフェニル基、置換されていてもよいナフチル基又は置換されていてもよい飽和若しくは不飽和のヘテロ環基を表し、
但し、Ｒ^３はベンゾイルではなく、
Ｒ^４及びＲ^５は、各々独立して、水素原子、ハロゲン原子、置換されていてもよい低級アルキル基、置換されていてもよいＣ_３−６シクロアルキル基、ＯＨ又はＯＲ^４ｂ（式中、Ｒ^４ｂは置換されていてもよいＣ_１−６アルキル基又は置換されていてもよいＣ_３−６シクロアルキル基を表す）を表し、
Ｘは酸素原子、硫黄原子、−Ｎ（Ｒ^６）−又は−Ｃ（Ｒ^７）（Ｒ^８）−（式中、Ｒ^６は水素原子、置換されていてもよい低級アルキル基又は置換されていてもよいフェニル基を表し、あるいは、Ｒ^２とＲ^６が一緒になって環状アミノを形成してもよく、Ｒ^７及びＲ^８は、各々独立して、水素原子、ハロゲン原子、置換されていてもよい低級アルキル基、置換されていてもよいＣ_３−６シクロアルキル基又は置換されていてもよいフェニル基を表し、あるいは、Ｒ^７とＲ^８が一緒になってシクロアルキル環を形成してもよい）を表し、
Ｙは下記式（ＩＩ）、（ＩＩＩ）、（ＩＶ）又は（Ｖ）から選ばれるいずれかを表し：

（式中、Ｒ^９は水素原子、置換されていてもよい低級アルキル基、置換されていてもよい低級シクロアルキル基、置換されていてもよいフェニル基又は置換されていてもよい飽和若しくは不飽和のヘテロ環基を表し、Ｚは酸素原子又は硫黄原子を表す）、
ｍは１を表し、
ｎは２を表す］。 [1] A pharmaceutical composition comprising a bicyclic pyrimidine compound represented by formula (I) or a physiologically acceptable salt thereof:

[Where:
R ¹ represents a hydrogen atom, an optionally substituted lower alkyl group, an optionally substituted lower alkenyl group, an optionally substituted lower cycloalkyl group, an optionally substituted lower cycloalkenyl group, a substituted An optionally substituted phenyl group, an optionally substituted naphthyl group or an optionally substituted saturated or unsaturated heterocyclic group;
R ² represents a hydrogen atom, an optionally substituted lower alkyl group, an optionally substituted lower alkenyl group, an optionally substituted lower alkynyl group, an optionally substituted lower cycloalkyl group, a substituted An optionally substituted lower alkenyl group, an optionally substituted lower alkanoyl group, an optionally substituted phenylcarbonyl group, an optionally substituted phenyl group, an optionally substituted naphthyl group or a substituted Represents a saturated or unsaturated heterocyclic group,
R ³ is a hydrogen atom, an optionally substituted alkyl group, an optionally substituted alkenyl group, an optionally substituted alkynyl group, an optionally substituted lower cycloalkyl group, or optionally substituted. A lower cycloalkenyl group, an optionally substituted phenyl group, an optionally substituted naphthyl group or an optionally substituted saturated or unsaturated heterocyclic group;
However, R ³ is not benzoyl,
R ⁴ and R ⁵ are each independently a hydrogen atom, a halogen atom, an optionally substituted lower alkyl group, an optionally substituted C _3-6 cycloalkyl group, OH or OR ^4b (wherein R ^4b represents an ^optionally substituted C _1-6 alkyl group or an optionally substituted C _3-6 cycloalkyl group),
X is an oxygen atom, a sulfur atom, -N (R ⁶ )-or -C (R ⁷ ) (R ⁸ )-(wherein R ⁶ is a hydrogen atom, an optionally substituted lower alkyl group or a substituted group). R ² and R ⁶ may be combined to form a cyclic amino, and R ⁷ and R ⁸ are each independently a hydrogen atom, a halogen atom, or a substituted group. Represents an optionally substituted lower alkyl group, an optionally substituted C _3-6 cycloalkyl group or an optionally substituted phenyl group, or R ⁷ and R ⁸ together form a cycloalkyl ring. May represent)
Y represents any one selected from the following formulas (II), (III), (IV) or (V):

(In the formula, R ⁹ is a hydrogen atom, an optionally substituted lower alkyl group, an optionally substituted lower cycloalkyl group, an optionally substituted phenyl group, or an optionally substituted saturated or unsaturated group. And Z represents an oxygen atom or a sulfur atom),
m represents 1,
n represents 2.]

［式中、各記号は［１］に定義されるとおりである］。 [2] The pharmaceutical composition according to [1], wherein the bicyclic pyrimidine compound represented by formula (I) or a physiologically acceptable salt thereof is represented by formula (Ia):

[Wherein each symbol is as defined in [1]].

［式中、
Ｒ^ａ２ａ、Ｒ^ａ２ｂ、Ｒ^ａ２ｃ、Ｒ^ａ２ｄ、Ｒ^ｂ２、Ｒ^ａ２ｆ及びＲ^ａ２ｇは、各々独立して、水素原子、ハロゲン原子、ＣＦ_３、ＣＮ、ＯＨ、Ｃ_１−６アルキル基、Ｃ_１−６アルコキシ基（ここに当該Ｃ_１−６アルキル基及びＣ_１−６アルコキシ基はＣＯ_２Ｈ又はＣＯ_２ＣＲ^１ｇ１Ｒ^１ｇ２Ｒ^１ｇ３で置換されていてもよい（ここに、Ｒ^１ｇ１、Ｒ^１ｇ２及びＲ^１ｇ３は、各々独立して、
水素原子、
Ｃ_１−４アルキル基（該基はＯＨ、Ｃ_１−４アルコキシ基、Ｃ_１−４アルコキシ基で置換されていてもよいＣ_３−６シクロアルキル基、５員若しくは６員の飽和ヘテロ環基、５員若しくは６員の飽和ヘテロ環オキシ基、又はＮＲ^１ｂ１Ｒ^１ｂ２で置換されていてもよく、Ｒ^１ｂ１及びＲ^１ｂ２は、各々独立して、水素原子又はＣ_１−１０アルキル基を表す）、
Ｃ_３−１０シクロアルキル基（該基は、フッ素原子及びＣ_１−４アルコキシ基から選ばれる１〜２個の置換基で置換されていてもよい）、
Ｃ_６−１０アリール基（該基はハロゲン原子又はＣ_１−４アルコキシで置換されていてもよい）、
５員若しくは６員の飽和ヘテロ環基、又は
５員〜１０員のヘテロアリール基（該基はＣ_１−４アルキル基又はＣ_１−４アルコキシ基で置換されていてもよい）を表し、
あるいは、Ｒ^１ｇ１とＲ^１ｇ２はこれらが結合する炭素原子と一緒になって３〜８員のシクロアルキル環又は５員若しくは６員の飽和ヘテロ環を形成してもよい））、
Ｃ_１−６アルキルカルボニル基、ＣＯ_２Ｒ^１ａ、ＮＲ^１ｂＲ^１ｃ又はＣ（＝Ｏ）ＮＲ^１ｄＲ^１ｅを表し、かつ、
Ｒ^ａ２ａ、Ｒ^ａ２ｂ、Ｒ^ａ２ｃ、Ｒ^ａ２ｄ、Ｒ^ａ２ｆ及びＲ^ａ２ｇは化学的に許容される限り、任意の位置にて複数個置換してもよく、
Ｒ^ａ２ｎは水素原子、ＣＦ_３、ＣＮ、Ｃ_１−６アルキル基、Ｃ_１−６アルキルカルボニル基、ＣＯ_２Ｒ^１ａ、ＮＲ^１ｂＲ^１ｃ又はＣ（＝Ｏ）ＮＲ^１ｄＲ^１ｅを表し、
Ｒ^１ａ、Ｒ^１ｂ、Ｒ^１ｃ、Ｒ^１ｄ及びＲ^１ｅは、各々独立して、水素原子又はＣ_１−１０アルキル基を表し、あるいは、Ｒ^１ｂとＲ^１ｃ、又はＲ^１ｄとＲ^１ｅはこれらがそれぞれ結合するＮと一緒になって４〜８員の環状アミノ基又はモルホリニル基を形成してもよく、
Ｒ^ｄ２ｅ及びＲ^ｅ２ｅは、相互に独立して、かつ、各基が複数ある場合には各々独立して、水素原子、ＯＨ、Ｃ_１−６アルキル基、ＣＯ_２Ｈ、ＣＯ_２−Ｃ_１−６アルキル基、Ｃ_１−６アルコキシ基又はフェニル基（ここに、当該フェニル基はハロゲン原子、ＣＦ_３、Ｃ_１−４アルキル基、ＣＯ_２Ｈ、ＣＯ_２−Ｃ_１−６アルキル基又はＣ_１−４アルコキシ基で置換されていてもよい）を表し、
あるいは、Ｒ^ｄ２ｅとＲ^ｅ２ｅはこれらが結合する一の炭素原子と一緒になって３〜８員のシクロアルキル環を形成してもよく、
あるいは、０〜３の炭素原子を介して隣接する炭素原子上に結合する２つのＲ^ｄ２ｅが、これらが結合する２つの炭素原子、及び当該炭素原子間の炭素鎖と一緒になって４〜８員のシクロアルキル環を形成してもよく、
Ｘ^２ｄは酸素原子又は−Ｎ（Ｒ^ｃ２）−（式中、Ｒ^ｃ２は水素原子又はＣ_１−１０アルキル基を表す）を表し、
Ｘ^２ｇは酸素原子又は硫黄原子を表し、
ｎ^２ａ、ｎ^２ｂ、ｐ^２ｃ、ｐ^２ｄ、ｎ^２ｆ及びｎ^２ｇは０〜４の整数を表し、
ｎ^２ｃは１〜６の整数を表し、
ｍ^２ｄは１〜３の整数を表し、
ｎ^２ｄは０〜３の整数を表し、
ｎ^２ｅは０〜８の整数を表す］；
Ｒ^２が下記式（３ａ）、（３ｂ）、（３ｃ）、（３ｄ）又は（３ｅ）のいずれかで示される基を表し：

［式中、
Ｒ^ａ３ａ、Ｒ^ａ３ｂ、Ｒ^ａ３ｃ、Ｒ^ａ３ｄ及びＲ^ｂ３は、各々独立して、水素原子、ハロゲン原子、ＣＦ_３、ＣＮ、ＯＨ、Ｃ_１−６アルキル基、Ｃ_１−６アルコキシ基（該基はＣ_１−４アルコキシ基で置換されていてもよい）、Ｃ_１−６アルキルカルボニル基、ＣＯ_２Ｒ^２ａ、ＮＲ^２ｂＲ^２ｃ又はＣ（＝Ｏ）ＮＲ^２ｄＲ^２ｅを表し、かつ、
Ｒ^ａ３ａ、Ｒ^ａ３ｂ、Ｒ^ａ３ｃ及びＲ^ａ３ｄは化学的に許容される限り、任意の位置にて複数個置換してもよく、
Ｒ^２ａ、Ｒ^２ｂ、Ｒ^２ｃ、Ｒ^２ｄ及びＲ^２ｅは、各々独立して、水素原子又はＣ_１−１０アルキル基を表し、あるいは、Ｒ^２ｂとＲ^２ｃ、又はＲ^２ｄとＲ^２ｅはこれらがそれぞれ結合するＮと一緒になって４〜８員の環状アミノを形成してもよく、
Ｘ^３ｄは酸素原子、硫黄原子又は−Ｎ（Ｒ^ｃ３）−（式中、Ｒ^ｃ３は水素原子又はＣ_１−１０アルキル基を表す）を表し、
ｎ^３ａは０〜６の整数を表し、
ｎ^３ｂは０〜６の整数を表し、
ｎ^３ｃは１〜６の整数を表し、
ｍ^３ｄは１〜３の整数を表し、
ｎ^３ｄは０〜３の整数を表し、
ｎ^３ｅは０〜８の整数を表す］；
Ｒ^３が下記式（４ｇ）、（４ｈ）又は（４ｉ）のいずれかで示される基を表し：

［式中、
Ａｒｍはベンゼン環又はヘテロ芳香環を表し、
Ｒ^ａ４ｇ、及びＲ^ａ４ｈは、各々独立して、水素原子、ハロゲン原子、ＣＦ_３、ＣＮ、ＯＨ、Ｃ_１−１０アルキル基、Ｃ_３−６シクロアルキル基、Ｃ_１−６アルコキシ基、Ｃ_３−６シクロアルコキシ基、Ｃ_１−６アルキルカルボニル基、ＣＯ_２Ｒ^３ａａ、ＮＲ^３ａｂＲ^３ａｃ、Ｃ（＝Ｏ）ＮＲ^３ａｄＲ^３ａｅ又はＣＨ＝ＣＨ−Ｒ^３ａｆ（式中、Ｒ^３ａａ、Ｒ^３ａｂ、Ｒ^３ａｃ、Ｒ^３ａｄ及びＲ^３ａｅは、各々独立して、水素原子又はＣ_１−１０アルキル基を表し、あるいは、Ｒ^３ａｂとＲ^３ａｃ、又はＲ^３ａｄとＲ^３ａｅはこれらがそれぞれ結合するＮと一緒になって４〜８員の環状アミノを形成してもよく；Ｒ^３ａｆはＣＮ、ＣＯ_２Ｈ、ＣＯ_２Ｒ^３ｆ１又はＣ（＝Ｏ）ＮＲ^３ｆ２Ｒ^３ｆ３を表し、Ｒ^３ｆ１、Ｒ^３ｆ２及びＲ^３ｆ３は、各々独立して、水素原子又はＣ_１−６アルキル基を表す）を表し、かつ、Ｒ^ａ４ｇ及びＲ^ａ４ｈは化学的に許容される限り、任意の位置にて複数個置換してもよく、
Ｒ^ｄ４ｇ及びＲ^ｅ４ｇ、Ｒ^ｄ４ｈ、Ｒ^ｅ４ｈ、Ｒ^ｆ４ｈ、Ｒ^ｇ４ｈ、Ｒ^ｈ４ｈ、Ｒ^ｉ４ｈ、Ｒ^ｊ４ｈ及びＲ^ｋ４ｈ、並びに、Ｒ^ｄ４ｉ、Ｒ^ｅ４ｉ、Ｒ^ｆ４ｉ及びＲ^ｇ４ｉは、
相互に独立して、かつ、各基が複数ある場合には各々独立して、水素原子、ＯＨ、Ｃ_１−６アルキル基、ＣＯ_２Ｈ、ＣＯ_２−Ｃ_１−６アルキル基、Ｃ_１−６アルコキシ基又はフェニル基（ここに、当該フェニル基はハロゲン原子、ＣＦ_３、Ｃ_１−４アルキル基、ＣＯ_２Ｈ、ＣＯ_２−Ｃ_１−６アルキル基又はＣ_１−４アルコキシ基で置換されていてもよい）を表し、
あるいは、Ｒ^ｄ４ｇとＲ^ｅ４ｇ、Ｒ^ｄ４ｈとＲ^ｅ４ｈ、Ｒ^ｆ４ｈとＲ^ｇ４ｈ、Ｒ^ｈ４ｈとＲ^ｉ４ｈ、Ｒ^ｊ４ｈとＲ^ｋ４ｈ、Ｒ^ｄ４ｉとＲ^ｅ４ｉ、及びＲ^ｆ４ｉとＲ^ｇ４ｉはこれらが結合する一の炭素原子とそれぞれ一緒になって３〜８員のシクロアルキル環又は５員若しくは６員の飽和ヘテロ環を形成してもよく、
あるいは、０〜３の炭素原子を介して隣接する炭素原子上に結合する２つのＲ^ｄ４ｇ、Ｒ^ｄ４ｈ、Ｒ^ｆ４ｈ、Ｒ^ｈ４ｈ、Ｒ^ｊ４ｈ、Ｒ^ｄ４ｉ又はＲ^ｆ４ｉが、これらが結合する２つの炭素原子、及び当該炭素原子間の炭素鎖と一緒になって４〜８員のシクロアルキル環を形成してもよく、
Ｒ^ｂ４ｈ及びＲ^ｂ４ｉは、各々独立して、以下の（ｉ）〜（ｘｉ）のいずれかで示される基を表す：
（ｉ）水素原子、
（ｉｉ）ハロゲン原子、
（ｉｉｉ）ＯＨ、
（ｉｖ）ＯＲ^３ｂ１、
（ｖ）ＣＮ、
（ｖｉ）ＣＯ_２Ｈ、
（ｖｉｉ）Ｃ（＝Ｏ）ＮＲ^３ｂ２Ｒ^３ｂ３、
（ｖｉｉｉ）ＳＯ_２ＮＲ^３ｂ４Ｒ^３ｂ５、
（ｉｘ）ＮＲ^３ｅＣ（＝Ｏ）ＮＲ^３ｂ６Ｒ^３ｂ７、
（ここに、Ｒ^３ｂ１は、水素原子、Ｃ_１−１０アルキル基又はＣ_１−１０アルカノイル基を表し；Ｒ^３ｂ２、Ｒ^３ｂ３、Ｒ^３ｂ４、Ｒ^３ｂ５、Ｒ^３ｂ６、Ｒ^３ｂ７及びＲ^３ｅは、各々独立して、水素原子又はＣ_１−１０アルキル基を表すか、又はＲ^３ｂ２とＲ^３ｂ３、Ｒ^３ｂ４とＲ^３ｂ５、もしくはＲ^３ｂ６とＲ^３ｂ７はこれらがそれぞれ結合するＮと一緒になって４〜８員の環状アミノを形成してもよい）、
（ｘ）下記式（４ｆ）で表されるいずれかの基：

（ここに、Ｒ^３４ｆは水素原子又はＣ_１−１０アルキル基を表す）、又は
（ｘｉ）ＣＯ_２ＣＲ^３ｇ１Ｒ^３ｇ２Ｒ^３ｇ３
（ここに、Ｒ^３ｇ１、Ｒ^３ｇ２及びＲ^３ｇ３は、各々独立して、
水素原子、
Ｃ_１−４アルキル基（該基はＯＨ、Ｃ_１−４アルコキシ基、Ｃ_１−４アルコキシ基で置換されていてもよいＣ_３−６シクロアルキル基、５員若しくは６員の飽和ヘテロ環基、５員若しくは６員の飽和ヘテロ環オキシ基、又はＮＲ^３ｂ８Ｒ^３ｂ９で置換されていてもよく、Ｒ^３ｂ８及びＲ^３ｂ９は、各々独立して、水素原子又はＣ_１−１０アルキル基を表す）、
Ｃ_３−１０シクロアルキル基（該基は、フッ素原子及びＣ_１−４アルコキシ基からなる群から選ばれる１〜２個の置換基で置換されていてもよい）、
Ｃ_６−１０アリール基（該基はハロゲン原子又はＣ_１−４アルコキシで置換されていてもよい）、
５員若しくは６員の飽和ヘテロ環基、又は
５員〜１０員のヘテロアリール基（該基はＣ_１−４アルキル基又はＣ_１−４アルコキシ基で置換されていてもよい）を表し、
あるいは、Ｒ^３ｇ１とＲ^３ｇ２はこれらが結合する炭素原子と一緒になって３〜８員のシクロアルキル環又は５員若しくは６員の飽和ヘテロ環を形成してもよい）、
ｍ^４ｇは、０〜１０の整数を表し、
ｍ^４ｈ、ｎ^４ｈ、ｐ^４ｈ及びｑ^４ｈ、並びに、ｍ^４ｉ及びｎ^４ｉは、各々独立して、０〜５の整数を表し、
ｒ^４ｈ、ｓ^４ｈ及びｓ^４ｉは、各々独立して、０又は１を表す
（ただし、ｒ^４ｈが１の場合、ｍ^４ｈは１〜５の整数を表し；ｓ^４ｉが１の場合、ｍ^４ｉは１〜５の整数を表し；ｓ^４ｈが１かつｎ^４ｈが０の場合、Ｒ^ｂ４ｈは上記（ｉ）、（ｖｉｉ）、（ｖｉｉｉ）、（ｘ）又は（ｘｉ）のいずれかで示される基を表し；ｓ^４ｉが１かつｎ^４ｉが０の場合、Ｒ^ｂ４ｉは上記（ｉ）、（ｖｉｉ）、（ｖｉｉｉ）、（ｘ）又は（ｘｉ）のいずれかで示される基を表す）］、［１］又は［２］のいずれか記載の医薬組成物。 [3] R ¹ is a group represented by any ^one of the following formulas (2a ′), (2b ′), (2c ′), (2d ′), (2e ′), (2f ′) or (2g ′) Representation:

[Where:
^{R a2a, R a2b, R a2c} , R a2d, R b2, R a2f and ^{R A2G} are each independently a hydrogen atom, a halogen _{atom, CF 3, CN, OH,} C 1-6 alkyl _{groups, C 1- 6} alkoxy groups (wherein the C _1-6 alkyl group and the C _1-6 alkoxy group may be substituted with CO ₂ H or CO ₂ CR ^1g1 R ^1g2 R ^1g3 (here, R ^1g1 , R ^1g2 and Each R ^1g3 is independently
Hydrogen atom,
C _1-4 alkyl group (the group is a C _3-6 cycloalkyl group, 5-membered or 6-membered saturated heterocyclic group optionally substituted with OH, C _1-4 alkoxy group, C _1-4 alkoxy group) , 5-membered or 6-membered saturated heterocyclic oxy group, or ^NR 1b1 ^{R 1b2} may be substituted ^{by, R 1b1} and ^{R 1b2} represent each independently a hydrogen atom or a _{C 1-10} alkyl group) ,
A C _3-10 cycloalkyl group (which group may be substituted with 1 to 2 substituents selected from a fluorine atom and a C _1-4 alkoxy group),
A C _6-10 aryl group (the group may be substituted with a halogen atom or C _1-4 alkoxy),
Represents a 5- or 6-membered saturated heterocyclic group, or a 5- to 10-membered heteroaryl group (the group may be substituted with a C _1-4 alkyl group or a C _1-4 alkoxy group);
Alternatively, R ^1g1 and R ^1g2 may combine with the carbon atom to which they are attached to form a 3-8 membered cycloalkyl ring or a 5 or 6 membered saturated heterocycle)),
_{Represents a} C _1-6 alkylcarbonyl group, CO ₂ R ^1a , NR ^1b R ^1c or C (═O) NR ^1d R ^1e , and
^{R a2a, R a2b, R a2c} , R a2d, R a2f and ^{R A2G} is as chemically permitted, it may be a plurality substituted at any position,
R ^a2n represents a hydrogen atom, CF ₃ , CN, C _1-6 alkyl group, C _1-6 alkylcarbonyl group, CO ₂ R ^1a , NR ^1b R ^1c or C (═O) NR ^1d R ^1e ,
R ^1a , R ^1b , R ^1c , R ^1d and R ^1e each independently represent a hydrogen atom or a C _1-10 alkyl group, or R ^1b and R ^1c , or R ^1d and R ^1e are Each may be combined with N to form a 4- to 8-membered cyclic amino group or morpholinyl group,
R ^d2e and R ^e2e are independently of each other and, when there are a plurality of groups, each independently represents a hydrogen atom, OH, a C _1-6 alkyl group, CO ₂ H, CO ₂ -C ₁ -C _{1- 6} alkyl group, C _1-6 alkoxy group or phenyl group (wherein the phenyl group is a halogen atom, CF ₃ , C _1-4 alkyl group, CO ₂ H, CO ₂ -C _1-6 alkyl group or C _{1 -4} may be substituted with an alkoxy group),
Alternatively, R ^d2e and R ^e2e may combine with one carbon atom to which they are attached to form a 3-8 membered cycloalkyl ring,
Alternatively, two R ^d2e bonded to adjacent carbon atoms through 0 to 3 carbon atoms together with the two carbon atoms to which they are bonded, and the carbon chain between the carbon atoms, 4 to 8 May form a membered cycloalkyl ring,
X ^2d represents an oxygen atom or —N (R ^c2 ) — (wherein R ^c2 represents a hydrogen atom or a C _1-10 alkyl group),
X ^2g represents an oxygen atom or a sulfur atom,
n ^2a , n ^2b , p ^2c , p ^2d , n ^2f and n ^2g represent an integer of 0 to 4,
n ^2c represents an integer of 1 to 6,
m ^2d represents an integer of 1 to 3,
n ^2d represents an integer of 0 to 3,
n ^2e represents an integer of 0 to 8];
R ² represents a group represented by any of the following formulas (3a), (3b), (3c), (3d) or (3e):

[Where:
R ^a3a , R ^a3b , R ^a3c , R ^a3d and R ^b3 each independently represent a hydrogen atom, a halogen atom, CF ₃ , CN, OH, a C _1-6 alkyl group, a C _1-6 alkoxy group (the group _{Represents a} C _1-4 alkoxy group), a C _1-6 alkylcarbonyl group, CO ₂ R ^2a , NR ^2b R ^2c or C (═O) NR ^2d R ^2e , and
R ^a3a , R ^a3b , R ^a3c, and R ^a3d may be substituted at any position as long as it is chemically acceptable,
R ^2a , R ^2b , R ^2c , R ^2d and R ^2e each independently represent a hydrogen atom or a C _1-10 alkyl group, or R ^2b and R ^2c , or R ^2d and R ^2e are In combination with each N bonded to form a 4-8 membered cyclic amino,
X ^3d represents an oxygen atom, a sulfur atom or —N (R ^c3 ) — (wherein R ^c3 represents a hydrogen atom or a C _1-10 alkyl group),
n ^3a represents an integer of 0 to 6;
n ^3b represents an integer of 0 to 6;
n ^3c represents an integer of 1 to 6,
m ^3d represents an integer of 1 to 3,
n ^3d represents an integer of 0 to 3,
n ^3e represents an integer of 0 to 8];
R ³ represents a group represented by any of the following formulas (4g), (4h) or (4i):

[Where:
Arm represents a benzene ring or a heteroaromatic ring,
R ^a4g and R ^a4h each independently represent a hydrogen atom, a halogen atom, CF ₃ , CN, OH, a C _1-10 alkyl group, a C _3-6 cycloalkyl group, a C _1-6 alkoxy group, C _{3 -6} cycloalkoxy _{group, C 1-6} alkylcarbonyl _{^{group, CO 2 R 3aa, NR 3ab}} R 3ac, C (= O) NR 3ad R 3ae or CH = ^{CH-R 3af (wherein, R 3aa,} R ^3ab, R ^{3ac, R 3ad} and ^{R 3 ae} each independently represent a hydrogen atom or a _{C 1-10} alkyl group, ^or, together with the N ^{R 3ab} and ^{R 3ac,} or ^{R 3ad} and ^{R 3 ae} is to which they are attached, respectively It is in the may form a cyclic amino having 4 to ^8-membered; R 3 af represents _CN, CO 2 _H, a CO ^{2 R 3f1} or ^{C (= O) NR 3f2 R} 3f3, R 3f , ^{R 3f2} and ^{R 3f3} each independently represent a hydrogen atom or a _{C 1-6} alkyl group), ^and, as long as ^{R A4g} and ^{R A4H} is a chemically acceptable, more at any position May be replaced,
R ^d4g and R ^e4g , R ^d4h , R ^e4h , R ^f4h , R ^g4h , R ^h4h , R ^i4h , R ^j4h and R ^k4h , and R ^d4i , R ^e4i , R ^f4i and R ^g4i ,
Independently of each other and when there are a plurality of groups, each independently represents a hydrogen atom, OH, C _1-6 alkyl group, CO ₂ H, CO ₂ -C _1-6 alkyl group, C _{1- 6} alkoxy group or phenyl group (wherein the phenyl group is substituted with a halogen atom, CF ₃ , C _1-4 alkyl group, CO ₂ H, CO ₂ -C _1-6 alkyl group or C _1-4 alkoxy group) May represent)
Alternatively, R ^d4g and R ^e4g , R ^d4h and R ^e4h , R ^f4h and R ^g4h , R ^h4h and R ^i4h , R ^j4h and R ^k4h , R ^d4i and R ^e4i , and R ^f4i and R ^g4i are combined. Each of the carbon atoms together may form a 3- to 8-membered cycloalkyl ring or a 5- or 6-membered saturated heterocycle,
Alternatively, two R ^d4g , R ^d4h , R ^f4h , R ^h4h , R ^j4h , R ^d4i, or R ^f4i bonded to adjacent carbon atoms through 0-3 carbon atoms are the two carbons to which they are bonded. Together with the atoms and carbon chains between the carbon atoms may form a 4-8 membered cycloalkyl ring;
R ^b4h and R ^b4i each independently represent a group represented by any one of the following (i) to (xi):
(I) a hydrogen atom,
(Ii) a halogen atom,
(Iii) OH,
(Iv) OR ^3b1 ,
(V) CN,
(Vi) CO ₂ H,
^{(Vii) C (= O)} NR 3b2 R 3b3,
(Viii) SO ₂ NR ^3b4 R ^3b5 ,
(Ix) NR ^3e C (═O) NR ^3b6 R ^3b7 ,
^{(Here, R 3b1} represents a hydrogen _{atom, C 1-10} alkyl or _{C 1-10} alkanoyl ^{group; R 3b2, R 3b3, R} 3b4, R 3b5, R 3b6, R 3b7 and ^{R 3e} are each independently represent hydrogen atom or _{C 1-10} alkyl group, or ^{R 3b2} and ^{R 3b3, R 3b4} and ^{R 3b5} or ^{R 3 b 6} and ^{R 3B7,} together with the N to which they are attached respectively 4 An 8-membered cyclic amino may be formed),
(X) any group represented by the following formula (4f):

^{(Here, R 34f} represents a hydrogen atom or a _{C 1-10} alkyl group), or _{^{(xi) CO 2 CR 3g1 R}} 3g2 R 3g3
^(Here, R ^{3g1, R 3g2} and ^{R 3G3} are each independently
Hydrogen atom,
C _1-4 alkyl group (the group is a C _3-6 cycloalkyl group, 5-membered or 6-membered saturated heterocyclic group optionally substituted with OH, C _1-4 alkoxy group, C _1-4 alkoxy group) A 5- or 6-membered saturated heterocyclic oxy group, or an NR ^3b8 R ^3b9 which may be substituted, each of R ^3b8 and R ^3b9 independently represents a hydrogen atom or a C _1-10 alkyl group) ,
A C _3-10 cycloalkyl group (which may be substituted with 1 to 2 substituents selected from the group consisting of a fluorine atom and a C _1-4 alkoxy group),
A C _6-10 aryl group (the group may be substituted with a halogen atom or C _1-4 alkoxy),
Represents a 5- or 6-membered saturated heterocyclic group, or a 5- to 10-membered heteroaryl group (the group may be substituted with a C _1-4 alkyl group or a C _1-4 alkoxy group);
Alternatively, R ^3g1 and R ^3g2 may form a saturated heterocyclic cycloalkyl ring or a 5- or 6-membered 3-8 membered together with the carbon atoms to which they are attached),
m ^4g represents an integer of 0 to 10,
m ^4h , n ^4h , p ^4h and q ^4h , and m ⁴ⁱ and n ⁴ⁱ each independently represent an integer of 0 to 5;
r ^4h , s ^4h and s ⁴ⁱ each independently represent 0 or 1 (provided that when r ^4h is 1, m ^4h represents an integer of 1 to 5; when s ⁴ⁱ is 1, m ^{4i Represents} an integer of 1 to 5; when s ^4h is 1 and n ^4h is 0, R ^b4h is represented by any one of (i), (vii), (viii), (x), or (xi) And when s ⁴ⁱ is 1 and n ⁴ⁱ is 0, R ^b4i represents a group represented by any one of (i), (vii), (viii), (x) or (xi))] [1] A pharmaceutical composition according to any one of [2].

［式中、
Ｒ^ａ２ａ、Ｒ^ａ２ｂ、Ｒ^ａ２ｃ、Ｒ^ａ２ｄ、Ｒ^ｂ２及びＲ^ａ２ｇは、各々独立して、水素原子、ハロゲン原子、ＣＦ_３、Ｃ_１−６アルキル基、又はＣ_１−６アルコキシ基（ここに当該Ｃ_１−６アルキル基及びＣ_１−６アルコキシ基はＣＯ_２Ｈ又はＣＯ_２ＣＲ^１ｇ１Ｒ^１ｇ２Ｒ^１ｇ３で置換されていてもよい（ここに、Ｒ^１ｇ１、Ｒ^１ｇ２及びＲ^１ｇ３は、各々独立して、
水素原子又はＣ_１−４アルキル基（該基はＯＨ、Ｃ_１−４アルコキシ基、５員若しくは６員の飽和ヘテロ環基又はＮＲ^１ｂ１Ｒ^１ｂ２で置換されていてもよく、Ｒ^１ｂ１及びＲ^１ｂ２は、各々独立して、水素原子又はＣ_１−６アルキル基を表す）を表す））を表し、
かつ、Ｒ^ａ２ａ、Ｒ^ａ２ｂ、Ｒ^ａ２ｃ、Ｒ^ａ２ｄ、及びＲ^ａ２ｇは化学的に許容される限り、任意の位置にて複数個置換してもよく、
Ｒ^ｄ２ｅ及びＲ^ｅ２ｅは、相互に独立して、かつ、各基が複数ある場合には各々独立して、水素原子、Ｃ_１−６アルキル基、Ｃ_１−６アルコキシ基又はフェニル基（ここに、当該フェニル基はハロゲン原子、ＣＦ_３、Ｃ_１−４アルキル基又はＣ_１−４アルコキシ基で置換されていてもよい）を表し、
あるいは、Ｒ^ｄ２ｅとＲ^ｅ２ｅはこれらが結合する一の炭素原子と一緒になって３〜８員のシクロアルキル環を形成してもよく、
あるいは、０〜３の炭素原子を介して隣接する炭素原子上に結合する２つのＲ^ｄ２ｅが、これらが結合する２つの炭素原子、及び当該炭素原子間の炭素鎖と一緒になって４〜８員のシクロアルキル環を形成してもよく、
Ｘ^２ｄは酸素原子又は−Ｎ（Ｒ^ｃ２）−（式中、Ｒ^ｃ２は水素原子又はＣ_１−６アルキル基を表す）を表し、
Ｘ^２ｇは酸素原子又は硫黄原子を表し、
ｎ^２ａ、ｎ^２ｂ、ｐ^２ｃ、ｐ^２ｄ及びｎ^２ｇは０〜４の整数を表し、
ｎ^２ｃは１〜６の整数を表し、
ｍ^２ｄは１〜３の整数を表し、
ｎ^２ｄは０〜３の整数を表し、
ｎ^２ｅは１〜６の整数を表す］；
Ｒ^２が下記式（３ａ）、（３ｃ）、（３ｄ）又は（３ｅ）のいずれかで示される基を表し：

［式中、
Ｒ^ａ３ａ、Ｒ^ａ３ｃ、Ｒ^ａ３ｄ及びＲ^ｂ３は、各々独立して、水素原子、ハロゲン原子、ＣＦ_３、Ｃ_１−６アルキル基、又はＣ_１−６アルコキシ基（該基はＣ_１−４アルコキシ基で置換されていてもよい）を表し、かつ、
Ｒ^ａ３ａ、Ｒ^ａ３ｃ及びＲ^ａ３ｄは化学的に許容される限り、任意の位置にて複数個置換してもよく、
Ｘ^３ｄは酸素原子、硫黄原子又は−Ｎ（Ｒ^ｃ３）−（式中、Ｒ^ｃ３は水素原子又はＣ_１−６アルキル基を表す）を表し、
ｎ^３ａは０〜４の整数を表し、
ｎ^３ｃは１〜６の整数を表し、
ｍ^３ｄは１〜３の整数を表し、
ｎ^３ｄは０〜３の整数を表し、
ｎ^３ｅは０〜８の整数を表す］；
Ｒ^３が下記式（４ｇ）、（４ｈ）又は（４ｉ）のいずれかで示される基を表し：

［式中、
Ａｒｍはベンゼン環又はヘテロ芳香環を表し、
Ｒ^ａ４ｇ、及びＲ^ａ４ｈは、各々独立して、水素原子、ハロゲン原子、ＣＦ_３、ＣＮ、ＯＨ、Ｃ_１−６アルキル基、Ｃ_１−６アルコキシ基、ＣＯ_２Ｒ^３ａａ、Ｃ（＝Ｏ）ＮＲ^３ａｄＲ^３ａｅ又はＣＨ＝ＣＨ−Ｒ^３ａｆ（式中、Ｒ^３ａａ、Ｒ^３ａｄ及びＲ^３ａｅは、各々独立して、水素原子又はＣ_１−６アルキル基を表し；Ｒ^３ａｆはＣＯ_２Ｈ、ＣＯ_２Ｒ^３ｆ１又はＣ（＝Ｏ）ＮＲ^３ｆ２Ｒ^３ｆ３を表し、Ｒ^３ｆ１、Ｒ^３ｆ２及びＲ^３ｆ３は、各々独立して、水素原子又はＣ_１−６アルキル基を表す）を表し、かつ、
Ｒ^ａ４ｇ及びＲ^ａ４ｈは化学的に許容される限り、任意の位置にて複数個置換してもよく、
Ｒ^ｄ４ｇ及びＲ^ｅ４ｇ、Ｒ^ｄ４ｈ、Ｒ^ｅ４ｈ、Ｒ^ｆ４ｈ、Ｒ^ｇ４ｈ、Ｒ^ｈ４ｈ、Ｒ^ｉ４ｈ、Ｒ^ｊ４ｈ及びＲ^ｋ４ｈ、並びに、Ｒ^ｄ４ｉ、Ｒ^ｅ４ｉ、Ｒ^ｆ４ｉ及びＲ^ｇ４ｉは、
相互に独立して、かつ、各基が複数ある場合には各々独立して、水素原子、Ｃ_１−６アルキル基、ＣＯ_２Ｈ又はＣＯ_２−Ｃ_１−６アルキル基を表し、
あるいは、Ｒ^ｄ４ｇとＲ^ｅ４ｇ、Ｒ^ｄ４ｈとＲ^ｅ４ｈ、Ｒ^ｆ４ｈとＲ^ｇ４ｈ、Ｒ^ｈ４ｈとＲ^ｉ４ｈ、Ｒ^ｊ４ｈとＲ^ｋ４ｈ、Ｒ^ｄ４ｉとＲ^ｅ４ｉ、及びＲ^ｆ４ｉとＲ^ｇ４ｉはこれらがそれぞれ結合する一の炭素原子とそれぞれ一緒になって３員〜６員のシクロアルキル環を形成してもよく、
Ｒ^ｂ４ｈ及びＲ^ｂ４ｉは、各々独立して、以下の（ｉｉｉ）、（ｉｖ）、（ｖｉ）、（ｖｉｉ）又は（ｘｉ）のいずれかで示される基を表し：
（ｉｉｉ）ＯＨ、
（ｉｖ）ＯＲ^３ｂ１、
（ｖｉ）ＣＯ_２Ｈ、
（ｖｉｉ）Ｃ（＝Ｏ）ＮＲ^３ｂ２Ｒ^３ｂ３、
（ここに、Ｒ^３ｂ１は、水素原子、Ｃ_１−６アルキル基又はＣ_１−６アルカノイル基を表し；Ｒ^３ｂ２及びＲ^３ｂ３は、各々独立して、水素原子又はＣ_１−６アルキル基を表すか、又はＲ^３ｂ２とＲ^３ｂ３はこれらがそれぞれ結合するＮと一緒になって５員〜７員の環状アミノを形成してもよい）、
（ｘｉ）ＣＯ_２ＣＲ^３ｇ１Ｒ^３ｇ２Ｒ^３ｇ３
（ここに、Ｒ^３ｇ１、Ｒ^３ｇ２及びＲ^３ｇ３は、各々独立して、
水素原子又はＣ_１−４アルキル基（該基はＯＨ、Ｃ_１−４アルコキシ基、５員若しくは６員の飽和ヘテロ環基又はＮＲ^３ｂ８Ｒ^３ｂ９で置換されていてもよく、Ｒ^３ｂ８及びＲ^３ｂ９は、各々独立して、水素原子又はＣ_１−６アルキル基を表す）を表す）
ｍ^４ｇは、１〜６の整数を表し、
ｍ^４ｈ、ｎ^４ｈ、ｐ^４ｈ及びｑ^４ｈ、並びに、ｍ^４ｉ及びｎ^４ｉは、各々独立して、０〜５の整数を表し、
ｒ^４ｈ、ｓ^４ｈ及びｓ^４ｉは、各々独立して、０又は１を表す
（ただし、ｒ^４ｈが１の場合、ｍ^４ｈは２〜５の整数を表し；ｓ^４ｉが１の場合、ｍ^４ｉは２〜５の整数を表し；ｓ^４ｈが１かつｎ^４ｈが０の場合、Ｒ^ｂ４ｈは上記（ｖｉｉ）又は（ｘｉ）のいずれかで示される基を表し；ｓ^４ｉが１かつｎ^４ｉが０の場合、Ｒ^ｂ４ｉは上記（ｖｉｉ）又は（ｘｉ）のいずれかで示される基を表す）］；
Ｒ^４及びＲ^５が、各々独立して、水素原子、フッ素原子又はフッ素原子で置換されていてもよいＣ_１−６アルキル基を表し、
Ｘが酸素原子、硫黄原子、−Ｎ（Ｒ^６）−又は−Ｃ（Ｒ^７）（Ｒ^８）−（式中、Ｒ^６は水素原子又はフッ素原子で置換されていてもよいＣ_１−６アルキル基を表し、Ｒ^７及びＲ^８は、各々独立して、水素原子又はフッ素原子で置換されていてもよいＣ_１−６アルキル基を表す）を表す、
［１］〜［３］のいずれか記載の医薬組成物。 [4] R ¹ represents a group represented by any of the following formulas (2a ′), (2b ′), (2c ′), (2d ′), (2e ′) or (2g ′):

