JP2008247781A - New fused pyrazole derivative - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a new fused pyrazole derivative useful as a medicine. <P>SOLUTION: The fused pyrazole derivative is a compound expressed by formula (1) [wherein, R<SP>1</SP>is an alkyl or the like; [-W<SP>4</SP>=W<SP>5</SP>-W<SP>6</SP>=W<SP>7</SP>-] is the formula: -CR<SP>4</SP>=CR<SP>5</SP>-CR<SP>6</SP>=CR<SP>7</SP>- (wherein, R<SP>4</SP>to R<SP>7</SP>are each independently the formula: -E-A (wherein, E is a single bond or the like: and A is H or an alkyl group or the like) or the like); R<SP>8</SP>is the formula: -OR<SP>11</SP>(wherein R<SP>11</SP>is a hydrogen atom or the like) or the like; R<SP>9</SP>is an alkyl substituted by one or more halogen atoms or the like; R<SP>10</SP>is a group expressed by the formula: -[C(R<SP>13</SP>)R<SP>14</SP>]n-R<SP>15</SP>(wherein, R<SP>13</SP>, R<SP>14</SP>are each independently the hydrogen atom or the like; (n) is an integer of 1 to 10; and R<SP>15</SP>is an alkyl group or the like)]. <P>COPYRIGHT: (C)2009,JPO&INPIT

Description

  The present invention relates to a novel condensed pyrazole derivative useful as a medicine. More specifically, the present invention relates to a novel condensed pyrazole derivative useful as a glucocorticoid receptor function modulator (modulator), that is, an anti-inflammatory agent or an antidiabetic agent.

  Steroidal anti-inflammatory drugs have strong anti-inflammatory and immunosuppressive effects and are used for inflammatory diseases and autoimmune diseases based on excessive immune responses. These are known to bind to a glucocorticoid receptor (hereinafter abbreviated as GR), which is known as a nuclear receptor, to exert an anti-inflammatory action and an immunomodulatory action. In the old days, it was a steroid that was highly effective against rheumatism, one of the intractable inflammatory diseases. However, it has a strong main drug, but it has abnormal glucose metabolism, impaired adrenal function, abnormal bone metabolism, and infectivity. It is also clear that it shows strong side effects such as. Therefore, in recent years, a novel GR-binding compound (GR ligand) has been desired as a new anti-inflammatory therapeutic agent with reduced side effects while maintaining the same anti-inflammatory action as steroids.

With regard to the anti-inflammatory action exhibited by steroidal anti-inflammatory agents and the metabolic actions such as sugar metabolism and bone metabolism, the following molecular mechanisms are becoming clear due to recent research progress.
GR usually stays in the cytoplasm, but once the steroid, a GR ligand, is bound, GR moves from the cytoplasm into the nucleus and regulates gene transcription. At that time, GR acts on inflammatory transcription factors such as AP1 and NF-κB or enzymes involved in the inflammatory reaction and suppresses their activity, thereby exerting an anti-inflammatory effect. On the other hand, the action mechanism that GR exerts metabolic actions such as sugar metabolism and bone metabolism is as follows. It is thought to regulate transcription by directly binding to a called gene sequence.

  Based on the above findings, attempts have been reported to search for compounds that have reduced metabolic effects while maintaining anti-inflammatory effects. In particular, when focusing on the reduction of side effects in steroidal anti-inflammatory agents, steroidal anti-inflammatory agents that have been used in the past have strong agonistic effects on GRE-mediated transcriptional regulation, and this agonistic action is a metabolic action. It is considered the body. Therefore, it is considered that compounds that exhibit weaker agonistic action than conventional steroidal anti-inflammatory drugs, that is, compounds with reduced side effects can be found by searching for partial agonists of GR. Inflammatory compounds have also been reported (see Patent Document 1).

