JPWO2006112331A1 - New condensed pyrrole derivatives - Google Patents

Abstract

Provided is a compound represented by the following formula (I) or a prodrug thereof, or a pharmaceutically acceptable salt thereof as a compound having high DPP-IV inhibitory activity or improved in safety, toxicity and the like. [Wherein R 1 represents a hydrogen atom, an optionally substituted alkyl group or the like. R2 represents a hydrogen atom, an optionally substituted alkyl group or the like. R3 represents a hydrogen atom, a halogen atom or the like. R4 represents a hydrogen atom, a halogen atom or the like. R5 represents a hydrogen atom, a halogen atom or the like. Y represents a group represented by the following formula (A). (M1 represents 0, 1, 2 or 3, and R6 does not exist, or 1 or 2 exists, and each independently represents a halogen atom or the like.]]

Description

  The present invention relates to a bicyclic pyrrole derivative useful as a medicine. More specifically, the present invention relates to a novel condensed pyrazole derivative effective as a dipeptidyl peptidase-IV (DPP-IV) inhibitor. Further, the present invention relates to a therapeutic agent for diabetes containing a condensed pyrrole derivative effective as a dipeptidyl peptidase-IV (DPP-IV) inhibitor as an active ingredient.

  DPP-IV is a serine protease widely present in the body, a kind of dipeptidylaminopeptidase that hydrolyzes and releases the N-terminal dipeptide, and acts particularly strongly on peptides whose second amino acid from the N-terminal is proline. For this reason, it is also called prolyl endopeptidase. DPP-IV is known to use various peptides derived from living bodies involved in endocrine system, neuroendocrine system, immune function, etc. as substrates. Pancreatic polypeptide family represented by pancreatic polypeptide (PP) and neuropeptide Y (NPY), vasoactive intestinal polypeptide (VIP), glucagon-like peptide-1 (GLP-1), glucose dependent Many bioactive peptides such as glucagon / VIP family, such as sex insulinotropic polypeptide (GIP) and growth hormone secretagogue (GRF), and chemokine family become substrates of DPP-IV, and are activated / inactive It is known to be affected by oxidization and metabolism promotion.

  DPP-IV cleaves 2 amino acids (His-Ala) from the N-terminus of GLP-1. Although the cleaved peptide binds weakly to the GLP-1 receptor, it is known that it does not have a receptor activation effect and acts as an antagonist. It is known that the metabolism of GLP-1 in the blood by DPP-IV is very rapid, and inhibition of DPP-IV increases the concentration of active GLP-1 in the blood. GLP-1 is a peptide secreted from the intestine by ingestion of sugar, and is a major promoter for glucose-responsive pancreatic insulin secretion. GLP-1 is known to have an action of promoting insulin synthesis in pancreatic β cells and an action of promoting β cell proliferation. Furthermore, GLP-1 receptors are known to be expressed in the digestive tract, liver, muscle, and adipose tissue. GLP-1 is also used in these tissues for gastrointestinal activity, gastric acid secretion, and glycogen synthesis. And is known to act on insulin-dependent glucose uptake. Therefore, the increase in blood GLP-1 concentration has effects such as promotion of insulin secretion depending on blood glucose level, improvement of pancreatic function, improvement of postprandial hyperglycemia, improvement of impaired glucose tolerance, improvement of insulin resistance, etc. Development of a DPP-IV inhibitor effective for type 2 diabetes (non-insulin-dependent diabetes) is expected.

Various DPP-IV inhibitors have been reported. For example, Patent Documents 1 and 2 report that derivatives having an imidazole ring are effective as DPP-IV inhibitors.
International Publication No. 02/068420 Pamphlet International Publication No. 03/104229 Pamphlet

  An object of the present invention is to provide a novel compound having excellent DPP-IV inhibitory activity.

  As a result of intensive studies to achieve the above-mentioned problems, the present inventors have found that the following compound or a prodrug thereof or a pharmaceutically acceptable salt thereof (hereinafter sometimes abbreviated as the present compound if necessary) is excellent. As a result, the present invention has been completed.

That is, the present invention:
[1] Formula (I):

[式中、Ｒ^１は、水素原子、置換されてもよいアルキル基、置換されてもよいシクロアルキル基、置換されてもよいアリール基または置換されてもよいヘテロアリール基を表し
；
Ｒ^２は、水素原子、置換されてもよいアルキル基、置換されてもよいアリール基、置換されてもよいヘテロアリール基、置換されてもよいアラルキル基、置換されてもよいヘテロアリールアルキル基、置換されてもよいアルケニル基、または置換されてもよいアルキニル基を表し；
Ｒ^３は、水素原子、ハロゲン原子、シアノ基、ホルミル基、カルボキシ基、置換されてもよいアルキル基、置換されてもよいアルケニル基、置換されてもよいアルキニル基、置換されてもよいシクロアルキル基、置換されてもよいアリール基、置換されてもよいヘテロアリール基、置換されてもよいアラルキル基、置換されてもよいヘテロアリールアルキル基、置換されてもよいアルキルカルボニル基、置換されてもよいシクロアルキルカルボニル基、置換されてもよいアロイル基、置換されてもよいヘテロアリールカルボニル基、置換されてもよいアルコキシカルボニル基、置換されてもよいアリールオキシカルボニル基、置換されてもよいカルバモイル基、または式：−Ｒ^ｄ−Ｃ（Ｏ）Ｏ−Ｒ^ｅ（式中、Ｒ^ｄは、単結合、アルキレン基、またはアルケニレン基を表し、Ｒ^ｅは、テトラヒドロフラニル、シンナミル、５−メチル−２−オキソ−１，３−ジオキソレン−４−イルメチル、５−（tert−ブチル）−２−オキソ−１，３−ジオキソレン−４−イルメチル、２−モルホリノエチル、または式：−ＣＨ（Ｒ^ｆ）ＯＣ（Ｏ）Ｒ^ｇを表す。Ｒ^ｆは、水素原子、アルキル基、アルケニル基、シクロアルキル基、またはアルコキシ基を表し、Ｒ^ｇは、置換されてもよいアルキル基、置換されてもよいアルケニル基、シクロアルキル基、シクロアルキルオキシ基、置換されてもよいアルコキシ基、置換されてもよいアルケニルオキシ基、２−インダニルオキシ基、５−インダニルオキシ基、または置換されてもよいアリールオキシ基を表す。）を表し；
Ｒ^４は、水素原子、ハロゲン原子、シアノ基、ホルミル基、置換されてもよいアルキル基、置換されてもよいシクロアルキル基、置換されてもよいシクロアルキルオキシ基、置換されてもよいアルケニル基、置換されてもよいアルキニル基、置換されてもよいアミノ基、置換されてもよいカルバモイル基、カルボキシ基、置換されてもよいアルコキシ基、置換されてもよいアリール基、置換されてもよいアリールオキシ基、置換されてもよいアラルキル基、置換されてもよいアラルキルオキシ基、置換されてもよいアロイル基、置換されてもよいアリールチオ基、置換されてもよいアリールスルフィニル基、置換されてもよいアリールスルホニル基、置換されてもよいアルキルチオ基、置換されてもよいアルキルスルフィニル基、置換されてもよいアルキルスルホニル基、置換されてもよいヘテロアリール基、置換されてもよいヘテロアリールアルキル基、置換されてもよいヘテロアリールカルボニル基、置換されてもよいヘテロアリールオキシ基、置換されてもよいアルキルカルボニル基、置換されてもよい含窒素飽和ヘテロ環基、置換されてもよいアルコキシカルボニル基、置換されてもよいアリールオキシカルボニル基、置換されてもよいアラルキルオキシカルボニル基、置換されてもよいシクロアルキルオキシカルボニル基、または式：−Ｒ^ｄ−Ｃ（Ｏ）Ｏ−Ｒ^ｅ（式中、Ｒ^ｄおよびＲ^ｅは、前記記載と同義である。）を表し；
Ｒ^５は、水素原子、ハロゲン原子、置換されてもよいアルキル基、カルボキシ基、置換されてもよいアリール基、置換されてもよいアルコキシカルボニル基、または式：−Ｒ^ｄ−Ｃ（Ｏ）Ｏ−Ｒ^ｅ（式中、Ｒ^ｄおよびＲ^ｅは、前記記載と同義である。）を表し；
Ｒ^４およびＲ^５は、隣接する炭素原子と共に置換されてもよいベンゼン環、置換されてもよいシクロアルケン環、または置換されてもよい５から６員の芳香族複素環を形成していてもよく；
−Ｙは、下記に示す、式（Ａ）、式（Ｂ）、式（Ｃ）または式（Ｄ）のいずれかの基を表す。

[Wherein, R ¹ represents a hydrogen atom, an optionally substituted alkyl group, an optionally substituted cycloalkyl group, an optionally substituted aryl group or an optionally substituted heteroaryl group;
R ² represents a hydrogen atom, an optionally substituted alkyl group, an optionally substituted aryl group, an optionally substituted heteroaryl group, an optionally substituted aralkyl group, an optionally substituted heteroarylalkyl group, Represents an optionally substituted alkenyl group or an optionally substituted alkynyl group;
R ³ represents a hydrogen atom, a halogen atom, a cyano group, a formyl group, a carboxy group, an optionally substituted alkyl group, an optionally substituted alkenyl group, an optionally substituted alkynyl group, or an optionally substituted cycloalkyl. Group, optionally substituted aryl group, optionally substituted heteroaryl group, optionally substituted aralkyl group, optionally substituted heteroarylalkyl group, optionally substituted alkylcarbonyl group, optionally substituted A good cycloalkylcarbonyl group, an optionally substituted aroyl group, an optionally substituted heteroarylcarbonyl group, an optionally substituted alkoxycarbonyl group, an optionally substituted aryloxycarbonyl group, an optionally substituted carbamoyl group or ^formula: -R d -C (O) O- R e ( wherein, ^{R d} represents a single bond, an alkylene , Or an alkenylene group, ^{R e} is tetrahydrofuranyl, cinnamyl, 5-methyl-2-oxo-1,3-dioxolen-4-ylmethyl, 5- (tert-butyl) -2-oxo-1,3 Dioxolen-4-ylmethyl, 2-morpholinoethyl, or —CH (R ^f ) OC (O) R ^g , where R ^f represents a hydrogen atom, an alkyl group, an alkenyl group, a cycloalkyl group, or an alkoxy group. R ^g represents an optionally substituted alkyl group, an optionally substituted alkenyl group, a cycloalkyl group, a cycloalkyloxy group, an optionally substituted alkoxy group, an optionally substituted alkenyloxy group, 2- Represents an indanyloxy group, a 5-indanyloxy group, or an optionally substituted aryloxy group);
R ⁴ represents a hydrogen atom, a halogen atom, a cyano group, a formyl group, an optionally substituted alkyl group, an optionally substituted cycloalkyl group, an optionally substituted cycloalkyloxy group, or an optionally substituted alkenyl group. , An optionally substituted alkynyl group, an optionally substituted amino group, an optionally substituted carbamoyl group, a carboxy group, an optionally substituted alkoxy group, an optionally substituted aryl group, an optionally substituted aryl An oxy group, an optionally substituted aralkyl group, an optionally substituted aralkyloxy group, an optionally substituted aroyl group, an optionally substituted arylthio group, an optionally substituted arylsulfinyl group, an optionally substituted Arylsulfonyl group, optionally substituted alkylthio group, optionally substituted alkylsulfinyl group, substituted May be an alkylsulfonyl group, an optionally substituted heteroaryl group, an optionally substituted heteroarylalkyl group, an optionally substituted heteroarylcarbonyl group, an optionally substituted heteroaryloxy group, an optionally substituted Alkylcarbonyl group, optionally substituted nitrogen-containing saturated heterocyclic group, optionally substituted alkoxycarbonyl group, optionally substituted aryloxycarbonyl group, optionally substituted aralkyloxycarbonyl group, optionally substituted A cycloalkyloxycarbonyl group, or a formula: —R ^d —C (O) O—R ^e (wherein R ^d and R ^e are as defined above);
R ⁵ represents a hydrogen atom, a halogen atom, an optionally substituted alkyl group, a carboxy group, an optionally substituted aryl group, an optionally substituted alkoxycarbonyl group, or a formula: —R ^d —C (O) O -R ^e (wherein R ^d and R ^e are as defined above);
R ⁴ and R ⁵ may form an optionally substituted benzene ring, an optionally substituted cycloalkene ring, or an optionally substituted 5- to 6-membered aromatic heterocyclic ring with adjacent carbon atoms. Often;
-Y represents any group of formula (A), formula (B), formula (C) or formula (D) shown below.

（式中、ｍ１は０、１、２または３を表し、ｍ２は１または２を表し、Ｒ^６は、存在しないか、１つまたは２つ存在し、各々独立して、ハロゲン原子、水酸基、オキソ基、置換されてもよいアルコキシ基、置換されてもよいアルキル基、置換されてもよいアリール基、置換されてもよいアラルキル基、置換されてもよいアミノ基、カルボキシ基、置換されてもよいアルコキシカルボニル基、もしくは置換されてもよいカルバモイル基を表すか、または２つのＲ^６が一緒になってメチレンもしくはエチレンを表し、環を構成する２つの炭素原子と結合し新たな環を形成することもできる。）、

(In the formula, m1 represents 0, 1, 2 or 3, m2 represents 1 or 2, R ⁶ does not exist, or 1 or 2 exists, and each independently represents a halogen atom, a hydroxyl group, Oxo group, alkoxy group which may be substituted, alkyl group which may be substituted, aryl group which may be substituted, aralkyl group which may be substituted, amino group which may be substituted, carboxy group, which may be substituted Represents a good alkoxycarbonyl group, or an optionally substituted carbamoyl group, or two R ⁶ together represent methylene or ethylene and combine with the two carbon atoms constituting the ring to form a new ring Can also be)

（式中、ｍ３は０、１、２または３を表し、Ｒ^７は、存在しないか、１つまたは２つ存在し、各々独立して、ハロゲン原子、水酸基、オキソ基、置換されてもよいアルコキシ基、置換されてもよいアルキル基、置換されてもよいアリール基、置換されてもよいアラルキル基、置換されてもよいアミノ基、カルボキシ基、置換されてもよいアルコキシカルボニル基、もしくは置換されてもよいカルバモイル基を表すか、または２つのＲ^７が一緒になってメチレンもしくはエチレンを表し、環を構成する２つの炭素原子と結合し新たな環を形成することもできる。）、

(In the formula, m3 represents 0, 1, 2 or 3, and R ⁷ does not exist, or 1 or 2 exist, and each independently represents a halogen atom, a hydroxyl group, an oxo group, or may be substituted. An alkoxy group, an optionally substituted alkyl group, an optionally substituted aryl group, an optionally substituted aralkyl group, an optionally substituted amino group, a carboxy group, an optionally substituted alkoxycarbonyl group, or a substituted It may represent a carbamoyl group which may be substituted, or two R ⁷ together represent methylene or ethylene, and can be bonded to two carbon atoms constituting the ring to form a new ring).

（式中、ｍ４およびｍ５はそれぞれ独立して、０または１を表し、Ｒ^８は、存在しないか、１つまたは２つ存在し、各々独立して、ハロゲン原子、水酸基、オキソ基、置換されてもよいアルコキシ基、置換されてもよいアルキル基、置換されてもよいアリール基、置換されてもよいアラルキル基、置換されてもよいアミノ基、カルボキシ基、置換されてもよいアルコキシカルボニル基、もしくは置換されてもよいカルバモイル基を表すか、または２つのＲ^８が一緒になってメチレンもしくはエチレンを表し、環を構成する２つの炭素原子と結合し新たな環を形成することもできる。）、

(In the formula, m4 and m5 each independently represent 0 or 1, and R ⁸ is not present, or 1 or 2 are present, and each independently represents a halogen atom, a hydroxyl group, an oxo group, or a substituted group. An optionally substituted alkoxy group, an optionally substituted alkyl group, an optionally substituted aryl group, an optionally substituted aralkyl group, an optionally substituted amino group, a carboxy group, an optionally substituted alkoxycarbonyl group, Alternatively, it represents a carbamoyl group which may be substituted, or two R ⁸ together represent methylene or ethylene, and can combine with two carbon atoms constituting the ring to form a new ring.) ,

（式中、ｍ６は１、２または３を表し、Ｒ^９は、存在しないか、１つまたは２つ存在し、各々独立して、ハロゲン原子、水酸基、オキソ基、置換されてもよいアルコキシ基、置換されてもよいアルキル基、置換されてもよいアリール基、置換されてもよいアラルキル基、置換されてもよいアミノ基、カルボキシ基、置換されてもよいアルコキシカルボニル基、もしくは置換されてもよいカルバモイル基を表すか、または２つのＲ^９が一緒になってメチレンもしくはエチレンを表し、環を構成する２つの炭素原子と結合し新たな環を形成することもでき、Ｒ^１０およびＲ^１１はそれぞれ独立して、水素原子、メチル、エチル、プロピル、またはイソプロピルを表すか、またはＲ^１０およびＲ^１１が一緒になってシクロプロピル、シクロブチルもしくはシクロペンチルを表す。）]で表される化合物もしくはそのプロドラッグ、またはそれらの薬学上許容される塩、
［２］
式（ＩＩ）：

(In the formula, m6 represents 1, 2 or 3, and R ⁹ does not exist, or 1 or 2 exist, and each independently represents a halogen atom, a hydroxyl group, an oxo group, or an optionally substituted alkoxy group. , An optionally substituted alkyl group, an optionally substituted aryl group, an optionally substituted aralkyl group, an optionally substituted amino group, a carboxy group, an optionally substituted alkoxycarbonyl group, or an optionally substituted It represents a good carbamoyl group, or two R ⁹ together represent methylene or ethylene, and can be bonded to two carbon atoms constituting the ring to form a new ring, and R ¹⁰ and R ¹¹ are each independently, hydrogen atom, methyl, ethyl, propyl or cyclopropyl or represents isopropyl, or R ¹⁰ and R ¹¹ together, Shikurobuchi Or cyclopentyl.)] A compound represented by or its prodrugs or their pharmaceutically acceptable salts,
[2]
Formula (II):

[式中、Ｒ^１、Ｒ^２、Ｒ^３、およびＹは、［１］記載と同義であり、Ｒ^１２は、水素原子、シアノ基、置換されてもよいアルキル基、置換されてもよいシクロアルキル基、置換されてもよいアルケニル基、置換されてもよいアルキニル基、置換されてもよいカルバモイル基、カルボキシ基、置換されてもよいアリール基、置換されてもよいアラルキル基、置換されてもよいアロイル基、置換されてもよいヘテロアリール基、置換されてもよいヘテロアリールアルキル基、置換されてもよいヘテロアリールカルボニル基、置換されてもよいアルキルカルボニル基、置換されてもよいアルコキシカルボニル基、置換されてもよいアリールオキシカルボニル基、置換されてもよいアラルキルオキシカルボニル基、置換されてもよいシクロアルキルオキシカルボニル基、または式：−Ｒ^ｄ−Ｃ（Ｏ）Ｏ−Ｒ^ｅ（式中、Ｒ^ｄおよびＲ^ｅは、［１］記載と同義である。）を表し、Ｒ^１３は、水素原子、置換されてもよいアルキル基、置換されてもよいアリール基、またはアルコシキカルボニルメチル基を表す。]で表される、［１］記載の化合物もしくはそのプロドラッグ、またはそれらの薬学上許容される塩、
［３］
式（ＩＩＩ）：

[Wherein, R ¹ , R ² , R ³ , and Y are as defined in [1], and R ¹² represents a hydrogen atom, a cyano group, an optionally substituted alkyl group, or an optionally substituted cyclo group. An alkyl group, an optionally substituted alkenyl group, an optionally substituted alkynyl group, an optionally substituted carbamoyl group, a carboxy group, an optionally substituted aryl group, an optionally substituted aralkyl group, and an optionally substituted Good aroyl group, optionally substituted heteroaryl group, optionally substituted heteroarylalkyl group, optionally substituted heteroarylcarbonyl group, optionally substituted alkylcarbonyl group, optionally substituted alkoxycarbonyl group An optionally substituted aryloxycarbonyl group, an optionally substituted aralkyloxycarbonyl group, an optionally substituted cycloalkyl Oxycarbonyl group, or a group of the ^formula: (. Wherein, ^{R d} and ^{R e} have the same meanings as [1], wherein) -R d -C (O) O -R e ^{represents, R 13} is a hydrogen atom, An alkyl group that may be substituted, an aryl group that may be substituted, or an alkoxycarbonylmethyl group. Or a prodrug thereof, or a pharmaceutically acceptable salt thereof,
[3]
Formula (III):

[式中、Ｒ^１、Ｒ^２、Ｒ^３、およびＹは、［１］記載と同義であり、環Ａ^１は、置換されてもよいベンゼン環、置換されてもよいシクロアルケン環、または置換されてもよい５から６員の芳香族複素環を表す。]で表される、［１］記載の化合物もしくはそのプロドラッグ、またはそれらの薬学上許容される塩、
［４］
式（IＶ）：

[Wherein R ¹ , R ² , R ³ and Y are as defined in [1], and ring A ¹ is an optionally substituted benzene ring, an optionally substituted cycloalkene ring, or a substituted atom. Represents a 5- to 6-membered aromatic heterocycle which may be substituted. Or a prodrug thereof, or a pharmaceutically acceptable salt thereof,
[4]
Formula (IV):

[式中、Ｒ^１、Ｒ^２、Ｒ^３、およびＹは、［１］記載と同義であり、Ｚ^１、Ｚ^２、Ｚ^３、およびＺ^４はそれぞれ独立して、式：Ｃ−Ｒ^１４または窒素原子を表す。ただし、Ｚ^１、Ｚ^２、Ｚ^３、およびＺ^４が同時に窒素原子であることはない。Ｒ^１４は、各々独立して、水素原子、水酸基、ハロゲン原子、シアノ基、カルボキシ基、置換されてもよいアルキル基、置換されてもよいシクロアルキル基、置換されてもよいシクロアルキルオキシ基、置換されてもよいアルケニル基、置換されてもよいカルバモイル基、置換されてもよいアルコキシ基、置換されてもよいアルコキシカルボニル基、置換されてもよいアリールオキシカルボニル基、置換されてもよいアルキルカルボニル基、置換されてもよいシクロアルキルオキシカルボニル基、置換されてもよいアラルキルオキシカルボニル基、テトラヒドロフラニルオキシカルボニル基、シンナミルオキシカルボニル基、または式：−Ｒ^ｄ−Ｃ（Ｏ）Ｏ−Ｒ^ｅ（式中、Ｒ^ｄおよびＲ^ｅは、［１］記載と同義である。）で表される基を表す。]で表される、［１］記載の化合物もしくはそのプロドラッグ、またはそれらの薬学上許容される塩、
［５］
Ｒ^２が、下記に示す、式（Ｅ）、式（Ｆ）、式（Ｇ）、式（Ｈ）、式（Ｉ）または式（Ｊ）のいずれかの基である、［１］〜［４］のいずれかに記載の化合物もしくはそのプロドラッグ、またはそれらの薬学上許容される塩、

[Wherein R ¹ , R ² , R ³ , and Y are as defined in [1], and Z ¹ , Z ² , Z ³ , and Z ⁴ are each independently represented by the formula: C—R ¹⁴ Or represents a nitrogen atom. However, Z ¹ , Z ² , Z ³ , and Z ⁴ are not simultaneously nitrogen atoms. R ¹⁴ each independently represents a hydrogen atom, a hydroxyl group, a halogen atom, a cyano group, a carboxy group, an optionally substituted alkyl group, an optionally substituted cycloalkyl group, an optionally substituted cycloalkyloxy group, An optionally substituted alkenyl group, an optionally substituted carbamoyl group, an optionally substituted alkoxy group, an optionally substituted alkoxycarbonyl group, an optionally substituted aryloxycarbonyl group, an optionally substituted alkylcarbonyl Group, an optionally substituted cycloalkyloxycarbonyl group, an optionally substituted aralkyloxycarbonyl group, a tetrahydrofuranyloxycarbonyl group, a cinnamyloxycarbonyl group, or a formula: —R ^d —C (O) O—R ^e Wherein R ^d and R ^e are as defined in [1]. To express. Or a prodrug thereof, or a pharmaceutically acceptable salt thereof,
[5]
R ² is a group of any one of formula (E), formula (F), formula (G), formula (H), formula (I) or formula (J) shown below: [1]-[ 4] or a prodrug thereof, or a pharmaceutically acceptable salt thereof,

（式中、Ｚ^５およびＺ^６は、酸素原子、式：Ｓ（Ｏ）ｐまたは式：Ｎ(Ｒ^２３)を表し、
Ｒ^１５およびＲ^２１は、存在しないか、１つまたは２つ存在し、各々独立して、ハロゲン原子、水酸基、ホルミル基、カルボキシ基、シアノ基、アルキルチオ基、アルキルスルフィニル基、アルキルスルホニル基、アルキル基、ハロアルキル基、シクロアルキル基、アルコキシ基、ハロアルコキシ基、置換されてもよいアミノ基、置換されてもよいカルバモイル基、アルコキシカルボニル基、置換されてもよいアルキルカルボニル基、シクロアルキルカルボニル基、置換されてもよいアリール基、置換されてもよいヘテロアリール基または置換されてもよい含窒素ヘテロアリール基を表すか、または２つのＲ^１５および２つのＲ^２１が一緒になってＣ_１−３アルキレンジオキシ基を表し、
Ｒ^１６およびＲ^２２は、存在しないか、１つまたは２つ存在し、各々独立して、ハロゲン原子、シアノ基、アルキル基、ハロアルキル基、シクロアルキル基、アルコキシ基またはハロアルコキシ基を表し、
Ｒ^１７はメチル、エチル、塩素原子または臭素原子を表し、
Ｒ^１８は水素原子、メチル、エチル、塩素原子または臭素原子を表し、
Ｒ^１９は水素原子、メチルまたはエチルを表し、
Ｒ^２０は水素原子、メチル、エチル、シクロプロピルまたはシクロブチルを表し、
ｐは０、１または２を表し、
Ｒ^２３は水素原子またはアルキル基を表す。）、
［６］
Ｒ^２が式（Ｅ）、式（Ｈ）、または式（Ｉ）のいずれかの基である、［１］〜［４］のいずれかに記載の化合物もしくはそのプロドラッグ、またはそれらの薬学上許容される塩、
［７］
Ｒ^２が式（Ｅ１）：

Wherein Z ⁵ and Z ⁶ represent an oxygen atom, formula: S (O) p or formula: N (R ²³ ),
R ¹⁵ and R ²¹ are not present, or one or two are present, and each independently represents a halogen atom, a hydroxyl group, a formyl group, a carboxy group, a cyano group, an alkylthio group, an alkylsulfinyl group, an alkylsulfonyl group, an alkyl Group, haloalkyl group, cycloalkyl group, alkoxy group, haloalkoxy group, amino group which may be substituted, carbamoyl group which may be substituted, alkoxycarbonyl group, alkylcarbonyl group which may be substituted, cycloalkylcarbonyl group, Represents an optionally substituted aryl group, an optionally substituted heteroaryl group or an optionally substituted nitrogen-containing heteroaryl group, or two R ¹⁵ and two R ²¹ together represent C _1-3 Represents an alkylenedioxy group,
R ¹⁶ and R ²² are not present, or one or two are present, and each independently represents a halogen atom, a cyano group, an alkyl group, a haloalkyl group, a cycloalkyl group, an alkoxy group or a haloalkoxy group,
R ¹⁷ represents a methyl, ethyl, chlorine atom or bromine atom;
R ¹⁸ represents a hydrogen atom, methyl, ethyl, chlorine atom or bromine atom;
R ¹⁹ represents a hydrogen atom, methyl or ethyl,
R ²⁰ represents a hydrogen atom, methyl, ethyl, cyclopropyl or cyclobutyl,
p represents 0, 1 or 2;
R ²³ represents a hydrogen atom or an alkyl group. ),
[6]
The compound according to any one of [1] to [4], wherein R ² is any group of formula (E), formula (H), or formula (I), or a prodrug thereof, or a pharmaceutically acceptable product thereof Acceptable salts,
[7]
R ² represents formula (E1):

[式中、Ｒ^２４は、塩素原子、臭素原子、ヨウ素原子、シアノ基、メチル、ジフルオロメチル、トリフルオロメチル、メトキシ、フルオロメトキシ、ジフルオロメトキシ、またはトリフルオロメトキシを表し、Ｒ^２５は、水素原子またはフッ素原子を表す。]である、［１］〜［４］のいずれかに記載の化合物もしくはそのプロドラッグ、またはそれらの薬学上許容される塩、
［８］
Ｒ^２４が、塩素原子またはシアノ基である、［７］記載の化合物もしくはそのプロドラッグ、またはそれらの薬学上許容される塩、
［９］
Ｒ^４が、水素原子、シアノ基、カルボキシ基、アルコキシカルボニル基、または式：−Ｒ^ｄ１−Ｃ（Ｏ）Ｏ−Ｒ^ｅ１（式中、Ｒ^ｄ１は、単結合を表し、Ｒ^ｅ１は、５−メチル−２−オキソ−１，３−ジオキソレン−４−イルメチル、２−モルホリノエチル、または式：−ＣＨ（Ｒ^ｆ１）ＯＣ（Ｏ）Ｒ^ｇ１を表す。Ｒ^ｆ１は、水素原子またはアルキル基を表し、Ｒ^ｇ１は、アルコキシ基またはシクロアルキルオキシ基を表す。）であり、
Ｒ^５が、水素原子であるか、もしくは
Ｒ^４およびＲ^５が、隣接する炭素原子と共に置換されてもよいベンゼン環を形成する、［１］〜［８］のいずれかに記載の化合物もしくはそのプロドラッグ、またはそれらの薬学上許容される塩、
［１０］
Ｒ^４およびＲ^５が、隣接する炭素原子と共に置換されてもよいベンゼン環を形成し、該置換基が、カルボキシ基、または式：−Ｒ^ｄ２−Ｃ（Ｏ）Ｏ−Ｒ^ｅ２（式中、Ｒ^ｄ２は、単結合を表し、Ｒ^ｅ２は、５−メチル−２−オキソ−１，３−ジオキソレン−４−イルメチル、２−モルホリノエチル、または式：−ＣＨ（Ｒ^ｆ２）ＯＣ（Ｏ）Ｒ^ｇ２を表す。Ｒ^ｆ２は、水素原子またはアルキル基を表し、Ｒ^ｇ２は、アルコキシ基またはシクロアルキルオキシ基を表す。）で表される基である、［１］〜［８］のいずれかに記載の化合物もしくはそのプロドラッグ、またはそれらの薬学上許容される塩、
［１１］
式（Ｖ）：

[Wherein, R ²⁴ represents a chlorine atom, a bromine atom, an iodine atom, a cyano group, methyl, difluoromethyl, trifluoromethyl, methoxy, fluoromethoxy, difluoromethoxy, or trifluoromethoxy, and R ²⁵ represents a hydrogen atom. Or represents a fluorine atom. Or a prodrug thereof, or a pharmaceutically acceptable salt thereof, according to any one of [1] to [4],
[8]
The compound according to [7] or a prodrug thereof, or a pharmaceutically acceptable salt thereof, wherein R ²⁴ is a chlorine atom or a cyano group,
[9]
R ⁴ is a hydrogen atom, a cyano group, a carboxy group, an alkoxycarbonyl group, or a formula: —R ^d1 —C (O) O—R ^e1 (wherein R ^d1 represents a single bond, and R ^e1 represents 5 —Methyl-2-oxo-1,3-dioxolen-4-ylmethyl, 2-morpholinoethyl, or —CH (R ^f1 ) OC (O) R ^g1 , where R ^f1 represents a hydrogen atom or an alkyl group. And R ^g1 represents an alkoxy group or a cycloalkyloxy group.)
The compound according to any one of [1] to [8] or a compound thereof, wherein R ⁵ is a hydrogen atom, or R ⁴ and R ⁵ form a benzene ring that may be substituted with an adjacent carbon atom. Prodrugs, or pharmaceutically acceptable salts thereof,
[10]
R ⁴ and R ⁵ together with an adjacent carbon atom form an optionally substituted benzene ring, and the substituent is a carboxy group or a formula: —R ^d2 —C (O) O—R ^e2 (wherein R ^d2 represents a single bond, and R ^e2 represents 5-methyl-2-oxo-1,3-dioxolen-4-ylmethyl, 2-morpholinoethyl, or a formula: —CH (R ^f2 ) OC (O) R ^{.R f2} representing the ^g2 represents a hydrogen atom or an alkyl ^{group, R g2} represents an alkoxy group or a cycloalkyl group.) is a group represented by any of [1] to [8] The described compound or a prodrug thereof, or a pharmaceutically acceptable salt thereof,
[11]
Formula (V):

[式中、Ｒ^１、Ｒ^３、およびＹは、［１］記載と同義であり、Ｚ^７およびＺ^８はそれぞれ独立して、式：Ｃ−Ｒ^１４または窒素原子を表す。Ｒ^１４は、各々独立して、水素原子、水酸基、ハロゲン原子、シアノ基、カルボキシ基、置換されてもよいアルキル基、置換されてもよいシクロアルキル基、置換されてもよいシクロアルキルオキシ基、置換されてもよいアルケニル基、置換されてもよいカルバモイル基、置換されてもよいアルコキシ基、置換されてもよいアルコキシカルボニル基、置換されてもよいアリールオキシカルボニル基、置換されてもよいアルキルカルボニル基、置換されてもよいシクロアルキルオキシカルボニル基、置換されてもよいアラルキルオキシカルボニル基、テトラヒドロフラニルオキシカルボニル基、シンナミルオキシカルボニル基、または式：−Ｒ^ｄ−Ｃ（Ｏ）Ｏ−Ｒ^ｅ（式中、Ｒ^ｄおよびＲ^ｅは、［１］記載と同義である。）で表される基を表す。Ｒ^２４は、塩素原子、臭素原子、ヨウ素原子、シアノ基、メチル、ジフルオロメチル、トリフルオロメチル、メトキシ、フルオロメトキシ、ジフルオロメトキシ、またはトリフルオロメトキシを表し、Ｒ^２５は、水素原子またはフッ素原子を表す。]で表される、［１］記載の化合物もしくはそのプロドラッグ、またはそれらの薬学上許容される塩、
［１２］
Ｚ^７およびＺ^８が式：Ｃ−Ｒ^１４で表される基である、［１１］記載の化合物もしくはそのプロドラッグ、またはそれらの薬学上許容される塩、
［１３］
Ｒ^１４が、各々独立して、水素原子、カルボキシ基、または式：−Ｒ^ｄ２−Ｃ（Ｏ）Ｏ−Ｒ^ｅ２（式中、Ｒ^ｄ２は、単結合を表し、Ｒ^ｅ２は、５−メチル−２−オキソ−１，３−ジオキソレン−４−イルメチル、２−モルホリノエチル、または式：−ＣＨ（Ｒ^ｆ２）ＯＣ（Ｏ）Ｒ^ｇ２を表す。Ｒ^ｆ２は、水素原子またはアルキル基を表し、Ｒ^ｇ２は、アルコキシ基またはシクロアルキルオキシ基を表す。）で表される基である、［１２］記載の化合物もしくはそのプロドラッグ、またはそれらの薬学上許容される塩、
［１４］
Ｒ^２４が、塩素原子またはシアノ基である、［１１］〜［１３］のいずれかに記載の化合物もしくはそのプロドラッグ、またはそれらの薬学上許容される塩、
［１５］
−Ｙが式（Ａ）で表される基であり、ｍ１およびｍ２がそれぞれ独立して１もしくは２であるか、−Ｙが式（Ｂ）で表される基であり、ｍ３が１もしくは２であるか、または−Ｙが式（Ｃ）で表される基であり、ｍ４およびｍ５が１である、［１］〜［１４］のいずれかに記載の化合物もしくはそのプロドラッグ、またはそれらの薬学上許容される塩、
［１６］
Ｒ^１が水素原子、置換されてもよいＣ_１〜Ｃ_３アルキル基、または、置換されてもよいアリール基であり、当該置換されてもよいアルキル基の置換基がフッ素原子、置換されてもよいアロイル基、カルボキシ基、置換されてもよいアルコキシカルボニル基、置換されてもよいアリール基および置換されてもよいアリールオキシ基から選ばれる、［１］〜［１５］のいずれかに記載の化合物もしくはそのプロドラッグ、またはそれらの薬学上許容される塩、
［１７］
Ｒ^１が式：−Ｒ^ａ−Ｒ^ｂ−Ｒ^ｃ（式中、Ｒ^ａはアルキレン基を、Ｒ^ｂは単結合またはカルボニル基を、Ｒ^ｃは置換されてもよいアルキル基、置換されてもよいアルコキシ基、置換されてもよいアリール基、または置換されてもよいアリールオキシ基を表す。）で表される基である、［１］〜［１５］のいずれかに記載の化合物もしくはそのプロドラッグ、またはそれらの薬学上許容される塩、
［１８］
Ｒ^１が水素原子またはアルキル基である、［１］〜［１５］のいずれかに記載の化合物もしくはそのプロドラッグ、またはそれらの薬学上許容される塩、
［１９］
Ｒ^１が水素原子、メチル、またはエチルである、［１］〜［１５］のいずれかに記載の化合物もしくはそのプロドラッグ、またはそれらの薬学上許容される塩、
［２０］
Ｙが式（Ａ）で表される基である、［１］〜［１９］のいずれかに記載の化合物もしくはそのプロドラッグ、またはそれらの薬学上許容される塩、
［２１］
−Ｙが式（Ａ）で表される基であり、ｍ１が２であり、ｍ２が１であり、Ｒ^６が存在しない、［１］〜［１９］のいずれかに記載の化合物もしくはそのプロドラッグ、またはそれらの薬学上許容される塩、
［２２］
Ｒ^３が水素原子またはシアノ基である、［１］〜［２１］のいずれかに記載の化合物もしくはそのプロドラッグ、またはそれらの薬学上許容される塩、
［２３］
Ｒ^１がメチルである、［１］〜［２２］のいずれかに記載の化合物もしくはそのプロドラッグ、またはそれらの薬学上許容される塩、
［２４］
［１］〜［２３］のいずれかに記載の化合物もしくはそのプロドラッグ、またはそれらの薬学上許容される塩を有効成分として含有する医薬、
［２５］
［１］〜［２３］のいずれかに記載の化合物もしくはそのプロドラッグ、またはそれらの薬学上許容される塩を有効成分として含有するジペプチジルペプチダーゼ-IV阻害剤、
［２６］
［１］〜［２３］のいずれかに記載の化合物もしくはそのプロドラッグ、またはそれらの薬学上許容される塩を有効成分として含有する糖尿病治療剤、
［２７］
ジペプチジルペプチダーゼ-IV阻害剤製造のための、［１］〜［２３］のいずれかに記載の化合物もしくはそのプロドラッグ、またはそれらの薬学上許容される塩の使用、
［２８］
糖尿病治療剤の製造のための、［１］〜［２３］のいずれかに記載の化合物もしくはそのプロドラッグ、またはそれらの薬学上許容される塩の使用、または
［２９］
治療を必要とする患者に、［１］〜［２３］のいずれかに記載の化合物もしくはそのプロドラッグ、またはそれらの薬学上許容される塩の有効量を投与することからなる、糖尿病の治療方法に関する。

[Wherein, R ¹ , R ³ , and Y have the same meanings as described in [1], and Z ⁷ and Z ⁸ each independently represent the formula: C—R ¹⁴ or a nitrogen atom. R ¹⁴ each independently represents a hydrogen atom, a hydroxyl group, a halogen atom, a cyano group, a carboxy group, an optionally substituted alkyl group, an optionally substituted cycloalkyl group, an optionally substituted cycloalkyloxy group, An optionally substituted alkenyl group, an optionally substituted carbamoyl group, an optionally substituted alkoxy group, an optionally substituted alkoxycarbonyl group, an optionally substituted aryloxycarbonyl group, an optionally substituted alkylcarbonyl Group, an optionally substituted cycloalkyloxycarbonyl group, an optionally substituted aralkyloxycarbonyl group, a tetrahydrofuranyloxycarbonyl group, a cinnamyloxycarbonyl group, or a formula: —R ^d —C (O) O—R ^e Wherein R ^d and R ^e are as defined in [1]. To express. R ²⁴ represents a chlorine atom, a bromine atom, an iodine atom, a cyano group, methyl, difluoromethyl, trifluoromethyl, methoxy, fluoromethoxy, difluoromethoxy, or trifluoromethoxy, and R ²⁵ represents a hydrogen atom or a fluorine atom. To express. Or a prodrug thereof, or a pharmaceutically acceptable salt thereof,
[12]
The compound according to [11] or a prodrug thereof, or a pharmaceutically acceptable salt thereof, wherein Z ⁷ and Z ⁸ are groups represented by the formula: C—R ¹⁴ ;
[13]
Each of R ¹⁴ independently represents a hydrogen atom, a carboxy group, or a formula: —R ^d2 —C (O) O—R ^e2 (wherein R ^d2 represents a single bond, R ^e2 represents 5-methyl; 2-oxo-1,3-dioxolen-4-ylmethyl, 2-morpholinoethyl, or the formula: —CH (R ^f2 ) OC (O) R ^g2 , where R ^f2 represents a hydrogen atom or an alkyl group; R ^g2 represents an alkoxy group or a cycloalkyloxy group.) The compound of [12] or a prodrug thereof, or a pharmaceutically acceptable salt thereof,
[14]
The compound according to any one of [11] to [13], wherein R ²⁴ is a chlorine atom or a cyano group, or a prodrug thereof, or a pharmaceutically acceptable salt thereof,
[15]
-Y is a group represented by the formula (A), and m1 and m2 are each independently 1 or 2, or -Y is a group represented by the formula (B), and m3 is 1 or 2 Or a compound represented by any one of [1] to [14], wherein -Y is a group represented by formula (C), and m4 and m5 are 1, or a prodrug thereof, A pharmaceutically acceptable salt,
[16]
R ¹ is a hydrogen atom, an optionally substituted C ₁ -C ₃ alkyl group, or an optionally substituted aryl group, and the substituent of the optionally substituted alkyl group may be a fluorine atom or substituted. The compound according to any one of [1] to [15], which is selected from a good aroyl group, a carboxy group, an optionally substituted alkoxycarbonyl group, an optionally substituted aryl group and an optionally substituted aryloxy group Or a prodrug thereof, or a pharmaceutically acceptable salt thereof,
[17]
R ¹ is represented by the formula: —R ^a —R ^b —R ^c (wherein R ^a is an alkylene group, R ^b is a single bond or a carbonyl group, R ^c is an optionally substituted alkyl group, A suitable alkoxy group, an optionally substituted aryl group, or an optionally substituted aryloxy group.) Or a compound thereof according to any one of [1] to [15] A drug, or a pharmaceutically acceptable salt thereof,
[18]
The compound or prodrug thereof according to any one of [1] to [15], wherein R ¹ is a hydrogen atom or an alkyl group, or a pharmaceutically acceptable salt thereof,
[19]
The compound according to any one of [1] to [15], wherein R ¹ is a hydrogen atom, methyl or ethyl, or a prodrug thereof, or a pharmaceutically acceptable salt thereof,
[20]
The compound or prodrug thereof according to any one of [1] to [19], wherein Y is a group represented by formula (A), or a pharmaceutically acceptable salt thereof;
[21]
-Y is a group represented by the formula (A), m1 is 2, m @ 2 is 1, ^{R 6} is absent, [1] A compound according to any one of - [19] or its pro A drug, or a pharmaceutically acceptable salt thereof,
[22]
The compound according to any one of [1] to [21], wherein R ³ is a hydrogen atom or a cyano group, or a prodrug thereof, or a pharmaceutically acceptable salt thereof,
[23]
The compound or prodrug thereof according to any one of [1] to [22], wherein R ¹ is methyl, or a pharmaceutically acceptable salt thereof;
[24]
[1] to [23] a pharmaceutical comprising a compound or prodrug thereof, or a pharmaceutically acceptable salt thereof as an active ingredient,
[25]
A dipeptidyl peptidase-IV inhibitor containing the compound according to any one of [1] to [23] or a prodrug thereof, or a pharmaceutically acceptable salt thereof as an active ingredient,
[26]
A therapeutic agent for diabetes containing the compound according to any one of [1] to [23] or a prodrug thereof, or a pharmaceutically acceptable salt thereof as an active ingredient,
[27]
Use of the compound according to any one of [1] to [23] or a prodrug thereof, or a pharmaceutically acceptable salt thereof for the production of a dipeptidyl peptidase-IV inhibitor,
[28]
Use of the compound according to any one of [1] to [23] or a prodrug thereof, or a pharmaceutically acceptable salt thereof for the manufacture of a therapeutic agent for diabetes, or [29]
A method for treating diabetes comprising administering to a patient in need of treatment an effective amount of a compound according to any one of [1] to [23] or a prodrug thereof, or a pharmaceutically acceptable salt thereof. About.

  The compound of the present invention has excellent DPP-IV inhibitory activity and is useful as a therapeutic agent for diabetes.

The present invention is described in further detail below.
In the present specification, the number of substituents in the group defined as “may be substituted” or “substituted” is not particularly limited as long as substitution is possible, and is one or more. In addition, unless otherwise specified, the description of each group also applies when the group is a part of another group or a substituent.