[Where:
^{R a2a, R a2b, R a2c} , R a2d, R b2 and ^{R A2G} are each independently a hydrogen atom, a halogen _atom, CF _{3, C 1-6} alkyl, or _{C 1-6} alkoxy groups (here The C _1-6 alkyl group and the C _1-6 alkoxy group may be substituted with CO ₂ H or CO ₂ CR ^1g1 R ^1g2 R ^1g3 (wherein R ^1g1 , R ^1g2 and R ^1g3 are independent of each other). do it,
Hydrogen atom or a _{C 1-4} alkyl (in which the group _{OH, C 1-4} alkoxy group, may be substituted with a saturated heterocyclic group, or ^NR 1b1 ^{R 1b2} of 5- or ^{6-membered, R 1b1} and ^{R 1b2} Each independently represents a hydrogen atom or a C _1-6 alkyl group))),
^{And, R a2a, R a2b, R} a2c, R a2d, and ^{R A2G} is as chemically permitted, may be a plurality substituted at any position,
R ^d2e and R ^e2e each independently represent a hydrogen atom, a C _1-6 alkyl group, a C _1-6 alkoxy group, or a phenyl group (wherein there are a plurality of groups) The phenyl group may be substituted with a halogen atom, CF ₃ , a C _1-4 alkyl group or a C _1-4 alkoxy group),
Alternatively, R ^d2e and R ^e2e may combine with one carbon atom to which they are attached to form a 3-8 membered cycloalkyl ring,
Alternatively, two R ^d2e bonded to adjacent carbon atoms through 0 to 3 carbon atoms together with the two carbon atoms to which they are bonded, and the carbon chain between the carbon atoms, 4 to 8 May form a membered cycloalkyl ring,
X ^2d represents an oxygen atom or —N (R ^c2 ) — (wherein R ^c2 represents a hydrogen atom or a C _1-6 alkyl group),
X ^2g represents an oxygen atom or a sulfur atom,
n ^2a , n ^2b , p ^2c , p ^2d and n ^2g represent an integer of 0 to 4,
n ^2c represents an integer of 1 to 6,
m ^2d represents an integer of 1 to 3,
n ^2d represents an integer of 0 to 3,
n ^2e represents an integer of 1 to 6];
R ² represents a group represented by any of the following formulas (3a), (3c), (3d) or (3e):

[Where:
R ^a3a , R ^a3c , R ^a3d and R ^b3 each independently represent a hydrogen atom, a halogen atom, CF ₃ , a C _1-6 alkyl group, or a C _1-6 alkoxy group (the group is a C _1-4 alkoxy group). And optionally substituted with a group, and
R ^a3a , R ^a3c, and R ^a3d may be substituted at any position as long as they are chemically acceptable,
X ^3d represents an oxygen atom, a sulfur atom, or —N (R ^c3 ) — (wherein R ^c3 represents a hydrogen atom or a C _1-6 alkyl group),
n ^3a represents an integer of 0 to 4,
n ^3c represents an integer of 1 to 6,
m ^3d represents an integer of 1 to 3,
n ^3d represents an integer of 0 to 3,
n ^3e represents an integer of 0 to 8];
R ³ represents a group represented by any of the following formulas (4g), (4h) or (4i):

[Where:
Arm represents a benzene ring or a heteroaromatic ring,
R ^a4g and R ^a4h are each independently a hydrogen atom, halogen atom, CF ₃ , CN, OH, C _1-6 alkyl group, C _1-6 alkoxy group, CO ₂ R ^3aa , C (═O) NR ^3ad R ^3ae or CH═CH—R ^3af (wherein R ^3aa , R ^3ad and R ^3ae each independently represents a hydrogen atom or a C _1-6 alkyl group; R ^3af represents CO ₂ H, CO ₂ R ^3f1 or C (═O) NR ^3f2 R ^3f3 , each of R ^3f1 , R ^3f2 and R ^3f3 independently represents a hydrogen atom or a C _1-6 alkyl group), and
A ^plurality of R ^a4g and R ^a4h may be substituted at any position as long as they are chemically acceptable.
R ^d4g and R ^e4g , R ^d4h , R ^e4h , R ^f4h , R ^g4h , R ^h4h , R ^i4h , R ^j4h and R ^k4h , and R ^d4i , R ^e4i , R ^f4i and R ^g4i ,
Independently of each other and when there are a plurality of groups, each independently represents a hydrogen atom, a C _1-6 alkyl group, a CO ₂ H or a CO ₂ -C _1-6 alkyl group,
Alternatively, R ^d4g and R ^e4g , R ^d4h and R ^e4h , R ^f4h and R ^g4h , R ^h4h and R ^i4h , R ^j4h and R ^k4h , R ^d4i and R ^e4i , and R ^f4i and R ^g4i are combined. Each with one carbon atom may form a 3- to 6-membered cycloalkyl ring;
R ^b4h and R ^b4i each independently represent a group represented by any of the following (iii), (iv), (vi), (vii) or (xi):
(Iii) OH,
(Iv) OR ^3b1 ,
(Vi) CO ₂ H,
^{(Vii) C (= O)} NR 3b2 R 3b3,
^{(Here, R 3b1} represents a hydrogen _{atom, C 1-6} alkyl group or a _{C 1-6} alkanoyl ^group; Table the ^{R 3b2} and ^{R 3b3} are each independently hydrogen atom or a _{C 1-6} alkyl group carded, or ^{R 3b2} and ^{R 3b3} may form a cyclic amino 5- to 7-membered together with the N to which they are attached, respectively),
_{^{(Xi) CO 2 CR 3g1 R}} 3g2 R 3g3
^(Here, R ^{3g1, R 3g2} and ^{R 3G3} are each independently
A hydrogen atom or a C _1-4 alkyl group (this group may be substituted with OH, C _1-4 alkoxy group, 5-membered or 6-membered saturated heterocyclic group or NR ^3b8 R ^3b9 , R ^3b8 and R ^3b9 Each independently represents a hydrogen atom or a C _1-6 alkyl group))
m ^4g represents an integer of 1 to 6,
m ^4h , n ^4h , p ^4h and q ^4h , and m ⁴ⁱ and n ⁴ⁱ each independently represent an integer of 0 to 5;
r ^4h , s ^4h and s ⁴ⁱ each independently represent 0 or 1 (provided that when r ^4h is 1, m ^4h represents an integer of 2 to 5; when s ⁴ⁱ is 1, m ^{4i Represents} an integer of 2 to 5; when s ^4h is 1 and n ^4h is 0, R ^b4h represents a group represented by either (vii) or (xi) above; s ⁴ⁱ is 1 and n ⁴ⁱ is In the case of 0, R ^b4i represents a group represented by either (vii) or (xi) above)];
R ⁴ and R ⁵ each independently represent a hydrogen atom, a fluorine atom or a C _1-6 alkyl group which may be substituted with a fluorine atom;
X is an oxygen atom, a sulfur atom, —N (R ⁶ ) — or —C (R ⁷ ) (R ⁸ ) — (wherein R ⁶ is a hydrogen atom or a C _{1-6 optionally} substituted with a fluorine atom) Represents an alkyl group, and R ⁷ and R ⁸ each independently represents a hydrogen atom or a C _1-6 alkyl group _optionally substituted with a fluorine atom).
[1] The pharmaceutical composition according to any one of [3].

［式中、各記号は［１］に定義されるとおりである］
で示される基である、［１］〜［４］のいずれか記載の医薬組成物。 [5] Y is the formula (II), (III) or (IV):

[Wherein each symbol is as defined in [1]]
The pharmaceutical composition according to any one of [1] to [4], which is a group represented by:

で示される基である、［１］〜［５］のいずれか記載の医薬組成物。 [6] Y is the formula (III):

The pharmaceutical composition according to any one of [1] to [5], which is a group represented by:

［式中、
Ａｒｍはベンゼン環又はピリジン環であり、
Ｒ^ａ４ｇは、水素原子、ハロゲン原子、ＣＮ、ＯＨ、ＣＯ_２Ｈ、ＣＯ_２−Ｃ_１−４アルキル基、又はＣＨ＝ＣＨ−Ｒ^３ａｆ（式中、Ｒ^３ａｆはＣＯ_２Ｈ又はＣＯ_２−Ｃ_１−４アルキル基を表す）を表し、
Ｒ^ｄ４ｇ及びＲ^ｅ４ｇは、相互に独立して、かつ、各基が複数ある場合には各々独立して、水素原子、Ｃ_１−４アルキル基、ＣＯ_２Ｈ、又はＣＯ_２−Ｃ_１−４アルキル基を表し、
ｍ^４ｇは、１〜３の整数を表す］
で示される基である、［３］〜［６］のいずれか記載の医薬組成物。 [7] R ³ is the formula (4g):

[Where:
Arm is a benzene ring or a pyridine ring,
R ^a4g is a hydrogen atom, a halogen atom, CN, OH, CO ₂ H, CO ₂ —C _1-4 alkyl group, or CH═CH—R ^3af (wherein R ^3af is CO ₂ H or CO ₂ —C _1-4 alkyl represents a group),
R ^d4g and R ^e4g each independently represent a hydrogen atom, a C _1-4 alkyl group, CO ₂ H, or CO ₂ -C _1-4 when there are a plurality of groups. Represents an alkyl group,
m ^4g represents an integer of 1 to 3]
The pharmaceutical composition according to any one of [3] to [6], which is a group represented by:

［式中、
Ａｒｍはベンゼン環又はピリジン環であり、
ｍ^４ｈ、ｎ^４ｈ、ｐ^４ｈ及びｑ^４ｈは、各々独立して、０〜３の整数を表し（但し、ｍ^４ｈ＋ｎ^４ｈ＋ｐ^４ｈ＋ｑ^４ｈは０〜１０の整数であり；ｒ^４ｈが１の場合、ｍ^４ｈは２又は３の整数を表し）、
他の各記号は［４］に定義されるとおりである］
で示される基である、［３］〜［６］のいずれか記載の医薬組成物。 [8] R ³ is the formula (4h):

[Where:
Arm is a benzene ring or a pyridine ring,
m ^4h , n ^4h , p ^4h and q ^4h each independently represent an integer of 0 to 3 (provided that m ^4h + n ^4h + p ^4h + q ^4h is an integer of 0 to 10; r ^4h is 1; ^{M 4h} represents an integer of 2 or 3,
Each other symbol is as defined in [4]]
The pharmaceutical composition according to any one of [3] to [6], which is a group represented by:

[9] R ^a4h is a hydrogen atom, a halogen atom, CF ₃ , a C _1-6 alkyl group or a C _1-6 alkoxy group,
R ^B4h is (vi) _CO 2 H, or _{^{(xi) CO 2 CR 3g1 R}} 3g2 R 3g3
^(Here, R ^{3g1, R 3g2} and ^{R 3G3} are each independently
A hydrogen atom, or
A C _1-4 alkyl group (the group may be substituted with OH, a C _1-4 alkoxy group, a 5- or 6-membered saturated heterocyclic group, or NR ^3b8 R ^3b9 , each of R ^3b8 and R ^3b9 is Independently represents a hydrogen atom or a C _1-4 alkyl group)
Represents)
R ^d4h , R ^e4h , R ^f4h , R ^g4h , R ^h4h , R ^i4h , R ^j4h and R ^k4h are
Independently of each other and when there are a plurality of groups, each independently represents a hydrogen atom or a C _1-4 alkyl group,
Alternatively, R ^f4h and R ^g4h together with the carbon atom to which they are attached may form a 3-6 membered cycloalkyl ring,
m ^4h is 1 or 2,
n ^4h is an integer of 1 to 3,
p ^4h , q ^4h , r ^4h and s ^4h are each independently 0 or 1 (provided that when r ^4h is 1, m ^4h is 2),
[8] The pharmaceutical composition according to [8].

^{[10] R} b4h is _{^{(xi) CO 2 CR 3g1 R}} 3g2 R 3g3
^(Here, R ^{3g1, R 3g2} and ^{R 3G3} is [9] is as defined) represented by, [8] or a pharmaceutical composition according to any one of [9].

^{[11] R} b4h is _{^{(xi) CO 2 CR 3g1 R}} 3g2 R 3g3
^(Here, R ^{3g1, R 3g2} and ^{R 3G3} are each independently
A hydrogen atom or a C _1-4 alkyl group (the group may be substituted with OH or a C _1-4 alkoxy group);
[8] The pharmaceutical composition according to any one of [10] to [10].

[12] The pharmaceutical composition according to any one of [8] to [11], wherein R ^a4h is a hydrogen atom or a halogen atom.

［式中、
Ｒ^ａ２ａ及びＲ^ａ２ｂは、各々独立して、水素原子、ハロゲン原子、Ｃ_１−４アルキル基又はＣ_１−４アルコキシ基であり、
ｎ^２ａ及びｎ^２ｂは０である］
で示される基である、［３］〜［１２］のいずれか記載の医薬組成物。 [13] R ¹ is represented by the following formula (2a ′) or (2b ′):

[Where:
R ^a2a and R ^a2b are each independently a hydrogen atom, a halogen atom, a C _1-4 alkyl group or a C _1-4 alkoxy group,
n ^2a and n ^2b are 0]
The pharmaceutical composition according to any one of [3] to [12], which is a group represented by:

［式中、
Ｒ^ａ２ｃは水素原子又はフッ素原子（該基は化学的に許容される限り、任意の位置にて複数個置換してもよい）であり、
ｐ^２ｃは０であり、
ｎ^２ｃは１〜４の整数である］
で示される基である、［３］〜［１２］のいずれか記載の医薬組成物。 [14] R ¹ is represented by the following formula (2c ′):

[Where:
R ^a2c is a hydrogen atom or a fluorine atom (a plurality of such groups may be substituted at any position as long as it is chemically acceptable);
p ^2c is 0,
n ^2c is an integer of 1 to 4]
The pharmaceutical composition according to any one of [3] to [12], which is a group represented by:

［式中、
Ｒ^ａ２ｄ及びＲ^ａ２ｇは水素原子であり、
Ｘ^２ｄ及びＸ^２ｇは酸素原子であり、
ｐ^２ｄ及びｎ^２ｇは１であり、
ｍ^２ｄは２〜３の整数であり、
ｎ^２ｄは０〜１の整数である］
で示される、［３］〜［１２］のいずれか記載の医薬組成物。 [15] R ¹ is represented by the following formula (2d ′) or (2g ′):

[Where:
R ^a2d and R ^a2g are hydrogen atoms,
X ^2d and X ^2g are oxygen atoms,
p ^2d and n ^2g are 1,
m ^2d is an integer of 2 to 3,
n ^2d is an integer of 0 to 1.]
The pharmaceutical composition according to any one of [3] to [12], which is represented by:

［式中、
Ｒ^ｂ２はＣ_１−４アルコキシ基であり、
Ｒ^ｄ２ｅ及びＲ^ｅ２ｅは、相互に独立して、かつ、各基が複数ある場合には各々独立して、水素原子又はＣ_１−４アルキル基であり、
ｎ^２ｅは２〜４の整数である］
で示される基である、［３］〜［１２］のいずれか記載の医薬組成物。 [16] R ¹ is represented by the following formula (2e ′):

[Where:
R ^b2 is a C _1-4 alkoxy group,
R ^d2e and R ^e2e are each independently a hydrogen atom or a C _1-4 alkyl group when there are a plurality of groups,
n ^2e is an integer of ² to 4]
The pharmaceutical composition according to any one of [3] to [12], which is a group represented by:

［式中、各記号は［４］に定義されるとおりである］
で示される基である、［３］〜［１６］のいずれか記載の医薬組成物。 [17] R ² is represented by the following formula (3c) or (3d):

[Where each symbol is as defined in [4]]
The pharmaceutical composition according to any one of [3] to [16], which is a group represented by:

［式中、Ｒ^ａ３ｃは水素原子であり、ｎ^３ｃは１〜４の整数である］
で示される基である、［３］〜［１７］のいずれか記載の医薬組成物。 [18] R ² is represented by the following formula (3c):

[ ^Wherein , R ^a3c is a hydrogen atom, and n ^3c is an integer of 1 to 4]
The pharmaceutical composition according to any one of [3] to [17], which is a group represented by:

[19] The pharmaceutical composition according to [18], wherein n ^3c is 2 to 4.

［式中、Ｒ^ａ３ａは水素原子、又はＣ_１−４アルコキシ基で置換されていてもよいＣ_１−６アルコキシ基であり、ｎ^３ａは０である］で示され、
Ｘが酸素原子である、［３］〜［１６］のいずれか記載の医薬組成物。 [20] R ² is represented by the following formula (3a):

[ ^Wherein , R ^a3a is a hydrogen atom or a C _1-6 alkoxy group optionally substituted with a C _1-4 alkoxy group, and n ^3a is 0],
The pharmaceutical composition according to any one of [3] to [16], wherein X is an oxygen atom.

［式中、
Ｒ^ａ２ａ、Ｒ^ａ２ｂ、Ｒ^ａ２ｃ、Ｒ^ａ２ｄ、Ｒ^ｂ２、Ｒ^ａ２ｆ及びＲ^ａ２ｇは、各々独立して、水素原子、ハロゲン原子、ＣＦ_３、ＣＮ、ＯＨ、Ｃ_１−６アルキル基、Ｃ_１−６アルコキシ基、Ｃ_１−６アルキルカルボニル基、ＣＯ_２Ｒ^１ａ、ＮＲ^１ｂＲ^１ｃ又はＣ（＝Ｏ）ＮＲ^１ｄＲ^１ｅを表し、
Ｒ^ａ２ｎは水素原子、ＣＦ_３、ＣＮ、Ｃ_１−６アルキル基、Ｃ_１−６アルキルカルボニル基、ＣＯ_２Ｒ^１ａ、ＮＲ^１ｂＲ^１ｃ又はＣ（＝Ｏ）ＮＲ^１ｄＲ^１ｅを表し、
Ｒ^１ａ、Ｒ^１ｂ、Ｒ^１ｃ、Ｒ^１ｄ及びＲ^１ｅは、各々独立して、水素原子又はＣ_１−１０アルキル基を表し、あるいは、Ｒ^１ｂとＲ^１ｃ、又はＲ^１ｄとＲ^１ｅがそれぞれ結合するＮと一緒になって４〜８員の環状アミノ基を形成してもよく、
Ｘ^２ｄは酸素原子又は−Ｎ（Ｒ^ｃ２）−（式中、Ｒ^ｃ２は水素原子又はＣ_１−１０アルキル基を表す）を表し、
Ｘ^２ｇは酸素原子又は硫黄原子を表し、
ｎ^２ｃは１〜６の整数を表し、
ｍ^２ｄは１〜３の整数を表し、
ｎ^２ｄは０〜３の整数を表し、
ｎ^２ｅは０〜８の整数を表す］；
Ｒ^２が下記式（３ａ）、（３ｂ）、（３ｃ）、（３ｄ）又は（３ｅ）のいずれかを表し：

［式中、
Ｒ^ａ３ａ、Ｒ^ａ３ｂ、Ｒ^ａ３ｃ、Ｒ^ａ３ｄ及びＲ^ｂ３は、各々独立して、水素原子、ハロゲン原子、ＣＦ_３、ＣＮ、ＯＨ、Ｃ_１−６アルキル基、Ｃ_１−６アルコキシ基、Ｃ_１−６アルキルカルボニル基、ＣＯ_２Ｒ^２ａ、ＮＲ^２ｂＲ^２ｃ又はＣ（＝Ｏ）ＮＲ^２ｄＲ^２ｅを表し、
Ｒ^２ａ、Ｒ^２ｂ、Ｒ^２ｃ、Ｒ^２ｄ及びＲ^２ｅは、各々独立して、水素原子又はＣ_１−１０アルキル基を表し、あるいは、Ｒ^２ｂとＲ^２ｃ、又はＲ^２ｄとＲ^２ｅがそれぞれ結合するＮと一緒になって４〜８員の環状アミノ基を形成してもよく、
Ｘ^３ｄは酸素原子、硫黄原子又は−Ｎ（Ｒ^ｃ３）−（式中、Ｒ^ｃ３は水素原子又はＣ_１−１０アルキル基を表す）を表し、
ｎ^３ａは０〜６の整数を表し、
ｎ^３ｂは０〜６の整数を表し、
ｎ^３ｃは１〜６の整数を表し、
ｍ^３ｄは１〜３の整数を表し、
ｎ^３ｄは０〜３の整数を表し、
ｎ^３ｅは０〜８の整数を表す］；
Ｒ^３が下記式（４ａ）、（４ｂ）、（４ｃ）、（４ｄ）又は（４ｅ）のいずれかを表す：

［式中、
Ｒ^ａ４ａ、Ｒ^ａ４ｂ、Ｒ^ａ４ｃ及びＲ^ａ４ｄは、各々独立して、水素原子、ハロゲン原子、ＣＦ_３、ＣＮ、ＯＨ、Ｃ_１−１０アルキル基、Ｃ_３−６シクロアルキル基、Ｃ_１−６アルコキシ基、Ｃ_３−６シクロアルコキシ基、Ｃ_１−６アルキルカルボニル基、ＣＯ_２Ｒ^３ａａ、ＮＲ^３ａｂＲ^３ａｃ、Ｃ（＝Ｏ）ＮＲ^３ａｄＲ^３ａｅ又はＣＨ＝ＣＨ−Ｒ^３ａｆ（式中、Ｒ^３ａａ、Ｒ^３ａｂ、Ｒ^３ａｃ、Ｒ^３ａｄ及びＲ^３ａｅは、各々独立して、水素原子又はＣ_１−１０アルキル基を表し、あるいは、Ｒ^３ａｂとＲ^３ａｃ、又はＲ^３ａｄとＲ^３ａｅがそれぞれ結合するＮと一緒になって４〜８員の環状アミノ基を形成してもよく；Ｒ^３ａｆはＣＮ、ＣＯ_２Ｈ、ＣＯ_２Ｒ^３ｆ１又はＣ（＝Ｏ）ＮＲ^３ｆ２Ｒ^３ｆ３を表し、Ｒ^３ｆ１、Ｒ^３ｆ２及びＲ^３ｆ３は、各々独立して、水素原子又はＣ_１−６アルキル基を表す）を表し、
Ｒ^ｄ４ａ及びＲ^ｅ４ａ、
Ｒ^ｄ４ｂ及びＲ^ｅ４ｂ、
Ｒ^ｄ４ｃ、Ｒ^ｅ４ｃ、Ｒ^ｆ４ｃ及びＲ^ｇ４ｃ、
Ｒ^ｄ４ｄ、Ｒ^ｅ４ｄ、Ｒ^ｆ４ｄ及びＲ^ｇ４ｄ、並びに
Ｒ^ｆ４ｅ及びＲ^ｇ４ｅは、相互に、又は複数ある場合には各々独立して、水素原子、ＯＨ、Ｃ_１−６アルキル基、ＣＯ_２Ｈ、ＣＯ_２−Ｃ_１−６アルキル、Ｃ_１−６アルコキシ基又はフェニル基（ここに、当該フェニル基はハロゲン原子、ＣＦ_３、Ｃ_１−４アルキル基、ＣＯ_２Ｈ、ＣＯ_２−Ｃ_１−６アルキル又はＣ_１−４アルコキシ基で置換されていてもよい）を表し、
あるいは、Ｒ^ｄ４ａとＲ^ｅ４ａ、Ｒ^ｄ４ｂとＲ^ｅ４ｂ、Ｒ^ｄ４ｃとＲ^ｅ４ｃ、Ｒ^ｆ４ｃとＲ^ｇ４ｃ、Ｒ^ｄ４ｄとＲ^ｅ４ｄ、Ｒ^ｆ４ｄとＲ^ｇ４ｄ、及びＲ^ｆ４ｅとＲ^ｇ４ｅがそれぞれ結合する同一炭素原子と一緒になって４〜８員のシクロアルキル環を形成してもよく、
あるいは、０〜３の炭素原子を介して隣接する炭素原子上に結合する２つのＲ^ｄ４ａ、Ｒ^ｄ４ｂ、Ｒ^ｄ４ｃ、Ｒ^ｆ４ｃ、Ｒ^ｄ４ｄ、Ｒ^ｆ４ｄ又はＲ^ｆ４ｅが、これらが結合する２つの炭素原子、及び両炭素原子間の炭素鎖と一緒になって４〜８員のシクロアルキル環を形成してもよく、
Ｒ^ｂ４ｃ、Ｒ^ｂ４ｄ及びＲ^ｂ４ｅは、各々独立して、以下の（ｉ）〜（ｘｉ）のいずれかを表し：
（ｉ）水素原子、
（ｉｉ）ハロゲン原子、
（ｉｉｉ）ＯＨ、
（ｉｖ）ＯＲ^３ｂ１、
（ｖ）ＣＮ、
（ｖｉ）ＣＯ_２Ｈ、
（ｖｉｉ）Ｃ（＝Ｏ）ＮＲ^３ｂ２Ｒ^３ｂ３、
（ｖｉｉｉ）ＳＯ_２ＮＲ^３ｂ４Ｒ^３ｂ５、
（ｉｘ）ＮＲ^３ｅＣ（＝Ｏ）ＮＲ^３ｂ６Ｒ^３ｂ７、
（ここに、Ｒ^３ｂ１、Ｒ^３ｂ２、Ｒ^３ｂ３、Ｒ^３ｂ４、Ｒ^３ｂ５、Ｒ^３ｂ６、Ｒ^３ｂ７及びＲ^３ｅは、各々独立して、水素原子又はＣ_１−１０アルキル基を表し、あるいは、Ｒ^３ｂ２とＲ^３ｂ３、Ｒ^３ｂ４とＲ^３ｂ５、又はＲ^３ｂ６とＲ^３ｂ７がそれぞれ結合するＮと一緒になって４〜８員の環状アミノ基を形成してもよい）、
（ｘ）下記式（４ｆ）で表されるいずれかの基：

（ここに、Ｒ^３４ｆは水素原子又はＣ_１−１０アルキル基を表す）、又は
（ｘｉ）ＣＯ_２ＣＲ^３ｇ１Ｒ^３ｇ２Ｒ^３ｇ３
（ここに、Ｒ^３ｇ１、Ｒ^３ｇ２及びＲ^３ｇ３は、各々独立して、
水素原子、
Ｃ_１−４アルキル基
（該基はＣ_１−４アルコキシ基、Ｃ_３−６シクロアルキル基（該基はＣ_１−４アルコキシ基で置換されていてもよい）、５員若しくは６員の飽和ヘテロ環基、又は５員若しくは６員の飽和ヘテロ環オキシで置換されていてもよい）、
Ｃ_３−１０シクロアルキル基
（該基は、フッ素原子及びＣ_１−４アルコキシ基から選ばれる１〜２個の置換基で置換されていてもよい）、
Ｃ_６−１０アリール基
（該基はハロゲン原子又はＣ_６−１０アリール基（該基はハロゲン原子又はＣ_１−４アルコキシで置換されていてもよい）で置換されていてもよい）、
５員若しくは６員の飽和ヘテロ環基、又は
５員〜１０員のヘテロアリール基
（該基はＣ_１−４アルキル基又はＣ_１−４アルコキシ基で置換されていてもよい）を表す）、
ｍ^４ａ、ｍ^４ｂ、ｍ^４ｃ及びｍ^４ｄは、各々独立して、０〜１０の整数を表し、
ｎ^４ｃ、ｎ^４ｄ及びｎ^４ｅは、各々独立して、０〜１０の整数を表す］；
［１］又は［２］のいずれか記載の医薬組成物。 [21] R ¹ represents any of the following formulas (2a), (2b), (2c), (2d), (2e), (2f), or (2g):

[Where:
^{R a2a, R a2b, R a2c} , R a2d, R b2, R a2f and ^{R A2G} are each independently a hydrogen atom, a halogen _{atom, CF 3, CN, OH,} C 1-6 alkyl _{groups, C 1-} Represents a ₆ alkoxy group, a C _1-6 alkylcarbonyl group, CO ₂ R ^1a , NR ^1b R ^1c or C (═O) NR ^1d R ^1e ,
R ^a2n represents a hydrogen atom, CF ₃ , CN, C _1-6 alkyl group, C _1-6 alkylcarbonyl group, CO ₂ R ^1a , NR ^1b R ^1c or C (═O) NR ^1d R ^1e ,
R ^1a , R ^1b , R ^1c , R ^1d and R ^1e each independently represent a hydrogen atom or a C _1-10 alkyl group, or R ^1b and R ^1c , or R ^1d and R ^1e are bonded to each other. Together with N to form a 4-8 membered cyclic amino group,
X ^2d represents an oxygen atom or —N (R ^c2 ) — (wherein R ^c2 represents a hydrogen atom or a C _1-10 alkyl group),
X ^2g represents an oxygen atom or a sulfur atom,
n ^2c represents an integer of 1 to 6,
m ^2d represents an integer of 1 to 3,
n ^2d represents an integer of 0 to 3,
n ^2e represents an integer of 0 to 8];
R ² represents any of the following formulas (3a), (3b), (3c), (3d) or (3e):

[Where:
R ^a3a , R ^a3b , R ^a3c , R ^a3d and R ^b3 each independently represent a hydrogen atom, a halogen atom, CF ₃ , CN, OH, a C _1-6 alkyl group, a C _1-6 alkoxy group, C _{1 -6} alkylcarbonyl ^_group, CO ² R _2a, represents ^NR 2b ^{R 2c} or ^{C (= O) NR 2d R} 2e,
R ^2a , R ^2b , R ^2c , R ^2d and R ^2e each independently represent a hydrogen atom or a C _1-10 alkyl group, or R ^2b and R ^2c , or R ^2d and R ^2e are bonded to each other. Together with N to form a 4-8 membered cyclic amino group,
X ^3d represents an oxygen atom, a sulfur atom or —N (R ^c3 ) — (wherein R ^c3 represents a hydrogen atom or a C _1-10 alkyl group),
n ^3a represents an integer of 0 to 6;
n ^3b represents an integer of 0 to 6;
n ^3c represents an integer of 1 to 6,
m ^3d represents an integer of 1 to 3,
n ^3d represents an integer of 0 to 3,
n ^3e represents an integer of 0 to 8];
R ³ represents any of the following formulas (4a), (4b), (4c), (4d) or (4e):

[Where:
R ^a4a , R ^a4b , R ^a4c and R ^a4d each independently represent a hydrogen atom, a halogen atom, CF ₃ , CN, OH, a C _1-10 alkyl group, a C _3-6 cycloalkyl group, or a C _1-6 alkoxy _{groups, C 3-6} cycloalkoxy _{group, C 1-6} alkylcarbonyl _{^{group, CO 2 R 3aa, NR 3ab}} R 3ac, C (= O) NR 3ad R 3ae or CH = ^{CH-R 3af} (wherein, R ^{3aa, R 3ab, R 3ac,} R 3ad and ^{R 3 ae} each independently represent a hydrogen atom or a _{C 1-10} alkyl group, ^{or, R 3ab} and ^{R 3ac,} or ^{R 3ad} and ^{R 3 ae} are respectively coupled ^May form a 4-8 membered cyclic amino group with N; R ^3af may be CN, CO ₂ H, CO ₂ R ^3f1 or C (═O) NR ^3f2 R ^3f3 R ^3f1 , R ^3f2 and R ^3f3 each independently represents a hydrogen atom or a C _1-6 alkyl group),
R ^d4a and R ^e4a ,
R ^d4b and R ^e4b ,
R ^d4c , R ^e4c , R ^f4c and R ^g4c ,
R ^d4d , R ^e4d , R ^f4d and R ^g4d , and R ^f4e and R ^g4e are each other or, when there are a plurality thereof, each independently a hydrogen atom, OH, a C _1-6 alkyl group, CO ₂ H, CO ₂ -C _1-6 alkyl, C _1-6 alkoxy group or phenyl group (wherein the phenyl group is a halogen atom, CF ₃ , C _1-4 alkyl group, CO ₂ H, CO ₂ -C _1-6 And optionally substituted with an alkyl or C _1-4 alkoxy group)
Alternatively, R ^d4a and R ^e4a , R ^d4b and R ^e4b , R ^d4c and R ^e4c , R ^f4c and R ^g4c , R ^d4d and R ^e4d , R ^f4d and R ^g4d , and R ^f4e and R ^g4e are bonded to each other. Together with the atoms may form a 4-8 membered cycloalkyl ring,
Alternatively, two R ^d4a , R ^d4b , R ^d4c , R ^f4c , R ^d4d , R ^f4d, or R ^f4e bonded to adjacent carbon atoms through 0-3 carbon atoms are the two carbons to which they are bonded. Together with the atom and the carbon chain between both carbon atoms may form a 4-8 membered cycloalkyl ring;
R ^b4c , R ^b4d and R ^b4e each independently represent any of the following (i) to (xi):
(I) a hydrogen atom,
(Ii) a halogen atom,
(Iii) OH,
(Iv) OR ^3b1 ,
(V) CN,
(Vi) CO ₂ H,
^{(Vii) C (= O)} NR 3b2 R 3b3,
(Viii) SO ₂ NR ^3b4 R ^3b5 ,
(Ix) NR ^3e C (═O) NR ^3b6 R ^3b7 ,
^{(Here, R 3b1, R 3b2, R} 3b3, R 3b4, R 3b5, R 3b6, R 3b7 and ^{R 3e} are each independently a hydrogen atom or a _{C 1-10} alkyl group, ^{or, R 3b2} and ^{R 3b3, R 3b4} and ^{R 3b5,} or ^{R 3 b 6} and ^{R 3B7} may form a cyclic amino group of 4-8 membered together with N to bind respectively),
(X) any group represented by the following formula (4f):

^{(Here, R 34f} represents a hydrogen atom or a _{C 1-10} alkyl group), or _{^{(xi) CO 2 CR 3g1 R}} 3g2 R 3g3
^(Here, R ^{3g1, R 3g2} and ^{R 3G3} are each independently
Hydrogen atom,
C _1-4 alkyl group (the group is a C _1-4 alkoxy group, C _3-6 cycloalkyl group (the group may be substituted with a C _1-4 alkoxy group)), 5-membered or 6-membered saturation Optionally substituted with a heterocyclic group, or a 5- or 6-membered saturated heterocyclic oxy),
A C _3-10 cycloalkyl group (which group may be substituted with 1 to 2 substituents selected from a fluorine atom and a C _1-4 alkoxy group),
A C _6-10 aryl group (the group may be substituted with a halogen atom or a C _6-10 aryl group (the group may be substituted with a halogen atom or C _1-4 alkoxy)),
A 5- or 6-membered saturated heterocyclic group, or a 5- to 10-membered heteroaryl group (the group may be substituted with a C _1-4 alkyl group or a C _1-4 alkoxy group),
m ^4a , m ^4b , m ^4c and m ^4d each independently represent an integer of 0 to 10;
n ^4c , n ^4d and n ^4e each independently represents an integer of 0 to 10];
The pharmaceutical composition according to any one of [1] or [2].

［式中、各記号は［１］に定義されるとおりである］
で示される、［１］、［２］又は［２１］のいずれか記載の医薬組成物。 [22] Y is the formula (II), (III) or (V):

[Wherein each symbol is as defined in [1]]
The pharmaceutical composition according to any one of [1], [2] or [21], which is represented by:

で示される、［１］、［２］、［２１］又は［２２］のいずれか記載の医薬組成物。 [23] Y is the formula (III):

The pharmaceutical composition according to any one of [1], [2], [21] or [22], which is represented by:

［式中、
ｍ^４ａ及びｍ^４ｂは、各々独立して、０〜８の整数を表し、
ｍ^４ｃ及びｎ^４ｃは、各々独立して、０〜１０の整数を表し（但し、ｍ^４ｃ＋ｎ^４ｃは１０以下であり）、
他の各記号は［２１］に定義されるとおりである］
で示される、［２１］〜［２３］のいずれか記載の医薬組成物。 [24] R ³ is the formula (4a), (4b), (4c) or (4e):

[Where:
m ^4a and m ^4b each independently represent an integer of 0 to 8,
m ^4c and n ^4c each independently represent an integer of 0 to 10 (provided that m ^4c + n ^4c is 10 or less),
Each other symbol is as defined in [21]]
The pharmaceutical composition according to any one of [21] to [23], which is represented by:

［式中、
Ｒ^ａ４ａ及びＲ^ａ４ｂは、各々独立して、水素原子、ハロゲン原子、ＣＮ、ＯＨ、Ｃ_１−６アルキル基、Ｃ_１−６アルコキシ基、ＣＯ_２Ｈ又はＣＯ_２−Ｃ_１−６アルキルであり、
ｍ^４ａ及びｍ^４ｂは、各々独立して、１〜３の整数であり、
他の記号は［２１］に定義されるとおりである］
で示される、［２１］〜［２４］のいずれか記載の医薬組成物。 [25] R ³ is the formula (4a) or (4b):

[Where:
R ^a4a and R ^a4b are each independently a hydrogen atom, a halogen atom, CN, OH, a C _1-6 alkyl group, a C _1-6 alkoxy group, CO ₂ H or CO ₂ -C _1-6 alkyl. ,
m ^4a and m ^4b are each independently an integer of 1 to 3,
Other symbols are as defined in [21]]
The pharmaceutical composition according to any one of [21] to [24].

[26] R ^a4a and R ^a4b are each independently a hydrogen atom, OH, or a C _1-4 alkoxy group, and m ^4a and m ^4b are each independently an integer of 1 or 2, 25] The pharmaceutical composition of description.

［式中、
ｍ^４ｃ及びｎ^４ｃは、各々独立して、０〜６の整数を表し（但し、ｍ^４ｃ＋ｎ^４ｃは１０以下であり）、
他の各記号は［２１］に定義されるとおりである］
で示される、［２１］〜［２４］のいずれか記載の医薬組成物。 [27] R ³ is the formula (4c):

[Where:
m ^4c and n ^4c each independently represent an integer of 0 to 6 (provided that m ^4c + n ^4c is 10 or less),
Each other symbol is as defined in [21]]
The pharmaceutical composition according to any one of [21] to [24].

（ここに、Ｒ^３４ｆは［２１］に定義されるとおりである）、又は
（ｘｉ）ＣＯ_２ＣＲ^３ｇ１Ｒ^３ｇ２Ｒ^３ｇ３
（ここに、Ｒ^３ｇ１、Ｒ^３ｇ２及びＲ^３ｇ３は、各々独立して、水素原子又はＣ_１−４アルキル基である）
であり、
Ｒ^ｄ４ｃ、Ｒ^ｅ４ｃ、Ｒ^ｆ４ｃ及びＲ^ｇ４ｃがいずれも水素原子であり、
ｍ^４ｃが１又は２の整数であり、
ｎ^４ｃが１〜３の整数である、［２７］記載の医薬組成物。 [28] R ^a4c is a hydrogen atom, a halogen atom, OH, a C _1-6 alkyl group, a C _1-6 alkoxy group, CO ₂ H or CO ₂ -C _1-6 alkyl,
R ^b4c is (v) CN,
(Vi) CO ₂ H,
^{(Vii) C (= O)} NR 3b2 R 3b3,
(X) any group represented by the following formula (4f):

^{(Here, R 34f} is as defined in [21]), or _{^{(xi) CO 2 CR 3g1 R}} 3g2 R 3g3
^(Here, R ^{3g1, R 3g2} and ^{R 3G3} are each independently hydrogen atom or a _{C 1-4} alkyl group)
And
R ^d4c , R ^e4c , R ^f4c and R ^g4c are all hydrogen atoms,
m ^4c is an integer of 1 or 2,
The pharmaceutical composition according to [27], wherein n ^4c is an integer of 1 to 3.

（ここに、Ｒ^３４ｆは［２１］に定義されるとおりである）、又は
（ｘｉｉ）ＣＯ_２Ｒ^３ｇ４
（ここに、Ｒ^３ｇ４はＣ_１−４アルキル基である）
である、［２８］記載の医薬組成物。 [29] R ^a4c is a hydrogen atom,
R ^b4c is (vi) CO ₂ H,
(X) any group represented by the following formula (4f):

(Where R ^34f is as defined in [21]), or (xii) CO ₂ R ^3g4
(Where R ^3g4 is a C _1-4 alkyl group)
The pharmaceutical composition according to [28].

［式中、各記号は［２１］に定義されるとおりである］
で示される、［２１］〜［２９］のいずれか記載の医薬組成物。 [30] R ¹ is represented by the following formula (2a), (2b) or (2g):

[Wherein each symbol is as defined in [21]]
The pharmaceutical composition according to any one of [21] to [29], which is represented by:

［式中、Ｒ^ａ２ａは［２１］に定義されるとおりである］
で示される、［２１］〜［３０］のいずれか記載の医薬組成物。 [31] R ¹ is represented by the following formula (2a):

[Wherein R ^a2a is as defined in [21]]
The pharmaceutical composition according to any one of [21] to [30], which is represented by:

[32] The pharmaceutical composition according to [31], wherein R ^a2a is a hydrogen atom, a halogen atom, CO ₂ H or CO ₂ -C _1-6 alkyl.

［式中、各記号は［２１］に定義されるとおりである］
で示される、［２１］〜［３２］のいずれか記載の医薬組成物。 [33] R ² is represented by the following formula (3c) or (3d):

[Wherein each symbol is as defined in [21]]
The pharmaceutical composition according to any one of [21] to [32], which is represented by:

［式中、Ｒ^ａ３ｃは水素原子であり、ｎ^３ｃは１〜４の整数である］
で示される、［２１］〜［３３］のいずれか記載の医薬組成物。 [34] R ² is represented by the following formula (3c):

[ ^Wherein , R ^a3c is a hydrogen atom, and n ^3c is an integer of 1 to 4]
The pharmaceutical composition according to any one of [21] to [33], which is represented by:

[35] The pharmaceutical composition according to [34], wherein n ^3c is 4.

[36] The medicament according to any one of [1] to [35], wherein X is a sulfur atom or —N (R ⁶ ) — (where R ⁶ represents a hydrogen atom or a C _1-4 alkyl group). Composition.

[37] The pharmaceutical composition according to [36], wherein X is -NH-.

[38] The pharmaceutical composition according to [36], wherein X is a sulfur atom.

[39] The pharmaceutical composition according to any one of [1] to [38], wherein R ⁴ and R ⁵ are both hydrogen atoms.