  On the other hand, in a state where blood cortisol concentration is high or GR can be excessively activated, such as Cushing's syndrome, it is useful to suppress excessive activation of GR. In addition, compounds that suppress the action of glucocorticoids via GR are thought to normalize those abnormal states in a state of reduced immune capacity, depression, or increased glucose metabolism, and GR antagonists have been reported. (See Patent Document 2). In particular, diabetes has increased gluconeogenesis, and excessive production of glucose by the liver is observed. It is known that GR increases the expression of various transaminases that convert amino acids into glucose precursors, glucose-6 phosphatase, phosphoenolpyruvate carboxykinase (PEPCK), and the like, and it is known that hyperglycemia occurs. Is expected to be a therapeutic drug for diabetes.

  Nuclear receptors with high homology with GR include nuclear receptors such as AR (Androgen receptor), MR (Mineralocorticoid receptor), and PR (Progesterone receptor). Widely known. In any nuclear receptor, low molecular ligands have been extensively studied. Among them, it has been reported that a compound having an indole skeleton has an action on a nuclear receptor (see Patent Document 3).

In addition, as a drug having a condensed pyrazole skeleton, for example, an indazole derivative that acts as a CRF (corticotropin releasing factor) antagonist and an indazole derivative that acts as a Rho kinase inhibitor have been disclosed (Patent Document 4,). 5).

International Publication No. 2004/058733 Pamphlet US Patent Application Publication No. 2004/0235810 International Publication No. 2004/067529 Pamphlet International Publication No. 2004/050634 Pamphlet International Publication No. 2005/035506 Pamphlet

The problem to be solved by the present invention is to provide a therapeutic or prophylactic agent for all pathological conditions involving GR, specifically, diseases such as inflammation. Specifically, the object is to provide a compound exhibiting partial agonistic properties to GR as a non-steroidal anti-inflammatory drug with reduced side effects compared to steroidal anti-inflammatory drugs.

As a result of intensive studies, the present inventors have found that the following compounds having a condensed pyrazole skeleton, prodrugs thereof, or pharmaceutically acceptable salts thereof function as a GR modulator, thereby completing the present invention. I came to let you.

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

［式中、Ｒ¹を伴う５員環Ｃｙは、式（２）：

[Wherein the 5-membered Cy with R ¹ is represented by the formula (2):

で表される環、又は式（３）：

Or a ring represented by formula (3):