Examples of the “halogen atom” include a fluorine atom, a chlorine atom, a bromine atom or an iodine atom.
Examples of the “alkyl group” include linear or branched alkyl groups having 1 to 6 carbon atoms, and specific examples include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec- Examples include butyl, tert-butyl, pentyl, isopentyl, neopentyl, 1-ethylpropyl, hexyl, isohexyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, 2-ethylbutyl and the like. Preferable examples include linear or branched alkyl groups having 1 to 4 carbon atoms, and specific examples include methyl, ethyl, propyl, isopropyl, butyl, tert-butyl and the like.
Examples of the “alkenyl group” include alkenyl groups having 2 to 6 carbon atoms, and specific examples include vinyl, propenyl, methylpropenyl, butenyl, methylbutenyl and the like.
Examples of the “alkynyl group” include an alkynyl group having 2 to 6 carbon atoms, and specific examples include ethynyl, 1-propynyl, 2-propynyl, 2-butynyl, pentynyl, hexynyl and the like.
Examples of the “cycloalkyl group” include a cycloalkyl group having 3 to 10 carbon atoms, and specific examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, adamantyl, norbornyl, and the like. Preferably, a C3-C6 cycloalkyl group etc. are mentioned, Specifically, a cyclopropyl, cyclobutyl, cyclopentyl, or a cyclohexyl etc. are mentioned, for example.
Examples of the “alkylene group” include an alkylene group having 1 to 3 carbon atoms, and specific examples include methylene, ethylene, trimethylene and the like.
Examples of the “alkenylene group” include an alkenylene group having 2 to 4 carbon atoms, and specific examples include vinylene, propenylene, and butenylene.

Examples of the “aryl group” include aryl groups having 6 to 10 carbon atoms, and specific examples include phenyl, 1-naphthyl, 2-naphthyl and the like.
Examples of the “aralkyl group” include those in which an aryl group is bonded to an alkylene group. Specific examples include benzyl, 2-phenylethyl, 1-naphthylmethyl and the like.
Examples of the “heteroaryl group” include a 5- to 10-membered, monocyclic or polycyclic group containing 1 or more (for example, 1 to 4) heteroatoms selected from a nitrogen atom, a sulfur atom, and an oxygen atom. Can be mentioned. Specifically, pyrrolyl, thienyl, benzothienyl, benzofuranyl, benzoxazolyl, benzthiazolyl, furyl, oxazolyl, thiazolyl, isoxazolyl, imidazolyl, pyrazolyl, pyridyl, pyrazyl, pyrimidyl, pyridadyl, quinolyl, isoquinolyl, triazolyl, triazinyl, tetrazolyl , Indolyl, imidazo [1,2-a] pyridyl, dibenzofuranyl, benzimidazolyl, quinoxalyl, cinnolyl, quinazolyl, indazolyl, naphthyridyl, quinolinolyl or isoquinolinolyl. Preferable examples include a 5- to 6-membered group containing one heteroatom selected from a nitrogen atom, a sulfur atom and an oxygen atom, and specific examples include pyridyl, thienyl or furyl.
Examples of the heteroaryl part of the “heteroarylalkyl group” include those exemplified as the aforementioned heteroaryl group.

Examples of the “alkylcarbonyl group” include, for example, an alkylcarbonyl group having 2 to 4 carbon atoms, and specific examples include acetyl, propionyl, butyryl and the like.
Examples of the “cycloalkylcarbonyl group” include a cycloalkylcarbonyl group having 4 to 11 carbon atoms. Specific examples include cyclopropylcarbonyl, cyclobutylcarbonyl, cyclopentylcarbonyl, cyclohexylcarbonyl, adamantylcarbonyl, norbornylcarbonyl, and the like. Preferably, a C4-C7 cycloalkyl carbonyl group etc. are mentioned, Specifically, a cyclopropyl carbonyl, cyclobutyl carbonyl, cyclopentyl carbonyl, or a cyclohexyl carbonyl etc. are mentioned, for example.
Examples of the “aroyl group” include an aroyl group having 7 to 11 carbon atoms, and specific examples include benzoyl, 1-naphthoyl, 2-naphthoyl and the like.
Examples of the heteroaryl moiety of the “heteroarylcarbonyl group” include those exemplified as the aforementioned heteroaryl group.
Examples of the “alkoxycarbonyl group” include an alkoxycarbonyl group having 2 to 5 carbon atoms, and specific examples include methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, 2-propoxycarbonyl, tert-butoxycarbonyl and the like. It is done.
Examples of the “aryloxycarbonyl group” include aryloxycarbonyl groups having 7 to 11 carbon atoms, and specific examples include phenyloxycarbonyl, 2-naphthyloxycarbonyl, 1-naphthyloxycarbonyl group and the like. It is done.

Examples of the “alkoxy group” include an alkoxy group having 1 to 4 carbon atoms, and specific examples include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy and the like. Can be mentioned.
Examples of the “cycloalkyloxy group” include a cycloalkyloxy group having 3 to 10 carbon atoms, and specifically include, for example, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, cycloheptyloxy, And adamantyloxy and norbornyloxy. Preferable examples include a cycloalkyloxy group having 3 to 6 carbon atoms, and specific examples include cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy and the like.
Examples of the cycloalkyloxy moiety of the “cycloalkyloxycarbonyl group” include those exemplified as the aforementioned cycloalkyloxy group.
Examples of the “aryloxy group” include aryloxy groups having 6 to 10 carbon atoms, and specific examples include phenoxy, 1-naphthyloxy, 2-naphthyloxy and the like.
Examples of the aralkyl moiety of the “aralkyloxy group” include those exemplified as the aralkyl group, and specific examples include benzyloxy and 2-phenylethyloxy.
Examples of the aralkyl moiety of the “aralkyloxycarbonyl group” include those exemplified as the aforementioned aralkyl group.
Examples of the heteroaryl moiety of the “heteroaryloxy group” include those exemplified as the aforementioned heteroaryl group.

Examples of the “alkylthio group” include an alkylthio group having 1 to 6 carbon atoms, and specifically include, for example, methylthio, ethylthio, propylthio, isopropylthio, butylthio, sec-butylthio, tert-butylthio, pentylthio or And hexylthio. Preferable examples include alkylthio groups having 1 to 4 carbon atoms, and specific examples include methylthio, ethylthio, propylthio, isopropylthio, butylthio, sec-butylthio, tert-butylthio and the like.
Examples of the “alkylsulfinyl group” include, for example, an alkylsulfinyl group having 1 to 6 carbon atoms, and specifically include, for example, methylsulfinyl, ethylsulfinyl, propylsulfinyl, isopropylsulfinyl, butylsulfinyl, pentylsulfinyl or hexyl. And sulfinyl. Preferable examples include an alkylsulfinyl group having 1 to 4 carbon atoms, and specific examples include methylsulfinyl, ethylsulfinyl, propylsulfinyl, isopropylsulfinyl, butylsulfinyl and the like.
The “alkylsulfonyl group” includes, for example, an alkylsulfonyl group having 1 to 6 carbon atoms, and specifically includes, for example, methylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, butylsulfonyl, pentylsulfonyl or hexyl. And sulfonyl. Preferable examples include an alkylsulfonyl group having 1 to 4 carbon atoms, and specific examples include methylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, and butylsulfonyl.
Examples of the “arylthio group” include an arylthio group having 6 to 10 carbon atoms, and specific examples include phenylthio, 1-naphthylthio, 2-naphthylthio and the like.
Examples of the “arylsulfinyl group” include an arylsulfinyl group having 6 to 10 carbon atoms, and specific examples include phenylsulfinyl, 1-naphthylsulfinyl, 2-naphthylsulfinyl and the like.
Examples of the “arylsulfonyl group” include arylsulfonyl groups having 6 to 10 carbon atoms, and specific examples include phenylsulfonyl, tosyl, 1-naphthylsulfonyl, 2-naphthylsulfonyl and the like.

  The “nitrogen-containing saturated heterocyclic group” includes, for example, a 5- to 6-membered saturated heterocyclic group having 1 to 2 nitrogen atoms and further having an oxygen atom or a sulfur atom. Specific examples include, Examples include dinyl, dioxooxazolidinyl, dioxothiazolidinyl, tetrahydrofuranyl or tetrahydropyridinyl.

  Examples of the substituent in the “optionally substituted alkyl group” include (1) a halogen atom, (2) a hydroxyl group, (3) a cyano group, (4) a carboxy group, and (5) an optionally substituted cycloalkyl group. (6) an optionally substituted aryl group, (7) an optionally substituted heteroaryl group, (8) an optionally substituted aroyl group, (9) an optionally substituted heteroarylcarbonyl group, (10 ) An optionally substituted arylaminocarbonyl group, (11) an optionally substituted heteroarylaminocarbonyl group, (12) an optionally substituted aryloxy group, (13) an optionally substituted arylsulfonyl group, (14) an aralkylsulfonyl group which may be substituted, (15) an alkoxy group which may be substituted, (16) a cycloalkyloxy group which may be substituted, (17 An optionally substituted alkoxycarbonyl group, (18) an optionally substituted aryloxycarbonyl group, (19) an optionally substituted amino group, (20) an optionally substituted carbamoyl group, (21) an alkylsulfonyl group (22) an optionally substituted alkylcarbonyl group, (23) a cycloalkyloxycarbonyl group, (24) a tetrahydrofuranyloxycarbonyl group, or (25) a tetrahydrofuranyl group.

Here, the above (1) to (25) will be described.
Examples of the substituent in the above (5) “optionally substituted cycloalkyl group” include an alkyl group, an aralkyl group, an alkoxy group, an alkoxycarbonyl group, a fluorine atom, and the like.
Examples of the substituent in the above (6) “aryl group that may be substituted” include those exemplified as the substituents in the “aryl group that may be substituted” described later.
As the substituent in the above (7) “optionally substituted heteroaryl group”, for example,
(a) a hydroxyl group,
(b) a halogen atom,
(c) an alkyl group,
(d) an alkyl group substituted with a halogen atom or an alkoxy group (for example, fluoromethyl, difluoromethyl, trifluoromethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, perfluoroethyl, 2- Fluoro-1- (fluoromethyl) ethyl, 1- (difluoromethyl) -2,2-difluoroethyl, methoxymethoxy, ethoxymethoxy, methoxyethoxy, ethoxyethoxy, methoxypropoxy, ethoxypropoxy, etc.).
(e) an alkoxy group,
(f) an alkoxy group substituted with a halogen atom or an alkoxy group (for example, fluoromethoxy, difluoromethoxy, trifluoromethoxy, 2,2-difluoroethoxy, 2,2,2-trifluoroethoxy, perfluoroethoxy, 2-fluoro Fluoro-1- (fluoromethyl) ethoxy, 1- (difluoromethyl) -2,2-difluoroethoxy, methoxymethoxy, ethoxymethoxy, methoxyethoxy, ethoxyethoxy, methoxypropoxy or ethoxypropoxy).
(g) a cyano group,
(h) a carboxy group,
(i) an alkoxycarbonyl group,
(j) a carbamoyl group which may be substituted with an alkyl group (for example, carbamoyl, methylcarbamoyl, dimethylcarbamoyl, ethylcarbamoyl or diethylcarbamoyl);
(k) an aryl group,
Or (l) an amino group etc. are mentioned.
Examples of the substituent in the above (8) “optionally substituted aroyl group” include those exemplified as the substituent in the “optionally substituted aryl group” in the above (6).
Examples of the substituent in the above (9) “optionally substituted heteroarylcarbonyl group” include those exemplified as the substituent in the “optionally substituted heteroarylcarbonyl” in the above (7).
Examples of the substituent in the above (10) “arylaminocarbonyl group which may be substituted” include those exemplified as the substituent in the “optionally substituted aryl group” in the above (6).
Examples of the substituent in the above (11) “optionally substituted heteroarylaminocarbonyl group” include those exemplified as the substituent in the “optionally substituted heteroaryl group” in the above (7).
As the substituent in the above (12) “optionally substituted aryloxy group” and (13) “optionally substituted arylsulfonyl group”, the substitution in the above “(6)“ optionally substituted aryl group ”” What was illustrated as a group is mentioned.
Examples of the aralkyl moiety of the above (14) “aralkylsulfonyl group which may be substituted” include those exemplified as the aforementioned aralkyl group.
Examples of the substituent of the “optionally substituted aralkylsulfonyl group” include those exemplified as the substituent in the “optionally substituted aryl group” of the above (6).
As the substituent in the above (15) “optionally substituted alkoxy group”, for example,
(a) a hydroxyl group,
(b) a carboxy group,
(c) an alkoxy group,
(d) an alkoxycarbonyl group,
(e) an amino group which may be substituted with an alkyl group (for example, amino, dimethylamino, diethylamino and the like),
(f) a carbamoyl group substituted with an alkyl group,
(g) a sulfamoyl group substituted with an alkyl group,
(h) a ureido group substituted with an alkyl group,
(i) a phenyl group which may be substituted with a halogen atom or an alkoxy group (for example, phenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 2- Methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 2-ethoxyphenyl, 3-ethoxyphenyl, 4-ethoxyphenyl, 2-isopropoxyphenyl, 3-isopropoxyphenyl, etc.).
(j) 5-oxo-2-tetrahydrofuranyl,
(k) 1,3-dihydro-3-oxo-1-isobenzofuranyl,
(l) tetrahydrofuranyl,
(m) a nitrogen-containing saturated heterocyclic group,
(n) An alkoxy group substituted with a halogen atom or an alkoxy group (for example, fluoromethoxy, difluoromethoxy, trifluoromethoxy, 2,2-difluoroethoxy, 2,2,2-trifluoroethoxy, perfluoroethoxy, 2- Fluoro-1- (fluoromethyl) ethoxy, 1- (difluoromethyl) -2,2-difluoroethoxy, methoxymethoxy, ethoxymethoxy, methoxyethoxy, ethoxyethoxy, methoxypropoxy or ethoxypropoxy).
(o) a cycloalkyl group,
(p) a cycloalkyl group substituted with a halogen atom or an alkoxy group (for example, 2-fluorocyclopropyl, 2-methoxycyclopropyl, 2-fluorocyclobutyl, 3-fluorocyclobutyl, 3-methoxycyclobutyl, etc.) Or)
(q) Halogen atoms and the like are mentioned.
As the substituent of the above (16) “optionally substituted cycloalkyloxy group” and (17) “optionally substituted alkoxycarbonyl group”, the above-mentioned (15) “optionally substituted alkoxy group” What was illustrated as a substituent is mentioned.
Examples of the substituent in the above (18) “aryloxycarbonyl group which may be substituted” include those exemplified as the substituent in the “optionally substituted aryl group” in the above (6).
Examples of the substituent of the above (19) “optionally substituted amino group” include
(a) an alkyl group,
(b) an alkylcarbonyl group,
(c) an aroyl group,
(d) an alkylsulfonyl group,
(e) an arylsulfonyl group,
(f) an aryl group which may be substituted (examples of the substituent include a halogen atom, an alkyl group, and an alkoxy group);
(g) an alkoxycarbonylmethyl group (the methyl carbon atom may be substituted with one or two alkyl groups, and two alkyl groups on the methyl carbon atom are bonded to form cyclopropyl together with the methyl carbon atom; Cyclobutyl or cyclopentyl may be formed).
Or (h) an aralkyl group and the like.
An amino group that may be substituted also includes (i) imide.
Examples of the substituent in the above (20) “optionally substituted carbamoyl group” include an alkyl group and a cycloalkyl group. Further, two substituents of the carbamoyl group are bonded to each other, for example, pyrrolidine (the pyrrolidine may be further substituted with a hydroxyl group), piperidine, morpholine, thiomorpholine, thiomorpholine oxide, thiomorpholine dioxide, Or you may form the aliphatic heterocyclic ring which may contain a carbon atom, a nitrogen atom, and an oxygen atom, such as piperazine (The nitrogen atom of this piperazine may be substituted by methyl and ethyl).
Specific examples of the “optionally substituted carbamoyl group” include, for example, carbamoyl, methylcarbamoyl, dimethylcarbamoyl, ethylcarbamoyl, diethylcarbamoyl, ethylmethylcarbamoyl, methylpropylcarbamoyl, cyclopropylcarbamoyl, cyclopropylmethylcarbamoyl, pyrrolidino Examples include carbonyl, piperidinocarbonyl, morpholinocarbonyl and the like.
As the substituent of the above (22) “optionally substituted alkylcarbonyl group”, for example,
(a) a halogen atom,
(b) an alkoxy group,
(c) a cycloalkyl group,
(d) alkoxycarbonyl group
(e) an aryl group which may be substituted (the substituent includes, for example, a halogen atom, an alkyl group, an alkoxy group or an alkoxycarbonyl group);
Or (f) a hydroxyl group and the like.

  Examples of the substituent of the “optionally substituted alkylthio group”, “optionally substituted alkylsulfinyl group”, and “optionally substituted alkylsulfonyl group” include the substitution in the above “optionally substituted alkyl group”. What was illustrated as a group is mentioned.

As the substituent of the “optionally substituted alkenyl group” or “optionally substituted alkynyl group”,
(1) hydroxyl group,
(2) a halogen atom,
(3) an alkyl group,
(4) an alkyl group substituted with a halogen atom or an alkoxy group (for example, fluoromethyl, difluoromethyl, trifluoromethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, perfluoroethyl, 2- And fluoro-1- (fluoromethyl) ethyl, 1- (difluoromethyl) -2,2-difluoroethyl, methoxymethyl, ethoxymethyl, methoxyethyl, ethoxyethyl, methoxypropyl, ethoxypropyl, etc.).
(5) an alkoxy group,
(6) An alkoxy group substituted with a halogen atom or an alkoxy group (for example, fluoromethoxy, difluoromethoxy, trifluoromethoxy, 2,2-difluoroethoxy, 2,2,2-trifluoroethoxy, perfluoroethoxy, 2- Fluoro-1- (fluoromethyl) ethoxy, 1- (difluoromethyl) -2,2-difluoroethoxy, methoxymethoxy, ethoxymethoxy, methoxyethoxy, ethoxyethoxy, methoxypropoxy or ethoxypropoxy).
(7) A phenyl group or an aroyl group which may be substituted with the following (aa), (bb) or (cc):
(aa) an alkoxy group which may be substituted with a halogen atom or an alkoxy group (for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, fluoromethoxy, difluoromethoxy, trifluoromethoxy, 2,2-difluoroethoxy, 2,2,2-trifluoroethoxy, perfluoroethoxy, 2-fluoro-1- (fluoromethyl) ethoxy, 1- (difluoromethyl) -2,2-difluoroethoxy, methoxymethoxy, Ethoxymethoxy, methoxyethoxy, ethoxyethoxy, methoxypropoxy or ethoxypropoxy).
(bb) an alkyl group which may be substituted with a halogen atom (for example, methyl, ethyl, propyl, isopropyl, butyl, fluoromethyl, difluoromethyl, trifluoromethyl, 2,2-difluoroethyl, 2,2,2-trimethyl) Fluoroethyl, perfluoroethyl, 2-fluoro-1- (fluoromethyl) ethyl or 1- (difluoromethyl) -2,2-difluoroethyl, etc.).
(cc) a halogen atom,
(8) a cyano group,
(9) a carboxy group,
(10) an alkoxycarbonyl group,
(11) A carbamoyl group that may be substituted with an alkyl group (for example, carbamoyl, methylcarbamoyl, dimethylcarbamoyl, ethylcarbamoyl, diethylcarbamoyl, etc.),
(12) an alkylsulfonyl group,
Or (13) phenyloxy and the like.

Examples of the substituent of the “optionally substituted vinyl group” include a halogen atom or an alkyl group.
Specific examples of the substituted vinyl group include 1-propylene, 2-methyl-1-propylene, 2-chloro-1-propylene and the like.
Examples of the substituent of the “optionally substituted cycloalkyl group” are the substituents in (5) “optionally substituted cycloalkyl group” as the substituent of the “optionally substituted alkyl group”. Things.

Examples of the substituent in the “aryl group that may be substituted” include, for example,
(1) hydroxyl group,
(2) a halogen atom,
(3) an alkyl group,
(4) An alkyl group substituted with a halogen atom, an alkoxy group or a cycloalkyl group (for example, fluoromethyl, difluoromethyl, trifluoromethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, perfluoro Examples include ethyl, 2-fluoro-1- (fluoromethyl) ethyl, 1- (difluoromethyl) -2,2-difluoroethyl, methoxymethyl, ethoxymethyl, methoxyethyl, ethoxyethyl, methoxypropyl, and ethoxypropyl.) ,
(5) A phenyl group which may be substituted with the following (aa), (bb) or (cc):
(aa) an alkoxy group which may be substituted with a halogen atom or an alkoxy group (for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, fluoromethoxy, difluoromethoxy, trifluoromethoxy, 2,2-difluoroethoxy, 2,2,2-trifluoroethoxy, perfluoroethoxy, 2-fluoro-1- (fluoromethyl) ethoxy, 1- (difluoromethyl) -2,2-difluoroethoxy, methoxymethoxy, Ethoxymethoxy, methoxyethoxy, ethoxyethoxy, methoxypropoxy or ethoxypropoxy).
(bb) an alkyl group which may be substituted with a halogen atom (for example, methyl, ethyl, propyl, isopropyl, butyl, fluoromethyl, difluoromethyl, trifluoromethyl, 2,2-difluoroethyl, 2,2,2-trimethyl) Fluoroethyl, perfluoroethyl, 2-fluoro-1- (fluoromethyl) ethyl or 1- (difluoromethyl) -2,2-difluoroethyl, etc.).
(cc) a halogen atom,
(6) a cyano group,
(7) a carboxy group,
(8) an alkoxycarbonyl group which may be substituted with a halogen atom (for example, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, sec-butoxycarbonyl, tert-butoxycarbonyl, fluoromethoxycarbonyl) , Difluoromethoxycarbonyl, 2,2-difluoroethoxycarbonyl, 2,2,2-trifluoroethoxycarbonyl, methoxycarbonyl, ethoxycarbonyl, etc.).
(9) A carbamoyl group that may be substituted with an alkyl group (for example, carbamoyl, methylcarbamoyl, dimethylcarbamoyl, ethylcarbamoyl, diethylcarbamoyl, etc.),
(10) an alkylsulfonyl group,
₍₁₁₎ C 1 _{~ 3} alkylenedioxy group,
(12) formyl group,
(13) A phenyloxy group which may be substituted (the substituent includes, for example, a halogen atom, an alkyl group or an alkoxy group),
(14) Nitrogen-containing saturated heterocyclic groups (for example, pyrrolidinyl, piperidinyl, morpholinyl, or piperazinyl (the nitrogen atom of the piperazine may be substituted with, for example, methyl, ethyl, or propyl)) and the like.
(15) Hydroxyl group, oxo group, carboxy group, carboxymethyl group, alkoxycarbonyl group, alkoxycarbonylalkyl group (for example, methoxycarbonylmethyl, ethoxycarbonylmethyl, isopropoxycarbonylmethyl etc.), alkyl group, fluoroalkyl Groups (for example, fluoromethyl, difluoromethyl, trifluoromethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, perfluoroethyl, etc.), alkoxyalkyl groups (for example, methoxymethyl, Ethoxymethyl or isopropoxymethyl), cycloalkyloxyalkyl groups (for example, cyclopropyloxymethyl, cyclopropyloxyethyl, cyclobutyloxy, etc.), alcohol Cy group, cycloalkyloxy group, or cycloalkyloxy group which may be substituted with halogen atom (for example, 3-carboxycyclobutyloxy, 3-methoxycarbonylcyclobutyloxy, 3-ethoxycarbonylbutyloxy, 2-methylcyclo Examples include propyloxy, 2-fluorocyclopropyloxy, 3-methoxycyclobutyloxy, 3-fluorocyclobutyloxy, 3,3-difluorocyclobutyloxy, or 3- (2-fluoroethyl) cyclobutyloxy. ),
(16) Hydroxyl group, oxo group, carboxy group, alkoxycarbonyl group, cycloalkyl group, alkoxy group, cycloalkyloxy group, optionally substituted oxygen-containing heterocyclic group (for example, a 5- to 6-membered ring having an oxygen atom) A saturated heterocyclic group, and the like, specifically, for example, tetrahydrofuranyl, tetrahydropyranyl, etc. Examples of the substituent include a halogen atom, an oxo group, an alkoxy group, and the like. An alkoxy group (for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, 2-hydroxyethoxy, carboxymethoxy, methoxycarbonylmethoxy, ethoxycarbonylmethoxy, tert- Butoxycarbonyl methoxy , Cyclopropylmethoxy, cyclobutylmethoxy, methoxymethoxy, ethoxymethoxy, methoxyethoxy, ethoxyethoxy, isopropoxymethoxy, cyclopropyloxymethoxy, cyclobutyloxymethoxy, fluoromethoxy, difluoromethoxy, trifluoromethoxy, 2,2- Difluoroethoxy, 2,2,2-trifluoroethoxy, perfluoroethoxy, 2-fluoro-1- (fluoromethyl) ethoxy, 1- (difluoromethyl) -2,2-difluoroethoxy, and the like).
(17) difluoromethylenedioxy,
(18) An alkenyl group that may be substituted with a halogen atom (for example, vinyl, propenyl, methylpropenyl, butenyl, methylbutenyl, etc.),
(19) An amino group which may be substituted with an alkyl group (for example, amino, methylamino, ethylamino, propylamino, dimethylamino, methylethylamino, diethylamino and the like),
(20) an alkylcarbonyl group which may be substituted (the substituent includes, for example, a halogen atom, an alkoxy group or a cycloalkyl group);
(21) alkylcarbonyloxy group (for example, methylcarbonyloxy, ethylcarbonyloxy, isopropylcarbonyloxy and the like),
(22) A cycloalkyl group which may be substituted with a fluorine atom (for example, cyclopropyl, cyclobutyl, cyclopentyl, 2-fluorocyclopropyl, 2-fluorocyclobutyl, 3-fluorocyclobutylcyclobutyl, adamantyl or norbornyl, etc.) ),
(23) a cycloalkylcarbonyl group which may be substituted with a fluorine atom (for example, cyclopropylcarbonyl, 2-fluorocyclopropylcarbonyl, cyclobutylcarbonyl, cyclopentylcarbonyl and the like);
(24) an alkylthio group,
(25) an alkylsulfinyl group,
(26) A heteroaryl group which may be substituted (the substituent includes, for example, a halogen atom, an alkyl group, an alkoxy group, a haloalkyl group, or a haloalkoxy group),
(27) Groups represented by the following formulas (T1) to (T16):

（式中、Ｒ^Ｔは、存在しないか、１つまたは複数存在し、各々独立して、ハロゲン原子、水酸基、オキソ基、カルボキシ基、置換されてもよいアルキル基（置換基としては、例えばハロゲン原子またはアルコキシ基等が挙げられる。）、置換されてもよいアルコキシカルボニル基（置換基としては、例えばハロゲン原子またはアルコキシ基等が挙げられる。）、置換されてもよいアルコキシ基（置換基としては、例えばハロゲン原子またはアルコキシ基等が挙げられる。）、置換されてもよいカルバモイル基（置換基としては、例えばアルキル基等が挙げられる。）もしくは飽和ヘテロ環基オキシカルボニル基（飽和ヘテロ環基としては、例えば、酸素原子、窒素原子および／または硫黄原子を１つまたは２つ有する、５から６員の飽和ヘテロ環基が挙げられ、具体的には、例えばテトラヒドロフラニル、テトラヒドロピラニル、ジヒドロフラニル、テトラヒドロチオピラニル、テトラヒドロジオキソチオピラニル、ピロリジニル、ピペリジル、ピペラジル、イミダゾリジニル、オキサゾリジニル、またはチアゾリジニル等が挙げられる。）を表すか、または２つのＲ^Ｔが一緒になってメチレン、エチレン、トリメチレン、テトラメチレンもしくはブテニレンを表し、環を構成する１つまたは２つの炭素原子と結合し新たな環を形成することもできる。Ｒ^ｘは水素原子またはアルキル基を表す。）、
（２８）アロイル基、または
（２９）式：−Ｒ^ｄ−ＣＯ（Ｏ）−Ｒ^ｅ（式中、Ｒ^ｄおよびＲ^ｅは前記記載と同義である。）で表される基等を表す。

(In the formula, R ^T is not present, or one or a plurality thereof are present, and each independently represents a halogen atom, a hydroxyl group, an oxo group, a carboxy group, or an alkyl group which may be substituted. Atom, an alkoxy group, etc.), an alkoxycarbonyl group which may be substituted (the substituent includes, for example, a halogen atom or an alkoxy group), an alkoxy group which may be substituted (as the substituent) , For example, a halogen atom or an alkoxy group), an optionally substituted carbamoyl group (the substituent includes, for example, an alkyl group) or a saturated heterocyclic group oxycarbonyl group (as a saturated heterocyclic group). Is, for example, a 5- to 6-membered saturated hete having one or two oxygen, nitrogen and / or sulfur atoms. Specific examples include tetrahydrofuranyl, tetrahydropyranyl, dihydrofuranyl, tetrahydrothiopyranyl, tetrahydrodioxothiopyranyl, pyrrolidinyl, piperidyl, piperazyl, imidazolidinyl, oxazolidinyl, and thiazolidinyl. Or two R ^T together represent methylene, ethylene, trimethylene, tetramethylene, or butenylene, and combine with one or two carbon atoms constituting the ring to form a new ring R ^x represents a hydrogen atom or an alkyl group),
(28) represents an aroyl group, or (29) a group represented by the formula: —R ^d —CO (O) —R ^e (wherein R ^d and R ^e are as defined above).

  “Optionally substituted heteroaryl group”, “optionally substituted aralkyl group”, “optionally substituted heteroarylalkyl group”, “optionally substituted aroyl group”, “optionally substituted heteroaryl group” "Arylcarbonyl group", "optionally substituted aryloxycarbonyl group", "optionally substituted aryloxy group", "optionally substituted aralkyloxy group", "optionally substituted aralkyloxycarbonyl group" , "Optionally substituted heteroaryloxy group", "optionally substituted arylthio group", "optionally substituted arylsulfinyl group", and "optionally substituted arylsulfonyl group" And those exemplified as the substituents in the “aryl group which may be substituted”.

Examples of the substituent of the “optionally substituted alkylcarbonyl group” include the substituent in (22) “optionally substituted alkylcarbonyl group” as the substituent in the above “optionally substituted alkyl group”. Can be mentioned.
Examples of the substituent of the “optionally substituted cycloalkylcarbonyl group” include a halogen atom or an alkoxy group.
As the substituent of the “optionally substituted alkoxy group” and the “optionally substituted alkoxycarbonyl group”, (15) “optionally substituted” as the substituent of the above “optionally substituted alkyl group” What was illustrated as a substituent in "an alkoxy group" is mentioned.
As the substituent of the “optionally substituted cycloalkyloxy group” and the “optionally substituted cycloalkyloxycarbonyl group”, (16) “Substitution” as the substituent of the above “optionally substituted alkyl group” And those exemplified as the substituent in the “cycloalkyloxy group that may be substituted”.

Examples of the substituent of the “optionally substituted amino group” include those exemplified as the substituent in (19) “optionally substituted amino group” as the substituent of the “optionally substituted alkyl group”. Can be mentioned.
As the substituent of the “optionally substituted carbamoyl group”, for example,
(1) an alkyl group,
(2) a cycloalkyl group,
(3) an aryl group optionally substituted by the following (aa), (bb), (cc) or (dd),
(aa) Halogen atom
(bb) an alkoxy group which may be substituted with a halogen atom (for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, fluoromethoxy, difluoromethoxy, trifluoromethoxy, 2,2 -Difluoroethoxy, 2,2,2-trifluoroethoxy, perfluoroethoxy, 2-fluoro-1- (fluoromethyl) ethoxy or 1- (difluoromethyl) -2,2-difluoroethoxy.
(cc) an alkyl group which may be substituted with a halogen atom (for example, methyl, ethyl, propyl, isopropyl, butyl, methyl, ethyl, propyl, isopropyl, butyl, fluoromethyl, difluoromethyl, trifluoromethyl, 2,2- And difluoroethyl, 2,2,2-trifluoroethyl, perfluoroethyl, 2-fluoro-1- (fluoromethyl) ethyl or 1- (difluoromethyl) -2,2-difluoroethyl.)
_(dd) C 1 _{~ 3} alkylenedioxy group (4) alkylsulfonyl groups,
(5) a cycloalkylsulfonyl group,
(6) Arylsulfonyl group which may be substituted (the substituent includes, for example, a halogen atom, an alkyl group, a haloalkyl group, an alkoxy group or a haloalkoxy group).
(7) an alkylcarbonyl group,
(8) an alkoxycarbonyl group,
The or (9) optionally substituted aroyl group (substituent, for example, a halogen atom, an alkyl group, a haloalkyl group, an alkoxy group, a haloalkoxy group, an alkoxycarbonyl group, or C ₁ ~ ₃ alkylenedioxy group, and the like .)
Specific examples of the “optionally substituted carbamoyl group” include, for example, carbamoyl, methylcarbamoyl, dimethylcarbamoyl, ethylcarbamoyl, diethylcarbamoyl, ethylmethylcarbamoyl, phenylcarbamoyl, phenylmethylcarbamoyl and the like.
In addition, two substituents of the carbamoyl group are bonded to pyrrolidine, piperidine, morpholine, thiomorpholine, thiomorpholine oxide, thiomorpholine dioxide, or piperazine (the nitrogen atom of the piperazine is, for example, methyl, ethyl, propyl) An aliphatic heterocycle that may contain carbon, nitrogen, oxygen, or sulfur, such as pyrrolidinocarbamoyl, piperidinocarbamoyl or morpholino And carbamoyl.

As the substituent of the “optionally substituted nitrogen-containing saturated heterocyclic group”, for example,
(1) a halogen atom,
(2) an alkyl group,
(3) An alkyl group substituted with a halogen atom or an alkoxy group (for example, fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 2,2-difluoroethyl, perfluoroethyl, methoxyethyl, etc.). ,
(4) an alkoxy group,
(5) An alkoxy group substituted with a halogen atom or an alkoxy group (for example, fluoromethoxy, difluoromethoxy, trifluoromethoxy, methoxymethoxy, ethoxymethoxy, methoxyethoxy, ethoxyethoxy, methoxypropoxy or ethoxypropoxy). ),
(6) a cyano group,
Or (7) an oxo group and the like.

When two R ⁶ , R ⁷ , R ⁸ , or R ⁹ are present, they may be on the same or different carbon.
The same or different when two R ⁶ , R ⁷ , R ⁸ , or R ⁹ together represent methylene or ethylene and are bonded to one or more carbon atoms constituting the ring to form a new ring. Forming a spiro ring or a bicyclo ring via carbon.
Methylene two R ^T together represent ethylene, trimethylene, tetramethylene or butenylene, and one or bound to two carbon atoms to form a new ring constituting the ring, via the same or different carbon It forms a spiro ring or a bicyclo ring.

Examples of the “haloalkoxy group” include an alkoxy group having 1 to 4 carbon atoms substituted with a halogen atom, and specific examples include fluoromethoxy, difluoromethoxy, trifluoromethoxy and the like.
Examples of the “haloalkyl group” include an alkyl group having 1 to 4 carbon atoms substituted with a halogen atom, and specifically include, for example, fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl or Examples include perfluoroethyl.
The "C ₁ ~ ₃ alkylenedioxy group", for example, methylenedioxy, ethylenedioxy or trimethylenedioxy, and the like.

Examples of the “substituted alkyl group” in R ^g include, for example, a cycloalkyl group having 3 to 7 carbon atoms (for example, cyclopentyl, cyclohexyl, cycloheptyl, etc.) or an optionally substituted aryl group (for example, And an alkyl group having 1 to 3 carbon atoms and the like, which are substituted with a phenyl group. Specific examples include benzyl, p-chlorobenzyl, p-methoxybenzyl, p-fluorobenzyl, cyclopentylmethyl, cyclohexylmethyl and the like.
Examples of the “substituted alkenyl group” for R ^g include a cycloalkyl group having 5 to 7 carbon atoms (for example, cyclopentyl, cyclohexyl, cycloheptyl and the like) or an aryl group (for example, phenyl and the like). And an alkenyl group having 2 to 3 carbon atoms and the like substituted with Examples thereof include vinyl, propenyl, allyl, isopropenyl and the like substituted with phenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like.
Examples of the “alkenyloxy group” for R ^g include linear or branched alkenyloxy groups having 2 to 8 carbon atoms. Specific examples include allyloxy and isobutenyloxy.
The “substituted alkoxy group” for R ^g is, for example, a cycloalkyl group having 3 to 7 carbon atoms (for example, cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl, etc.) or aryl which may be substituted. Examples thereof include an alkoxy group having 1 to 3 carbon atoms substituted with a group (for example, phenyl and the like). Specific examples include benzyloxy, phenethyloxy, cyclopropylmethyloxy, cyclopropylethyloxy, cyclopentylmethyloxy and the like.
The “substituted alkenyloxy group” for R ^g may be, for example, a cycloalkyl group having 3 to 7 carbon atoms (for example, cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl, etc.) or substituted. Examples thereof include an alkenyloxy group having 2 to 3 carbon atoms substituted with an aryl group (for example, phenyl and the like). Examples thereof include vinyloxy, propenyloxy, allyloxy, isopropenyloxy substituted with phenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like.
Specific examples of the “aryloxy group which may be substituted” in R ^g include phenoxy, p-nitrophenoxy, p-methoxyphenoxy, p-fluorophenoxy, naphthoxy and the like.

Examples included in the “substituted alkoxycarbonyl group” and the formula: —R ^d —C (O) O—R ^e (wherein R ^d and R ^e are as defined above). Specific examples of such groups include, for example, pivaloyloxymethoxycarbonyl, 1- (pivaloyloxy) ethoxycarbonyl, 1- (cyclohexyloxycarbonyloxy) ethoxycarbonyl, 5-methyl-2-oxo-1,3-dioxolene 4-ylmethoxycarbonyl, 5- (tert-butyl) -2-oxo-1,3-dioxolen-4-ylmethoxycarbonyl, acetoxymethyloxycarbonyl, propyloxymethoxycarbonyl, n-butyloxymethoxycarbonyl, isobutyloxymethoxy Carbonyl, 1- (ethoxycarbonyloxy) ethoxycarbonyl 1- (tert-butoxycarbonyloxy) ethoxycarbonyl, 1- (acetyloxy) ethoxycarbonyl, 1- (isobutyloxy) ethoxycarbonyl, cyclohexylcarbonyloxymethoxycarbonyl, 1- (cyclohexylcarbonyloxy) ethoxycarbonyl, cyclopentylcarbonyloxy Examples include methoxycarbonyl, 1- (cyclopentylcarbonyloxy) ethoxycarbonyl, 2-morpholinoethoxycarbonyl, and the like.

Examples of the substituent in the “optionally substituted alkyl group” and the “optionally substituted alkoxy group” in R ^c include a halogen atom, an alkoxy group, and a cycloalkyl group.
Examples of the substituent in the “optionally substituted aryl group” and the “optionally substituted aryloxy group” in R ^c include those exemplified as the substituents in the above “optionally substituted aryl group”.

^Examples of the “alkylene group” for R ^d include those described above, and preferably include methylene.
Examples of the “alkenylene group” for R ^d include those described above, and preferably vinylene.

“R ⁴ and R ⁵ form an optionally substituted benzene ring, an optionally substituted cycloalkene ring, or an optionally substituted 5- to 6-membered aromatic heterocycle with adjacent carbon atoms. “May be” means, for example, formula (I):

が、式（ＩＩＩ）：

In the formula (III):

[式中、環Ａ^１は、置換されてもよいベンゼン環、置換されてもよいシクロアルケン環、または置換されてもよい５から６員の芳香族複素環を表す。]で表されること等が挙げられる。環Ａ^１の置換基としては、例えばカルボキシ基、またはそのプロドラッグ体であってもよい。また、環Ａ^１の置換基が生体内等で生物学的または化学的にカルボキシ基に変換せしめられるものであってもよい。

[Wherein, ring A ¹ represents an optionally substituted benzene ring, an optionally substituted cycloalkene ring, or an optionally substituted 5- to 6-membered aromatic heterocyclic ring. ] Etc. are mentioned. Examples of the substituent of ring A ^1, for example, a carboxy group, or a prodrug thereof thereof. Further, it may be one ring substituents A ¹ is made to convert the biologically or chemically carboxy group in vivo, or the like.

Specifically, “ring A ¹ forms a benzene ring” means that formula (III) is represented by formula (IIIa):

で表されることを意味する。
環Ａ^１における「置換されてもよいベンゼン環」部分の置換基としては、前記Ｒ^１４として表される基の他に、「置換されてもよいアリール基」における置換基として例示したもの等が挙げられる。
環Ａ^１における「置換されてもよいシクロアルケン環」におけるシクロアルケン環としては、例えば、炭素数４から１０のシクロアルケン環等が挙げられ、具体的には例えば、シクロブテン、シクロペンテン、シクロヘキセン、シクロヘプテンまたはノルボルニレン等が挙げられる。
「環Ａ^１がシクロアルケン環を形成する」としては、具体的には式（ＩＩＩ）が、例えば式（ＩＩＩｂ）：

Means that
Examples of the substituent of the “optionally substituted benzene ring” moiety in ring A ¹ include those exemplified as the substituent in the “optionally substituted aryl group” in addition to the group represented by R ^14. Can be mentioned.
Examples of the cycloalkene ring in the “optionally substituted cycloalkene ring” in ring A ¹ include a cycloalkene ring having 4 to 10 carbon atoms, and specific examples include cyclobutene, cyclopentene, cyclohexene, cycloheptene. Or norbornylene etc. are mentioned.
“Ring A ¹ forms a cycloalkene ring” is specifically exemplified by formula (III), for example, formula (IIIb):

［式中、ｉは０から６の整数を表す。］となること等が挙げられる。また、上記シクロアルケン環に酸素原子を含んでもよく、具体的には、例えば式（ＩＩＩｂ−１）：

[Wherein i represents an integer of 0 to 6. And the like. The cycloalkene ring may contain an oxygen atom. Specifically, for example, the formula (IIIb-1):

[式中、ｊおよびｋは、それぞれ０から３の整数を表す。但し、ｊ、ｋの一方が０の場合、他方は２または３である。]となった化合物等が挙げられる。
環Ａ^１における「置換されてもよいシクロアルケン環」部分の置換基としては、例えば、アルキル基、アラルキル基、アルコキシカルボニル基、アルコキシ基、オキソ基またはフッ素原子等が挙げられる。

[Wherein j and k each represents an integer of 0 to 3. However, when one of j and k is 0, the other is 2 or 3. And the like.
Examples of the substituent of the “optionally substituted cycloalkene ring” in ring A ¹ include an alkyl group, an aralkyl group, an alkoxycarbonyl group, an alkoxy group, an oxo group, a fluorine atom, and the like.

The 5- to 6-membered aromatic heterocycle in the “optionally substituted 5- to 6-membered aromatic heterocycle” in ring A ¹ is, for example, selected from a nitrogen atom, a sulfur atom and an oxygen atom in addition to the carbon atom Examples include 1 or 2 5- to 6-membered aromatic heterocycles containing 1 to 3 heteroatoms. Specific examples include thiophene, furan, pyrrole, imidazole, pyrazole, oxazole, pyridine, pyrazine, pyrimidine, pyridazine, thiazole, isothiazole, oxazole or isoxazole.
As "ring A forms a 5- to 6-membered aromatic heterocycle", specifically, formula (III) is represented by, for example, formula (IIIc-1), (IIIc-2), (IIIc-3), (IIIc-4), (IIIc-5), (IIIc-6), (IIIc-7), (IIIc-8), (IIIc-9), (IIIc-10), (IIIc-11) or (IIIc) -12)

となること等が挙げられる。
環Ａ^１における「置換されてもよい５から６員の芳香族複素環」部分の置換基としては、「置換されてもよいヘテロアリール基」における置換基として例示したものの他に、例えば、「置換されてもよいアルコキシカルボニル基」または式：−Ｒ^ｄ−Ｃ（Ｏ）Ｏ−Ｒ^ｅ（式中、Ｒ^ｄおよびＲ^eは、前記記載と同義である。）で表される基等が挙げられる。

And so on.
Examples of the substituent of the “optionally substituted 5- to 6-membered aromatic heterocyclic ring” moiety in ring A ¹ include those exemplified as the substituents in the “optionally substituted heteroaryl group”, for example, “ An optionally substituted alkoxycarbonyl group ”or a group represented by the formula: —R ^d —C (O) O—R ^e (wherein R ^d and R ^e are as defined above), and the like. Can be mentioned.