[40] The pharmaceutical composition according to [1], comprising a bicyclic pyrimidine compound selected from the following group or a physiologically acceptable salt thereof:
Methyl {4-[(3-{[2- (cyclohexylsulfanyl) -4-oxo-3-phenyl-3,5,7,8-tetrahydropyrido [4,3-d] pyrimidine-6 (4H)- Yl] carbonyl} azetidin-1-yl) methyl] phenyl} acetate (Example 59),
Methyl (2E) -3- {4-[(3-{[2- (cyclohexylsulfanyl) -4-oxo-3-phenyl-3,5,7,8-tetrahydropyrido [4,3-d] pyrimidine -6 (4H) -yl] carbonyl} azetidin-1-yl) methyl] phenyl} prop-2-enoate (Example 19),
Ethyl ({4-[(3-{[2- (cyclohexylsulfanyl) -4-oxo-3-phenyl-3,5,7,8-tetrahydropyrido [4,3-d] pyrimidine-6 (4H) -Yl] carbonyl} azetidin-1-yl) methyl] benzyl} oxy) acetate (Example 77),
Ethyl 4- (3-{[2- (cyclohexylsulfanyl) -4-oxo-3-phenyl-3,5,7,8-tetrahydropyrido [4,3-d] pyrimidin-6 (4H) -yl] Carbonyl} azetidin-1-yl) butanoate (Example 81),
Methyl 4- [2- (3-{[2- (cyclohexylsulfanyl) -4-oxo-3-phenyl-3,5,7,8-tetrahydropyrido [4,3-d] pyrimidine-6 (4H) -Yl] carbonyl} azetidin-1-yl) ethyl] benzoate (Example 79),
Methyl 3- {4-[(3-{[2- (cyclohexylsulfanyl) -4-oxo-3-phenyl-3,5,7,8-tetrahydropyrido [4,3-d] pyrimidine-6 (4H ) -Yl] carbonyl} azetidin-1-yl) methyl] phenyl} propanoate (Example 78),
Methyl 3- {4-[(3-{[2- (cyclohexylamino) -4-oxo-3-phenyl-3,5,7,8-tetrahydropyrido [4,3-d] pyrimidine-6 (4H ) -Yl] carbonyl} azetidin-1-yl) methyl] phenyl} propanoate (Example 21),
Ethyl 6- (3-{[2- (cyclohexylsulfanyl) -4-oxo-3-phenyl-3,5,7,8-tetrahydropyrido [4,3-d] pyrimidin-6 (4H) -yl] Carbonyl} azetidin-1-yl) hexanoate (Example 82),
Methyl 4- [2- (3-{[2- (cyclohexylamino) -4-oxo-3-phenyl-3,5,7,8-tetrahydropyrido [4,3-d] pyrimidine-6 (4H) -Yl] carbonyl} azetidin-1-yl) ethyl] benzoate (Example 24),
Ethyl 3- {4-[(3-{[2- (cyclohexylsulfanyl) -4-oxo-3-phenyl-3,5,7,8-tetrahydropyrido [4,3-d] pyrimidine-6 (4H ) -Yl] carbonyl} azetidin-1-yl) methyl] phenyl} propanoate (Example 65),
Ethyl 9- (3-{[2- (cyclohexylsulfanyl) -4-oxo-3-phenyl-3,5,7,8-tetrahydropyrido [4,3-d] pyrimidin-6 (4H) -yl] Carbonyl} azetidin-1-yl) nonanoate (Example 83),
Methyl {3-[(3-{[2- (cyclohexylsulfanyl) -4-oxo-3-phenyl-3,5,7,8-tetrahydropyrido [4,3-d] pyrimidine-6 (4H)- Yl] carbonyl} azetidin-1-yl) methyl] phenyl} acetate (Example 118),
Methyl {3-[(3-{[2- (cyclopentylsulfanyl) -4-oxo-3-phenyl-3,5,7,8-tetrahydropyrido [4,3-d] pyrimidine-6 (4H)- Yl] carbonyl} azetidin-1-yl) methyl] phenyl} acetate (Example 119),
Methyl {3-[(3-{[2- (cyclohexylsulfanyl) -3- (3,3-difluorocyclobutyl) -4-oxo-3,5,7,8-tetrahydropyrido [4,3-d Pyrimidin-6 (4H) -yl] carbonyl} azetidin-1-yl) methyl] phenyl} acetate (Example 107),
Methyl {4-[(3-{[2- (cyclopentylsulfanyl) -4-oxo-3-phenyl-3,5,7,8-tetrahydropyrido [4,3-d] pyrimidine-6 (4H)- Yl] carbonyl} azetidin-1-yl) methyl] phenyl} acetate (Example 151),
Ethyl 3- {4-[(3-{[2- (cyclohexylsulfanyl) -4-oxo-3-phenyl-3,5,7,8-tetrahydropyrido [4,3-d] pyrimidine-6 (4H ) -Yl] carbonyl} azetidin-1-yl) methyl] -2-fluorophenyl} propanoate (Example 97),
Ethyl {4- [2- (3-{[2- (cyclohexylsulfanyl) -4-oxo-3-phenyl-3,5,7,8-tetrahydropyrido [4,3-d] pyrimidine-6 (4H ) -Yl] carbonyl} azetidin-1-yl) ethyl] phenyl} acetate (Example 98),
Ethyl {4-[(3-{[2- (cyclohexylsulfanyl) -4-oxo-3-phenyl-3,5,7,8-tetrahydropyrido [4,3-d] pyrimidine-6 (4H)- Yl] carbonyl} azetidin-1-yl) methyl] phenoxy} acetate (Example 100),
Ethyl {3-[(3-{[2- (cyclohexylsulfanyl) -4-oxo-3-phenyl-3,5,7,8-tetrahydropyrido [4,3-d] pyrimidine-6 (4H)- Yl] carbonyl} azetidin-1-yl) methyl] phenoxy} acetate (Example 101),
Methyl {4-[(3-{[2- (cyclohexylsulfanyl) -3- (3,3-difluorocyclobutyl) -4-oxo-3,5,7,8-tetrahydropyrido [4,3-d Pyrimidin-6 (4H) -yl] carbonyl} azetidin-1-yl) methyl] phenyl} acetate (Example 125),
Ethyl {4-[(3-{[2- (cyclohexylsulfanyl) -3- (3,3-difluorocyclobutyl) -4-oxo-3,5,7,8-tetrahydropyrido [4,3-d ] Pyrimidin-6 (4H) -yl] carbonyl} azetidin-1-yl) methyl] phenoxy} acetate (Example 114),
Ethyl 3- {4-[(3-{[2- (cyclopentylsulfanyl) -4-oxo-3-phenyl-3,5,7,8-tetrahydropyrido [4,3-d] pyrimidine-6 (4H ) -Yl] carbonyl} azetidin-1-yl) methyl] phenyl} propanoate (Example 152),
Ethyl {4-[(3-{[2- (cyclopentylsulfanyl) -4-oxo-3-phenyl-3,5,7,8-tetrahydropyrido [4,3-d] pyrimidine-6 (4H)- Yl] carbonyl} azetidin-1-yl) methyl] phenoxy} acetate (Example 120),
Methyl {4-[(3-{[2- (cyclobutylsulfanyl) -4-oxo-3-phenyl-3,5,7,8-tetrahydropyrido [4,3-d] pyrimidine-6 (4H) -Yl] carbonyl} azetidin-1-yl) methyl] phenyl} acetate (Example 153),
Methyl 1- {4-[(3-{[2- (cyclohexylsulfanyl) -4-oxo-3-phenyl-3,5,7,8-tetrahydropyrido [4,3-d] pyrimidine-6 (4H ) -Yl] carbonyl} azetidin-1-yl) methyl] phenyl} cyclopropanecarboxylate (Example 99),
Methyl {4-[(3-{[2- (cyclohexylsulfanyl) -4-oxo-3- (pyridin-3-yl) -3,5,7,8-tetrahydropyrido [4,3-d] pyrimidine -6 (4H) -yl] carbonyl} azetidin-1-yl) methyl] phenyl} acetate (Example 130),
Methyl ({5-[(3-{[2- (cyclohexylsulfanyl) -4-oxo-3-phenyl-3,5,7,8-tetrahydropyrido [4,3-d] pyrimidine-6 (4H) -Yl] carbonyl} azetidin-1-yl) methyl] pyridin-2-yl} oxy) acetate (Example 103),
(+/-)-methyl {4-[(3-{[2- (cyclohexylsulfanyl) -4-oxo-3- [tetrahydrofuran-2-ylmethyl] -3,5,7,8-tetrahydropyrido [4 , 3-d] pyrimidin-6 (4H) -yl] carbonyl} azetidin-1-yl) methyl] phenyl} acetate (Example 129),
Methyl {4-[(3-{[2- (cyclohexylsulfanyl) -4-oxo-3-[(2R) -tetrahydrofuran-2-ylmethyl] -3,5,7,8-tetrahydropyrido [4,3 -D] pyrimidin-6 (4H) -yl] carbonyl} azetidin-1-yl) methyl] phenyl} acetate (Example 135),
Methyl {4-[(3-{[2- (cyclohexylsulfanyl) -4-oxo-3-[(2S) -tetrahydrofuran-2-ylmethyl] -3,5,7,8-tetrahydropyrido [4,3 -D] pyrimidin-6 (4H) -yl] carbonyl} azetidin-1-yl) methyl] phenyl} acetate (Example 137),
2-methoxyethyl 3- {4-[(3-{[2- (cyclohexylsulfanyl) -4-oxo-3-phenyl-3,5,7,8-tetrahydropyrido [4,3-d] pyrimidine- 6 (4H) -yl] carbonyl} azetidin-1-yl) methyl] phenyl} propanoate (Example 203),
2-hydroxyethyl 3- {4-[(3-{[2- (cyclohexylsulfanyl) -4-oxo-3-phenyl-3,5,7,8-tetrahydropyrido [4,3-d] pyrimidine- 6 (4H) -yl] carbonyl} azetidin-1-yl) methyl] phenyl} propanoate (Example 204),
Methyl {4-[(3-{[2- (cyclohexylsulfanyl) -3- (furan-2-ylmethyl) -4-oxo-3,5,7,8-tetrahydropyrido [4,3-d] pyrimidine -6 (4H) -yl] carbonyl} azetidin-1-yl) methyl] phenyl} acetate (Example 139),
Methyl {4-[(3-{[2- (cyclohexylsulfanyl) -3- (2-methoxyethyl) -4-oxo-3,5,7,8-tetrahydropyrido [4,3-d] pyrimidine- 6 (4H) -yl] carbonyl} azetidin-1-yl) methyl] phenyl} acetate (Example 140),
Methyl 6- (3-{[2- (cyclohexylsulfanyl) -4-oxo-3-phenyl-3,5,7,8-tetrahydropyrido [4,3-d] pyrimidin-6 (4H) -yl] Carbonyl} azetidin-1-yl) hexanoate (Example 105),
Methyl 4-[(3-{[2- (cyclohexylsulfanyl) -4-oxo-3-phenyl-3,5,7,8-tetrahydropyrido [4,3-d] pyrimidin-6 (4H) -yl ] Carbonyl} azetidin-1-yl) methyl] benzoate (Example 123),
Methyl {4- [2- (3-{[2- (cyclohexylsulfanyl) -4-oxo-3-phenyl-3,5,7,8-tetrahydropyrido [4,3-d] pyrimidine-6 (4H ) -Yl] carbonyl} azetidin-1-yl) ethoxy] phenyl} acetate (Example 102),
(+/-)-methyl {4-[(3-{[2- (cyclohexylsulfanyl) -4-oxo-3- (tetrahydrofuran-3-ylmethyl) -3,5,7,8-tetrahydropyrido [4 , 3-d] pyrimidin-6 (4H) -yl] carbonyl} azetidin-1-yl) methyl] phenyl} acetate (Example 146),
Ethyl {4-[(3-{[2- (cyclohexylsulfanyl) -4-oxo-3-[(2R) -tetrahydrofuran-2-ylmethyl] -3,5,7,8-tetrahydropyrido [4,3 -D] pyrimidin-6 (4H) -yl] carbonyl} azetidin-1-yl) methyl] phenoxy} acetate (Example 117),
Ethyl 3- {4-[(3-{[2- (cyclohexylsulfanyl) -4-oxo-3-[(2R) -tetrahydrofuran-2-ylmethyl] -3,5,7,8-tetrahydropyrido [4 , 3-d] pyrimidin-6 (4H) -yl] carbonyl} azetidin-1-yl) methyl] phenyl} propanoate (Example 149),
Ethyl {4-[(3-{[2- (3-butoxyphenoxy) -4-oxo-3-phenyl-3,5,7,8-tetrahydropyrido [4,3-d] pyrimidine-6 (4H ) -Yl] carbonyl} azetidin-1-yl) methyl] phenoxy} acetate (Example 214),
Methyl {4-[(3-{[2- (3-butoxyphenoxy) -4-oxo-3-phenyl-3,5,7,8-tetrahydropyrido [4,3-d] pyrimidine-6 (4H ) -Yl] carbonyl} azetidin-1-yl) methyl] phenyl} acetate (Example 95), and methyl {4-[(3-{[2- (cyclohexylsulfanyl) -3-[(2R) -2- Methoxypropyl] -4-oxo-3,5,7,8-tetrahydropyrido [4,3-d] pyrimidin-6 (4H) -yl] carbonyl} azetidin-1-yl) methyl] phenyl} acetate Example 150).

［式中、
Ｐ^２は、アミノ基の保護基であり、１〜３個のフェニル基（該フェニル基は１〜２個のメトキシ基で置換されてもよい）若しくはＣ_１−４アルカノイルオキシ基で置換されたメチル基、（Ｃ＝Ｏ）ＯＲ^ｐ１、又は（Ｃ＝Ｏ）Ｒ^ｐ２を表し、
Ｒ^ｐ１はＣ_１−４アルキル基（該基は１〜３個のハロゲン原子で置換されてもよく、但し、該基がメチル基の場合、１〜３個のハロゲン原子、フェニル基又は９−フルオレニル基で置換されてもよい）又はＣ_１−４アルケニル基を表し、
Ｒ^ｐ２は、水素原子、Ｃ_１−４アルキル基（該基は１〜３個のハロゲン原子で置換されてもよく、但し、該基がＣ_１−２アルキル基の場合、１〜３個のハロゲン原子、又はＣ_１−４アルカノイルオキシ基で置換されてもよい）又はフェニル基を表し、
Ｒ^１、Ｒ^２、Ｒ^４、Ｒ^５及びＸは［４］に定義されるとおりである］。 [41] A bicyclic pyrimidine compound represented by the formula (Ib) or a chemically stable salt thereof:

[Where:
P ² is an amino-protecting group, and is substituted with 1 to 3 phenyl groups (the phenyl group may be substituted with 1 to 2 methoxy groups) or C _1-4 alkanoyloxy groups. Represents a methyl group, (C═O) OR ^p1 , or (C═O) R ^p2 ,
R ^p1 represents a C _1-4 alkyl group (the group may be substituted with 1 to 3 halogen atoms, provided that when the group is a methyl group, 1 to 3 halogen atoms, a phenyl group, or 9- Which may be substituted with a fluorenyl group) or a C _1-4 alkenyl group,
R ^p2 represents a hydrogen atom, a C _1-4 alkyl group (the group may be substituted with 1 to 3 halogen atoms, provided that when the group is a C _1-2 alkyl group, 1 to 3 A halogen atom or a C _1-4 alkanoyloxy group which may be substituted) or a phenyl group,
R ¹ , R ² , R ⁴ , R ⁵ and X are as defined in [4]].

を脱保護して、式（Ｉｃ）で表される二環性ピリミジン化合物又はその化学的に安定な塩：

とし、次いでこれを式（ＶＩａ）で表される化合物：

と反応させる二工程を含む、式（Ｉｄ）で表される二環性ピリミジン化合物又はその生理的に許容される塩：

の製造方法：
［式中、
Ｌは脱離基であり、ハロゲン原子、又は、ＯＳＯ_２Ｒ^Ｌを表す；ここに、Ｒ^Ｌは、フッ素原子で置換されてもよいＣ_１−４アルキル基又はＣ_１−４アルキルで置換されてもよいフェニル基を意味し、
Ｐ^２は［４１］に定義されるとおりであり、
Ｒ^１、Ｒ^２、Ｒ^３、Ｒ^４、Ｒ^５及びＸは［４］に定義されるとおりである］。 [42] The bicyclic pyrimidine compound represented by the formula (Ib) according to [41] or a chemically stable salt thereof:

And a bicyclic pyrimidine compound represented by the formula (Ic) or a chemically stable salt thereof:

And then this is a compound of formula (VIa):

A bicyclic pyrimidine compound represented by formula (Id) or a physiologically acceptable salt thereof, comprising two steps of reacting with:

Manufacturing method:
[Where:
L is a leaving group and represents a halogen atom or OSO ₂ ^RL ; wherein ^RL is a C _1-4 alkyl group which may be substituted with a fluorine atom or a C _1-4 alkyl group Meaning a phenyl group,
P ² is as defined in [41],
R ¹ , R ² , R ³ , R ⁴ , R ⁵ and X are as defined in [4]].

を脱保護して、式（Ｉｃ）で表される二環性ピリミジン化合物又はその化学的に安定な塩：

とし、次いでこれを式（ＶＩｂ）で表される化合物：

と反応させる二工程を含む、式（Ｉｅ）で表される二環性ピリミジン化合物又はその生理的に許容される塩：

の製造方法：
［式中、
Ｒ^３ｐ１は下記式（４ｇｐ）、（４ｈｐ）又は（４ｉｐ）のいずれかで示される基を表し：

ｍ^４ｇｐは、０〜５の整数を表し、
ｍ^４ｈｐ及びｍ^４ｉｐは、各々独立して、０〜４の整数を表し（ただし、ｒ^４ｈが１の場合、ｍ^４ｈｐは１〜４の整数を表し；ｓ^４ｉが１の場合、ｍ^４ｉｐは１〜４の整数を表す）、
Ｒ^３ｐ２は水素原子又はＣ_１−６アルキル基を表し、
Ｐ^２は［４１］に定義されるとおりであり、
Ｒ^１、Ｒ^２、Ｒ^４、Ｒ^５、Ｘ、Ａｒｍ、Ｒ^ａ４ｇ、Ｒ^ａ４ｈ、Ｒ^ｂ４ｈ、Ｒ^ｂ４ｉ、Ｒ^ｄ４ｇ、Ｒ^ｅ４ｇ、Ｒ^ｄ４ｈ、Ｒ^ｅ４ｈ、Ｒ^ｆ４ｈ、Ｒ^ｇ４ｈ、Ｒ^ｈ４ｈ、Ｒ^ｉ４ｈ、Ｒ^ｊ４ｈ、Ｒ^ｋ４ｈ、Ｒ^ｄ４ｉ、Ｒ^ｅ４ｉ、Ｒ^ｆ４ｉ、Ｒ^ｇ４ｉ、ｎ^４ｈ、ｐ^４ｈ、ｑ^４ｈ、ｎ^４ｉ、ｒ^４ｈ、ｓ^４ｈ及びｓ^４ｉは［４］に定義されるとおりである］。 [43] The bicyclic pyrimidine compound represented by the formula (Ib) according to [41] or a chemically stable salt thereof:

And a bicyclic pyrimidine compound represented by the formula (Ic) or a chemically stable salt thereof:

And then this is a compound of formula (VIb):

A bicyclic pyrimidine compound represented by formula (Ie) or a physiologically acceptable salt thereof, comprising two steps of reacting with:

Manufacturing method:
[Where:
R ^3p1 represents a group represented by any of the following formulas (4gp), (4hp) or (4ip):

m ^4gp represents an integer of 0 to 5;
m ^4hp and m ^4ip each independently represent an integer of 0 to 4 (provided that when r ^4h is 1, m ^4hp represents an integer of 1 to 4; when s ⁴ⁱ is 1, m ^4ip is Represents an integer of 1 to 4),
R ^3p2 represents a hydrogen atom or a C _1-6 alkyl group,
P ² is as defined in [41],
R ¹ , R ² , R ⁴ , R ⁵ , X, Arm, R ^a4g , R ^a4h , R ^b4h , R ^b4i , R ^d4g , R ^e4g , R ^d4h , R ^e4h , R ^f4h , R ^g4h , R ^{h4 i4h, R j4h, R k4h,} R d4i, R e4i, R f4i, R g4i, n 4h, p 4h, q 4h, n 4i, r 4h, s 4h and ^{s 4i} is as defined in [4] is there].

［式中、
Ｒ^ｂ４ｈはＣＯ_２ＣＲ^３ｇ１Ｒ^３ｇ２Ｒ^３ｇ３（ここに、Ｒ^３ｇ１、Ｒ^３ｇ２及びＲ^３ｇ３は、各々独立して、水素原子、又は、Ｃ_１−４アルキル基（該基はＯＨ、又は、Ｃ_１−４アルコキシ基で置換されていてもよい）を表す）を表し、
Ａｒｍ、Ｒ^ａ４ｈ、Ｒ^ｄ４ｈ、Ｒ^ｅ４ｈ、Ｒ^ｆ４ｈ、Ｒ^ｇ４ｈ、Ｒ^ｈ４ｈ、Ｒ^ｉ４ｈ、Ｒ^ｊ４ｈ、Ｒ^ｋ４ｈ、ｍ^４ｈ、ｎ^４ｈ、ｐ^４ｈ、ｑ^４ｈ、ｒ^４ｈ、ｓ^４ｈ、Ｒ^４及びＲ^５は［４］に定義されるとおりである］。 [44] A substituted azetidine compound represented by the formula (VII) or a chemically stable salt thereof:

[Where:
R ^B4h the _{^{CO 2 CR 3g1 R 3g2 R 3g3}} ( ^here, R ^{3g1, R 3g2} and ^{R 3G3} is independently a hydrogen atom, _{or, C 1-4} alkyl (in which the group OH, or, C Represents an optionally substituted with _1-4 alkoxy group),
^{Arm, R a4h, R d4h,} R e4h, R f4h, R g4h, R h4h, R i4h, R j4h, R k4h, m 4h, n 4h, p 4h, q 4h, r 4h, s 4h, R 4 and R ⁵ is as defined in [4]].

を式（ＶＩＩＩ）で表される二環性ピリミジン化合物又はその化学的に安定な塩：

と反応させる工程を含む、式（Ｉｆ）で表される二環性ピリミジン化合物又はその生理的に許容される塩：

の製造方法：
［式中、
Ｒ^ｂ４ｈは［４４］に定義されるとおりであり、
Ａｒｍ、Ｒ^ａ４ｈ、Ｒ^ｄ４ｈ、Ｒ^ｅ４ｈ、Ｒ^ｆ４ｈ、Ｒ^ｇ４ｈ、Ｒ^ｈ４ｈ、Ｒ^ｉ４ｈ、Ｒ^ｊ４ｈ、Ｒ^ｋ４ｈ、ｍ^４ｈ、ｎ^４ｈ、ｐ^４ｈ及びｑ^４ｈ、ｒ^４ｈ、及びｓ^４ｈ、並びにＲ^１、Ｒ^２、Ｒ^４、Ｒ^５及びＸは［４］に定義されるとおりである］。 [45] The substituted azetidine compound represented by the formula (VII) according to [44] or a chemically stable salt thereof:

Is a bicyclic pyrimidine compound represented by the formula (VIII) or a chemically stable salt thereof:

A bicyclic pyrimidine compound represented by formula (If) or a physiologically acceptable salt thereof, comprising a step of reacting with

Manufacturing method:
[Where:
R ^b4h is as defined in [44],
^{Arm, R a4h, R d4h,} R e4h, R f4h, R g4h, R h4h, R i4h, R j4h, R k4h, m 4h, n 4h, p 4h and ^{q 4h, r 4h,} and ^{s 4h,} and R ¹ , R ² , R ⁴ , R ⁵ and X are as defined in [4].

[46] A pharmaceutical product comprising the pharmaceutical composition according to any one of [1] to [40] or [49].

[47] The pharmaceutical composition according to any one of [1] to [40] or [49] as a prophylactic and / or therapeutic agent for MGAT-related diseases.

［式中、
Ｒ^ａ２ａ及びＲ^ａ２ｂは、各々独立して、水素原子、ハロゲン原子、Ｃ_１−４アルキル基又はＣ_１−４アルコキシ基であり、
ｎ^２ａ及びｎ^２ｂは０である］、
下記式（２ｃ’）：

［式中、
Ｒ^ａ２ｃは水素原子又はフッ素原子（該基は化学的に許容される限り、任意の位置にて複数個置換してもよい）であり、
ｐ^２ｃは０であり、
ｎ^２ｃは１〜４の整数である］、又は、
下記式（２ｄ’）：

［式中、
Ｒ^ａ２ｄは水素原子であり、
Ｘ^２ｄは酸素原子であり、
ｐ^２ｄは１であり、
ｍ^２ｄは２〜３の整数であり、
ｎ^２ｄは０〜１の整数である］
で示される基であり、
Ｒ^２が下記式（３ｃ）：

［式中、Ｒ^ａ３ｃは水素原子であり、ｎ^３ｃは２〜４の整数である］
で示される基であり、
Ｒ^３が式（４ｈ）：

［式中、
Ａｒｍはベンゼン環又はピリジン環であり、
Ｒ^ａ４ｈは水素原子、ハロゲン原子、ＣＦ_３、Ｃ_１−６アルキル基又はＣ_１−６アルコキシ基であり、
Ｒ^ｂ４ｈは
（ｘｉ）ＣＯ_２ＣＲ^３ｇ１Ｒ^３ｇ２Ｒ^３ｇ３
（ここに、Ｒ^３ｇ１、Ｒ^３ｇ２及びＲ^３ｇ３は、各々独立して、
水素原子、又は、
Ｃ_１−４アルキル基（該基はＯＨ、Ｃ_１−４アルコキシ基、５員若しくは６員の飽和ヘテロ環基又はＮＲ^３ｂ８Ｒ^３ｂ９で置換されていてもよく、Ｒ^３ｂ８及びＲ^３ｂ９は、各々独立して、水素原子又はＣ_１−４アルキル基を表す）
を表す）であり、
Ｒ^ｄ４ｈ、Ｒ^ｅ４ｈ、Ｒ^ｆ４ｈ、Ｒ^ｇ４ｈ、Ｒ^ｈ４ｈ、Ｒ^ｉ４ｈ、Ｒ^ｊ４ｈ及びＲ^ｋ４ｈは、
相互に独立して、かつ、各基が複数ある場合には各々独立して、水素原子又はＣ_１−４アルキル基を表し、
あるいは、Ｒ^ｆ４ｈとＲ^ｇ４ｈはこれらが結合する炭素原子と一緒になって３〜６員のシクロアルキル環を形成してもよく、
ｍ^４ｈは１又は２であり、
ｎ^４ｈは１〜３の整数であり、
ｐ^４ｈ、ｑ^４ｈ、ｒ^４ｈ及びｓ^４ｈは、各々独立して、０又は１である
（ただし、ｒ^４ｈが１の場合、ｍ^４ｈは２である）］
で示される基であり、
Ｒ^４及びＲ^５がいずれも水素原子であり、
Ｘが硫黄原子又は−ＮＨ−であり、
Ｙが式（ＩＩＩ）：

で示される基である、［４］記載の医薬組成物。 [48] [1] to [1] as a prophylactic and / or therapeutic agent for obesity, metabolic syndrome, hyperlipidemia, hypertriglyceridemia, hyperVLDL, hyperfattyemia, diabetes or arteriosclerosis 40] or [49].
[49] R ¹ is represented by the following formula (2a ′) or (2b ′):

[Where:
R ^a2a and R ^a2b are each independently a hydrogen atom, a halogen atom, a C _1-4 alkyl group or a C _1-4 alkoxy group,
n ^2a and n ^2b are 0],
The following formula (2c ′):

[Where:
R ^a2c is a hydrogen atom or a fluorine atom (a plurality of such groups may be substituted at any position as long as it is chemically acceptable);
p ^2c is 0,
n ^2c is an integer from 1 to 4], or
The following formula (2d ′):

[Where:
R ^a2d is a hydrogen atom,
X ^2d is an oxygen atom,
p ^2d is 1,
m ^2d is an integer of 2 to 3,
n ^2d is an integer of 0 to 1.]
A group represented by
R ² represents the following formula (3c):

[ ^Wherein , R ^a3c is a hydrogen atom, and n ^3c is an integer of 2 to 4]
A group represented by
R ³ represents formula (4h):

[Where:
Arm is a benzene ring or a pyridine ring,
R ^a4h is a hydrogen atom, a halogen atom, CF ₃ , a C _1-6 alkyl group or a C _1-6 alkoxy group,
R ^B4h is _{^{(xi) CO 2 CR 3g1 R}} 3g2 R 3g3
^(Here, R ^{3g1, R 3g2} and ^{R 3G3} are each independently
A hydrogen atom, or
A C _1-4 alkyl group (the group may be substituted with OH, a C _1-4 alkoxy group, a 5- or 6-membered saturated heterocyclic group, or NR ^3b8 R ^3b9 , each of R ^3b8 and R ^3b9 is Independently represents a hydrogen atom or a C _1-4 alkyl group)
Represents)
R ^d4h , R ^e4h , R ^f4h , R ^g4h , R ^h4h , R ^i4h , R ^j4h and R ^k4h are
Independently of each other and when there are a plurality of groups, each independently represents a hydrogen atom or a C _1-4 alkyl group,
Alternatively, R ^f4h and R ^g4h together with the carbon atom to which they are attached may form a 3-6 membered cycloalkyl ring,
m ^4h is 1 or 2,
n ^4h is an integer of 1 to 3,
p ^4h , q ^4h , r ^4h and s ^4h are each independently 0 or 1 (provided that when r ^4h is 1, m ^4h is 2)]
A group represented by
R ⁴ and R ⁵ are both hydrogen atoms,
X is a sulfur atom or -NH-,
Y is the formula (III):

[4] The pharmaceutical composition according to [4].

  The bicyclic pyrimidine derivatives of the present invention and physiologically acceptable salts thereof have an MGAT inhibitory action, and pharmaceutical compositions containing these include obesity, metabolic syndrome, hyperlipidemia, hypertriglyceridemia It is useful as a preventive and / or therapeutic agent for hypertension, hyperVLDL, hyperfattyemia, diabetes and arteriosclerosis.

Terms used in this specification are explained below.
The “alkyl group” and the “alkyl” part mean, for example, a linear or branched alkyl group having 1 to 10 carbon atoms (also referred to as “C _1-10 ” in the present specification). Examples thereof include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, tert-pentyl, hexyl, isohexyl, octyl, nonyl, decyl and the like. Preferably, R ¹ , R ² , R ⁴ and R ⁵ have 1 to 6 carbon atoms (also referred to herein as “C _1-6 ”), and R ³ has 1 to 10 carbon atoms. (C _1-10 ). More preferably, it is 1 to 6 carbon atoms (C _1-6 ) in R ³ . Preferable specific examples include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, tert-pentyl, hexyl and the like.

The “lower alkyl group” and the “lower alkyl” part mean a linear or branched alkyl group having 1 to 8 carbon atoms (also referred to as “C _1-8 ” in the present specification), specifically Examples include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, tert-pentyl, hexyl, isohexyl, octyl and the like. Preferably, it is 1 to 6 carbon atoms (C _1-6 ) in R ¹ , R ² , R ⁴ and R ⁵ , and 1 to 8 carbon atoms (C _1-8 ) in R ³ . More preferably, it is 1 to 6 carbon atoms (C _1-6 ) in R ³ . More preferably, it is 1 to 4 carbon atoms in R ¹ , R ² , R ³ , R ⁴ and R ⁵ (also referred to as “C _1-4 ” in this specification). Preferable specific examples include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, tert-pentyl, hexyl and the like.

The “alkenyl group” and the “alkenyl” part include, for example, at least a carbon-carbon single bond of an “alkyl group” having 2 to 10 carbon atoms (also referred to as “C _2-10 ” in this specification). This means a carbon chain in which one place is replaced with a double bond. Specific examples include vinyl, allyl, 3-butenyl, isobutenyl, 3-pentenyl, 8-nonenyl, 1,4-heptadienyl, 2,4,7- Decatrienyl and the like can be mentioned. Preferably, R ¹ , R ² , R ⁴ and R ⁵ have 2 to 6 carbon atoms (also referred to herein as “C _2-6 ”), and R ³ has 3 to 10 carbon atoms. (Also referred to as “C _3-10 ” in this specification). Preferable specific examples include vinyl, isobutenyl, 1,4-heptadienyl, 8-nonenyl and the like.

The “lower alkenyl group” and the “lower alkenyl” moiety are carbon-carbon single bonds of the “lower alkyl group” having 2 to 8 carbon atoms (also referred to herein as “C _2-8 ”). , Means a carbon chain in which at least one site is replaced with a double bond, and specific examples include vinyl, allyl, 3-butenyl, isobutenyl, 1,4-heptadienyl, and the like. Preferably, R ¹ , R ² , R ⁴ and R ⁵ have 2 to 6 carbon atoms (C _2-6 ), and R ³ has 2 to 8 carbon atoms (C _2-8 ). More preferably, R ³ has 3 to 6 carbon atoms (also referred to as “C _3-6 ” in this specification). Preferable specific examples include vinyl, isobutenyl, 1,4-heptadienyl and the like.

“Alkynyl group” and “alkynyl” part is a carbon chain in which at least one of carbon-carbon single bonds of an “alkyl group” having 2 to 10 carbon atoms (C _2-10 ) is replaced with a triple bond Specific examples thereof include ethynyl, propargyl, 2-butynyl, 3-butynyl, 4-heptynyl, 3-hexynyl, 2,4-octadiynyl and the like. Preferably, it has 2 to 6 carbon atoms (C _2-6 ) in R ¹ , R ² , R ⁴ and R ⁵ , and 2 to 10 carbon atoms (C _2-10 ) in R ³ . More preferably, it has 3 to 6 carbon atoms (C _3-6 ) in R ³ . Preferable specific examples include ethynyl, propargyl, 2-butynyl, 3-butynyl and the like.

The “lower alkynyl group” and “lower alkynyl” moiety is a carbon-carbon single bond of a “lower alkyl group” having 2 to 8 carbon atoms (C _2-8 ) and is replaced with a triple bond. Specific examples include ethynyl, propargyl, 2-butynyl, 3-butynyl, 4-heptynyl and the like. Preferably, it has 2 to 6 carbon atoms (C _2-6 ) in R ¹ , R ² , R ⁴ and R ⁵ , and 2 to 8 carbon atoms (C _2-8 ) in R ³ . More preferably, it has 3 to 6 carbon atoms (C _3-6 ) in R ³ . Preferable specific examples include ethynyl, propargyl, 2-butynyl, 3-butynyl and the like.

The “lower cycloalkyl group” and the “lower cycloalkyl” part mean a cyclic alkyl group having 3 to 8 carbon atoms (also referred to as “C _3-8 ” in this specification). , Cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and the like. Preferably, the number of carbon atoms is 5 to 7 (also referred to as “C _5-7 ” in this specification). Preferably, R ² has 3 to 6 carbon atoms (C _3-6 ), more preferably 5 or 6 carbon atoms (also referred to as “C _5-6 ” in this specification). is there. Preferred specific examples include cyclopentyl, cyclohexyl, cycloheptyl and the like.

The “lower cycloalkenyl group” and the “lower cycloalkenyl” moiety are bonded to one or two of the carbon-carbon single bonds of the “lower cycloalkyl group” having 3 to 8 carbon atoms (C _3-8 ). This means a carbon chain converted to a double bond, and specific examples include cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl and the like. Preferably, it is 5 or 6 carbon atoms (C _5-6 ). Preferable specific examples include cyclopentenyl, cyclohexenyl and the like.

The “lower alkoxy group” and the “lower alkoxy” part mean a straight or branched alkoxy group having 1 to 8 carbon atoms (C _1-8 ). Specific examples thereof include methoxy, ethoxy, propoxy. , Isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy and the like. Preferably, it is 1 to 6 carbon atoms (C _1-6 ) in R ¹ , R ² , R ⁴ and R ⁵ , and 1 to 8 carbon atoms (C _1-8 ) in R ³ . More preferably, it is 1 to 6 carbon atoms (C _1-6 ) in R ³ . More preferably, it is 1 to 4 carbon atoms (C _1-4 ) in R ¹ , R ² , R ³ , R ⁴ and R ⁵ .

The “lower alkylthio group” means a group in which one sulfur atom is bonded to the bonding site of a linear or branched alkyl group having 1 to 8 carbon atoms (C _1-8 ). For example, methylthio, Examples include ethylthio, propylthio, isopropylthio, butylthio, isobutylthio, sec-butylthio, tert-butylthio and the like. Preferably, it is 1 to 6 carbon atoms (C _1-6 ) in R ¹ , R ² , R ⁴ and R ⁵ , and 1 to 8 carbon atoms (C _1-8 ) in R ³ . More preferably, it is 1 to 6 carbon atoms (C _1-6 ) in R ³ . More preferably, it is 1 to 4 carbon atoms (C _1-4 ) in R ¹ , R ² , R ³ , R ⁴ and R ⁵ .

“Halogen atom” means a fluorine atom, a chlorine atom, a bromine atom or an iodine atom. The substituents in R ¹ , R ² and R ³ are preferably a fluorine atom and a chlorine atom, and more preferably a fluorine atom.

  The “cyclic amino group” and the “cyclic amino” moiety contain at least one nitrogen atom and optionally contain a 4- to 7-membered cyclic amino group which may contain an oxygen atom or a sulfur atom, or at least 1 nitrogen atom. Means a 4- to 7-membered cyclic amino group fused to a benzene ring, which may contain an oxygen atom or a sulfur atom, and examples thereof include azetidinyl, pyrrolidyl, piperidyl, morpholinyl, thiomorpholinyl, Examples include hexahydroazepinyl, tetrahydroquinolyl, tetrahydroisoquinolyl, indolyl, isoindolyl, 1-oxoisoindolyl, 1,3-dioxoisoindolyl and the like. Preferably, the thing of a 5-membered ring or a 6-membered ring is mentioned. Preferable specific examples include pyrrolidyl, piperidyl, morpholinyl and the like.

The “lower alkanoyl group” and “lower alkanoyl” moiety means a straight or branched alkanoyl group having 1 to 8 carbon atoms (C _1-8 ). Specific examples thereof include formyl, acetyl, propionyl, Examples include butyryl, isobutyryl, valeryl, pivaloyl and the like. Preferably, those from 1 to 6 carbon atoms or a _{(C 1-6).} More preferably, it is 1 to 4 carbon atoms (C _1-4 ).

The “aryl group” and the “aryl” moiety are also expressed as a 6-membered to 14-membered monocyclic, bicyclic or tricyclic aromatic hydrocarbon (also referred to herein as “C _6-14 aryl”). Preferably 6- to 10-membered monocyclic, bicyclic or tricyclic aromatic hydrocarbons (also referred to herein as “C _6-10 aryl”) . Specific examples include phenyl, naphthyl, phenanthryl, anthryl and the like. Preferred examples include phenyl, 1-naphthyl, 2-naphthyl, and the like, and more preferred is phenyl.

In addition to the substituent R ^a4g or R ^a4h , the “benzene ring” represented as a preferred embodiment of Arm in the formulas (4g) and (4h) is an alkylene which may be mediated by oxygen as described in the formula Benzene substituted at any substitutable position by one or two side chains. In the formula (4h), when two alkylene side chains are present, Arm represents phenylene, and the bonding positions of the two side chains are the ortho (o) position (1, 2 position), the meta (m) position (1 , 3 position) or para (p) position (1, 4 position), preferably meta position (1, 3 position) or para position (1, 4 position), more preferably para position. (1st, 4th).

“Heteroaryl” and “heteroaryl” moieties are 4- to 10-membered monocyclic or bicyclic aromatics containing 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen atoms. Means a heterocyclic group. Specific examples include, for example, pyrrolyl, furanyl (furyl), thienyl, oxazolyl, oxadiazolyl, thiazolyl, thiadiazolyl, isothiazolyl, pyrazolyl, indolyl, azaindolyl, imidazolyl, isoxazolyl, triazolyl, thiadiazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, quinolyl, Examples thereof include isoquinolyl, benzothiazolyl, thiazolopyridinyl, thiazolopyrazinyl, thiazolopyrimidinyl, indazolyl, benzodiazinyl, benzofuranyl, benzodioxalyl, benzothienyl, benzoimidazolyl, and benzoxazolyl. Preferably, it is a 5-membered or 6-membered monocyclic aromatic heterocyclic group. Preferable specific examples include pyrrolyl, furanyl (furyl), thienyl, oxazolyl, oxadiazolyl, thiazolyl, thiadiazolyl, isothiazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyridazinyl and the like. More preferred specific examples include pyridyl, furanyl (furyl), thienyl and the like. Preferably, R ¹ is pyrrolyl, furanyl (furyl), thienyl and pyridyl. More preferably, R ¹ is furanyl (furyl) and pyridyl.

The “heteroaromatic ring” represented as an embodiment of Arm in the formulas (4g) and (4h) is an alkylene which may be mediated by oxygen as described in the formula in addition to the substituent R ^a4g or R ^a4h. Unsaturated heterocycle substituted at any substitutable position by one or two side chains and containing 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen Means a 5- to 10-membered monocyclic or bicyclic aromatic heterocycle. Specific examples include, for example, pyrrole, furan, thiophene, oxazole, oxadiazole, thiazole, thiadiazole, isothiazole, pyrazole, indole, azaindole, imidazole, isoxazole, triazole, thiadiazole, pyridine, pyrimidine, pyridazine, pyrazine, Examples of the ring include quinoline, isoquinoline, benzothiazoline, thiazolopyridine, thiazolopyrazine, thiazolopyrimidine, indazoline, benzodiazine, benzofuran, benzothiophene, benzimidazole, and benzoxazole. Preferably, it is a 5-membered or 6-membered monocyclic aromatic heterocycle. Preferable specific examples include pyrrole, furan, thiophene, oxazole, oxadiazole, thiazole, thiadiazole, isothiazole, pyrazole, imidazole, pyridine, pyrimidine, pyridazine, pyrazine and the like. More preferably, it is a 5-membered or 6-membered monocyclic aromatic heterocycle containing only 1 or 2 nitrogen atoms as a hetero atom. More preferable specific examples include each ring such as pyrrole, pyrazole, imidazole, pyridine, pyrimidine, pyridazine, and pyrazine, more preferably a pyrazole ring and a pyridine ring, and most preferably a pyridine ring.
In the “heteroaromatic ring”, as described in formula (4h), when there are two or more alkylene side chains which may be oxygenated, as long as it is chemically acceptable, the bonding positions of these side chains May be any arrangement that can be combined. For example, when Arm is a “pyridine ring”, Arm is a pyridine ring substituted at any position on the carbon atom that can be substituted by the side chain described in the formula, and as described in formula (4h), When there are two alkylene side chains that may be through oxygen, the bonding positions of the two side chains are other than the nitrogen atom, and are any two positions selected from the 2nd to 6th positions of the pyridine ring, Preferred are 2,4, 3,5, 4,6, 2,5 or 3,6, and more preferred is 2,5 or 3,6.