で表される環を表し、
Ｒ¹は、置換のアルキル基、置換もしくは無置換のアルケニル基、置換もしくは無置換のアルキニル基、置換もしくは無置換のシクロアルキル基、置換もしくは無置換のシクロアルケニル基、置換もしくは無置換のアリール基、置換もしくは無置換のヘテロアリール基、置換もしくは無置換のアラルキル基、置換もしくは無置換のヘテロアラルキル基、置換もしくは無置換のアルコキシ基、置換もしくは無置換のアルカノイル基、置換もしくは無置換のアルコキシカルボニル基、置換もしくは無置換のアルキルスルホニル基、置換もしくは無置換のシクロアルキルオキシ基、置換もしくは無置換のシクロアルキルカルボニル基、置換もしくは無置換のシクロアルキルオキシカルボニル基、置換もしくは無置換のシクロアルキルスルホニル基、置換もしくは無置換のアリールオキシ基、置換もしくは無置換のアロイル基、置換もしくは無置換のアリールオキシカルボニル基、置換もしくは無置換のアリールスルホニル基、置換もしくは無置換のヘテロアリールオキシ基、置換もしくは無置換のヘテロアリールカルボニル基、置換もしくは無置換のヘテロアリールオキシカルボニル基、置換もしくは無置換のヘテロアリールスルホニル基、置換もしくは無置換のアラルキルオキシ基、置換もしくは無置換のアラルキルカルボニル基、置換もしくは無置換のアラルキルオキシカルボニル基、置換もしくは無置換のアラルキルスルホニル基、置換もしくは無置換のヘテロアラルキルオキシ基、置換もしくは無置換のヘテロアラルキルカルボニル基、置換もしくは無置換のヘテロアラルキルオキシカルボニル基、置換もしくは無置換のヘテロアラルキルスルホニル基、置換もしくは無置換の飽和もしくは不飽和の脂肪族ヘテロ環基、置換もしくは無置換の飽和もしくは不飽和の脂肪族ヘテロ環カルボニル基、置換もしくは無置換の飽和もしくは不飽和の脂肪族ヘテロ環スルホニル基、置換もしくは無置換のカルバモイル基、又は置換もしくは無置換のスルファモイル基を表し、
−Ｗ⁴＝Ｗ⁵−Ｗ⁶＝Ｗ⁷−は、以下の式（ａ）〜（ｈ）：
（ａ） −ＣＲ⁴＝ＣＲ⁵−ＣＲ⁶＝ＣＲ⁷−；
（ｂ） −Ｎ＝ＣＲ⁵−ＣＲ⁶＝ＣＲ⁷−；
（ｃ） −ＣＲ⁴＝Ｎ−ＣＲ⁶＝ＣＲ⁷−；
（ｄ） −ＣＲ⁴＝ＣＲ⁵−Ｎ＝ＣＲ⁷−；
（ｅ） −ＣＲ⁴＝ＣＲ⁵−ＣＲ⁶＝Ｎ−；
（ｆ） −Ｎ＝ＣＲ⁵−Ｎ＝ＣＲ⁷−；
（ｇ） −ＣＲ⁴＝Ｎ−ＣＲ⁶＝Ｎ−；
（ｈ） −ＣＲ⁴＝Ｎ−Ｎ＝ＣＲ⁷−
〔式中、Ｒ⁴、Ｒ⁵、Ｒ⁶及びＲ⁷は、各々独立して、同一又は異なって、式：−Ｅ−Ａを表し、式中、Ｅは、単結合、又は以下の式1）〜14）：
1） −Ｃ（Ｒ¹⁶）Ｒ¹⁷−，
2） −Ｏ−，
3） −Ｓ（＝Ｏ）ｍ−，
4） −Ｓ（＝Ｏ）₂ＮＲ¹⁶−，
5） −Ｃ（＝Ｏ）−，
6） −Ｃ（＝Ｏ）Ｏ−，
7） −Ｃ（＝Ｏ）ＮＲ¹⁶−，
8） −Ｃ（＝ＮＲ¹⁶）ＮＲ¹⁷−，
9） −ＮＲ¹⁶−，
10） −Ｎ（Ｒ¹⁶）Ｃ（＝Ｏ）−，
11） −Ｎ（Ｒ¹⁶）Ｓ（＝Ｏ）₂−，
12） −Ｎ（Ｒ¹⁶）Ｃ（＝Ｏ）Ｎ（Ｒ¹⁷）−，
13） −Ｎ（Ｒ¹⁶）Ｓ（＝Ｏ）₂Ｎ（Ｒ¹⁷）−，
14） −Ｐ（＝Ｏ）（ＯＲ¹⁶）₂−
（式中、Ｒ¹⁶及びＲ¹⁷は、各々独立して、水素原子、炭素原子数が１〜３のアルキル基、又は炭素原子数が１〜３のアルコキシ基を表すか、又は式8）、12）及び13）においては、Ｒ¹⁶とＲ¹⁷は結合して、炭素原子数２〜４のアルキレン基を表してもよく、ｍは、０、１又は２を表す。）から選択される基を表し、
Ｅが単結合である時、Ａは、水素原子、ハロゲン原子、シアノ基、ニトロ基、水酸基、カルボキシル基、置換もしくは無置換のアルキル基、置換もしくは無置換のアルケニル基、置換もしくは無置換のアルキニル基、置換もしくは無置換のシクロアルキル基、置換もしくは無置換のシクロアルケニル基、置換もしくは無置換のアリール基、置換もしくは無置換のヘテロアリール基、置換もしくは無置換のアラルキル基、置換もしくは無置換のヘテロアラルキル基、又は置換もしくは無置換の飽和もしくは不飽和の脂肪族ヘテロ環基を表し、
Ｅが前記式1）〜14）から選択される基を表す時、Ａは、水素原子、置換もしくは無置換のアルキル基、置換もしくは無置換のアルケニル基、置換もしくは無置換のアルキニル基、置換もしくは無置換のシクロアルキル基、置換もしくは無置換のシクロアルケニル基、置換もしくは無置換のアリール基、置換もしくは無置換のヘテロアリール基、置換もしくは無置換のアラルキル基、置換もしくは無置換のヘテロアラルキル基、又は置換もしくは無置換の飽和もしくは不飽和の脂肪族ヘテロ環基を表す。〕
から選択される基を表し、
Ｒ⁸は、式：−ＯＲ¹¹、又は−Ｎ（Ｒ¹¹）Ｒ¹²で表される基を表し（式中、Ｒ¹¹及びＲ¹²は、各々独立して、水素原子、又は置換もしくは無置換の炭素原子数が１〜５のアルキル基を表す）、