The “prodrug” is one that can be easily hydrolyzed in vivo to regenerate the compound (I) of the present invention. Specifically, for example, the amino group of the compound represented by the formula (I) , -NHQ ^X , and the like. Here, examples of Q ^X include the following.
(1)

(2)−ＣＯＲ^２６
(3)−ＣＯＯ−ＣＲ^２７(Ｒ^２８)−ＯＣＯＲ^２９
(4)−ＣＯＯＲ^３０
［式中、Ｒ^２６は水素原子、アルキル基、または置換されてもよいアリール基を表す。Ｒ^２７およびＲ^２８は独立して水素原子またはアルキル基を表す。Ｒ^２９は水素原子、アルキル、アリール基またはベンジル基を表す。Ｒ^３０は、アルキル基またはベンジル基を表す。］
好ましいＱ^Ｘとしては、(1)の基および(3)の基が挙げられる。(3)の基の好ましいものとして、Ｒ^２７が水素原子であり、Ｒ^２８が水素原子、メチルまたはエチルであり、Ｒ^２９がメチルまたはエチルであるものが挙げられる。これらの化合物は、常法に従って製造することができる(例えばJ. Med. Chem. 35, 4727 (1992)、WO 01/40180等)。また、プロドラッグは、廣川書店１９９０年刊「医薬品の開発 第７巻 分子設計」第１６３頁から第１９８頁に記載されているような、生理的条件で元の化合物に変化するものであってもよい。

(2) -COR ²⁶
(3) -COO-CR ²⁷ (R ²⁸ ) -OCOR ²⁹
(4) -COOR ³⁰
[Wherein R ²⁶ represents a hydrogen atom, an alkyl group, or an optionally substituted aryl group. R ²⁷ and R ²⁸ independently represent a hydrogen atom or an alkyl group. R ²⁹ represents a hydrogen atom, an alkyl group, an aryl group, or a benzyl group. R ³⁰ represents an alkyl group or a benzyl group. ]
Preferable Q ^X includes the group (1) and the group (3). Preferred examples of the group (3) include those in which R ²⁷ is a hydrogen atom, R ²⁸ is a hydrogen atom, methyl or ethyl, and R ²⁹ is methyl or ethyl. These compounds can be produced according to a conventional method (for example, J. Med. Chem. 35, 4727 (1992), WO 01/40180, etc.). Prodrugs may also be those that change to the original compound under physiological conditions, as described in Yodogawa Shoten, 1990, “Pharmaceutical Development Vol. 7 Molecular Design”, pages 163 to 198. Good.

  “Pharmaceutically acceptable salts” include, for example, inorganic acid salts such as hydrochloride, hydrobromide, sulfate, phosphate or nitrate, or acetate, propionate, oxalate, succinate, Examples include organic acid salts such as lactate, malate, tartrate, citrate, maleate, fumarate, methanesulfonate, benzenesulfonate, p-toluenesulfonate, and ascorbate. .

  In addition, the present invention includes a compound represented by the formula (I) or a prodrug thereof, or a pharmaceutically acceptable salt thereof. Moreover, solvates, such as these hydrates or ethanol solvates, are also included. Furthermore, the present invention also includes all tautomers, all stereoisomers present, and crystal forms of all embodiments of the compound (I) of the present invention.

Preferred examples of the compound of the present invention include the following compounds. In the exemplified compounds in the following table, the following abbreviations may be used for the sake of simplicity.
2-Py: 2-pyridyl group, 3-Py: 3-pyridyl group, 4-Py: 4-pyridyl group, Ph: phenyl group, Et: ethyl group, Me: methyl group, n-Pr: n-propyl group I-Pr: isopropyl group, n-Bu: n-butyl group, t-Bu: tert-butyl group, Bn: benzyl group, Ac: acetyl group, cycpro: cyclopropyl group, cycbu: cyclobutyl group, cychex: cyclohexyl Group, etoet: ethoxyethyl group, meoet: methoxyethyl group, f2etoet: 2,2-difluoroethoxyethyl group, f2meoet: difluoromethoxyethyl group, cycprooet: cyclopropyloxyethyl group, isoproet: isopropoxyethyl group, ms: methane Sulfonyl group, etomet: ethoxymethyl group, meomet: methoxymethyl group, f2meomet: difluoromethoxymethyl group, f2etomet: 2,2-difluoroethoxymethyl group.
Moreover, the following abbreviations may be used as a partial structure.

In the compounds of the above compound numbers 1 to 313, the moiety corresponding to Y in item [1] is an unsubstituted or substituted 3-aminopyrrolidin-1-yl group, an unsubstituted or substituted 3-aminopiperidine-1 In the case of -yl group or unsubstituted or substituted (3-amino) hexahydroazepin-1-yl group, the 3-position amino group has an absolute configuration represented by the following formula (F ₁ ) A pyrrole derivative is more preferred.

（式中、ｍ１およびＲ^６は項［１］記載と同義である。）
また、上記の化合物番号１〜３１３の化合物において、項［１］記載のＹに相当する部分が、無置換もしくは置換の(2-アミノシクロアルキル)アミノ基である場合は、1位および2位アミノ基が下記式（Ｆ_２）または式（Ｆ_３）で表される絶対配置を有する化合物が、より好ましい。

(Wherein m1 and R ⁶ have the same meanings as described in item [1].)
In the compounds of Compound Nos. 1 to 313, when the moiety corresponding to Y in Item [1] is an unsubstituted or substituted (2-aminocycloalkyl) amino group, the 1-position and the 2-position A compound in which the amino group has an absolute configuration represented by the following formula (F ₂ ) or formula (F ₃ ) is more preferable.

（式中、ｍ３およびＲ^７は項［１］記載と同義である。）
また、1位および2位アミノ基が下記式（Ｆ_４）で表される絶対配置を有する化合物がさらに好ましい。

(Wherein m3 and R ⁷ have the same meanings as described in item [1].)
Further, a compound in which the 1-position and 2-position amino groups have an absolute configuration represented by the following formula (F ₄ ) is more preferable.

（式中、ｍ３およびＲ^７は項［１］記載と同義である。）

(Wherein m3 and R ⁷ have the same meanings as described in item [1].)

In the following description, when the bond is represented by a wedge shape with a solid line and a broken line as in formula (J ₁ ) and formula (J ₂ ), it represents the absolute configuration of the amino group, and as in formula (J ₃ ) When the bond is represented by a bold line, the relative arrangement of the amino group (for example, the formula (J ₃ ) represents a (±) -cis form) is assumed.

（式中、ｍ３およびＲ^７は項［１］記載と同義である。）

(Wherein m3 and R ⁷ have the same meanings as described in item [1].)

In the compounds of the above compound numbers 1 to 313, in the compound represented by the formula (I) described in item [1], “alkoxycarbonyl group”, “optionally substituted alkoxycarbonyl group”, “substituted” A “good cycloalkoxycarbonyl group”, “an optionally substituted aryloxycarbonyl group”, “an optionally substituted aralkyloxycarbonyl group”, or a formula: —R ^d —C (O) O—R ^e (wherein R ^d and R ^e have the same meanings as described above.) In the formula, a compound containing the above-mentioned compound is substituted by oxidation, reduction, hydrolysis, etc. by an enzyme, hydrolysis by stomach acid, etc. under physiological conditions in vivo. Each group may be changed to a “carboxy group”.

Hereinafter, the method for producing the compound represented by the formula (I) in the present invention will be described with reference to examples, but the present invention is not limited thereto. In this specification, the following abbreviations may be used for the sake of simplicity.
Alloc: allyloxycarbonyl group Boc: tert-butoxycarbonyl group Cbz: benzyloxycarbonyl group TMS: trimethylsilyl group TBS: tert-butyldimethylsilyl group SEM: 2-[(trimethylsilyl) ethoxy] methyl group Ac: acetyl group Me: methyl Group Et: ethyl group Pr: propyl group i-Pr: isopropyl group Bu: butyl group i-Bu: isobutyl group t-Bu: t-butyl group Ph: phenyl group Bn: benzyl group Ms: methanesulfonyl group TFA: trifluoro Acetic acid

  The compound represented by the formula (I) can be synthesized from known compounds by combining known synthesis methods. For example, it can be synthesized by the following method.

Manufacturing method 1
Among the compounds represented by formula (I), the compounds represented by formula (1-17) and formula (1-18) or salts thereof are produced, for example, by the method shown below.

［式中、ｍ１、ｍ２、ｍ３、ｍ４、ｍ５、ｍ６、Ｒ^２、Ｒ^６、Ｒ^７、Ｒ^８、Ｒ^９、Ｒ^１０、Ｒ^１１およびＹは前記記載と同義であり、Ｘは、脱離基（例えば、ヨウ素原子、臭素原子、塩素原子、メタンスルホニルオキシ、トリフルオロメタンスルホニルオキシまたはｐ−トルエンスルホニルオキシ等）を表し、Ｒ^５０は、アルキル基を表し、Ｒ^５１は、ＮＨＡｌｌｏｃ、Ｎ＝Ｃ（Ｐｈ）_２、ＮＨＢｏｃ、ＮＨＣｂｚまたは下記式（Ｇ１）

[Wherein, m1, m2, m3, m4, m5, m6, R ² , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ and Y are as defined above; Represents a leaving group (for example, an iodine atom, a bromine atom, a chlorine atom, methanesulfonyloxy, trifluoromethanesulfonyloxy, p-toluenesulfonyloxy, etc.), R ⁵⁰ represents an alkyl group, R ⁵¹ represents NHAlloc, N = C (Ph) ₂ , NHBoc, NHCbz or the following formula (G1)

を表し、Ｒ^５２は、Ａｌｌｏｃ、ＢｏｃまたはＣｂｚを表し、Ｒ^５３は、アルキル基を表し、Ｒ^５４は、水素原子、または「置換されてもよいアルキル基」を表し、Ｒ^５５は、アセチルまたはベンゾイルを表し、Ｒ^５６は、アルキル基を表し、Ｙ^１は、項［１］記載のＹにおける１級アミノ基または２級アミノ基が保護された状態を表す。]
１）工程１
化合物（１−８）は、化合物（１−１）と、化合物（１−２）、化合物（１−３）、化合物（１−４）、化合物（１−５）、化合物（１−６）および化合物（１−７）から１つ選択される化合物を、不活性溶媒中、塩基の存在下または非存在下、反応させることにより製造することができる。塩基としては、例えば、有機塩基（１−ヒドロキシベンズトリアゾール、Ｎ-メチルモルホリン、トリエチルアミン、ジイソプロピルエチルアミン、トリブチルアミン、１，８-ジアザビシクロ[５．４．０]ウンデカ-７-エン，１，５-ジアザビシクロ[４．３．０]ノナ-５-エン、１，４-ジアザビシクロ[５．４．０]ウンデカ-７-エン、ピリジン、ジメチルアミノピリジン、もしくはピコリン等）、または無機塩基（ナトリウムエトキシド、ナトリウムメトキシド、カリウムtert-ブトキシド、または水素化ナトリウム等）が挙げられる。塩基の使用量としては、化合物（１−１）に対し通常１〜５当量の範囲から選択される。化合物（１−２）、化合物（１−３）、化合物（１−４）、化合物（１−５）、化合物（１−６）および化合物（１−７）の使用量としては、化合物（１−１）に対し通常１〜２当量の範囲から選択される。不活性溶媒としては、例えば、アルコール系溶媒（メタノール、エタノール、または２−プロパノール等）、エーテル系溶媒（テトラヒドロフラン、または１，４−ジオキサン等）、またはこれらの混合溶媒等が挙げられる。反応温度としては、約５０℃〜約１２０℃の範囲から選択することができる。
化合物（１−２）は、後に述べる製造法３３記載の方法によって、化合物（１−３）は、後に述べる製造法３４記載の方法によって、化合物（１−５）は、後に述べる製造法３５記載の方法によって、化合物（１−６）は、後に述べる製造法３６記載の方法によって、それぞれ製造することができる。また、化合物（１−６）は、市販の試薬を用いるか、文献（例えばSynthesis 391 (1994)、Org. Lett. 5, 1591 (2003)、Synthesis 1065 (1992)、Synlett 755 (2002)、J. Org. Chem. 56, 3063 (1991)、J. Org. Chem. 60, 4177 (1995)、およびJ. Org. Chem. 57, 6653 (1992) 等）に記載の方法によって、製造することができる。化合物（１−７）は、文献（例えばJ. Org. Chem. 61, 6700 (1996) 等）に記載されている方法等と同様な方法によって、製造することができる。
２）工程２
化合物（１−１０）は、化合物（１−８）と化合物（１−９）を、不活性溶媒中反応させることにより製造される。化合物（１−９）の使用量としては、化合物（１−８）に対して、通常１当量〜過剰量の範囲から選択される。不活性溶媒としては、例えば、有機塩基（１−ヒドロキシベンズトリアゾール、Ｎ-メチルモルホリン、トリエチルアミン、ジイソプロピルエチルアミン、トリブチルアミン、１，８-ジアザビシクロ[５．４．０]ウンデカ-７-エン，１，５-ジアザビシクロ[４．３．０]ノナ-５-エン、１，４-ジアザビシクロ[５．４．０]ウンデカ-７-エン、ピリジン、ジメチルアミノピリジン、もしくはピコリン等）、アルコール系溶媒（メタノール、エタノールまたは２−プロパノール等）、酢酸、またはこれらの混合溶媒等が挙げられる。反応温度としては、約５０℃〜約１５０℃の範囲から選択されるが、通常還流下に反応を行う。
３）工程３
化合物（１−１２）は、不活性溶媒中、塩基の存在下または非存在下、化合物（１−１０）と化合物（１−１１）を反応させることにより製造することができる（例えば、J. Heterocycl. Chem. 37, 1033 (2000)、 J. Chem. Soc., Perkin Trans. 1, 13, 1833 (1999)、およびJ. Med. Chem. 38, 3838 (1995) 等参照）。化合物（１−１１）の使用量としては、化合物（１−１０）に対して通常１〜５当量の範囲から選択される。塩基としては、例えば炭酸アルカリ(炭酸カリウム、炭酸ナトリウム、炭酸水素カリウムまたは炭酸水素ナトリウム等)、水素化アルカリ（水素化ナトリウムまたは水素化カリウム等）または水酸化アルカリ(水酸化カリウムまたは水酸化ナトリウム等)等が挙げられ、好適には、炭酸カリウム等が挙げられる。塩基の使用量としては、化合物（１−１０）に対して通常１〜３当量の範囲から選択される。不活性溶媒としては、非プロトン性溶媒(Ｎ，Ｎ−ジメチルホルムアミドまたはジメチルスルホキシド等)、エーテル系溶媒(ジエチルエーテル、テトラヒドロフランまたは1,4-ジオキサン等)、ケトン(アセトン等)、またはこれらの混合溶媒等が挙げられ、好適には、アセトン、Ｎ，Ｎ−ジメチルホルムアミド、またはジメチルスルホキシド等が挙げられる。反応温度としては、約１０℃〜約１８０℃の範囲から選択することができる。
また、化合物（１−１２）の製造において、一般にＲ^５３ＯＣ（Ｏ）ＣＨ_２基が異なる窒素原子に導入されたものも副生しうるが、その副生成物は通常の精製方法で容易に除くことができる。
４）工程４
化合物（１−１３）は、不活性溶媒中、化合物（１−１２）と塩基を反応させることにより製造することができる（例えばＷＯ０２/０６８４２０等参照）。塩基としては、水素化アルカリ（水素化ナトリウムまたは水素化カリウム等）等が挙げられ、好適には、水素化ナトリウム等が挙げられる。塩基の使用量としては、化合物（１−１２）に対して通常１〜３当量の範囲から選択される。不活性溶媒としては、Ｎ，Ｎ−ジメチルホルムアミド、エーテル系溶媒(ジエチルエーテル、テトラヒドロフランまたは1,4-ジオキサン等)、またはこれらの混合溶媒等が挙げられ、好適には、テトラヒドロフラン等が挙げられる。反応温度としては、約-１０℃〜約１００℃の範囲から選択することができる。
５）工程５
文献（例えば、J. Med. Chem. 34, 778 (1991)等）に記載された製造法と同様な方法によって、化合物（１−１３）から化合物（１−１４）を製造することができる。
６）工程６
文献（例えば Tetrahedron Letters 43, 5079 (2002) 等）に記載された製造法と同様な方法によって、化合物（１−１４）から化合物（１−１５）を製造することができる。
７）工程７
化合物（１−１６）は、不活性溶媒中、添加物の存在下または非存在下、塩基の存在下または非存在下、化合物（１−１５）を反応させることにより製造することができる。添加物としては、例えば４-(ジメチルアミノ)ピリジン等が挙げられ、塩基としては、例えば水酸化アルカリ(水酸化カリウムまたは水酸化ナトリウム等)、水素化アルカリ(水素化ナトリウムまたは水素化カリウム等)、またはアルコキシアルカリ(ナトリウムメトキシド、ナトリウムエトキシドまたはｔ-ブトキシカリウム等)等が挙げられ、好適には、ナトリウムメトキシドまたはナトリウムエトキシド等が挙げられる。塩基の使用量としては、化合物（１−１５）に対し通常１〜大過剰の範囲から選択される。不活性溶媒としては、例えばアルコール系溶媒(エタノール、メタノールまたは２−プロパノール等)、エーテル系溶媒(テトラヒドロフラン等)、またはこれらの混合溶媒等が挙げられる。反応温度としては、約１０℃〜約１００℃の範囲から選択することができる。
本工程において、化合物（１−１６）のＲ^５６ＯＣ（Ｏ）基が加水分解され、ＣＯ_２Ｈ基に変換された化合物（１−１９）：

R ⁵² represents Alloc, Boc or Cbz, R ⁵³ represents an alkyl group, R ⁵⁴ represents a hydrogen atom or an “optionally substituted alkyl group”, and R ⁵⁵ represents acetyl or Represents benzoyl, R ⁵⁶ represents an alkyl group, and Y ¹ represents a state in which the primary amino group or secondary amino group in Y described in item [1] is protected. ]
1) Step 1
Compound (1-8) includes Compound (1-1), Compound (1-2), Compound (1-3), Compound (1-4), Compound (1-5), and Compound (1-6) And a compound selected from compound (1-7) can be produced by reacting in an inert solvent in the presence or absence of a base. Examples of the base include organic bases (1-hydroxybenztriazole, N-methylmorpholine, triethylamine, diisopropylethylamine, tributylamine, 1,8-diazabicyclo [5.4.0] undec-7-ene, 1,5- Diazabicyclo [4.3.0] non-5-ene, 1,4-diazabicyclo [5.4.0] undec-7-ene, pyridine, dimethylaminopyridine, picoline, etc.) or an inorganic base (sodium ethoxide) Sodium methoxide, potassium tert-butoxide, or sodium hydride). The amount of the base used is usually selected from the range of 1 to 5 equivalents relative to compound (1-1). The amount of the compound (1-2), compound (1-3), compound (1-4), compound (1-5), compound (1-6) and compound (1-7) used is the compound (1). -1) is usually selected from the range of 1 to 2 equivalents. Examples of the inert solvent include alcohol solvents (methanol, ethanol, 2-propanol, etc.), ether solvents (tetrahydrofuran, 1,4-dioxane, etc.), and mixed solvents thereof. The reaction temperature can be selected from the range of about 50 ° C to about 120 ° C.
Compound (1-2) is described in the following Production Method 33, Compound (1-3) is described in the following Production Method 34, and Compound (1-5) is described in the following Production Method 35. Compound (1-6) can be produced by the method described in Production Method 36, which will be described later. Compound (1-6) may be a commercially available reagent, or a literature (for example, Synthesis 391 (1994), Org. Lett. 5, 1591 (2003), Synthesis 1065 (1992), Synlett 755 (2002), J Org. Chem. 56, 3063 (1991), J. Org. Chem. 60, 4177 (1995), and J. Org. Chem. 57, 6653 (1992)). it can. Compound (1-7) can be produced by a method similar to the method described in literature (eg, J. Org. Chem. 61, 6700 (1996)).
2) Step 2
Compound (1-10) is produced by reacting compound (1-8) and compound (1-9) in an inert solvent. The amount of compound (1-9) to be used is generally selected from the range of 1 equivalent to excess with respect to compound (1-8). Examples of the inert solvent include organic bases (1-hydroxybenztriazole, N-methylmorpholine, triethylamine, diisopropylethylamine, tributylamine, 1,8-diazabicyclo [5.4.0] undec-7-ene, 1, 5-diazabicyclo [4.3.0] non-5-ene, 1,4-diazabicyclo [5.4.0] undec-7-ene, pyridine, dimethylaminopyridine, picoline, etc.), alcohol solvent (methanol , Ethanol or 2-propanol), acetic acid, or a mixed solvent thereof. The reaction temperature is selected from the range of about 50 ° C. to about 150 ° C., but the reaction is usually carried out under reflux.
3) Step 3
Compound (1-12) can be produced by reacting compound (1-10) with compound (1-11) in an inert solvent in the presence or absence of a base (for example, J. Heterocycl. Chem. 37, 1033 (2000), J. Chem. Soc., Perkin Trans. 1, 13, 1833 (1999), and J. Med. Chem. 38, 3838 (1995), etc.). The amount of compound (1-11) to be used is generally selected from the range of 1 to 5 equivalents relative to compound (1-10). Examples of the base include alkali carbonate (potassium carbonate, sodium carbonate, potassium hydrogen carbonate, sodium hydrogen carbonate, etc.), alkali hydride (sodium hydride, potassium hydride, etc.) or alkali hydroxide (potassium hydroxide, sodium hydroxide, etc.) ) And the like, and potassium carbonate and the like are preferable. The amount of base used is usually selected from the range of 1 to 3 equivalents relative to compound (1-10). As an inert solvent, an aprotic solvent (such as N, N-dimethylformamide or dimethyl sulfoxide), an ether solvent (such as diethyl ether, tetrahydrofuran or 1,4-dioxane), a ketone (such as acetone), or a mixture thereof Examples of the solvent include acetone, N, N-dimethylformamide, and dimethyl sulfoxide. The reaction temperature can be selected from the range of about 10 ° C to about 180 ° C.
In addition, in the production of the compound (1-12), in general, R ⁵³ OC (O) CH ₂ group introduced into a different nitrogen atom may be produced as a by-product, but the by-product can be easily obtained by an ordinary purification method. Can be excluded.
4) Step 4
Compound (1-13) can be produced by reacting compound (1-12) with a base in an inert solvent (see, for example, WO 02/068420). Examples of the base include alkali hydrides (such as sodium hydride or potassium hydride), and preferred examples include sodium hydride. The amount of the base used is usually selected from the range of 1 to 3 equivalents relative to the compound (1-12). Examples of the inert solvent include N, N-dimethylformamide, ether solvents (diethyl ether, tetrahydrofuran, 1,4-dioxane and the like), and mixed solvents thereof, and preferably tetrahydrofuran and the like. The reaction temperature can be selected from the range of about −10 ° C. to about 100 ° C.
5) Step 5
Compound (1-14) can be produced from compound (1-13) by a method similar to the production method described in the literature (for example, J. Med. Chem. 34, 778 (1991)).
6) Step 6
Compound (1-15) can be produced from compound (1-14) by a method similar to the production method described in the literature (eg, Tetrahedron Letters 43, 5079 (2002)).
7) Step 7
Compound (1-16) can be produced by reacting compound (1-15) in an inert solvent in the presence or absence of an additive and in the presence or absence of a base. Examples of the additive include 4- (dimethylamino) pyridine, and examples of the base include alkali hydroxide (potassium hydroxide, sodium hydroxide, etc.), alkali hydride (sodium hydride, potassium hydride, etc.), and the like. Or alkoxyalkali (sodium methoxide, sodium ethoxide, t-butoxypotassium, etc.) and the like, preferably sodium methoxide, sodium ethoxide and the like. The amount of base used is usually selected from a range of 1 to a large excess relative to compound (1-15). Examples of the inert solvent include alcohol solvents (ethanol, methanol, 2-propanol, etc.), ether solvents (tetrahydrofuran, etc.), and mixed solvents thereof. The reaction temperature can be selected from the range of about 10 ° C to about 100 ° C.
In this step, compound (1-19) in which R ⁵⁶ OC (O) group of compound (1-16) was hydrolyzed and converted to CO ₂ H group:

が生成した場合には、文献（例えばProtective Groups in Organic Synthesis 2nd Edition (John Wiley & Sons, Inc.)など）に記載されている方法等と同様な方法によって、化合物（１−１９）から化合物（１−１６）を製造することができる。
８）工程８
文献（例えばProtective Groups in Organic Synthesis 2nd Edition (John Wiley & Sons, Inc.)など）に記載されている方法等と同様な方法によって、化合物（１−１６）から化合物（１−１７）を製造することができる。
９）工程９
文献（例えば、J. Org. Chem. 61, 215 (1996)、J. Org. Chem. 61, 9437 (1996)およびJ. Org. Chem. 59, 6147 (1994)等）に記載された製造法と同様な方法によって、化合物（１−１７）から化合物（１−１８）を製造することができる。

Is produced from compound (1-19) by a method similar to the method described in the literature (for example, Protective Groups in Organic Synthesis 2nd Edition (John Wiley & Sons, Inc.)). 1-16) can be produced.
8) Step 8
Compound (1-17) is produced from Compound (1-16) by a method similar to the method described in literature (for example, Protective Groups in Organic Synthesis 2nd Edition (John Wiley & Sons, Inc.), etc.) be able to.
9) Step 9
Production methods described in literature (for example, J. Org. Chem. 61, 215 (1996), J. Org. Chem. 61, 9437 (1996) and J. Org. Chem. 59, 6147 (1994), etc.) The compound (1-18) can be produced from the compound (1-17) by the same method.

Manufacturing method 2
Among the compounds represented by the formula (I), the compounds represented by the formula (2-3), the formula (2-4) and the formula (2-7) or a salt thereof are produced by, for example, the method shown below. Is done.

[式中、Ｒ^２、Ｒ^５４、Ｒ^５６、Ｘ、Ｙ^１およびＹは、前記記載と同義であり、Ｒ^５７ＯＣ（Ｏ）は、「置換されてもよいアルコキシカルボニル基」、「置換されてもよいアリールオキシカルボニル基」、「置換されてもよいアラルキルオキシカルボニル基」、「置換されてもよいシクロアルキルオキシカルボニル基」、または式：Ｒ^ｅＯＣ（Ｏ）を表す。Ｒ^ｅは前記記載と同義である。]
１）工程１
製造法１における工程９に記載された製造法と同様な方法によって、化合物（１−１６）から化合物（２−１）を製造することができる。
２）工程２
文献（例えば、Heterocycles 53, 797 (2000)、Bioorg. Med. Chem. Lett. 7, 739 (1997)およびOrg. Prep. Proced. Int. 26, 429 (1994) 等）に記載された製造方法と同様な方法によって、化合物（２−１）から化合物（２−２）を製造することができる。
本工程において、化合物（２−２）のＢｏｃ基が脱保護された化合物（２−３）が生成した場合には、文献（例えばProtective Groups in Organic Synthesis 2nd Edition (John Wiley & Sons, Inc.)など）に記載されている方法等と同様な方法によって、化合物（２−３）から化合物（２−２）を製造することができる。
３）工程３
製造法１における工程８に記載された製造法と同様な方法によって、化合物（２−２）から化合物（２−３）を製造することができる。
４）工程４
文献（例えば、Synth. Commun. 22, 2811 (1992)等）に記載された製造方法と同様な方法によって、化合物（２−２）から化合物（２−４）を製造することができる。
本工程において、化合物（２−４）のＹにおける１級アミノ基または２級アミノ基が保護された状態を示す式

[Wherein, R ² , R ⁵⁴ , R ⁵⁶ , X, Y ¹ and Y are as defined above, and R ⁵⁷ OC (O) represents “an optionally substituted alkoxycarbonyl group”, “substituted” Represents an “optionally substituted aryloxycarbonyl group”, “an optionally substituted aralkyloxycarbonyl group”, “an optionally substituted cycloalkyloxycarbonyl group”, or the formula: R ^e OC (O). ^Re is as defined above. ]
1) Step 1
Compound (2-1) can be produced from compound (1-16) by a method similar to the production method described in Step 9 of Production Method 1.
2) Step 2
Production methods described in literature (for example, Heterocycles 53, 797 (2000), Bioorg. Med. Chem. Lett. 7, 739 (1997) and Org. Prep. Proced. Int. 26, 429 (1994), etc.) By a similar method, compound (2-2) can be produced from compound (2-1).
In this step, when a compound (2-3) in which the Boc group of the compound (2-2) is deprotected is produced, literature (for example, Protective Groups in Organic Synthesis 2nd Edition (John Wiley & Sons, Inc.) The compound (2-2) can be produced from the compound (2-3) by a method similar to the method described in the above.
3) Step 3
Compound (2-3) can be produced from compound (2-2) by the same production process as described in Process 8 in Production Process 1.
4) Step 4
Compound (2-4) can be produced from compound (2-2) by a method similar to the production method described in the literature (for example, Synth. Commun. 22, 2811 (1992)).
In this step, formula (1) shows a state where the primary amino group or secondary amino group in Y of compound (2-4) is protected

[式中、Ｒ^２、Ｒ^５４およびＹ^１は、前記記載と同義である。]で表される化合物（２−９）が生成した場合には、製造法１における工程８に記載された製造法と同様な方法によって、化合物（２−９）から化合物（２−４）を製造することができる。
５）工程５
製造法３における工程１に記載された製造法と同様な方法によって、化合物（２−１）から化合物（２−６）を製造することができる。化合物（２−５）は、市販の試薬を用いるか、文献（例えば、ＷＯ０３/０２７０９８、ＷＯ００/０６５８１、Comprehensive Organic transformation, R. C. ラロック著, VCH publisher Inc., 1989 等）に記載された製造法と同様な方法によって製造することができる。
６）工程６
製造法１における工程８に記載された製造法と同様な方法によって、化合物（２−６）から化合物（２−７）を製造することができる。

[Wherein, R ² , R ⁵⁴ and Y ¹ are as defined above. When the compound (2-9) represented by formula (1) is produced, the compound (2-9) is converted from the compound (2-9) by the same production method as described in Step 8 of Production Method 1. Can be manufactured.
5) Step 5
Compound (2-6) can be produced from compound (2-1) by the same production process as described in the step 1 in the production process 3. Compound (2-5) may be a commercially available reagent, or a production method described in the literature (for example, WO 03/027098, WO 00/066581, Comprehensive Organic transformation, RC Laroc, VCH publisher Inc., 1989). It can be manufactured by a similar method.
6) Step 6
Compound (2-7) can be produced from compound (2-6) by the same production process as described in the step 8 in the production process 1.

Production method 3
Among the compounds represented by formula (I), the compounds represented by formula (3-4) and formula (3-6) or salts thereof are produced, for example, by the method shown below.

[式中、Ｒ^２、Ｒ^５４、Ｒ^５６、Ｒ^５７、Ｘ、ＹおよびＹ^１は、前記記載と同義であり、Ｒ^５８は、「置換されてもよいアルキル基」または「置換されてもよいシクロアルキル基」を表す。]
１）工程１
化合物（３−２）は、不活性溶媒中、塩基の存在下、化合物（１−１６）を化合物（３−１）と反応させることにより製造することができる。化合物（３−１）の使用量としては、化合物（１−１６）に対して通常１〜３当量の範囲から選択される。塩基としては、例えば炭酸アルカリ(炭酸カリウム、炭酸ナトリウム、炭酸水素カリウムまたは炭酸水素ナトリウム等)、水酸化アルカリ(水酸化カリウムまたは水酸化ナトリウム等)、水素化アルカリ(水素化ナトリウムまたは水素化カリウム等)、またはアルコキシアルカリ(ｔ-ブトキシカリウム等)等が挙げられ、好適には、炭酸カリウムまたは水素化ナトリウム等が挙げられる。塩基の使用量としては、化合物（１−１６）に対し通常１〜５当量の範囲から選択される。不活性溶媒としては、例えば非プロトン性溶媒(Ｎ，Ｎ−ジメチルホルムアミドまたはジメチルスルホキシド等)、エーテル系溶媒(ジエチルエーテル、テトラヒドロフランまたは1,4-ジオキサン等)、ケトン(アセトン等)、またはこれらの混合溶媒等が挙げられ、好適にはＮ，Ｎ−ジメチルホルムアミド等が挙げられる。反応温度としては、約１０℃〜約１００℃の範囲から選択することができる。
２）工程２
製造法１における工程９に記載された製造法と同様な方法によって、化合物（３−２）から化合物（３−３）を製造することができる。
３）工程３
製造法１における工程８に記載された製造法と同様な方法によって、化合物(３−３)から化合物（３−４）を製造することができる。
４）工程４
製造法３における工程１に記載された製造法と同様な方法によって、化合物(３−３)から化合物（３−５）を製造することができる。
５）工程５
製造法１における工程８に記載された製造法と同様な方法によって、化合物(３−５)から化合物（３−６）を製造することができる。

[Wherein, R ² , R ⁵⁴ , R ⁵⁶ , R ⁵⁷ , X, Y and Y ¹ are as defined above, and R ⁵⁸ represents an “optionally substituted alkyl group” or “substituted”. Represents a "good cycloalkyl group". ]
1) Step 1
Compound (3-2) can be produced by reacting compound (1-16) with compound (3-1) in the presence of a base in an inert solvent. The amount of compound (3-1) to be used is generally selected from the range of 1 to 3 equivalents relative to compound (1-16). Examples of the base include alkali carbonate (potassium carbonate, sodium carbonate, potassium hydrogen carbonate, sodium hydrogen carbonate, etc.), alkali hydroxide (potassium hydroxide, sodium hydroxide, etc.), alkali hydride (sodium hydride, potassium hydride, etc.) ) Or alkoxyalkali (such as t-butoxypotassium) and the like, and preferably potassium carbonate, sodium hydride and the like. The amount of the base used is usually selected from the range of 1 to 5 equivalents relative to compound (1-16). Examples of the inert solvent include aprotic solvents (N, N-dimethylformamide, dimethyl sulfoxide, etc.), ether solvents (diethyl ether, tetrahydrofuran, 1,4-dioxane, etc.), ketones (acetone, etc.), or these A mixed solvent etc. are mentioned, N, N- dimethylformamide etc. are mentioned suitably. The reaction temperature can be selected from the range of about 10 ° C to about 100 ° C.
2) Step 2
Compound (3-3) can be produced from compound (3-2) by a method similar to the production method described in Step 9 of Production Method 1.
3) Step 3
Compound (3-4) can be produced from compound (3-3) by the same production process as described in Process 8 in production process 1.
4) Step 4
Compound (3-5) can be produced from compound (3-3) by the same production process as described in the step 1 in the production process 3.
5) Step 5
Compound (3-6) can be produced from compound (3-5) by the same production process as described in the step 8 in the production process 1.

Manufacturing method 4
Among the compounds represented by formula (I), the compound represented by formula (4-1) or a salt thereof is produced, for example, by the method shown below.

[式中、Ｒ^２、Ｒ^５４、Ｒ^５６、Ｒ^５８、Ｙ^１およびＹは、前記記載と同義である。]
１）工程１
製造法１における工程８に記載された製造法と同様な方法によって,化合物(３−２)から化合物（４−１）を製造することができる。

[Wherein, R ² , R ⁵⁴ , R ⁵⁶ , R ⁵⁸ , Y ¹ and Y are as defined above. ]
1) Step 1
Compound (4-1) can be produced from compound (3-2) by a method similar to the production method described in Step 8 of Production Method 1.

Manufacturing method 5
Among the compounds represented by the formula (I), the compound represented by the formula (5-3) or a salt thereof is produced, for example, by the method shown below.

[式中、Ｒ^２、Ｒ^５４、Ｒ^５８、Ｘ、Ｙ^１およびＹは、前記記載と同義である。]
１）工程１
製造法３における工程１に記載された製造法と同様な方法によって、化合物(２−１)から化合物（５−２）を製造することができる。
２）工程２
製造法１における工程８に記載された製造法と同様な方法によって、化合物(５−２)から化合物（５−３）を製造することができる。

[Wherein, R ² , R ⁵⁴ , R ⁵⁸ , X, Y ¹ and Y are as defined above. ]
1) Step 1
Compound (5-2) can be produced from compound (2-1) by the same production process as described in Step 1 of Production Process 3.
2) Step 2
Compound (5-3) can be produced from compound (5-2) by the same production process as described in the step 8 in the production process 1.

Manufacturing method 6
Of the compounds represented by the formula (I), the compound represented by the formula (6-3) or a salt thereof is produced, for example, by the method shown below.

[式中、Ｒ^２、Ｒ^５４、Ｒ^５８、Ｙ^１およびＹは、前記記載と同義であり、Ｒ^５９Ｒ^６０ＮＣ（Ｏ）は、「置換されてもよいカルバモイル基」を表す。]
１）工程１
文献（例えば、Comprehensive Organic transformation, R. C. ラロック著, VCH publisher Inc. (1989)等）に記載された製造方法と同様な方法によって、化合物（３−３）から化合物（６−２）を製造することができる。
２）工程２
製造法１における工程８に記載された製造法と同様な方法によって,化合物(６−２)から化合物（６−３）を製造することができる。

[Wherein R ² , R ⁵⁴ , R ⁵⁸ , Y ¹ and Y have the same meanings as described above, and R ⁵⁹ R ⁶⁰ NC (O) represents an “optionally substituted carbamoyl group”. ]
1) Step 1
The compound (6-2) is produced from the compound (3-3) by a method similar to the production method described in the literature (for example, Comprehensive Organic transformation, RC Larro, VCH publisher Inc. (1989)). Can do.
2) Step 2
Compound (6-3) can be produced from compound (6-2) by a method similar to the production method described in Step 8 of Production Method 1.

Manufacturing method 7
Among the compounds represented by formula (I), the compound represented by formula (7-4) or a salt thereof is produced, for example, by the method shown below.

[式中、Ｒ^２、Ｒ^５４、Ｒ^５８、Ｙ^１およびＹは、前記記載と同義であり、Ｍ^１は、リチウム、マグネシウムクロライド、またはマグネシウムブロマイドを表し、Ｃ（Ｏ）Ｒ^６１は、「置換されてもよいアルキルカルボニル基」、「置換されてもよいアロイル基」、または「置換されてもよいヘテロアリールカルボニル基」を表す。]
１）工程１〜工程２
文献（例えば、Bioorg. Med. Chem. Lett. 11, 2951 (2001)、Tetrahedron Letters 42, 8955 (2001)、Synthesis 1852 (2000)、Organic Letters 2, 4091 (2000)、Tetrahedron Letters 42, 5609 (2001)、Synthesis 2239 (2001)、Synlett 5, 715 (2002)、J. Org. Chem. 67, 5032 (2002)、Bioorg. Med. Chem. Lett. 11, 287 (2001)およびTetrahedron Letters 42, 3763 (2001)等）に記載された製造法と同様な方法によって、化合物（３−３）から化合物（７−３）を製造することができる。
化合物（７−２）は、市販品を用いるか、実験化学講座(日本化学会編、丸善)２５巻等に記載された方法によって製造することができる。
２）工程３
製造法１における工程８に記載された製造法と同様な方法によって、化合物(７−３)から化合物（７−４）を製造することができる。

[Wherein R ² , R ⁵⁴ , R ⁵⁸ , Y ¹ and Y have the same meanings as described above, M ¹ represents lithium, magnesium chloride or magnesium bromide, and C (O) R ⁶¹ represents “ It represents an “optionally substituted alkylcarbonyl group”, an “optionally substituted aroyl group”, or an “optionally substituted heteroarylcarbonyl group”. ]
1) Step 1 to Step 2
Literature (for example, Bioorg. Med. Chem. Lett. 11, 2951 (2001), Tetrahedron Letters 42, 8955 (2001), Synthesis 1852 (2000), Organic Letters 2, 4091 (2000), Tetrahedron Letters 42, 5609 (2001) ), Synthesis 2239 (2001), Synlett 5, 715 (2002), J. Org. Chem. 67, 5032 (2002), Bioorg. Med. Chem. Lett. 11, 287 (2001) and Tetrahedron Letters 42, 3763 ( 2001), etc.) can be produced from compound (3-3) by a method similar to the production method described in US Pat.
Compound (7-2) may be a commercially available product, or can be produced by the method described in Experimental Chemistry Course (Edited by Chemical Society of Japan, Maruzen), Vol.
2) Step 3
Compound (7-4) can be produced from compound (7-3) by the same production process as described in Process 8 in Production Process 1.

Manufacturing method 8
Among the compounds represented by formula (I), the compound represented by formula (8-5) or a salt thereof is produced, for example, by the method shown below.

[式中、Ｒ^２、Ｒ^５４、Ｒ^５６、Ｒ^５８、Ｙ^１およびＹは、前記記載と同義であり、Ｒ^６２Ｏは、「置換されてもよいアルキル基」における置換基として示される「置換されてもよいアリールオキシ基」または「置換されてもよいアルコキシ基」を表す。]
１）工程１
実験化学講座(日本化学会編、丸善)２０巻等に記載された製造法と同様な方法によって、化合物（３−２）から化合物（８−１）を製造することができる。
２）工程２
実験化学講座(日本化学会編、丸善)１９巻等に記載された製造法と同様な方法によって、化合物（８−１）から化合物（８−２）を製造することができる。
３）工程３
実験化学講座(日本化学会編、丸善)２０巻等に記載された製造法と同様な方法によって、化合物（８−２）から化合物（８−４）を製造することができる。
４）工程４
製造法１における工程８に記載された製造法と同様な方法によって、化合物(８−
４)から化合物（８−５）を製造することができる。

[Wherein, R ² , R ⁵⁴ , R ⁵⁶ , R ⁵⁸ , Y ¹ and Y have the same meanings as described above, and R ⁶² O is shown as a substituent in the “optionally substituted alkyl group”. It represents an “aryloxy group that may be substituted” or an “alkoxy group that may be substituted”. ]
1) Step 1
The compound (8-1) can be produced from the compound (3-2) by a method similar to the production method described in Experimental Chemistry Course (Edited by The Chemical Society of Japan, Maruzen) Vol.
2) Step 2
Compound (8-2) can be produced from compound (8-1) by a method similar to the production method described in Experimental Chemistry Course (Edited by Chemical Society of Japan, Maruzen) Vol.
3) Step 3
Compound (8-4) can be produced from compound (8-2) by a method similar to the production method described in Experimental Chemistry Course (Edited by Chemical Society of Japan, Maruzen) Volume 20 and the like.
4) Step 4
By a method similar to the production method described in the step 8 in the production method 1, the compound (8-
The compound (8-5) can be produced from 4).

Manufacturing method 9
Among the compounds represented by formula (I), the compound represented by formula (9-6) or a salt thereof is produced, for example, by the method shown below.

[式中、Ｒ^２、Ｒ^５３、Ｙ^１およびＹは、前記記載と同義であり、Ｒ^６３は、水素原子、「置換されてもよいアルキル基」、「置換されてもよいシクロアルキル基」、「置換されてもよいアリール基」、「置換されてもよいアラルキル基」、「置換されてもよいへテロアリール基」、または「置換されてもよいへテロアリールアルキル基」、もしくはトリメチルシリル基を表す。]
１）工程１
製造法１における工程９に記載された製造法と同様な方法によって、化合物(１−１４)から化合物（９−１）を製造することができる。
２）工程２
製造法２における工程２に記載された製造法と同様な方法によって、化合物（９−１）から化合物（９−２）を製造することができる。
３）工程３〜４
文献（例えば、Chem. Pharm. Bull. 44, 288 (1996)、J. Med. Chem. 34, 778 (1991)およびTetrahedron 49,557 (1993)等）に記載された製造法と同様な方法によって、化合物（９−２）から化合物（９−５）を製造することができる。また、工程３については、文献（例えば、Chem. Rev. 103, 1979 (2003)およびChem. Rev. 103, 1875 (2003)等）に記載された製造法を参考にすることもできる。
４）工程５
製造法１における工程８に記載された製造法と同様な方法によって、化合物(９−５)から化合物（９−６）を製造することができる。

[Wherein R ² , R ⁵³ , Y ¹ and Y are as defined above, and R ⁶³ represents a hydrogen atom, an “optionally substituted alkyl group”, an “optionally substituted cycloalkyl group”. , “An optionally substituted aryl group”, “an optionally substituted aralkyl group”, “an optionally substituted heteroaryl group”, or “an optionally substituted heteroarylalkyl group”, or a trimethylsilyl group To express. ]
1) Step 1
Compound (9-1) can be produced from compound (1-14) by a method similar to the production method described in Step 9 of Production Method 1.
2) Step 2
Compound (9-2) can be produced from compound (9-1) by the same production process as described in the step 2 in the production process 2.
3) Steps 3-4
Compound by a method similar to that described in the literature (for example, Chem. Pharm. Bull. 44, 288 (1996), J. Med. Chem. 34, 778 (1991) and Tetrahedron 49,557 (1993), etc.) Compound (9-5) can be produced from (9-2). For step 3, the production methods described in the literature (for example, Chem. Rev. 103, 1979 (2003) and Chem. Rev. 103, 1875 (2003)) can also be referred to.
4) Step 5
Compound (9-6) can be produced from compound (9-5) by the same production process as described in Process 8 in production process 1.

Manufacturing method 10
Among the compounds represented by the formula (I), the compounds represented by the formula (10-3), the formula (10-6) and the formula (10-8) or a salt thereof are produced by, for example, the method shown below. Is done.

[式中、Ｒ^２、Ｒ^５３、Ｒ^６３、Ｘ、Ｙ^１およびＹは、前記記載と同義であり、Ｒ^６４は、メチル、エチル、プロピル、または２−プロピルを表す。]
１）工程１
製造法３における工程１に記載された製造法と同様な方法によって,化合物(９−５)から化合物（１０−２）を製造することができる。
２）工程２
製造法１における工程８に記載された製造法と同様な方法によって、化合物(１０−２)から化合物（１０−３）を製造することができる。
３）工程３
製造法３における工程１に記載された製造法と同様な方法によって,化合物(９−５)から化合物（１０−５）を製造することができる。
４）工程４
製造法１における工程８に記載された製造法と同様な方法によって、化合物(１０−５)から化合物（１０−６）を製造することができる。
５）工程５
製造法１における工程９に記載された製造法と同様な方法によって、化合物(１０−５)から化合物（１０−７）を製造することができる。
６）工程６
製造法１における工程８に記載された製造法と同様な方法によって、化合物(１０−７)から化合物（１０−８）を製造することができる。

[Wherein, R ² , R ⁵³ , R ⁶³ , X, Y ¹ and Y have the same meanings as described above, and R ⁶⁴ represents methyl, ethyl, propyl, or 2-propyl. ]
1) Step 1
Compound (10-2) can be produced from compound (9-5) by a method similar to the production method described in Step 1 of Production Method 3.
2) Step 2
Compound (10-3) can be produced from compound (10-2) by the same production process as described in the step 8 in the production process 1.
3) Step 3
Compound (10-5) can be produced from compound (9-5) by a method similar to the production method described in Step 1 of Production Method 3.
4) Step 4
Compound (10-6) can be produced from compound (10-5) by the same production process as described in the step 8 in the production process 1.
5) Step 5
Compound (10-7) can be produced from compound (10-5) by a method similar to the production method described in Step 9 of Production Method 1.
6) Step 6
Compound (10-8) can be produced from compound (10-7) by the same production process as described in the step 8 in the production process 1.