The “heterocyclic group” and “heterocyclic” moiety are 3- to 12-membered monocyclic, bicyclic or tricyclic containing 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen atoms. It means a cyclic saturated or unsaturated heterocyclic group. Specific examples include, for example, pyrrolyl, furanyl (furyl), thienyl, oxazolyl, oxadiazolyl, thiazolyl, thiadiazolyl, isothiazolyl, pyrazolyl, indolyl, azaindolyl, imidazolyl, isoxazolyl, triazolyl, thiadiazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, quinolyl, Isoquinolyl, benzothiazolyl, thiazolopyridinyl, thiazolopyrazinyl, thiazolopyrimidinyl, indazolyl, benzodiazinyl, benzofuranyl, benzodioxalyl, benzothienyl, benzimidazolyl, benzoxazolyl, oxetanyl, azetidinyl, pyrrolidinyl, tetrahydrofuryl, dioxolanyl Piperidinyl, piperazinyl, homopiperazinyl, tetrahydropyranyl, A cyclohexyl, morpholinyl, thiomorpholinyl, cyclohexanol thiazolyl, dihydro thiazolopyridinyl, tetrahydro thiazolopyridinyl or the like. Preferably, R ¹ is tetrahydrofuryl.

The “optionally substituted lower alkyl group” or “optionally substituted alkyl group” includes a halogen atom, a lower cycloalkyl group, and a phenyl group (the phenyl group is a halogen atom; CF ₃ ; a lower alkoxy group; Substituted with 1 to 3 substituents selected from a carboxyl group; a lower alkoxycarbonyl group; a cyano group; a hydroxyl group; and an alkyl group optionally substituted with either a halogen atom, a carboxyl group or a lower alkoxycarbonyl group May be substituted), phenyloxy group, lower alkoxy group (the lower alkoxy group may be substituted with a lower alkoxycarbonyl group), trifluoromethoxy group, lower alkylthio group, hydroxyl group, nitro group, cyano group, Carboxyl group, lower alkoxycarbonyl group, benzyloxycarbonyl group Lower alkanoyloxy group, carbamoyl group, mono- or di-substituted lower alkylaminocarbonyl group, cyclic aminocarbonyl group, amino group, mono- or di-substituted lower alkylamino group, cyclic amino group, lower alkylsulfonylamino group, benzenesulfonylamino group, Lower alkanoylamino group, benzoylamino group, lower alkoxycarbonylamino group, carbamoylamino group, mono or disubstituted lower alkylaminocarbonylamino group, cyclic aminocarbonylamino group, sulfamoyl group, mono or disubstituted lower alkylaminosulfonyl group, cyclic An aminosulfonyl group and a saturated or unsaturated heterocyclic group (the heterocyclic group is a halogen atom; a carboxyl group; a lower alkoxycarbonyl group; and a halogen atom, a carboxyl group or Substituted with 1 to 3 substituents selected from alkyl groups optionally substituted with any of lower alkoxycarbonyl groups (optionally substituted with 1 to 3 substituents). Meaning lower alkyl group or alkyl group which may be, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, chloromethyl, methoxymethyl, 2-methoxyethyl, 2-methoxy Propyl, cyclopropylmethyl, benzyldiphenylmethyl, benzyl, phenethyl, 3-phenylpropyl, 4-phenylbutyl, hydroxymethyl, methoxycarbonylmethyl, hydroxycarbonylmethyl, carbamoylmethyl, 2-chloroethyl, 2-bromoethyl, 2,2- Dichloroethyl, 2,2,2 Trifluoroethyl, 2-aminoethyl, 3-chloropropyl, 3-nitropropyl, 3-cyanopropyl, 3- (methylamino) propyl, 3- (dimethylamino) propyl, 3- (1-pyrrolidyl) propyl, cyclohexyl Methyl, phenylmethyl, phenylethyl, 2-, 3- or 4-methylphenylmethyl, 2-, 3- or 4-methoxyphenylmethyl, 2-, 3- or 4-chlorophenylmethyl, 2-, 3- or 4 -Fluorophenylmethyl, 3-aminophenylmethyl, 3-dimethylaminophenylmethyl, 3-acetylaminophenylmethyl, 3-carboxylphenylmethyl, 2-, 3- or 4-pyridylmethyl (2-, 3- or 4 -The pyridine ring of pyridylmethyl is a halogen atom; a carboxyl group; a lower alkoxy A carbonyl group; and optionally substituted with 1 to 3 substituents selected from a halogen atom, a carboxyl group or an alkyl group optionally substituted with a lower alkoxycarbonyl group), 5-benzo Examples include dioxalylmethyl, 2-thienylmethyl, 2-furylmethyl, 2- or 3-tetrahydrofurylmethyl, 4-tetrahydropyranylmethyl and the like. When R ³ is an “optionally substituted alkyl group”, the substituent in R ³ includes a phenyl group, a phenyloxy group, a phenyl lower alkoxy group, a heteroaryl group, a heteroaryloxy group, or a heteroaryl. The lower alkoxy group (the “heteroaryl group” and “heteroaryl” are, for example, 5 to 10 members, preferably 5 or 6 members, more preferably pyridyl or pyrazolyl, and more preferably pyridyl. Each substituent in R ³ is independently at any position on the aromatic ring (ie, phenyl or heteroaryl), as long as it is chemically acceptable, _3, CN, OH, carboxyl group, lower alkoxycarbonyl group, a lower alkyl group, a lower alkoxy group, a lower alkenyl group, lower The lower alkyl group, the lower alkoxy group, the lower alkenyl group, the lower cycloalkyl group and the lower alkoxyalkyl group may be further substituted with one to two substituents selected from a cycloalkyl group and a lower alkoxyalkyl group; Carboxyl group, aminocarbonyl group, mono- or di-substituted lower alkylaminocarbonyl group, lower alkoxycarbonyl group, C _1-4 alkoxy-C _2-4 alkoxycarbonyl group or hydroxy- It may be substituted with a C _2-4 alkoxycarbonyl group or the like.

  The “optionally substituted lower alkenyl group” or “optionally substituted alkenyl group” is a halogen atom, lower cycloalkyl group, phenyl group, phenyloxy group, lower alkoxy group, trifluoromethoxy group, lower alkylthio group. Group, hydroxyl group, nitro group, cyano group, carboxyl group, lower alkoxycarbonyl group, benzyloxycarbonyl group, carbamoyl group, mono- or di-substituted lower alkylaminocarbonyl group, cyclic aminocarbonyl group, amino group, mono- or di-substituted lower alkyl Amino group, cyclic amino group, lower alkylsulfonylamino group, benzenesulfonylamino group, lower alkanoylamino group, benzoylamino group, lower alkoxycarbonylamino group, carbamoylamino group, mono- or disubstituted lower alkylamino group Substituted with 1 to 3 substituents selected from a bonylamino group, a cyclic aminocarbonylamino group, a sulfamoyl group, a mono- or di-substituted lower alkylaminosulfonyl group, a cyclic aminosulfonyl group and a saturated or unsaturated heterocyclic group Lower alkenyl group or alkenyl group which may be, for example, styryl, 2- or 3-phenylpropenyl, 3-phenylallyl, 4- (fluoro) styryl, 4- (methyl) styryl, 4- (methoxy) styryl 4- (trifluoromethyl) styryl, 3- (4-fluoro) phenylpropenyl, 3- (4-methyl) phenylpropenyl, 3- (4-methoxy) phenylpropenyl, 3- (4-trifluoromethyl) phenyl Propenyl, 2- (carboxyl) vinyl, 2- (methoxycarbo) Le) vinyl and the like.

  The “optionally substituted lower cycloalkyl group” is a halogen atom, lower alkyl group, lower cycloalkyl group, phenyl group, phenyloxy group, lower alkoxy group, trifluoromethyl group, trifluoromethoxy group, lower alkylthio group. Hydroxyl group, hydroxy lower alkyl group, nitro group, cyano group, carboxyl group, lower alkoxycarbonyl group, benzyloxycarbonyl group, carbamoyl group, mono or disubstituted lower alkylaminocarbonyl group, cyclic aminocarbonyl group, amino group, mono or Di-substituted lower alkylamino group, cyclic amino group, lower alkylsulfonylamino group, benzenesulfonylamino group, lower alkanoylamino group, benzoylamino group, lower alkoxycarbonylamino group, carbamoylamino group, mono or young It may be substituted with 1 to 3 substituents selected from disubstituted lower alkylaminocarbonylamino groups, cyclic aminocarbonylamino groups, sulfamoyl groups, mono- or disubstituted lower alkylaminosulfonyl groups and cyclic aminosulfonyl groups. Means a lower cycloalkyl group, for example, 3,3-difluorocyclobutyl, 2- or 3-methylcyclopentyl, 2- or 3-fluorocyclohexyl, 2-, 3- or 4-methylcyclohexyl, 2- , 3- or 4-fluorocyclohexyl, 2-, 3- or 4-chlorocyclohexyl, 4,4-dimethylcyclohexyl, 4,4-difluorocyclohexyl, 2- or 3-methoxycyclohexyl, and the like.

  The “optionally substituted lower cycloalkenyl group” is a halogen atom, a lower alkyl group, a lower cycloalkyl group, a phenyl group, a phenyloxy group, a lower alkoxy group, a trifluoromethyl group, a trifluoromethoxy group, a lower alkylthio group. Hydroxyl group, hydroxy lower alkyl group, nitro group, cyano group, carboxyl group, lower alkoxycarbonyl group, benzyloxycarbonyl group, carbamoyl group, mono or disubstituted lower alkylaminocarbonyl group, cyclic aminocarbonyl group, amino group, mono or Disubstituted lower alkylamino group, cyclic amino group, lower alkylsulfonylamino group, benzenesulfonylamino group, lower alkanoylamino group, benzoylamino group, lower alkoxycarbonylamino group, carbamoylamino group, mono or mono May be substituted with 1 to 3 substituents selected from a disubstituted lower alkylaminocarbonylamino group, a cyclic aminocarbonylamino group, a sulfamoyl group, a mono- or disubstituted lower alkylaminosulfonyl group and a cyclic aminosulfonyl group. Means a good lower cycloalkenyl group, such as 2-methylcyclohexen-2-yl, 3-methylcyclohexen-2-yl, 4-methylcyclohexen-2-yl, 4-methylcyclohexen-3-yl, 4,4 -Dimethylcyclohexen-2-yl etc. are mentioned.

  The “optionally substituted lower alkynyl group” or “optionally substituted alkynyl group” is a halogen atom, lower cycloalkyl group, phenyl group, phenyloxy group, lower alkoxy group, trifluoromethoxy group, lower alkylthio group. Group, hydroxyl group, nitro group, cyano group, carboxyl group, lower alkoxycarbonyl group, benzyloxycarbonyl group, carbamoyl group, mono- or di-substituted lower alkylaminocarbonyl group, cyclic aminocarbonyl group, amino group, mono- or di-substituted lower alkyl Amino group, cyclic amino group, lower alkylsulfonylamino group, benzenesulfonylamino group, lower alkanoylamino group, benzoylamino group, lower alkoxycarbonylamino group, carbamoylamino group, mono- or disubstituted lower alkylamino group Substituted with 1 to 3 substituents selected from a bonylamino group, a cyclic aminocarbonylamino group, a sulfamoyl group, a mono- or di-substituted lower alkylaminosulfonyl group, a cyclic aminosulfonyl group and a saturated or unsaturated heterocyclic group It means a lower alkynyl group or alkynyl group which may be used, and examples thereof include phenylethynyl, phenylprop-1-yl, 4- (fluoro) phenylethynyl, 4- (methyl) phenylethynyl and the like.

  The “optionally substituted lower alkanoyl group” includes halogen atom, lower cycloalkyl group, phenyl group, phenyloxy group, lower alkoxy group, trifluoromethoxy group, lower alkylthio group, hydroxyl group, nitro group, cyano group, carboxyl Group, lower alkoxycarbonyl group, benzyloxycarbonyl group, carbamoyl group, mono- or di-substituted lower alkylaminocarbonyl group, cyclic aminocarbonyl group, amino group, mono- or di-substituted lower alkylamino group, cyclic amino group, lower alkylsulfonylamino Group, benzenesulfonylamino group, lower alkanoylamino group, benzoylamino group, lower alkoxycarbonylamino group, carbamoylamino group, mono- or disubstituted lower alkylaminocarbonylamino group, cyclic aminocarbonyl Lower alkanoyl group which may be substituted with 1 to 3 substituents selected from mino group, sulfamoyl group, mono- or di-substituted lower alkylaminosulfonyl group, cyclic aminosulfonyl group and saturated or unsaturated heterocyclic group For example, trifluoroacetyl, trichloroacetyl, methoxycarbonyl, ethoxycarbonylmethoxyacetyl, cyclopentanoyl, cyclopentenoyl, cyclohexanoyl, cyclohexenoyl and the like.

  The "optionally substituted phenyl group" and the "optionally substituted phenyl" moiety are a halogen atom, an alkyl group (the alkyl group may be substituted with a lower alkoxycarbonyl group), a phenyl group, a phenyl group Oxy group, lower alkoxy group (the alkoxy group may be substituted with lower alkoxy group or lower alkoxycarbonyl group), trifluoromethyl group, trifluoromethoxy group, lower alkylthio group, hydroxyl group, hydroxy lower alkyl group, nitro Group, cyano group, carboxyl group, lower alkoxycarbonyl group, benzyloxycarbonyl group, carbamoyl group, mono- or di-substituted lower alkylaminocarbonyl group, cyclic aminocarbonyl group, amino group, mono- or di-substituted lower alkylamino group, cyclic amino Group, lower alkyl Sulfonylamino group, benzenesulfonylamino group, lower alkanoylamino group, benzoylamino group, lower alkoxycarbonylamino group, carbamoylamino group, mono- or disubstituted lower alkylaminocarbonylamino group, cyclic aminocarbonylamino group, sulfamoyl group, mono or It means a phenyl group which may be substituted with 1 to 3 substituents selected from a di-substituted lower alkylaminosulfonyl group and a cyclic aminosulfonyl group, and examples thereof include phenyl, 2-, 3- or 4-chlorophenyl, 2-, 3- or 4-bromophenyl, 2-, 3- or 4-fluorophenyl, 2,4-dichlorophenyl, 2,5-dichlorophenyl, 3,4-dichlorophenyl, 3,5-dichlorophenyl, 2,3- Dibromophenyl, 2,4-di Fluorophenyl, 2,5-difluorophenyl, 3,4-difluorophenyl, 3,5-difluorophenyl, 3-chloro-2-fluorophenyl, 4-chloro-2-fluorophenyl, 3-chloro-4-fluorophenyl, 2-, 3- or 4-methylphenyl, 2-chloro-4-methylphenyl, 2-chloro-5-methylphenyl, 2-fluoro-5-methylphenyl, 3-chloro-4-methylphenyl, 3-fluoro -4-methylphenyl, 4-chloro-2-methylphenyl, 5-chloro-2-methylphenyl, 5-fluoro-2-methylphenyl, 4-fluoro-3-methylphenyl, 2-, 3- or 4- Methoxyphenyl, 5-chloro-2-methoxyphenyl, 3-chloro-4-methoxyphenyl, 2-, 3- or 4-aminopheny 4-methylaminophenyl, 2-, 3- or 4-trifluoromethylphenyl, 2-chloro-4-trifluoromethylphenyl, 2-fluoro-3-trifluoromethylphenyl, 3-fluoro-5-tri Fluoromethylphenyl, 4-chloro-2-trifluoromethylphenyl, 4-fluoro-2-trifluoromethylphenyl, 4-chloro-3-trifluoromethylphenyl, 4-fluoro-3-trifluoromethylphenyl, 3- Dimethylaminophenyl, 2-, 3- or 4-cyanophenyl, 2-, 3- or 4-nitrophenyl, 4-biphenyl, 2-, 3- or 4-trifluoromethoxyphenyl, 4-ethylthiophenyl, 2 -, 3- or 4-hydroxyphenyl, 4-hydroxymethylphenyl, 2-, 3- or 4-cal Alkylphenyl, 4-methoxycarbonylphenyl, 2- (methanesulfonylamino) phenyl, 4- (benzenesulfonylamino) phenyl, 2-, 3- or 4- (acetylamino) phenyl, 4- (benzoylamino) phenyl, 4- (Ethoxycarbonylamino) phenyl, phenyloxyphenyl and the like can be mentioned.

  The “optionally substituted naphthyl group” is a halogen atom, a lower alkyl group, a phenyl group, a phenyloxy group, a lower alkoxy group, a trifluoromethyl group, a trifluoromethoxy group, a lower alkylthio group, a hydroxyl group, a hydroxy lower alkyl group. Nitro group, cyano group, carboxyl group, lower alkoxycarbonyl group, benzyloxycarbonyl group, carbamoyl group, mono- or di-substituted lower alkylaminocarbonyl group, cyclic aminocarbonyl group, amino group, mono- or di-substituted lower alkylamino group, Cyclic amino group, lower alkylsulfonylamino group, benzenesulfonylamino group, lower alkanoylamino group, benzoylamino group, lower alkoxycarbonylamino group, carbamoylamino group, mono- or disubstituted lower alkylaminocarbo Means a naphthyl group optionally substituted by 1 to 3 substituents selected from a ruamino group, a cyclic aminocarbonylamino group, a sulfamoyl group, a mono- or di-substituted lower alkylaminosulfonyl group and a cyclic aminosulfonyl group; For example, naphthyl, 2-, 3-, 4-, 5-, 6-, 7- or 8-chloronaphthyl, 2-, 3-, 4-, 5-, 6-, 7- or 8-methylnaphthyl, 2-, 3-, 4-, 5-, 6-, 7- or 8-methoxynaphthyl, 6,7-dibromo-2-naphthyl, 3-acetylamino-1-naphthyl and the like.

  The “saturated or unsaturated heterocyclic group which may be substituted” means a halogen atom, an alkyl group (the alkyl group may be substituted with a lower alkoxycarbonyl group), a phenyl group, a phenyloxy group, a lower group. An alkoxy group (the alkoxy group may be substituted with a lower alkoxy group or a lower alkoxycarbonyl group), a trifluoromethyl group, a trifluoromethoxy group, a lower alkylthio group, a hydroxyl group, a hydroxy lower alkyl group, a nitro group, a cyano group; , Carboxyl group, lower alkoxycarbonyl group, benzyloxycarbonyl group, carbamoyl group, mono- or di-substituted lower alkylaminocarbonyl group, cyclic aminocarbonyl group, amino group, mono- or di-substituted lower alkylamino group, cyclic amino group, lower alkyl Sulfonylamino , Benzenesulfonylamino group, lower alkanoylamino group, benzoylamino group, lower alkoxycarbonylamino group, carbamoylamino group, mono- or di-substituted lower alkylaminocarbonylamino group, cyclic aminocarbonylamino group, sulfamoyl group, mono- or di-substituted lower Means a saturated or unsaturated heterocyclic group optionally substituted by 1 to 3 substituents selected from alkylaminosulfonyl group and cyclic aminosulfonyl group, for example, pyrrolyl, furanyl, thienyl, furyl, imidazolyl , Oxazolyl, thiazolyl, oxadiazolyl, pyridyl, pyrimidyl, pyrazyl, pyrazolyl, indolyl, isoxazolyl, isothiazolyl, imidazolyl, oxazolyl, thiazolyl, triazolyl, indazolyl Benzofuranyl, benzodioxalyl, benzothienyl, benzothiazolyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, quinolinyl, isoquinolinyl, 2-chloro-3-thienyl, 3-methyl-2-thienyl, 2-methyl-3-indolyl, 4- Methylamino-3-pyridyl, 6-cyano-2-isoquinolinyl, oxetanyl, azetidinyl, pyrrolidinyl, tetrahydrofuryl, dioxolanyl, piperidinyl, piperazinyl, homopiperazinyl, tetrahydropyranyl, thiacyclohexyl, morpholinyl, thiomorpholinyl, cyclohexanothiazolyl, dihydro Thiazolopyridinyl, tetrahydrothiazolopyridinyl and the like can be mentioned.

  The “mono- or di-substituted lower alkylamino group” and the “mono- or di-substituted lower alkylamino” moiety mean a group in which one or two lower alkyl groups are substituted on the amino group, for example, methylamino, dimethylamino, Examples include ethylamino, diethylamino, isopropylamino and the like.

In the compound represented by the general formula of the present invention, when the bonding position of each substituent is not specified (here, the substituent is, for example, Y, R ⁴ , R ⁵ , R ^a2a , R ^a2b , R ^a2c , R ^a2d , R ^a2f , R ^a2g , R ^a3a , R ^a3b , R ^a3c , R ^a3d , R ^a4a , R ^a4b , R ^a4c , R ^a4d , R ^a4g and R ^a4h groups each May be combined at any position as long as it is allowed.

  In each production process of the compound of the present invention, when the structure of the starting material contains a functional group that may participate in the reaction, such as an amino group, the protection generally used for these groups It may be protected by introducing a group, and in that case, the target compound can be obtained by removing the protecting group as appropriate.

  When protection and deprotection are required in each production process of the compound of the present invention, known methods such as Protective Groups in Organic Synthesis (Theodora W. Greene, Peter GM Wuts, John Wiley & Sons, Inc., 1999) Year).

  Examples of the “amino-protecting group” include substituents commonly used in the field of organic synthesis, which can be easily eliminated by reduction or hydrolysis, such as Protective Groups in Organic Synthesis (by Theodora W. Greene, Peter GM Wuts). In addition to the protecting group described in John Wiley & Sons, Inc. (1999), it means a substituent that can be removed enzymatically or non-enzymatically in vivo.

Examples of the “amino-protecting group” include methoxycarbonyl group, ethoxycarbonyl group, 2,2,2-trichloroethoxycarbonyl group, isobutoxycarbonyl group, allyloxycarbonyl group, tert-butoxycarbonyl group, benzyloxycarbonyl group , Vinyloxycarbonyl group, 9-fluorenylmethoxycarbonyl group, formyl group, acetyl group, propionyl group, benzoyl group, trifluoroacetyl group, p-toluenesulfonyl group, benzenesulfonyl group, methanesulfonyl group, benzyl group, 4 -Methoxybenzyl group, 2,4-dimethoxybenzyl group, diphenylmethyl group, triphenylmethyl group, pivaloyloxymethyl group, acetoxymethyl group, acetoxymethoxycarbonyl group, 1-acetoxyethoxycarbonyl group, An alanyl group etc. are mentioned.
For example, P ² in the intermediate of the compound of the present invention represented by the formula (Ib) described in [41] is 1 to 3 phenyl groups (the phenyl group is substituted with 1 to 2 methoxy groups). Or a methyl group substituted with a C _1-4 alkanoyloxy group, (C═O) OR ^p1 , or (C═O) R ^p2
R ^p1 represents a C _1-4 alkyl group (the group may be substituted with 1 to 3 halogen atoms, provided that when the group is a methyl group, 1 to 3 halogen atoms, a phenyl group, or 9- Which may be substituted with a fluorenyl group) or a C _1-4 alkenyl group,
R ^p2 represents a hydrogen atom, a C _1-4 alkyl group (the group may be substituted with 1 to 3 halogen atoms, provided that when the group is a C _1-2 alkyl group, 1 to 3 A halogen atom or a C _1-4 alkanoyloxy group which may be substituted) or a phenyl group,
Specifically, P ² is, for example, a methoxycarbonyl group, an ethoxycarbonyl group, a 2,2,2-trichloroethoxycarbonyl group, an isobutoxycarbonyl group, an allyloxycarbonyl group, a tert-butoxycarbonyl group, a benzyloxycarbonyl group, Vinyloxycarbonyl group, 9-fluorenylmethoxycarbonyl group, formyl group, acetyl group, propionyl group, benzoyl group, trifluoroacetyl group, benzyl group, 4-methoxybenzyl group, 2,4-dimethoxybenzyl group, diphenylmethyl Group, triphenylmethyl group, pivaloyloxymethyl group, acetoxymethyl group, acetoxymethoxycarbonyl group, 1-acetoxyethoxycarbonyl group, etc., preferably 2,2,2-trichloroethoxycarbonyl group, allyloxy. Examples include a xycarbonyl group, a tert-butoxycarbonyl group, a benzyloxycarbonyl group, a formyl group, an acetyl group, a trifluoroacetyl group, a benzyl group, a triphenylmethyl group, and more preferably a tert-butoxycarbonyl group, a benzyloxy group. A carbonyl group, a trifluoroacetyl group, a benzyl group, etc. are mentioned, Most preferably, it is a tert-butoxycarbonyl group or a benzyloxycarbonyl group.

  The production method of the compound of the present invention is described below. The compound of the present invention represented by the formula (Ia) can be produced, for example, by the following production methods A to G. Hereinafter, the compound represented by the formula (Ia) will be mainly described. Among the compounds represented by the formula (I), the compounds other than the formula (Ia) are also obtained from the corresponding regioisomer raw materials. It can be similarly produced by the following production method.

（式中、Ｒ^１〜Ｒ^６は上記［１］に定義されるとおりであり、Ｒは低級アルキル基であり、Ｐ^１及びＰ^２はアミノ基の保護基を意味する） Manufacturing method A
Of the compounds represented by the formula (Ia), a compound represented by the formula [A] wherein X is —N (R ⁶ ) — and Y is —CO— (hereinafter also referred to as “compound A”) Can be produced, for example, by the following production method.

(In the formula, R ^{1 to} R ⁶ are as defined in the above [1], R is a lower alkyl group, and P ¹ and P ² are amino-protecting groups)

[Step A-1]
This step is a step of obtaining compound a2 by reacting compound a1 with ammonia in a suitable solvent. The solvent used in this step is selected from the solvents exemplified below, and is preferably methanol or water. More specifically, this step is performed, for example, by the method described in Step (i) of Reference Example 1 described later or a method analogous thereto.

[Step A-2]
This step is a step of obtaining compound a3 by reacting compound a2 with compound a2 obtained in step A-1. This step is performed by the method described in Heterocycles, 55 (2001) 115-126 or step (ii) of Reference Example 1 described later, or a method analogous thereto.

[Step A-3]
This step is a step of obtaining compound a4 by reacting compound i3 obtained in step A-2 with methyl iodide in the presence of various bases in an appropriate solvent. The base used in this step is selected from the bases exemplified below, and is preferably 1,8-diazabicyclo [5.4.0] -7-undecene (DBU). The solvent used in this step is selected from the solvents exemplified below, and preferably N, N-dimethylformamide (DMF). More specifically, this step is performed, for example, by the method described in Step (iii) of Reference Example 1 described later or a method analogous thereto.

[Step A-4]
This step is a step of obtaining compound a5 by allowing various oxidizing agents to act on compound a4 obtained in step A-3 above in an appropriate solvent. The oxidizing agent used in this step is, for example, m-chloroperbenzoic acid, hydrogen peroxide, etc., preferably m-chloroperbenzoic acid. The solvent used in this step is selected from the solvents exemplified below, and is preferably methylene chloride. More specifically, this step is performed, for example, by the method described in Step (iv) of Reference Example 1 described later or a method analogous thereto.

[Step A-5]
This step is a step of obtaining compound a6 by reacting compound a5 obtained in step A-4 with compound a11 in an appropriate solvent in the presence of various bases. The base used in this step is selected from the bases exemplified below, and is preferably diisopropylethylamine and / or 4-dimethylaminopyridine (DMAP). The solvent used in this step is selected from the solvents exemplified below, and is preferably dioxane. More specifically, this step is performed, for example, by the method described in Step (v) of Reference Example 1 described later or a method analogous thereto.

[Step A-6]
This step is a protecting group P ¹ of the amino group of the compound a6 obtained above Step A-5, is deprotected, to give compound compound a7. This step is performed according to the method described in Protective Groups in Organic Synthesis (Theodora W. Greene, Peter GM Wuts, published by John Wiley & Sons, Inc., 1999) or step (vi) of Reference Example 1 described later. be able to.

[Step A-7]
This step is a step of obtaining compound a8 by reacting compound a7 obtained in the above step A-6 with compound a12 in a suitable solvent in the presence of various condensing agents. The condensing agent used in this step is selected from various materials exemplified below (step A-9 ′), but preferably 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide (hydrochloride). Included). The solvent used in this step is selected from the solvents exemplified below. More specifically, this step is performed, for example, by the method described in Example 1 below or a method analogous thereto.

[Step A-8]
This step is a protecting group P ² of the amino group of the compound a8 obtained in A-7 process, by deprotection, to give compound compound a9. This step should be carried out in accordance with the method described in Example 2 or Reference Example 3 below, Protective Groups in Organic Synthesis (written by Theodora W. Greene, Peter GM Wuts, published by John Wiley & Sons, Inc., 1999) Can do.

[Step A-9]
This process
(I) Substitution reaction:
An organic halogen compound (ie, R ³ -Hal; where Hal means a halogen atom, preferably a chlorine atom, a bromine atom or an iodine atom) or an organic sulfonic acid ester compound (ie, R ³ -OSO ₂ R ^L ; Here, R ^L means a C _1-4 alkyl group which may be substituted with a fluorine atom or a phenyl group which may be substituted with C _1-4 alkyl, and includes methyl, trifluoromethyl, 4- Methylphenyl, phenyl, etc.)
Or (ii) reductive amination reaction in which L is also represented as a reactive agent (ie, “R ³ -L”; L is a leaving group and represents a halogen atom or the above OSO ₂ ^RL ) :
A compound having a formyl group or a ketone group (that is, R ³ is represented by R ^{3 ′} —C (R ^{3 ″} ) H— among R ³ defined in [1] above, The compound having a formyl group or a ketone group is R ^{3 ′} —C (═O) —R ^{3 ″} ;
Here, R ^{3 ″} means a hydrogen atom, a lower alkyl group, or an optionally substituted phenyl group, and R ^{3 ′} is R ³ to “—C (R ³ ″) defined in [1] above. ) H- "part. )
In this step, compound A is obtained from compound a9 obtained in step A-8 by either reductive amination reaction using a reducing agent such as NaBH (OAc) ₃ or NaBH ₃ CN.

  The substitution reaction (i) is carried out in an appropriate solvent in the presence of various bases as necessary, and the base and the solvent are selected from those exemplified below. More specifically, for example, It is carried out by the method described in Example 3 or a method analogous thereto. The substitution reaction (i) can be used in the method for producing a compound represented by the formula (Id) in item [42].

In the reductive amination reactions described above (ii), a compound having a formyl group or a ketone group, R ^{3 'in} the ^{R 3' -C (= O)} -R 3 '' , more specifically, a hydrogen atom, An optionally substituted lower alkyl group, an optionally substituted lower alkenyl group, an optionally substituted lower cycloalkyl group, an optionally substituted phenyl group, an optionally substituted phenyloxy lower alkyl A group, an optionally substituted phenyl lower alkoxy lower alkyl group, an optionally substituted heteroaryl group, an optionally substituted heteroaryloxy lower alkyl group, or an optionally substituted heteroaryl lower alkoxy lower group Represents an alkyl group (the “heteroaryl group” and “heteroaryl” are preferably 5- to 10-membered, more preferably Or a 6-membered, more preferably a pyridyl or pyrazolyl, etc.); each group R 3 ^'are each independently at any position as chemically permitted, a halogen atom, CF _3, CN , OH, and R ³¹ may be substituted with one or more groups selected from the group consisting of R ³¹ ; R ³¹ represents a hydrogen atom, a C _1-6 alkyl group, a C _1-6 alkoxy group, or C _{1- 6} alkoxy-C _1-6 alkyl group, the hydrogen atom, C _1-6 alkyl group, C _1-6 alkoxy group and C _1-6 alkoxy-C _1-6 alkyl group are further represented by CO ₂ R ³² , OCOR. ³³ or C (═O) NR ³⁴ R ³⁵ ; each of R ³² , R ³³ , R ³⁴ and R ³⁵ is independently a hydrogen atom or a lower alkyl group, and the lower alkyl The group is chemical It may be further substituted with one or more lower alkoxy groups or OH at any position as long as it is acceptable,
Preferably, R ^{3 ′} is a phenyl group, a phenyloxy lower alkyl group, a phenyl lower alkoxy lower alkyl group, a heteroaryl group (the “heteroaryl group” is preferably pyridyl or pyrazolyl, more preferably pyridyl Each group of R ^{3 ′} is independently at any position on the aromatic ring (ie, phenyl or heteroaryl) as long as it is chemically acceptable, and a halogen atom, CF ₃ CN, OH, carboxyl group, lower alkoxycarbonyl group, lower alkyl group, lower alkoxy group, lower alkenyl group, lower cycloalkyl group and lower alkoxy lower alkyl group may be substituted with 1 to 2 substituents. Well; the lower alkyl group, lower alkoxy group, lower alkenyl group, lower cycloalkyl group and At Grade alkoxy lower alkyl group more chemically acceptable as long as any position, carboxyl group, aminocarbonyl group, mono- or di-substituted lower alkylamino group, a lower alkoxycarbonyl group, C _1-4 alkoxy -C _{2 May} be substituted with a _-4 alkoxycarbonyl group or a hydroxy- _C2-4 alkoxycarbonyl group.
R ^{3 ″} represents a hydrogen atom, a lower alkyl group or an optionally substituted phenyl group as described above, and is preferably a hydrogen atom or a lower alkyl group.

Examples of the compound R ^{3 ′} —C (═O) —R ^{3 ″} include the compound represented by the formula (VIb) in the item [43], R ^3p1 —C (═O) —R ^3p2 . That is, the reductive amination reaction of (ii) can be used in the method for producing a compound represented by the formula (Ie) in item [43].
In the formula (VIb), R ^3p1 represents a group represented by any one of the formulas (4gp), (4hp), and (4ip) in the term [43], and preferably in the formula (4gp) or (4hp) Represents a group represented by formula (4hp), more preferably a group represented by formula (4hp).
In the formula (4hp), m ^4hp represents an integer of 0 to 4 (provided that when r ^4h is 1, m ^4hp represents an integer of 1 to 4), preferably an integer of 0 to 2 (provided that In this case, n ^4h , p ^4h and q ^4h each independently represent an integer of 0 to 3, and m ^4hp + n ^4h + p ^4h + q ^4h is an integer of 0 to 9; r ^4h is 1 ^{M 4hp} represents an integer of 1 or 2, more preferably an integer of 0 or 1 (provided that when r ^4h is 1, m ^4hp is 1); Arm, R ^a4h , R ^b4h , R ^d4h , R ^e4h , R ^f4h , R ^g4h , R ^h4h , R ^i4h , R ^j4h , R ^k4h , n ^4h , p ^4h , q ^4h , r ^4h and s ^4h are as defined in [4] above. Yes, preferably in any one of Items [8] to [12] As defined.
In the formula (4gp), m ^4gp represents an integer of 0 to 5, preferably an integer of 0 to 2, and Arm, R ^a4g , R ^d4g and R ^e4g are as defined in the above item [4]. Yes, preferably as defined in paragraph [7].
R ^3p2 is a hydrogen atom or a C _1-6 alkyl group as described in Item [43], preferably a hydrogen atom.

The reductive amination reaction (ii) is carried out in a suitable solvent using various boron-based reducing agents or formic acid, and the solvent is selected from those exemplified below. More specifically, for example, The method described in Example 19 or Reference Example 7 (r7-i) described later, or a method analogous thereto. The reductive amination reaction may be carried out by (a) dehydrating with a Dean-Stark apparatus or a dehydrating agent in the presence of various acid or base catalysts, if necessary, or using them together to convert the carbonyl compound and the amine compound to an imine. Alternatively, iminium is formed and (b) this is reduced with a boron-based reducing agent or formic acid, and this comprises two steps, (a) and (b) may be carried out in the same system, after (a) If necessary, isolation, purification, solvent substitution, etc. may be carried out to carry out (b). Examples of the boron reducing agent include sodium cyanoborohydride and sodium triacetoxyborohydride, sodium borohydride, 2-picoline-borane and the like. Examples of the acid catalyst include organic acids such as acetic acid, and Lewis acids such as titanium (IV) tetrachloride. Base catalysts are selected from the bases exemplified below. Examples of the dehydrating agent include molecular sieves, anhydrous sodium sulfate, anhydrous magnesium sulfate and the like.
The compound represented by the formula (Ib) of item [41] can be synthesized in the same manner as the compounds b3, c3, or d3 described below in addition to the above a8. In each formula in the terms [41], [42], [43], [44] and [45], each symbol defined in the term [4] (for example, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , X, Arm, R ^a4g , R ^a4h , R ^b4h , R ^b4i , R ^d4g , R ^e4g , R ^d4h , R ^e4h , R ^f4h , R ^g4h , R ^h4h , R ^{j4 h} , R ^{j4 h} , R ^{j4 h d4i} , R ^e4i , R ^f4i , R ^g4i , m ^4h , n ^4h , p ^4h , q ^4h , n ⁴ⁱ , r ^4h , s ^4h , s ^4i, etc. are preferably the above items [7] to [20] , [36] to [38] or [39].

In the compounds of the present invention that can be produced using the reaction (i) or (ii) above, for example, R ^d4g , R ^e4g , R ^d4h , R ^e4h , R ^f4h , R ^g4h , R ^h4h , R ^i4h , R ^j4h , R ^k4h , R ^d4i , R ^e4i , R ^f4i and R ^g4i are as ^defined in the terms [3], [4], [7], [9], etc., and are preferably independent of each other. In addition, when there are a plurality of groups, each independently represents a hydrogen atom or a C _1-4 alkyl group, more preferably a hydrogen atom. Alternatively, R ^f4h and R ^g4h may form a 3- to 6-membered cycloalkyl ring together with the carbon atom to which they are bonded, as described in item [9], and the cycloalkyl ring is preferably Is 3 to 5 members, more preferably 3 members (that is, cyclopropane ring). Moreover, r ^4h and s ^4h each independently represent 0 or 1 as described in the term [3] or [4], and preferably both are 0 or one is 1, and the other is 0 is represented. Alternatively, particularly when Arm is a heteroaromatic ring (for example, a pyridine ring or a pyrazole ring), r ^4h and s ^4h are preferably such that r ^4h represents 0 and s ^4h represents 0 or 1.

本工程は化合物Ａの製造方法の上記とは別の態様である。本工程の一つの好ましい態様として、本工程は上記Ａ−６工程で得られた化合物a7に、種々の縮合剤存在下、適当な溶媒中、化合物a13を反応させることにより、化合物Ａを得る工程である。本工程において使用される縮合剤は、後記に例示する種々のものから選択されるが、好ましくは1-エチル-3-(3-ジメチルアミノプロピル)カルボジイミド（塩酸塩を含む）である。本工程において使用される溶媒は、後記に例示する溶媒等から選択される。より具体的には、本工程は例えば、上記Ａ−７工程同様に後記実施例１もしくは実施例８７に記載の方法、又はこれらに準じた方法で行われる。
より詳細には、本工程は、上記縮合剤を用いる方法に限定されず、化合物a13又はその塩を活性化して、必要に応じて塩基の存在下に、化合物a7又はその塩と反応させる縮合反応である。化合物a13又はその塩の活性化方法としては、例えば、そのカルボキシル基を酸ハロゲン化物、混合酸無水物などに変換する方法、または上記の縮合剤を用いる方法等が挙げられる。 [Step A-9 ′]

This step is an embodiment different from the above-described method for producing Compound A. As one preferred embodiment of this step, this step is a step of obtaining compound A by reacting compound a13 obtained in step A-6 with compound a13 in an appropriate solvent in the presence of various condensing agents. It is. The condensing agent used in this step is selected from various compounds exemplified below, but is preferably 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide (including hydrochloride). The solvent used in this step is selected from the solvents exemplified below. More specifically, this step is performed, for example, by the method described in Example 1 or Example 87 described later, or a method analogous thereto, as in step A-7 above.
More specifically, this step is not limited to the method using the condensing agent, but a condensation reaction in which compound a13 or a salt thereof is activated and reacted with compound a7 or a salt thereof in the presence of a base as necessary. It is. Examples of the method for activating compound a13 or a salt thereof include a method for converting the carboxyl group into an acid halide, mixed acid anhydride, or the like, or a method using the above condensing agent.

  When the acid halide method is used, first, compound a13 is added in an inert solvent, if necessary, in the presence or absence of an additive, such as oxalyl chloride, thionyl chloride, phosphorus oxychloride, phosphorus pentachloride, etc. A halogenated reagent is reacted to obtain an acid halide. Examples of the additive include N, N-dimethylformamide, N, N-diethylformamide and the like. Examples of the inert solvent include halogenated hydrocarbon solvents such as dichloromethane, dichloroethane, and chloroform, aromatic hydrocarbon solvents such as toluene and xylene, and esters such as ethyl acetate. After completion of the reaction, if necessary, the reaction solution is concentrated under reduced pressure in the presence of a hydrocarbon solvent such as benzene or toluene, and the resulting acid halide is added in an inert solvent, if necessary, in the presence of a base. Compound A or a salt thereof can be obtained by reacting with compound a7 or a salt thereof. Here, examples of the base and the solvent include those exemplified below.

  When using the mixed acid anhydride method, compound a13 or a salt thereof is reacted with an acid halide in the presence of a base to form a mixed acid anhydride, and then reacted with compound a7 or a salt thereof to give compound A or a salt thereof. Can lead to salt. Examples of the acid halide include methoxycarbonyl chloride, ethoxycarbonyl chloride, isopropyloxycarbonyl chloride, isobutyloxycarbonyl chloride, paranitrophenoxycarbonyl chloride, t-butylcarbonyl chloride, and the like. Here, examples of the base and the solvent include those exemplified below.