Ｒ⁹は、１つ以上のハロゲン原子で置換されたアルキル基、又は１つ以上のハロゲン原子で置換されたシクロアルキル基を表し、
Ｒ¹⁰は、式：−［Ｃ（Ｒ¹³）Ｒ¹⁴］ｎ−Ｒ¹⁵で表される基を表す（式中、Ｒ¹³及びＲ¹⁴は、各々独立して、水素原子、アルキル基又はハロゲン原子を表すか、Ｒ¹³とＲ¹⁴が一緒になってオキソ基を表すか、又はＲ¹³とＲ¹⁴が結合して、それらが結合する炭素原子と共に、シクロアルカンを形成してもよく、当該シクロアルカンにおける１もしくは２個の−ＣＨ₂−基は、−ＮＨ−、−Ｓ−、−Ｓ（＝Ｏ）−、−Ｓ（＝Ｏ）₂−、−Ｃ（＝Ｏ）−及び−Ｏ−から選ばれる基によって、同一又は異なって、置き換えられていてもよく、
ｎは、１〜１０の整数を表し、ｎが２〜１０の整数である時、Ｃ（Ｒ¹³）Ｒ¹⁴は同一または異なってよく、
Ｒ¹⁵は、水酸基、置換もしくは無置換のアルキル基、置換もしくは無置換のアルケニル基、置換もしくは無置換のアルキニル基、置換もしくは無置換のシクロアルキル基、置換もしくは無置換のシクロアルケニル基、置換もしくは無置換のアリール基、置換もしくは無置換のヘテロアリール基、置換もしくは無置換のアルコキシ基、置換もしくは無置換のアルキルチオ基、置換もしくは無置換のアルキルスルフィニル基、置換もしくは無置換のアルキルスルホニル基、置換もしくは無置換のシクロアルキルオキシ基、置換もしくは無置換のシクロアルキルチオ基、置換もしくは無置換のシクロアルキルスルフィニル基、置換もしくは無置換のシクロアルキルスルホニル基、置換もしくは無置換のアリールオキシ基、置換もしくは無置換のアリールチオ基、置換もしくは無置換のアリールスルフィニル基、置換もしくは無置換のアリールスルホニル基、置換もしくは無置換のヘテロアリールオキシ基、置換もしくは無置換のヘテロアリールチオ基、置換もしくは無置換のヘテロアリールスルフィニル基、置換もしくは無置換のヘテロアリールスルホニル基、置換もしくは無置換のカルバモイル基、置換もしくは無置換のスルファモイル基、置換もしくは無置換のチオカルバモイル基、置換もしくは無置換の飽和もしくは不飽和の脂肪族ヘテロ環基、置換もしくは無置換の飽和もしくは不飽和の脂肪族ヘテロ環オキシ基、置換もしくは無置換の飽和もしくは不飽和の脂肪族ヘテロ環チオ基、置換もしくは無置換の飽和もしくは不飽和の脂肪族ヘテロ環スルフィニル基、置換もしくは無置換の飽和もしくは不飽和の脂肪族ヘテロ環スルホニル基、又は式：Ｎ（Ｒ¹⁸）Ｒ¹⁹で表される基（式中、Ｒ¹⁸及びＲ¹⁹は、独立して、水素原子、置換もしくは無置換のアルキル基、置換もしくは無置換のアルケニル基、置換もしくは無置換のアルキニル基、置換もしくは無置換のシクロアルキル基、置換もしくは無置換のシクロアルケニル基、置換もしくは無置換のアリール基、置換もしくは無置換のヘテロアリール基、置換もしくは無置換のアラルキル基、置換もしくは無置換のヘテロアラルキル基、置換もしくは無置換のアルカノイル基、置換もしくは無置換のアルコキシカルボニル基、置換もしくは無置換のアルキルスルホニル基、置換もしくは無置換のシクロアルキルカルボニル基、置換もしくは無置換のシクロアルキルオキシカルボニル基、置換もしくは無置換のシクロアルキルスルホニル基、置換もしくは無置換のアロイル基、置換もしくは無置換のアリールオキシカルボニル基、置換もしくは無置換のアリールスルホニル基、置換もしくは無置換のヘテロアリールカルボニル基、置換もしくは無置換のヘテロアリールオキシカルボニル基、置換もしくは無置換のヘテロアリールスルホニル基、置換もしくは無置換のアラルキルカルボニル基、置換もしくは無置換のアラルキルオキシカルボニル基、置換もしくは無置換のアラルキルスルホニル基、置換もしくは無置換のヘテロアラルキルカルボニル基、置換もしくは無置換のヘテロアラルキルオキシカルボニル基、置換もしくは無置換のヘテロアラルキルスルホニル基、置換もしくは無置換のカルバモイル基、置換もしくは無置換のスルファモイル基、置換もしくは無置換のチオカルバモイル基、置換もしくは無置換の飽和もしくは不飽和の脂肪族ヘテロ環基、置換もしくは無置換の飽和もしくは不飽和の脂肪族ヘテロ環カルボニル基、置換もしくは無置換の飽和もしくは不飽和の脂肪族ヘテロ環スルホニル基を表すか、又はＲ¹⁸とＲ¹⁹は結合して、それらが結合する窒素原子と共に、置換もしくは無置換の、飽和もしくは不飽和の、０〜２個の酸素原子、０〜２個の硫黄原子及び１〜４個の窒素原子から選択される１〜４個のヘテロ原子を含む単環、二環もしくは三環の含窒素ヘテロ環を形成してもよい。）を表す。］
で表される化合物もしくはそのプロドラッグ、又はそれらの薬学上許容される塩；
〔２〕 Ｒ¹を伴う５員環Ｃｙが、式（２）：