Manufacturing method 11
Among the compounds represented by the formula (I), the compound represented by the formula (11-3) or a salt thereof is produced, for example, by the method shown below.

[式中、Ｒ^２、Ｒ^６３、Ｒ^５９、Ｒ^６０、Ｙ^１およびＹは、前記記載と同義である。]
１）工程１
製造法６における工程１に記載された製造法と同様な方法によって、化合物(１０−７)から化合物（１１−２）を製造することができる。
２）工程２
製造法１における工程８に記載された製造法と同様な方法によって、化合物(１１−２)から化合物（１１−３）を製造することができる。

[Wherein, R ² , R ⁶³ , R ⁵⁹ , R ⁶⁰ , Y ¹ and Y have the same meanings as described above. ]
1) Step 1
Compound (11-2) can be produced from compound (10-7) by the same production process as described in the step 1 in the production process 6.
2) Step 2
Compound (11-3) can be produced from compound (11-2) by the same production process as described in the step 8 in the production process 1.

Production method 12
Among the compounds represented by the formula (I), the compound represented by the formula (12-4) or a salt thereof is produced, for example, by the method shown below.

[式中、Ｒ^２、Ｒ^６１、Ｒ^６３、Ｍ^１、Ｙ^１およびＹは、前記記載と同義である。]
１）工程１〜工程２
製造法７における工程１〜工程２に記載された製造法と同様な方法によって、化合物（１０−７）から化合物（１２−３）を製造することができる。化合物（１２−２）は、市販品を用いるか、実験化学講座(日本化学会編、丸善)２５巻等に記載された方法によって製造することができる。
２）工程３
製造法１における工程８に記載された製造法と同様な方法によって、化合物(１２−３)から化合物（１２−４）を製造することができる。

[Wherein, R ² , R ⁶¹ , R ⁶³ , M ¹ , Y ¹ and Y have the same meanings as described above. ]
1) Step 1 to Step 2
Compound (12-3) can be produced from compound (10-7) by the same production process as described in Process 1 to Process 2 in Production Process 7. Compound (12-2) may be a commercially available product, or can be produced by the method described in Experimental Chemistry Course (Edited by The Chemical Society of Japan, Maruzen) Vol.
2) Step 3
Compound (12-4) can be produced from compound (12-3) by a method similar to the production method described in Step 8 of Production Method 1.

Production method 13
Of the compounds represented by formula (I), the compound represented by formula (13-5) or a salt thereof is produced, for example, by the method shown below.

[式中、Ｒ^２、Ｒ^５４、Ｒ^５６、Ｒ^５８、Ｘ、Ｙ^１およびＹは、前記記載と同義である。]
１）工程１
製造法３における工程１に記載された製造法と同様な方法によって、化合物(１−１６)から化合物（１３−２）を製造することができる。
２）工程２
製造法１における工程９に記載された製造法と同様な方法によって、化合物(１３−２)から化合物（１３−３）を製造することができる。
３）工程３
製造法２における工程２に記載された製造法と同様な方法によって、化合物（１３−３）から化合物（１３−４）を製造することができる。
４）工程４
製造法２における工程４に記載された製造法と同様な方法によって、化合物（１３−４）から化合物（１３−５）を製造することができる。
本工程において、化合物（１３−５）のＹにおける１級アミノ基または２級アミノ基が保護された状態を示す式

[Wherein, R ² , R ⁵⁴ , R ⁵⁶ , R ⁵⁸ , X, Y ¹ and Y have the same meanings as described above. ]
1) Step 1
Compound (13-2) can be produced from compound (1-16) by the same production process as described in the step 1 in the production process 3.
2) Step 2
Compound (13-3) can be produced from compound (13-2) by the same production process as described in Step 9 of Production Process 1.
3) Step 3
Compound (13-4) can be produced from compound (13-3) by the same production process as described in the step 2 in the production process 2.
4) Step 4
Compound (13-5) can be produced from compound (13-4) by the same production process as described in Process 4 in production process 2.
In this step, the formula showing a state in which the primary amino group or secondary amino group in Y of the compound (13-5) is protected

[式中、Ｒ^２、Ｒ^５４、Ｒ^５８、Ｙ^１およびＹは、前記記載と同義である。]で表される化合物（１３−６）が生成した場合には、製造法１における工程８に記載された製造法と同様な方法によって、化合物（１３−６）から化合物（１３−５）を製造することができる。

[Wherein, R ² , R ⁵⁴ , R ⁵⁸ , Y ¹ and Y are as defined above. When the compound (13-6) represented by formula (1) is produced, the compound (13-6) is converted from the compound (13-6) by the same production method as described in Step 8 of Production Method 1. Can be manufactured.

Production method 14
Of the compounds represented by formula (I), the compounds represented by formula (14-5) and formula (14-7) or salts thereof are produced, for example, by the method shown below.

[式中、Ｒ^２、Ｒ^５４、Ｒ^５８、Ｙ^１およびＹは、前記記載と同義であり、Ｒ^６５-Ｑ^１は、「置換されてもよいアリールオキシ基」、「置換されてもよいアリールチオ基」、「置換されてもよいへテロアリールオキシ基」を表し、Ｒ^６５-Ｑ^２は、「置換されてもよいアリールスルホニル基」を表し、Ｅ^１は、塩素原子または臭素原子を表し、Ｍ^２は、リチウム、ナトリウム、カリウムまたはセシウムを表す。]
１）工程１
文献（例えば、Comprehensive Organic transformation, R. C. ラロック著, VCH publisher Inc. (1989)およびEur. J. Org. Chem. 1353 (2000) 等）に記載された製造法と同様な方法によって、化合物（１３−３）から化合物（１４−１）を製造することができる。
本工程において、化合物（１４−１）のＹ^１における保護基としてＢｏｃ基が脱保護された状態を示す式：

[Wherein, R ² , R ⁵⁴ , R ⁵⁸ , Y ¹ and Y have the same meanings as described above, and R ⁶⁵ -Q ¹ represents “an optionally substituted aryloxy group” or “optionally substituted”. Represents an "arylthio group", "an optionally substituted heteroaryloxy group", R ⁶⁵ -Q ² represents an "optionally substituted arylsulfonyl group", and E ¹ represents a chlorine atom or a bromine atom , M ² represents lithium, sodium, potassium or cesium. ]
1) Step 1
Compound (13-) was prepared by a method similar to the production method described in the literature (for example, Comprehensive Organic transformation, RC Larro, VCH publisher Inc. (1989) and Eur. J. Org. Chem. 1353 (2000)). The compound (14-1) can be produced from 3).
In this step, the formula showing a state in which the Boc group is deprotected as a protecting group for Y ¹ of the compound (14-1):

[式中、Ｒ^２、Ｒ^５４、Ｒ^５８およびＹは、前記記載と同義である。]で表される化合物（１４−８）が生成した場合には、以下の方法によって、化合物（１４−１）を製造することができる。すなわち、化合物（１４−８）と二炭酸ジ−tert-ブチルを、塩基の存在下、不活性溶媒中反応させる。二炭酸ジ−tert-ブチルの使用量としては、化合物（１４−８）に対し、通常３〜６当量の範囲から選択される。塩基としては、例えば、水酸化ナトリウムまたは炭酸カリウム等の無機塩基、またはトリエチルアミン等の有機塩基が挙げられる。不活性溶媒としては、例えばエーテル系溶媒（テトラヒドロフランまたは１，４−ジオキサン等）等が挙げられる。反応温度としては、約−１０℃〜約４０℃の範囲から選択される。
２）工程２
文献（例えば、Comprehensive Organic transformation, R. C. ラロック著, VCH publisher Inc. (1989)等）に記載された製造法と同様な方法によって、化合物（１４−１）から化合物（１４−２）を製造することができる。本工程において、化合物（１４−２）のＢｏｃ基が脱保護された場合には、製造法１４における工程１に記載された製造法と同様な方法によって、Ｂｏｃ化を行い、化合物（１４−２）を製造することができる。
３）工程３
文献（例えば、Heterocycles 52, 253 (2000)等）に記載された製造法と同様な方法によって、化合物（１４−２）から化合物（１４−４）を製造することができる。
４）工程４
製造法１における工程８に記載された製造法と同様な方法によって、化合物（１４−４）から化合物（１４−５）を製造することができる。
５）工程５
化合物（１４−４）のＱ^１が硫黄原子の場合、文献（例えば、Comprehensive Organic transformation, R. C. ラロック著, VCH publisher Inc. (1989)およびEur. J. Org. Chem. 1353 (2000)等）に記載された製造法と同様な方法によって、化合物（１４−４）のＱ^１（すなわちＳ）をＱ^２（すなわちＳＯ_２）に変換した化合物（１４−６）を製造することができる。
６）工程６
製造法１における工程８に記載された製造法と同様な方法によって、化合物（１４−６）から化合物（１４−７）を製造することができる。

[Wherein, R ² , R ⁵⁴ , R ⁵⁸ and Y are as defined above. When the compound (14-8) represented by this is produced | generated, a compound (14-1) can be manufactured with the following method. That is, the compound (14-8) and di-tert-butyl dicarbonate are reacted in an inert solvent in the presence of a base. The amount of di-tert-butyl dicarbonate used is usually selected from the range of 3 to 6 equivalents relative to compound (14-8). Examples of the base include an inorganic base such as sodium hydroxide or potassium carbonate, or an organic base such as triethylamine. Examples of the inert solvent include ether solvents (tetrahydrofuran or 1,4-dioxane). The reaction temperature is selected from the range of about −10 ° C. to about 40 ° C.
2) Step 2
The compound (14-2) is produced from the compound (14-1) by a method similar to the production method described in the literature (for example, Comprehensive Organic transformation, RC Larro, VCH publisher Inc. (1989)). Can do. In this step, when the Boc group of compound (14-2) is deprotected, it is converted to Boc by the same method as the production method described in step 1 of production method 14, and compound (14-2) ) Can be manufactured.
3) Step 3
Compound (14-4) can be produced from compound (14-2) by a method similar to the production method described in the literature (for example, Heterocycles 52, 253 (2000)).
4) Step 4
Compound (14-5) can be produced from compound (14-4) by the same production process as described in Process 8 in production process 1.
5) Step 5
If to Q ¹ Compound (14-4) is a sulfur atom, in the literature (e.g., in Comprehensive Organic transformation, RC Rarokku al, VCH publisher Inc. (1989) and Eur. J. Org. Chem. 1353 (2000) , etc.) A compound (14-6) obtained by converting Q ¹ (ie, S) of compound (14-4) into Q ² (ie, SO ₂ ) can be produced by a method similar to the production method described.
6) Step 6
Compound (14-7) can be produced from compound (14-6) by the same production process as described in Process 8 in production process 1.

Production method 15
Of the compounds represented by formula (I), the compound represented by formula (15-3) or a salt thereof is produced, for example, by the method shown below.

[式中、Ｒ^２、Ｒ^５４、Ｒ^５８、Ｅ^１、Ｙ^１およびＹは、前記記載と同義であり、Ｒ^６６は、「置換されてもよいアルケニル基」、「置換されてもよいアリール基」、「置換されてもよいヘテロアリール基」を表し、Ｍ^３は、トリメチルスズ、トリエチルスズ、トリブチルスズ、カテコールボランまたはＢ（ＯＲ^３００）_２(式中、Ｒ^３００は、水素原子、メチル、エチルまたはイソプロピルを表す。)を表す。]
１）工程１
文献（例えば、Angew. Chem. Int Ed. Engl. 25, 508 (1986)、Chem. Rev. 95, 2457 (1995)、Org. Lett. 26, 4263 (2001)、Tetrahedron 58, 10137 (2002)およびJ. Org. Chem. 66, 9033 (2001) 等）に記載された製造法と同様な方法によって、化合物（１４−２）から化合物（１５−２）を製造することができる。
２）工程２
製造法１記載の工程８と同様な方法によって、化合物（１５−２）から化合物（１５−３）を製造することができる。

[Wherein R ² , R ⁵⁴ , R ⁵⁸ , E ¹ , Y ¹ and Y are as defined above, and R ⁶⁶ represents “optionally substituted alkenyl group” and “optionally substituted aryl”. Group "and" optionally substituted heteroaryl group ", M ³ represents trimethyltin, triethyltin, tributyltin, catecholborane or B (OR ³⁰⁰ ) ₂ (wherein R ³⁰⁰ represents a hydrogen atom, methyl, Represents ethyl or isopropyl). ]
1) Step 1
References (eg Angew. Chem. Int Ed. Engl. 25, 508 (1986), Chem. Rev. 95, 2457 (1995), Org. Lett. 26, 4263 (2001), Tetrahedron 58, 10137 (2002) and The compound (15-2) can be produced from the compound (14-2) by the same production method as described in J. Org. Chem. 66, 9033 (2001), etc.).
2) Step 2
Compound (15-3) can be produced from compound (15-2) by the same method as in Step 8 described in Production Method 1.

Production method 16
Among the compounds represented by formula (I), the compound represented by formula (16-2) or a salt thereof is produced, for example, by the method shown below.

[式中、Ｒ^２、Ｒ^６３、Ｙ^１およびＹは、前記記載と同義であり、Ｒ^６７は、「置換されてもよいアリール基」および「置換されてもよいヘテロアリール基」を表す。]
１）工程１
文献（例えば、Tetrahedron 55, 12757 (1999)、Tetrahedron Lett. 43, 3091 (2002)およびChem. Pharm. Bull. 45, 719 (1997)等）に記載された製造法と同様な方法によって、化合物（９−５）から化合物（１６−１）を製造することができる。
２）工程２
製造法１記載の工程８と同様な方法によって、化合物（１６−１）から化合物（１６−２）を製造することができる。

[Wherein, R ² , R ⁶³ , Y ¹ and Y have the same meanings as described above, and R ⁶⁷ represents an “optionally substituted aryl group” and an “optionally substituted heteroaryl group”. ]
1) Step 1
Compounds (eg, Tetrahedron 55, 12757 (1999), Tetrahedron Lett. 43, 3091 (2002) and Chem. Pharm. Bull. 45, 719 (1997) etc.) are used to produce the compound ( The compound (16-1) can be produced from 9-5).
2) Step 2
Compound (16-2) can be produced from compound (16-1) by the same method as in Step 8 described in Production Method 1.

Manufacturing method 17
Of the compounds represented by Compound (3-2) described in Production Method 3, the compound represented by Formula (17-8) can be produced, for example, according to the following production method.

［式中、Ｒ^２、Ｒ^５４、Ｒ^５６、Ｒ^５８、およびＹ^１は前記記載と同義であり、Ｒ^６８またはＲ^１５６は、アルキル基を表し、Ｒ^１５５は、水素原子、または「置換されてもよいアルキル基」を表す。］
１）工程１
化合物（１７−１）を用いた場合、文献（Tetrahedron 60, 12177 (2004)、Tetrahedron Letters 45, 2389 (2004)、Tetrahedron Letters 45, 2343 (2004)、Tetrahedron Letters 45, 461 (2004)等）に記載された製造法と同様な方法によって、化合物（１−１４）から化合物（１７−４）を製造することができる。
化合物（１７−２）を用いた場合、文献（Chem. Rev. 103, 4095 (2003)等）に記載された製造法と同様な方法によって、化合物（１−１４）から化合物（１７−４）を製造することができる。
化合物（１７−３）を用いた場合、文献（Tetrahedron: Asymmetry 11, 1405 (2000)、Eur. J. Org. Chem. 671 (1998)、Tetrahedron Letters 45, 1885 (2004)等）に記載された製造法と同様な方法によって、化合物（１−１４）から化合物（１７−４）を製造することができる。
２）工程２
製造法１における工程９に記載された製造法と同様な方法によって、化合物（１７−４）から化合物（１７−５）を製造することができる。
３）工程３
文献（例えば、Comprehensive Organic transformation, R. C. ラロック著, VCH publisher Inc. (1989)等）に記載された製造方法と同様な方法によって、化合物（１７−５）から化合物（１７−７）を製造することができる。
４）工程４
化合物（１７−８）は、不活性溶媒中、有機塩基を化合物（１７−７）と反応させることにより製造することができる。有機塩基の使用量としては、化合物（１７−７）に対して通常１〜大過剰の範囲から選択される。有機塩基としては、例えばＮ-メチルモルホリン、トリエチルアミン、ジイソプロピルエチルアミン、トリブチルアミン、１，８-ジアザビシクロ[５．４．０]ウンデカ-７-エン（ＤＢＵ），１，５-ジアザビシクロ[４．３．０]ノナ-５-エン（ＤＢＮ）、１，４-ジアザビシクロ[５．４．０]ウンデカ-７-エン（ＤＡＢＣＯ）、ピリジン、ジメチルアミノピリジン、もしくはピコリン等が挙げられる。これらの塩基が液体の場合、これらを溶媒として用いることもできる。好適には、１，８-ジアザビシクロ[５．４．０]ウンデカ-７-エン（ＤＢＵ）等が挙げられる。不活性溶媒としては、トルエンもしくはベンゼンなどの炭化水素系溶媒等が挙げられる。好適には、トルエン等が挙げられる。反応温度としては、約５０℃〜約１５０℃の範囲から選択することができる。また、本製造工程においては、Dean-Stark装置を用いて、副生する水を留去することが望ましい。

[Wherein, R ² , R ⁵⁴ , R ⁵⁶ , R ⁵⁸ , and Y ¹ are as defined above, R ⁶⁸ or R ¹⁵⁶ represents an alkyl group, R ¹⁵⁵ represents a hydrogen atom, or “substituted” Represents an optionally substituted alkyl group. ]
1) Step 1
When the compound (17-1) is used, the literature (Tetrahedron 60, 12177 (2004), Tetrahedron Letters 45, 2389 (2004), Tetrahedron Letters 45, 2343 (2004), Tetrahedron Letters 45, 461 (2004), etc.) Compound (17-4) can be produced from compound (1-14) by a method similar to the production method described.
When compound (17-2) is used, compound (1-14) to compound (17-4) are prepared by a method similar to the production method described in the literature (Chem. Rev. 103, 4095 (2003), etc.). Can be manufactured.
When the compound (17-3) was used, it was described in literature (Tetrahedron: Asymmetry 11, 1405 (2000), Eur. J. Org. Chem. 671 (1998), Tetrahedron Letters 45, 1885 (2004), etc.). Compound (17-4) can be produced from compound (1-14) by a method similar to the production method.
2) Step 2
Compound (17-5) can be produced from compound (17-4) by the same production process as described in Process 9 in production process 1.
3) Step 3
The compound (17-7) is produced from the compound (17-5) by a method similar to the production method described in the literature (for example, Comprehensive Organic transformation, RC Larro, VCH publisher Inc. (1989)). Can do.
4) Step 4
Compound (17-8) can be produced by reacting an organic base with compound (17-7) in an inert solvent. The amount of the organic base used is usually selected from a range of 1 to a large excess relative to the compound (17-7). Examples of the organic base include N-methylmorpholine, triethylamine, diisopropylethylamine, tributylamine, 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU), 1,5-diazabicyclo [4.3. 0] nona-5-ene (DBN), 1,4-diazabicyclo [5.4.0] undec-7-ene (DABCO), pyridine, dimethylaminopyridine, or picoline. When these bases are liquid, they can also be used as a solvent. Preferable examples include 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU). Examples of the inert solvent include hydrocarbon solvents such as toluene or benzene. Preferably, toluene etc. are mentioned. The reaction temperature can be selected from the range of about 50 ° C to about 150 ° C. In this production process, it is desirable to distill off the by-product water using a Dean-Stark apparatus.

Production method 18
Among the compounds represented by formula (I), the compound represented by formula (18-7) or a salt thereof is produced, for example, by the method shown below.

[式中、Ａ^１、Ｒ^２、Ｒ^５３、Ｒ^５８、Ｘ、Ｙ^１およびＹは、前記記載と同義である。]
１）工程１
製造法１における工程５に記載された製造法と同様な方法によって、化合物（１−１３）から化合物（１８−１）を製造することができる。
２）工程２
製造法１における工程９に記載された製造法と同様な方法によって、化合物（１８−１）から化合物（１８−２）を製造することができる。
３）工程３
工程３として、下記の製造法（Ａ）および製造法（Ｂ）を用いることができる。
製造法（Ａ）：化合物（１８−４）は、不活性溶媒中、ジシクロヘキシルカルボジイミド、もしくはカルボニルジイミダゾール等の脱水縮合剤を用いて、必要に応じて４−（ジメチルアミノ）ピリジン等の添加剤の存在下に、化合物（１８−２）と化合物（１８−３）を縮合させることにより製造することができる。不活性溶媒としては、例えばジエチルエーテル、テトラヒドロフラン、１，４-ジオキサン等のエーテル系溶媒、Ｎ，Ｎ−ジメチルホルムアミド等の非プロトン性溶媒、またはジクロロメタン、もしくはジクロロエタン等のハロゲン化炭化水素系溶媒等が挙げられ、これらの混合溶媒であってもよい。好適には、Ｎ，Ｎ−ジメチルホルムアミド等が挙げられる。反応温度は、通常約０℃〜約５０℃の範囲から選択される。
製造法（Ｂ）：下記に示す（１）〜（２）の反応を行うことによって、化合物（１８−２）から化合物（１８−４）を製造することができる。
（１）化合物（１８−２）と、不活性溶媒中、添加物の存在下または非存在下、オキサリルクロリド等を反応させる。添加物としては、例えばジメチルホルムアミド等が挙げられる。オキサリルクロリドの使用量としては、通常１〜３当量（モル比）の範囲から選択される。不活性溶媒としては、例えばジクロロメタン、ジクロロエタン、もしくはクロロホルム等のハロゲン化炭化水素系溶媒等が挙げられる。反応温度は、通常約-1０℃〜約５０℃の範囲から選択される。
（２）上記（１）の反応溶液を、トルエンもしくはベンゼンなどの炭化水素系溶媒の共存下または非共存下、濃縮する。濃縮後の残渣を不活性溶媒中、有機塩基の存在下、化合物（１８−３）と反応させる。不活性溶媒としては、例えばジクロロメタン、ジクロロエタン、もしくはクロロホルム等のハロゲン化炭化水素系溶媒、トルエンもしくはベンゼンなどの炭化水素系溶媒等が挙げられる。有機塩基としては、例えばＮ-メチルモルホリン、トリエチルアミン、ジイソプロピルエチルアミン、トリブチルアミン、１，８-ジアザビシクロ[５．４．０]ウンデカ-７-エン（ＤＢＵ），１，５-ジアザビシクロ[４．３．０]ノナ-５-エン（ＤＢＮ）、１，４-ジアザビシクロ[５．４．０]ウンデカ-７-エン（ＤＡＢＣＯ）、ピリジン、ジメチルアミノピリジン、もしくはピコリン等が挙げられる。これらの塩基が液体の場合、これらを溶媒として用いることもできる。好適には、ジイソプロピルエチルアミン等が挙げられる。化合物（１８−３）の使用量としては、化合物（１８−２）に対して、通常１〜３当量（モル比）の範囲から選択される。有機塩基の使用量としては、化合物（１８−２）に対して、通常１〜２０当量（モル比）の範囲から選択される。反応温度は、通常約１０℃〜約１５０℃の範囲から選択される。
４）工程４
製造法３における工程１に記載された製造法と同様な方法によって、化合物(１８−４)から化合物（１８−５）を製造することができる。
５）工程５
文献（例えば、Synthesis 444 (2001)等）に記載された製造法と同様な方法によって、化合物（１８−５）から化合物（１８−６）を製造することができる。
６）工程６
製造法１記載の工程８と同様な方法によって、化合物（１８−６）から化合物（１８−７）を製造することができる。

[Wherein, A ¹ , R ² , R ⁵³ , R ⁵⁸ , X, Y ¹ and Y are as defined above. ]
1) Step 1
Compound (18-1) can be produced from compound (1-13) by the same production process as described in Process 5 in production process 1.
2) Step 2
Compound (18-2) can be produced from compound (18-1) by the same production process as described in Process 9 in production process 1.
3) Step 3
As step 3, the following production method (A) and production method (B) can be used.
Production method (A): Compound (18-4) is prepared by using a dehydrating condensing agent such as dicyclohexylcarbodiimide or carbonyldiimidazole in an inert solvent, and if necessary an additive such as 4- (dimethylamino) pyridine. In the presence of the compound, it can be produced by condensing the compound (18-2) and the compound (18-3). Examples of the inert solvent include ether solvents such as diethyl ether, tetrahydrofuran and 1,4-dioxane, aprotic solvents such as N, N-dimethylformamide, and halogenated hydrocarbon solvents such as dichloromethane and dichloroethane. These may be mixed solvents. Preferable examples include N, N-dimethylformamide. The reaction temperature is usually selected from the range of about 0 ° C to about 50 ° C.
Production method (B): Compound (18-4) can be produced from compound (18-2) by carrying out the following reactions (1) to (2).
(1) The compound (18-2) is reacted with oxalyl chloride in an inert solvent in the presence or absence of an additive. Examples of the additive include dimethylformamide. The amount of oxalyl chloride used is usually selected from the range of 1 to 3 equivalents (molar ratio). Examples of the inert solvent include halogenated hydrocarbon solvents such as dichloromethane, dichloroethane, and chloroform. The reaction temperature is usually selected from the range of about -10 ° C to about 50 ° C.
(2) The reaction solution of (1) above is concentrated in the presence or absence of a hydrocarbon solvent such as toluene or benzene. The residue after concentration is reacted with compound (18-3) in the presence of an organic base in an inert solvent. Examples of the inert solvent include halogenated hydrocarbon solvents such as dichloromethane, dichloroethane, and chloroform, and hydrocarbon solvents such as toluene and benzene. Examples of the organic base include N-methylmorpholine, triethylamine, diisopropylethylamine, tributylamine, 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU), 1,5-diazabicyclo [4.3. 0] nona-5-ene (DBN), 1,4-diazabicyclo [5.4.0] undec-7-ene (DABCO), pyridine, dimethylaminopyridine, or picoline. When these bases are liquid, they can also be used as a solvent. Preferable examples include diisopropylethylamine. The amount of compound (18-3) to be used is generally selected from the range of 1 to 3 equivalents (molar ratio) with respect to compound (18-2). The amount of the organic base used is usually selected from the range of 1 to 20 equivalents (molar ratio) with respect to the compound (18-2). The reaction temperature is usually selected from the range of about 10 ° C to about 150 ° C.
4) Step 4
Compound (18-5) can be produced from compound (18-4) by the same production process as described in the step 1 in the production process 3.
5) Step 5
Compound (18-6) can be produced from compound (18-5) by a method similar to the production method described in the literature (for example, Synthesis 444 (2001)).
6) Step 6
Compound (18-7) can be produced from compound (18-6) by the same method as in Step 8 described in Production Method 1.

Production method 19
Of the compounds represented by formula (I), the compounds represented by formula (19-3) and formula (19-5) or salts thereof are produced, for example, by the method shown below.

[式中、Ａ^１、Ｒ^２、Ｒ^５７、Ｒ^５８、Ｘ、ＹおよびＹ^１は、前記記載と同義であり、Ｒ^７０は、「置換されてもよいアルキル基」または「置換されてもよいシクロアルキル基」を表し、Ｔ^Ａは、単結合または酸素原子を表し、Ｔ^Ｂは、単結合または置換されてもよいアルキレン鎖を表す。]
１）工程１
文献（例えば、Protective Groups in Organic Synthesis, T. W. Greene, P. G. M. Wuts共著、第２版、John Wiley & Sons, Inc. (1991) 等）に記載された製造法と同様な方法によって、化合物（１９−１）から化合物（１９−２）を製造することができる。本反応において、Ｙにおける１級アミノ基の保護基が脱離した化合物が生成する場合もあるが、文献（例えば、Protective Groups in Organic Synthesis, T. W. Greene, P. G. M. Wuts共著、第２版、John Wiley & Sons, Inc. (1991) 等）に記載された製造法と同様な方法によって、Ｙにおける１級アミノ基を再び保護基（例えば、ＢｏｃまたはＣｂｚ等）で保護することができる。
２）工程２
製造法１における工程８に記載された製造法または文献（例えば、Protective Groups in Organic Synthesis, T. W. Greene, P. G. M. Wuts共著、第２版、John Wiley & Sons, Inc. (1991) 等）に記載された製造法と同様な方法によって、化合物（１９−２）から化合物（１９−３）を製造することができる。
３）工程３
製造法３における工程１に記載された製造法と同様な方法によって、化合物（１９−２）から化合物（１９−４）を製造することができる。
４）工程４
上記工程２に記載された製造法と同様な方法によって、化合物（１９−４）から化合物（１９−５）を製造することができる。
５）工程５
文献（例えば、Protective Groups in Organic Synthesis, T. W. Greene, P. G. M. Wuts共著、第２版、John Wiley & Sons, Inc. (1991) 等）に記載された製造法と同様な方法によって、化合物（１９−３）から化合物（１９−２）を製造することができる。

[Wherein, A ¹ , R ² , R ⁵⁷ , R ⁵⁸ , X, Y and Y ¹ are as defined above, and R ⁷⁰ represents an “optionally substituted alkyl group” or “substituted”. Represents a “good cycloalkyl group”, T ^A represents a single bond or an oxygen atom, and T ^B represents a single bond or an optionally substituted alkylene chain. ]
1) Step 1
Compound (19-1) was prepared by a method similar to the production method described in the literature (for example, Protective Groups in Organic Synthesis, TW Greene, PGM Wuts, 2nd edition, John Wiley & Sons, Inc. (1991)). ) To produce compound (19-2). In this reaction, a compound in which the protecting group of the primary amino group in Y is eliminated may be generated, but literature (for example, Protective Groups in Organic Synthesis, TW Greene, PGM Wuts, 2nd edition, John Wiley & The primary amino group in Y can be protected again with a protecting group (for example, Boc or Cbz) by a method similar to the production method described in Sons, Inc. (1991), etc.).
2) Step 2
The manufacturing method described in Step 8 of the manufacturing method 1 or the literature (for example, Protective Groups in Organic Synthesis, TW Greene, PGM Wuts, 2nd edition, John Wiley & Sons, Inc. (1991)) Compound (19-3) can be produced from compound (19-2) by a method similar to the production method.
3) Step 3
Compound (19-4) can be produced from compound (19-2) by the same production process as described in the step 1 in the production process 3.
4) Step 4
Compound (19-5) can be produced from compound (19-4) by the same production process as described in the above step 2.
5) Step 5
The compound (19-3) was prepared by a method similar to that described in the literature (for example, Protective Groups in Organic Synthesis, TW Greene, PGM Wuts, 2nd edition, John Wiley & Sons, Inc. (1991)). ) To produce compound (19-2).

Manufacturing method 20
Of the compounds represented by formula (I), the compounds represented by formula (20-2) and formula (20-4) or salts thereof are produced, for example, by the method shown below.

[式中、Ａ^１、Ｒ^２、Ｒ^５８、Ｒ^５９、Ｒ^６０、Ｙ^１、Ｙ、Ｔ^ＡおよびＴ^Ｂは、前記記載と同義である。]
１）工程１
製造法６における工程１に記載された製造法と同様な方法によって、化合物（１９−２）から化合物（２０−１）を製造することができる。
２）工程２
製造法１における工程８に記載された製造法と同様な方法によって、化合物（２０−１）から化合物（２０−２）を製造することができる。
３）工程３
文献（例えば、Synth Commun 32, 2535 (2002)、Comprehensive Organic transformation, R. C. ラロック著, VCH publisher Inc., (1989) 等）に記載された製造法と同様な方法によって、Ｒ^５９およびＲ^６０が水素原子である化合物（２０−１）から化合物（２０−３）を製造することができる。
４）工程４
製造法１における工程８に記載された製造法と同様な方法によって、化合物（２０−３）から化合物（２０−４）を製造することができる。

^{Wherein, A 1, R 2, R} 58, R 59, R 60, Y 1, Y, T A and ^{T B} are the same as defined above. ]
1) Step 1
Compound (20-1) can be produced from compound (19-2) by a method similar to the production method described in Step 1 of Production Method 6.
2) Step 2
Compound (20-2) can be produced from compound (20-1) by the same production process as described in the step 8 in the production process 1.
3) Step 3
R ⁵⁹ and R ⁶⁰ are hydrogenated by a method similar to that described in the literature (for example, Synth Commun 32, 2535 (2002), Comprehensive Organic transformation, RC Larroc, VCH publisher Inc., (1989)). Compound (20-3) can be produced from compound (20-1) which is an atom.
4) Step 4
Compound (20-4) can be produced from compound (20-3) by the same production process as described in the step 8 in the production process 1.

Production method 21
Among the compounds represented by formula (I), the compound represented by formula (21-3) or a salt thereof is produced, for example, by the method shown below.

[式中、Ａ^１、Ｒ^２、Ｒ^５８、Ｙ^１、Ｙ、Ｘ、Ｔ^ＡおよびＴ^Ｂは、前記記載と同義である。Ｒ^５８aは、「置換されてもよいアルキル基」または「置換されてもよいシクロアルキル基」を表す。]
１）工程１
下記に示す（１）〜（２）の反応を行うことによって、化合物（１９−２）から化合物（２１−１）を製造することができる。
（１）化合物（１９−２）を、不活性溶媒中、有機塩基の存在下、クロロギ酸アルキルと反応させる。有機塩基としては、例えばＮ-メチルモルホリン、トリエチルアミン、ジイソプロピルエチルアミン、トリブチルアミン、１，８-ジアザビシクロ[５．４．０]ウンデカ-７-エン（ＤＢＵ），１，５-ジアザビシクロ[４．３．０]ノナ-５-エン（ＤＢＮ）、１，４-ジアザビシクロ[５．４．０]ウンデカ-７-エン（ＤＡＢＣＯ）、ピリジン、ジメチルアミノピリジン、もしくはピコリン等が挙げられる。有機塩基の使用量としては、化合物（１９−２）に対して、通常１〜３当量（モル比）の範囲から選択される。クロロギ酸アルキルとしては、例えばクロロギ酸イソプロピル、クロロギ酸イソブチル、またはクロロギ酸ｎ−ブチル等が挙げられ、好ましくは、クロロギ酸イソプロピル、またはクロロギ酸イソブチルが挙げられる。クロロギ酸アルキルの使用量としては、通常１〜３当量（モル比）の範囲から選択される。不活性溶媒としては、例えばエーテル系溶媒(ジエチルエーテル、テトラヒドロフランまたは1,4-ジオキサン等)等が挙げられる。反応温度は、通常約-1０℃〜約５０℃の範囲から選択される。
（２）上記（１）の反応溶液に、還元剤を加え、反応を行う。還元剤としては、例えば水素化リチウムアルミニウム、水素化ホウ素ナトリウム、もしくはシアノ水素化ホウ素ナトリウム等の水素化物等が挙げられ、好適には、水素化ホウ素ナトリウムが挙げられる。還元剤の使用量としては、化合物（１９−２）に対して、通常１〜３当量（モル比）の範囲から選択される。反応温度は、通常約-1０℃〜約５０℃の範囲から選択される。
２）工程２
製造法３における工程１に記載された製造法と同様な方法によって、化合物（２１−１）から化合物（２１−２）を製造することができる。
３）工程３
製造法１における工程８に記載された製造法と同様な方法によって、化合物（２１−２）から化合物（２１−３）を製造することができる。

^{Wherein, A 1, R 2, R} 58, Y 1, Y, X, T A and ^{T B} are the same as defined above. R ^58a represents an “optionally substituted alkyl group” or “an optionally substituted cycloalkyl group”. ]
1) Step 1
Compound (21-1) can be produced from compound (19-2) by carrying out the following reactions (1) to (2).
(1) The compound (19-2) is reacted with an alkyl chloroformate in an inert solvent in the presence of an organic base. Examples of the organic base include N-methylmorpholine, triethylamine, diisopropylethylamine, tributylamine, 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU), 1,5-diazabicyclo [4.3. 0] nona-5-ene (DBN), 1,4-diazabicyclo [5.4.0] undec-7-ene (DABCO), pyridine, dimethylaminopyridine, or picoline. The amount of the organic base used is usually selected from the range of 1 to 3 equivalents (molar ratio) with respect to the compound (19-2). Examples of the alkyl chloroformate include isopropyl chloroformate, isobutyl chloroformate, n-butyl chloroformate, and the like, and preferably isopropyl chloroformate or isobutyl chloroformate. The amount of alkyl chloroformate used is usually selected from the range of 1 to 3 equivalents (molar ratio). Examples of the inert solvent include ether solvents (diethyl ether, tetrahydrofuran, 1,4-dioxane and the like). The reaction temperature is usually selected from the range of about -10 ° C to about 50 ° C.
(2) A reaction is performed by adding a reducing agent to the reaction solution of (1) above. Examples of the reducing agent include hydrides such as lithium aluminum hydride, sodium borohydride, or sodium cyanoborohydride, and preferably sodium borohydride. The amount of the reducing agent to be used is usually selected from the range of 1 to 3 equivalents (molar ratio) with respect to the compound (19-2). The reaction temperature is usually selected from the range of about -10 ° C to about 50 ° C.
2) Step 2
Compound (21-2) can be produced from compound (21-1) by the same production process as described in the step 1 in the production process 3.
3) Step 3
Compound (21-3) can be produced from compound (21-2) by the same production process as described in the step 8 in the production process 1.

Production method 22
Among the compounds represented by the formula (I), the compound represented by the formula (22-3), the formula (22-5), and the formula (22-7) or a salt thereof is, for example, by the method shown below. Manufactured.

[式中、Ｒ^２、Ｒ^５８、Ｘ、Ｙ^１、Ｙ、Ｔ^Ａ、Ｔ^Ｂ、およびＡ^１は、前記記載と同義であり、Ｒ^６９は、「アルキル基」を表し、Ｒ^７０は、「置換されてもよいアルキル基」を表す。]
１）工程１
文献（例えば、Comprehensive Organic transformation, R. C. ラロック著, VCH publisher Inc. (1989)、 Tetrahedron 59, 6739 (2003)、Tetrahedron Letters 44, 2553 (2003)、Synlett 1735 (2001)、J. Org. Chem. 66, 7907 (2001) 等）に記載された製造方法と同様な方法によって、化合物（２１−１）から化合物（２２−１）を製造することができる。
２）工程２
文献（例えば、Comprehensive Organic transformation, R. C. ラロック著, VCH publisher Inc. (1989)、J. Org. Chem. 68, 6440 (2003)、Eur. J. Med. Chem. 36, 673 (2001)、 Synth. Commun. 31, 89 (2001)、Synth. Commun. 26, 1921 (1996) 等）に記載された製造方法と同様な方法によって、化合物（２２−１）から化合物（２２−２）を製造することができる。
３）工程３
製造法１における工程８に記載された製造法と同様な方法によって、化合物（２２−２）から化合物（２２−３）を製造することができる。
４）工程４
製造法１における工程９に記載された製造法と同様な方法によって、化合物（２２−２）から化合物（２２−４）を製造することができる。
５）工程５
製造法１における工程８に記載された製造法と同様な方法によって、化合物（２２−４）から化合物（２２−５）を製造することができる。
６）工程６
製造法２における工程５に記載された製造法と同様な方法によって、化合物（２２−４）から化合物（２２−６）を製造することができる。
７）工程７
製造法１における工程８に記載された製造法と同様な方法によって、化合物（２２−６）から化合物（２２−７）を製造することができる。

[Wherein, R ² , R ⁵⁸ , X, Y ¹ , Y, T ^A , T ^B , and A ¹ are as defined above, R ⁶⁹ represents an “alkyl group”, and R ⁷⁰ represents An “optionally substituted alkyl group” is represented. ]
1) Step 1
Literature (eg Comprehensive Organic transformation, RC Larroc, VCH publisher Inc. (1989), Tetrahedron 59, 6739 (2003), Tetrahedron Letters 44, 2553 (2003), Synlett 1735 (2001), J. Org. Chem. 66 , 7907 (2001) etc.), the compound (22-1) can be produced from the compound (21-1) by a method similar to the production method described in US Pat.
2) Step 2
Literature (for example, Comprehensive Organic transformation, RC Larroc, VCH publisher Inc. (1989), J. Org. Chem. 68, 6440 (2003), Eur. J. Med. Chem. 36, 673 (2001), Synth. Commun. 31, 89 (2001), Synth. Commun. 26, 1921 (1996), etc.) and producing compound (22-2) from compound (22-1) by the same method as described in Can do.
3) Step 3
Compound (22-3) can be produced from compound (22-2) by the same production process as described in the step 8 in the production process 1.
4) Step 4
Compound (22-4) can be produced from compound (22-2) by the same production process as described in the step 9 in the production process 1.
5) Step 5
Compound (22-5) can be produced from compound (22-4) by the same production process as described in Process 8 in production process 1.
6) Step 6
Compound (22-6) can be produced from compound (22-4) by the same production process as described in Process 5 in production process 2.
7) Step 7
Compound (22-7) can be produced from compound (22-6) by the same production process as described in the step 8 in the production process 1.

Manufacturing method 23
Among the compounds represented by the formula (I), the compound represented by the formula (23-5), the formula (23-7), and the formula (23-9) or a salt thereof is, for example, by the method shown below. Manufactured.

[式中、Ｒ^２、Ｒ^５７、Ｒ^５８、Ｒ^６９、Ｒ^７０、Ｍ^１、Ｘ、Ｙ^１、Ｙ、Ｔ^Ａ、Ｔ^Ｂ、およびＡ^１は、前記記載と同義であり、Ｒ^７１は、「置換されてもよいアルキル基」を表す。]
１）工程１
文献（例えば、Comprehensive Organic transformation, R. C. ラロック著, VCH publisher Inc. (1989)等）に記載された製造方法と同様な方法によって、化合物（２２−１）から化合物（２２−２）を製造することができる。
２）工程２
文献（例えば、Comprehensive Organic transformation, R. C. ラロック著, VCH publisher Inc. (1989)、Org. Lett. 4, 3935 (2002)、Org. Lett. 5, 4425 (2003)、Tetrahedron Letters 44, 2553 (2003)等）に記載された製造方法と同様な方法によって、化合物（２３−２）から化合物（２３−３）を製造することができる。
３）工程３
文献（例えば、Comprehensive Organic transformation, R. C. ラロック著, VCH publisher Inc. (1989)、Tetrahedron 59, 9433 (2003)、Bioorg. Med. Chem. Lett. 13, 2227 (2003) 等）に記載された製造方法と同様な方法によって、化合物（２３−３）から化合物（２３−４）を製造することができる。
４）工程４
製造法１における工程８に記載された製造法と同様な方法によって、化合物（２３−４）から化合物（２３−５）を製造することができる。
５）工程５
製造法１における工程９に記載された製造法と同様な方法によって、化合物（２３−４）から化合物（２３−６）を製造することができる。
６）工程６
製造法１における工程８に記載された製造法と同様な方法によって、化合物（２３−６）から化合物（２３−７）を製造することができる。
７）工程７
製造法２における工程５に記載された製造法と同様な方法によって、化合物（２３−６）から化合物（２３−８）を製造することができる。
８）工程８
製造法１における工程８に記載された製造法と同様な方法によって、化合物（２３−８）から化合物（２３−９）を製造することができる。

[Wherein R ² , R ⁵⁷ , R ⁵⁸ , R ⁶⁹ , R ⁷⁰ , M ¹ , X, Y ¹ , Y, T ^A , T ^B , and A ¹ are as defined above, and R ⁷¹ is , Represents an “optionally substituted alkyl group”. ]
1) Step 1
The compound (22-2) is produced from the compound (22-1) by a method similar to the production method described in the literature (for example, Comprehensive Organic transformation, RC Larro, VCH publisher Inc. (1989)). Can do.
2) Step 2
Literature (eg Comprehensive Organic transformation, RC Larroc, VCH publisher Inc. (1989), Org. Lett. 4, 3935 (2002), Org. Lett. 5, 4425 (2003), Tetrahedron Letters 44, 2553 (2003) The compound (23-3) can be produced from the compound (23-2) by a method similar to the production method described in the above.
3) Step 3
Production methods described in literature (for example, Comprehensive Organic transformation, RC Larroc, VCH publisher Inc. (1989), Tetrahedron 59, 9433 (2003), Bioorg. Med. Chem. Lett. 13, 2227 (2003), etc.) The compound (23-3) can be produced from the compound (23-3) by the same method as described above.
4) Step 4
Compound (23-5) can be produced from compound (23-4) by the same production process as described in the step 8 in the production process 1.
5) Step 5
Compound (23-6) can be produced from compound (23-4) by the same production process as described in Process 9 in production process 1.
6) Step 6
Compound (23-7) can be produced from compound (23-6) by the same production process as described in the step 8 in the production process 1.
7) Step 7
Compound (23-8) can be produced from compound (23-6) by the same production process as described in Process 5 in production process 2.
8) Step 8
Compound (23-9) can be produced from compound (23-8) by the same production process as described in the step 8 in the production process 1.