Alternatively, compound A13 or a salt thereof and compound a7 or a salt thereof can be reacted in an inert solvent, if necessary, in the presence of a base using various condensing agents to produce compound A or a salt thereof. . In some cases, a phase transfer catalyst and other additives may be used. Here, examples of the condensing agent include those described in Experimental Chemistry Course (Edited by Chemical Society of Japan, Maruzen) Vol. For example, phosphate esters such as diethyl cyanophosphate and diphenylphosphoryl azide, carbodiimides such as 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (WSC · HCl), dicyclohexylcarbodiimide (DCC), 2 , 2'-dipyridyldisulfide and other disulfides in combination with phosphines such as triphenylphosphine, N, N'-bis (2-oxo-3-oxazolidinyl) phosphinic chloride (BOPCl) and other phosphorus halides, azo Combinations of azodicarboxylic acid diesters such as diethyl dicarboxylate and phosphines such as triphenylphosphine, 2-halo-1-lower alkylpyridinium halides such as 2-chloro-1-methylpyridinium iodide, 1,1'-carbonyldi Imidazole (CDI), diphenylphosphoryl azide DPPA), diethyl phosphorylcyanide (DEPC), 2- (1H-benzotriazol-1-yl) -1,1,3,3-tetramethyluronium tetrafluoroborate (TBTU), 2- (1H-benzotriazole -1-yl) -1,1,3,3-tetramethyluronium hexafluorophosphate (HBTU), benzotriazol-1-yloxytris (dimethylamino) phosphonium hexafluorophosphate (BOP), benzotriazole-1- Iroxytris (pyrrolidino) phosphonium hexafluorophosphate (PYBOP), 2- (7-aza-1H-benzotriazol-1-yl) -1,1,3,3-tetramethyluronium hexafluorophosphate (HATU), Alternatively, 2-chloro-1,3-dimethylimidazolidinium tetrafluoroborate (CIB) and the like can be given. Examples of the inert solvent and the base include those exemplified below. Examples of the phase transfer catalyst include quaternary ammonium salts such as tetrabutylammonium bromide or benzyltriethylammonium bromide, or crown ethers such as 18-crown-6-ether, and are used when the base is an inorganic base. . Examples of other additives include 1-hydroxybenzotriazole (HOBt), 1-hydroxy-7-azabenzotriazole (HOAt) and the like, and the condensing agent is 1-ethyl-3- (3-dimethylaminopropyl). Used in the case of carbodiimides such as carbodiimide hydrochloride (WSC · HCl).
In addition, the condensation reaction (that is, the above-described acid halide method, mixed acid anhydride method, and method using a condensing agent) of the step A-9 ′ is the compound represented by the formula (If) in the item [45]. It can be used in a manufacturing method.

本工程は、上記Ａ−９工程で得られた化合物Ａ（ここに、Ｒ^１、Ｒ^２、Ｒ^３、Ｒ^４、Ｒ^５又はＲ^６のいずれかはエステル基を含む）を、必要に応じて、対応するカルボン酸化合物Ａ^１に変換する工程である（上記反応式中のＱは、化合物Ａの中で当該エステル基以外の部分を表し、Ｒ^Ａは当該エステル基中の化学基を表す）。本工程はProtective Groups in Organic Synthesis（Theodora W. Greene, Peter G. M. Wuts著、John Wiley & Sons, Inc.発行、1999年）に記載の方法等に準じて行うことができる。より具体的には、本工程は例えば、後記実施例２０に記載の方法、又はこれに準じた方法で行われる。 [Step A-10]

In this step, compound A obtained in the above step A-9 (wherein R ¹ , R ² , R ³ , R ⁴ , R ^5, or R ⁶ contains an ester group) is added as necessary. Te, Q in is a process of converting a corresponding carboxylic acid compound a ¹ (the reaction formula represents a portion other than the ester group in the compounds a, R ^a represents a chemical group in the ester group ). This step can be carried out according to the method described in Protective Groups in Organic Synthesis (Theodora W. Greene, Peter GM Wuts, John Wiley & Sons, Inc., 1999). More specifically, this step is performed, for example, by the method described in Example 20 below or a method analogous thereto.

（式中、Ｒ^１〜Ｒ^５は上記［１］に定義されるとおりであり、Ｈａｌはハロゲン原子であり、Ｐ^１及びＰ^２はアミノ基の保護基を意味する） Manufacturing method B
Of the compounds represented by the formula (Ia), a compound represented by the formula [B] wherein X is —S— and Y is —CO— (hereinafter also referred to as “compound B”) is, for example, It can manufacture by the manufacturing method of.

(Wherein R ^{1 to} R ⁵ are as defined in [1] above, Hal is a halogen atom, and P ¹ and P ² are amino-protecting groups)

[Step B-1]
This step is a step of obtaining compound b1 by reacting compound b3 obtained in step A-2 with compound b5 in the same manner as in step A-3.
[Step B-2]
This step is a step of obtaining compound b2 by treating compound b1 obtained in step B-1 in the same manner as in step A-6.
[Step B-3]
This step is a step of obtaining compound b3 by treating compound b2 obtained in step B-2 with the same method as in step A-7.
[Step B-4]
This step is a step of obtaining compound b4 by treating compound b3 obtained in step B-3 in the same manner as in step A-8.
[Step B-5]
This step is represented by the formula [B] by treating the compound b4 obtained in the step B-4 in the same manner as in the step A-9 (and step A-10 if necessary). This is a step of obtaining a compound.

（式中、Ｒ^１〜Ｒ^５、Ｒ^７及びＲ^８は上記［１］に定義されるとおりであり、Ｈａｌはハロゲン原子であり、Ｐ^１及びＰ^２はアミノ基の保護基を意味する） Manufacturing method C
Among the compounds represented by the formula (Ia), a compound represented by the formula [C] wherein X is —C (R ⁷ ) (R ⁸ ) — and Y is —CO— (hereinafter referred to as “compound C”). For example, can be produced by the following production method.

(Wherein R ^{1 to} R ⁵ , R ⁷ and R ⁸ are as defined in [1] above, Hal is a halogen atom, and P ¹ and P ² are amino-protecting groups)

[Step C-1]
This step is a step of obtaining compound c1 by reacting compound c5 with compound a5 obtained in step A-4. More specifically, this step is performed by, for example, the method described in the step (xv) of Example 18 described later or a method analogous thereto.
[Step C-2]
This step is a step of obtaining compound c2 by treating compound c1 obtained in step C-1 in the same manner as in step A-6.
[Step C-3]
This step is a step of obtaining compound c3 by treating compound c2 obtained in step C-2 in the same manner as in step A-7.
[Step C-4]
This step is a step of obtaining compound c4 by treating compound c3 obtained in step C-3 in the same manner as in step A-8.
[Step C-5]
This step is represented by the formula [C] by treating the compound c4 obtained in the above step C-4 in the same manner as in the above step A-9 (and step A-10 if necessary). This is a step of obtaining a compound.

In addition, in the compound of the present invention in which X is represented by —C (R ⁷ ) (R ⁸ ) —, which can be produced using, for example, the above production method C or the production method I described later, or a method analogous thereto, R ⁷ and R ⁸ are as defined in the item [1] or the item [4], and preferably, R ⁷ and R ⁸ each independently represent a hydrogen atom or a C _1-4 alkyl group. More preferably, at least one of R ⁷ and R ⁸ represents a hydrogen atom, and the other represents a hydrogen atom or a C _1-4 alkyl group.

（式中、Ｒ^１〜Ｒ^５は上記［１］に定義されるとおりであり、Ｐ^１及びＰ^２はアミノ基の保護基を意味する） Manufacturing method D
Of the compounds represented by the formula (Ia), a compound represented by the formula [D] wherein X is —O— and Y is —CO— (hereinafter also referred to as “compound D”) is, for example, It can manufacture by the manufacturing method of.

(In the formula, R ^{1 to} R ⁵ are as defined in [1] above, and P ¹ and P ² represent amino-protecting groups)

[Step D-1]
This step is a step of obtaining compound d1 by reacting compound d5 obtained in step A-4 with compound d5 in the presence of various bases in a suitable solvent. The base used in this step is selected from the bases exemplified below, and is preferably sodium hydride.
[Step D-2]
This step is a step of obtaining compound d2 by treating compound d1 obtained in step D-1 in the same manner as in step A-6.
[Step D-3]
This step is a step of obtaining compound d3 by treating compound d2 obtained in step D-2 with the same method as in step A-7.
[Step D-4]
This step is a step of obtaining compound d4 by treating compound d3 obtained in step D-3 in the same manner as in step A-8.
[Step D-5]
This step is represented by the formula [D] by treating the compound d4 obtained in the step D-4 in the same manner as in the step A-9 (and step A-10 if necessary). This is a step of obtaining a compound.

In addition, in the compound of the present invention in which X is represented by -O-, which can be produced using, for example, the above production method D, production method H or production method J described later, or a method according thereto, R ² is: As defined in the terms [1], [3], [4], [17] to [20], etc., preferably R ² is as defined in the term [20], more preferably In formula (3a) of item [20], R ^a3a represents a meta-position (3-position) substituted C _1-6 alkoxy group which may be substituted with a C _1-4 alkoxy group.

（式中、Ｒ^１〜Ｒ^５及びＸは上記［１］に定義されるとおりであり、Ｚ^１はＮＲ^９又はＯであり（ここに、Ｒ^９は上記［１］に定義されるとおりである）、Ｐ^２はアミノ基の保護基を意味する） Manufacturing method E
Among the compounds represented by the formula (Ia), a compound represented by the formula [E] wherein Y is —C (O) NR ⁹ — or —C (O) O— (hereinafter also referred to as “compound E”) ) Can be produced, for example, by the following production method.

(Wherein R ^{1 to} R ⁵ and X are as defined in [1] above, and Z ¹ is NR ⁹ or O (where R ⁹ is as defined in [1] above). there), P ² means a protecting group of amino group)

[Step E-1]
In this step, compound a7, b2, c2 or d2 obtained by production methods A to D is mixed with triphosgene in the presence of various bases and stirred, and then compound e4 is added to obtain compound e2. More specifically, this step is performed, for example, by the method described in Example 84 described later or a method analogous thereto.
[Step E-2]
This step is a step of obtaining compound e3 by treating compound e2 obtained in step E-1 in the same manner as in step A-8.
[Step E-3]
This step is represented by the formula [E] by treating the compound e3 obtained in the step E-2 with the same method as the step A-9 (and step A-10 if necessary). This is a step of obtaining a compound. More specifically, the previous E-2 step and this step are performed by, for example, the method described in Example 85, or a method analogous thereto.

（式中、Ｒ^１〜Ｒ^５及びＸは上記［１］に定義されるとおりであり、Ｚ^１はＮＲ^９又はＯであり（ここに、Ｒ^９は上記［１］に定義されるとおりである）、Ｐ^２はアミノ基の保護基を意味する） Manufacturing method Ea
Among the compounds represented by the formula (Ia), a compound represented by the formula [Ea] wherein Y is —C (S) NR ⁹ — or —C (S) O— (hereinafter also referred to as “compound Ea”). ) Can be produced, for example, by the following production method.

(Wherein R ^{1 to} R ⁵ and X are as defined in [1] above, and Z ¹ is NR ⁹ or O (where R ⁹ is as defined in [1] above). there), P ² means a protecting group of amino group)

[Step Ea-1]
The above-mentioned [E In the same manner as in [Step-1], compound e2a is obtained.
[Step E-2] to [Step E-3]
These steps are steps for obtaining a compound represented by the formula [Ea] by treating the compound e2a obtained in the step Ea-1 in the same manner as in the steps E-2 and E-3. is there.

Compound E and Compound Ea are compounds in which Y is represented by Formula (II) and Formula (V) among the compounds represented by Formula (I) in Item [1]. In formula (II) of item [1], R ⁹ is a hydrogen atom, an optionally substituted lower alkyl group, an optionally substituted lower cycloalkyl group, an optionally substituted phenyl group or a substituted group. Represents a saturated or unsaturated heterocyclic group which may be substituted, preferably represents a hydrogen atom or an optionally substituted lower alkyl group, and more preferably represents a hydrogen atom. In the formula (II) and the formula (V) of the term [1], Z represents an oxygen atom or a sulfur atom, preferably an oxygen atom.

（式中、Ｘ及びＲ^１〜Ｒ^５は上記［１］に定義されるとおりであり、Ｐ^２はアミノ基の保護基を意味する） Manufacturing method F
Of the compounds represented by the general formula (Ia), the compound represented by the formula [F] in which Y is —SO ₂ — (hereinafter, also referred to as “compound F”) is produced by, for example, the following production method. Can do.

(Wherein X and R ^{1 to} R ⁵ are as defined in [1] above, and P ² represents an amino-protecting group)

[Step F-1]
In this step, compound f2 is obtained by reacting compound a7, b2, c2 or d2 obtained by the above production methods A, B, C and D with compound f4 in the presence of various bases in an appropriate solvent. It is. The solvent used in this step is selected from the solvents exemplified below. More specifically, this step is performed by, for example, the method described in the step (ex208-i) of Example 208 described later or a method analogous thereto.
[Step F-2]
This step is a protecting group P ² of the amino group of the compound f2 obtained in the above F-1 step, by deprotection, to give compound compound f3. This step can be performed, for example, by the method described in the above step A-8 or the step (ex208-ii) of Example 208 described later, or a method analogous thereto.
[Step F-3]
In this step, compound f3 obtained in step F-2 is treated in the same manner as in step A-9 or step (ex208-iii) in Example 208 (and step A-10 if necessary). This is a step of obtaining a compound represented by the formula [F].

（式中、Ｘは酸素原子、硫黄原子又は−ＣＲ^７Ｒ^８−を表し、Ｒ^１〜Ｒ^５、Ｒ^７及びＲ^８は上記［１］に定義されるとおりである） Manufacturing method G
Among the compounds represented by the general formula (Ia), the compounds B, C and D obtained by the production methods B, C and D can be produced, for example, by the following production method.

(In the formula, X represents an oxygen atom, a sulfur atom or —CR ⁷ R ⁸ —, and R ^{1 to} R ⁵ , R ⁷ and R ⁸ are as defined in [1] above).

[Step G-1]
This step is a step of obtaining compound B, C or D by reacting compound b2, c2 or d2 obtained by the above production methods B, C and D with compound a13 in the same manner as in step A-9 ′ above. is there.

（式中、Ｘは酸素原子、硫黄原子又は−Ｎ（Ｒ^６）−を表し、Ｒ^１、Ｒ^２及びＲ^６は上記［１］に定義されるとおりであり、Ｒは低級アルキル基であり、Ｐ^１はアミノ基の保護基を意味する） The intermediate production method of the compound of the present invention will be described below.
Manufacturing method H
Compound a6, b1, or d1 that is an intermediate of production method A, B, or D can also be produced, for example, by the following production method.

(Wherein X represents an oxygen atom, a sulfur atom or —N (R ⁶ ) —, R ¹ , R ² and R ⁶ are as defined in [1] above, and R is a lower alkyl group. , P ¹ means an amino-protecting group)

[Step H-1]
This step is a step of obtaining compound h1 by reacting compound h2 obtained in step A-1 with compound h2 in the same manner as in step A-2. More specifically, this step is performed, for example, by the method described in Step (r4-i) of Reference Example 4 described later or a method analogous thereto.
[Step H-2]
This step is a step of obtaining compound a6, b1 or d1 by reacting compound a11, h3 or d5 with compound h1 obtained in step H-1. This step is performed by the method described in The Journal of Organic Chemistry, 72 (2007) 10194-10210 or step (r4-ii) of Reference Example 4 described later, or a method analogous thereto.

（式中、Ｒ^ｉ及びＲ^ｉｉは低級アルキル基、又は、これらが結合するＮと一緒になって環状アミノ基を表し、Ｒ^１、Ｒ^２、Ｒ^７、及びＲ^８は上記［１］に定義されるとおりであり、Ｐ^１はアミノ基の保護基を意味する） Manufacturing method I
Compound c1, which is an intermediate of production method C, can also be produced, for example, by the following production method.

(Wherein, ^{R i} and ^{R ii} represents a lower alkyl group, or, taken together with the N to which they are attached represent a cyclic amino ^group, R ^1, R 2, ^{R 7,} and ^{R 8} in the above [1] As defined, and P ¹ means an amino protecting group)

[Step I-1]
This step is a step of obtaining compound i2 by reacting compound i1 with amine i7 in an appropriate solvent in the presence of an acid catalyst. The acid catalyst used in this step is preferably tosylic acid. The amine i7 used in this step is a secondary amine, preferably morpholine. The solvent used in this step is selected from the solvents exemplified below, and is preferably toluene.
[Step I-2]
This step is a step of obtaining compound i3 by reacting compound i2 obtained in the above step I-1 with isocyanate h2 in an appropriate solvent. This step is performed by the method described in the document Tetrahedron, 45, 3189 (1989) or a method analogous thereto.
[Step I-3]
This step is a step of obtaining compound i4 by treating compound i3 obtained in step I-2 with an acid aqueous solution in an appropriate solvent. The acid aqueous solution is preferably hydrochloric acid. The solvent used in this step is selected from the solvents exemplified below, and is preferably toluene. More specifically, the above-mentioned step I-1 to this step are performed, for example, by the method described in the step (r5-i) of Reference Example 5 described later or a method analogous thereto.
[Step I-4]
This step is a step of obtaining compound i5 by treating compound i4 obtained in step I-3 above in the same manner as in step A-1. More specifically, this step is performed, for example, by the method described in the step (r5-ii) of Reference Example 5 described later or a method analogous thereto.
[Step I-5]
This step is a step of obtaining compound i6 by treating compound i5 obtained in step I-4 above with various carboxylic acids i8 and phosphorus oxychloride in the presence of a base. The base used in this step is selected from the bases exemplified below, and is preferably pyridine. More specifically, this step is performed, for example, by the method described in the step (r5-iii) of Reference Example 5 described later or a method analogous thereto.
[Step I-6]
This step is a step of obtaining compound c1 from compound i6 obtained in the above step I-5. More specifically, this step is performed by, for example, the method described in the document Tetrahedron, 61, 4297 (2005) or the step (r5-iv) of Reference Example 5 described later, or a method analogous thereto.

（式中、Ｒ^１、及びＲ^２は上記［１］に定義されるとおりであり、Ｐ^１はアミノ基の保護基を意味する） Manufacturing method J
Compound d1, which is an intermediate of production method D, can also be produced, for example, by the following production method.

(Wherein R ¹ and R ² are as defined in [1] above, and P ¹ represents an amino-protecting group)

[Step J-1]
This step is a step of obtaining compound d1 by reacting compound h1 obtained in step H-1 with an alkylating agent in the presence of various bases in an appropriate solvent. The alkylating agent used in this step (that is, also expressed as “R ² -L”; L is a leaving group, and represents a halogen atom or OSO ₂ R ^L described below) is an organic halogen compound (that is, R ² -Hal; here, Hal means halogen atom, preferably a chlorine atom, a bromine atom or an iodine atom) or an organic sulfonic acid ester compound ^(i.e., R ₂ -OSO 2 R ^L; here, R ^L represents a C _1-4 alkyl group which may be substituted with a fluorine atom or a phenyl group which may be substituted with C _1-4 alkyl, and includes methyl, trifluoromethyl, 4-methylphenyl, phenyl and the like. And alkyl iodide and the like are preferable. The base used in this step is selected from the bases exemplified below, and is preferably potassium carbonate. The solvent used in this step is selected from the solvents exemplified below, and preferably N, N-dimethylformamide. More specifically, this step is performed, for example, by the method described in the step (r6-ii) of Reference Example 6 described later or a method analogous thereto.

（式中、Ｒは低級アルキル基又はベンジル基であり、Ｒ^３、Ｒ^４、及びＲ^５は上記［１］に定義されるとおりである） Manufacturing method K
Compound a13, which is an intermediate between production methods A and G, can be produced, for example, by the following production method.

(In the formula, R is a lower alkyl group or a benzyl group, and R ³ , R ⁴ , and R ⁵ are as defined in [1] above).

[Step K-1]
This step is a step of obtaining compound a13 from compound k1 by a reductive amination reaction using a compound having a formyl group or a ketone group and a reducing agent such as NaBH (OAc) ₃ or NaBH ₃ CN. About reductive amination reaction, it is the same as that of the said A-9 process (ii). More specifically, this step is performed, for example, by the method described in the step (r7-i) of Reference Example 7 described later or a method analogous thereto.

In the formula, R ³ is represented by R ^{3 ′} —C (R ^{3 ″} ) H— among R ³ defined in the above [1], and a compound having the formyl group or ketone group Is R ^{3 ′} —C (═O) —R ^{3 ″} ;
Here, R ^{3 ″} means a hydrogen atom, a lower alkyl group, or an optionally substituted phenyl group, and R ^{3 ′} is R ³ to “—C (R ³ ″) defined in [1] above. ) H- "part.

More specifically, R ^{3 ′} is a hydrogen atom, an optionally substituted lower alkyl group, an optionally substituted lower alkenyl group, an optionally substituted lower cycloalkyl group, or optionally substituted. Phenyl group, phenyloxy lower alkyl group which may be substituted, phenyl lower alkoxy lower alkyl group which may be substituted, heteroaryl group which may be substituted, heteroaryloxy lower alkyl group which may be substituted Or an optionally substituted heteroaryl lower alkoxy lower alkyl group (the “heteroaryl group” and “heteroaryl” are preferably 5 to 10 members, more preferably 5 or 6 members, More preferably pyridyl or pyrazolyl); each group of R ^{3 ′} is independently a chemically acceptable group. Optionally substituted with one or more groups selected from the group consisting of a halogen atom, CF ₃ , CN, OH and R ³¹ ; R ³¹ is a hydrogen atom, C _1-6 An alkyl group, a C _1-6 alkoxy group, or a C _1-6 alkoxy-C _1-6 alkyl group, the hydrogen atom, a C _1-6 alkyl group, a C _1-6 alkoxy group, and a C _1-6 alkoxy- The C _1-6 alkyl group may be further substituted with CO ₂ R ³² , OCOR ³³ or C (═O) NR ³⁴ R ³⁵ ; each of R ³² , R ³³ , R ³⁴ and R ³⁵ is independently , A hydrogen atom, or a lower alkyl group, and the lower alkyl group may be further substituted with one or more lower alkoxy groups or OH at any position as long as it is chemically acceptable.

Preferably, R ^{3 ′} is a phenyl group, a phenyloxy lower alkyl group, a phenyl lower alkoxy lower alkyl group, a heteroaryl group (the “heteroaryl group” is preferably pyridyl or pyrazolyl, more preferably pyridyl Each group of R ^{3 ′} is independently at any position on the aromatic ring (ie, phenyl or heteroaryl) as long as it is chemically acceptable, and a halogen atom, CF ₃ CN, OH, carboxyl group, lower alkoxycarbonyl group, lower alkyl group, lower alkoxy group, lower alkenyl group, lower cycloalkyl group and lower alkoxy lower alkyl group may be substituted with 1 to 2 substituents. Well; the lower alkyl group, lower alkoxy group, lower alkenyl group, lower cycloalkyl group and At Grade alkoxy lower alkyl group more chemically acceptable as long as any position, carboxyl group, aminocarbonyl group, mono- or di-substituted lower alkylamino group, a lower alkoxycarbonyl group, C _1-4 alkoxy -C _{2 May} be substituted with a _-4 alkoxycarbonyl group or a hydroxy- _C2-4 alkoxycarbonyl group.
R ^{3 ″} is preferably a hydrogen atom or a lower alkyl group.

[Step K-2] to [Step K-4]
After protecting the compound k1 which is a carboxylic acid form into a compound k2 which is an appropriate lower alkyl ester form or benzyl ester form, an organic halogen compound (ie, R ³ -Hal; where Hal means a halogen atom, preferably a chlorine atom, a bromine atom or an iodine atom) or an organic sulfonic acid ester compound ^(i.e., R 3 -OSO ₂ R ^L; here, ^{R L} is optionally _{C 1-4} be substituted by fluorine atoms An alkyl group or a phenyl group that may be substituted with C _1-4 alkyl means methyl, trifluoromethyl, 4-methylphenyl, phenyl, etc.) and a reactive agent (ie, “R ³ -L”) L represents a leaving group, and represents a compound k3 from a compound k2 by a substitution reaction used as a halogen atom or OSO ₂ R ^L described above. Then, deprotection of compound k3 is followed by a series of steps to obtain compound a13. The substitution reaction in this step is carried out in an appropriate solvent in the presence of various bases, and the base and the solvent are selected from those exemplified below, and more specifically, for example, as described in Example 3 below It is performed by a method or a method according to this. The protection and deprotection of the carboxylic acid can be performed according to the method described in the Protective Groups in Organic Synthesis.
Compound a13 that can be produced by this production method K includes the compound represented by formula (VII) in item [44], and R ^{3 of} compound a13 is represented by formula (4h) in item [4]. Is a compound represented by the formula (VII). That is, this manufacturing method can be used for the manufacturing method of the compound represented by Formula (VII).
In formula (VII) of item [44], R ^b4h is as defined in [44], preferably CO ₂ R ^3g4 (where R ^3g4 represents a C _1-4 alkyl group). . Similarly, in formula (VII), Arm, R ^a4h , R ^d4h , R ^e4h , R ^f4h , R ^g4h , R ^h4h , R ^i4h , R ^j4h , R ^k4h , m ^4h , n ^4h , p ^4h , q 4 ^h r ^4h , s ^4h , R ⁴ and R ⁵ are as defined in [4] above, preferably as defined in [8], [9], [12] or [39].

（式中、Ｒ^ｂ４ｈは上記［４４］に定義されるエステルであり、Ａｒｍ、Ｒ^ａ４ｈ、Ｒ^ｄ４ｈ、Ｒ^ｆ４ｈ、Ｒ^ｇ４ｈ、Ｒ^４及びＲ^５は上記［４］に定義されるとおりである） Production method Ka
The compound represented by the formula [a13a] contained in the compound a13 which is an intermediate between the production methods A and G (hereinafter also referred to as “compound a13a”) can be produced, for example, by the following production method.

( ^Wherein R ^b4h is an ester defined in [44] above, and Arm, R ^a4h , R ^d4h , R ^f4h , R ^g4h , R ⁴ and R ⁵ are as defined in [4] above. )

[Ka-1 process]
This step is a step of obtaining compound k2a by reacting compound k1a with compound k1 in the same manner as in step K-1. More specifically, this step is performed, for example, by the method described in the step (r7-i) of Reference Example 7 described later or a method analogous thereto.
[Ka-2 process]
In this step, the compound k2a obtained in the Ka-1 step is reduced to a double bond to a single bond, for example, a hydrogenation reaction in the presence of various metal catalysts (palladium carbon, platinum carbon, etc.), or hydride reduction. In this step, compound a13a is obtained by a reduction reaction using an agent or the like. More specifically, this step is performed, for example, by the method described in the step (r7-ii) of Reference Example 7 described later or a method analogous thereto.
In addition, the compound a13a which can be manufactured with this manufacturing method Ka is contained in the compound represented by Formula (VII) of said [44] as one preferable aspect.

（式中、Ｒ^１は上記［１］に定義されるとおりである）
［Ｍ−１工程］
本工程は化合物m1に、適当な溶媒中、チオホスゲンを反応させることにより、化合物a10を得る工程である。本工程において使用される溶媒は、後記に例示する溶媒等から選択されるが、好ましくは塩化メチレンと水の二層系である。より具体的には、本工程は例えば、後記参考例８に記載の方法、又はこれに準じた方法で行われる。 Manufacturing method M
The compound represented by compound a10 of production method A can be produced, for example, by the following production method.

(Wherein R ¹ is as defined in [1] above)
[Step M-1]
This step is a step of obtaining compound a10 by reacting compound m1 with thiophosgene in a suitable solvent. The solvent used in this step is selected from the solvents exemplified below, and preferably a two-layer system of methylene chloride and water. More specifically, this step is performed by, for example, the method described in Reference Example 8 described later or a method analogous thereto.

The substitution reaction with azetidine nitrogen using the reaction agent R ³ -L described in the above production method A, production method K, etc. is also an aromatic halogen compound represented by the Buchwald-Hartwig reaction. R ³ is substituted by using general coupling reaction conditions in which an aromatic sulfonic acid ester compound and an amine are bonded in the presence of a metal catalyst such as a palladium catalyst or a copper catalyst and an appropriate base. In addition to the compound of the present invention that may be an alkyl group, for example, a compound of the present invention in which R ³ is an optionally substituted aryl group, an optionally substituted heteroaryl group, or the like can be produced.

Compounds that are raw materials and intermediates in each of the above production methods (wherein the compounds include, for example, compounds a1, a10, a11, a12, a13, b5, c5, d5, e4, f4, h2, h3, i1, i7 from ^{i8, k1, k1a, m1,} R 2 -L, R 3 is -L and ^{R 3 '-C (= O)} -R 3'') or is used to purchase commercially available compounds, or commercially available compounds What was manufactured by the well-known method can be used.

  The compound used in each of the above production methods may form a salt, and examples of such a salt include the same salts as the salts of the compound of the present invention.

  The base used in each of the above production methods should be selected as appropriate depending on the reaction, the type of raw material compound, and the like. For example, alkali bicarbonates such as sodium bicarbonate and potassium bicarbonate; sodium carbonate and potassium carbonate Alkali carbonates such as: metal hydrides such as sodium hydride and potassium hydride; alkali metal hydroxides such as sodium hydroxide and potassium hydroxide; alkali alkoxides such as sodium methoxide and sodium tert-butoxide Organometallic bases such as butyllithium and lithium diisopropylamide; triethylamine, diisopropylethylamine, pyridine, 4-dimethylaminopyridine (DMAP), 1,8-diazabicyclo [5.4.0] -7-undecene (DBU) Such organic bases.

  The solvent used in each of the above production methods should be appropriately selected depending on the reaction, the type of raw material compound, etc., for example, alcohols such as methanol, ethanol and isopropanol; ketones such as acetone and methyl ketone; Halogenated hydrocarbons such as methylene and chloroform; Ethers such as tetrahydrofuran (THF) and dioxane; Aromatic hydrocarbons such as toluene and benzene; Aliphatic hydrocarbons such as hexane and heptane; Ethyl acetate Esters such as propyl acetate; Amides such as N, N-dimethylformamide (DMF) and N-methyl-2-pyrrolidone; Sulfoxides such as dimethyl sulfoxide (DMSO); Nitriles such as acetonitrile Yes; these solvents may be used alone or in combination of two or more. Depending on the type of reaction, organic bases may be used as a solvent.

  The reaction temperature in each of the above production methods should be selected in a timely manner depending on the reaction, the raw material compound or the type of solvent used, and is usually -100 ° C to 200 ° C, preferably -70 ° C to 100 ° C. It is.

  The reaction time in each of the above production methods should be selected in a timely manner depending on the reaction, the raw material compound or the type of solvent used, and is usually 10 minutes to 48 hours, preferably 30 minutes to 24 hours. .

  In each compound including an intermediate obtained in each of the above production methods, the functional group in the molecule is obtained by a known method such as Comprehensive Organic Transformations (Richard C. Larock, John Wiley & Sons, Inc., 1999). ) Can be converted into the desired functional group. For example, another compound of the present invention having various esters, amides, carbamates and the like, useful as an MGAT2 inhibitor, using the compound having a carboxylic acid, alcohol or primary or secondary amine as an intermediate in the present invention Can be converted to

  The product obtained in each of the above production methods can be isolated and purified according to conventional methods such as extraction, column chromatography, recrystallization, reprecipitation and the like.

  “Physiologically acceptable salt” means a physiologically acceptable acid addition salt, alkali metal salt, alkaline earth metal salt or salt with an organic base. Specifically, examples of the acid addition salt include inorganic acid salts such as hydrochloride, hydrobromide, hydroiodide, sulfate, phosphate, and oxalate, maleate, and fumarate. And organic acid salts such as malonate, lactate, malate, citrate, tartrate, benzoate, methanesulfonate, p-toluenesulfonate, and gluconate. Examples of the alkali metal salt include inorganic alkali salts such as sodium salt and potassium salt. Examples of the alkaline earth metal salt include calcium salt and magnesium salt. Examples of the salt as the organic base include And salts with ammonia, methylamine, triethylamine, N-methylmorpholine.

The compound of this invention can be made into an acid addition salt as one preferable aspect, Preferably, the acid used includes hydrochloric acid, phosphoric acid, fumaric acid, and the like.
“Chemically stable salt” means an acid addition salt, alkali metal salt, alkaline earth metal salt, or salt with an organic base having storage stability to the extent acceptable as an intermediate for chemical reaction. Specifically, examples of the acid addition salt include inorganic acid salts such as hydrochloride, hydrobromide, hydroiodide, sulfate, phosphate, acetate, trifluoroacetate, and oxalate. , Maleate, fumarate, malonate, lactate, malate, citrate, tartrate, benzoate, methanesulfonate, benzenesulfonate, p-toluenesulfonate, gluconic acid Organic acid salts such as salts can be mentioned. Examples of the alkali metal salt include inorganic alkali salts such as sodium salt and potassium salt. Examples of the alkaline earth metal salt include calcium salt and magnesium salt. Examples of the salt as the organic base include Examples include salts with ammonia, methylamine, triethylamine, and N-methylmorpholine, but are not limited thereto.

  Since the compounds represented by formula (I) and physiologically acceptable salts thereof may exist in the form of hydrates and / or solvates, these hydrates and solvates are also present. Included in the compounds of the invention.

  In addition, the compound represented by the formula (I) may have one or more asymmetric carbon atoms, and may cause geometric isomerism and axial chirality, and thus may exist as several stereoisomers. . These stereoisomers, mixtures thereof and racemates are also included in the compounds of the present invention. Furthermore, the present invention includes all tautomers of the compounds of the present invention.

  The present invention also includes a prodrug of the compound represented by formula (I) or a physiologically acceptable salt thereof. The present invention also includes these hydrates and / or solvates.

  In the present specification, the term “prodrug of the compound represented by formula (I)” is a compound that is converted into a compound of formula (I) by a reaction with an enzyme, gastric acid or the like under physiological conditions in vivo, for example, A compound that is enzymatically oxidized, reduced, hydrolyzed, etc. to be converted to a compound of formula (I); a compound that is hydrolyzed by gastric acid or the like to be converted to a compound of formula (I). Specifically, for example, a compound obtained by converting a compound of the present invention having a carboxylic acid, an alcohol, a primary or secondary amine, or the like into an ester, amide, carbamate or the like that can be easily hydrolyzed by the above reaction in vivo. And is preferably an ester.

  The compounds of the present invention include ante-drugs. In the present specification, the term “ante-drug” refers to the expression of a desired action, followed by a reaction with an enzyme or the like (eg, enzymatic oxidation, reduction, hydrolysis, etc.) under physiological conditions in the living body. It means a compound that is quickly converted to a compound with relatively low burden (such as undesirable side effects). Specific examples include compounds such as esters, amides, carbamates and the like that can be easily hydrolyzed by reactions with enzymes in the living body among the compounds of the present invention, with esters being preferred.

In addition, a deuterium converter obtained by converting any one or two or more ¹ H of the compounds of the present invention into ² H (D) is also included in the compounds of the present invention. These are well-known methods such as synthesis from commercially available deuterated compounds and reagents, hydrogenation reactions using deuterium, or reduction reactions with deuterated reducing agents (eg, sodium deuteride borohydride). It can be obtained by a method.

  The compounds of the present invention can be obtained in the form of salts, free acids or free bases depending on the reaction conditions, but these compounds can be converted into the desired salts, free acids or free bases by conventional methods.

  The compound of the present invention or a physiologically acceptable salt thereof may be a crystal, and these can be obtained by a known crystallization method or the like. When the compound of the present invention or a physiologically acceptable salt thereof can take a plurality of crystal forms, all forms of the crystal form are also included in the compound of the present invention.

  In the compound of the present invention, when an optical isomer, a stereoisomer, a rotational isomer and / or a positional isomer can exist, these are also included in the compound of the present invention. These can be obtained by a known method such as a synthesis from an optically active raw material compound or a separation method such as an optical resolution method or a preferential crystallization method.

The compound of the present invention or a physiologically acceptable salt thereof has an MGAT inhibitory action and is useful as a prophylactic and / or therapeutic agent for MGAT-related diseases.
“MGAT-related disease” means a disease caused by excessive triglyceride accumulation in the body due to excessive intake of triglyceride or abnormal metabolism of triglyceride, such as obesity, metabolic syndrome, high Lipemia, hypertriglyceridemia, hyperVLDL (where "VLDL" stands for very low-density lipoprotein), hyperfattyemia, diabetes, arteriosclerosis Etc.
Therefore, the compound of the present invention and physiologically acceptable salts thereof are obesity, metabolic syndrome, hyperlipidemia, hypertriglyceridemia, hyperVLDLemia, hyperfattyemia, diabetes, arteriosclerosis. It is useful as a prophylactic and / or therapeutic agent.

  When the compound of the present invention or a physiologically acceptable salt thereof is used as an MGAT inhibitor, it may be administered orally, parenterally or rectally, but oral administration is preferred. The dose varies depending on the administration method, patient symptom / age, treatment mode (prevention or treatment), etc., but is usually 10 ng / kg / day to 10 mg / kg / day, preferably 0.1 μg / kg / day to 1 mg. / Kg / day, more preferably 1 μg / kg / day to 100 μg / kg / day is administered once a day or divided into 2 to 3 times a day. It can also be administered once every few days to several weeks. Alternatively, 1 μg / day to 1 g / day, preferably 10 μg / day to 100 mg / day, more preferably 100 μg / day to 10 mg / day per adult is administered once or twice or three times a day. To do. It can also be administered once every few days to several weeks.

  The compound of the present invention is usually administered in the form of a preparation prepared by mixing with a pharmaceutical carrier. As a pharmaceutical carrier, a substance that is commonly used in the pharmaceutical field and does not react with the compound of the present invention is used. Specifically, for example, lactose, glucose, mannitol, dextrin, starch, sucrose, magnesium aluminate metasilicate, synthetic aluminum silicate, crystalline cellulose, sodium carboxymethylcellulose, hydroxypropyl starch, carboxymethylcellulose calcium, ion exchange resin, methylcellulose , Gelatin, gum arabic, hydroxypropylcellulose, low substituted hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, polyvinyl alcohol, light anhydrous silicic acid, magnesium stearate, talc, carboxyvinyl polymer, titanium oxide, sorbitan fatty acid ester, lauryl Sodium sulfate, glycerin, fatty acid glycerin ester, purified lanolin, glycerogelatin Polysorbate, macrogol, vegetable oils, waxes, nonionic surfactants, propylene glycol, water and the like.

  Examples of the dosage form include tablets, capsules, granules, powders, syrups, suspensions, suppositories, gels, injections and the like. These preparations are prepared according to a conventional method. In the case of a liquid preparation, it may be dissolved or suspended in water or other appropriate medium at the time of use. Tablets and granules may be coated by a known method. In the case of an injection, it is prepared by dissolving the compound represented by formula (I) or a physiologically acceptable salt thereof in water, but an isotonic agent may be dissolved if necessary. In addition, pH adjusting agents, buffers and preservatives may be added.

  These preparations can contain the compound of the present invention or a physiologically acceptable salt thereof in an amount of 0.01% by weight or more, preferably 0.05 to 70% by weight. These formulations may also contain other therapeutically effective ingredients.

  The compounds of the present invention are drugs such as anti-obesity agents, anti-diabetic agents, anti-diabetic complication agents, anti-hyperlipidemic agents, antihypertensive agents, diuretics, anti-ventilants, etc. , Abbreviated as “concomitant drug”). The administration time of the compound of the present invention and the concomitant drug is not limited, and these may be administered to the administration subject at the same time or may be administered with a time difference. Moreover, it is good also as a mixture of the compound of this invention and a concomitant drug. The dose of the concomitant drug can be appropriately selected based on the clinically used dose. The mixing ratio of the compound of the present invention and the concomitant drug can be appropriately selected depending on the administration subject, administration route, target disease, symptom, combination and the like. For example, when the administration subject is a human, the concomitant drug may be used in an amount of 0.01 to 100 parts by weight per 1 part by weight of the compound of the present invention.

  As the anti-obesity agent, for example, as a central anti-obesity agent, dexfenfluramine, fenfluramine, phentermine, topiramate, bupropion, sibutramine, lorcaserine, ampepramon, dexamphetamine, mazindol, tesofensin, phenylpropanolamine, Clobenzolex, zonisamide, MCH receptor antagonist (eg, BMS-830216, etc.), neuropeptide Y5 receptor antagonist (eg, S-2367, etc.), neuropeptide Y2 receptor agonist (eg, AC-162352, etc.) ), Opioid μ receptor antagonists (eg, naltrexone, etc.), opioid μ receptor inverse agonists (eg, GSK-1521498, etc.), histamine H3 receptor antagonists (eg, HPP-404, etc.), etc. , Peptide appetite suppressants (eg, Leptin, etc.), GLP-1 analogs (eg, liraglutide, etc.), cannabinoid receptor antagonists (eg, TM388837, etc.), agouti related protein (AgRP) inhibitors (eg, TTP-435, etc.), pancreatic lipase inhibitors (eg, , Orlistat, cetiristat, etc.), glucokinase activator (eg, AZD-5658, etc.), microsomal triglyceride transfer protein (MTP) inhibitor (eg, JNJ-16269110, etc.), acylcoenzyme A: diacylglycerol acyltransferase (DGAT) inhibitors (eg, AZD-5658, etc.), sodium-dependent glucose transporter (SGLT) 2 inhibitors (eg, canagliflozin, etc.), β3 agonists (eg, LY-377604, etc.), methionine amino Peptidase (MetAP) 2 inhibitors (eg, ZG -433 etc.), 11.beta.-position hydroxide dehydrogenase type 1 (ll [beta] HSDl) inhibitors (e.g., such as AZD-8329), and the like.

  Antidiabetic agents include insulin preparations (eg, animal insulin preparations extracted from bovine and porcine pancreas, human insulin preparations genetically engineered using E. coli / yeast, insulin zinc, protamine insulin zinc, insulin fragments or Derivatives, oral insulin preparations), insulin sensitizers (eg, pioglitazone or its hydrochloride, rosiglitazone or its maleate, alleglitazar, ZYH1, robeglitazone, valaglitazone, THR-0921, GFT-505, indeglita Saar, siglitazar, MBX-2044, MBX-102, INT-131, DSP-8658, etc.), α-glucosidase inhibitors (eg, voglibose, acarbose, miglitol, emiglitate, etc.), biguanides ( , Metformin, etc.), insulin secretagogues (eg, tolbutamide, glibenclamide, gliclazide, chlorpropamide, tolazamide, acetohexamide, glyclopyramide, glimepiride, glipizide and other sulfonylureas; repaglinide, nateglinide, mitiglinide, etc.), dipeptidyl Peptidase (DPP) IV inhibitors (eg, sitagliptin, vildagliptin, saxagliptin, linagliptin, alogliptin, teneligliptin, anagliptin, gemigliptin, trelagliptin, etc.), GLP-1, GLP-1 analogues (eg, exenatide, liraglutide, albiglutide, albiglutide) Glutatide, lixisenatide, etc.), sodium-dependent glucose transporter (SGLT) 2 inhibitors (eg, dapagliflozin, potassium Nagliflozin, empagliflozin, ipragliflozin, tofogliflozin, etc.), SGLT1 inhibitor (eg, LX-4211, DSP-3235, etc.), 11β-hydroxysteroid dehydrogenase type 1 (11βHSD1) inhibitor (eg, BMS-) 770767, INCB013739, LY2523199, etc.), glucokinase activator (eg, ARRY-403, TTP399, etc.), glycogen phosphorylase inhibitor (eg, GSK-1362885 etc.), glucagon receptor antagonist (eg, LY2409021, MK) -3577), GPR40 agonist (eg, TAK-875) and the like.

  As therapeutic agents for diabetic complications, aldose reductase inhibitors (eg, epalrestat, lanirestat, etc.), neurotrophic factors (eg, NGF, TAK-428, etc.), PKC inhibitors (eg, ruboxistaurine mesylate, etc.) AGE inhibitors (eg, pyridoxamine, etc.), active oxygen scavengers (eg, thioctic acid, etc.), cerebral vasodilators (eg, thioprid, mexiletine, etc.), angiogenesis inhibitors (eg, defibrotide, ranibizumab, etc.) , Nrf2 activator (eg, RTA-402, etc.), endothelin antagonist (eg, atrasentan, etc.), phosphodiesterase inhibitor (eg, PF-489791, etc.), CCR2 receptor antagonist (eg, CCX-140, etc.) , T-type calcium channel antagonists (eg, ABT-639, etc.), GABA receptor modulators (eg, BMS-954) 61, etc.) and the like.

  Antihyperlipidemic agents include HMG-CoA reductase inhibitors (eg, pravastatin, simvastatin, lovastatin, atorvastatin, fluvastatin, pitavastatin, rosuvastatin or their salts (eg, sodium salt, calcium salt)), fibrate Compounds (eg, bezafibrate, clofibrate, simfibrate, clinofibrate, etc.), anion exchange resins (eg, cholestyramine, etc.), cholesterol absorption inhibitors (eg, ezetimibe, etc.), probucol, nicotinic acid drugs (eg, niacin) And icosapentate, etc.), CETP inhibitors (eg, anacetrapib, darcetrapib, etc.), ACAT inhibitors (eg, K604 etc.), and the like.

  Antihypertensive agents include angiotensin-converting enzyme inhibitors (eg, captopril, enalapril, alacepril, delapril, lizinopril, imidapril, benazepril, cilazapril, temocapril, trandolapril, etc.), angiotensin II antagonists (eg, olmesartan medoxomilyl canxetilmil, candesartyl, Azilsartan medoxomil, losartan, eprosartan, valsantan, telmisartan, irbesartan, tasosartan, etc.), calcium antagonists (eg, nicardipine hydrochloride, manidipine hydrochloride, nisoldipine, nitrendipine, nilvadipine, amlodipine, etc.), renin inhibitors (eg, aliskiren, etc.) , Β-blockers (eg, atenolol, bisoprolol, betaxolol, metoprolol, etc.), α-blockers (eg, urapidil) Terazosin, doxazosin, bunazosin, etc.), αβ blockers (eg, amosulalol, arotinolol, labetalol, carvedilol, etc.), clonidine and the like.

  Examples of diuretics include xanthine derivatives (eg, sodium salicylate theobromine, calcium salicylate theobromine, etc.), thiazide preparations (eg, etiazide, cyclopentiazide, trichloromethiazide, hydrochlorothiazide, hydroflumethiazide, benchylhydrochlorothiazide, pentfurizide, polythiazide, Methiclotiazide, etc.), anti-aldosterone preparations (eg, eplerenone, spironolactone, triamterene, etc.), carbonic anhydrase inhibitors (eg, acetazolamide, etc.), chlorobenzenesulfonamide preparations (eg, chlorthalidone, mefluside, indapamide, etc.), azosemide, Examples include isosorbide, ethacrynic acid, piretanide, bumetanide, furosemide and the like.

  Anti-ventilants include allopurinol, probenecid, colchicine, benzbromarone, febuxostat, citrate and the like.

Two or more of the above concomitant drugs may be used in combination at an appropriate ratio.
When the compound of the present invention is used in combination with a concomitant drug, the amount of these drugs used can be reduced within a safe range considering the side effects of the drug. Therefore, side effects that may be caused by these drugs can be safely prevented.

EXAMPLES The present invention will be specifically described below with reference to examples, but the present invention is not limited to these examples.
The following abbreviations may be used in Examples and Reference Examples.
Me: methyl Et: ethyl Ph: phenyl Boc: tert-butoxycarbonyl N: normal (for example, 2N HCl indicates 2N hydrochloric acid)
THF: Tetrahydrofuran NaBH (OAc) ₃ : Sodium triacetoxyborohydride (Boc) ₂ O: Di-tert-butyl dicarbonate Cbz: Benzyloxycarbonyl Pd / C: Palladium carbon Pt / C: Platinum carbon HPLC: High performance liquid chromatography Graphic DMF: N, N-dimethylformamide DIEA: N, N-diisopropylethylamine DMSO: Dimethyl sulfoxide M: Molar concentration (mol / L) (For example, 2M methylamine indicates a 2 mol / L methylamine solution.)
BSA: bovine serum albumin Palmitoyl-CoA: Palmitoyl coenzyme A
NaOH: Sodium hydroxide

工程(i)：
化合物I（65.88 g）に25％アンモニア水溶液（660 mL）を加え、2時間加熱還流を行った。反応液を酢酸エチルで希釈し、有機層を分離後、水層を酢酸エチルで再度抽出した。有機層を合わせて無水硫酸ナトリウムで乾燥後、減圧濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー（ヘキサン/酢酸エチル＝5/3）で精製後、得られた粗精製物を再結晶（ヘキサン/ジエチルエーテル＝9/1）し、化合物II（37.67 g）を得た。
MS-APCI: m/z: 271 ([M+H]⁺).
¹H-NMR(400MHz, DMSO-d₆):δ(ppm)= 7.00 (br.s, 2H), 4.05 (q, J = 7.1, 2H), 3.92 (s, 2H), 3.37 (t, J = 6.0, 2H), 2.26 (t, J = 6.0, 2H), 1.40 (s, 9H), 1.18 (t, J = 7.1, 3H). Reference Example 1: Preparation of 2- (cyclohexylamino) -3-phenyl-5,6,7,8-tetrahydropyrido [4,3-d] pyrimidin-4 (3H) -one hydrochloride

Process (i):
A 25% aqueous ammonia solution (660 mL) was added to compound I (65.88 g), and the mixture was heated to reflux for 2 hours. The reaction solution was diluted with ethyl acetate, the organic layer was separated, and the aqueous layer was extracted again with ethyl acetate. The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate = 5/3), and the resulting crude product was recrystallized (hexane / diethyl ether = 9/1) to give compound II (37.67 g) Got.
MS-APCI: m / z: 271 ([M + H] ⁺ ).
¹ H-NMR (400 MHz, DMSO-d ₆ ): δ (ppm) = 7.00 (br.s, 2H), 4.05 (q, J = 7.1, 2H), 3.92 (s, 2H), 3.37 (t, J = 6.0, 2H), 2.26 (t, J = 6.0, 2H), 1.40 (s, 9H), 1.18 (t, J = 7.1, 3H).

Step (ii):
Phenyl isothiocyanate (17.1 mL) was added to a solution of compound II (19.3 g) in pyridine (165 mL), and the mixture was heated and stirred at 90 ° C. overnight. The reaction mixture was concentrated under reduced pressure, toluene was added, and the mixture was concentrated again under reduced pressure. The obtained crude crystals were washed with diethyl ether to obtain Compound III (26.75 g). Compound III was used in the next reaction without further purification.

Step (iii):
To a solution of Compound III (26.75 g) in N, N-dimethylformamide (320 mL) at 0 ° C. was added 1,8-diazabicyclo [5.4.0] -7-undecene (10.6 mL) and methyl iodide (4.9 mL). added. The reaction mixture was stirred at 0 ° C. for 0.5 hr, quenched with saturated aqueous sodium hydrogen carbonate solution, and extracted with methylene chloride. The organic layer was washed with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate = 3/1) to give Compound IV (22.03 g).
¹ H-NMR (400 MHz, DMSO-d ₆ ): δ (ppm) = 7.52-7.57 (m, 3H), 7.34-7.37 (m, 2H), 4.17 (s, 2H), 3.61 (t, J = 5.8 , 2H), 2.65 (t, J = 5.7, 2H), 2.39 (s, 3H), 1.43 (s, 9H).

Step (iv):
Anhydrous magnesium sulfate (20 g) and sodium acetate (2.31 g) were added to a solution of compound IV (5.0 g) in methylene chloride (100 mL). The reaction mixture was cooled to −70 ° C., and a solution of m-chloroperbenzoic acid (9.89 g) in methylene chloride (150 mL) was added dropwise. The reaction mixture was stirred at −70 ° C. for 3.5 hours, quenched by adding 10% aqueous sodium thiosulfate at −30 ° C., and then extracted with dichloromethane. The organic layer was washed successively with 10% aqueous sodium thiosulfate solution and saturated aqueous sodium hydrogen carbonate solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give compound V (6.15 g). Compound V was used in the next reaction without further purification.

Process (v):
Cyclohexylamine (499 mg), diisopropylethylamine (977 mg) and 4-dimethylaminopyridine (0.03 g) were added to a solution of compound V (980 mg) in dioxane (19 mL), and the mixture was heated and stirred at 50 ° C. for 15 hours. The reaction mixture was quenched by adding water and extracted with ethyl acetate. The organic layer was washed successively with water, saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate = 1/1) to give Compound VI (630 mg).
¹ H-NMR (400 MHz, CDCl ₃ ): δ (ppm) = 7.43-7.52 (m, 3H), 7.16-7.22 (m, 2H), 4.22 (s, 2H), 3.81 (s, 2H), 3.55 ( t, J = 5.8, 2H), 2.54 (s, 2H), 1.97-1.98 (m, 2H), 1.47-1.56 (m, 3H), 1.41 (s, 9H), 1.25-1.33 (m, 2H), 0.92-1.06 (m, 3H).

Process (vi):
To a solution of compound VI (630 mg) in dioxane (5 mL) was added 4 mol / l dioxane hydrochloride solution (10 mL) at 0 ° C. The reaction mixture was stirred at room temperature for 2 hours, concentrated under reduced pressure, dichloromethane was added, and the mixture was concentrated again under reduced pressure to obtain Compound VII (700 mg).
¹ H-NMR (400 MHz, DMSO-d ₆ ): δ (ppm) = 7.63-7.68 (m, 3H), 7.38-7.40 (m, 2H), 4.01 (s, 2H), 3.37-3.38 (m, 1H ), 3.56-3.59 (m, 2H), 3.01-3.12 (m, 2H), 1.87-1.90 (m, 2H), 1.73-1.76 (m, 2H), 1.62-1.66 (m, 1H), 1.32-1.42 (m, 4H), 1.09-1.12 (m, 1H).

化合物VII（360 mg）のN,N−ジメチルホルムアミド（5 mL）溶液に1-(tert-ブトキシカルボニル)アゼチジン-3-カルボン酸（201 mg）、トリエチルアミン（0.416 mL）、1-ヒドロキシベンゾトリアゾール（405 mg）及び1-エチル-3-(3-ジメチルアミノプロピル)カルボジイミド塩酸塩（619 mg）を加えた。反応混合物を25℃で15時間撹拌した後、飽和炭酸水素ナトリウム水溶液を加え、酢酸エチルを用いて抽出した。有機層を飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥後、減圧濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル）で精製後、実施例化合物１（335 mg）を得た。
¹H-NMR(400MHz, DMSO-d₆):δ(ppm)= 7.50-7.59 (m, 3H), 7.25-7.27 (m, 2H), 5.03-5.09 (m, 1H), 3.68-4.18 (m, 9H), 3.49 (t, J = 5.8 Hz, 1H), 2.45-2.51 (m, 2H), 1.67-1.69 (m, 2H), 1.49-1.56 (m, 3H), 1.36-1.37 (m, 9H), 0.95-1.26 (m, 5H). Example 1: tert-butyl 3-{[2- (cyclohexylamino) -4-oxo-3-phenyl-3,5,7,8-tetrahydropyrido [4,3-d] pyrimidine-6 (4H) Preparation of -yl] carbonyl} azetidine-1-carboxylate

To a solution of compound VII (360 mg) in N, N-dimethylformamide (5 mL) was added 1- (tert-butoxycarbonyl) azetidine-3-carboxylic acid (201 mg), triethylamine (0.416 mL), 1-hydroxybenzotriazole ( 405 mg) and 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (619 mg) were added. The reaction mixture was stirred at 25 ° C. for 15 hours, saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate) to give Example Compound 1 (335 mg).
¹ H-NMR (400 MHz, DMSO-d ₆ ): δ (ppm) = 7.50-7.59 (m, 3H), 7.25-7.27 (m, 2H), 5.03-5.09 (m, 1H), 3.68-4.18 (m , 9H), 3.49 (t, J = 5.8 Hz, 1H), 2.45-2.51 (m, 2H), 1.67-1.69 (m, 2H), 1.49-1.56 (m, 3H), 1.36-1.37 (m, 9H ), 0.95-1.26 (m, 5H).

実施例化合物１（270 mg）の1,4−ジオキサン（4 mL）溶液に、4 mol/L塩酸ジオキサン溶液（4 mL）を加えた。反応混合物を25℃で1時間撹拌し、減圧濃縮後、実施例化合物２（330 mg）を得た。
¹H-NMR(400MHz, DMSO-d₆):δ(ppm)= 7.53-7.60 (m, 3H), 7.27-7.30 (m, 2H), 4.01-4.45 (m, 10H), 3.50-3.58 (m, 2H), 2.58-2.72 (m, 2H), 1.66-1.73 (m, 2H), 1.47-1.58 (m, 3H), 0.99-1.30 (m, 5H). Example 2: 6- (azetidin-3-ylcarbonyl) -2- (cyclohexylamino) -3-phenyl-5,6,7,8-tetrahydropyrido [4,3-d] pyrimidine-4 (3H) -On Production of hydrochloride

To a solution of Example Compound 1 (270 mg) in 1,4-dioxane (4 mL) was added 4 mol / L dioxane hydrochloride solution (4 mL). The reaction mixture was stirred at 25 ° C. for 1 hr and concentrated under reduced pressure to give Example Compound 2 (330 mg).
¹ H-NMR (400 MHz, DMSO-d ₆ ): δ (ppm) = 7.53-7.60 (m, 3H), 7.27-7.30 (m, 2H), 4.01-4.45 (m, 10H), 3.50-3.58 (m , 2H), 2.58-2.72 (m, 2H), 1.66-1.73 (m, 2H), 1.47-1.58 (m, 3H), 0.99-1.30 (m, 5H).

実施例化合物２（330 mg）のN,N−ジメチルホルムアミド（5 mL）溶液にベンジルブロミド（0.065 mL）及びジイソプロピルエチルアミン（0.33 mL）を加えた。反応混合物を25℃で16時間撹拌した後、水を加え、酢酸エチルを用いて抽出した。有機層を無水硫酸ナトリウムで乾燥後、減圧濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー（メタノール/クロロホルム＝5/95）で精製後、実施例化合物３（98 mg）を得た。
¹H-NMR(400MHz, DMSO-d₆):δ(ppm)= 7.51-7.58 (m, 3H), 7.21-7.32 (m, 7H), 5.01-5.06 (m, 1H), 3.32-4.16 (m, 10H), 3.15-3.19 (m, 2H), 2.44-2.50 (m, 2H), 1.66-1.69 (m, 2H), 1.47-1.54 (m, 3H), 0.99-1.23 (m, 5H). Example 3: 6-[(1-Benzylazetidin-3-yl) carbonyl] -2- (cyclohexylamino) -3-phenyl-5,6,7,8-tetrahydropyrido [4,3-d] Production of pyrimidine-4 (3H) -one

Benzyl bromide (0.065 mL) and diisopropylethylamine (0.33 mL) were added to a solution of Example Compound 2 (330 mg) in N, N-dimethylformamide (5 mL). The reaction mixture was stirred at 25 ° C. for 16 hours, water was added, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (methanol / chloroform = 5/95) to give Example Compound 3 (98 mg).
¹ H-NMR (400 MHz, DMSO-d ₆ ): δ (ppm) = 7.51-7.58 (m, 3H), 7.21-7.32 (m, 7H), 5.01-5.06 (m, 1H), 3.32-4.16 (m , 10H), 3.15-3.19 (m, 2H), 2.44-2.50 (m, 2H), 1.66-1.69 (m, 2H), 1.47-1.54 (m, 3H), 0.99-1.23 (m, 5H).

Examples 4-16:
According to the method of Example 3, using Example Compound 2 synthesized in Example 2, the compounds of Examples 4 to 16 were synthesized.

工程(x)：
化合物III（5.64 g）のN,N-ジメチルホルムアミド（60 mL）溶液に、1,8-ジアザビシクロ[5.4.0]-7-ウンデセン（2.28 g）及びヨウ化シクロヘキシル（3.50 g）を加えた。反応混合物を40℃で20時間撹拌後、飽和炭酸水素ナトリウム水溶液で反応をクエンチし、ヘキサン/酢酸エチル（1/1）で抽出した。有機層を水洗し、無水硫酸ナトリウムで乾燥後、減圧濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー（ヘキサン/酢酸エチル＝4/1）で精製後、化合物VIII（4.15 g）を得た。
¹H-NMR(400MHz, DMSO-d₆):δ(ppm)= 7.50-7.53 (m, 3H), 7.21-7.26 (m, 2H), 4.34 (s, 2H), 3.73-3.79 (m, 1H), 3.68-3.71 (m, 2H), 2.70-2.72 (m, 2H), 1.98-2.05 (m, 2H), 1.68-1.72 (m, 2H), 1.55-1.60 (m, 1H), 1.48 (s, 9H), 1.34-1.42 (m, 4H), 1.23-1.28 (m, 1H). Reference Example 2: tert-Butyl 2- (cyclohexylsulfanyl) -4-oxo-3-phenyl-3,5,7,8-tetrahydropyrido [4,3-d] pyrimidine-6 (4H) -carboxylate Manufacturing

Process (x):
1,8-diazabicyclo [5.4.0] -7-undecene (2.28 g) and cyclohexyl iodide (3.50 g) were added to a solution of compound III (5.64 g) in N, N-dimethylformamide (60 mL). The reaction mixture was stirred at 40 ° C. for 20 hours, quenched with saturated aqueous sodium hydrogen carbonate solution, and extracted with hexane / ethyl acetate (1/1). The organic layer was washed with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate = 4/1) to give Compound VIII (4.15 g).
¹ H-NMR (400 MHz, DMSO-d ₆ ): δ (ppm) = 7.50-7.53 (m, 3H), 7.21-7.26 (m, 2H), 4.34 (s, 2H), 3.73-3.79 (m, 1H ), 3.68-3.71 (m, 2H), 2.70-2.72 (m, 2H), 1.98-2.05 (m, 2H), 1.68-1.72 (m, 2H), 1.55-1.60 (m, 1H), 1.48 (s , 9H), 1.34-1.42 (m, 4H), 1.23-1.28 (m, 1H).

工程(xi)〜(xiv)は、参考例１及び実施例１〜３の工程(vi)〜(ix)に準じて合成し、実施例１７の化合物を得た。
¹H-NMR(400MHz, DMSO-d₆):δ(ppm)= 7.50-7.56 (m, 3H), 7.19-7.32 (m, 7H), 4.26 (s, 1H), 4.08 (s, 1H), 3.37-3.75 (m, 8H), 3.19 (t, J = 7.36 Hz, 2H), 2.59-2.63 (m, 2H), 1.91-1.96 (m, 2H), 1.47-1.65 (m, 3H), 1.13-1.39 (m, 5H). Example 17: 6-[(1-Benzylazetidin-3-yl) carbonyl] -2- (cyclohexylsulfanyl) -3-phenyl-5,6,7,8-tetrahydropyrido [4,3-d] Production of pyrimidine-4 (3H) -one

Steps (xi) to (xiv) were synthesized according to steps (vi) to (ix) of Reference Example 1 and Examples 1 to 3, and the compound of Example 17 was obtained.
¹ H-NMR (400 MHz, DMSO-d ₆ ): δ (ppm) = 7.50-7.56 (m, 3H), 7.19-7.32 (m, 7H), 4.26 (s, 1H), 4.08 (s, 1H), 3.37-3.75 (m, 8H), 3.19 (t, J = 7.36 Hz, 2H), 2.59-2.63 (m, 2H), 1.91-1.96 (m, 2H), 1.47-1.65 (m, 3H), 1.13- 1.39 (m, 5H).

工程(xv)：
化合物V（780 mg）のテトラヒドロフラン（10 mL）溶液を、窒素雰囲気下、-78℃に冷却し、2 mol/Lペンチルマグネシウムブロミドのジエチルエーテル溶液（1.0 mL）を滴下した。反応混合物を-78℃で1時間撹拌した後、飽和塩化アンモニウム水溶液を加え、酢酸エチルを用いて抽出した。有機層を飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥後、減圧濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー（ヘキサン/酢酸エチル＝1/1）で精製後、化合物XII（385 mg）を得た。
¹H-NMR(400MHz, DMSO-d₆):δ(ppm)= 7.48-7.57 (m, 3H), 7.34-7.36 (m, 2H), 4.16 (s, 2H), 3.60 (t, J = 5.7 Hz, 2H), 2.62 (t, J = 5.7 Hz, 2H), 2.23 (t, J = 7.9 Hz, 2H), 1.47-1.54 (m, 2H), 1.42 (s, 9H), 1.07-1.11 (m, 4H), 0.75 (t, J = 7.0 Hz, 3H). Example 18: 6-[(1-Benzylazetidin-3-yl) carbonyl] -2-pentyl-3-phenyl-5,6,7,8-tetrahydropyrido [4,3-d] pyrimidine-4 (3H) -ON production

Process (xv):
A solution of compound V (780 mg) in tetrahydrofuran (10 mL) was cooled to −78 ° C. in a nitrogen atmosphere, and 2 mol / L pentylmagnesium bromide in diethyl ether (1.0 mL) was added dropwise. The reaction mixture was stirred at −78 ° C. for 1 hr, saturated aqueous ammonium chloride solution was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate = 1/1) to give Compound XII (385 mg).
¹ H-NMR (400 MHz, DMSO-d ₆ ): δ (ppm) = 7.48-7.57 (m, 3H), 7.34-7.36 (m, 2H), 4.16 (s, 2H), 3.60 (t, J = 5.7 Hz, 2H), 2.62 (t, J = 5.7 Hz, 2H), 2.23 (t, J = 7.9 Hz, 2H), 1.47-1.54 (m, 2H), 1.42 (s, 9H), 1.07-1.11 (m , 4H), 0.75 (t, J = 7.0 Hz, 3H).

Steps (xvi) to (xix) were synthesized according to steps (vi) to (ix) of Reference Example 1 and Examples 1 to 3, and the compound of Example 18 was obtained.
¹ H-NMR (400 MHz, CD ₃ OD): δ (ppm) = 7.52-7.60 (m, 3H), 7.24-7.34 (m, 7H), 4.44 (s, 1H), 4.23 (s, 1H), 3.87 (t, J = 5.9 Hz, 1H), 3.57-3.70 (m, 6H), 3.36-3.43 (m, 2H), 2.74-2.76 (m, 2H), 2.33-2.37 (m, 2H), 1.55-1.59 (m, 2H), 1.18-1.42 (m, 4H), 0.80 (t, J = 6.8 Hz, 3H).

化合物X（524 mg）にトルエン（10 mL）を加えて、氷水冷下で撹拌した。さらに、トリフルオロ酢酸（5 mL）を加えて、室温で1時間撹拌した。反応混合物を減圧濃縮し、化合物XVI(630 mg)得た。 Reference Example 3: 6- (azetidin-3-ylcarbonyl) -2- (cyclohexylsulfanyl) -3-phenyl-5,6,7,8-tetrahydropyrido [4,3-d] pyrimidine-4 (3H) -ON Production of trifluoroacetate

Toluene (10 mL) was added to compound X (524 mg), and the mixture was stirred under ice-water cooling. Furthermore, trifluoroacetic acid (5 mL) was added, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure to obtain Compound XVI (630 mg).

化合物XVI(135 mg) のジクロロメタン(2 mL)溶液に(E)-メチル3-(4-ホルミルフェニル)アクリレート (47 mg)及びジイソプロピルエチルアミン (0.050 mL) を加え、窒素雰囲気下25℃で30分間撹拌した後、NaBH(OAc)₃ (53 mg) を加えた。反応混合物を25℃で15時間撹拌した後、飽和塩化アンモニウム水溶液を加え、クロロホルムを用いて抽出し、有機層を無水硫酸ナトリウムで乾燥後、減圧濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー(メタノール/クロロホルム: 1/10)で精製後、実施例化合物１９(34 mg) を得た。
ＭＳ（Ｍ＋Ｈ^＋）＝５９９ Example 19: Methyl (2E) -3- {4-[(3-{[2- (cyclohexylsulfanyl) -4-oxo-3-phenyl-3,5,7,8-tetrahydropyrido [4,3 Preparation of -d] pyrimidin-6 (4H) -yl] carbonyl} azetidin-1-yl) methyl] phenyl} prop-2-enoate

Add (E) -methyl 3- (4-formylphenyl) acrylate (47 mg) and diisopropylethylamine (0.050 mL) to a solution of compound XVI (135 mg) in dichloromethane (2 mL), and add nitrogen at 25 ° C for 30 minutes. After stirring, NaBH (OAc) ₃ (53 mg) was added. The reaction mixture was stirred at 25 ° C. for 15 hours, saturated aqueous ammonium chloride solution was added, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (methanol / chloroform: 1/10) to give Example Compound 19 (34 mg).
MS (M + H ⁺ ) = 599

実施例化合物１９(20 mg) のメタノール (3 mL) 溶液に1 mol/L水酸化ナトリウム水溶液 (1 mL) を加えた。反応混合物を50℃で45分間撹拌した後、1 mol/L塩酸水溶液で中和し、減圧濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー(メタノール/クロロホルム: 1/10) で精製後、実施例化合物２０(12 mg) を得た。
¹H-NMR(400MHz, DMSO-d₆):δ(ppm)= 7.65-7.52 (m, 6H), 7.34-7.27 (m, 4H), 6.52-6.47 (m, 1H), 4.26-3.24 (m, 10H), 2.68-2.59 (m, 2H), 1.97-1.90 (m, 2H), 1.60-1.15 (m, 10H). Example 20: (2E) -3- {4-[(3-{[2- (cyclohexylsulfanyl) -4-oxo-3-phenyl-3,5,7,8-tetrahydropyrido [4,3- d] Preparation of pyrimidin-6 (4H) -yl] carbonyl} azetidin-1-yl) methyl] phenyl} prop-2-enoic acid

To a solution of Example Compound 19 (20 mg) in methanol (3 mL) was added 1 mol / L aqueous sodium hydroxide solution (1 mL). The reaction mixture was stirred at 50 ° C. for 45 min, neutralized with 1 mol / L aqueous hydrochloric acid solution, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (methanol / chloroform: 1/10) to give Example Compound 20 (12 mg).
¹ H-NMR (400 MHz, DMSO-d ₆ ): δ (ppm) = 7.65-7.52 (m, 6H), 7.34-7.27 (m, 4H), 6.52-6.47 (m, 1H), 4.26-3.24 (m , 10H), 2.68-2.59 (m, 2H), 1.97-1.90 (m, 2H), 1.60-1.15 (m, 10H).

Examples 21-75:
The compounds of Examples 21 to 75 were synthesized according to the method of Example 3, Example 17, Example 19 or Example 20.

The compounds of Examples 76 to 83 were synthesized according to the method of Example 17 or Example 19.

化合物VII（150 mg）にテトラヒドロフラン（8 mL）を加えて、氷水冷下で撹拌した。さらに、ジイソプロピルエチルアミン（312 mg）及びトリホスゲン（41 mg）を加えて、30分間撹拌した。この溶液に1-Boc-3-(アミノ)アゼチジン（103 mg）のテトラヒドロフラン（1 mL）溶液を加え、50℃で7時間加熱撹拌した。反応混合物に水を加えてクエンチし、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥後、減圧濃縮した。得られた残渣をアミノプロピルカラムクロマトグラフィー（ヘキサン/酢酸エチル＝1/1→酢酸エチル）で精製後、実施例化合物８４（90 mg）を得た。
¹H-NMR(400MHz, CD₃OD):δ(ppm)= 7.90 (s, 1H), 7.58-7.62 (m, 3H), 7.26-7.29 (m, 2H), 4.42-4.45 (m, 1H), 4.20 (s, 2H), 4.12-4.16 (m, 2H), 3.89-3.91 (m, 1H), 3.80-3.83 (m, 2H), 3.64-3.68 (m, 2H), 3.29-3.31 (m, 1H), 2.61-2.64 (m, 1H), 1.81-1.84 (m, 2H), 1.58-1.62 (m, 3H), 1.43 (s, 9H), 1.31-1.34 (m, 2H), 1.09-1.14 (m, 3H). Example 84: tert-butyl 3-({[2- (cyclohexylamino) -4-oxo-3-phenyl-3,5,7,8-tetrahydropyrido [4,3-d] pyrimidine-6 (4H ) -Yl] carbonyl} amino) azetidine-1-carboxylate

Tetrahydrofuran (8 mL) was added to Compound VII (150 mg), and the mixture was stirred under ice-water cooling. Furthermore, diisopropylethylamine (312 mg) and triphosgene (41 mg) were added and stirred for 30 minutes. To this solution was added 1-Boc-3- (amino) azetidine (103 mg) in tetrahydrofuran (1 mL), and the mixture was stirred with heating at 50 ° C. for 7 hr. The reaction mixture was quenched by adding water and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by aminopropyl column chromatography (hexane / ethyl acetate = 1/1 → ethyl acetate) to give Example Compound 84 (90 mg).
¹ H-NMR (400 MHz, CD ₃ OD): δ (ppm) = 7.90 (s, 1H), 7.58-7.62 (m, 3H), 7.26-7.29 (m, 2H), 4.42-4.45 (m, 1H) , 4.20 (s, 2H), 4.12-4.16 (m, 2H), 3.89-3.91 (m, 1H), 3.80-3.83 (m, 2H), 3.64-3.68 (m, 2H), 3.29-3.31 (m, 1H), 2.61-2.64 (m, 1H), 1.81-1.84 (m, 2H), 1.58-1.62 (m, 3H), 1.43 (s, 9H), 1.31-1.34 (m, 2H), 1.09-1.14 ( m, 3H).

実施例化合物８４（100 mg）にトルエン（3 mL）を加えて、氷水冷下で撹拌した。さらに、トリフルオロ酢酸（1 mL）を加えて、室温で3時間撹拌した。反応混合物を減圧濃縮した後、得られた残渣にジエチルエーテル（5 mL）を加えて析出した固体を濾過した。得られた固体にN,N-ジメチルホルムアミド（5 mL）及び炭酸カリウム（87 mg）を加えて室温にて撹拌した。4-フルオロベンジルブロミド（適量）のN,N-ジメチルホルムアミド（1 mL）溶液を滴下して、4時間撹拌した。反応混合物に水を加えてクエンチし、酢酸エチルで抽出した。有機層を水及び飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥後、減圧濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー（メタノール/クロロホルム＝1/20）で精製後、実施例化合物８５（37 mg）を得た。
¹H-NMR(400MHz, CD₃OD):δ(ppm)= 7.55-7.67 (m, 3H), 7.26-7.33 (m, 4H), 7.01-7.07 (m, 2H), 4.34-4.41 (m, 1H), 4.20 (s, 2H), 3.86-3.93 (m, 1H), 3.59-3.68 (m, 6H), 3.07-3.11 (m, 2H), 2.61-2.64 (m, 2H), 1.81-1.89 (m, 2H), 1.55-1.63 (m, 3H), 1.29-1.39 (m, 2H), 1.06-1.19 (m, 3H). Example 85: 2- (Cyclohexylamino) -N- [1- (4-fluorobenzyl) azetidin-3-yl] -4-oxo-3-phenyl-3,5,7,8-tetrahydropyrido [4 , 3-d] pyrimidine-6 (4H) -carboxamide

Toluene (3 mL) was added to Example Compound 84 (100 mg), and the mixture was stirred under ice-water cooling. Furthermore, trifluoroacetic acid (1 mL) was added, and the mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure, diethyl ether (5 mL) was added to the obtained residue, and the precipitated solid was filtered. N, N-dimethylformamide (5 mL) and potassium carbonate (87 mg) were added to the obtained solid, and the mixture was stirred at room temperature. A solution of 4-fluorobenzyl bromide (appropriate amount) in N, N-dimethylformamide (1 mL) was added dropwise and stirred for 4 hours. The reaction mixture was quenched by adding water and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (methanol / chloroform = 1/20) to give Example Compound 85 (37 mg).
¹ H-NMR (400 MHz, CD ₃ OD): δ (ppm) = 7.55-7.67 (m, 3H), 7.26-7.33 (m, 4H), 7.01-7.07 (m, 2H), 4.34-4.41 (m, 1H), 4.20 (s, 2H), 3.86-3.93 (m, 1H), 3.59-3.68 (m, 6H), 3.07-3.11 (m, 2H), 2.61-2.64 (m, 2H), 1.81-1.89 ( m, 2H), 1.55-1.63 (m, 3H), 1.29-1.39 (m, 2H), 1.06-1.19 (m, 3H).

化合物VII（５４ mg）のN,N−ジメチルホルムアミド（３ mL）溶液に1-ベンジルアゼチジン-２-カルボン酸（３４ mg）、ジイソプロピルエチルアミン（５８ mg）、1-ヒドロキシベンゾトリアゾール（34 mg）及び1-エチル-3-(3-ジメチルアミノプロピル)カルボジイミド塩酸塩（43 mg）を加えた。反応混合物を25℃で6時間撹拌した後、飽和炭酸水素ナトリウム水溶液を加え、酢酸エチルを用いて抽出した。有機層を飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥後、減圧濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー（メタノール/クロロホルム＝５/９５）で精製し、実施例化合物８６（51 mg）を得た。
¹H-NMR (400MHz, CD₃OD):δ(ppm)= 7.55-7.67 (m, 3H), 7.15-7.35 (m, 7H), 4.24-4.36 (m, 1H), 4.09-4.17 (m, 2H), 3.84-3.93 (m, 2H), 3.74-3.77 (m, 1H), 3.51-3.59 (m, 2H), 3.21-3.25 (m, 1H), 3.01-3.07 (m, 1H), 2.58-2.61 (m, 1H), 2.50-2.53 (m, 1H), 2.21-2.32 (m, 2H), 1.81-1.83 (m, 2H), 1.55-1.62 (m, 3H), 1.32-1.34 (m, 2H), 1.10-1.15 (m, 3H). Example 86: 6-[(1-Benzylazetidin-2-yl) carbonyl] -2- (cyclohexylamino) -3-phenyl-5,6,7,8-tetrahydropyrido [4,3-d] Production of pyrimidine-4 (3H) -one

To a solution of Compound VII (54 mg) in N, N-dimethylformamide (3 mL), 1-benzylazetidine-2-carboxylic acid (34 mg), diisopropylethylamine (58 mg), 1-hydroxybenzotriazole (34 mg) And 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (43 mg) was added. The reaction mixture was stirred at 25 ° C. for 6 hr, saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (methanol / chloroform = 5/95) to give Example Compound 86 (51 mg).
¹ H-NMR (400 MHz, CD ₃ OD): δ (ppm) = 7.55-7.67 (m, 3H), 7.15-7.35 (m, 7H), 4.24-4.36 (m, 1H), 4.09-4.17 (m, 2H), 3.84-3.93 (m, 2H), 3.74-3.77 (m, 1H), 3.51-3.59 (m, 2H), 3.21-3.25 (m, 1H), 3.01-3.07 (m, 1H), 2.58- 2.61 (m, 1H), 2.50-2.53 (m, 1H), 2.21-2.32 (m, 2H), 1.81-1.83 (m, 2H), 1.55-1.62 (m, 3H), 1.32-1.34 (m, 2H ), 1.10-1.15 (m, 3H).

工程(r4-i)：
化合物II（20 g）のピリジン溶液（150 mL）に、フェニルイソシアネート（16 mL）を加え、8時間加熱還流を行った。反応混合物を減圧濃縮後、ジエチルエーテルを加え、析出した固体を濾取した。ジエチルエーテル、及びクロロホルム/テトラヒドロフラン（1:1）溶液で洗浄後、化合物XVII（17 g）を得た。化合物XVIIをこれ以上精製することなく、次の反応に用いた。
¹H-NMR(300MHz, DMSO-d₆):δ(ppm)= 11.50-11.30 (br, 1H), 7.48-7.35 (m, 3H), 7.23-7.18 (m, 2H), 4.02 (s, 2H), 3.56 (t, J = 5.7, 2H), 2.46 (t, J = 5.5, 2H), 1.41 (s, 9H). Reference Example 4: tert-Butyl 2- (cyclohexylamino) -4-oxo-3-phenyl-3,5,7,8-tetrahydropyrido [4,3-d] pyrimidine-6 (4H) -carboxylate Manufacturing

Process (r4-i):
Phenyl isocyanate (16 mL) was added to a pyridine solution (150 mL) of compound II (20 g), and the mixture was heated to reflux for 8 hours. The reaction mixture was concentrated under reduced pressure, diethyl ether was added, and the precipitated solid was collected by filtration. After washing with diethyl ether and chloroform / tetrahydrofuran (1: 1) solution, compound XVII (17 g) was obtained. Compound XVII was used in the next reaction without further purification.
¹ H-NMR (300 MHz, DMSO-d ₆ ): δ (ppm) = 11.50-11.30 (br, 1H), 7.48-7.35 (m, 3H), 7.23-7.18 (m, 2H), 4.02 (s, 2H ), 3.56 (t, J = 5.7, 2H), 2.46 (t, J = 5.5, 2H), 1.41 (s, 9H).

Process (r4-ii):
1,8-diazabicyclo [5,4,0] -7-undecene (140 μL) was added to a solution of compound XVII (200 mg) in tetrahydrofuran (4 mL), and then 1H-benzotriazol-1-yloxy-trisdimethyl was added. Aminophosphonium hexafluorophosphate (387 mg) was added and stirred. After 4 hours, cyclohexylamine (100 μL) was added and stirred overnight. The reaction mixture was diluted with ethyl acetate, washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate = 1/1) to obtain Compound VI (210 mg).
¹ H-NMR (400 MHz, CDCl ₃ ): δ (ppm) = 7.43-7.52 (m, 3H), 7.16-7.22 (m, 2H), 4.22 (s, 2H), 3.81 (s, 2H), 3.55 ( t, J = 5.8, 2H), 2.54 (s, 2H), 1.97-1.98 (m, 2H), 1.47-1.56 (m, 3H), 1.41 (s, 9H), 1.25-1.33 (m, 2H), 0.92-1.06 (m, 3H). (According to NMR data of compound VI of Reference Example 1)

工程(r5-i)：
化合物XVIII（4.67 g）のトルエン（50 mL）溶液にモルホリン（2.0 mL）及びトシル酸一水和塩（0.19 g）を加え、14時間加熱還流を行い、化合物XIXを含む反応溶液を得た。放冷後、0℃でフェニルイソシアネート（2.9 mL）を加え、室温で21時間撹拌し、化合物XXを含む反応溶液を得た。反応溶液に2規定塩酸（9 mL）を加え、室温で22時間撹拌した後、酢酸エチルを加え不溶物をろ過した。ろ液を酢酸エチルで抽出した後、有機層を水、飽和食塩水で洗った。無水硫酸ナトリウムで乾燥後、減圧濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー（ヘキサン/酢酸エチル）で精製後、化合物XXI（5.28 g）を得た。
LC/MS : m/z = 353 (MH⁺) Reference Example 5: Preparation of 2- (4-methylbenzyl) -3-phenyl-5,6,7,8-tetrahydropyrido [4,3-d] pyrimidin-4 (3H) -one

Process (r5-i):
To a solution of compound XVIII (4.67 g) in toluene (50 mL) were added morpholine (2.0 mL) and tosylic acid monohydrate (0.19 g), and the mixture was heated to reflux for 14 hours to obtain a reaction solution containing compound XIX. After allowing to cool, phenyl isocyanate (2.9 mL) was added at 0 ° C., and the mixture was stirred at room temperature for 21 hours to obtain a reaction solution containing compound XX. 2N Hydrochloric acid (9 mL) was added to the reaction solution, and the mixture was stirred at room temperature for 22 hr. Ethyl acetate was added and the insoluble material was filtered off. The filtrate was extracted with ethyl acetate, and the organic layer was washed with water and saturated brine. The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give Compound XXI (5.28 g).
LC / MS: m / z = 353 (MH ⁺ )

Step (r5-ii):
To a solution of compound XXI (0.84 g) in methanol (8 mL) was added 8N ammonia / methanol solution (3 mL). The reaction mixture was stirred with heating under reflux for 4 hr, and concentrated under reduced pressure to give compound XXII (0.85 g).
¹ H-NMR (400 MHz, CDCl ₃ ): δ (ppm) = 7.46-7.29 (m, 10H), 7.10 (t, J = 7.4 Hz, 1H), 6.53 (brs, 2H), 5.18 (s, 2H) , 4.26 (s, 2H), 3.64 (t, J = 5.7, 2H), 2.34 (brs, 2H).