Production method 24
Among the compounds represented by the formula (I), the compound represented by the formula (24-1) or a salt thereof is produced, for example, by the method shown below.

[式中、Ｒ^１、Ｒ^１５、Ｘ、Ｙ^１、ＹおよびＡ^１は、前記記載と同義である。Ｒ^１５０は、「置換されてもよいアリール」、「置換されてもよいヘテロアリール」、「置換されてもよいビニル」、または「置換されてもよいアルキニル基」を表す。]
１）工程１
文献（例えば、Protective Groups in Organic Synthesis, T. W. Greene, P. G. M. Wuts共著、第２版、John Wiley & Sons, Inc. (1991) 等）に記載された製造法と同様な方法によって、化合物（２４−１）から化合物（２４−２）を製造することができる。
２）工程２
化合物（２４−３）は、不活性溶媒中、添加物の存在下または非存在下、化合物（２４−２）を触媒存在下に水素添加により製造することができる。触媒としては、白金炭素等の白金触媒またはパラジウム炭素もしくは水酸化パラジウム炭素などのパラジウム触媒等が挙げられる。添加物としては、ギ酸アンモニウム等が挙げられる。不活性溶媒としては、例えばアルコール系溶媒(エタノール、メタノールまたは２−プロパノール等)、エーテル系溶媒(テトラヒドロフラン、1,4-ジオキサン等)、またはこれらの混合溶媒等が挙げられる。反応温度としては、約２０℃〜約１００℃の範囲から選択することができる。
３）工程３
製造法２における工程５に記載された製造法と同様な方法によって、化合物（２４−３）から化合物（２４−２）を製造することができる。
４）工程４
製造法１における工程８に記載された製造法と同様な方法によって、化合物（２４−２）から化合物（２４−１）を製造することができる。
５）工程５
製造法２における工程５に記載された製造法と同様な方法によって、化合物（２４−３）から化合物（２４−６）を製造することができる。
６）工程６
製造法１における工程８に記載された製造法と同様な方法によって、化合物（２４−６）から化合物（２４−７）を製造することができる。

[Wherein, R ¹ , R ¹⁵ , X, Y ¹ , Y and A ¹ have the same meanings as described above. R ¹⁵⁰ represents “optionally substituted aryl”, “optionally substituted heteroaryl”, “optionally substituted vinyl”, or “optionally substituted alkynyl group”. ]
1) Step 1
The compound (24-1 ) To produce the compound (24-2).
2) Step 2
Compound (24-3) can be produced by hydrogenation of compound (24-2) in the presence of a catalyst in the presence or absence of an additive in an inert solvent. Examples of the catalyst include a platinum catalyst such as platinum carbon or a palladium catalyst such as palladium carbon or palladium hydroxide carbon. Examples of the additive include ammonium formate. Examples of the inert solvent include alcohol solvents (ethanol, methanol, 2-propanol, etc.), ether solvents (tetrahydrofuran, 1,4-dioxane, etc.), and mixed solvents thereof. The reaction temperature can be selected from the range of about 20 ° C to about 100 ° C.
3) Step 3
Compound (24-2) can be produced from compound (24-3) by the same production process as described in Process 5 in production process 2.
4) Step 4
Compound (24-1) can be produced from compound (24-2) by the same production process as described in the step 8 in the production process 1.
5) Step 5
Compound (24-6) can be produced from compound (24-3) by the same production process as described in Process 5 in production process 2.
6) Step 6
Compound (24-7) can be produced from compound (24-6) by the same production process as described in the step 8 in the production process 1.

Production method 25
Among the compounds represented by formula (I), the compound represented by formula (25-5) or a salt thereof is produced, for example, by the method shown below.

[式中、Ｒ^１、Ｒ^４、Ｒ^５、Ｒ^１５、Ｘ、Ｙ^１およびＹは、前記記載と同義であり、Ｒ^１５１は、「置換されてもよいアルキル基」、「置換されてもよいアリール基」、「置換されてもよいヘテロアリール基」、「置換されてもよいアラルキル基」、「置換されてもよいヘテロアリールアルキル基」、「置換されてもよいアルケニル基」、または「置換されてもよいアルキニル基」を表し、Ｒ^１５２は、「置換されてもよいアリール基」、または「置換されてもよいヘテロアリール基」を表し、Ｘａは、Ｂ（ＯＲ^３００）_２（式中、Ｒ^３００は、前記記載と同義である。）を表し、Ｒ^１６０は、「置換されてもよいアルキル基」、「置換されてもよいアリール基」、「置換されてもよいヘテロアリール基」、「置換されてもよいアラルキル基」、「置換されてもよいヘテロアリールアルキル基」、「置換されてもよいアルケニル基」、または「置換されてもよいアルキニル基」を表し、式（２５−１）で表される化合物は、製造法１記載の化合物（１−１８）、製造法２記載の化合物（２−３）、製造法２記載の化合物（２−４）、製造法２記載の化合物（２−７）、製造法３記載の化合物（３−４）、製造法３記載の化合物（３−６）、製造法４記載の化合物（４−１）、製造法５記載の化合物（５−３）、製造法６記載の化合物（６−３）、製造法７記載の化合物（７−４）、製造法８記載の化合物（８−５）、製造法９記載の化合物（９−６）、製造法１０記載の化合物（１０−３）、製造法１０記載の化合物（１０−６）、製造法１０記載の化合物（１０−８）、製造法１１記載の化合物（１１−３）、製造法１２記載の化合物（１２−４）、製造法１３記載の化合物（１３−５）、製造法１４記載の化合物（１４−５）、製造法１４記載の化合物（１４−７）、製造法１５記載の化合物（１５−３）、製造法１６記載の化合物（１６−２）、製造法１８記載の化合物（１８−７）、製造法１９記載の化合物（１９−３）、製造法１９記載の化合物（１９−５）、製造法２０記載の化合物（２０−２）、製造法２０記載の化合物（２０−４）、製造法２１記載の化合物（２１−３）、製造法２２記載の化合物（２２−３）、製造法２２記載の化合物（２２−５）、製造法２２記載の化合物（２２−７）、製造法２３記載の化合物（２３−５）、製造法２３記載の化合物（２３−７）、製造法２３記載の化合物（２３−９）、および製造法２４記載の化合物（２４−１）を含む。]
１）工程１
製造法２４における工程２に記載された製造法と同様な方法によって、化合物（２５−１）から化合物（２５−２）を製造することができる。
２）工程２
文献（例えば、Protective Groups in Organic Synthesis, T. W. Greene, P. G. M. Wuts共著、第２版、John Wiley & Sons, Inc. (1991) 等）に記載された製造法と同様な方法によって、化合物（２５−２）から化合物（２５−３）を製造することができる。
３）工程３
化合物（２５−６）において、Ｒ^１５１が、「置換されてもよいアルキル基」、「置換されてもよいアラルキル基」、「置換されてもよいヘテロアリールアルキル基」、「置換されてもよいアルケニル基」、または「置換されてもよいアルキニル基」の場合、製造法３における工程１に記載された製造法と同様な方法によって、化合物（２５−３）から化合物（２５−４）を製造することができる。
化合物（２５−６）において、Ｒ^１５１が、「置換されてもよいアリール基」、または「置換されてもよいヘテロアリール基」の場合、文献（例えば、J. Am. Chem. Soc. 120, 827 (1998) 、Angew. Chem. Int. Ed. 41, 4177 (2002)等）に記載された製造法と同様な方法によって、化合物（２５−２）から化合物（２５−３）を製造することができる。
化合物（２５−７）を用いた場合、文献（ＷＯ０３/１０４２２９等）に記載された製造法と同様な方法によって、化合物（２５−２）から化合物（２５−３）を製造することができる。
４）工程４
製造法１における工程８に記載された製造法と同様な方法によって、化合物（２５−４）から化合物（２５−５）を製造することができる。

[Wherein, R ¹ , R ⁴ , R ⁵ , R ¹⁵ , X, Y ¹ and Y have the same meanings as described above, and R ¹⁵¹ represents “an alkyl group which may be substituted”, “which may be substituted” A “good aryl group”, “an optionally substituted heteroaryl group”, “an optionally substituted aralkyl group”, “an optionally substituted heteroarylalkyl group”, “an optionally substituted alkenyl group”, or “ Represents an “optionally substituted alkynyl group”, R ¹⁵² represents an “optionally substituted aryl group” or “an optionally substituted heteroaryl group”, and Xa represents B (OR ³⁰⁰ ) ₂ (formula Wherein R ³⁰⁰ represents the same as described above, and R ¹⁶⁰ represents “an optionally substituted alkyl group”, “an optionally substituted aryl group”, “an optionally substituted heteroaryl group”. "," A compound represented by the formula (25-1), which represents a “alkyl group”, “optionally substituted heteroarylalkyl group”, “optionally substituted alkenyl group”, or “optionally substituted alkynyl group” Are the compound (1-18) described in Production Method 1, the compound (2-3) described in Production Method 2, the compound (2-4) described in Production Method 2, the compound (2-7) described in Production Method 2, Compound (3-4) described in Production Method 3, Compound (3-6) described in Production Method 3, Compound (4-1) described in Production Method 4, Compound (5-3) described in Production Method 5, Production Method The compound (6-3) described in 6, the compound (7-4) described in the manufacturing method 7, the compound (8-5) described in the manufacturing method 8, the compound (9-6) described in the manufacturing method 9, and the manufacturing method 10 described. Compound (10-3), Compound (10-6) described in Preparation Method 10, Compound (10-8) described in Preparation Method 10 Compound (11-3) described in Production Method 11, Compound (12-4) described in Production Method 12, Compound (13-5) described in Production Method 13, Compound (14-5) described in Production Method 14, Production Method 14 compound (14-7), the production method 15 compound (15-3), the production method 16 compound (16-2), the production method 18 compound (18-7), the production method 19 description Compound (19-3), Compound (19-5) described in Production Method 19, Compound (20-2) described in Production Method 20, Compound (20-4) described in Production Method 20, and Compound described in Production Method 21 (21-3), Compound (22-3) described in Production Method 22, Compound (22-5) described in Production Method 22, Compound (22-7) described in Production Method 22, Compound (23) described in Production Method 23 -5), compound (23-7) described in Production Method 23, and compound described in Production Method 23 Compound (23-9) and Compound (24-1) described in Production Method 24 are included. ]
1) Step 1
Compound (25-2) can be produced from compound (25-1) by the same production process as described in the step 2 in the production process 24.
2) Step 2
Compound (25-2) was prepared by a method similar to the production method described in the literature (for example, Protective Groups in Organic Synthesis, TW Greene, PGM Wuts, 2nd edition, John Wiley & Sons, Inc. (1991)). ) To produce the compound (25-3).
3) Step 3
In the compounds (25-6), R ¹⁵¹ is "an optionally substituted alkyl group", "optionally substituted aralkyl group", "an optionally substituted heteroarylalkyl group", "optionally substituted In the case of “alkenyl group” or “optionally substituted alkynyl group”, compound (25-4) is produced from compound (25-3) by a method similar to the production method described in Step 1 of Production Method 3. can do.
In the compound (25-6), when R ¹⁵¹ is an “optionally substituted aryl group” or “an optionally substituted heteroaryl group”, the literature (for example, J. Am. Chem. Soc. 120, 827 (1998), Angew. Chem. Int. Ed. 41, 4177 (2002), etc.) to produce compound (25-3) from compound (25-2) Can do.
When compound (25-7) is used, compound (25-3) can be produced from compound (25-2) by a method similar to the production method described in the literature (WO03 / 104229, etc.).
4) Step 4
Compound (25-5) can be produced from compound (25-4) by the same production process as described in the step 8 in the production process 1.

Manufacturing method 26
Of the compounds represented by formula (I), the compounds represented by formula (26-2) and formula (26-4) or salts thereof are produced, for example, by the method shown below.

[式中、Ｒ^１、Ｒ^１６０、Ｒ^４、Ｒ^５、Ｙ^１およびＹは、前記記載と同義であり、Ｌ^１は塩素原子、臭素原子またはヨウ素原子を表し、Ｒ^１７０は、「置換されてもよいアルキル基」、「置換されてもよいアルケニル基」、「置換されてもよいアルキニル基」、「置換されてもよいシクロアルキル基」、「置換されてもよいアリール基」、「置換されてもよいへテロアリール基」、「置換されてもよいアラルキル基」、「置換されてもよいへテロアリールアルキル基」、「カルボキシ基」を表す。]
１）工程１
文献（例えばSynth. Commun. 33, 2671 (2003)、Tetrahedron Letters 42, 863 (2001)、Synthesis 926 (1995)、Tetrahedron Letters 37, 1095 (1996)、J. Org. Chem. 64, 5366 (1999)、Indian J. Chem., Sect B 35, 141 (1996), および J. Heterocycl. Chem. 24, 1313 (1987)等）に記載された製造法と同様な方法によって、化合物（２５−４）から化合物（２６−１）を製造することができる。
２）工程２
製造法１記載の工程８と同様な方法によって、化合物（２６−１）から化合物（２６−２）を製造することができる
３）工程３
文献（例えばChem. Rev. 103, 4095 (2003)、Chem. Rev. 95, 2457 (1995)、Chem. Rev. 103, 1979 (2003)、 Chem. Rev. 100, 3009 (2000)、Organic Process Research & Development 5, 254 (2001)、 J. Med. Chem. 45, 999 (2002)、 Synthesis 563 (1997)、 J. Org. Chem. 65, 9001 (2000)、J. Org. Chem. 64, 4196 (1999)、 J. Org. Chem. 67, 3904 (2002)、Adv. Synth. Catal. 345, 620 (2003)、J. Med. Chem. 43, 675 (2000)、J. Org. Chem. 55, 6317 (1990)およびJ. Fluorine. Chem. 117, 167 (2002)等）に記載された製造法と同様な方法によって、化合物（２６−１）から化合物（２６−３）を製造することができる。
４）工程４
製造法１記載の工程８と同様な方法によって、化合物（２６−３）から化合物（２６−４）を製造することができる。

[Wherein, R ¹ , R ¹⁶⁰ , R ⁴ , R ⁵ , Y ¹ and Y have the same meanings as described above, L ¹ represents a chlorine atom, a bromine atom or an iodine atom, and R ¹⁷⁰ represents “substituted” An optionally substituted alkyl group, an optionally substituted alkenyl group, an optionally substituted alkynyl group, an optionally substituted cycloalkyl group, an an optionally substituted aryl group, and a substituted Represents an optionally substituted heteroaryl group, “an optionally substituted aralkyl group”, “an optionally substituted heteroarylalkyl group”, and “carboxy group”. ]
1) Step 1
Literature (eg Synth. Commun. 33, 2671 (2003), Tetrahedron Letters 42, 863 (2001), Synthesis 926 (1995), Tetrahedron Letters 37, 1095 (1996), J. Org. Chem. 64, 5366 (1999) , Indian J. Chem., Sect B 35, 141 (1996), and J. Heterocycl. Chem. 24, 1313 (1987)), from the compound (25-4). Compound (26-1) can be produced.
2) Step 2
Compound (26-2) can be produced from compound (26-1) by the same method as in Step 8 described in Production Method 1) 3) Step 3
Literature (for example, Chem. Rev. 103, 4095 (2003), Chem. Rev. 95, 2457 (1995), Chem. Rev. 103, 1979 (2003), Chem. Rev. 100, 3009 (2000), Organic Process Research & Development 5, 254 (2001), J. Med. Chem. 45, 999 (2002), Synthesis 563 (1997), J. Org. Chem. 65, 9001 (2000), J. Org. Chem. 64, 4196 (1999), J. Org. Chem. 67, 3904 (2002), Adv. Synth. Catal. 345, 620 (2003), J. Med. Chem. 43, 675 (2000), J. Org. Chem. 55 , 6317 (1990) and J. Fluorine. Chem. 117, 167 (2002), etc.) can be used to produce compound (26-3) from compound (26-1). it can.
4) Step 4
Compound (26-4) can be produced from compound (26-3) by the same method as in Step 8 described in Production Method 1.

Manufacturing method 27
Among the compounds represented by formula (I), the compound represented by formula (27-4) or a salt thereof is produced, for example, by the method shown below.

[式中、Ｒ^１、Ｒ^１６０、Ｒ^４、Ｒ^５、Ｍ^１、Ｙ^１およびＹは、前記記載と同義であり、Ｒ^７２は、「置換されてもよいアルキル基」、「置換されてもよいシクロアルキル基」、「置換されてもよいアリール基」、または「置換されてもよいへテロアリール基」を表す。]
１）工程１
文献（例えばJ. Heterocycl. Chem. 30, 957 (1993)、Chem. Pharm. Bull. 42, 237 (1994)、Aust. J. Chem. 47, 1009 (1994)、J. Heterocycl. Chem. 12, 517 (1975) 等）に記載された製造法と同様な方法によって、化合物（２５−４）から化合物（２７−１）を製造することができる。
２）工程２
文献（例えばComprehensive Organic transformation, R. C. ラロック著, VCH publisher Inc., 1989 等）に記載されている製造法と同様な方法によって、化合物（２７−１）から化合物（２７−３）を製造することができる。
化合物（２７−２）は、市販品を用いるか、実験化学講座(日本化学会編、丸善)２５巻等に記載された方法によって製造することができる。
３）工程３
製造法１記載の工程８と同様な方法によって、化合物（２７−３）から化合物（２７−４）を製造することができる。

[Wherein, R ¹ , R ¹⁶⁰ , R ⁴ , R ⁵ , M ¹ , Y ¹ and Y are as defined above, and R ⁷² represents “an optionally substituted alkyl group”, “substituted A cycloalkyl group that may be substituted, an aryl group that may be substituted, or a heteroaryl group that may be substituted. ]
1) Step 1
Literature (eg J. Heterocycl. Chem. 30, 957 (1993), Chem. Pharm. Bull. 42, 237 (1994), Aust. J. Chem. 47, 1009 (1994), J. Heterocycl. Chem. 12, 517 (1975) etc.), compound (27-1) can be produced from compound (25-4) by a method similar to the production method described in US Pat.
2) Step 2
The compound (27-3) can be produced from the compound (27-1) by a method similar to the production method described in the literature (for example, Comprehensive Organic transformation, RC Larro, VCH publisher Inc., 1989). it can.
Compound (27-2) may be a commercially available product, or can be produced by the method described in Experimental Chemistry Course (Edited by Chemical Society of Japan, Maruzen), Vol.
3) Step 3
Compound (27-4) can be produced from compound (27-3) by the same method as in Process 8 described in Production Method 1.

Production method 28
Among the compounds represented by formula (I), the compound represented by formula (28-2) or a salt thereof is produced, for example, by the method shown below.

[式中、Ｒ^１、Ｒ^１６０、Ｒ^４、Ｒ^５、Ｒ^７２、Ｙ^１およびＹは、前記記載と同義である。]
１）工程１
文献（例えばComprehensive Organic transformation, R. C. ラロック著, VCH publisher Inc., 1989 等）に記載されている製造法と同様な方法によって、化合物（２７−３）から化合物（２８−１）を製造することができる。
２）工程２
製造法１記載の工程８と同様な方法によって、化合物（２８−１）から化合物（２８−２）を製造することができる。

[Wherein, R ¹ , R ¹⁶⁰ , R ⁴ , R ⁵ , R ⁷² , Y ¹ and Y have the same meanings as described above. ]
1) Step 1
Compound (28-1) can be produced from Compound (27-3) by a method similar to the production method described in the literature (for example, Comprehensive Organic transformation, RC Larro, VCH publisher Inc., 1989). it can.
2) Step 2
Compound (28-2) can be produced from compound (28-1) by the same method as in Step 8 described in Production Method 1.

Production method 29
Among the compounds represented by formula (I), the compound represented by formula (29-4) or a salt thereof is produced, for example, by the method shown below.

[式中、Ｒ^１、Ｒ^１６０、Ｒ^４、Ｒ^５、Ｘ、Ｙ^１およびＹは、前記記載と同義であり、Ｒ^７３Ｏは、「置換されてもよいアルコキシ基」、「置換されてもよいアリールオキシ基」、「置換されてもよいアラルキルオキシ基」、「置換されてもよいヘテロアリールオキシ基」、または「置換されてもよいシクロアルキルオキシ基」を表す。]
１）工程１〜工程２
文献（例えばComprehensive Organic transformation, R. C. ラロック著, VCH publisher Inc., (1989)、Organic Reactions (New York) 42, 335-656 (1992)、Tetrahedron Lett. 44, 4873 (2003)、およびJ. Am. Chem. Soc. 125, 4978 (2003) 等）に記載されている製造法と同様な方法によって、化合物（２７−１）から化合物（２９−３）を製造することができる。
２）工程３
製造法１記載の工程８と同様な方法によって、化合物（２９−３）から化合物（２９−４）を製造することができる。

[Wherein, R ¹ , R ¹⁶⁰ , R ⁴ , R ⁵ , X, Y ¹ and Y are as defined above, and R ⁷³ O represents “an optionally substituted alkoxy group”, “substituted Represents an “optionally substituted aryloxy group”, “an optionally substituted aralkyloxy group”, “an optionally substituted heteroaryloxy group”, or “an optionally substituted cycloalkyloxy group”. ]
1) Step 1 to Step 2
Literature (eg Comprehensive Organic transformation, RC Larroch, VCH publisher Inc., (1989), Organic Reactions (New York) 42, 335-656 (1992), Tetrahedron Lett. 44, 4873 (2003), and J. Am. Chem. Soc. 125, 4978 (2003), etc.) can be used to produce compound (29-3) from compound (27-1) by a method similar to the production method described in US Pat.
2) Step 3
Compound (29-4) can be produced from compound (29-3) by the same method as in Step 8 described in Production Method 1.

Production method 30
Among the compounds represented by formula (I), the compound represented by formula (30-2) or a salt thereof is produced, for example, by the method shown below.

[式中、Ｒ^１、Ｒ^１６０、Ｒ^４、Ｒ^５、Ｒ^７２、Ｙ^１およびＹは、前記記載と同義である。]
１）工程１
文献（例えばComprehensive Organic transformation, R. C. ラロック著, VCH publisher Inc., (1989)、J. Org. Chem. 65, 6179 (2000)、J. Org. Chem. 58, 6913 (1993)、Bull. Chem. Soc. Jpn. 67, 1107 (1994)、および J. Org. Chem. 60, 2430 (1995) 等）に記載されている製造法と同様な方法によって、化合物（２７−３）から化合物（３０−１）を製造することができる。
２）工程２
製造法１記載の工程８と同様な方法によって、化合物（３０−１）から化合物（３０−２）を製造することができる。

[Wherein, R ¹ , R ¹⁶⁰ , R ⁴ , R ⁵ , R ⁷² , Y ¹ and Y have the same meanings as described above. ]
1) Step 1
Literature (for example, Comprehensive Organic transformation, RC Larroc, VCH publisher Inc., (1989), J. Org. Chem. 65, 6179 (2000), J. Org. Chem. 58, 6913 (1993), Bull. Chem. Soc. Jpn. 67, 1107 (1994), and J. Org. Chem. 60, 2430 (1995), etc.) by a method similar to the production method described in Compound (27-3) to compound (30- 1) can be manufactured.
2) Step 2
Compound (30-2) can be produced from compound (30-1) by the same method as in Step 8 described in Production Method 1.

Production method 31
Among the compounds represented by formula (I), the compound represented by formula (31-2) or a salt thereof is produced, for example, by the method shown below.

[式中、Ｒ^１、Ｒ^１６０、Ｒ^４、Ｒ^５、Ｙ^１およびＹは、前記記載と同義であり、Ｒ^７４Ｃ（Ｏ）は、カルボキシ基、「置換されてもよいカルバモイル基」、「置換されてもよいアルコキシカルボニル基」、「置換されてもよいアリールオキシカルボニル基」、「置換されてもよいアラルキルオキシカルボニル基」、「置換されてもよいシクロアルキルオキシカルボニル基」、「置換されてもよいアルキルカルボニル基」、「置換されてもよいへテロアリールカルボニル基」、または「置換されてもよいアロイル基」、「置換されてもよいシクロアルキルカルボニル基」を表す。]
１）工程１
文献（例えばComprehensive Organic transformation, R. C. ラロック著, VCH publisher Inc., (1989)、Organic Synthesis Based On Name Reactions And Unnamed Reactions, A. Hassnerら著, Elsevier Science Ltd., (1994)等）に記載されている製造法と同様な方法によって、化合物（２７−１）から化合物（３１−１）を製造することができる。
Ｒ^７４Ｃ（Ｏ）が、「置換されてもよいアルコキシカルボニル基」、「置換されてもよいアリールオキシカルボニル基」、「置換されてもよいアラルキルオキシカルボニル基」、および「置換されてもよいシクロアルキルオキシカルボニル基」である化合物（３１−１）の場合、文献（例えばProtective Groups in Organic Synthesis 2nd Edition (John Wiley & Sons, Inc.)等）に記載されている方法等と同様な方法によって、Ｒ^７４Ｃ（Ｏ）が、カルボキシ基である化合物（３１−１）へと変換することも出来る。
２）工程２
製造法１記載の工程８と同様な方法によって、化合物（３１−１）から化合物（３１−２）を製造することができる。

[Wherein, R ¹ , R ¹⁶⁰ , R ⁴ , R ⁵ , Y ¹ and Y are as defined above, and R ⁷⁴ C (O) is a carboxy group, “optionally substituted carbamoyl group”, “Optionally substituted alkoxycarbonyl group”, “optionally substituted aryloxycarbonyl group”, “optionally substituted aralkyloxycarbonyl group”, “optionally substituted cycloalkyloxycarbonyl group”, “substituted” An “optionally substituted alkylcarbonyl group”, an “optionally substituted heteroarylcarbonyl group”, or an “optionally substituted aroyl group”, an “optionally substituted cycloalkylcarbonyl group”. ]
1) Step 1
It is described in literature (for example, Comprehensive Organic transformation, RC Larroque, VCH publisher Inc., (1989), Organic Synthesis Based On Name Reactions And Unnamed Reactions, A. Hassner et al., Elsevier Science Ltd., (1994)). Compound (31-1) can be produced from compound (27-1) by a method similar to the production method described above.
R ⁷⁴ C (O) is an “optionally substituted alkoxycarbonyl group”, an “optionally substituted aryloxycarbonyl group”, an “optionally substituted aralkyloxycarbonyl group”, and an “optionally substituted”. In the case of the compound (31-1) which is a “cycloalkyloxycarbonyl group”, a method similar to the method described in the literature (for example, Protective Groups in Organic Synthesis 2nd Edition (John Wiley & Sons, Inc.)) is used. , R ⁷⁴ C (O) can be converted to a compound (31-1) which is a carboxy group.
2) Step 2
Compound (31-2) can be produced from compound (31-1) by the same method as in Step 8 described in Production Method 1.

Production method 32
Among the compounds represented by the formula (I), the compound represented by the formula (32-3) or a salt thereof is produced, for example, by the method shown below.

[式中、Ｒ^１、Ｒ^１６０、Ｒ^３、Ｒ^４、Ｒ^５、Ｙ^１およびＹは、前記記載と同義であり、化合物（３２−１）中に表記されたＣＯ_２Ｈは、式（Ｉ）で表されるＲ^３またはＲ^４がカルボキシ基であるか、Ｒ^３、Ｒ^４またはＲ^５の部分構造にカルボキシ基が存在することを示し、化合物（３２−２）および化合物（３２−３）中に表記されたＣＯ_２Ｒ^７５は、化合物（３２−１）のＣＯ_２Ｈが、ＣＯ_２Ｒ^７５に変換された状態を示し、具体的には、ＣＯ_２Ｒ^７５は、式：Ｃ（Ｏ）Ｏ−Ｒ^ｅ（式中、Ｒ^ｅは、前記記載と同義である。）等を表す。]
１）工程１
化合物（３２−２）は、不活性溶媒中、塩基の存在下、化合物（３２−１）を化合物（３２−４）と反応させることにより製造することができる。化合物（３２−４）の使用量としては、化合物（３２−１）に対して通常約１〜３当量の範囲から選択される。塩基としては、例えば炭酸アルカリ(炭酸カリウム、炭酸ナトリウム、炭酸水素カリウムまたは炭酸水素ナトリウム等)、水酸化アルカリ(水酸化カリウムまたは水酸化ナトリウム等)、水素化アルカリ(水素化ナトリウムまたは水素化カリウム等)、またはアルコキシアルカリ(tert-ブトキシカリウム等)等が挙げられ、好適には、炭酸カリウムまたは水素化ナトリウム等が挙げられる。塩基の使用量としては、化合物（３２−１）に対し通常１〜５当量の範囲から選択される。不活性溶媒としては、例えば非プロトン性溶媒(Ｎ，Ｎ−ジメチルホルムアミドまたはジメチルスルホキシド等)、エーテル系溶媒(ジエチルエーテル、テトラヒドロフランまたは1,4-ジオキサン等)、ケトン(アセトン等)、またはこれらの混合溶媒等が挙げられ、好適にはＮ，Ｎ−ジメチルホルムアミド等が挙げられる。反応温度としては、約１０℃〜約１００℃の範囲から選択することができる。
化合物（３２−４）は、市販の試薬を用いるか、文献（例えば、ＷＯ０３/０２７０９８、ＷＯ００/０６５８１、Comprehensive Organic transformation, R. C. ラロック著, VCH publisher Inc., 1989 等）に記載された製造法と同様な方法によって製造することができる。
２）工程２
製造法１記載の工程８と同様な方法によって、化合物（３２−２）から化合物（３２−３）を製造することができる。

[Wherein, R ¹ , R ¹⁶⁰ , R ³ , R ⁴ , R ⁵ , Y ¹ and Y have the same meanings as described above, and CO ₂ H represented in the compound (32-1) is represented by the formula ( R ³ or R ⁴ represented by I) is a carboxy group or a carboxy group is present in the partial structure of R ³ , R ⁴ or R ⁵ , and the compound (32-2) and the compound (32- 3) CO ₂ R ⁷⁵ described in FIG. 3 indicates a state in which CO ₂ H of the compound (32-1) is converted to CO ₂ R ^75. Specifically, CO ₂ R ⁷⁵ is represented by the formula: C (O) O—R ^e (wherein R ^e is as defined above) and the like. ]
1) Step 1
Compound (32-2) can be produced by reacting compound (32-1) with compound (32-4) in the presence of a base in an inert solvent. The amount of compound (32-4) to be used is generally selected from the range of about 1 to 3 equivalents relative to compound (32-1). Examples of the base include alkali carbonate (potassium carbonate, sodium carbonate, potassium hydrogen carbonate, sodium hydrogen carbonate, etc.), alkali hydroxide (potassium hydroxide, sodium hydroxide, etc.), alkali hydride (sodium hydride, potassium hydride, etc.) ), Or alkoxyalkali (such as tert-butoxypotassium), and the like, preferably potassium carbonate, sodium hydride, and the like. The amount of the base used is usually selected from the range of 1 to 5 equivalents relative to compound (32-1). Examples of the inert solvent include aprotic solvents (N, N-dimethylformamide, dimethyl sulfoxide, etc.), ether solvents (diethyl ether, tetrahydrofuran, 1,4-dioxane, etc.), ketones (acetone, etc.), or these A mixed solvent etc. are mentioned, N, N- dimethylformamide etc. are mentioned suitably. The reaction temperature can be selected from the range of about 10 ° C to about 100 ° C.
Compound (32-4) may be a commercially available reagent, or a production method described in the literature (for example, WO 03/027098, WO 00/066581, Comprehensive Organic transformation, RC Laroc, VCH publisher Inc., 1989). It can be manufactured by a similar method.
2) Step 2
Compound (32-3) can be produced from compound (32-2) by the same method as in Step 8 described in Production Method 1.

Production method 33
Among the compounds represented by formula (1-2), the compound represented by formula (33-3) can be produced, for example, according to the method shown below.

［式中、ｍ１、Ｒ^６、およびＲ^５１は、前記記載と同義である。］
１）工程１
文献（例えばJ. Org. Chem. 58, 879 (1993) 等）に記載された製造法と同様な方法によって、化合物（３３−１）から化合物（３３−２）を製造することができる。
２）工程２
文献（例えばProtective Groups in Organic Synthesis 2nd Edition (John Wiley & Sons, Inc.)等）に記載されている方法等と同様な方法によって、化合物（３３−２）から化合物（３３−３）を製造することができる。

[Wherein, m1, R ⁶ and R ⁵¹ have the same meanings as described above. ]
1) Step 1
Compound (33-2) can be produced from compound (33-1) by a method similar to the production method described in the literature (for example, J. Org. Chem. 58, 879 (1993)).
2) Step 2
The compound (33-3) is produced from the compound (33-2) by a method similar to that described in the literature (for example, Protective Groups in Organic Synthesis 2nd Edition (John Wiley & Sons, Inc.)). be able to.

Manufacturing method 34
Among the compounds represented by formula (1-3), the compound represented by formula (34-5) can be produced, for example, according to the method shown below.

［式中、ｍ１、Ｒ^６、およびＲ^５１は、前記記載と同義である。Ｒ^８０はアルキル基を表す。］
１）工程１
化合物（３４−２）は、アルコール系溶媒中、化合物（３４−１）を塩化チオニルと反応させることにより、製造することができる。アルコール系溶媒としては、メタノール、エタノール等が挙げられる。塩化チオニルの使用量としては、化合物（３４−１）に対し通常２〜１０当量の範囲から選択される。反応温度としては、約-９０℃〜約３０℃の範囲から選択することができる。
２）工程２
化合物（３４−３）は、水溶媒中、化合物（３４−２）を塩基と反応させることにより、製造することができる。塩基としては、炭酸水素ナトリウム、炭酸水素カリウム、炭酸ナトリウム、炭酸カリウム等が挙げられる。反応温度は、約３０℃〜約１００℃の範囲から選択することができる。
３）工程３
文献（例えばProtective Groups in Organic Synthesis 2nd Edition (John Wiley & Sons, Inc.)等）などに記載されている方法等と同様な方法によって、化合物（３４−３）から化合物（３４−４）を製造することができる。
４）工程４
化合物（３４−５）は、不活性溶媒中、化合物（３４−４）を還元剤と反応させることにより、製造することができる。還元剤としては、水素化リチウムアルミニウム、またはボラン錯体（ボラン−ジメチルスルフィド錯体またはボラン−テトラヒドロフラン錯体等）等が挙げられる。不活性溶媒としては、テトラヒドロフラン、１，４−ジオキサン、これらの混合溶媒等が挙げられる。反応温度としては、約−２０℃〜約６０℃の範囲から選択される。

[Wherein, m1, R ⁶ and R ⁵¹ have the same meanings as described above. R ⁸⁰ represents an alkyl group. ]
1) Step 1
Compound (34-2) can be produced by reacting compound (34-1) with thionyl chloride in an alcohol solvent. Examples of alcohol solvents include methanol and ethanol. The amount of thionyl chloride to be used is generally selected from the range of 2 to 10 equivalents relative to compound (34-1). The reaction temperature can be selected from the range of about -90 ° C to about 30 ° C.
2) Step 2
Compound (34-3) can be produced by reacting compound (34-2) with a base in an aqueous solvent. Examples of the base include sodium hydrogen carbonate, potassium hydrogen carbonate, sodium carbonate, potassium carbonate and the like. The reaction temperature can be selected from the range of about 30 ° C to about 100 ° C.
3) Step 3
The compound (34-4) is produced from the compound (34-3) by a method similar to the method described in the literature (for example, Protective Groups in Organic Synthesis 2nd Edition (John Wiley & Sons, Inc.)). can do.
4) Step 4
Compound (34-5) can be produced by reacting compound (34-4) with a reducing agent in an inert solvent. Examples of the reducing agent include lithium aluminum hydride, borane complex (borane-dimethyl sulfide complex, borane-tetrahydrofuran complex, etc.) and the like. Examples of the inert solvent include tetrahydrofuran, 1,4-dioxane, a mixed solvent thereof, and the like. The reaction temperature is selected from the range of about -20 ° C to about 60 ° C.

  As a specific example of the compound (1-2), a synthesis example of the compound (1-2p) from the compound (1-2a) is shown below. Compound (1-2a) to Compound (1-2p) include a pharmaceutically acceptable salt.

[式中、Ｒ^５１は前記記載と同義である。]

[Wherein, R ⁵¹ has the same meaning as described above. ]

[式中、Ｒ^５１は前記記載と同義である。]

[Wherein, R ⁵¹ has the same meaning as described above. ]

  A commercial item can also be used for the hydrochloride of compound (1-2e). In addition, compound (1-2a) to compound (1-2j) can also be synthesized from substituted DL-ornithine by a known method. Specific examples include methods described in literature (for example, Comprehensive Organic transformation, RC Lallock, VCH publisher Inc., 1989).

  As a specific example of the compound (1-3), a synthesis example of the compound (1-3i) from the compound (1-3a) is shown below. Compound (1-3a) to Compound (1-3i) include pharmaceutically acceptable salts.

[式中、Ｒ^５１は前記記載と同義である。]

[Wherein, R ⁵¹ has the same meaning as described above. ]

[式中、Ｒ^５１は前記記載と同義である。Ｙ^１０はＮＨ_２、ＮＨＡｌｌｏｃ、ＮＨＢｏｃ、ＮＨＣｂｚを表す。]

[Wherein, R ⁵¹ has the same meaning as described above. Y ¹⁰ represents _NH 2, NHAlloc, NHBoc, the NHCbz. ]

  As a specific example of the compound (1-3), a synthesis example of the compound (1-3v) from the compound (1-3j) is shown below. Compound (1-3j) to Compound (1-3v) include pharmaceutically acceptable salts.

[式中、Ｒ^５１は前記記載と同義である。]

[Wherein, R ⁵¹ has the same meaning as described above. ]

[式中、Ｒ^５１は前記記載と同義である。]

[Wherein, R ⁵¹ has the same meaning as described above. ]

  As a specific example of the compound (1-3), a synthesis example of the compound (1-3dd) from the compound (1-3w) is shown below. The compound (1-3w) to the compound (1-3dd) include a pharmaceutically acceptable salt.

[式中、Ｒ^５1は前記記載と同義である。]
化合物（１−３）の具体的な例として、化合物（１−３ee）から化合物（１−３gg）の合成例を以下に示す。化合物（１−３ee）から化合物（１−３gg）は、薬学上許容される塩を含む。

Wherein R ⁵¹ is as defined above. ]
As a specific example of the compound (1-3), a synthesis example of the compound (1-3gg) from the compound (1-3ee) is shown below. The compound (1-3ee) to the compound (1-3gg) include a pharmaceutically acceptable salt.

[式中、Ｒ^５1は前記記載と同義である。]

Wherein R ⁵¹ is as defined above. ]

  Compound (1-3a) to compound (1-3dd) can be synthesized from substituted D-ornithine by a known method. Specific examples include methods described in literature (for example, Comprehensive Organic transformation ", R. C. Larlock, VCH publisher Inc., 1989).

Production method 35
Of the compounds represented by formula (1-5), the compound represented by formula (35-5) can be produced, for example, according to the method shown below.

［式中、ｍ３、Ｒ^７、およびＲ^５１は、前記記載と同義である。]
１）工程１
文献（例えばProtective Groups in Organic Synthesis 2nd Edition (John Wiley & Sons, Inc.)等）などに記載されている方法等と同様な方法によって、化合物（３５−１）から化合物（３５−２）を製造することができる。
２）工程２〜工程４
文献（例えばComprehensive Organic transformation", R. C. ラロック著, VCH publisher Inc., 1989 等）に記載された同様な方法によって、化合物（３５−２）から化合物（３５−５）を製造することができる。

[Wherein, m3, R ⁷ and R ⁵¹ are as defined above. ]
1) Step 1
Compound (35-2) is produced from Compound (35-1) by a method similar to the method described in the literature (for example, Protective Groups in Organic Synthesis 2nd Edition (John Wiley & Sons, Inc.), etc.) can do.
2) Step 2 to Step 4
The compound (35-5) can be produced from the compound (35-2) by a similar method described in the literature (for example, Comprehensive Organic transformation ", RC Laroc, VCH publisher Inc., 1989).

As a specific example of compound (1-5), a synthesis example of compound (1-5aa) from compound (1-5a) is shown below. The compound (1-5a) to the compound (1-5aa) include a pharmaceutically acceptable salt.
Compound (1-5a) to compound (1-5aa) can be produced according to the methods described in the literature (for example, WO01 / 74774, Comprehensive Organic transformation, RC Larroque, VCH publisher Inc., 1989). .

［式中、Ｒ^５１は前記記載と同義である。］

[Wherein, R ⁵¹ has the same meaning as described above. ]

As a specific example of compound (1-5), a synthesis example of compound (1-5tt) from compound (1-5bb) is shown below. The compound (1-5bb) to the compound (1-5tt) include a pharmaceutically acceptable salt.
Compound (1-5bb) to Compound (1-5tt) can be obtained from literature (for example, WO01 / 74774, Comprehensive Organic transformation, RC Laroc, VCH publisher Inc., 1989, Protective Groups in Organic Synthesis 2nd Edition (John Wiley & Sons, Inc.) and the like.

［式中、Ｒ^５１は前記記載と同義である。］

[Wherein, R ⁵¹ has the same meaning as described above. ]

Production method 36
Among the compounds represented by formula (1-6), the compound represented by formula (36-5) can be produced, for example, according to the method shown below.

［式中、Ｒ^１００、Ｒ^１０１およびＲ^１０２は、各々独立して、水素原子、「置換されてもよいアルキル基」、「置換されてもよいアリール基」または「置換されてもよいアラルキル基」を表し、Ｒ^９９は、水素原子またはメトキシを表す。]
１）工程１
文献（例えばComprehensive Organic transformation, R. C. ラロック著, VCH publisher Inc., 1989 等）に記載された同様な方法によって、化合物（３６−１）と化合物（３６−２）を用いて還元アミノ化反応を行い、化合物（３６−３）を製造することができる。
２）工程２〜４
文献（ＷＯ０１/０７４３６等）に記載された製造法と同様な方法によって、化合物（３６−３）から化合物（３６−７）を製造することができる。
３）工程５
文献（例えば、Protective Groups in Organic Synthesis 2nd Edition (John Wiley & Sons, Inc.) 等）に記載された製造法と同様な方法によって、化合物（３６−７）から化合物（３６−８）を製造することができる。
４）工程６
文献（例えばJ. Chem. Soc. Perkin Trans. I 3281 (2001)、Heterocycles 38, 17 (1994)、Tetrahedron Lett. 34, 6673 (1993)、J. Org. Chem. 60, 4602 (1995)、J. Med. Chem. 38, 2866 (1995) 等）に記載された製造法と同様な方法によって、化合物（３６−８）から化合物（３６−９）を製造することができる。
５）工程７
文献（例えばComprehensive Organic transformation, R. C. ラロック著, VCH publisher Inc., 1989 等）に記載されている方法等と同様な方法によって、化合物（３６−９）から化合物（３６−１０）を製造することができる。

[Wherein R ¹⁰⁰ , R ¹⁰¹ and R ¹⁰² each independently represents a hydrogen atom, an “optionally substituted alkyl group”, an “optionally substituted aryl group” or an “optionally substituted aralkyl group”. R ⁹⁹ represents a hydrogen atom or methoxy. ]
1) Step 1
A reductive amination reaction is performed using compound (36-1) and compound (36-2) by a similar method described in the literature (for example, Comprehensive Organic transformation, RC Larro, VCH publisher Inc., 1989). Compound (36-3) can be produced.
2) Steps 2-4
Compound (36-7) can be produced from compound (36-3) by a method similar to the production method described in the literature (WO01 / 07436, etc.).
3) Step 5
Compound (36-8) is produced from compound (36-7) by a method similar to the production method described in the literature (for example, Protective Groups in Organic Synthesis 2nd Edition (John Wiley & Sons, Inc.), etc.) be able to.
4) Step 6
References (eg J. Chem. Soc. Perkin Trans. I 3281 (2001), Heterocycles 38, 17 (1994), Tetrahedron Lett. 34, 6673 (1993), J. Org. Chem. 60, 4602 (1995), J Med. Chem. 38, 2866 (1995), etc.) can be used to produce compound (36-9) from compound (36-8).
5) Step 7
Compound (36-10) can be produced from Compound (36-9) by a method similar to the method described in the literature (for example, Comprehensive Organic transformation, RC Larro, VCH publisher Inc., 1989). it can.

  As a specific example of compound (1-6), a synthesis example of compound (1-6l) from compound (1-6a) is shown below. Compound (1-6a) to Compound (1-6l) include pharmaceutically acceptable salts.

Production method 37
Of the compounds represented by formula (I), the compound represented by formula (37-10) can be produced, for example, according to the method shown below.