Step (r5-iii):
2- (p-toluyl) acetic acid (126 mg) and phosphorus oxychloride (98 μL) were added to a solution of compound XXII (423 mg) in pyridine (3.5 mL) at 0 ° C. The reaction mixture was stirred at 0 ° C. for 5 minutes and then at room temperature overnight. Water was added and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give Compound XXIII (205 mg).
¹ H-NMR (400 MHz, CDCl ₃ ): δ (ppm) = 7.46-7.44 (m, 2H), 7.31-7.27 (m, 7H), 7.16-7.09 (m, 5H), 6.50 (brs, 1H), 5.17 (s, 2H), 4.56-4.52 (m, 1H), 4.42 (dd, J = 18.3, 4.2 Hz, 1H), 3.87 (dt, J = 2.6, 18.3 Hz, 1H), 3.57 (s, 2H) , 3.31-3.28 (m, 1H), 3.07 (brs, 1H), 2.33 (s, 3H).
LC / MS: m / z = 484 (MH ⁺ )

Process (r5-iv):
Trimethylsilyl chloride (0.52 mL) and triethylamine (1.7 mL) were added to a solution of compound XXIII (133 mg) in dichloroethane (5 mL). After the reaction mixture was stirred at 90 ° C., water was added. The reaction solution was concentrated and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give Compound XXIV (57 mg).
¹ H-NMR (400 MHz, CDCl ₃ ): δ (ppm) = 7.52-7.31 (m, 8H), 6.96 (d, J = 7.9 Hz, 2H), 6.92-6.89 (m, 2H), 6.69 (d, J = 7.9 Hz, 2H), 5.18 (s, 2H), 4.45 (s, 2H), 3.81 (t, J = 5.8 Hz, 2H), 2.82 (brs, 2H), 2.29 (s, 3H).
LC / MS: m / z = 466 (MH ⁺ )

Process (r5-v):
To a solution of compound XXIV (69 mg) in ethanol (3 mL) were added ammonium formate (284 mg) and 10% Pd-C (64 mg), and the mixture was stirred for 6 hours under reflux with heating. After filtration using celite, the reaction solution was concentrated. Aqueous ammonia was added and extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give compound XXV (45 mg).
¹ H-NMR (400 MHz, CDCl ₃ ): δ (ppm) = 7.60-7.35 (m, 3H), 7.00-6.95 (m, 2H), 6.90 (d, J = 8.0 Hz, 2H), 6.69 (d, J = 8.0 Hz, 2H), 3.80 (t, J = 1.7 Hz, 2H), 3.74 (s, 2H), 3.18 (t, J = 5.8 Hz, 2H), 2.75 (tt, J = 5.8, 1.7 Hz, 2H), 2.29 (s, 3H).
LC / MS: m / z = 332 (MH ⁺ )

工程(r6-i)
化合物XXVI（1.46 g）のクロロホルム（6 mL）溶液にトリフルオロ酢酸（2.3 mL）を加えた。反応混合物を室温で3.5時間撹拌した後、減圧濃縮し化合物XXVII（335 mg）を得た。化合物XXVIIのテトラヒドロフラン（6 mL）溶液に、0℃でトリエチルアミン(4.2 mL)及びクロロギ酸ベンジル(0.45 mL)を加えた。反応混合物を室温で一晩撹拌し、減圧濃縮後、水を加えた。反応溶液を濃縮した後、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥後、減圧濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー（ヘキサン/酢酸エチル）で精製後、化合物XXVIII（486 mg）を得た。
¹H-NMR(400MHz, CDCl₃):δ(ppm)= 9.52 (brs, 1H), 7.52-7.18 (m, 10H), 5.17 (s, 2H), 4.31 (s, 2H), 3.69 (s, 2H), 2.37 (brs, 2H).
LC/MS : m/z = 332 (MH⁺) Reference Example 6: Preparation of 2- (cyclopentyloxy) -3-phenyl-5,6,7,8, -tetrahydropyrido [4,3-d] pyrimidin-4 (3H) -one

Process (r6-i)
Trifluoroacetic acid (2.3 mL) was added to a solution of compound XXVI (1.46 g) in chloroform (6 mL). The reaction mixture was stirred at room temperature for 3.5 hours and then concentrated under reduced pressure to obtain Compound XXVII (335 mg). Triethylamine (4.2 mL) and benzyl chloroformate (0.45 mL) were added to a solution of compound XXVII in tetrahydrofuran (6 mL) at 0 ° C. The reaction mixture was stirred at room temperature overnight, concentrated under reduced pressure, and water was added. The reaction solution was concentrated and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give Compound XXVIII (486 mg).
¹ H-NMR (400 MHz, CDCl ₃ ): δ (ppm) = 9.52 (brs, 1H), 7.52-7.18 (m, 10H), 5.17 (s, 2H), 4.31 (s, 2H), 3.69 (s, 2H), 2.37 (brs, 2H).
LC / MS: m / z = 332 (MH ⁺ )

Step (r6-ii):
To a solution of compound XXVIII (574 mg) in acetonitrile / N, N-dimethylformamide (3 mL / 1 mL) was added iodocyclopentane (0.23 mL) and potassium carbonate (420 mg), and the mixture was stirred at 110 ° C. for 7 hours. Water was added and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give Compound XXIX (109 mg).
¹ H-NMR (400 MHz, CDCl ₃ ): δ (ppm) = 7.52-7.31 (m, 8H), 7.14-7.11 (m, 2H), 5.43-5.41 (m, 1H), 5.18 (s, 2H), 4.41 (s, 2H), 3.77 (t, J = 5.8, 2H), 2.67 (brs, 2H), 1.81-1.76 (m, 2H), 1.66-1.42 (m, 6H).
LC / MS: m / z = 446 (MH ⁺ )

Step (r6-iii):
Compound XXIX (105 mg) was dissolved in ethanol (2.5 mL), and 10% Pd / C (50% water-containing product) (40 mg) was added. The reaction vessel was purged with hydrogen and stirred at room temperature and normal pressure for 8 hours. After filtering off Pd / C, the filtrate was concentrated under reduced pressure to obtain Compound XXXI (70 mg). Compound XXX was used in the next reaction without purification.
LC / MS: m / z = 312 (MH ⁺ )

工程(r7-i)：
化合物XXXI（3.30 g）のアセトニトリル（30 mL）懸濁液に3-カルボキシアゼチジン（1.65 g）、酢酸（1.40 mL）、およびトリアセトキシ水素化ホウ素ナトリウム（5.18 g）を加え、室温で1時間攪拌した。反応混合物に水を加えて減圧下濃縮し、アセトニトリルを留去した。水層をヘキサン/酢酸エチル（1:1）で洗浄した。水層に酢酸を加え、クロロホルム/エタノール（3:1）溶液で抽出した。合わせ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、減圧下濃縮することにより化合物XXXII（4.31 g）を白色固体として得た。
¹H-NMR(300MHz, DMSO-d₆):δ(ppm)= 7.66 (d, J = 8.6, 2H), 7.62 (d, J = 16.7, 1H), 7.32 (d, J = 8.1, 2H), 6.59 (d, J = 16.0, 1H), 4.17 (q, J = 7.1, 2H), 3.60-3.10 (m, 7H), 1.90 (s, 3H), 1.24 (t, J = 7.1, 3H). Reference Example 7: Preparation of 1- [4- (3-ethoxy-3-oxopropyl) benzyl] azetidine-3-carboxylic acid trifluoroacetate

Process (r7-i):
To a suspension of compound XXXI (3.30 g) in acetonitrile (30 mL) was added 3-carboxyazetidine (1.65 g), acetic acid (1.40 mL), and sodium triacetoxyborohydride (5.18 g), and at room temperature for 1 hour. Stir. Water was added to the reaction mixture and the mixture was concentrated under reduced pressure, and acetonitrile was distilled off. The aqueous layer was washed with hexane / ethyl acetate (1: 1). Acetic acid was added to the aqueous layer, and the mixture was extracted with a chloroform / ethanol (3: 1) solution. The combined organic layers were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give compound XXXII (4.31 g) as a white solid.
¹ H-NMR (300 MHz, DMSO-d ₆ ): δ (ppm) = 7.66 (d, J = 8.6, 2H), 7.62 (d, J = 16.7, 1H), 7.32 (d, J = 8.1, 2H) , 6.59 (d, J = 16.0, 1H), 4.17 (q, J = 7.1, 2H), 3.60-3.10 (m, 7H), 1.90 (s, 3H), 1.24 (t, J = 7.1, 3H).

Step (r7-ii):
To a solution of compound XXXII (3.29 g) in tetrahydrofuran / ethanol / acetic acid (1: 1: 1) (50 mL) is added 5% Pt / C (50% water-containing product) (658 mg), and hydrogen atmosphere at room temperature for 2 hours. Stir. The reaction mixture was filtered through celite, and the filtrate was concentrated under reduced pressure. The residue was dissolved in ethanol (33 mL), trifluoroacetic acid (837 μL) was added, and the mixture was concentrated under reduced pressure. Water was added, the aqueous layer was washed with a hexane / ethyl acetate (1: 1) solution, and the target product was extracted from the aqueous layer with chloroform / ethanol (3: 1). The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was dissolved in a hexane / ethyl acetate (1: 2) solution, the target product was precipitated, and hexane was further added and stirred for 30 minutes. The precipitated solid was collected by filtration and dried to obtain Compound XXXIII (2.49 g) as a white solid.
¹ H-NMR (300 MHz, DMSO-d ₆ ): δ (ppm) = 7.34 (d, J = 8.1, 2H), 7.27 (d, J = 8.3, 2H), 4.24 (s, 2H), 4.13-3.97 (m, 4H), 4.02 (q, J = 7.2, 2H), 3.61-3.47 (m, 1H), 2.85 (t, J = 7.5, 2H), 2.60 (t, J = 7.5, 2H), 1.13 ( t, J = 7.2, 3H).

化合物XXX（34 mg）のN,N−ジメチルホルムアミド（1 mL）溶液に化合物XXXIII（49 mg）、トリエチルアミン（0.02 mL）、１−ヒドロキシベンゾトリアゾール（16 mg）及び１−エチル−３−（３−ジメチルアミノプロピル）カルボジイミド塩酸塩（25 mg）を加えて室温で終夜撹拌した。その後、反応液に飽和炭酸水素ナトリウム溶液を加え、酢酸エチルを用いて抽出した。有機層を飽和食塩水で洗浄した後、無水硫酸マグネシウムで乾燥した。ろ過、減圧濃縮して得られた残渣をシリカカラムクロマトグラフィー（クロロホルム/メタノール）、次いで、逆相分取ＨＰＬＣ（水/アセトニトリル）にて精製し、実施例化合物８７（13 mg）を得た。
¹H-NMR(400MHz, CDCl₃):δ(ppm)= 7.45-7.40 (m, 3H), 7.22-7.08 (m, 6H), 5.42-5.35 (m, 1H), 4.45 (s, 0.6H), 4.14 (s, 1.4H), 4.11-4.08 (m, 2H), 3.84 (t, J = 5.92 Hz, 2H), 3.64-3.52 (m, 5H), 3.43 (t, J = 7.10 Hz, 1H), 3.34 (t, J = 7.12 Hz, 1H), 2.90 (m, 2H), 2.64-2.55 (m, 4H), 1.77-1.74 (m, 2H), 1.60-1.57 (m, 2H), 1.48-1.41 (m, 4H), 1.22-1.18 (m, 3H).
LC/MS : m/z = 585 (MH⁺)
なお、参考例７及び本実施例と同様の方法によって、例えば前記実施例６５の化合物は、前記実施例１７の化合物IXから合成することができる。 Example 87: Ethyl 3- {4-[(3-{[2- (cyclopentyloxy) -4-oxo-3-phenyl-3,5,7,8-tetrahydropyrido [4,3-d] pyrimidine Preparation of -6 (4H) -yl] carbonyl} azetidin-1-yl) methyl] phenyl} propanoate

Compound XXXIII (49 mg), triethylamine (0.02 mL), 1-hydroxybenzotriazole (16 mg) and 1-ethyl-3- (3) were added to a solution of compound XXX (34 mg) in N, N-dimethylformamide (1 mL). -Dimethylaminopropyl) carbodiimide hydrochloride (25 mg) was added and stirred at room temperature overnight. Thereafter, a saturated sodium bicarbonate solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate. The residue obtained by filtration and concentration under reduced pressure was purified by silica column chromatography (chloroform / methanol) and then reverse-phase preparative HPLC (water / acetonitrile) to give Example Compound 87 (13 mg).
¹ H-NMR (400 MHz, CDCl ₃ ): δ (ppm) = 7.45-7.40 (m, 3H), 7.22-7.08 (m, 6H), 5.42-5.35 (m, 1H), 4.45 (s, 0.6H) , 4.14 (s, 1.4H), 4.11-4.08 (m, 2H), 3.84 (t, J = 5.92 Hz, 2H), 3.64-3.52 (m, 5H), 3.43 (t, J = 7.10 Hz, 1H) , 3.34 (t, J = 7.12 Hz, 1H), 2.90 (m, 2H), 2.64-2.55 (m, 4H), 1.77-1.74 (m, 2H), 1.60-1.57 (m, 2H), 1.48-1.41 (m, 4H), 1.22-1.18 (m, 3H).
LC / MS: m / z = 585 (MH ⁺ )
For example, the compound of Example 65 can be synthesized from Compound IX of Example 17 by the same method as in Reference Example 7 and this Example.

化合物XXXIV(298 mg)のクロロホルム溶液 (4 mL)に炭酸カルシウム (519 mg)の水溶液 (4 mL)を加え、氷浴に浸した。チオホスゲン (0.16 mL)を滴下した後、室温へ昇温し、4時間激しく攪拌した。反応液に水を加え、クロロホルムで2回抽出した。有機層を合わせて無水硫酸ナトリウムで乾燥後、減圧濃縮し、化合物XXXV (219 mg)を得た。化合物XXXVは精製せずに次の反応に使用した。
¹H-NMR(400MHz, CDCl₃):δ(ppm)= 4.18-4.08 (m, 1H), 3.13-2.99 (m, 2H), 2.91-2.76 (m, 2H). Reference Example 8: Production of 1,1-difluoro-3-isothiocyanate cyclobutane

An aqueous solution (4 mL) of calcium carbonate (519 mg) was added to a chloroform solution (4 mL) of compound XXXIV (298 mg) and immersed in an ice bath. After thiophosgene (0.16 mL) was added dropwise, the mixture was warmed to room temperature and stirred vigorously for 4 hours. Water was added to the reaction mixture, and the mixture was extracted twice with chloroform. The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give compound XXXV (219 mg). Compound XXXV was used in the next reaction without purification.
¹ H-NMR (400 MHz, CDCl ₃ ): δ (ppm) = 4.18-4.08 (m, 1H), 3.13-2.99 (m, 2H), 2.91-2.76 (m, 2H).

Examples 88-200:
Examples 88 to 96 were synthesized by the method according to Example 87 using the compound synthesized according to Reference Example 1 or Reference Example 4 and the compound synthesized according to Reference Example 7. Examples 97 to 124 were synthesized according to Example 17 or Example 19. Examples 125 to 153 were synthesized by a method according to Example 87 using a compound synthesized according to Reference Example 7 and a compound synthesized according to the production method of Compound IX of Example 17. Examples 154 to 160 were synthesized by a method according to Example 87 using a compound synthesized according to the production method of Compound XXV of Reference Example 5 and a compound synthesized according to Reference Example 7. Example 161 was synthesized by the method according to Example 87 using the compound synthesized according to Reference Example 7 and compound XXX. Examples 162 to 200 were synthesized by a method according to Example 20 using the corresponding ester compounds described in this Example.
In the production of each of the above Example compounds, the corresponding isothiocyanate was used in place of phenylisothiocyanate in Step (ii) of Reference Example 1 as necessary. About the said isothiocyanate, the commercial item which can be obtained was used, or what was prepared according to the method of the reference example 8, or this was used.

実施例化合物１２１（23 mg）のTHF（0.5 mL）溶液に氷冷下で3N水酸化リチウム水溶液（0.2 mL）を加えた。反応液を室温で3時間撹拌した後、減圧濃縮でTHFを留去した。クロロホルムで抽出し、有機層を飽和食塩水で洗浄した。無水硫酸マグネシウムで乾燥後、ろ過、減圧濃縮して実施例２０１（19 mg）を得た。
¹H-NMR (400MHz, CDCl₃):δ(ppm)= 7.53-7.50 (m, 3H), 7.23-7.20 (m, 2H), 4.51 (s, 0.6H), 4.21 (s, 1.4H), 3.88 (t, J = 5.88 Hz, 2H), 3.74-3.39 (m, 9H), 2.72-2.61 (m, 4H), 2.17 (s, 1H), 2.01-1.99 (br, 2H), 1.71-1.58 (m, 3H), 1.43-1.34 (m, 4H). Example 201: 2- (cyclohexylsulfanyl) -6-{[1- (2-hydroxyethyl) azetidin-3-yl] carbonyl} -3-phenyl-5,6,7,8-tetrahydropyrido [4 Preparation of 3-d] pyrimidin-4 (3H) -one

To a solution of Example Compound 121 (23 mg) in THF (0.5 mL) was added 3N lithium hydroxide aqueous solution (0.2 mL) under ice cooling. After the reaction solution was stirred at room temperature for 3 hours, THF was distilled off by concentration under reduced pressure. Extraction was performed with chloroform, and the organic layer was washed with saturated brine. After drying over anhydrous magnesium sulfate, filtration and concentration under reduced pressure gave Example 201 (19 mg).
¹ H-NMR (400MHz, CDCl ₃ ): δ (ppm) = 7.53-7.50 (m, 3H), 7.23-7.20 (m, 2H), 4.51 (s, 0.6H), 4.21 (s, 1.4H), 3.88 (t, J = 5.88 Hz, 2H), 3.74-3.39 (m, 9H), 2.72-2.61 (m, 4H), 2.17 (s, 1H), 2.01-1.99 (br, 2H), 1.71-1.58 ( m, 3H), 1.43-1.34 (m, 4H).

実施例化合物１２２を用いて実施例２０１に準じて実施例２０２（68 mg）を得た。
¹H-NMR (400MHz, CDCl₃):δ(ppm)= 7.54-7.51 (m, 3H), 7.23-7.20 (m, 2H), 4.51 (s, 0.7H), 4.20 (s, 1.3H), 3.87 (t, J = 5.88 Hz, 1H), 3.79-3.64 (m, 4H), 3.61-3.53 (m, 4H), 3.35-3.29 (m, 2H), 2.73-2.71 (m, 2H), 2.54-2.48 (m, 2H), 2.01-1.99 (m, 2H), 1.69-1.35 (m, 11H). Example 202: 2- (cyclohexylsulfanyl) -6-{[1- (4-hydroxybutyl) azetidin-3-yl] carbonyl} -3-phenyl-5,6,7,8-tetrahydropyrido [4 Preparation of 3-d] pyrimidin-4 (3H) -one

Example 202 (68 mg) was obtained according to Example 201 using Example Compound 122.
¹ H-NMR (400MHz, CDCl ₃ ): δ (ppm) = 7.54-7.51 (m, 3H), 7.23-7.20 (m, 2H), 4.51 (s, 0.7H), 4.20 (s, 1.3H), 3.87 (t, J = 5.88 Hz, 1H), 3.79-3.64 (m, 4H), 3.61-3.53 (m, 4H), 3.35-3.29 (m, 2H), 2.73-2.71 (m, 2H), 2.54- 2.48 (m, 2H), 2.01-1.99 (m, 2H), 1.69-1.35 (m, 11H).

実施例化合物６４（50 mg）のN,N−ジメチルホルムアミド（2 mL）溶液に2-メトキシエタノール（65 mg）、1-ヒドロキシベンゾトリアゾール（17 mg）及び1-エチル-3-(3-ジメチルアミノプロピル)カルボジイミド塩酸塩（25 mg）を加えた。反応混合物を室温で20時間撹拌した後、飽和炭酸水素ナトリウム水溶液を加え、酢酸エチルを用いて抽出した。有機層を飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥後、減圧濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー（メタノール/クロロホルム＝５/９５）で精製し、実施例化合物２０３（32 mg）を得た。
¹H-NMR (300MHz, CDCl₃):δ(ppm)= 7.58-7.45 (m, 3H), 7.25-7.08 (m, 6H), 4.51 (s, 0.6H), 4.28-4.16 (m, 3.4H), 3.92-3.83 (m, 1H), 3.82-3.65 (m, 1H), 3.65-3.48 (m, 8H), 3.43-3.28 (m, 5H), 3.00-2.87 (m, 2H), 2.75-2.60 (m, 4H), 2.05-1.92 (m, 2H), 1.80-1.50 (m, 3H), 1.50-1.12 (m, 5H). Example 203: 2-methoxyethyl 3- {4-[(3-{[2- (cyclohexylsulfanyl) -4-oxo-3-phenyl-3,5,7,8-tetrahydropyrido [4,3- d] Preparation of Pyrimidin-6 (4H) -yl] carbonyl} azetidin-1-yl) methyl] phenyl} propanoate

To a solution of Example Compound 64 (50 mg) in N, N-dimethylformamide (2 mL) was added 2-methoxyethanol (65 mg), 1-hydroxybenzotriazole (17 mg) and 1-ethyl-3- (3-dimethyl). Aminopropyl) carbodiimide hydrochloride (25 mg) was added. The reaction mixture was stirred at room temperature for 20 hours, saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (methanol / chloroform = 5/95) to give Example Compound 203 (32 mg).
¹ H-NMR (300MHz, CDCl ₃ ): δ (ppm) = 7.58-7.45 (m, 3H), 7.25-7.08 (m, 6H), 4.51 (s, 0.6H), 4.28-4.16 (m, 3.4H ), 3.92-3.83 (m, 1H), 3.82-3.65 (m, 1H), 3.65-3.48 (m, 8H), 3.43-3.28 (m, 5H), 3.00-2.87 (m, 2H), 2.75-2.60 (m, 4H), 2.05-1.92 (m, 2H), 1.80-1.50 (m, 3H), 1.50-1.12 (m, 5H).

Examples 204-206:
According to the method of Example 203, the compounds of Examples 204 to 206 were synthesized from the corresponding carboxylic acid described in this Example and ethylene glycol, dimethylamine or ammonia.

Reference Example 9: Production of methyl (3-aminophenyl) acetate

Process (r9-i):
To a solution of compound XXXVI (1.00 g) in DMF (5.00 g) were added potassium carbonate (921 mg) and methyl iodide, and the mixture was 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 saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain Compound XXXVII (1.00 g) in a yield of 93%.
¹ H-NMR (300 MHz, CDCl ₃ ): δ (ppm) = 8.15 (s, 1H), 8.13 (d, J = 7.5 Hz, 1H), 7.61 (d, J = 7.5 Hz, 1H), 7.50 (t , J = 7.5Hz, 1H), 3.73 (s, 2H), 3.71 (s, 3H).

Step (r9-ii):
10% Pd / C (200 mg) was added to a solution of compound XXXVII (1.00 g) in methanol (5.00 g), and the mixture was stirred at room temperature for 4.5 hours under a hydrogen atmosphere. The reaction mixture was filtered through celite and concentrated under reduced pressure to give Compound XXXVIII (832 mg) in 98% yield. Used in the next step without purification.
¹ H-NMR (300 MHz, CDCl ₃ ): δ (ppm) = 7.09 (t, J = 7.5 Hz, 1H), 6.53-6.50 (m, 3H), 3.67 (s, 3H), 3.52 (s, 2H) .

参考例９で得られた化合物XXXVIIIを用いて参考例１、参考例２、次いで実施例１７に準じた方法により、実施例２０７の化合物を得た。
¹H-NMR (300MHz, CDCl₃):δ(ppm)= 7.51-7.35 (m, 2H), 7.35-7.20 (m, 5H), 7.20-7.05 (m, 2H), 4.48 (s, 0.9H), 4.17 (s, 1.1H), 3.83 (t, J = 5.7Hz, 2H), 3.80-3.15 (m, 13H), 2.68 (t, J = 5.7Hz, 2H), 2.05-1.95 (m, 2H), 1.75-1.48 (m, 2H), 1.48-1.12 (m, 6H). Example 207: Methyl (3- {6 [(1-benzylazetidin-3-yl) carbonyl] -2- (cyclohexylsulfanyl) -4-oxo-5,6,7,8-tetrahydropyrido [4 3-d] Preparation of pyrimidine-3 (4H) -yl} phenyl) acetate

The compound of Example 207 was obtained by the method according to Reference Example 1, Reference Example 2, and then Example 17 using Compound XXXVIII obtained in Reference Example 9.
¹ H-NMR (300MHz, CDCl ₃ ): δ (ppm) = 7.51-7.35 (m, 2H), 7.35-7.20 (m, 5H), 7.20-7.05 (m, 2H), 4.48 (s, 0.9H) , 4.17 (s, 1.1H), 3.83 (t, J = 5.7Hz, 2H), 3.80-3.15 (m, 13H), 2.68 (t, J = 5.7Hz, 2H), 2.05-1.95 (m, 2H) , 1.75-1.48 (m, 2H), 1.48-1.12 (m, 6H).

4-ブロモベンズアルデヒド (XXXIX, 4.00 g)のDMF (21.6 mL)溶液に3,3-ジエトキシプロパ-1-エン (8.44 g)、トリエチルアミン (6.03 mL)、テトラブチルアンモニウムクロリド (6.01 g)及び酢酸パラジウム（II）(146 mg)を加え、90℃で12時間加熱攪拌した。反応液を室温まで冷却し、水 (86.4 mL)を加え、酢酸エチルで抽出した。得られた有機層を順次、0.2規定塩酸、飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥後、減圧濃縮した。得られた残渣をシリカゲルクロマトグラフィー (ヘキサン/酢酸エチル = 3/1)で精製し、掲題化合物(XXXX, 3.13 g)を得た。
¹H-NMR (300MHz, CDCl₃) :δ(ppm)= 9.98 (s, 1H), 7.81 (d, J = 8.2 Hz, 2H), 7.37 (d, J = 8.2 Hz, 2H), 4.12 (q, J = 7.1 Hz, 2H), 3.03 (t, J = 7.7 Hz, 2H), 2.66 (t, J = 7.7 Hz, 2H), 1.23 (t, J = 7.1 Hz, 3H).
LC/MS : m/z = 207 (MH⁺)
なお、化合物XXXXは、例えば前記実施例６５,１４９，１５２等の化合物の合成に用いることができる。 Reference Example 10: Preparation of ethyl 3- (4-formylphenyl) propanoate

To a solution of 4-bromobenzaldehyde (XXXIX, 4.00 g) in DMF (21.6 mL), 3,3-diethoxyprop-1-ene (8.44 g), triethylamine (6.03 mL), tetrabutylammonium chloride (6.01 g) and acetic acid Palladium (II) (146 mg) was added, and the mixture was heated with stirring at 90 ° C. for 12 hours. The reaction mixture was cooled to room temperature, water (86.4 mL) was added, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed successively with 0.2N hydrochloric acid and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography (hexane / ethyl acetate = 3/1) to give the title compound (XXXX, 3.13 g).
¹ H-NMR (300MHz, CDCl ₃ ): δ (ppm) = 9.98 (s, 1H), 7.81 (d, J = 8.2 Hz, 2H), 7.37 (d, J = 8.2 Hz, 2H), 4.12 (q , J = 7.1 Hz, 2H), 3.03 (t, J = 7.7 Hz, 2H), 2.66 (t, J = 7.7 Hz, 2H), 1.23 (t, J = 7.1 Hz, 3H).
LC / MS: m / z = 207 (MH ⁺ )
Compound XXXX can be used, for example, for the synthesis of the compounds of Examples 65, 149, 152 and the like.

工程(ex208-i)
化合物IX (75 mg)をN,N-ジメチルホルムアミド (2 ｍL)に溶解し、氷水冷下でトリエチルアミン (0.07 mL)を滴下した。次に、3−クロロスルフォニル−アゼチジン−１−カルボン酸tert-ブチルエステル (77 mg)を加えた後、室温で終夜撹拌した。反応液に飽和炭酸水素ナトリウム溶液を加え、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥後、減圧濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー（ヘキサン/酢酸エチル）で精製して、化合物XXXXI (122 mg)を得た。
¹H-NMR (400MHz, CDCl₃):δ(ppm)= 7.53-7.49 (m, 3H), 7.21-7.20 (m, 2H), 4.25-4.22 (m, 4H), 4.17-4.08 (m, 2H), 4.03-3.97 (m, 1H), 3.74-3.71 (m, 1H), 3.66-3.64 (m, 2H), 2.80-2.77 (m, 2H), 2.03 (s, 1H), 1.99-1.97 (m, 2H), 1.70-1.67 (m, 2H), 1.43 (s, 9H), 1.40-1.33 (m, 3H), 1.24 (t, J = 7.20 Hz, 2H).
LC/MS : m/z = 561 (MH⁺) Example 208: Ethyl 3- {4-[(3-{[2- (cyclohexylsulfanyl) -4-oxo-3-phenyl-3,5,7,8-tetrahydropyrido [4,3-d] pyrimidine Preparation of -6 (4H) -yl] sulfonyl} azetidin-1-yl) methyl] phenyl} propanoate

Process (ex208-i)
Compound IX (75 mg) was dissolved in N, N-dimethylformamide (2 mL), and triethylamine (0.07 mL) was added dropwise under ice-water cooling. Next, 3-chlorosulfonyl-azetidine-1-carboxylic acid tert-butyl ester (77 mg) was added, and the mixture was stirred overnight at room temperature. Saturated sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give Compound XXXXI (122 mg).
¹ H-NMR (400MHz, CDCl ₃ ): δ (ppm) = 7.53-7.49 (m, 3H), 7.21-7.20 (m, 2H), 4.25-4.22 (m, 4H), 4.17-4.08 (m, 2H ), 4.03-3.97 (m, 1H), 3.74-3.71 (m, 1H), 3.66-3.64 (m, 2H), 2.80-2.77 (m, 2H), 2.03 (s, 1H), 1.99-1.97 (m , 2H), 1.70-1.67 (m, 2H), 1.43 (s, 9H), 1.40-1.33 (m, 3H), 1.24 (t, J = 7.20 Hz, 2H).
LC / MS: m / z = 561 (MH ⁺ )

In step (ex208-ii), compound XXXXII was obtained according to the method of Reference Example 3. Next, in Step (ex208-iii), Example Compound 208 (51 mg) was synthesized according to the method of Example 19 using Compound XXXXII and Compound XXXX obtained in Reference Example 10.
¹ H-NMR (400MHz, DMSO-d ₆ ): δ (ppm) = 7.54-7.51 (m, 3H), 7.31-7.29 (m, 2H), 7.16 (S, 4H), 4.34 (m, 1H), 4.05-4.00 (m, 4H), 3.70 (br, 1H), 3.55-3.48 (m, 6H), 3.38-3.28 (m, 2H), 2.81 (t, J = 7.44 Hz, 1H), 2.72-2.69 ( m, 2H), 2.58 (t, J = 7.72 Hz), 1.61-1.60 (m, 1H), 1.54-1.51 (m, 1H), 1.33 (m, 4H), 1.23-1.17 (m, 1H), 1.13 (t, J = 7.08 Hz, 3H).

実施例化合物１３５（200 mg）の酢酸エチル溶液（8 mL）を40℃に加温し、フマル酸（39 mg）を加える。40℃を保持したまま、1時間撹拌した後、4時間かけて室温まで放冷、次に、氷浴で0℃まで冷却して1時間撹拌した。その後、晶析物を濾取し、終夜、室温で減圧乾燥して実施例化合物２０９（195 mg）を得た。
¹H-NMR (400MHz, DMSO-d₆):δ(ppm)= 7.29-7.21 (m, 4H), 6.64 (s, 2H), 4.28 (s, 1.2H), 4.28-4.19 (m, 1H), 4.10 (s, 0.8H), 4.17-3.90 (m, 2H), 3.90-3.77 (m, 2H), 3.77-3.71 (m, 1H), 3.71-3.58 (m, 9H), 3.58-3.43 (m, 3H), 3.34-3.25 (m, 2H), 2.67-2.52 (m, 2H), 2.11-2.01 (m, 2H), 2.01-1.89 (m, 2H), 1.89- 1.78 (m, 1H), 1.78-1.63 (m, 3H), 1.63-1.26 (m, 6H).
m.p.: 119 ℃
XRD: 2θ= 5.3，6.2，6.9，8.5，9.5，10.5，13.1，13.8，14.5，15.0，15.8，16.9，18.2，19.0，20.2，22.0，23.0，27.4，32.3，37.3
なお、X線回折（XRD）測定には、X-ray Diffraction system X'pert MPD (PANAlytical )を用い、anode materialをCopper、K-Alpha1を1.54オングストローム、Tensionを45 kV、Currentを40 mA、Start Angle (2θ)を4°、End Angle (2θ)を40°、step size (2θ)を0.017°及びTime per stepを100sの条件で測定した。具体的には、測定試料板には無反射Si板を用い、無反射Si板に測定試料を約5 mgを塗布し、上記測定条件にて測定を実施した。以下のX線回折測定も、同様に行った。 Example 209: methyl {4-[(3-{[2- (cyclohexylsulfanyl) -4-oxo-3-[(2R) -tetrahydrofuran-2-ylmethyl] -3,5,7,8-tetrahydropyrido Preparation of [4,3-d] pyrimidin-6 (4H) -yl] carbonyl} azetidin-1-yl) methyl] phenyl} acetate (2E) -but-2-enedioate

A solution of Example Compound 135 (200 mg) in ethyl acetate (8 mL) is heated to 40 ° C., and fumaric acid (39 mg) is added. The mixture was stirred for 1 hour while maintaining 40 ° C., then allowed to cool to room temperature over 4 hours, then cooled to 0 ° C. in an ice bath and stirred for 1 hour. Thereafter, the crystallized product was collected by filtration and dried overnight at room temperature under reduced pressure to obtain Example Compound 209 (195 mg).
¹ H-NMR (400MHz, DMSO-d ₆ ): δ (ppm) = 7.29-7.21 (m, 4H), 6.64 (s, 2H), 4.28 (s, 1.2H), 4.28-4.19 (m, 1H) , 4.10 (s, 0.8H), 4.17-3.90 (m, 2H), 3.90-3.77 (m, 2H), 3.77-3.71 (m, 1H), 3.71-3.58 (m, 9H), 3.58-3.43 (m , 3H), 3.34-3.25 (m, 2H), 2.67-2.52 (m, 2H), 2.11-2.01 (m, 2H), 2.01-1.89 (m, 2H), 1.89- 1.78 (m, 1H), 1.78 -1.63 (m, 3H), 1.63-1.26 (m, 6H).
mp: 119 ° C
XRD: 2θ = 5.3, 6.2, 6.9, 8.5, 9.5, 10.5, 13.1, 13.8, 14.5, 15.0, 15.8, 16.9, 18.2, 19.0, 20.2, 22.0, 23.0, 27.4, 32.3, 37.3
X-ray diffraction (XRD) measurement uses X-ray Diffraction system X'pert MPD (PANAlytical), anode material is Copper, K-Alpha1 is 1.54 angstrom, Tension is 45 kV, Current is 40 mA, Start Angle (2θ) was measured at 4 °, End Angle (2θ) at 40 °, step size (2θ) at 0.017 °, and Time per step at 100 s. Specifically, a non-reflective Si plate was used as the measurement sample plate, about 5 mg of the measurement sample was applied to the non-reflective Si plate, and the measurement was performed under the above measurement conditions. The following X-ray diffraction measurement was performed in the same manner.

Examples 210-213:
Using the corresponding Example compounds (Examples 65, 142, 59 and 118), the compounds of Examples 210 to 213 were synthesized according to the method of Example 209.

Examples 214-216:
Example 214 was conducted in accordance with Reference Example 4 except that a compound synthesized using 3-butoxyphenol instead of cyclohexylamine in Step (r4-ii) was used. Steps (xi) to (xii) in Example 17 This was synthesized according to Reference Example 3 and then Example 19. Examples 215 and 216 were synthesized by the method according to Example 20 using the corresponding ester compounds of Example 95 and Example 214, respectively.

Pharmacological Test The pharmacological action of representative compounds of the present invention was examined.

Test example 1:
(1) Preparation of human MGAT2 recombinant protein The human MGAT2 gene described in the literature (American Journal of Physiology, 285, E927-E937, 2003) was introduced into a cell line according to a conventional method to prepare a human MGAT2 recombinant protein.

(2) Human MGAT activity measurement (Measurement method-1)
(Condition A) A DMSO solution containing a test compound having a predetermined concentration of 2 μL was added to a 2.0 mL Eppendorf tube. 22 mM Tris solution containing 0.88 mg / mL BSA, 2.3 mM MgCl ₂ , 60 μM ¹⁴ C-palmitoyl-CoA (GE Healthcare) and 1.59 mg / mL (diluted according to specific activity) human MGAT2 recombinant protein in the tube ( 198 μL of pH 7.4) was added and incubated at 37 ° C. for 5 minutes. After 5 minutes, 2 μL of 25 μM (as a final concentration) monoolein was added to the tube, and the mixture was further incubated at 37 ° C. for 5 minutes. Ten minutes later, 0.167 mL of isopropanol was added to the tube, and 1.35 mL of Microcinci-E (MicroScint ^™ -E, PerkinElmer) was added and shaken again, and then the radioactivity was quantified.
(Condition B) A DMSO solution containing a test compound having a predetermined concentration of 2 μL was added to a 2.0 mL Eppendorf tube. 196 μL of 28 mM Tris solution (pH 7.4) containing 1.1 mg / mL BSA, 3.1 mM MgCl ₂ , 24 μM ¹⁴ C-palmitoyl-CoA (GE Healthcare) and 12.8 μg / mL human MGAT2 recombinant protein was added to the tube. And kept at 37 ° C. for 5 minutes. After 5 minutes, 2 μL of 2.5 mM monoolein was added to the tube to a final concentration of 25 μM, and further incubated at 37 ° C. for 5 minutes. Ten minutes later, 0.167 mL of isopropanol was added to the tube, and 1.35 mL of Microcinci-E (MicroScint ^™ -E, PerkinElmer) was added and shaken again, and then the radioactivity was quantified.
Radioactivity determined by (Condition A) or (Condition B) was defined as MGAT activity.

When the MGAT activity when the DMSO solution was added was A and the MGAT activity when the test compound was added was B, the MGAT activity inhibition rate (%) of the test compound was expressed as {1- (B / A )} × 100 (%). Calculate the inhibition rate at multiple concentrations, add concentration X, inhibition rate Y, approximate formula: Y = 100 / (1 + exp {-s * [log (X) -log (a)]}) to 50% Inhibitory concentration a was determined (where s represents the slope of the inflection point). Listed in Table 8 50% inhibitory concentration a determined manner as IC _50.

(3) Human MGAT activity measurement (Measurement method-2)
A DMSO solution containing 2 μL of a predetermined concentration of the test compound was added to a 2.0 mL Eppendorf tube. Add 196 μL of 28 mM Tris solution (pH 7.4) containing 1.1 mg / mL BSA, 3.1 mM MgCl ₂ , 26 μM ¹⁴ C-palmitoyl-CoA (Perkin Elmer), 12.8 μg / mL human MGAT2 recombinant protein And kept at 37 ° C. for 5 minutes. After 5 minutes, 2 μL of 2.5 mM monoolein was added to the tube, and further incubated at 37 ° C. for 5 minutes. The reaction was stopped by adding 0.2 mL of isopropanol / heptane (4: 1) to the tube, and then 0.4 mL of heptane was further added and mixed well. After centrifugation, the upper layer was collected, and 150 μL of ethanol / 0.1N NaOH / H ₂ O (50: 5: 45) was added and mixed. After centrifugation, the upper layer was collected, shaken after adding 500 μL of Ecoscint ^™ O (Ecoscint ^™ O, National Diagnostics), and then the radioactivity was measured as MGAT activity using a liquid scintillation counter (Hitachi Aloka Medical).
The compound concentration IC ₅₀ that inhibits the enzyme activity by 50% was determined from the MGAT activity at the time of adding multiple concentrations of the compound in the same manner as in the above (2) (Measurement method-1) and listed in Table 9.

Test Example 2: Fat absorption inhibitory action in the small intestine The fat absorption inhibitory action in the small intestine of the bicyclic pyrimidine compound of the present invention can be confirmed as follows.
Mice (ICR, 8-9 weeks old, male, Japan SLC) are fasted overnight (about 24 hours), and the test compound (eg 30 mg / kg) is suspended in 5% methylcellulose (MC) solution and administered. (Note that the MC solution may be a diluted MC solution of 0.5% or the like, or a 5% gum arabic solution or the like may be used instead). Ten minutes later, intralipid 20% (Terumo) (10 mL / kg) is administered by oral gavage (this time is 0 min). Blood is collected from the tail vein over time (0, 1, 2, 3, 4 hr), and the transition of plasma triglyceride (TG) concentration is measured using Triglyceride E-Test Wako (Wako Pure Chemical Industries). By the above method, the effect of suppressing the increase in plasma TG of the test compound can be confirmed by comparing with the transition of plasma TG in the solvent administration group.

  From the above results, the compound of the present invention has an action as an MGAT inhibitor and is expected to be effective as a prophylactic and / or therapeutic agent for MGAT-related diseases.

  The bicyclic pyrimidine derivatives of the present invention and physiologically acceptable salts thereof have an MGAT inhibitory action, and pharmaceutical compositions containing these include obesity, metabolic syndrome, hyperlipidemia, hypertriglyceridemia It is useful as an agent for preventing and / or treating symptom, hyperVLDL, hyperfattyemia, diabetes and arteriosclerosis.

Claims (27)

A pharmaceutical composition comprising a bicyclic pyrimidine compound represented by formula (I) or a physiologically acceptable salt thereof:

[Where:
R ¹ represents a hydrogen atom, an optionally substituted lower alkyl group, an optionally substituted lower alkenyl group, an optionally substituted lower cycloalkyl group, an optionally substituted lower cycloalkenyl group, a substituted An optionally substituted phenyl group, an optionally substituted naphthyl group or an optionally substituted saturated or unsaturated heterocyclic group;
R ² represents a hydrogen atom, an optionally substituted lower alkyl group, an optionally substituted lower alkenyl group, an optionally substituted lower alkynyl group, an optionally substituted lower cycloalkyl group, a substituted An optionally substituted lower alkenyl group, an optionally substituted lower alkanoyl group, an optionally substituted phenylcarbonyl group, an optionally substituted phenyl group, an optionally substituted naphthyl group or a substituted Represents a saturated or unsaturated heterocyclic group,
R ³ is a hydrogen atom, an optionally substituted alkyl group, an optionally substituted alkenyl group, an optionally substituted alkynyl group, an optionally substituted lower cycloalkyl group, or optionally substituted. A lower cycloalkenyl group, an optionally substituted phenyl group, an optionally substituted naphthyl group or an optionally substituted saturated or unsaturated heterocyclic group;
However, R ³ is not benzoyl,
R ⁴ and R ⁵ are each independently a hydrogen atom, a halogen atom, an optionally substituted lower alkyl group, an optionally substituted C _3-6 cycloalkyl group, OH or OR ^4b (wherein R ^4b represents an ^optionally substituted C _1-6 alkyl group or an optionally substituted C _3-6 cycloalkyl group),
X is an oxygen atom, a sulfur atom, -N (R ⁶ )-or -C (R ⁷ ) (R ⁸ )-(wherein R ⁶ is a hydrogen atom, an optionally substituted lower alkyl group or a substituted group). R ² and R ⁶ may be combined to form a cyclic amino, and R ⁷ and R ⁸ are each independently a hydrogen atom, a halogen atom, or a substituted group. Represents an optionally substituted lower alkyl group, an optionally substituted C _3-6 cycloalkyl group or an optionally substituted phenyl group, or R ⁷ and R ⁸ together form a cycloalkyl ring. May represent)
Y represents any one selected from the following formulas (II), (III), (IV) or (V):

(In the formula, R ⁹ is a hydrogen atom, an optionally substituted lower alkyl group, an optionally substituted lower cycloalkyl group, an optionally substituted phenyl group, or an optionally substituted saturated or unsaturated group. And Z represents an oxygen atom or a sulfur atom),
m represents 1,
n represents 2.] The pharmaceutical composition according to claim 1, wherein the bicyclic pyrimidine compound represented by formula (I) or a physiologically acceptable salt thereof is represented by formula (Ia):

[Wherein each symbol is as defined in claim 1]. R ¹ represents a group represented by any one of the following formulas (2a ′), (2b ′), (2c ′), (2d ′), (2e ′), (2f ′), or (2g ′):

[Where:
^{R a2a, R a2b, R a2c} , R a2d, R b2, R a2f and ^{R A2G} are each independently a hydrogen atom, a halogen _{atom, CF 3, CN, OH,} C 1-6 alkyl _{groups, C 1- 6} alkoxy groups (wherein the C _1-6 alkyl group and the C _1-6 alkoxy group may be substituted with CO ₂ H or CO ₂ CR ^1g1 R ^1g2 R ^1g3 (here, R ^1g1 , R ^1g2 and Each R ^1g3 is independently
Hydrogen atom,
C _1-4 alkyl group (the group is a C _3-6 cycloalkyl group, 5-membered or 6-membered saturated heterocyclic group optionally substituted with OH, C _1-4 alkoxy group, C _1-4 alkoxy group) , 5-membered or 6-membered saturated heterocyclic oxy group, or ^NR 1b1 ^{R 1b2} may be substituted ^{by, R 1b1} and ^{R 1b2} represent each independently a hydrogen atom or a _{C 1-10} alkyl group) ,
A C _3-10 cycloalkyl group (which group may be substituted with 1 to 2 substituents selected from a fluorine atom and a C _1-4 alkoxy group),
A C _6-10 aryl group (the group may be substituted with a halogen atom or C _1-4 alkoxy),
Represents a 5- or 6-membered saturated heterocyclic group, or a 5- to 10-membered heteroaryl group (the group may be substituted with a C _1-4 alkyl group or a C _1-4 alkoxy group);
Alternatively, R ^1g1 and R ^1g2 may combine with the carbon atom to which they are attached to form a 3-8 membered cycloalkyl ring or a 5 or 6 membered saturated heterocycle)),
_{Represents a} C _1-6 alkylcarbonyl group, CO ₂ R ^1a , NR ^1b R ^1c or C (═O) NR ^1d R ^1e , and
^{R a2a, R a2b, R a2c} , R a2d, R a2f and ^{R A2G} is as chemically permitted, it may be a plurality substituted at any position,
R ^a2n represents a hydrogen atom, CF ₃ , CN, C _1-6 alkyl group, C _1-6 alkylcarbonyl group, CO ₂ R ^1a , NR ^1b R ^1c or C (═O) NR ^1d R ^1e ,
R ^1a , R ^1b , R ^1c , R ^1d and R ^1e each independently represent a hydrogen atom or a C _1-10 alkyl group, or R ^1b and R ^1c , or R ^1d and R ^1e are Each may be combined with N to form a 4- to 8-membered cyclic amino group or morpholinyl group,
R ^d2e and R ^e2e are independently of each other and, when there are a plurality of groups, each independently represents a hydrogen atom, OH, a C _1-6 alkyl group, CO ₂ H, CO ₂ -C ₁ -C _{1- 6} alkyl group, C _1-6 alkoxy group or phenyl group (wherein the phenyl group is a halogen atom, CF ₃ , C _1-4 alkyl group, CO ₂ H, CO ₂ -C _1-6 alkyl group or C _{1 -4} may be substituted with an alkoxy group),
Alternatively, R ^d2e and R ^e2e may combine with one carbon atom to which they are attached to form a 3-8 membered cycloalkyl ring,
Alternatively, two R ^d2e bonded to adjacent carbon atoms through 0 to 3 carbon atoms together with the two carbon atoms to which they are bonded, and the carbon chain between the carbon atoms, 4 to 8 May form a membered cycloalkyl ring,
X ^2d represents an oxygen atom or —N (R ^c2 ) — (wherein R ^c2 represents a hydrogen atom or a C _1-10 alkyl group),
X ^2g represents an oxygen atom or a sulfur atom,
n ^2a , n ^2b , p ^2c , p ^2d , n ^2f and n ^2g represent an integer of 0 to 4,
n ^2c represents an integer of 1 to 6,
m ^2d represents an integer of 1 to 3,
n ^2d represents an integer of 0 to 3,
n ^2e represents an integer of 0 to 8];
R ² represents a group represented by any of the following formulas (3a), (3b), (3c), (3d) or (3e):

[Where:
R ^a3a , R ^a3b , R ^a3c , R ^a3d and R ^b3 each independently represent a hydrogen atom, a halogen atom, CF ₃ , CN, OH, a C _1-6 alkyl group, a C _1-6 alkoxy group (the group _{Represents a} C _1-4 alkoxy group), a C _1-6 alkylcarbonyl group, CO ₂ R ^2a , NR ^2b R ^2c or C (═O) NR ^2d R ^2e , and
R ^a3a , R ^a3b , R ^a3c, and R ^a3d may be substituted at any position as long as it is chemically acceptable,
R ^2a , R ^2b , R ^2c , R ^2d and R ^2e each independently represent a hydrogen atom or a C _1-10 alkyl group, or R ^2b and R ^2c , or R ^2d and R ^2e are In combination with each N bonded to form a 4-8 membered cyclic amino,
X ^3d represents an oxygen atom, a sulfur atom or —N (R ^c3 ) — (wherein R ^c3 represents a hydrogen atom or a C _1-10 alkyl group),
n ^3a represents an integer of 0 to 6;
n ^3b represents an integer of 0 to 6;
n ^3c represents an integer of 1 to 6,
m ^3d represents an integer of 1 to 3,
n ^3d represents an integer of 0 to 3,
n ^3e represents an integer of 0 to 8];
R ³ represents a group represented by any of the following formulas (4g), (4h) or (4i):

[Where:
Arm represents a benzene ring or a heteroaromatic ring,
R ^a4g and R ^a4h each independently represent a hydrogen atom, a halogen atom, CF ₃ , CN, OH, a C _1-10 alkyl group, a C _3-6 cycloalkyl group, a C _1-6 alkoxy group, C _{3 -6} cycloalkoxy _{group, C 1-6} alkylcarbonyl _{^{group, CO 2 R 3aa, NR 3ab}} R 3ac, C (= O) NR 3ad R 3ae or CH = ^{CH-R 3af (wherein, R 3aa,} R ^3ab, R ^{3ac, R 3ad} and ^{R 3 ae} each independently represent a hydrogen atom or a _{C 1-10} alkyl group, ^or, together with the N ^{R 3ab} and ^{R 3ac,} or ^{R 3ad} and ^{R 3 ae} is to which they are attached, respectively It is in the may form a cyclic amino having 4 to ^8-membered; R 3 af represents _CN, CO 2 _H, a CO ^{2 R 3f1} or ^{C (= O) NR 3f2 R} 3f3, R 3f , ^{R 3f2} and ^{R 3f3} each independently represent a hydrogen atom or a _{C 1-6} alkyl group), ^and, as long as ^{R A4g} and ^{R A4H} is a chemically acceptable, more at any position May be replaced,
R ^d4g and R ^e4g , R ^d4h , R ^e4h , R ^f4h , R ^g4h , R ^h4h , R ^i4h , R ^j4h and R ^k4h , and R ^d4i , R ^e4i , R ^f4i and R ^g4i ,
Independently of each other and when there are a plurality of groups, each independently represents a hydrogen atom, OH, C _1-6 alkyl group, CO ₂ H, CO ₂ -C _1-6 alkyl group, C _{1- 6} alkoxy group or phenyl group (wherein the phenyl group is substituted with a halogen atom, CF ₃ , C _1-4 alkyl group, CO ₂ H, CO ₂ -C _1-6 alkyl group or C _1-4 alkoxy group) May represent)
Alternatively, R ^d4g and R ^e4g , R ^d4h and R ^e4h , R ^f4h and R ^g4h , R ^h4h and R ^i4h , R ^j4h and R ^k4h , R ^d4i and R ^e4i , and R ^f4i and R ^g4i are combined. Each of the carbon atoms together may form a 3- to 8-membered cycloalkyl ring or a 5- or 6-membered saturated heterocycle,
Alternatively, two R ^d4g , R ^d4h , R ^f4h , R ^h4h , R ^j4h , R ^d4i, or R ^f4i bonded to adjacent carbon atoms through 0-3 carbon atoms are the two carbons to which they are bonded. Together with the atoms and carbon chains between the carbon atoms may form a 4-8 membered cycloalkyl ring;
R ^b4h and R ^b4i each independently represent a group represented by any of the following (i) to (xi):
(I) a hydrogen atom,
(Ii) a halogen atom,
(Iii) OH,
(Iv) OR ^3b1 ,
(V) CN,
(Vi) CO ₂ H,
^{(Vii) C (= O)} NR 3b2 R 3b3,
(Viii) SO ₂ NR ^3b4 R ^3b5 ,
(Ix) NR ^3e C (═O) NR ^3b6 R ^3b7 ,
^{(Here, R 3b1} represents a hydrogen _{atom, C 1-10} alkyl or _{C 1-10} alkanoyl ^{group; R 3b2, R 3b3, R} 3b4, R 3b5, R 3b6, R 3b7 and ^{R 3e} are each independently represent hydrogen atom or _{C 1-10} alkyl group, or ^{R 3b2} and ^{R 3b3, R 3b4} and ^{R 3b5} or ^{R 3 b 6} and ^{R 3B7,} together with the N to which they are attached respectively 4 An 8-membered cyclic amino may be formed),
(X) any group represented by the following formula (4f):

^{(Here, R 34f} represents a hydrogen atom or a _{C 1-10} alkyl group), or _{^{(xi) CO 2 CR 3g1 R}} 3g2 R 3g3
^(Here, R ^{3g1, R 3g2} and ^{R 3G3} are each independently
Hydrogen atom,
C _1-4 alkyl group (the group is a C _3-6 cycloalkyl group, 5-membered or 6-membered saturated heterocyclic group optionally substituted with OH, C _1-4 alkoxy group, C _1-4 alkoxy group) A 5- or 6-membered saturated heterocyclic oxy group, or an NR ^3b8 R ^3b9 which may be substituted, each of R ^3b8 and R ^3b9 independently represents a hydrogen atom or a C _1-10 alkyl group) ,
A C _3-10 cycloalkyl group (which may be substituted with 1 to 2 substituents selected from the group consisting of a fluorine atom and a C _1-4 alkoxy group),
A C _6-10 aryl group (the group may be substituted with a halogen atom or C _1-4 alkoxy),
Represents a 5- or 6-membered saturated heterocyclic group, or a 5- to 10-membered heteroaryl group (the group may be substituted with a C _1-4 alkyl group or a C _1-4 alkoxy group);
Alternatively, R ^3g1 and R ^3g2 may form a saturated heterocyclic cycloalkyl ring or a 5- or 6-membered 3-8 membered together with the carbon atoms to which they are attached),
m ^4g represents an integer of 0 to 10,
m ^4h , n ^4h , p ^4h and q ^4h , and m ⁴ⁱ and n ⁴ⁱ each independently represent an integer of 0 to 5;
r ^4h , s ^4h and s ⁴ⁱ each independently represent 0 or 1 (provided that when r ^4h is 1, m ^4h represents an integer of 1 to 5; when s ⁴ⁱ is 1, m ^{4i Represents} an integer of 1 to 5; when s ^4h is 1 and n ^4h is 0, R ^b4h is represented by any one of (i), (vii), (viii), (x), or (xi) And when s ⁴ⁱ is 1 and n ⁴ⁱ is 0, R ^b4i represents a group represented by any one of (i), (vii), (viii), (x) or (xi))] ,
The pharmaceutical composition according to claim 2. R ¹ represents a group represented by any of the following formulas (2a ′), (2b ′), (2c ′), (2d ′), (2e ′) or (2g ′):

[Where:
^{R a2a, R a2b, R a2c} , R a2d, R b2 and ^{R A2G} are each independently a hydrogen atom, a halogen _atom, CF _{3, C 1-6} alkyl, or _{C 1-6} alkoxy groups (here The C _1-6 alkyl group and the C _1-6 alkoxy group may be substituted with CO ₂ H or CO ₂ CR ^1g1 R ^1g2 R ^1g3 (wherein R ^1g1 , R ^1g2 and R ^1g3 are independent of each other). do it,
Hydrogen atom or a _{C 1-4} alkyl (in which the group _{OH, C 1-4} alkoxy group, may be substituted with a saturated heterocyclic group, or ^NR 1b1 ^{R 1b2} of 5- or ^{6-membered, R 1b1} and ^{R 1b2} Each independently represents a hydrogen atom or a C _1-6 alkyl group))),
^{And, R a2a, R a2b, R} a2c, R a2d and ^{R A2G} is as chemically permitted, it may be a plurality substituted at any position,
R ^d2e and R ^e2e each independently represent a hydrogen atom, a C _1-6 alkyl group, a C _1-6 alkoxy group, or a phenyl group (wherein there are a plurality of groups) The phenyl group may be substituted with a halogen atom, CF ₃ , a C _1-4 alkyl group or a C _1-4 alkoxy group),
Alternatively, R ^d2e and R ^e2e may combine with one carbon atom to which they are attached to form a 3-8 membered cycloalkyl ring,
Alternatively, two R ^d2e bonded to adjacent carbon atoms through 0 to 3 carbon atoms together with the two carbon atoms to which they are bonded, and the carbon chain between the carbon atoms, 4 to 8 May form a membered cycloalkyl ring,
X ^2d represents an oxygen atom or —N (R ^c2 ) — (wherein R ^c2 represents a hydrogen atom or a C _1-6 alkyl group),
X ^2g represents an oxygen atom or a sulfur atom,
n ^2a , n ^2b , p ^2c , p ^2d and n ^2g represent an integer of 0 to 4,
n ^2c represents an integer of 1 to 6,
m ^2d represents an integer of 1 to 3,
n ^2d represents an integer of 0 to 3,
n ^2e represents an integer of 1 to 6];
R ² represents a group represented by any of the following formulas (3a), (3c), (3d) or (3e):

[Where:
R ^a3a , R ^a3c , R ^a3d and R ^b3 each independently represent a hydrogen atom, a halogen atom, CF ₃ , a C _1-6 alkyl group, or a C _1-6 alkoxy group (the group is a C _1-4 alkoxy group). And optionally substituted with a group, and
R ^a3a , R ^a3c, and R ^a3d may be substituted at any position as long as they are chemically acceptable,
X ^3d represents an oxygen atom, a sulfur atom, or —N (R ^c3 ) — (wherein R ^c3 represents a hydrogen atom or a C _1-6 alkyl group),
n ^3a represents an integer of 0 to 4,
n ^3c represents an integer of 1 to 6,
m ^3d represents an integer of 1 to 3,
n ^3d represents an integer of 0 to 3,
n ^3e represents an integer of 0 to 8];
R ³ represents a group represented by any of the following formulas (4g), (4h) or (4i):

[Where:
Arm represents a benzene ring or a heteroaromatic ring,
R ^a4g and R ^a4h are each independently a hydrogen atom, halogen atom, CF ₃ , CN, OH, C _1-6 alkyl group, C _1-6 alkoxy group, CO ₂ R ^3aa , C (═O) NR ^3ad R ^3ae or CH═CH—R ^3af (wherein R ^3aa , R ^3ad and R ^3ae each independently represents a hydrogen atom or a C _1-6 alkyl group; R ^3af represents CO ₂ H, CO ₂ R ^3f1 or C (═O) NR ^3f2 R ^3f3 , each of R ^3f1 , R ^3f2 and R ^3f3 independently represents a hydrogen atom or a C _1-6 alkyl group), and
A ^plurality of R ^a4g and R ^a4h may be substituted at any position as long as they are chemically acceptable.
R ^d4g and R ^e4g , R ^d4h , R ^e4h , R ^f4h , R ^g4h , R ^h4h , R ^i4h , R ^j4h and R ^k4h , and R ^d4i , R ^e4i , R ^f4i and R ^g4i ,
Independently of each other and when there are a plurality of groups, each independently represents a hydrogen atom, a C _1-6 alkyl group, a CO ₂ H or a CO ₂ -C _1-6 alkyl group,
Alternatively, R ^d4g and R ^e4g , R ^d4h and R ^e4h , R ^f4h and R ^g4h , R ^h4h and R ^i4h , R ^j4h and R ^k4h , R ^d4i and R ^e4i , and R ^f4i and R ^g4i are combined. Each with one carbon atom may form a 3- to 6-membered cycloalkyl ring;
R ^b4h and R ^b4i each independently represent a group represented by any of the following (iii), (iv), (vi), (vii) or (xi):
(Iii) OH,
(Iv) OR ^3b1 ,
(Vi) CO ₂ H,
^{(Vii) C (= O)} NR 3b2 R 3b3,
^{(Here, R 3b1} represents a hydrogen _{atom, C 1-6} alkyl group or a _{C 1-6} alkanoyl ^group; Table the ^{R 3b2} and ^{R 3b3} are each independently hydrogen atom or a _{C 1-6} alkyl group carded, or ^{R 3b2} and ^{R 3b3} may form a cyclic amino 5- to 7-membered together with the N to which they are attached, respectively),
_{^{(Xi) CO 2 CR 3g1 R}} 3g2 R 3g3
^(Here, R ^{3g1, R 3g2} and ^{R 3G3} are each independently
A hydrogen atom or a C _1-4 alkyl group (this group may be substituted with OH, C _1-4 alkoxy group, 5-membered or 6-membered saturated heterocyclic group or NR ^3b8 R ^3b9 , R ^3b8 and R ^3b9 Each independently represents a hydrogen atom or a C _1-6 alkyl group))
m ^4g represents an integer of 1 to 6,
m ^4h , n ^4h , p ^4h and q ^4h , and m ⁴ⁱ and n ⁴ⁱ each independently represent an integer of 0 to 5;
r ^4h , s ^4h and s ⁴ⁱ each independently represent 0 or 1 (provided that when r ^4h is 1, m ^4h represents an integer of 2 to 5; when s ⁴ⁱ is 1, m ^{4i Represents} an integer of 2 to 5; when s ^4h is 1 and n ^4h is 0, R ^b4h represents a group represented by either (vii) or (xi) above; s ⁴ⁱ is 1 and n ⁴ⁱ is In the case of 0, R ^b4i represents a group represented by either (vii) or (xi) above)];
R ⁴ and R ⁵ each independently represent a hydrogen atom, a fluorine atom or a C _1-6 alkyl group which may be substituted with a fluorine atom;
X is an oxygen atom, a sulfur atom, —N (R ⁶ ) — or —C (R ⁷ ) (R ⁸ ) — (wherein R ⁶ is a hydrogen atom or a C _{1-6 optionally} substituted with a fluorine atom) Represents an alkyl group, and R ⁷ and R ⁸ each independently represents a hydrogen atom or a C _1-6 alkyl group _optionally substituted with a fluorine atom).
The pharmaceutical composition according to claim 3. Y is the formula (II), (III) or (IV):

[Wherein each symbol is as defined in claim 1]
The pharmaceutical composition of Claim 3 which is group shown by these. Y is the formula (III):

The pharmaceutical composition of Claim 5 which is group shown by these. R ³ is the formula (4 g):

[Where:
Arm is a benzene ring or a pyridine ring,
R ^a4g is a hydrogen atom, a halogen atom, CN, OH, CO ₂ H, CO ₂ —C _1-4 alkyl group, or CH═CH—R ^3af (wherein R ^3af is CO ₂ H or CO ₂ —C _1-4 alkyl represents a group),
R ^d4g and R ^e4g each independently represent a hydrogen atom, a C _1-4 alkyl group, CO ₂ H, or CO ₂ -C _1-4 when there are a plurality of groups. Represents an alkyl group,
m ^4g represents an integer of 1 to 3]
The pharmaceutical composition of Claim 3 which is group shown by these. R ³ represents formula (4h):

[Where:
Arm is a benzene ring or a pyridine ring,
m ^4h , n ^4h , p ^4h and q ^4h each independently represent an integer of 0 to 3 (provided that m ^4h + n ^4h + p ^4h + q ^4h is an integer of 0 to 10; r ^4h is 1; ^{M 4h} represents an integer of 2 or 3,
Each other symbol is as defined in claim 4]
The pharmaceutical composition of Claim 3 which is group shown by these. R ^a4h is a hydrogen atom, a halogen atom, CF ₃ , a C _1-6 alkyl group or a C _1-6 alkoxy group,
R ^B4h is (vi) _CO 2 H, or _{^{(xi) CO 2 CR 3g1 R}} 3g2 R 3g3
^(Here, R ^{3g1, R 3g2} and ^{R 3G3} are each independently
A hydrogen atom, or
A C _1-4 alkyl group (the group may be substituted with OH, a C _1-4 alkoxy group, a 5- or 6-membered saturated heterocyclic group, or NR ^3b8 R ^3b9 , each of R ^3b8 and R ^3b9 is Independently represents a hydrogen atom or a C _1-4 alkyl group)
Represents)
R ^d4h , R ^e4h , R ^f4h , R ^g4h , R ^h4h , R ^i4h , R ^j4h and R ^k4h are
Independently of each other and when there are a plurality of groups, each independently represents a hydrogen atom or a C _1-4 alkyl group,
Alternatively, R ^f4h and R ^g4h together with the carbon atom to which they are attached may form a 3-6 membered cycloalkyl ring,
m ^4h is 1 or 2,
n ^4h is an integer of 1 to 3,
p ^4h , q ^4h , r ^4h and s ^4h are each independently 0 or 1 (provided that when r ^4h is 1, m ^4h is 2),
The pharmaceutical composition according to claim 8. R ^B4h is _{^{(xi) CO 2 CR 3g1 R}} 3g2 R 3g3
^(Here, R ^{3g1, R 3g2} and ^{R 3G3} is claim 9 as in is defined to) represented by the claims 3～6,8 or pharmaceutical composition according to any one of 9. R ¹ is represented by the following formula (2a ′) or (2b ′):

[Where:
R ^a2a and R ^a2b are each independently a hydrogen atom, a halogen atom, a C _1-4 alkyl group or a C _1-4 alkoxy group,
n ^2a and n ^2b are 0]
The pharmaceutical composition of Claim 3 which is group shown by these. R ¹ is represented by the following formula (2c ′):

[Where:
R ^a2c is a hydrogen atom or a fluorine atom (a plurality of such groups may be substituted at any position as long as it is chemically acceptable);
p ^2c is 0,
n ^2c is an integer of 1 to 4]
The pharmaceutical composition of Claim 3 which is group shown by these. R ¹ is the following formula (2d ′) or (2g ′):

[Where:
R ^a2d and R ^a2g are hydrogen atoms,
X ^2d and X ^2g are oxygen atoms,
p ^2d and n ^2g are 1,
m ^2d is an integer of 2 to 3,
n ^2d is an integer of 0 to 1.]
The pharmaceutical composition of Claim 3 shown by these. R ¹ is represented by the following formula (2e ′):

[Where:
R ^b2 is a C _1-4 alkoxy group,
R ^d2e and R ^e2e are each independently a hydrogen atom or a C _1-4 alkyl group when there are a plurality of groups,
n ^2e is an integer of ² to 4]
The pharmaceutical composition of Claim 3 which is group shown by these. R ² represents the following formula (3c) or (3d):

[Wherein each symbol is as defined in claim 4]
The pharmaceutical composition of Claim 3 which is group shown by these. R ² represents the following formula (3c):

[ ^Wherein , R ^a3c is a hydrogen atom, and n ^3c is an integer of 1 to 4]
The pharmaceutical composition of Claim 15 which is group shown by these. The pharmaceutical composition according to claim 16, wherein n ^3c is 2-4. R ² represents the following formula (3a):

[ ^Wherein , R ^a3a is a hydrogen atom or a C _1-6 alkoxy group optionally substituted with a C _1-4 alkoxy group, and n ^3a is 0],
The pharmaceutical composition according to claim 3, wherein X is an oxygen atom. X is a sulfur atom or -N ^(R 6) - ^{(here, R 6} represents a hydrogen atom or a _{C 1-4} alkyl group), according to claim 3 pharmaceutical composition.   The pharmaceutical composition according to claim 19, wherein X is -NH-.   20. A pharmaceutical composition according to claim 19, wherein X is a sulfur atom. The pharmaceutical composition according to claim 3, wherein R ⁴ and R ⁵ are both hydrogen atoms. R ¹ is represented by the following formula (2a ′) or (2b ′):

[Where:
R ^a2a and R ^a2b are each independently a hydrogen atom, a halogen atom, a C _1-4 alkyl group or a C _1-4 alkoxy group,
n ^2a and n ^2b are 0],
The following formula (2c ′):

[Where:
R ^a2c is a hydrogen atom or a fluorine atom (a plurality of such groups may be substituted at any position as long as it is chemically acceptable);
p ^2c is 0,
n ^2c is an integer from 1 to 4], or
The following formula (2d ′):

[Where:
R ^a2d is a hydrogen atom,
X ^2d is an oxygen atom,
p ^2d is 1,
m ^2d is an integer of 2 to 3,
n ^2d is an integer of 0 to 1.]
A group represented by
R ² represents the following formula (3c):

[ ^Wherein , R ^a3c is a hydrogen atom, and n ^3c is an integer of 2 to 4]
A group represented by
R ³ represents formula (4h):

[Where:
Arm is a benzene ring or a pyridine ring,
R ^a4h is a hydrogen atom, a halogen atom, CF ₃ , a C _1-6 alkyl group or a C _1-6 alkoxy group,
R ^B4h is _{^{(xi) CO 2 CR 3g1 R}} 3g2 R 3g3
^(Here, R ^{3g1, R 3g2} and ^{R 3G3} are each independently
A hydrogen atom, or
A C _1-4 alkyl group (the group may be substituted with OH, a C _1-4 alkoxy group, a 5- or 6-membered saturated heterocyclic group, or NR ^3b8 R ^3b9 , each of R ^3b8 and R ^3b9 is Independently represents a hydrogen atom or a C _1-4 alkyl group)
Represents)
R ^d4h , R ^e4h , R ^f4h , R ^g4h , R ^h4h , R ^i4h , R ^j4h and R ^k4h are
Independently of each other and when there are a plurality of groups, each independently represents a hydrogen atom or a C _1-4 alkyl group,
Alternatively, R ^f4h and R ^g4h together with the carbon atom to which they are attached may form a 3-6 membered cycloalkyl ring,
m ^4h is 1 or 2,
n ^4h is an integer of 1 to 3,
p ^4h , q ^4h , r ^4h and s ^4h are each independently 0 or 1 (provided that when r ^4h is 1, m ^4h is 2)]
A group represented by
R ⁴ and R ⁵ are both hydrogen atoms,
X is a sulfur atom or -NH-,
Y is the formula (III):

The pharmaceutical composition of Claim 4 which is group shown by these. The pharmaceutical composition according to claim 1, comprising a bicyclic pyrimidine compound selected from the following group or a physiologically acceptable salt thereof:
Methyl {4-[(3-{[2- (cyclohexylsulfanyl) -4-oxo-3-phenyl-3,5,7,8-tetrahydropyrido [4,3-d] pyrimidine-6 (4H)- Yl] carbonyl} azetidin-1-yl) methyl] phenyl} acetate,
Methyl (2E) -3- {4-[(3-{[2- (cyclohexylsulfanyl) -4-oxo-3-phenyl-3,5,7,8-tetrahydropyrido [4,3-d] pyrimidine -6 (4H) -yl] carbonyl} azetidin-1-yl) methyl] phenyl} prop-2-enoate,
Ethyl ({4-[(3-{[2- (cyclohexylsulfanyl) -4-oxo-3-phenyl-3,5,7,8-tetrahydropyrido [4,3-d] pyrimidine-6 (4H) -Yl] carbonyl} azetidin-1-yl) methyl] benzyl} oxy) acetate,
Ethyl 4- (3-{[2- (cyclohexylsulfanyl) -4-oxo-3-phenyl-3,5,7,8-tetrahydropyrido [4,3-d] pyrimidin-6 (4H) -yl] Carbonyl} azetidin-1-yl) butanoate,
Methyl 4- [2- (3-{[2- (cyclohexylsulfanyl) -4-oxo-3-phenyl-3,5,7,8-tetrahydropyrido [4,3-d] pyrimidine-6 (4H) -Yl] carbonyl} azetidin-1-yl) ethyl] benzoate,
Methyl 3- {4-[(3-{[2- (cyclohexylsulfanyl) -4-oxo-3-phenyl-3,5,7,8-tetrahydropyrido [4,3-d] pyrimidine-6 (4H ) -Yl] carbonyl} azetidin-1-yl) methyl] phenyl} propanoate,
Methyl 3- {4-[(3-{[2- (cyclohexylamino) -4-oxo-3-phenyl-3,5,7,8-tetrahydropyrido [4,3-d] pyrimidine-6 (4H ) -Yl] carbonyl} azetidin-1-yl) methyl] phenyl} propanoate,
Ethyl 6- (3-{[2- (cyclohexylsulfanyl) -4-oxo-3-phenyl-3,5,7,8-tetrahydropyrido [4,3-d] pyrimidin-6 (4H) -yl] Carbonyl} azetidin-1-yl) hexanoate,
Methyl 4- [2- (3-{[2- (cyclohexylamino) -4-oxo-3-phenyl-3,5,7,8-tetrahydropyrido [4,3-d] pyrimidine-6 (4H) -Yl] carbonyl} azetidin-1-yl) ethyl] benzoate,
Ethyl 3- {4-[(3-{[2- (cyclohexylsulfanyl) -4-oxo-3-phenyl-3,5,7,8-tetrahydropyrido [4,3-d] pyrimidine-6 (4H ) -Yl] carbonyl} azetidin-1-yl) methyl] phenyl} propanoate,
Ethyl 9- (3-{[2- (cyclohexylsulfanyl) -4-oxo-3-phenyl-3,5,7,8-tetrahydropyrido [4,3-d] pyrimidin-6 (4H) -yl] Carbonyl} azetidin-1-yl) nonanoate,
Methyl {3-[(3-{[2- (cyclohexylsulfanyl) -4-oxo-3-phenyl-3,5,7,8-tetrahydropyrido [4,3-d] pyrimidine-6 (4H)- Yl] carbonyl} azetidin-1-yl) methyl] phenyl} acetate,
Methyl {3-[(3-{[2- (cyclopentylsulfanyl) -4-oxo-3-phenyl-3,5,7,8-tetrahydropyrido [4,3-d] pyrimidine-6 (4H)- Yl] carbonyl} azetidin-1-yl) methyl] phenyl} acetate,
Methyl {3-[(3-{[2- (cyclohexylsulfanyl) -3- (3,3-difluorocyclobutyl) -4-oxo-3,5,7,8-tetrahydropyrido [4,3-d ] Pyrimidin-6 (4H) -yl] carbonyl} azetidin-1-yl) methyl] phenyl} acetate,
Methyl {4-[(3-{[2- (cyclopentylsulfanyl) -4-oxo-3-phenyl-3,5,7,8-tetrahydropyrido [4,3-d] pyrimidine-6 (4H)- Yl] carbonyl} azetidin-1-yl) methyl] phenyl} acetate,
Ethyl 3- {4-[(3-{[2- (cyclohexylsulfanyl) -4-oxo-3-phenyl-3,5,7,8-tetrahydropyrido [4,3-d] pyrimidine-6 (4H ) -Yl] carbonyl} azetidin-1-yl) methyl] -2-fluorophenyl} propanoate,
Ethyl {4- [2- (3-{[2- (cyclohexylsulfanyl) -4-oxo-3-phenyl-3,5,7,8-tetrahydropyrido [4,3-d] pyrimidine-6 (4H ) -Yl] carbonyl} azetidin-1-yl) ethyl] phenyl} acetate,
Ethyl {4-[(3-{[2- (cyclohexylsulfanyl) -4-oxo-3-phenyl-3,5,7,8-tetrahydropyrido [4,3-d] pyrimidine-6 (4H)- Yl] carbonyl} azetidin-1-yl) methyl] phenoxy} acetate,
Ethyl {3-[(3-{[2- (cyclohexylsulfanyl) -4-oxo-3-phenyl-3,5,7,8-tetrahydropyrido [4,3-d] pyrimidine-6 (4H)- Yl] carbonyl} azetidin-1-yl) methyl] phenoxy} acetate,
Methyl {4-[(3-{[2- (cyclohexylsulfanyl) -3- (3,3-difluorocyclobutyl) -4-oxo-3,5,7,8-tetrahydropyrido [4,3-d ] Pyrimidin-6 (4H) -yl] carbonyl} azetidin-1-yl) methyl] phenyl} acetate,
Ethyl {4-[(3-{[2- (cyclohexylsulfanyl) -3- (3,3-difluorocyclobutyl) -4-oxo-3,5,7,8-tetrahydropyrido [4,3-d ] Pyrimidin-6 (4H) -yl] carbonyl} azetidin-1-yl) methyl] phenoxy} acetate,
Ethyl 3- {4-[(3-{[2- (cyclopentylsulfanyl) -4-oxo-3-phenyl-3,5,7,8-tetrahydropyrido [4,3-d] pyrimidine-6 (4H ) -Yl] carbonyl} azetidin-1-yl) methyl] phenyl} propanoate,
Ethyl {4-[(3-{[2- (cyclopentylsulfanyl) -4-oxo-3-phenyl-3,5,7,8-tetrahydropyrido [4,3-d] pyrimidine-6 (4H)- Yl] carbonyl} azetidin-1-yl) methyl] phenoxy} acetate,
Methyl {4-[(3-{[2- (cyclobutylsulfanyl) -4-oxo-3-phenyl-3,5,7,8-tetrahydropyrido [4,3-d] pyrimidine-6 (4H) -Yl] carbonyl} azetidin-1-yl) methyl] phenyl} acetate,
Methyl 1- {4-[(3-{[2- (cyclohexylsulfanyl) -4-oxo-3-phenyl-3,5,7,8-tetrahydropyrido [4,3-d] pyrimidine-6 (4H ) -Yl] carbonyl} azetidin-1-yl) methyl] phenyl} cyclopropanecarboxylate,
Methyl {4-[(3-{[2- (cyclohexylsulfanyl) -4-oxo-3- (pyridin-3-yl) -3,5,7,8-tetrahydropyrido [4,3-d] pyrimidine -6 (4H) -yl] carbonyl} azetidin-1-yl) methyl] phenyl} acetate,
Methyl ({5-[(3-{[2- (cyclohexylsulfanyl) -4-oxo-3-phenyl-3,5,7,8-tetrahydropyrido [4,3-d] pyrimidine-6 (4H) -Yl] carbonyl} azetidin-1-yl) methyl] pyridin-2-yl} oxy) acetate,
(+/-)-methyl {4-[(3-{[2- (cyclohexylsulfanyl) -4-oxo-3- [tetrahydrofuran-2-ylmethyl] -3,5,7,8-tetrahydropyrido [4 , 3-d] pyrimidin-6 (4H) -yl] carbonyl} azetidin-1-yl) methyl] phenyl} acetate,
Methyl {4-[(3-{[2- (cyclohexylsulfanyl) -4-oxo-3-[(2R) -tetrahydrofuran-2-ylmethyl] -3,5,7,8-tetrahydropyrido [4,3 -D] pyrimidin-6 (4H) -yl] carbonyl} azetidin-1-yl) methyl] phenyl} acetate,
Methyl {4-[(3-{[2- (cyclohexylsulfanyl) -4-oxo-3-[(2S) -tetrahydrofuran-2-ylmethyl] -3,5,7,8-tetrahydropyrido [4,3 -D] pyrimidin-6 (4H) -yl] carbonyl} azetidin-1-yl) methyl] phenyl} acetate,
2-methoxyethyl 3- {4-[(3-{[2- (cyclohexylsulfanyl) -4-oxo-3-phenyl-3,5,7,8-tetrahydropyrido [4,3-d] pyrimidine- 6 (4H) -yl] carbonyl} azetidin-1-yl) methyl] phenyl} propanoate,
2-hydroxyethyl 3- {4-[(3-{[2- (cyclohexylsulfanyl) -4-oxo-3-phenyl-3,5,7,8-tetrahydropyrido [4,3-d] pyrimidine- 6 (4H) -yl] carbonyl} azetidin-1-yl) methyl] phenyl} propanoate,
Methyl {4-[(3-{[2- (cyclohexylsulfanyl) -3- (furan-2-ylmethyl) -4-oxo-3,5,7,8-tetrahydropyrido [4,3-d] pyrimidine -6 (4H) -yl] carbonyl} azetidin-1-yl) methyl] phenyl} acetate,
Methyl {4-[(3-{[2- (cyclohexylsulfanyl) -3- (2-methoxyethyl) -4-oxo-3,5,7,8-tetrahydropyrido [4,3-d] pyrimidine- 6 (4H) -yl] carbonyl} azetidin-1-yl) methyl] phenyl} acetate,
Methyl 6- (3-{[2- (cyclohexylsulfanyl) -4-oxo-3-phenyl-3,5,7,8-tetrahydropyrido [4,3-d] pyrimidin-6 (4H) -yl] Carbonyl} azetidin-1-yl) hexanoate,
Methyl 4-[(3-{[2- (cyclohexylsulfanyl) -4-oxo-3-phenyl-3,5,7,8-tetrahydropyrido [4,3-d] pyrimidin-6 (4H) -yl ] Carbonyl} azetidin-1-yl) methyl] benzoate,
Methyl {4- [2- (3-{[2- (cyclohexylsulfanyl) -4-oxo-3-phenyl-3,5,7,8-tetrahydropyrido [4,3-d] pyrimidine-6 (4H ) -Yl] carbonyl} azetidin-1-yl) ethoxy] phenyl} acetate,
Methyl {4-[(3-{[2- (cyclohexylsulfanyl) -4-oxo-3- (tetrahydrofuran-3-ylmethyl) -3,5,7,8-tetrahydropyrido [4,3-d] pyrimidine -6 (4H) -yl] carbonyl} azetidin-1-yl) methyl] phenyl} acetate,
Ethyl {4-[(3-{[2- (cyclohexylsulfanyl) -4-oxo-3-[(2R) -tetrahydrofuran-2-ylmethyl] -3,5,7,8-tetrahydropyrido [4,3 -D] pyrimidin-6 (4H) -yl] carbonyl} azetidin-1-yl) methyl] phenoxy} acetate,
Ethyl 3- {4-[(3-{[2- (cyclohexylsulfanyl) -4-oxo-3-[(2R) -tetrahydrofuran-2-ylmethyl] -3,5,7,8-tetrahydropyrido [4 , 3-d] pyrimidin-6 (4H) -yl] carbonyl} azetidin-1-yl) methyl] phenyl} propanoate,
Ethyl {4-[(3-{[2- (3-butoxyphenoxy) -4-oxo-3-phenyl-3,5,7,8-tetrahydropyrido [4,3-d] pyrimidine-6 (4H ) -Yl] carbonyl} azetidin-1-yl) methyl] phenoxy} acetate,
Methyl {4-[(3-{[2- (3-butoxyphenoxy) -4-oxo-3-phenyl-3,5,7,8-tetrahydropyrido [4,3-d] pyrimidine-6 (4H ) -Yl] carbonyl} azetidin-1-yl) methyl] phenyl} acetate, and methyl {4-[(3-{[2- (cyclohexylsulfanyl) -3-[(2R) -2-methoxypropyl] -4 -Oxo-3,5,7,8-tetrahydropyrido [4,3-d] pyrimidin-6 (4H) -yl] carbonyl} azetidin-1-yl) methyl] phenyl} acetate.   Pharmaceutical product containing the pharmaceutical composition in any one of Claims 1-24.   The pharmaceutical composition according to any one of claims 1 to 24, which is used as a prophylactic and / or therapeutic agent for MGAT-related diseases.   Any one of claims 1 to 24 as a prophylactic and / or therapeutic agent for obesity, metabolic syndrome, hyperlipidemia, hypertriglyceridemia, hyperVLDL, hyperfattyemia, diabetes or arteriosclerosis The pharmaceutical composition as described.