[式中、Ｒ^１、Ｒ^４、Ｒ^５、Ｒ^６、Ｒ^７、Ｒ^８、Ｒ^９、Ｒ^１０、Ｒ^１１、Ｒ^５１、ｍ１、ｍ２、ｍ３、ｍ４、ｍ５、ｍ６、Ｘ、Ｒ^５３、Ｙ^１およびＹは、前記記載と同義であり、Ｒ^１８０は、「置換されてもよいアルキル基」、「置換されてもよいアラルキル基」、２−ブチニル、または３−メチル−２−ブテニルを表す。]
１）工程１
化合物（３７−２）は、不活性溶媒中、塩基の存在下、化合物（３７−１）と二硫化炭素を反応させ、さらにヨウ化メチルと反応させることにより製造することができる。塩基としては、炭酸アルカリ(炭酸セシウム、炭酸カリウム、炭酸ナトリウム、炭酸水素カリウムまたは炭酸水素ナトリウム等)、水素化アルカリ（水素化ナトリウムまたは水素化カリウム等）または水酸化アルカリ(水酸化カリウムまたは水酸化ナトリウム等)等が挙げられ、好適には、炭酸カリウム等が挙げられる。塩基の使用量としては、化合物（３７−１）に対し通常１〜５当量（モル比）の範囲から選択される。二硫化炭素の使用量としては、化合物（３７−１）に対し通常１〜３当量（モル比）の範囲から選択される。ヨウ化メチルの使用量としては、化合物（３７−１）に対し通常２〜５当量（モル比）の範囲から選択される。不活性溶媒としては、非プロトン性溶媒(アセトニトリル、Ｎ，Ｎ−ジメチルホルムアミドまたはジメチルスルホキシド等)、エーテル系溶媒(ジエチルエーテル、テトラヒドロフランまたは1,4-ジオキサン等)またはこれらの混合溶媒等が挙げられ、好適には、Ｎ，Ｎ−ジメチルホルムアミド等が挙げられる。反応温度としては、約-１０℃〜約４０℃の範囲から選択することができる。
２）工程２
化合物（３７−３）は、化合物（３７−２）と、化合物（１−２）、化合物（１−３）、化合物（１−４）、化合物（１−５）、化合物（１−６）および化合物（１−７）から１つ選択される化合物を、不活性溶媒中、反応させることにより製造することができる。化合物（１−２）、化合物（１−３）、化合物（１−４）、化合物（１−５）、化合物（１−６）および化合物（１−７）の使用量としては、化合物（３７−２）に対し通常１〜２当量（モル比）の範囲から選択される。不活性溶媒としては、トルエンもしくはベンゼンなどの炭化水素系溶媒等が挙げられる。好適には、トルエン等が挙げられる。反応温度としては、約１０℃〜約６０℃の範囲から選択することができる。
３）工程３
化合物（３７−５）は、不活性溶媒中、有機塩基の存在下、化合物（３７−３）と化合物（３７−４）を反応させることにより製造することができる。有機塩基としては、例えばＮ-メチルモルホリン、トリエチルアミン、ジイソプロピルエチルアミン、トリブチルアミン、１，８-ジアザビシクロ[５．４．０]ウンデカ-７-エン（ＤＢＵ），１，５-ジアザビシクロ[４．３．０]ノナ-５-エン（ＤＢＮ）、１，４-ジアザビシクロ[５．４．０]ウンデカ-７-エン（ＤＡＢＣＯ）、ピリジン、ジメチルアミノピリジン、もしくはピコリン等が挙げられ、好適には、ＤＢＵ等が挙げられる。有機塩基の使用量としては、化合物（３７−３）に対し通常１〜３当量（モル比）の範囲から選択される。不活性溶媒としては、例えば、エーテル系溶媒（テトラヒドロフラン、または１，４−ジオキサン等）が挙げられ、好適には、テトラヒドロフラン等が挙げられる。反応温度は、通常約1０℃〜約５０℃の範囲から選択される。
４）工程４
化合物（３７−６）は、不活性溶媒中、塩基の存在下、化合物（３７−５）と化合物（１−１１）を反応させることにより製造することができる。塩基としては、炭酸アルカリ(炭酸セシウム、炭酸カリウム、炭酸ナトリウム、炭酸水素カリウムまたは炭酸水素ナトリウム等)、水素化アルカリ（水素化ナトリウムまたは水素化カリウム等）等が挙げられ、好適には、炭酸セシウム等が挙げられる。塩基の使用量としては、化合物（３７−５）に対し通常１〜５当量（モル比）の範囲から選択される。化合物（１−１１）の使用量としては、化合物（３７−５）に対し通常１〜３当量（モル比）の範囲から選択される。不活性溶媒としては、非プロトン性溶媒(アセトニトリル、Ｎ，Ｎ−ジメチルホルムアミドまたはジメチルスルホキシド等)等が挙げられ、好適には、アセトニトリル等が挙げられる。反応温度としては、約１０℃〜約４０℃の範囲から選択することができる。
５）工程５
製造法１における工程４に記載された製造法と同様な方法によって、化合物（３７−６）から化合物（３７−７）を製造することができる。
６）工程６
製造法１における工程５に記載された製造法と同様な方法によって、化合物（３７−７）から化合物（３７−８）を製造することができる。
７）工程７
化合物（３７−９）は、例えば、以下に示す製造法（(i)〜(iii)）と同様な方法によって、化合物（３７−８）から製造することができる。
(i)製造法１における工程６〜工程７
(ii)製造法９における工程１〜工程４
(iii)製造法１７における工程１〜工程４
８）工程８
化合物（３７−１０）は、不活性溶媒中、化合物（３７−９）と酸を反応させることにより製造することができる。酸としては、トリフルオロ酢酸、塩酸、臭化水素酸、硫酸、リン酸または硝酸等が挙げられ、好適には、トリフルオロ酢酸または硫酸等が挙げられる。酸の使用量としては、化合物（３７−９）に対し通常１当量〜大過剰の範囲から選択される。不活性溶媒としては、1,4-ジオキサン、水等が挙げられる。また、酸としてトリフルオロ酢酸を用いる場合、トリフルオロ酢酸を溶媒として用いることもできる。反応温度としては、約１０℃〜約１００℃の範囲から選択することができる。
９）工程９
文献（例えばProtective Groups in Organic Synthesis 2nd Edition (John Wiley & Sons, Inc.)等）に記載されている方法等と同様な方法によって、化合物（３７−１０）から化合物（３７−１１）を製造することができる。化合物（３７−１１）は、製造法２６および製造法２７の出発原料として用いることが出来る。

[Wherein R ¹ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ , R ⁵¹ , m1, m2, m3, m4, m5, m6, X, R ⁵³ , Y ¹ and Y are as defined above, and R ¹⁸⁰ is “an optionally substituted alkyl group”, “an optionally substituted aralkyl group”, 2-butynyl, or 3-methyl-2-butenyl. Represents. ]
1) Step 1
Compound (37-2) can be produced by reacting compound (37-1) with carbon disulfide in an inert solvent in the presence of a base, and further reacting with methyl iodide. Bases include alkali carbonates (cesium carbonate, potassium carbonate, sodium carbonate, potassium bicarbonate or sodium bicarbonate), alkali hydrides (such as sodium hydride or potassium hydride) or alkali hydroxides (potassium hydroxide or hydroxide). Sodium) and the like, and preferably potassium carbonate and the like. The amount of the base used is usually selected from the range of 1 to 5 equivalents (molar ratio) with respect to the compound (37-1). The amount of carbon disulfide used is usually selected from the range of 1 to 3 equivalents (molar ratio) with respect to compound (37-1). The amount of methyl iodide to be used is usually selected from the range of 2 to 5 equivalents (molar ratio) with respect to compound (37-1). Examples of the inert solvent include an aprotic solvent (acetonitrile, N, N-dimethylformamide, dimethylsulfoxide, etc.), an ether solvent (diethyl ether, tetrahydrofuran, 1,4-dioxane, etc.) or a mixed solvent thereof. Preferable examples include N, N-dimethylformamide. The reaction temperature can be selected from the range of about −10 ° C. to about 40 ° C.
2) Step 2
The compound (37-3) includes the compound (37-2), the compound (1-2), the compound (1-3), the compound (1-4), the compound (1-5), and the compound (1-6). And one compound selected from compound (1-7) can be produced by reacting in an inert solvent. The amount of compound (1-2), compound (1-3), compound (1-4), compound (1-5), compound (1-6), and compound (1-7) used is compound (37). -2) is usually selected from the range of 1 to 2 equivalents (molar ratio). Examples of the inert solvent include hydrocarbon solvents such as toluene or benzene. Preferably, toluene etc. are mentioned. The reaction temperature can be selected from the range of about 10 ° C to about 60 ° C.
3) Step 3
Compound (37-5) can be produced by reacting compound (37-3) with compound (37-4) in the presence of an organic base in an inert solvent. Examples of the organic base include N-methylmorpholine, triethylamine, diisopropylethylamine, tributylamine, 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU), 1,5-diazabicyclo [4.3. 0] non-5-ene (DBN), 1,4-diazabicyclo [5.4.0] undec-7-ene (DABCO), pyridine, dimethylaminopyridine, picoline and the like, preferably DBU Etc. The amount of the organic base used is usually selected from the range of 1 to 3 equivalents (molar ratio) with respect to the compound (37-3). Examples of the inert solvent include ether solvents (tetrahydrofuran, 1,4-dioxane and the like), and preferably tetrahydrofuran and the like. The reaction temperature is usually selected from the range of about 10 ° C to about 50 ° C.
4) Step 4
Compound (37-6) can be produced by reacting compound (37-5) with compound (1-11) in the presence of a base in an inert solvent. Examples of the base include alkali carbonate (cesium carbonate, potassium carbonate, sodium carbonate, potassium hydrogen carbonate, sodium hydrogen carbonate, etc.), alkali hydride (sodium hydride, potassium hydride, etc.), and preferably cesium carbonate. Etc. The amount of the base used is usually selected from the range of 1 to 5 equivalents (molar ratio) with respect to the compound (37-5). The amount of compound (1-11) to be used is generally selected from the range of 1 to 3 equivalents (molar ratio) with respect to compound (37-5). Examples of the inert solvent include aprotic solvents (acetonitrile, N, N-dimethylformamide, dimethyl sulfoxide and the like), and acetonitrile and the like are preferable. The reaction temperature can be selected from the range of about 10 ° C to about 40 ° C.
5) Step 5
Compound (37-7) can be produced from compound (37-6) by a method similar to the production method described in Step 4 of Production Method 1.
6) Step 6
Compound (37-8) can be produced from compound (37-7) by the same production process as described in Process 5 in production process 1.
7) Step 7
Compound (37-9) can be produced, for example, from compound (37-8) by a method similar to the production method ((i) to (iii)) shown below.
(i) Step 6 to Step 7 in Production Method 1
(ii) Step 1 to Step 4 in Production Method 9
(iii) Step 1 to Step 4 in Production Method 17
8) Step 8
Compound (37-10) can be produced by reacting compound (37-9) with an acid in an inert solvent. Examples of the acid include trifluoroacetic acid, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, and nitric acid, and preferred examples include trifluoroacetic acid or sulfuric acid. The amount of the acid used is usually selected from the range of 1 equivalent to a large excess relative to the compound (37-9). Examples of the inert solvent include 1,4-dioxane, water and the like. Moreover, when using trifluoroacetic acid as an acid, trifluoroacetic acid can also be used as a solvent. The reaction temperature can be selected from the range of about 10 ° C to about 100 ° C.
9) Step 9
Compound (37-11) is produced from Compound (37-10) by a method similar to that described in the literature (for example, Protective Groups in Organic Synthesis 2nd Edition (John Wiley & Sons, Inc.)). be able to. Compound (37-11) can be used as a starting material for production method 26 and production method 27.

Production method 38
Of the compounds represented by formula (I), the compound represented by formula (38-3) can be produced, for example, according to the method shown below.

[式中、Ｒ^１、Ｒ^５３、Ｒ^１８０、Ａ^１、Ｙ^１およびＹは、前記記載と同義である。]
１）工程１
製造法１８における工程２〜工程５に記載された製造法と同様な方法によって、化合物（３７−８）から化合物（３８−１）を製造することができる。
２）工程２
製造法３７における工程８に記載された製造法と同様な方法によって、化合物（３８−１）から化合物（３８−２）を製造することができる。
３）工程３
製造法３７における工程９に記載された製造法と同様な方法によって、化合物（３８−２）から化合物（３８−３）を製造することができる。

[Wherein, R ¹ , R ⁵³ , R ¹⁸⁰ , A ¹ , Y ¹ and Y have the same meanings as described above. ]
1) Step 1
Compound (38-1) can be produced from compound (37-8) by the same production process as described in Process 2 to Process 5 in Production Process 18.
2) Step 2
Compound (38-2) can be produced from compound (38-1) by the same production process as described in the step 8 in the production process 37.
3) Step 3
Compound (38-3) can be produced from compound (38-2) by a method similar to the production method described in Step 9 of Production Method 37.

In each of the above production steps, when the starting compound of each reaction has a group active in the reaction such as a hydroxyl group, an amino group or a carboxy group, these groups other than the site to be reacted are preliminarily added as necessary. The compound of interest can be obtained by protecting with an appropriate protecting group and removing the protecting group after each reaction or several reactions. As a protecting group for protecting a hydroxyl group, an amino group, a carboxy group, etc., a usual protecting group used in the field of organic synthetic chemistry may be used, and introduction and removal of such a protecting group can be carried out according to ordinary methods. (For example, the method described in Protective Groups in Organic Synthesis, TW Greene, PGM Wuts, 2nd edition, John Wiley & Sons, Inc. (1991)).
For example, examples of the hydroxyl-protecting group include a tert-butyldimethylsilyl group, a methoxymethyl group, and a tetrahydropyranyl group. Examples of the amino-protecting group include a tert-butyloxycarbonyl group and a benzyloxycarbonyl group. It is done. Such a hydroxyl-protecting group can be removed by reacting in a solvent such as hydrous methanol, hydrous ethanol, hydrous tetrahydrofuran or the like in the presence of an acid such as a base, sulfuric acid or acetic acid. In the case of a tert-butyldimethylsilyl group, for example, the reaction can be carried out in a solvent such as tetrahydrofuran in the presence of tetrabutylammonium fluoride. In the case of a tert-butyloxycarbonyl group, the amino-protecting group is removed in the presence of an acid such as hydrochloric acid or trifluoroacetic acid in a solvent such as hydrous tetrahydrofuran, methylene chloride, chloroform or hydrous methanol. In the case of a benzyloxycarbonyl group, for example, it can be carried out by reacting in a solvent such as acetic acid in the presence of an acid such as hydrobromic acid.
Examples of the form of protection when protecting the carboxy group include tert-butyl ester, ortho ester, acid amide and the like. In the case of tert-butyl ester, such removal of the protecting group is carried out by reaction in a water-containing solvent, for example, in the presence of hydrochloric acid. In the case of ortho ester, water-containing methanol, water-containing tetrahydrofuran, water-containing 1 In the case of acid amide, for example, in the presence of an acid such as hydrochloric acid or sulfuric acid, water is treated with an acid in a solvent such as 1,2-dimethoxyethane and subsequently with an alkali such as sodium hydroxide. The reaction can be carried out in a solvent such as hydrous methanol or hydrous tetrahydrofuran.

  The compounds of formula (I) also include those having an optically active center, so that they can be obtained as racemates or in optically active form when optically active starting materials are used. it can. If necessary, the racemates obtained can be physically or chemically resolved into their optical enantiomers by known methods. Preferably, diastereomers are formed from the racemate by a reaction using an optically active resolving agent. Different forms of diastereomers can be resolved by known methods such as fractional crystallization.

  The compound of the present invention and a prodrug thereof can be converted into a salt by mixing with a pharmaceutically acceptable acid in a solvent such as water, methanol, ethanol, and acetone. Examples of pharmaceutically acceptable acids include inorganic acids such as hydrochloric acid, hydrobromic acid, sulfate, phosphoric acid and nitric acid, or acetic acid, propionic acid, oxalic acid, succinic acid, lactic acid, malic acid, tartaric acid and citric acid. And organic acids such as maleic acid, fumaric acid, methanesulfonic acid, p-toluenesulfonic acid, and ascorbic acid.

  The compound of the present invention can be applied to the treatment of various diseases because of its inhibitory action on DPP-IV. The compounds described herein inhibit postprandial hyperglycemia in pre-diabetic conditions, treat non-insulin dependent diabetes, treat autoimmune diseases such as arthritis and rheumatoid arthritis, treat intestinal mucosal diseases, promote growth, transplant organs It is useful for inhibiting fragment rejection, treating obesity, treating eating disorders, treating HIV infection, inhibiting cancer metastasis, treating benign prostatic hyperplasia, treating periodontitis, and treating osteoporosis.

  The compounds of the present invention, when used therapeutically, are used as pharmaceutical compositions as oral or parenteral (eg, intravenous, subcutaneous, or intramuscular injection, topical, rectal, transdermal, or nasal Administration). Examples of compositions for oral administration include tablets, capsules, pills, granules, powders, solutions, suspensions, etc. Examples of compositions for parenteral administration include, for example, injections. Aqueous agents or oily agents, ointments, creams, lotions, aerosols, suppositories, patches and the like can be mentioned. These preparations can be prepared using conventionally known techniques, and can contain non-toxic and inert carriers or excipients usually used in the pharmaceutical field.

  The dose varies depending on the individual compound and the patient's disease, age, body weight, sex, symptom, route of administration, etc. / Day, preferably 1 to 300 mg / day, once a day or in 2 to 3 divided doses. It can also be administered once every few days to several weeks.

  The compound of the present invention is for the purpose of enhancing its effect, and is a drug such as a therapeutic agent for diabetes, a therapeutic agent for diabetic complications, an antihyperlipidemic agent, an antihypertensive agent, an antiobesity agent, a diuretic agent (hereinafter abbreviated as a concomitant drug). Can be used in combination. The administration timing 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 this invention compound and a concomitant drug. The dose of the concomitant drug can be appropriately selected based on the clinically used dose. The compounding 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.

  Examples of the therapeutic agent for diabetes include insulin preparations (eg, animal insulin preparations extracted from bovine and porcine pancreas; human insulin preparations genetically engineered using Escherichia coli and yeast), insulin resistance improving agents ( Examples, pioglitazone or its hydrochloride, troglitazone, rosiglitazone or its maleate, GI-262570, JTT-501, MCC-555, YM-440, KRP-297, CS-011, etc.), α-glucosidase inhibitor ( Examples, voglibose, acarbose, miglitol, emiglitate, etc.), biguanides (eg, metformin, etc.), insulin secretagogues (eg, tolbutamide, glibenclamide, gliclazide, chlorpropamide, tolazamide, acetohexamide, glyclopyramide, glimepiride, etc. Sulfonyl urea agents; repaglinide, senagrinide, nateglinide, mitiglinide, etc.), GLP-1, GLP-1 analogues (exenatide, liraglutide, SUN-E7001, AVE010, BIM-51077, CJC1131, etc.), protein tyrosine phosphatase inhibitors (eg, vanadic acid) Etc.) and β3 agonists (eg, GW-427353B, N-5984, etc.).

  Examples of the therapeutic agent for diabetic complications include aldose reductase inhibitors (eg, torrestat, epalrestat, zenarestat, zopolestat, minarestat, fidarestat, SK-860, CT-112, etc.), neurotrophic factors (eg, NGF, NT -3, BDNF, etc.), PKC inhibitors (eg, LY-333531, etc.), AGE inhibitors (eg, ALT946, pimagedin, pyratoxatin, N-phenacylthiazolium bromide (ALT766), etc.), active oxygen scavengers (eg, ALT766) Examples, thioctic acid, etc.) and cerebral vasodilators (eg, thioprid, mexiletine, etc.). Antihyperlipidemic agents include HMG-CoA reductase inhibitors (eg, pravastatin, simvastatin, lovastatin, atorvastatin, fluvastatin, itavastatin, or their sodium salts), squalene synthase inhibitors, ACAT inhibitors, etc. Can be mentioned. As an antihypertensive agent, an angiotensin converting enzyme inhibitor (eg, captopril, enalapril, alacepril, delapril, lizinopril, imidapril, benazepril, cilazapril, temocapril, trandolapril, etc.), angiotensin II antagonist (eg, olmesartan, medoxomil, candesalmil, candesalmil) Cilexetil, losartan, eprosartan, valsantan, telmisartan, irbesartan, tasosartan, etc.), calcium antagonists (eg, nicardipine hydrochloride, manidipine hydrochloride, nisoldipine, nitrendipine, nilvadipine, amlodipine, etc.).

  Examples of anti-obesity agents include central anti-obesity agents (eg, phentermine, sibutramine, ampepramon, dexamphetamine, mazindol, SR-141716A, etc.), pancreatic lipase inhibitors (eg, orlistat, etc.), peptide anorectic agents (Eg, leptin, CNTF (ciliary neurotrophic factor), etc.), cholecystokinin agonists (eg, lynchtrypto, FPL-15849, etc.) and the like. Examples of diuretics include xanthine derivatives (eg, sodium salicylate theobromine, calcium salicylate theobromine, etc.), thiazide preparations (eg, etiazide, cyclopenthiazide, trichloromethiazide, hydrochlorothiazide, hydroflumethiazide, benchylhydrochlorothiazide, pentfurizide, polythiazide. , Methiclotiazide, etc.), anti-aldosterone preparations (eg, spironolactone, triamterene, etc.), carbonic anhydrase inhibitors (eg, acetazolamide, etc.), chlorobenzenesulfonamide preparations (eg, chlorthalidone, mefluside, indapamide, etc.), azosemide, isosorbide , Ethacrynic acid, piretanide, bumetanide, furosemide and the like.

  The concomitant drugs are preferably GLP-1, GLP-1 analogs, α-glucosidase inhibitors, biguanides, insulin secretion promoters, insulin resistance improvers, 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. In particular, biguanides can be reduced from normal dosages. Therefore, side effects that may be caused by these drugs can be safely prevented. In addition, the dosage of diabetic complications, antihyperlipidemic agents, antihypertensives, etc. can be reduced, and as a result, side effects that may be caused by these agents can be effectively prevented.

EXAMPLES The present invention will be described more specifically with reference examples, examples and test examples. However, the present invention is not limited to these examples. In addition, the compound names shown in the following Reference Examples and Examples do not necessarily follow the IUPAC nomenclature. Note that abbreviations may be used to simplify the description, but these abbreviations have the same meanings as described above.

Example 1
Ethyl 2-[(3R) -3-aminopiperidin-1-yl] -1- (2-chlorobenzyl) -3-cyano-7-oxo-6,7-dihydro-1H-pyrrolo [2,3-c ] Pyridine-5-carboxylate hydrochloride

エチル 2-{(3R)-3-[(tert-ブトキシカルボニル)アミノ]ピペリジン-1-イル}-1-(2-クロロベンジル)-3-シアノ-7-オキソ-6,7-ジヒドロ-1H-ピロロ[2,3-c]ピリジン-5-カルボキシレート(120 mg)の1,4-ジオキサン(1 mL)溶液に４Ｍ塩化水素/1,4-ジオキサン(1 mL)溶液を加えて25℃で2時間撹拌した。反応液を減圧濃縮後、トルエンを加えて減圧下濃縮することによって、表題の化合物（110 mg）を白色固体として得た。
¹H NMR (400 MHz, DMSO-d₆) δ 7.51-7.49 (m, 1H), 7.32-7.27 (m, 1H), 7.24-7.19 (m, 1H), 7.18 (s, 1H), 6.45-6.41 (m, 1H), 5.74 (d, J = 17.0 Hz, 1H), 5.70 (d, J = 17.0 Hz, 1H), 4.33 (q, J = 7.0 Hz, 2H), 3.55-3.46 (m, 1H), 3.24-3.12 (m, 1H), 3.10-2.96 (m, 2H), 2.90-2.81 (m, 1H), 2.00-1.89 (m, 1H), 1.77-1.65 (m, 1H), 1.52-1.34 (m, 2H), 1.33 (t, J = 7.0 Hz, 3H).
MS (ESI+) 454 (M⁺+1, 87%).

Ethyl 2-{(3R) -3-[(tert-butoxycarbonyl) amino] piperidin-1-yl} -1- (2-chlorobenzyl) -3-cyano-7-oxo-6,7-dihydro-1H To a solution of 4-pyrrolo [2,3-c] pyridine-5-carboxylate (120 mg) in 1,4-dioxane (1 mL) was added 4M hydrogen chloride / 1,4-dioxane (1 mL) solution at 25 ° C. For 2 hours. The reaction mixture was concentrated under reduced pressure, toluene was added, and the mixture was concentrated under reduced pressure to give the title compound (110 mg) as a white solid.
¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.51-7.49 (m, 1H), 7.32-7.27 (m, 1H), 7.24-7.19 (m, 1H), 7.18 (s, 1H), 6.45-6.41 (m, 1H), 5.74 (d, J = 17.0 Hz, 1H), 5.70 (d, J = 17.0 Hz, 1H), 4.33 (q, J = 7.0 Hz, 2H), 3.55-3.46 (m, 1H) , 3.24-3.12 (m, 1H), 3.10-2.96 (m, 2H), 2.90-2.81 (m, 1H), 2.00-1.89 (m, 1H), 1.77-1.65 (m, 1H), 1.52-1.34 ( m, 2H), 1.33 (t, J = 7.0 Hz, 3H).
MS (ESI +) 454 (M ⁺ +1, 87%).

Example 2
2-[(3R) -3-Aminopiperidin-1-yl] -1- (2-chlorobenzyl) -3-cyano-7-oxo-6,7-dihydro-1H-pyrrolo [2,3-c] Pyridine-5-carboxylic acid hydrochloride

実施例1と同様の方法で、参考例２の化合物から実施例2の化合物を合成した。
¹H NMR (400 MHz, CD₃OD) δ 7.47-7.40 (m, 1H), 7.38 (s, 1H), 7.31-7.13 (m, 2H), 6.50-6.42 (m, 1H), 5.90-5.82 (m, 2H), 3.70-3.60 (m, 1H), 3.60-3.49 (m, 1H), 3.29-3.15 (m, 1H), 3.14-2.98 (m, 2H), 2.14-2.04 (m, 1H), 1.84-1.73 (m, 1H), 1.67-1.43 (m, 2H).
MS (ESI+) 426 (M⁺+1, 100%).

In the same manner as in Example 1, the compound of Example 2 was synthesized from the compound of Reference Example 2.
¹ H NMR (400 MHz, CD ₃ OD) δ 7.47-7.40 (m, 1H), 7.38 (s, 1H), 7.31-7.13 (m, 2H), 6.50-6.42 (m, 1H), 5.90-5.82 ( m, 2H), 3.70-3.60 (m, 1H), 3.60-3.49 (m, 1H), 3.29-3.15 (m, 1H), 3.14-2.98 (m, 2H), 2.14-2.04 (m, 1H), 1.84-1.73 (m, 1H), 1.67-1.43 (m, 2H).
MS (ESI +) 426 (M ⁺ +1, 100%).

Example 3
2-[(3R) -3-Aminopiperidin-1-yl] -3- (2-chlorobenzyl) -1-cyano-5-methyl-4-oxo-4,5-dihydro-3H-pyrrolo [2, 3-c] quinoline-7-carboxylic acid hydrochloride

tert-ブチル 2-{(3R)-3-[(tert-ブトキシカルボニル)アミノ]ピペリジン-1-イル}-3-(2-クロロベンジル)-1-シアノ-5-メチル-4-オキソ-4,5-ジヒドロ-3H-ピロロ[2,3-c]キノリン-7-カルボキシレート (95 mg)の1,4-ジオキサン(1 mL)溶液に４Ｍ塩化水素／１，４−ジオキサン(1 mL)を加え、50℃で3時間撹拌して25℃に冷却した。反応溶液を減圧濃縮し、生じた固体にアセトニトリルを加えて、洗浄、ろ過して減圧乾燥させることで表題の化合物(75 mg)を得た。
¹H NMR (400 MHz, CD₃OD) δ 8.47-8.41 (m, 1H), 8.17 (m, 1H), 7.98-7.92 (m, 1H), 7.50-7.43 (m, 1H), 7.30-7.10 (m, 2H), 6.50-6.41 (m, 1H), 5.92 (d, J = 17.0 Hz, 1H), 5.86 (d, J = 17.0 Hz, 1H), 3.72 (s, 3H), 3.68-3.43 (m, 2H), 3.30-3.19 (m, 1H), 3.11-3.01 (m, 2H), 2.20-2.09 (m, 1H), 1.89-1.79 (m, 1H), 1.71-1.48 (m, 2H).
MS (ESI+) 490 (M⁺+1, 100%).

tert-butyl 2-{(3R) -3-[(tert-butoxycarbonyl) amino] piperidin-1-yl} -3- (2-chlorobenzyl) -1-cyano-5-methyl-4-oxo-4 , 5-Dihydro-3H-pyrrolo [2,3-c] quinoline-7-carboxylate (95 mg) in 1,4-dioxane (1 mL) in 4M hydrogen chloride / 1,4-dioxane (1 mL) And stirred at 50 ° C. for 3 hours and cooled to 25 ° C. The reaction solution was concentrated under reduced pressure, acetonitrile was added to the resulting solid, washed, filtered and dried under reduced pressure to give the title compound (75 mg).
¹ H NMR (400 MHz, CD ₃ OD) δ 8.47-8.41 (m, 1H), 8.17 (m, 1H), 7.98-7.92 (m, 1H), 7.50-7.43 (m, 1H), 7.30-7.10 ( m, 2H), 6.50-6.41 (m, 1H), 5.92 (d, J = 17.0 Hz, 1H), 5.86 (d, J = 17.0 Hz, 1H), 3.72 (s, 3H), 3.68-3.43 (m , 2H), 3.30-3.19 (m, 1H), 3.11-3.01 (m, 2H), 2.20-2.09 (m, 1H), 1.89-1.79 (m, 1H), 1.71-1.48 (m, 2H).
MS (ESI +) 490 (M ⁺ +1, 100%).

Example 4
(5-Methyl-2-oxo-1,3-dioxol-4-yl) methyl 2-[(3R) -3-aminopiperidin-1-yl] -3- (2-chlorobenzyl) -1-cyano- 5-Methyl-4-oxo-4,5-dihydro-3H-pyrrolo [2,3-c] quinoline-8-carboxylate hydrochloride

実施例1と同様の製造方法で、参考例12の化合物から表題の化合物を合成した。
¹H NMR (400 MHz, CD₃OD) δ 8.90-8.89 (m, 1H), 8.08-8.01 (m, 1H), 7.59-7.43 (m, 2H), 7.30-7.09 (m, 2H), 6.49-6.41 (m, 1H), 5.85-5.80 (m, 2H), 5.22 (s, 2H), 3.71-3.59 (m, 1H), 3.67 (s, 3H), 3.45-3.32 (m, 1H), 3.25-3.03 (m, 3H), 2.27 (s, 3H), 2.18-2.08 (m, 1H), 1.89-1.78 (m, 1H), 1.70-1.47 (m, 2H).
MS (ESI+) 602 (M⁺+1, 100%).

The title compound was synthesized from the compound of Reference Example 12 by the same production method as in Example 1.
¹ H NMR (400 MHz, CD ₃ OD) δ 8.90-8.89 (m, 1H), 8.08-8.01 (m, 1H), 7.59-7.43 (m, 2H), 7.30-7.09 (m, 2H), 6.49- 6.41 (m, 1H), 5.85-5.80 (m, 2H), 5.22 (s, 2H), 3.71-3.59 (m, 1H), 3.67 (s, 3H), 3.45-3.32 (m, 1H), 3.25- 3.03 (m, 3H), 2.27 (s, 3H), 2.18-2.08 (m, 1H), 1.89-1.78 (m, 1H), 1.70-1.47 (m, 2H).
MS (ESI +) 602 (M ⁺ +1, 100%).

Example 5
2-morpholin-4-ylethyl 2-[(3R) -3-aminopiperidin-1-yl] -3- (2-chlorobenzyl) -1-cyano-5-methyl-4-oxo-4,5-dihydro -3H-pyrrolo [2,3-c] quinoline-8-carboxylate hydrochloride

実施例1と同様の製造方法で、参考例13の化合物から表題の化合物を合成した。
¹H NMR (400 MHz, CD₃OD) δ 9.16-9.15 (m, 1H), 8.29-8.21 (m, 1H), 7.78-7.70 (m, 1H), 7.50-7.11 (m, 3H), 6.51-6.42 (m, 1H), 5.96-5.85 (m, 2H), 4.82-4.78 (m, 2H), 4.26-3.33 (m, 12H), 3.75 (s, 3H), 3.15-3.06 (m, 2H), 2.17-2.07 (m, 1H), 1.88-1.78 (m, 1H), 1.70-1.45 (m, 3H).
MS (ESI+) 603 (M⁺+1, 100%).

The title compound was synthesized from the compound of Reference Example 13 by the same production method as in Example 1.
¹ H NMR (400 MHz, CD ₃ OD) δ 9.16-9.15 (m, 1H), 8.29-8.21 (m, 1H), 7.78-7.70 (m, 1H), 7.50-7.11 (m, 3H), 6.51- 6.42 (m, 1H), 5.96-5.85 (m, 2H), 4.82-4.78 (m, 2H), 4.26-3.33 (m, 12H), 3.75 (s, 3H), 3.15-3.06 (m, 2H), 2.17-2.07 (m, 1H), 1.88-1.78 (m, 1H), 1.70-1.45 (m, 3H).
MS (ESI +) 603 (M ⁺ +1, 100%).

Example 6
2-[(3R) -3-Aminopiperidin-1-yl] -1- (2-chlorobenzyl) -7-oxo-6,7-dihydro-1H-pyrrolo [2,3-c] pyridine-5- Carboxylic acid hydrochloride

3-(tert-ブトキシカルボニル)-2-{(3R)-3-[(tert-ブトキシカルボニル)アミノ]ピペリジン-1-イル}-1-(2-クロロベンジル)-7-オキソ-6,7-ジヒドロ-1H-ピロロ[2,3-c]ピリジン-5-カルボン酸(60 mg)の1,4-ジオキサン(1 mL)溶液に４Ｍ塩化水素／１，４−ジオキサン(1 mL)を加え、80℃で6時間撹拌して25℃に冷却した。反応液を減圧濃縮後、トルエンを加えて減圧下濃縮することによって、表題の化合物（40 mg）を白色固体として得た。
MS (ESI+) 401 (M⁺+1, 100%).

3- (tert-Butoxycarbonyl) -2-{(3R) -3-[(tert-butoxycarbonyl) amino] piperidin-1-yl} -1- (2-chlorobenzyl) -7-oxo-6,7 4M hydrogen chloride / 1,4-dioxane (1 mL) was added to a solution of 2-dihydro-1H-pyrrolo [2,3-c] pyridine-5-carboxylic acid (60 mg) in 1,4-dioxane (1 mL). The mixture was stirred at 80 ° C. for 6 hours and cooled to 25 ° C. The reaction mixture was concentrated under reduced pressure, toluene was added, and the mixture was concentrated under reduced pressure to give the title compound (40 mg) as a white solid.
MS (ESI +) 401 (M ⁺ +1, 100%).

Example 7
1-[(Ethoxycarbonyl) oxy] ethyl 2-[(3R) -3-aminopiperidin-1-yl] -1- (2-chlorobenzyl) -7-oxo-6,7-dihydro-1H-pyrrolo [ 2,3-c] pyridine-5-carboxylate hydrochloride

3-tert-ブチル 5-{1-[(エトキシカルボニル)オキシ]エチル}-2-{(3R)-3-[(tert-ブトキシカルボニル)アミノ]ピペリジン-1-イル}-1-(2-クロロベンジル)-7-オキソ-6,7-ジヒドロ-1H-ピロロ[2,3-c]ピリジン-3,5-ジカルボキシレート (27 mg)にトリフルオロ酢酸(2 mL)を滴下し、25℃で2時間攪拌した。反応溶液に飽和炭酸水素ナトリウム水溶液を滴下して中和し、クロロホルムで抽出した。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、ろ過、減圧濃縮した。得られた化合物に４Ｍ塩化水素／１，４−ジオキサンを加えて減圧濃縮することで表題の化合物(15 mg)を白色固体として得た。
¹H NMR (400 MHz, CDCl₃) δ 9.55 (brs, 1H), 8.30 (brs, 3H), 7.44-6.95 (m, 5H), 6.44-6.34 (m, 1H), 6.13 (s, 1H), 5.92 (d, J = 17.0 Hz, 1H), 5.74 (d, J = 17.0 Hz, 1H), 4.27-4.20 (m, 2H), 3.45-3.27 (m, 2H), 3.13-3.00 (m, 1H), 2.72-2.65 (m, 2H), 2.15-1.70 (m, 3H), 1.67-1.65 (m, 3H), 1.60-1.45 (m, 1H), 1.47-1.33 (m, 3H).
MS (ESI+) 517 (M⁺+1, 100%).

3-tert-butyl 5- {1-[(ethoxycarbonyl) oxy] ethyl} -2-{(3R) -3-[(tert-butoxycarbonyl) amino] piperidin-1-yl} -1- (2- Chlorobenzyl) -7-oxo-6,7-dihydro-1H-pyrrolo [2,3-c] pyridine-3,5-dicarboxylate (27 mg) was added dropwise with trifluoroacetic acid (2 mL), and 25 The mixture was stirred at ° C for 2 hours. The reaction solution was neutralized with a saturated aqueous sodium hydrogen carbonate solution, and extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. 4M Hydrogen chloride / 1,4-dioxane was added to the obtained compound and the mixture was concentrated under reduced pressure to give the title compound (15 mg) as a white solid.
¹ H NMR (400 MHz, CDCl ₃ ) δ 9.55 (brs, 1H), 8.30 (brs, 3H), 7.44-6.95 (m, 5H), 6.44-6.34 (m, 1H), 6.13 (s, 1H), 5.92 (d, J = 17.0 Hz, 1H), 5.74 (d, J = 17.0 Hz, 1H), 4.27-4.20 (m, 2H), 3.45-3.27 (m, 2H), 3.13-3.00 (m, 1H) , 2.72-2.65 (m, 2H), 2.15-1.70 (m, 3H), 1.67-1.65 (m, 3H), 1.60-1.45 (m, 1H), 1.47-1.33 (m, 3H).
MS (ESI +) 517 (M ⁺ +1, 100%).

Example 8
1-[(Cyclohexyloxy) carbonyl] oxy] ethyl 2-[(3R) -3-aminopiperidin-1-yl] -1- (2-chlorobenzyl) -7-oxo-6,7-dihydro-1H- Pyrrolo [2,3-c] pyridine-5-carboxylate hydrochloride

実施例7と同様の製造方法で、参考例20の化合物から表題の化合物を合成した。
¹H NMR (400 MHz, CDCl₃) δ 9.25 (brs, 1H), 8.32 (brs, 3H), 7.41-6.95 (m, 5H), 6.42-6.37 (m, 1H), 6.12 (s, 1H), 5.96 (d, J = 15.0 Hz, 1H), 5.78 (d, J = 15.0 Hz, 1H), 4.68-4.63 (m, 1H), 3.50-3.03 (m, 3H), 2.73-2.65 (m, 2H), 2.10-1.23 (m, 14H) , 1.67-1.66 (m, 3H).
MS (ESI+) 571 (M⁺+1, 100%).

The title compound was synthesized from the compound of Reference Example 20 by the same production method as in Example 7.
¹ H NMR (400 MHz, CDCl ₃ ) δ 9.25 (brs, 1H), 8.32 (brs, 3H), 7.41-6.95 (m, 5H), 6.42-6.37 (m, 1H), 6.12 (s, 1H), 5.96 (d, J = 15.0 Hz, 1H), 5.78 (d, J = 15.0 Hz, 1H), 4.68-4.63 (m, 1H), 3.50-3.03 (m, 3H), 2.73-2.65 (m, 2H) , 2.10-1.23 (m, 14H), 1.67-1.66 (m, 3H).
MS (ESI +) 571 (M ⁺ +1, 100%).

Example 9
2-[(3R) -3-Aminopiperidin-1-yl] -1- (2-chloro-5-fluorobenzyl) -6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo [2, 3-c] pyridine-5-carbonitrile hydrochloride

実施例7と同様の製造方法で、参考例25の化合物から表題の化合物を合成した。
¹H NMR (400 MHz, CDCl₃) δ 8.51 (brs, 3H), 7.36-7.30 (m, 1H), 7.11 (s, 1H), 6.91-6.85 (m, 1H), 6.12-6.06 (m, 1H), 6.06 (s, 1H), 5.84 (d, J = 17.0 Hz, 1H), 5.74 (d, J = 17.0 Hz, 1H), 3.71 (s, 3H), 3.48-3.30 (m, 2H), 3.10-3.03 (m, 1H), 2.79-2.60 (m, 2H), 2.15-2.03 (m, 1H), 1.85-1.50 (m, 3H).
MS (ESI+) 414 (M⁺+1, 100%).

The title compound was synthesized from the compound of Reference Example 25 by the same production method as in Example 7.
¹ H NMR (400 MHz, CDCl ₃ ) δ 8.51 (brs, 3H), 7.36-7.30 (m, 1H), 7.11 (s, 1H), 6.91-6.85 (m, 1H), 6.12-6.06 (m, 1H ), 6.06 (s, 1H), 5.84 (d, J = 17.0 Hz, 1H), 5.74 (d, J = 17.0 Hz, 1H), 3.71 (s, 3H), 3.48-3.30 (m, 2H), 3.10 -3.03 (m, 1H), 2.79-2.60 (m, 2H), 2.15-2.03 (m, 1H), 1.85-1.50 (m, 3H).
MS (ESI +) 414 (M ⁺ +1, 100%).

Example 10
2-[(3R) -3-Aminopiperidin-1-yl] -3- (2-cyanobenzyl) -5-methyl-4-oxo-4,5-dihydro-3H-pyrrolo [2,3-c] Quinoline-8-carboxylic acid trifluoroacetate

1-(tert-ブトキシカルボニル)-2-{(3R)-3-[(tert-ブトキシカルボニル)アミノ]ピペリジン-1-イル}-3-(2-シアノベンジル)-5-メチル-4-オキソ-4,5-ジヒドロ-3H-ピロロ[2,3-c]キノリン-8-カルボン酸 (60 mg)のトリフルオロ酢酸(5 mL)溶液を50℃で5時間撹拌して25℃に冷却した。反応溶液を減圧濃縮し、生じた固体にジエチルエーテルを加えて洗浄し、減圧乾燥させることで表題の化合物(42 mg)を得た。
¹H NMR (300 MHz, DMSO-d₆) δ 8.57 (s, 1H), 8.00-7.97 (m, 4H), 7.86 (d, J = 7.5 Hz, 1H), 7.58 (d, J = 9.0 Hz, 1H), 7.53-7.37 (m, 2H), 6.94 (s, 1H), 6.50 (d, J = 8.1 Hz, 1H), 5.90 (d, J = 16.0 Hz, 1H), 5.79 (d, J = 16.0 Hz, 1H), 3.60 (s, 3H), 3.41-3.27 (m, 2H), 2.93-2.83 (m, 3H), 1.94-1.79 (m, 2H), 1.55-1.52 (m, 2H).
MS (ESI+) 456 (M⁺+1, 100%).

1- (tert-butoxycarbonyl) -2-{(3R) -3-[(tert-butoxycarbonyl) amino] piperidin-1-yl} -3- (2-cyanobenzyl) -5-methyl-4-oxo A solution of -4,5-dihydro-3H-pyrrolo [2,3-c] quinoline-8-carboxylic acid (60 mg) in trifluoroacetic acid (5 mL) was stirred at 50 ° C. for 5 hours and cooled to 25 ° C. . The reaction solution was concentrated under reduced pressure, and the resulting solid was washed with diethyl ether added and dried under reduced pressure to give the title compound (42 mg).
¹ H NMR (300 MHz, DMSO-d ₆ ) δ 8.57 (s, 1H), 8.00-7.97 (m, 4H), 7.86 (d, J = 7.5 Hz, 1H), 7.58 (d, J = 9.0 Hz, 1H), 7.53-7.37 (m, 2H), 6.94 (s, 1H), 6.50 (d, J = 8.1 Hz, 1H), 5.90 (d, J = 16.0 Hz, 1H), 5.79 (d, J = 16.0 Hz, 1H), 3.60 (s, 3H), 3.41-3.27 (m, 2H), 2.93-2.83 (m, 3H), 1.94-1.79 (m, 2H), 1.55-1.52 (m, 2H).
MS (ESI +) 456 (M ⁺ +1, 100%).

Example 11
1-[(Ethoxycarbonyl) oxy] ethyl 2-[(3R) -3-aminopiperidin-1-yl] -3- (2-cyanobenzyl) -5-methyl-4-oxo-4,5-dihydro- 3H-pyrrolo [2,3-c] quinoline-8-carboxylate trifluoroacetate

1-[(tert-ブトキシカルボニル)オキシ]エチル 2-{(3R)-3-[(tert-ブトキシカルボニル)アミノ]ピペリジン-1-イル}-3-(2-シアノベンジル)-5-メチル-4-オキソ-4,5-ジヒドロ-3H-ピロロ[2,3-c]キノリン-8-カルボキシレート (120 mg)のクロロホルム(7 mL)溶液にトリフルオロ酢酸(3 mL)を加え25℃で3時間撹拌した。反応溶液を減圧濃縮し、クロロホルム／へキサン(1/4)で析出した白色固体を減圧乾燥させることで、表題の化合物(84 mg)を得た。
¹H NMR (300 MHz, DMSO-d₆) δ 8.59 (d, J = 2.1 Hz, 1H), 8.02-7.95 (m, 4H), 7.86 (d, J = 7.5 Hz, 1H), 7.63 (d, J = 9.0 Hz, 1H), 7.53-7.37 (m, 2H), 6.98 (s, 1H), 6.96-6.90 (m, 1H), 6.50 (d, J = 7.8 Hz, 1H), 5.90 (d, J = 16.8 Hz, 1H), 5.79 (d, J = 16.8 Hz, 1H), 4.16 (dd, J = 13.8, 6.9 Hz, 2H), 3.61 (s, 3H), 3.45-3.28 (m, 2H), 2.89-2.85 (m, 3H), 1.93-1.90 (m, 2H), 1.63 (d, J = 5.4 Hz, 3H), 1.55-1.52 (m, 2H), 1.21 (d, J = 7.0 Hz, 3H).
MS (ESI+) 572 (M⁺+1, 94%).

1-[(tert-butoxycarbonyl) oxy] ethyl 2-{(3R) -3-[(tert-butoxycarbonyl) amino] piperidin-1-yl} -3- (2-cyanobenzyl) -5-methyl- Add trifluoroacetic acid (3 mL) to a solution of 4-oxo-4,5-dihydro-3H-pyrrolo [2,3-c] quinoline-8-carboxylate (120 mg) in chloroform (7 mL) at 25 ° C. Stir for 3 hours. The reaction solution was concentrated under reduced pressure, and the white solid precipitated with chloroform / hexane (1/4) was dried under reduced pressure to obtain the title compound (84 mg).
¹ H NMR (300 MHz, DMSO-d ₆ ) δ 8.59 (d, J = 2.1 Hz, 1H), 8.02-7.95 (m, 4H), 7.86 (d, J = 7.5 Hz, 1H), 7.63 (d, J = 9.0 Hz, 1H), 7.53-7.37 (m, 2H), 6.98 (s, 1H), 6.96-6.90 (m, 1H), 6.50 (d, J = 7.8 Hz, 1H), 5.90 (d, J = 16.8 Hz, 1H), 5.79 (d, J = 16.8 Hz, 1H), 4.16 (dd, J = 13.8, 6.9 Hz, 2H), 3.61 (s, 3H), 3.45-3.28 (m, 2H), 2.89 -2.85 (m, 3H), 1.93-1.90 (m, 2H), 1.63 (d, J = 5.4 Hz, 3H), 1.55-1.52 (m, 2H), 1.21 (d, J = 7.0 Hz, 3H).
MS (ESI +) 572 (M ⁺ +1, 94%).

Example 12
1-{[(Cyclohexyloxy) carbonyl] oxy] ethyl 2-[(3R) -3-aminopiperidin-1-yl] -3- (2-cyanobenzyl) -5-methyl-4-oxo-4,5 -Dihydro-3H-pyrrolo [2,3-c] quinoline-8-carboxylate trifluoroacetate

実施例11と同様の製造方法で、参考例28の化合物から表題の化合物を合成した。
¹H NMR (300 MHz, DMSO-d₆) δ 8.58 (d, J = 2.1 Hz, 1H), 8.01-7.93 (m, 4H), 7.86 (d, J = 7.8 Hz, 1H), 7.63 (d, J = 8.7 Hz, 1H), 7.53-7.37 (m, 2H), 6.98 (s, 1H), 6.95-6.90 (m, 1H), 6.50 (d, J = 7.8 Hz, 1H), 5.90 (d, J = 16.5 Hz, 1H), 5.79 (d, J = 16.5 Hz, 1H), 4.58-4.56 (m, 1H), 3.61 (s, 3H), 3.31-3.27 (m, 2H), 2.88-2.86 (m, 3H), 1.90-1.80 (m, 4H), 1.62 (d, J = 5.1 Hz, 3H), 1.55-1.22 (m, 10H).
MS (ESI+) 626 (M⁺+1, 70%).

The title compound was synthesized from the compound of Reference Example 28 by the same production method as in Example 11.
¹ H NMR (300 MHz, DMSO-d ₆ ) δ 8.58 (d, J = 2.1 Hz, 1H), 8.01-7.93 (m, 4H), 7.86 (d, J = 7.8 Hz, 1H), 7.63 (d, J = 8.7 Hz, 1H), 7.53-7.37 (m, 2H), 6.98 (s, 1H), 6.95-6.90 (m, 1H), 6.50 (d, J = 7.8 Hz, 1H), 5.90 (d, J = 16.5 Hz, 1H), 5.79 (d, J = 16.5 Hz, 1H), 4.58-4.56 (m, 1H), 3.61 (s, 3H), 3.31-3.27 (m, 2H), 2.88-2.86 (m, 3H), 1.90-1.80 (m, 4H), 1.62 (d, J = 5.1 Hz, 3H), 1.55-1.22 (m, 10H).
MS (ESI +) 626 (M ⁺ +1, 70%).

Reference example 1
Ethyl 2-{(3R) -3-[(tert-butoxycarbonyl) amino] piperidin-1-yl} -1- (2-chlorobenzyl) -3-cyano-7-oxo-6,7-dihydro-1H -Pyrrolo [2,3-c] pyridine-5-carboxylate

2-{(3R)-3-[(tert-ブトキシカルボニル)アミノ]ピペリジン-1-イル}-1-(2-クロロベンジル)-3-シアノ-7-オキソ-6,7-ジヒドロ-1H-ピロロ[2,3-c]ピリジン-5-カルボン酸(180 mg)のエタノール(3 mL)溶液に、1-ヒドロキシベンゾトリアゾール(68 mg)、1−エチル−3−（ジメチルアミノプロピル）カルボジイミド・塩酸塩(85 mg)を加えて、25℃で12時間撹拌した。反応溶液に水を加えて酢酸エチルで抽出し、有機層を飽和食塩水で洗浄し、硫酸マグネシウムで乾燥、ろ過後、減圧濃縮した。残渣をシリカゲルカラムクロマトグラフィー(ヘキサン／酢酸エチル＝2/1)で精製し、表題の化合物(110 mg)を白色アモルファスとして得た。
MS (ESI+) 554 (M⁺+1, 37%).

2-{(3R) -3-[(tert-butoxycarbonyl) amino] piperidin-1-yl} -1- (2-chlorobenzyl) -3-cyano-7-oxo-6,7-dihydro-1H- To a solution of pyrrolo [2,3-c] pyridine-5-carboxylic acid (180 mg) in ethanol (3 mL), 1-hydroxybenzotriazole (68 mg), 1-ethyl-3- (dimethylaminopropyl) carbodiimide, Hydrochloric acid salt (85 mg) was added and stirred at 25 ° C. for 12 hours. Water was added to the reaction solution and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate = 2/1) to give the title compound (110 mg) as a white amorphous.
MS (ESI +) 554 (M ⁺ +1, 37%).

Reference example 2
2-{(3R) -3-[(tert-butoxycarbonyl) amino] piperidin-1-yl} -1- (2-chlorobenzyl) -3-cyano-7-oxo-6,7-dihydro-1H- Pyrrolo [2,3-c] pyridine-5-carboxylic acid

窒素雰囲気下、エチル 5-{(3R)-3-[(tert-ブトキシカルボニル)アミノ]ピペリジン-1-イル}-1-(2-クロロベンジル)-4-シアノ-3-ヨード-1H-ピロール-2-カルボキシレート(580 mg)のN,N-ジメチルホルムアミド溶液に2-アセトアミドアクリル酸メチル(202 mg)、ベンジルトリエチルアンモニウムクロリド(236 mg)、ジシクロヘキシルメチルアミン(0.22 mL)、酢酸パラジウム(43 mg)を加えて80℃で4時間撹拌した。反応溶液を25℃に冷却し、水を加えて酢酸エチルで抽出した。有機層を水および飽和食塩水で洗浄し、硫酸ナトリウムで乾燥、ろ過、減圧濃縮後、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＝2/1)で精製することで、生成物(380 mg)を褐色アモルファスとして得た[MS (ESI+) 628 (M⁺+1, 18%)]。
本生成物(380 mg)のエタノール(1.5 mL)溶液にナトリウムエトキシド(21％エタノール溶液、1.5 mL)を加えて3時間加熱還流した。反応溶液を25℃に冷却後、１Ｎ水酸化ナトリウム(1 mL)を加え、50℃で1時間撹拌した。反応溶液を25℃に冷却後、飽和塩化アンモニウム水溶液を加えて酢酸エチルで抽出し、有機層を飽和食塩水で洗浄後、硫酸ナトリウムで乾燥、ろ過、減圧濃縮し、得られた残渣をシリカゲルカラムクロマトグラフィー(クロロホルム/メタノール＝ 10/1)により精製することで、表題の化合物(220 mg)を褐色アモルファスとして得た。
MS (ESI+) 526 (M⁺+1, 27%).

Ethyl 5-{(3R) -3-[(tert-butoxycarbonyl) amino] piperidin-1-yl} -1- (2-chlorobenzyl) -4-cyano-3-iodo-1H-pyrrole under nitrogen atmosphere 2-Carboxylate (580 mg) in N, N-dimethylformamide solution with methyl 2-acetamidoacrylate (202 mg), benzyltriethylammonium chloride (236 mg), dicyclohexylmethylamine (0.22 mL), palladium acetate (43 mg) was added and stirred at 80 ° C. for 4 hours. The reaction solution was cooled to 25 ° C., water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate = 2/1) to give the product. (380 mg) was obtained as a brown amorphous [MS (ESI +) 628 (M ⁺ +1, 18%)].
Sodium ethoxide (21% ethanol solution, 1.5 mL) was added to a solution of this product (380 mg) in ethanol (1.5 mL), and the mixture was heated to reflux for 3 hours. The reaction solution was cooled to 25 ° C., 1N sodium hydroxide (1 mL) was added, and the mixture was stirred at 50 ° C. for 1 hr. The reaction solution is cooled to 25 ° C, saturated aqueous ammonium chloride solution is added, and the mixture is extracted with ethyl acetate. The organic layer is washed with saturated brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. Purification by chromatography (chloroform / methanol = 10/1) gave the title compound (220 mg) as a brown amorphous.
MS (ESI +) 526 (M ⁺ +1, 27%).

Reference example 3
tert-butyl 2-{(3R) -3-[(tert-butoxycarbonyl) amino] piperidin-1-yl} -3- (2-chlorobenzyl) -1-cyano-5-methyl-4-oxo-4 , 5-Dihydro-3H-pyrrolo [2,3-c] quinoline-7-carboxylate

3-[{[5-{(3R)-3-[(tert-ブトキシカルボニル)アミノ]ピペリジン-1-イル}-1-(2-クロロベンジル)-4-シアノ-3-ヨード-1H-ピロール-2-イル]カルボニル}(メチル)アミノ]安息香酸 tert-ブチル エステル(500 mg)のN,N-ジメチルホルムアミド(15 mL)溶液に酢酸パラジウム(43 mg)、トリフェニルホスフィン(102 mg)、炭酸銀(358 mg)を加えて120℃で3時間撹拌し、さらに140℃に昇温して3時間撹拌した。反応溶液を25℃に冷却し、セライトろ過により不溶物を除いた。ろ液に飽和塩化アンモニウム水溶液を加えて、酢酸エチルで抽出した。有機層を水、飽和食塩水で洗浄し、硫酸ナトリウムで乾燥、ろ過後、シリカゲルカラムクロマトグラフィー(ヘキサン/酢酸エチル=2/1〜1/1)で精製することで表題の化合物(150 mg)を淡黄色アモルファスとして得た。
MS (ESI+) 646 (M⁺+1, 37%).

3-[{[5-{(3R) -3-[(tert-butoxycarbonyl) amino] piperidin-1-yl} -1- (2-chlorobenzyl) -4-cyano-3-iodo-1H-pyrrole -2-yl] carbonyl} (methyl) amino] benzoic acid tert-butyl ester (500 mg) in N, N-dimethylformamide (15 mL) solution in palladium acetate (43 mg), triphenylphosphine (102 mg), Silver carbonate (358 mg) was added, and the mixture was stirred at 120 ° C. for 3 hours, further heated to 140 ° C. and stirred for 3 hours. The reaction solution was cooled to 25 ° C., and insoluble matters were removed by Celite filtration. A saturated aqueous ammonium chloride solution was added to the filtrate, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over sodium sulfate, filtered, and purified by silica gel column chromatography (hexane / ethyl acetate = 2/1 to 1/1) to give the title compound (150 mg) Was obtained as a pale yellow amorphous.
MS (ESI +) 646 (M ⁺ +1, 37%).

Reference example 4
tert-Butyl-[{[5-{(3R) -3-[(tert-butoxycarbonyl) amino] piperidin-1-yl} -1- (2-chlorobenzyl) -4-cyano-3-iodo-1H -Pyrrol-2-yl] carbonyl} (methyl) amino] benzoate

tert-ブチル-[{[5-{(3R)-3-[(tert-ブトキシカルボニル)アミノ]ピペリジン-1-イル}-1-(2-クロロベンジル)-4-シアノ-3-ヨード-1H-ピロール-2-イル]カルボニル}アミノ]ベンゾエート(810 mg)のN,N-ジメチルホルムアミド(10 ml)溶液に炭酸カリウム(237 mg)、ヨウ化メチル(140 μL)を加えて室温で12時間撹拌した。反応溶液に水を加えて、酢酸エチルで抽出した。有機層を水、飽和食塩水で洗浄し、硫酸ナトリウムで乾燥、ろ過後、シリカゲルカラムクロマトグラフィー(ヘキサン/酢酸エチル=2/1)で精製することで表題の化合物(500 mg)を淡黄色アモルファスとして得た。
MS (ESI+) 774 (M⁺+1, 48%).

tert-Butyl-[{[5-{(3R) -3-[(tert-butoxycarbonyl) amino] piperidin-1-yl} -1- (2-chlorobenzyl) -4-cyano-3-iodo-1H -Pyrrol-2-yl] carbonyl} amino] benzoate (810 mg) in N, N-dimethylformamide (10 ml) with potassium carbonate (237 mg) and methyl iodide (140 μL) added at room temperature for 12 hours Stir. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over sodium sulfate, filtered, and purified by silica gel column chromatography (hexane / ethyl acetate = 2/1) to give the title compound (500 mg) as a pale yellow amorphous product. Got as.
MS (ESI +) 774 (M ⁺ +1, 48%).

Reference Example 5
tert-Butyl-[{[5-{(3R) -3-[(tert-butoxycarbonyl) amino] piperidin-1-yl} -1- (2-chlorobenzyl) -4-cyano-3-iodo-1H -Pyrrole-2-yl] carbonyl} amino] benzoate

5-{(3R)-3-[(tert-ブトキシカルボニル)アミノ]ピペリジン-1-イル}-1-(2-クロロベンジル)-4-シアノ-3-ヨード-1H-ピロール-2-カルボン酸(670 mg)のジクロロメタン(13 mL)溶液を0℃に冷却し、二塩化オキサリル(160μL)を加えて、0℃で1時間撹拌した。トルエン(5 mL)を加えて減圧下、ジクロロメタンを除去し、得られた溶液にトルエン(8 mL)、tert-ブチル 3-アミノベンゾエート(330 mg)、ジイソプロピルエチルアミン(436μL)を加えて80℃で3時間撹拌した。反応溶液を25℃に冷却後、飽和塩化アンモニウム水溶液を加えて酢酸エチルで抽出した。有機層を飽和食塩水で洗浄し、硫酸ナトリウムで乾燥、ろ過後、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＝1/0〜5/1)で精製することで表題の化合物(580 mg)を淡黄色アモルファスとして得た。
MS (ESI+) 760 (M⁺+1, 39%).

5-{(3R) -3-[(tert-butoxycarbonyl) amino] piperidin-1-yl} -1- (2-chlorobenzyl) -4-cyano-3-iodo-1H-pyrrole-2-carboxylic acid A solution of (670 mg) in dichloromethane (13 mL) was cooled to 0 ° C., oxalyl dichloride (160 μL) was added, and the mixture was stirred at 0 ° C. for 1 hr. Toluene (5 mL) was added and dichloromethane was removed under reduced pressure.Toluene (8 mL), tert-butyl 3-aminobenzoate (330 mg) and diisopropylethylamine (436 μL) were added to the resulting solution at 80 ° C. Stir for 3 hours. The reaction solution was cooled to 25 ° C., 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 sodium sulfate, filtered, and purified by silica gel column chromatography (hexane / ethyl acetate = 1 / 0-5 / 1) to give the title compound (580 mg) Obtained as a yellow amorphous.
MS (ESI +) 760 (M ⁺ +1, 39%).

Reference Example 6
5-{(3R) -3-[(tert-butoxycarbonyl) amino] piperidin-1-yl} -1- (2-chlorobenzyl) -4-cyano-3-iodo-1H-pyrrole-2-carboxylic acid

エチル 3-アミノ-5-{(3R)-3-[(tert-ブトキシカルボニル)アミノ]ピペリジン-1-イル}-1-(2-クロロベンジル)-4-シアノ-1H-ピロール-2-カルボキシレート(780 mg)のエタノール(5 mL)溶液に1N水酸化ナトリウム水溶液(2 mL)を加えて80℃で1時間撹拌した。反応溶液を25℃に冷却後減圧濃縮し、飽和塩化アンモニウム水溶液を加え、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥、ろ過後、減圧濃縮し、表題の化合物(670 mg)を淡黄色アモルファスとして得た。
MS (ESI+) 585 (M⁺+1, 26%).

Ethyl 3-amino-5-{(3R) -3-[(tert-butoxycarbonyl) amino] piperidin-1-yl} -1- (2-chlorobenzyl) -4-cyano-1H-pyrrole-2-carboxyl To a solution of the rate (780 mg) in ethanol (5 mL) was added 1N aqueous sodium hydroxide solution (2 mL), and the mixture was stirred at 80 ° C. for 1 hr. The reaction solution was cooled to 25 ° C. and concentrated under reduced pressure, a 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, filtered and concentrated under reduced pressure to give the title compound (670 mg) as a pale yellow amorphous product.
MS (ESI +) 585 (M ⁺ +1, 26%).

Reference Example 7
Ethyl 5-{(3R) -3-[(tert-butoxycarbonyl) amino] piperidin-1-yl} -1- (2-chlorobenzyl) -4-cyano-3-iodo-1H-pyrrole-2-carboxyl rate

エチル 3-アミノ-5-{(3R)-3-[(tert-ブトキシカルボニル)アミノ]ピペリジン-1-イル}-1-(2-クロロベンジル)-4-シアノ-1H-ピロール-2-カルボキシレート(500 mg)のトルエン(4 mL)溶液に亜硝酸イソアミル(0.67 mL)、ジヨードメタン(0.81 mL)を加えて100℃で2時間撹拌した。反応溶液を25℃に冷却後、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＝1/0〜5/1)で精製することで表題の化合物(580 mg)を淡黄色アモルファスとして得た。
¹H NMR (400 MHz, CDCl₃) δ 7.42-7.39 (m, 1H), 7.24-7.15 (m, 2H), 6.43-6.41 (m, 1H), 5.65-5.54 (m, 2H), 4.22 (q, J = 7.1 Hz, 2H), 3.78-3.67 (m, 1H), 3.42-3.33 (m, 1H), 2.98-2.82 (m, 3H), 1.89-1.77 (m, 1H), 1.67-1.45 (m, 3H), 1.42 (s, 9H), 1.25 (t, J = 7.1 Hz, 3H).
MS (ESI+) 613 (M⁺+1, 23%).

Ethyl 3-amino-5-{(3R) -3-[(tert-butoxycarbonyl) amino] piperidin-1-yl} -1- (2-chlorobenzyl) -4-cyano-1H-pyrrole-2-carboxyl To a solution of rate (500 mg) in toluene (4 mL) were added isoamyl nitrite (0.67 mL) and diiodomethane (0.81 mL), and the mixture was stirred at 100 ° C. for 2 hr. The reaction solution was cooled to 25 ° C. and purified by silica gel column chromatography (hexane / ethyl acetate = 1/0 to 5/1) to give the title compound (580 mg) as a pale yellow amorphous.
¹ H NMR (400 MHz, CDCl ₃ ) δ 7.42-7.39 (m, 1H), 7.24-7.15 (m, 2H), 6.43-6.41 (m, 1H), 5.65-5.54 (m, 2H), 4.22 (q , J = 7.1 Hz, 2H), 3.78-3.67 (m, 1H), 3.42-3.33 (m, 1H), 2.98-2.82 (m, 3H), 1.89-1.77 (m, 1H), 1.67-1.45 (m , 3H), 1.42 (s, 9H), 1.25 (t, J = 7.1 Hz, 3H).
MS (ESI +) 613 (M ⁺ +1, 23%).

Reference Example 8
Ethyl 3-amino-5-{(3R) -3-[(tert-butoxycarbonyl) amino] piperidin-1-yl} -1- (2-chlorobenzyl) -4-cyano-1H-pyrrole-2-carboxyl rate

N-(1-{(3R)-3-[(tert-ブトキシカルボニル)アミノ]ピペリジン-1-イル}-2,2-ジシアノビニル)-N-(2-クロロベンジル)グリシン エチルエステル(320 mg)のテトラヒドロフラン(5 mL)溶液を0℃に冷却し、水素化ナトリウム(33 mg)を加え、25℃に昇温しながら1時間撹拌した。反応溶液に水を加えて酢酸エチルで抽出し、有機層を飽和食塩水で洗浄後、硫酸ナトリウムで乾燥し、ろ過、減圧濃縮後、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＝ 3/1〜1/1)で精製することにより表題の化合物(300 mg)を得た。
¹H NMR (400 MHz, CDCl₃) δ 7.40-7.35 (m, 1H), 7.21-7.09 (m, 2H), 6.57-6.49 (m, 1H), 5.47-5.30 (m, 2H), 4.07 (q, J = 7.0 Hz, 2H), 3.76-3.64 (m, 1H), 3.40-3.30 (m, 1H), 3.00-2.82 (m, 3H), 1.87-1.74 (m, 1H), 1.72-1.46 (m, 3H), 1.41 (s, 9H), 1.07 (t, J = 7.0 Hz, 3H).
MS (ESI+) 502 (M⁺+1, 29%).

N- (1-{(3R) -3-[(tert-butoxycarbonyl) amino] piperidin-1-yl} -2,2-dicyanovinyl) -N- (2-chlorobenzyl) glycine ethyl ester (320 mg ) In tetrahydrofuran (5 mL) was cooled to 0 ° C., sodium hydride (33 mg) was added, and the mixture was stirred for 1 hour while warming to 25 ° C. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate = The title compound (300 mg) was obtained by purification from 3/1 to 1/1).
¹ H NMR (400 MHz, CDCl ₃ ) δ 7.40-7.35 (m, 1H), 7.21-7.09 (m, 2H), 6.57-6.49 (m, 1H), 5.47-5.30 (m, 2H), 4.07 (q , J = 7.0 Hz, 2H), 3.76-3.64 (m, 1H), 3.40-3.30 (m, 1H), 3.00-2.82 (m, 3H), 1.87-1.74 (m, 1H), 1.72-1.46 (m , 3H), 1.41 (s, 9H), 1.07 (t, J = 7.0 Hz, 3H).
MS (ESI +) 502 (M ⁺ +1, 29%).

Reference Example 9
N- (1-{(3R) -3-[(tert-butoxycarbonyl) amino] piperidin-1-yl} -2,2-dicyanovinyl) -N- (2-chlorobenzyl) glycine ethyl ester

tert-ブチル ((3R)-1-{1-[(2-クロロベンジル)アミノ]-2,2-ジシアノビニル}ピペリジン-3-イル)カルバメート(24.9 g)、ブロモ酢酸エチル(9.9 mL)、炭酸カリウム(24.8 g)のアセトン(350 mL)溶液を60℃で8時間撹拌した。反応溶液を25℃に冷却し、水を加えて酢酸エチルで抽出し、有機層を食塩水で洗浄し、硫酸ナトリウムで乾燥し、ろ過後、減圧濃縮し、得られた残渣をシリカゲルカラムクロマトグラフィー(ヘキサン/酢酸エチル＝1/1)で精製することにより表題の化合物(30.6 g)を白色アモルファスとして得た。
MS (ESI+) 502 (M⁺+1, 25%).

tert-butyl ((3R) -1- {1-[(2-chlorobenzyl) amino] -2,2-dicyanovinyl} piperidin-3-yl) carbamate (24.9 g), ethyl bromoacetate (9.9 mL), A solution of potassium carbonate (24.8 g) in acetone (350 mL) was stirred at 60 ° C. for 8 hours. The reaction solution is cooled to 25 ° C., water is added and the mixture is extracted with ethyl acetate. The organic layer is washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue is subjected to silica gel column chromatography. Purification by (hexane / ethyl acetate = 1/1) gave the title compound (30.6 g) as a white amorphous.
MS (ESI +) 502 (M ⁺ +1, 25%).

Reference Example 10
tert-butyl ((3R) -1- {1-[(2-chlorobenzyl) amino] -2,2-dicyanovinyl} piperidin-3-yl) carbamate

tert-ブチル{(3R)-1-[2,2-ジシアノ-1-(メチルチオ)ビニル]ピペリジン-3-イル}カルバメート (31 g)のピリジン(290 mL)溶液に、2-クロロベンジルアミン(58 mL)を加えて130 ℃で6時間攪拌した。反応溶液を25℃に冷却後、ピリジンを減圧下除去し、さらに残渣にトルエン(100 mL)を加えて減圧濃縮した。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＝ 3/1〜1/1)により精製することで、表題の化合物(30.3 g)を褐色アモルファスとして得た。
MS (ESI+) 416 (M⁺+1, 10%).

To a solution of tert-butyl {(3R) -1- [2,2-dicyano-1- (methylthio) vinyl] piperidin-3-yl} carbamate (31 g) in pyridine (290 mL) was added 2-chlorobenzylamine ( 58 mL) was added and the mixture was stirred at 130 ° C. for 6 hours. After the reaction solution was cooled to 25 ° C., pyridine was removed under reduced pressure, and toluene (100 mL) was further added to the residue, followed by concentration under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate = 3/1 to 1/1) to give the title compound (30.3 g) as a brown amorphous product.
MS (ESI +) 416 (M ⁺ +1, 10%).

Reference Example 11
tert-butyl {(3R) -1- [2,2-dicyano-1- (methylthio) vinyl] piperidin-3-yl} carbamate

[ビス(メチルチオ)メチレン]プロパンジニトリル(10 g)および(R)-tert-3-ブチルピペリジン-3-イルカルバメート(11.8 g)のエタノール(350 mL)溶液を80℃で3時間撹拌し、反応溶液を25℃に冷却した後、減圧濃縮することで、表題の化合物(19 g)を淡黄色アモルファスとして得た。
¹H NMR (400 MHz, CDCl₃) δppm 4.60-4.48 (m, 1H), 4.18-4.03 (m, 1H), 3.94-3.80 (m,1H), 3.77-3.61 (m, 1H), 3.59-3.35 (m, 2H), 2.61 (s, 3H), 2.12-2.00 (m, 1H), 1.98-1.86 (m, 1H), 1.82-1.68 (m, 1H), 1.68-1.50 (m, 1H), 1.46 (s, 9H).
MS (ESI+) 323 (M⁺+1, 40%).

A solution of [bis (methylthio) methylene] propanedinitrile (10 g) and (R) -tert-3-butylpiperidin-3-ylcarbamate (11.8 g) in ethanol (350 mL) was stirred at 80 ° C. for 3 hours, The reaction solution was cooled to 25 ° C. and concentrated under reduced pressure to give the title compound (19 g) as a pale yellow amorphous.
¹ H NMR (400 MHz, CDCl ₃ ) δppm 4.60-4.48 (m, 1H), 4.18-4.03 (m, 1H), 3.94-3.80 (m, 1H), 3.77-3.61 (m, 1H), 3.59-3.35 (m, 2H), 2.61 (s, 3H), 2.12-2.00 (m, 1H), 1.98-1.86 (m, 1H), 1.82-1.68 (m, 1H), 1.68-1.50 (m, 1H), 1.46 (s, 9H).
MS (ESI +) 323 (M ⁺ +1, 40%).

Reference Example 12
(5-Methyl-2-oxo-1,3-dioxol-4-yl) methyl 2-{(3R) -3-[(tert-butoxycarbonyl) amino] piperidin-1-yl} -3- (2- Chlorobenzyl) -1-cyano-5-methyl-4-oxo-4,5-dihydro-3H-pyrrolo [2,3-c] quinoline-8-carboxylate

2-{(3R)-3-[(tert-ブトキシカルボニル)アミノ]ピペリジン-1-イル}-3-(2-クロロベンジル)-1-シアノ-5-メチル-4-オキソ-4,5-ジヒドロ-3H-ピロロ[2,3-c]キノリン-8-カルボン酸(220 mg)のＮ，Ｎ−ジメチルホルムアミド(10 mL)溶液に炭酸カリウム(113 mg)、4-(クロロメチル)-5-メチル-1,3-ジオキソール-2-オン(98 mg)を加え、室温で終夜撹拌した。反応溶液に飽和塩化アンモニウム水溶液を注ぎ、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄し、硫酸ナトリウムで乾燥、ろ過後、減圧濃縮し、得られた残渣をヘキサン/酢酸エチルで再結晶することで表題の化合物（155 mg）を淡黄色固体として得た。
MS (ESI+) 702 (M⁺+1, 100%).

2-{(3R) -3-[(tert-butoxycarbonyl) amino] piperidin-1-yl} -3- (2-chlorobenzyl) -1-cyano-5-methyl-4-oxo-4,5- To a solution of dihydro-3H-pyrrolo [2,3-c] quinoline-8-carboxylic acid (220 mg) in N, N-dimethylformamide (10 mL) was added potassium carbonate (113 mg), 4- (chloromethyl) -5. -Methyl-1,3-dioxol-2-one (98 mg) was added, and the mixture was stirred at room temperature overnight. A saturated aqueous ammonium chloride solution was poured into the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The obtained residue was recrystallized from hexane / ethyl acetate to give the title compound (155 mg) as a pale yellow solid. It was.
MS (ESI +) 702 (M ⁺ +1, 100%).

Reference Example 13
2-morpholin-4-ylethyl 2-{(3R) -3-[(tert-butoxycarbonyl) amino] piperidin-1-yl} -3- (2-chlorobenzyl) -1-cyano-5-methyl-4 -Oxo-4,5-dihydro-3H-pyrrolo [2,3-c] quinoline-8-carboxylate

2-{(3R)-3-[(tert-ブトキシカルボニル)アミノ]ピペリジン-1-イル}-3-(2-クロロベンジル)-1-シアノ-5-メチル-4-オキソ-4,5-ジヒドロ-3H-ピロロ[2,3-c]キノリン-8-カルボン酸(180 mg)のＮ，Ｎ−ジメチルホルムアミド(10 mL)溶液に炭酸カリウム(126 mg)、N-(2-クロロエチル)モルホリン 塩酸塩 (113 mg)を加え、80℃で2時間撹拌した。反応溶液を25℃に冷却し、飽和塩化アンモニウム水溶液を注ぎ、酢酸エチルで抽出した。有機層を水、飽和食塩水で洗浄し、硫酸ナトリウムで乾燥、ろ過後、減圧濃縮し、得られた残渣をヘキサン/酢酸エチルで再結晶することで表題の化合物（167 mg）を淡黄色固体として得た。
MS (ESI+) 703 (M⁺+1, 100%).

2-{(3R) -3-[(tert-butoxycarbonyl) amino] piperidin-1-yl} -3- (2-chlorobenzyl) -1-cyano-5-methyl-4-oxo-4,5- To a solution of dihydro-3H-pyrrolo [2,3-c] quinoline-8-carboxylic acid (180 mg) in N, N-dimethylformamide (10 mL) was added potassium carbonate (126 mg), N- (2-chloroethyl) morpholine. Hydrochloric acid salt (113 mg) was added, and the mixture was stirred at 80 ° C. for 2 hr. The reaction solution was cooled to 25 ° C., saturated aqueous ammonium chloride solution was poured, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The obtained residue was recrystallized from hexane / ethyl acetate to give the title compound (167 mg) as a pale yellow solid. Got as.
MS (ESI +) 703 (M ⁺ +1, 100%).

Reference Example 14
2-{(3R) -3-[(tert-butoxycarbonyl) amino] piperidin-1-yl} -3- (2-chlorobenzyl) -1-cyano-5-methyl-4-oxo-4,5- Dihydro-3H-pyrrolo [2,3-c] quinoline-8-carboxylic acid

メチル 2-{(3R)-3-[(tert-ブトキシカルボニル)アミノ]ピペリジン-1-イル}-3-(2-クロロベンジル)-1-シアノ-5-メチル-4-オキソ-4,5-ジヒドロ-3H-ピロロ[2,3-c]キノリン-8-カルボキシレート(3.89 g)のエタノール/テトラヒドロフラン(50 mL/50 mL)溶液に１Ｎ水酸化ナトリウム水溶液(25 mL)を加え、60℃で3時間撹拌した。反応溶液を25℃に冷却後、10％硫酸水素カリウム水溶液を注ぎ、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄し、硫酸ナトリウムで乾燥、ろ過後、減圧濃縮することで表題の化合物（3.55 g）を褐色固体として得た。
MS (ESI+) 590 (M⁺+1, 15%).

Methyl 2-{(3R) -3-[(tert-butoxycarbonyl) amino] piperidin-1-yl} -3- (2-chlorobenzyl) -1-cyano-5-methyl-4-oxo-4,5 1N aqueous sodium hydroxide solution (25 mL) was added to an ethanol / tetrahydrofuran (50 mL / 50 mL) solution of 2-dihydro-3H-pyrrolo [2,3-c] quinoline-8-carboxylate (3.89 g) at 60 ° C. For 3 hours. The reaction solution was cooled to 25 ° C., 10% aqueous potassium hydrogen sulfate solution was poured, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure to give the title compound (3.55 g) as a brown solid.
MS (ESI +) 590 (M ⁺ +1, 15%).

Reference Example 15
Methyl 2-{(3R) -3-[(tert-butoxycarbonyl) amino] piperidin-1-yl} -3- (2-chlorobenzyl) -1-cyano-5-methyl-4-oxo-4,5 -Dihydro-3H-pyrrolo [2,3-c] quinoline-8-carboxylate

参考例3と同様の製造方法で、参考例16の化合物から表題の化合物を合成した。
MS (ESI+) 604 (M⁺+1, 13%).

The title compound was synthesized from the compound of Reference Example 16 by the same production method as in Reference Example 3.
MS (ESI +) 604 (M ⁺ +1, 13%).

Reference Example 16
Methyl 4-[{[5-{(3R) -3-[(tert-butoxycarbonyl) amino] piperidin-1-yl} -1- (2-chlorobenzyl) -4-cyano-3-iodo-1H- Pyrrol-2-yl] carbonyl} (methyl) amino] benzoate

参考例4と同様の製造方法で、参考例17の化合物から表題の化合物を合成した。
MS (ESI+) 732 (M⁺+1, 15%).

The title compound was synthesized from the compound of Reference Example 17 by the same production method as in Reference Example 4.
MS (ESI +) 732 (M ⁺ +1, 15%).

Reference Example 17
Methyl 4-({[5-{(3R) -3-[(tert-butoxycarbonyl) amino] piperidin-1-yl} -1- (2-chlorobenzyl) -4-cyano-3-iodo-1H- Pyrrol-2-yl] carbonyl} amino) benzoate

参考例5と同様の製造方法で、参考例6の化合物から表題の化合物を合成した。
MS (ESI+) 718 (M⁺+1, 18%).

The title compound was synthesized from the compound of Reference Example 6 by the same production method as in Reference Example 5.
MS (ESI +) 718 (M ⁺ +1, 18%).

Reference Example 18
3- (tert-Butoxycarbonyl) -2-{(3R) -3-[(tert-butoxycarbonyl) amino] piperidin-1-yl} -1- (2-chlorobenzyl) -7-oxo-6,7 -Dihydro-1H-pyrrolo [2,3-c] pyridine-5-carboxylic acid

参考例2と同様の製造方法で、参考例39の化合物から表題の化合物を合成した。
MS (ESI+) 601 (M⁺+1, 100%).

The title compound was synthesized from the compound of Reference Example 39 by the same production method as in Reference Example 2.
MS (ESI +) 601 (M ⁺ +1, 100%).

Reference Example 19
3-tert-butyl 5- {1-[(ethoxycarbonyl) oxy] ethyl} 2-{(3R) -3-[(tert-butoxycarbonyl) amino] piperidin-1-yl} -1- (2-chloro (Benzyl) -7-oxo-6,7-dihydro-1H-pyrrolo [2,3-c] pyridine-3,5-dicarboxylate

3-(tert-ブトキシカルボニル)-2-{(3R)-3-[(tert-ブトキシカルボニル)アミノ]ピペリジン-1-イル}-1-(2-クロロベンジル)-7-オキソ-6,7-ジヒドロ-1H-ピロロ[2,3-c]ピリジン-5-カルボン酸(120 mg)のN,N-ジメチルホルムアミド(2 ml)溶液にカリウム-tert-ブトキシド(20 mg)を加えて、25℃で0.5時間攪拌した。反応溶液に1-クロロエチル エチルカルボネート(62 mg)を加えて70℃で3時間攪拌した。反応溶液に飽和塩化アンモニウム水溶液を加えて酢酸エチルで抽出し、有機層を水、飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥、ろ過後、減圧濃縮した。得られた残渣を分取液体クロマトグラフィーにより精製することにより、表題の化合物(27 mg)を白色アモルファスとして得た。
MS (ESI+) 717 (M⁺+1, 100%).

3- (tert-Butoxycarbonyl) -2-{(3R) -3-[(tert-butoxycarbonyl) amino] piperidin-1-yl} -1- (2-chlorobenzyl) -7-oxo-6,7 To a solution of 2-dihydro-1H-pyrrolo [2,3-c] pyridine-5-carboxylic acid (120 mg) in N, N-dimethylformamide (2 ml) was added potassium tert-butoxide (20 mg), and 25 Stir at 0 ° C. for 0.5 hour. 1-Chloroethyl ethyl carbonate (62 mg) was added to the reaction solution and stirred at 70 ° C. for 3 hours. A saturated aqueous ammonium chloride solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by preparative liquid chromatography to give the title compound (27 mg) as a white amorphous product.
MS (ESI +) 717 (M ⁺ +1, 100%).

Reference Example 20
3-tert-butyl 5- {1-{[(cyclohexyloxy) carbonyl] oxy} ethyl} 2-{(3R) -3-[(tert-butoxycarbonyl) amino] piperidin-1-yl} -1- ( 2-Chlorobenzyl) -7-oxo-6,7-dihydro-1H-pyrrolo [2,3-c] pyridine-3,5-dicarboxylate

参考例19と同様の製造方法で、参考例18の化合物から表題の化合物を合成した。
MS (ESI+) 771 (M⁺+1, 40%).

The title compound was synthesized from the compound of Reference Example 18 by the same production method as in Reference Example 19.
MS (ESI +) 771 (M + +1, 40%).

Reference Example 21
3-tert-butyl 5-methyl 2-{(3R) -3-[(tert-butoxycarbonyl) amino] piperidin-1-yl} -1- (2-chloro-5-fluorobenzyl) -7-oxo- 6,7-Dihydro-1H-pyrrolo [2,3-c] pyridine-3,5-dicarboxylate

窒素雰囲気下、4-tert-ブチル 2-エチル 5-{(3R)-3-[(tert-ブトキシカルボニル)アミノ]ピペリジン-1-イル}-1-(2-クロロ-5-フルオロベンジル)-3-ヨード-1H-ピロール-2,4-カルボキシレート(18.7 g)のN,N-ジメチルホルムアミド(120 ml)溶液に2-アセトアミドアクリル酸メチル(5.7 g)、ベンジルトリエチルアンモニウムクロリド(6.6 g)、炭酸水素ナトリウム(4.9 g)、酢酸パラジウム(1.5 g)を加えて80℃で8時間撹拌した。反応溶液を25℃に冷却し、水を加えて酢酸エチルで抽出した。有機層を水および飽和食塩水で洗浄し、硫酸ナトリウムで乾燥、ろ過、減圧濃縮後、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＝2/1)で精製することで、生成物(8.6 g)を淡黄色アモルファスとして得た。
MS (ESI+) 633 (M⁺+1, 76%).

4-tert-butyl 2-ethyl 5-{(3R) -3-[(tert-butoxycarbonyl) amino] piperidin-1-yl} -1- (2-chloro-5-fluorobenzyl)-under nitrogen atmosphere To a solution of 3-iodo-1H-pyrrole-2,4-carboxylate (18.7 g) in N, N-dimethylformamide (120 ml), methyl 2-acetamidoacrylate (5.7 g), benzyltriethylammonium chloride (6.6 g) , Sodium hydrogen carbonate (4.9 g) and palladium acetate (1.5 g) were added, and the mixture was stirred at 80 ° C. for 8 hr. The reaction solution was cooled to 25 ° C., water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate = 2/1) to give the product. (8.6 g) was obtained as a pale yellow amorphous.
MS (ESI +) 633 (M ⁺ +1, 76%).

Reference Example 22
3-tert-butyl 5-methyl 2-{(3R) -3-[(tert-butoxycarbonyl) amino] piperidin-1-yl} -1- (2-chloro-5-fluorobenzyl) -6-methyl- 7-oxo-6,7-dihydro-1H-pyrrolo [2,3-c] pyridine-3,5-dicarboxylate

参考例4と同様の製造方法で、参考例21の化合物から表題の化合物を合成した。
MS (ESI+) 647 (M⁺+1, 91%).

The title compound was synthesized from the compound of Reference Example 21 by the same production method as in Reference Example 4.
MS (ESI +) 647 (M ⁺ +1, 91%).

Reference Example 23
3- (tert-Butoxycarbonyl) -2-{(3R) -3-[(tert-butoxycarbonyl) amino] piperidin-1-yl} -1- (2-chloro-5-fluorobenzyl) -6-methyl -7-Oxo-6,7-dihydro-1H-pyrrolo [2,3-c] pyridine-5-carboxylic acid

参考例6と同様の製造方法で、参考例22の化合物から表題の化合物を合成した。
MS (ESI+) 633 (M⁺+1, 76%).

The title compound was synthesized from the compound of Reference Example 22 by the same production method as in Reference Example 6.
MS (ESI +) 633 (M ⁺ +1, 76%).

Reference Example 24
tert-butyl 5- (aminocarbonyl) -2-{(3R) -3-[(tert-butoxycarbonyl) amino] piperidin-1-yl} -1- (2-chloro-5-fluorobenzyl) -6- Methyl-7-oxo-6,7-dihydro-1H-pyrrolo [2,3-c] pyridine-3-carboxylate

3-(tert-ブトキシカルボニル)-2-{(3R)-3-[(tert-ブトキシカルボニル)アミノ]ピペリジン-1-イル}-1-(2-クロロ-5-フルオロベンジル)-6-メチル-7-オキソ-6,7-ジヒドロ-1H-ピロロ[2,3-c]ピリジン-5-カルボン酸(250 mg)をN,N-ジメチルホルムアミド(4 mL)に溶かし、1-ヒドロキシベンゾトリアゾール(210 mg)、１−エチル−３−（ジメチルアミノプロピル）カルボジイミド・塩酸塩(300 mg)、トリエチルアミン(0.44 mL)、塩化アンモニウム(83 mg)を加え、25 ℃で14時間撹拌した。反応混合物に水を加えて酢酸エチルで抽出し、有機層を水、飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥、ろ過後、減圧濃縮し、表題の化合物(200 mg)を淡黄色アモルファスとして得た。
MS (ESI+) 632 (M⁺+1, 92%).

3- (tert-Butoxycarbonyl) -2-{(3R) -3-[(tert-butoxycarbonyl) amino] piperidin-1-yl} -1- (2-chloro-5-fluorobenzyl) -6-methyl -7-oxo-6,7-dihydro-1H-pyrrolo [2,3-c] pyridine-5-carboxylic acid (250 mg) dissolved in N, N-dimethylformamide (4 mL) to give 1-hydroxybenzotriazole (210 mg), 1-ethyl-3- (dimethylaminopropyl) carbodiimide hydrochloride (300 mg), triethylamine (0.44 mL) and ammonium chloride (83 mg) were added, and the mixture was stirred at 25 ° C. for 14 hours. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate.The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the title compound (200 mg) as a pale yellow amorphous product. Obtained.
MS (ESI +) 632 (M ⁺ +1, 92%).

Reference Example 25
tert-butyl 2-{(3R) -3-[(tert-butoxycarbonyl) amino] piperidin-1-yl} -1- (2-chloro-5-fluorobenzyl) -5-cyano-6-methyl-7 -Oxo-6,7-dihydro-1H-pyrrolo [2,3-c] pyridine-3-carboxylate

tert-ブチル 5-(アミノカルボニル)-2-{(3R)-3-[(tert-ブトキシカルボニル)アミノ]ピペリジン-1-イル}-1-(2-クロロ-5-フルオロベンジル)-6-メチル-7-オキソ-6,7-ジヒドロ-1H-ピロロ[2,3-c]ピリジン-3-カルボキシレート(200 mg)のテトラヒドロフラン(3 mL)溶液に無水トリフルオロ酢酸(315μL)を滴下後、室温で2時間撹拌した。反応後、反応混合物を減圧濃縮し、残渣をメタノール(3 mL)に溶かし、炭酸カリウム(207 mg)を加えて室温で撹拌した。2時間後、水を加えて酢酸エチルで抽出し、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、ろ過後、減圧濃縮し、得られた残渣をシリカゲルカラムクロマトグラフィー(ヘキサン/酢酸エチル = 1/1)で精製し、表題の化合物（107 mg）を白色固体として得た。
MS (ESI+) 614 (M⁺+1, 69%).

tert-butyl 5- (aminocarbonyl) -2-{(3R) -3-[(tert-butoxycarbonyl) amino] piperidin-1-yl} -1- (2-chloro-5-fluorobenzyl) -6- After dropwise addition of trifluoroacetic anhydride (315 μL) to a solution of methyl-7-oxo-6,7-dihydro-1H-pyrrolo [2,3-c] pyridine-3-carboxylate (200 mg) in tetrahydrofuran (3 mL) And stirred at room temperature for 2 hours. After the reaction, the reaction mixture was concentrated under reduced pressure, the residue was dissolved in methanol (3 mL), potassium carbonate (207 mg) was added, and the mixture was stirred at room temperature. After 2 hours, water was added and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was subjected to silica gel column chromatography (hexane / acetic acid). Purification with ethyl = 1/1) gave the title compound (107 mg) as a white solid.
MS (ESI +) 614 (M ⁺ +1, 69%).

Reference Example 26
2-{(3R) -3-[(tert-butoxycarbonyl) amino] piperidin-1-yl} -3- (2-cyanobenzyl) -5-methyl-4-oxo-4,5-dihydro-3H- Pyrrolo [2,3-c] quinoline-8-carboxylic acid

2-[(3R)-3-アミノピペリジン-1-イル]-3-(2-シアノベンジル)-5-メチル-4-オキソ-4,5-ジヒドロ-3H-ピロロ[2,3-c]キノリン-8-カルボン酸 トリフルオロ酢酸塩(110 mg)のテトラヒドロフラン(10 mL)溶液に10％炭酸カリウム水溶液(5 mL)、ジtertブチルジカーボネート(120 mg)を加え、50℃で6時間激しく撹拌した。反応溶液を25℃に冷却し、飽和硫酸水素カリウム水溶液を注いで液性をpH2とし、酢酸エチルで抽出した。有機層を硫酸ナトリウムで乾燥、ろ過後、減圧濃縮することで表題の化合物（120 mg）を得た。
MS (ESI+) 556 (M⁺+1, 69%).

2-[(3R) -3-Aminopiperidin-1-yl] -3- (2-cyanobenzyl) -5-methyl-4-oxo-4,5-dihydro-3H-pyrrolo [2,3-c] To a solution of quinoline-8-carboxylic acid trifluoroacetate salt (110 mg) in tetrahydrofuran (10 mL) was added 10% aqueous potassium carbonate solution (5 mL) and ditertbutyl dicarbonate (120 mg), and vigorously at 50 ° C. for 6 hours. Stir. The reaction solution was cooled to 25 ° C., saturated aqueous potassium hydrogen sulfate solution was poured to adjust the liquid to pH 2, and the mixture was extracted with ethyl acetate. The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure to give the title compound (120 mg).
MS (ESI +) 556 (M ⁺ +1, 69%).

Reference Example 27
1-[(Ethoxycarbonyl) oxy] ethyl 2-{(3R) -3-[(tert-butoxycarbonyl) amino] piperidin-1-yl} -3- (2-cyanobenzyl) -5-methyl-4- Oxo-4,5-dihydro-3H-pyrrolo [2,3-c] quinoline-8-carboxylate

2-{(3R)-3-[(tert-ブトキシカルボニル)アミノ]ピペリジン-1-イル}-3-(2-シアノベンジル)-5-メチル-4-オキソ-4,5-ジヒドロ-3H-ピロロ[2,3-c]キノリン-8-カルボン酸(120 mg)のＮ，Ｎ−ジメチルホルムアミド(10 mL)溶液に炭酸カリウム(72 mg)、炭酸1-クロロエチル エチル (53 mg)を加え、50℃で4時間撹拌した。反応溶液を25℃に冷却し、硫酸水素カリウム水溶液を注ぎ液性をpH2とした後に、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄し、硫酸ナトリウムで乾燥、ろ過後、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(展開溶媒：ヘキサン/酢酸エチル = 2/1)で精製し、表題の化合物(87 mg)を得た。
MS (ESI+) 672 (M⁺+1, 100%).

2-{(3R) -3-[(tert-butoxycarbonyl) amino] piperidin-1-yl} -3- (2-cyanobenzyl) -5-methyl-4-oxo-4,5-dihydro-3H- To a solution of pyrrolo [2,3-c] quinoline-8-carboxylic acid (120 mg) in N, N-dimethylformamide (10 mL) was added potassium carbonate (72 mg) and 1-chloroethyl ethyl carbonate (53 mg). Stir at 50 ° C. for 4 hours. The reaction solution was cooled to 25 ° C., an aqueous potassium hydrogen sulfate solution was poured to adjust the pH to 2, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: hexane / ethyl acetate = 2/1) to give the title compound (87 mg).
MS (ESI +) 672 (M ⁺ +1, 100%).

Reference Example 28
1-{[(Cyclohexyloxy) carbonyl] oxy} ethyl 2-{(3R) -3-[(tert-butoxycarbonyl) amino] piperidin-1-yl} -3- (2-cyanobenzyl) -5-methyl -4-oxo-4,5-dihydro-3H-pyrrolo [2,3-c] quinoline-8-carboxylate

2-{(3R)-3-[(tert-ブトキシカルボニル)アミノ]ピペリジン-1-イル}-3-(2-シアノベンジル)-5-メチル-4-オキソ-4,5-ジヒドロ-3H-ピロロ[2,3-c]キノリン-8-カルボン酸(120 mg)のN,N-ジメチルホルムアミド(10 mL)溶液に炭酸カリウム(73 mg)、炭酸1-クロロエチル シクロヘキシル (73 mg)を加え、50℃で4時間撹拌した。反応溶液を25℃に冷却し、硫酸水素カリウム水溶液を注ぎ液性をpH2とした後に、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄し、硫酸ナトリウムで乾燥、ろ過後、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 = 2/1)で精製し、表題の化合物(89 mg)を得た。
MS (ESI+) 726 (M⁺+1, 100%).

2-{(3R) -3-[(tert-butoxycarbonyl) amino] piperidin-1-yl} -3- (2-cyanobenzyl) -5-methyl-4-oxo-4,5-dihydro-3H- To a solution of pyrrolo [2,3-c] quinoline-8-carboxylic acid (120 mg) in N, N-dimethylformamide (10 mL) was added potassium carbonate (73 mg) and 1-chloroethyl cyclohexyl carbonate (73 mg). Stir at 50 ° C. for 4 hours. The reaction solution was cooled to 25 ° C., an aqueous potassium hydrogen sulfate solution was poured to adjust the pH to 2, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate = 2/1) to give the title compound (89 mg).
MS (ESI +) 726 (M ⁺ +1, 100%).

Reference Example 29
1- (tert-butoxycarbonyl) -2-{(3R) -3-[(tert-butoxycarbonyl) amino] piperidin-1-yl} -3- (2-cyanobenzyl) -5-methyl-4-oxo -4,5-Dihydro-3H-pyrrolo [2,3-c] quinoline-8-carboxylic acid

1-tert-ブチル 8-メチル 2-{(3R)-3-[(tert-ブトキシカルボニル)アミノ]ピペリジン-1-イル}-3-(2-シアノベンジル)-5-メチル-4-オキソ-4,5-ジヒドロ-3H-ピロロ[2,3-c]キノリン-1,8-ジカルボキシレート(420 mg)のテトラヒドロフラン(20 mL)、メタノール(20 mL)の溶液に、1Ｎ水酸化ナトリウム水溶液(3.75 mL)を加えて60 ℃で3時間攪拌した。25℃に冷却して有機層を減圧濃縮後、硫酸水素カリウム水溶液を注ぎ液性をpH2とした後に、酢酸エチルで抽出した。有機層を硫酸ナトリウムで乾燥、ろ過後、減圧濃縮して表題の化合物(407 mg)を得た。
MS (ESI+) 656 (M⁺+1, 91%).

1-tert-butyl 8-methyl 2-{(3R) -3-[(tert-butoxycarbonyl) amino] piperidin-1-yl} -3- (2-cyanobenzyl) -5-methyl-4-oxo- To a solution of 4,5-dihydro-3H-pyrrolo [2,3-c] quinoline-1,8-dicarboxylate (420 mg) in tetrahydrofuran (20 mL) and methanol (20 mL), 1N aqueous sodium hydroxide solution (3.75 mL) was added, and the mixture was stirred at 60 ° C. for 3 hr. After cooling to 25 ° C. and concentrating the organic layer under reduced pressure, an aqueous potassium hydrogen sulfate solution was poured to adjust the pH to 2, followed by extraction with ethyl acetate. The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure to give the title compound (407 mg).
MS (ESI +) 656 (M ⁺ +1, 91%).

Reference Example 30
1-tert-butyl 8-methyl 2-{(3R) -3-[(tert-butoxycarbonyl) amino] piperidin-1-yl} -3- (2-cyanobenzyl) -5-methyl-4-oxo- 4,5-Dihydro-3H-pyrrolo [2,3-c] quinoline-1,8-dicarboxylate

1-tert-ブチル 8-メチル 2-{(3R)-3-[(tert-ブトキシカルボニル)アミノ]ピペリジン-1-イル}-5-メチル-4-オキソ-4,5-ジヒドロ-3H-ピロロ[2,3-c]キノリン-1,8-ジカルボキシレート(533 mg)のＮ，Ｎ−ジメチルアセトアミド溶液(10 mL)に、2-シアノベンジルブロミド(230 mg)と炭酸カリウム(200 mg)を加えて、70℃で4時間撹拌した。反応終了後、反応液に水を加えて、酢酸エチル(200 mL)で抽出し、有機層を10%硫酸水素カリウム水溶液、飽和食塩水で洗浄した。有機層を硫酸ナトリウムで乾燥、ろ過し、減圧濃縮して得られた残渣をジエチルエーテルで析出した固体をろ取することで、表題の化合物(425 mg)を白色固体として得た。
MS (ESI+) 670 (M⁺+1, 83%).

1-tert-butyl 8-methyl 2-{(3R) -3-[(tert-butoxycarbonyl) amino] piperidin-1-yl} -5-methyl-4-oxo-4,5-dihydro-3H-pyrrolo [2,3-c] quinoline-1,8-dicarboxylate (533 mg) in N, N-dimethylacetamide solution (10 mL), 2-cyanobenzyl bromide (230 mg) and potassium carbonate (200 mg) And stirred at 70 ° C. for 4 hours. After completion of the reaction, water was added to the reaction solution, followed by extraction with ethyl acetate (200 mL), and the organic layer was washed with 10% aqueous potassium hydrogen sulfate solution and saturated brine. The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue obtained by precipitation with diethyl ether was collected by filtration to give the title compound (425 mg) as a white solid.
MS (ESI +) 670 (M ⁺ +1, 83%).

Reference Example 31
1-tert-butyl 8-methyl 2-{(3R) -3-[(tert-butoxycarbonyl) amino] piperidin-1-yl} -5-methyl-4-oxo-4,5-dihydro-3H-pyrrolo [2,3-c] quinoline-1,8-dicarboxylate

1-tert-ブチル 8-メチル 3-ベンジル-2-{(3R)-3-[(tert-ブトキシカルボニル)アミノ]ピペリジン-1-イル}-5-メチル-4-オキソ-4,5-ジヒドロ-3H-ピロロ[2,3-c]キノリン-1,8-ジカルボキシレート(794 mg)のメタノール溶液(100 mL)に、ギ酸アンモニウム(2.40 g)と10%パラジウム−炭素(2.40 g)を加えて、窒素気流下、80℃で2時間加熱撹拌した。反応終了後、パラジウム−炭素をろ過して除き、メタノールを減圧留去した後に10%炭酸カリウム水溶液を加えて、クロロホルム(100 mL)で2回抽出した。有機層を硫酸ナトリウムで乾燥ろ過し、減圧濃縮することで、表題の化合物（533 mg）を得た。
MS (ESI+) 555 (M⁺+1, 100%).

1-tert-butyl 8-methyl 3-benzyl-2-{(3R) -3-[(tert-butoxycarbonyl) amino] piperidin-1-yl} -5-methyl-4-oxo-4,5-dihydro -3H-pyrrolo [2,3-c] quinoline-1,8-dicarboxylate (794 mg) in methanol (100 mL) was added ammonium formate (2.40 g) and 10% palladium-carbon (2.40 g). In addition, the mixture was heated and stirred at 80 ° C. for 2 hours under nitrogen flow. After completion of the reaction, palladium-carbon was removed by filtration, methanol was distilled off under reduced pressure, 10% aqueous potassium carbonate solution was added, and the mixture was extracted twice with chloroform (100 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure to give the title compound (533 mg).
MS (ESI +) 555 (M ⁺ +1, 100%).

Reference Example 32
1-tert-butyl 8-methyl 3-benzyl-2-{(3R) -3-[(tert-butoxycarbonyl) amino] piperidin-1-yl} -5-methyl-4-oxo-4,5-dihydro -3H-pyrrolo [2,3-c] quinoline-1,8-dicarboxylate

参考例3と同様の製造方法で、参考例33の化合物から表題の化合物を合成した。
MS (ESI+) 645 (M⁺+1, 77%).

The title compound was synthesized from the compound of Reference Example 33 by the same production method as in Reference Example 3.
MS (ESI +) 645 (M ⁺ +1, 77%).

Reference Example 33
tert-butyl 1-benzyl-2-{(3R) -3-[(tert-butoxycarbonyl) amino] piperidin-1-yl} -4-iodo-5-{[[4- (methoxycarbonyl) phenyl] ( Methyl) amino] carbonyl} -1H-pyrrole-3-carboxylate

参考例4と同様の製造方法で、参考例34の化合物から表題の化合物を合成した。
MS (ESI+) 773 (M⁺+1, 100%).

The title compound was synthesized from the compound of Reference Example 34 by the same production method as in Reference Example 4.
MS (ESI +) 773 (M ⁺ +1, 100%).

Reference Example 34
tert-butyl 1-benzyl-2-{(3R) -3-[(tert-butoxycarbonyl) amino] piperidin-1-yl} -4-iodo-5-{[[4- (methoxycarbonyl) phenyl] amino ] Carbonyl} -1H-pyrrole-3-carboxylate

参考例17と同様の製造方法で、参考例41の化合物から表題の化合物を合成した。
MS (ESI+) 759 (M⁺+1, 100%).

The title compound was synthesized from the compound of Reference Example 41 by a production method similar to that of Reference Example 17.
MS (ESI +) 759 (M ⁺ +1, 100%).

Reference Example 39
4-tert-butyl 2-ethyl 5-{(3R) -3-[(tert-butoxycarbonyl) amino] piperidin-1-yl} -1- (2-chlorobenzyl) -3-iodo-1H-pyrrole- 2,4-carboxylate

参考例7と同様の製造方法で、参考例43の化合物から表題の化合物を合成した。
MS (ESI+) 688 (M⁺+1, 80%).

The title compound was synthesized from the compound of Reference Example 43 by the same production method as in Reference Example 7.
MS (ESI +) 688 (M + +1, 80%).

Reference Example 40
4-tert-butyl 2-ethyl 5-{(3R) -3-[(tert-butoxycarbonyl) amino] piperidin-1-yl} -1- (2-chloro-5-fluorobenzyl) -3-iodo- 1H-pyrrole-2,4-carboxylate

参考例7と同様の製造方法で、参考例44の化合物から表題の化合物を合成した。
MS (ESI+) 706 (M⁺+1, 79%).
参考例４１
1-ベンジル-4-(tert-ブトキシカルボニル)-5-{(3R)-3-[(tert-ブトキシカルボニル)アミノ]ピペリジン-1-イル}-3-ヨード-1H-ピロール-3-カルボン酸

The title compound was synthesized from the compound of Reference Example 44 by the same production method as in Reference Example 7.
MS (ESI +) 706 (M ⁺ +1, 79%).
Reference Example 41
1-Benzyl-4- (tert-butoxycarbonyl) -5-{(3R) -3-[(tert-butoxycarbonyl) amino] piperidin-1-yl} -3-iodo-1H-pyrrole-3-carboxylic acid

参考例6と同様の製造方法で、参考例42の化合物から表題の化合物を合成した。
MS (ESI+) 626 (M⁺+1, 100%).

The title compound was synthesized from the compound of Reference Example 42 by the same production method as in Reference Example 6.
MS (ESI +) 626 (M ⁺ +1, 100%).

Reference Example 42
4-tert-butyl 2-ethyl 1-benzyl-5-{(3R) -3-[(tert-butoxycarbonyl) amino] piperidin-1-yl} -3-iodo-1H-pyrrole-2,4-di Carboxylate

参考例７と同様の製造方法で、参考例45の化合物から表題の化合物を合成した。
MS (ESI+) 654 (M⁺+1, 100%).

The title compound was synthesized from the compound of Reference Example 45 by the same production method as in Reference Example 7.
MS (ESI +) 654 (M ⁺ +1, 100%).

Reference Example 43
4-tert-butyl 2-ethyl 3-amino-5-{(3R) -3-[(tert-butoxycarbonyl) amino] piperidin-1-yl} -1- (2-chlorobenzyl) -1H-pyrrole- 2,4-dicarboxylate

窒素雰囲気下、リチウムアミド(10.4 g)のtert-ブチルアルコール(210 mL)溶液にtert-ブチル (2E)-3-{(3R)-3-[(tert-ブトキシカルボニル)アミノ]ピペリジン-1-イル}-3-[(2-クロロベンジル)(2-エトキシ-2-オキソエチル)アミノ]-2-シアノアクリレート(116 g)のテトラヒドロフラン(210 mL)溶液をゆっくり滴下して25℃で1.5時間撹拌した。反応終了後、5%硫酸水素カリウム水溶液を加えて液性をpH2にして酢酸エチルで抽出した。有機層を飽和食塩水で洗浄後、硫酸ナトリウムで乾燥し、ろ過、減圧濃縮後、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)で精製することにより表題の化合物(69.0 g)を得た。
MS (ESI+) 577 (M⁺+1, 100%).

To a solution of lithium amide (10.4 g) in tert-butyl alcohol (210 mL) under a nitrogen atmosphere, tert-butyl (2E) -3-{(3R) -3-[(tert-butoxycarbonyl) amino] piperidine-1- Yl} -3-[(2-chlorobenzyl) (2-ethoxy-2-oxoethyl) amino] -2-cyanoacrylate (116 g) in tetrahydrofuran (210 mL) was slowly added dropwise and stirred at 25 ° C. for 1.5 hours. did. After completion of the reaction, 5% aqueous potassium hydrogen sulfate solution was added to adjust the pH to 2, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate = 4/1) to give the title compound ( 69.0 g) was obtained.
MS (ESI +) 577 (M ⁺ +1, 100%).

Reference Example 44
4-tert-butyl 2-ethyl 3-amino-5-{(3R) -3-[(tert-butoxycarbonyl) amino] piperidin-1-yl} -1- (2-chloro-5-fluorobenzyl)- 1H-pyrrole-2,4-dicarboxylate

参考例43と同様の製造方法で、参考例47の化合物から表題の化合物を合成した。
MS (ESI+) 595 (M⁺+1, 100%).

The title compound was synthesized from the compound of Reference Example 47 by a method similar to that of Reference Example 43.
MS (ESI +) 595 (M ⁺ +1, 100%).

Reference Example 45
4-tert-butyl 2-ethyl 3-amino-1-benzyl-5-{(3R) -3-[(tert-butoxycarbonyl) amino] piperidin-1-yl} -1H-pyrrole-2,4-di Carboxylate

参考例43と同様の製造方法で、参考例48の化合物から表題の化合物を合成した。
MS (ESI+) 543 (M⁺+1, 100%).

The title compound was synthesized from the compound of Reference Example 48 by the same production method as in Reference Example 43.
MS (ESI +) 543 (M ⁺ +1, 100%).

Reference Example 46
tert-butyl (2E) -3-{(3R) -3-[(tert-butoxycarbonyl) amino] piperidin-1-yl} -3-[(2-chlorobenzyl) (2-ethoxy-2-oxoethyl) Amino] -2-cyanoacrylate

tert-ブチル(2E)-3-{(3R)-3-[(tert-ブトキシカルボニル)アミノ]ピペリジン-1-イル}-2-シアノ-3-(メチルチオ)アクリレート (143.11 g)のテトラヒドロフラン(450 mL)溶液に、1,8-ジアザビシクロ[5.4.0]ウンデク-7-エン(82.0 g)、2-クロロベンジルアミン(76.4 g)を加えて25 ℃で終夜攪拌した。テトラヒドロフランを減圧留去し、酢酸エチルで希釈した。5%硫酸水素カリウム水溶液で洗浄し、有機層を硫酸ナトリウムで乾燥し、ろ過後、減圧濃縮した。(MS (ESI+) 491 (M⁺+1, 24%))
得られた残渣のアセトニトリル(500 mL)溶液に、ブロモ酢酸エチル(90.0 g)、炭酸セシウム(199.0 g)を加え、25℃で2時間撹拌した。系内の不溶固体をろ過で除き、ろ液を減圧濃縮して得られた残渣をシリカゲルカラムクロマトグラフィー(ヘキサン/酢酸エチル＝1/1)で精製することにより表題の化合物(116 g)を得た。
MS (ESI+) 577 (M⁺+1, 53%).

tert-Butyl (2E) -3-{(3R) -3-[(tert-butoxycarbonyl) amino] piperidin-1-yl} -2-cyano-3- (methylthio) acrylate (143.11 g) in tetrahydrofuran (450 To the solution was added 1,8-diazabicyclo [5.4.0] undec-7-ene (82.0 g) and 2-chlorobenzylamine (76.4 g), and the mixture was stirred at 25 ° C. overnight. Tetrahydrofuran was distilled off under reduced pressure and diluted with ethyl acetate. The organic layer was washed with 5% aqueous potassium hydrogen sulfate solution, dried over sodium sulfate, filtered, and concentrated under reduced pressure. (MS (ESI +) 491 (M ⁺ +1, 24%))
To a solution of the obtained residue in acetonitrile (500 mL), ethyl bromoacetate (90.0 g) and cesium carbonate (199.0 g) were added, and the mixture was stirred at 25 ° C. for 2 hours. The insoluble solid in the system was removed by filtration, and the residue obtained by concentrating the filtrate under reduced pressure was purified by silica gel column chromatography (hexane / ethyl acetate = 1/1) to give the title compound (116 g). It was.
MS (ESI +) 577 (M ⁺ +1, 53%).

Reference Example 47
tert-butyl (2E) -3-{(3R) -3-[(tert-butoxycarbonyl) amino] piperidin-1-yl} -3-[(2-chloro-5-fluorobenzyl) (2-ethoxy- 2-Oxoethyl) amino] -2-cyanoacrylate

参考例46と同様の製造方法で、参考例49の化合物から表題の化合物を合成した。
MS (ESI+) 595 (M⁺+1, 54%).

The title compound was synthesized from the compound of Reference Example 49 by a production method similar to that of Reference Example 46.
MS (ESI +) 595 (M ⁺ +1, 54%).

Reference Example 48
tert-butyl (2E) -3- [benzyl (2-ethoxy-2-oxoethyl) amino] -3-{(3R) -3-[(tert-butoxycarbonyl) amino] piperidin-1-yl} -2- Cyanoacrylate

参考例46と同様の製造方法で、参考例49の化合物から表題の化合物を合成した。
MS (ESI+) 543 (M⁺+1, 27%).

The title compound was synthesized from the compound of Reference Example 49 by a production method similar to that of Reference Example 46.
MS (ESI +) 543 (M ⁺ +1, 27%).

Reference Example 49
tert-butyl (2E) -3-{(3R) -3-[(tert-butoxycarbonyl) amino] piperidin-1-yl} -2-cyano-3- (methylthio) acrylate

tert-ブチル-2-シアノ-3,3-ビス(メチルチオ)アクリレート(45.0 g)のトルエン(190 mL)溶液にtert-ブチル(3R)-ピペリジン-3-イルカルバメート(39.77 g)を加えて20℃で1.5時間撹拌し、その後40℃で2.5時間撹拌した。反応溶液を減圧濃縮することで、表題の化合物(87 g)を得た。
MS (ESI+) 398 (M⁺+1, 18%).

Add tert-butyl (3R) -piperidin-3-ylcarbamate (39.77 g) to a solution of tert-butyl-2-cyano-3,3-bis (methylthio) acrylate (45.0 g) in toluene (190 mL) and add 20 The mixture was stirred at ° C for 1.5 hours and then at 40 ° C for 2.5 hours. The reaction solution was concentrated under reduced pressure to give the title compound (87 g).
MS (ESI +) 398 (M ⁺ +1, 18%).

Reference Example 50
tert-Butyl-2-cyano-3,3-bis (methylthio) acrylate

tert-ブチルシアノアセテート(98.03 g)のＮ，Ｎ−ジメチルホルムアミド(347 mL)溶液を0℃に冷却し炭酸カリウム(287.92 g)を加え、二硫化炭素(62.88 mL)をゆっくり滴下して0℃で１時間撹拌した。その後ヨウ化メチル(107.5 mL)を滴下して徐々に25℃に昇温して終夜撹拌した。系内の不溶固体をろ過で除き、ろ液に水を加えてトルエンで抽出した。飽和食塩水で洗浄して有機層を硫酸ナトリウムで乾燥し、ろ過後、減圧濃縮し表題の化合物(190 g)を得た。
MS (ESI+) 246 (M⁺+1, 27%).

A solution of tert-butyl cyanoacetate (98.03 g) in N, N-dimethylformamide (347 mL) is cooled to 0 ° C., potassium carbonate (287.92 g) is added, and carbon disulfide (62.88 mL) is slowly added dropwise at 0 ° C. For 1 hour. Thereafter, methyl iodide (107.5 mL) was added dropwise, the temperature was gradually raised to 25 ° C., and the mixture was stirred overnight. Insoluble solids in the system were removed by filtration, water was added to the filtrate, and the mixture was extracted with toluene. The organic layer was washed with saturated brine, dried over sodium sulfate, filtered and concentrated under reduced pressure to obtain the title compound (190 g).
MS (ESI +) 246 (M ⁺ +1, 27%).

In vitro DPP-IV inhibitory activity assay
Human serum containing DPP-IV enzyme is diluted 9-20 times in assay buffer and added to the microassay plate. Add test compound solutions of various concentrations, and then add substrate (Glycyl-L-Proline 4-Methyl-Coumaryl-7-Amide, Peptide Institute) to a final concentration of 10-100 μM and react at room temperature I let you. Acetic acid was added to a final concentration of 0.5% to stop the reaction, and the fluorescence intensity at an excitation wavelength of 360 nm and a measurement wavelength of 460 nm was measured using a fluorescence plate reader. The compound concentration that inhibits 50% was calculated as the IC ₅₀ value from the enzyme inhibitory activity when multiple concentrations of the test compound were added.

According to the present invention, a compound having DPP-IV inhibitory activity and improved in safety, toxicity and the like can be provided.
The compound of the present invention suppresses postprandial hyperglycemia in a prediabetic state, treatment of non-insulin-dependent diabetes, treatment of autoimmune diseases such as arthritis and rheumatoid arthritis, treatment of intestinal mucosal disease, growth promotion, rejection of transplanted organ fragments It is useful for suppression, obesity treatment, eating disorder treatment, HIV infection treatment, cancer metastasis inhibition, prostate hypertrophy treatment, periodontitis treatment, and osteoporosis treatment.

Claims (29)

Formula (I):

[Wherein, R ¹ represents a hydrogen atom, an optionally substituted alkyl group, an optionally substituted cycloalkyl group, an optionally substituted aryl group or an optionally substituted heteroaryl group;
R ² represents a hydrogen atom, an optionally substituted alkyl group, an optionally substituted aryl group, an optionally substituted heteroaryl group, an optionally substituted aralkyl group, an optionally substituted heteroarylalkyl group, Represents an optionally substituted alkenyl group or an optionally substituted alkynyl group;
R ³ represents a hydrogen atom, a halogen atom, a cyano group, a formyl group, a carboxy group, an optionally substituted alkyl group, an optionally substituted alkenyl group, an optionally substituted alkynyl group, or an optionally substituted cycloalkyl. Group, optionally substituted aryl group, optionally substituted heteroaryl group, optionally substituted aralkyl group, optionally substituted heteroarylalkyl group, optionally substituted alkylcarbonyl group, optionally substituted A good cycloalkylcarbonyl group, an optionally substituted aroyl group, an optionally substituted heteroarylcarbonyl group, an optionally substituted alkoxycarbonyl group, an optionally substituted aryloxycarbonyl group, an optionally substituted carbamoyl group or ^formula: -R d -C (O) O- R e ( wherein, ^{R d} represents a single bond, an alkylene , Or an alkenylene group, ^{R e} is tetrahydrofuranyl, cinnamyl, 5-methyl-2-oxo-1,3-dioxolen-4-ylmethyl, 5- (tert-butyl) -2-oxo-1,3 Dioxolen-4-ylmethyl, 2-morpholinoethyl, or —CH (R ^f ) OC (O) R ^g , where R ^f represents a hydrogen atom, an alkyl group, an alkenyl group, a cycloalkyl group, or an alkoxy group. R ^g represents an optionally substituted alkyl group, an optionally substituted alkenyl group, a cycloalkyl group, a cycloalkyloxy group, an optionally substituted alkoxy group, an optionally substituted alkenyloxy group, 2- Represents an indanyloxy group, a 5-indanyloxy group, or an optionally substituted aryloxy group);
R ⁴ represents a hydrogen atom, a halogen atom, a cyano group, a formyl group, an optionally substituted alkyl group, an optionally substituted cycloalkyl group, an optionally substituted cycloalkyloxy group, or an optionally substituted alkenyl group. , An optionally substituted alkynyl group, an optionally substituted amino group, an optionally substituted carbamoyl group, a carboxy group, an optionally substituted alkoxy group, an optionally substituted aryl group, an optionally substituted aryl An oxy group, an optionally substituted aralkyl group, an optionally substituted aralkyloxy group, an optionally substituted aroyl group, an optionally substituted arylthio group, an optionally substituted arylsulfinyl group, an optionally substituted Arylsulfonyl group, optionally substituted alkylthio group, optionally substituted alkylsulfinyl group, substituted May be an alkylsulfonyl group, an optionally substituted heteroaryl group, an optionally substituted heteroarylalkyl group, an optionally substituted heteroarylcarbonyl group, an optionally substituted heteroaryloxy group, an optionally substituted Alkylcarbonyl group, optionally substituted nitrogen-containing saturated heterocyclic group, optionally substituted alkoxycarbonyl group, optionally substituted aryloxycarbonyl group, optionally substituted aralkyloxycarbonyl group, optionally substituted A cycloalkyloxycarbonyl group, or a formula: —R ^d —C (O) O—R ^e (wherein R ^d and R ^e are as defined above);
R ⁵ represents a hydrogen atom, a halogen atom, an optionally substituted alkyl group, a carboxy group, an optionally substituted aryl group, an optionally substituted alkoxycarbonyl group, or a formula: —R ^d —C (O) O—R ^e (wherein R ^d and R ^e are as defined above);
R ⁴ and R ⁵ may form an optionally substituted benzene ring, an optionally substituted cycloalkene ring, or an optionally substituted 5- to 6-membered aromatic heterocyclic ring with adjacent carbon atoms. Often;
-Y represents any group of formula (A), formula (B), formula (C) or formula (D) shown below.

(In the formula, m1 represents 0, 1, 2 or 3, m2 represents 1 or 2, R ⁶ does not exist, or 1 or 2 exists, and each independently represents a halogen atom, a hydroxyl group, Oxo group, alkoxy group which may be substituted, alkyl group which may be substituted, aryl group which may be substituted, aralkyl group which may be substituted, amino group which may be substituted, carboxy group, which may be substituted Represents a good alkoxycarbonyl group, or an optionally substituted carbamoyl group, or two R ⁶ together represent methylene or ethylene and combine with the two carbon atoms constituting the ring to form a new ring Can also be)

(In the formula, m3 represents 0, 1, 2 or 3, and R ⁷ does not exist, or 1 or 2 exist, and each independently represents a halogen atom, a hydroxyl group, an oxo group, or may be substituted. An alkoxy group, an optionally substituted alkyl group, an optionally substituted aryl group, an optionally substituted aralkyl group, an optionally substituted amino group, a carboxy group, an optionally substituted alkoxycarbonyl group, or a substituted It may represent a carbamoyl group which may be substituted, or two R ⁷ together represent methylene or ethylene, and can be bonded to two carbon atoms constituting the ring to form a new ring).

(In the formula, m4 and m5 each independently represent 0 or 1, and R ⁸ is not present, or 1 or 2 are present, and each independently represents a halogen atom, a hydroxyl group, an oxo group, or a substituted group. An optionally substituted alkoxy group, an optionally substituted alkyl group, an optionally substituted aryl group, an optionally substituted aralkyl group, an optionally substituted amino group, a carboxy group, an optionally substituted alkoxycarbonyl group, Alternatively, it represents a carbamoyl group which may be substituted, or two R ⁸ together represent methylene or ethylene, and can combine with two carbon atoms constituting the ring to form a new ring.) ,

(In the formula, m6 represents 1, 2 or 3, and R ⁹ does not exist, or 1 or 2 exist, and each independently represents a halogen atom, a hydroxyl group, an oxo group, or an optionally substituted alkoxy group. , An optionally substituted alkyl group, an optionally substituted aryl group, an optionally substituted aralkyl group, an optionally substituted amino group, a carboxy group, an optionally substituted alkoxycarbonyl group, or an optionally substituted It represents a good carbamoyl group, or two R ⁹ together represent methylene or ethylene, and can be bonded to two carbon atoms constituting the ring to form a new ring, and R ¹⁰ and R ¹¹ are each independently, hydrogen atom, methyl, ethyl, propyl or cyclopropyl or represents isopropyl, or R ¹⁰ and R ¹¹ together, Shikurobuchi Or cyclopentyl.) Compound represented by or a prodrug or pharmaceutically acceptable salt thereof. Formula (II):

[Wherein R ¹ , R ² , R ³ , and Y are as defined in claim 1, and R ¹² represents a hydrogen atom, a cyano group, an optionally substituted alkyl group, or an optionally substituted cyclo group. An alkyl group, an optionally substituted alkenyl group, an optionally substituted alkynyl group, an optionally substituted carbamoyl group, a carboxy group, an optionally substituted aryl group, an optionally substituted aralkyl group, and an optionally substituted Good aroyl group, optionally substituted heteroaryl group, optionally substituted heteroarylalkyl group, optionally substituted heteroarylcarbonyl group, optionally substituted alkylcarbonyl group, optionally substituted alkoxycarbonyl group An optionally substituted aryloxycarbonyl group, an optionally substituted aralkyloxycarbonyl group, an optionally substituted cycloalkyl Le oxycarbonyl group, or a group of the ^formula: (. Wherein, ^{R d} and ^{R e} have the same meanings as claim 1) -R d -C (O) O -R e ^{represents, R 13} is a hydrogen atom Represents an optionally substituted alkyl group, an optionally substituted aryl group, or an alkoxycarbonylmethyl group. Or a prodrug thereof, or a pharmaceutically acceptable salt thereof. Formula (III):

[Wherein R ¹ , R ² , R ³ , and Y are as defined in claim 1, and ring A ¹ is an optionally substituted benzene ring, an optionally substituted cycloalkene ring, or a substituted Represents a 5- to 6-membered aromatic heterocycle which may be substituted. Or a prodrug thereof, or a pharmaceutically acceptable salt thereof. Formula (IV):

[Wherein R ¹ , R ² , R ³ , and Y are as defined in claim 1, and Z ¹ , Z ² , Z ³ , and Z ⁴ are each independently represented by the formula: C—R ¹⁴ Or represents a nitrogen atom. However, Z ¹ , Z ² , Z ³ , and Z ⁴ are not simultaneously nitrogen atoms. R ¹⁴ each independently represents a hydrogen atom, a hydroxyl group, a halogen atom, a cyano group, a carboxy group, an optionally substituted alkyl group, an optionally substituted cycloalkyl group, an optionally substituted cycloalkyloxy group, An optionally substituted alkenyl group, an optionally substituted carbamoyl group, an optionally substituted alkoxy group, an optionally substituted alkoxycarbonyl group, an optionally substituted aryloxycarbonyl group, an optionally substituted alkylcarbonyl Group, an optionally substituted cycloalkyloxycarbonyl group, an optionally substituted aralkyloxycarbonyl group, a tetrahydrofuranyloxycarbonyl group, a cinnamyloxycarbonyl group, or a formula: —R ^d —C (O) O—R ^e Wherein R ^d and R ^e are as defined in claim 1. Represents. Or a prodrug thereof, or a pharmaceutically acceptable salt thereof. R ² is a group of any one of formula (E), formula (F), formula (G), formula (H), formula (I) or formula (J) shown below. Or a prodrug thereof, or a pharmaceutically acceptable salt thereof.

Wherein Z ⁵ and Z ⁶ represent an oxygen atom, formula: S (O) p or formula: N (R ²³ ),
R ¹⁵ and R ²¹ are not present, or one or two are present, and each independently represents a halogen atom, a hydroxyl group, a formyl group, a carboxy group, a cyano group, an alkylthio group, an alkylsulfinyl group, an alkylsulfonyl group, an alkyl Group, haloalkyl group, cycloalkyl group, alkoxy group, haloalkoxy group, amino group which may be substituted, carbamoyl group which may be substituted, alkoxycarbonyl group, alkylcarbonyl group which may be substituted, cycloalkylcarbonyl group, Represents an optionally substituted aryl group, an optionally substituted heteroaryl group or an optionally substituted nitrogen-containing heteroaryl group, or two R ¹⁵ and two R ²¹ together represent C _1-3 Represents an alkylenedioxy group,
R ¹⁶ and R ²² are not present, or one or two are present, and each independently represents a halogen atom, a cyano group, an alkyl group, a haloalkyl group, a cycloalkyl group, an alkoxy group or a haloalkoxy group,
R ¹⁷ represents a methyl, ethyl, chlorine atom or bromine atom;
R ¹⁸ represents a hydrogen atom, methyl, ethyl, chlorine atom or bromine atom;
R ¹⁹ represents a hydrogen atom, methyl or ethyl,
R ²⁰ represents a hydrogen atom, methyl, ethyl, cyclopropyl or cyclobutyl,
p represents 0, 1 or 2;
R ²³ represents a hydrogen atom or an alkyl group. ) The compound according to any one of claims 1 to 4, wherein R ² is any group of formula (E), formula (H), or formula (I), or a prodrug thereof, or a pharmaceutical thereof Acceptable salt. R ² represents formula (E1):

[Wherein, R ²⁴ represents a chlorine atom, a bromine atom, an iodine atom, a cyano group, methyl, difluoromethyl, trifluoromethyl, methoxy, fluoromethoxy, difluoromethoxy, or trifluoromethoxy, and R ²⁵ represents a hydrogen atom. Or represents a fluorine atom. Or a prodrug thereof, or a pharmaceutically acceptable salt thereof. The compound according to claim 7 or a prodrug thereof, or a pharmaceutically acceptable salt thereof, wherein R ²⁴ is a chlorine atom or a cyano group. R ⁴ is a hydrogen atom, a cyano group, a carboxy group, an alkoxycarbonyl group, or a formula: —R ^d1 —C (O) O—R ^e1 (wherein R ^d1 represents a single bond, and R ^e1 represents 5 —Methyl-2-oxo-1,3-dioxolen-4-ylmethyl, 2-morpholinoethyl, or —CH (R ^f1 ) OC (O) R ^g1 , where R ^f1 represents a hydrogen atom or an alkyl group. And R ^g1 represents an alkoxy group or a cycloalkyloxy group.)
The compound according to any one of claims 1 to 8, wherein R ⁵ is a hydrogen atom, or R ⁴ and R ⁵ together with an adjacent carbon atom form a benzene ring that may be substituted. Prodrugs, or pharmaceutically acceptable salts thereof. R ⁴ and R ⁵ form an optionally substituted benzene ring with an adjacent carbon atom, and the substituent is a carboxy group, or a group represented by the formula: —R ^d2 —C (O) O—R ^e2 (wherein R ^d2 represents a single bond, and R ^e2 represents 5-methyl-2-oxo-1,3-dioxolen-4-ylmethyl, 2-morpholinoethyl, or a formula: —CH (R ^f2 ) OC (O) R .R ^f2 representing the ^g2 represents a hydrogen atom or an alkyl group, R ^g2 represents an alkoxy group or cycloalkyl group.) is a group represented by any one of claims 1 to 8 The described compound or a prodrug thereof, or a pharmaceutically acceptable salt thereof. Formula (V):

[Wherein, R ¹ , R ³ , and Y are as defined in claim 1, and Z ⁷ and Z ⁸ each independently represent the formula: C—R ¹⁴ or a nitrogen atom. R ¹⁴ each independently represents a hydrogen atom, a hydroxyl group, a halogen atom, a cyano group, a carboxy group, an optionally substituted alkyl group, an optionally substituted cycloalkyl group, an optionally substituted cycloalkyloxy group, An optionally substituted alkenyl group, an optionally substituted carbamoyl group, an optionally substituted alkoxy group, an optionally substituted alkoxycarbonyl group, an optionally substituted aryloxycarbonyl group, an optionally substituted alkylcarbonyl Group, an optionally substituted cycloalkyloxycarbonyl group, an optionally substituted aralkyloxycarbonyl group, a tetrahydrofuranyloxycarbonyl group, a cinnamyloxycarbonyl group, or a formula: —R ^d —C (O) O—R ^e Wherein R ^d and R ^e are as defined in claim 1. Represents. R ²⁴ represents a chlorine atom, a bromine atom, an iodine atom, a cyano group, methyl, difluoromethyl, trifluoromethyl, methoxy, fluoromethoxy, difluoromethoxy, or trifluoromethoxy, and R ²⁵ represents a hydrogen atom or a fluorine atom. To express. Or a prodrug thereof, or a pharmaceutically acceptable salt thereof. The compound according to claim 11 or a prodrug thereof, or a pharmaceutically acceptable salt thereof, wherein Z ⁷ and Z ⁸ are a group represented by the formula: C—R ¹⁴ . Each of R ¹⁴ independently represents a hydrogen atom, a carboxy group, or a formula: —R ^d2 —C (O) O—R ^e2 (wherein R ^d2 represents a single bond, R ^e2 represents 5-methyl; 2-oxo-1,3-dioxolen-4-ylmethyl, 2-morpholinoethyl, or the formula: —CH (R ^f2 ) OC (O) R ^g2 , where R ^f2 represents a hydrogen atom or an alkyl group; R ^g2 represents an alkoxy group or a cycloalkyloxy group.) The compound according to claim 12, a prodrug thereof, or a pharmaceutically acceptable salt thereof. The compound according to any one of claims 11 to 13, wherein R ²⁴ is a chlorine atom or a cyano group, or a prodrug thereof, or a pharmaceutically acceptable salt thereof.   -Y is a group represented by the formula (A), and m1 and m2 are each independently 1 or 2, or -Y is a group represented by the formula (B), and m3 is 1 or 2 Or -Y is a group represented by the formula (C), and m4 and m5 are 1, or a prodrug thereof or a prodrug thereof, or A pharmaceutically acceptable salt. R ¹ is a hydrogen atom, optionally substituted C ₁ -C ₃ alkyl group, or a optionally substituted aryl group, the substituent of alkyl group which may be the substituted fluorine atoms, optionally substituted The compound according to any one of claims 1 to 15, which is selected from a good aroyl group, a carboxy group, an optionally substituted alkoxycarbonyl group, an optionally substituted aryl group and an optionally substituted aryloxy group. Or a prodrug thereof, or a pharmaceutically acceptable salt thereof. R ¹ is represented by the formula: —R ^a —R ^b —R ^c (wherein R ^a is an alkylene group, R ^b is a single bond or a carbonyl group, R ^c is an optionally substituted alkyl group, A compound represented by any one of claims 1 to 15 or a pro thereof, which is a group represented by: a good alkoxy group, an optionally substituted aryl group, or an optionally substituted aryloxy group. Drugs, or pharmaceutically acceptable salts thereof. The compound according to any one of claims 1 to 15, wherein R ¹ is a hydrogen atom or an alkyl group, or a prodrug thereof, or a pharmaceutically acceptable salt thereof. The compound according to any one of claims 1 to 15, wherein R ¹ is a hydrogen atom, methyl, or ethyl, or a pharmaceutically acceptable salt thereof.   The compound or prodrug thereof, or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 19, wherein Y is a group represented by the formula (A). -Y is a group represented by Formula (A), m1 is 2, m @ 2 is 1, there is no R ^6, the compound or a professional according to any one of claims 1-19 Drugs, or pharmaceutically acceptable salts thereof. The compound according to any one of claims 1 to 21, wherein R ³ is a hydrogen atom or a cyano group, or a prodrug thereof, or a pharmaceutically acceptable salt thereof. R ¹ is methyl, compound or a prodrug thereof according to any one of claims 1 to 22 or a pharmaceutically acceptable salt thereof.   24. A medicament comprising the compound according to any one of claims 1 to 23 or a prodrug thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.   A dipeptidyl peptidase-IV inhibitor comprising the compound according to any one of claims 1 to 23 or a prodrug thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.   A therapeutic agent for diabetes containing the compound according to any one of claims 1 to 23 or a prodrug thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.   Use of the compound according to any one of claims 1 to 23 or a prodrug thereof, or a pharmaceutically acceptable salt thereof for the production of a dipeptidyl peptidase-IV inhibitor.   Use of the compound according to any one of claims 1 to 23 or a prodrug thereof, or a pharmaceutically acceptable salt thereof for the manufacture of a therapeutic agent for diabetes. A method for treating diabetes, comprising administering an effective amount of the compound according to any one of claims 1 to 23 or a prodrug thereof, or a pharmaceutically acceptable salt thereof to a patient in need of treatment. .