Represents a ring represented by
R ¹ represents a substituted alkyl group, a substituted or unsubstituted alkenyl group, a substituted or unsubstituted alkynyl group, a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted cycloalkenyl group, a substituted or unsubstituted aryl group Substituted or unsubstituted heteroaryl group, substituted or unsubstituted aralkyl group, substituted or unsubstituted heteroaralkyl group, substituted or unsubstituted alkoxy group, substituted or unsubstituted alkanoyl group, substituted or unsubstituted alkoxycarbonyl Group, substituted or unsubstituted alkylsulfonyl group, substituted or unsubstituted cycloalkyloxy group, substituted or unsubstituted cycloalkylcarbonyl group, substituted or unsubstituted cycloalkyloxycarbonyl group, substituted or unsubstituted cycloalkylsulfonyl Group, Substituted or unsubstituted aryloxy group, substituted or unsubstituted aroyl group, substituted or unsubstituted aryloxycarbonyl group, substituted or unsubstituted arylsulfonyl group, substituted or unsubstituted heteroaryloxy group, substituted or unsubstituted Heteroarylcarbonyl group, substituted or unsubstituted heteroaryloxycarbonyl group, substituted or unsubstituted heteroarylsulfonyl group, substituted or unsubstituted aralkyloxy group, substituted or unsubstituted aralkylcarbonyl group, substituted or unsubstituted Aralkyloxycarbonyl group, substituted or unsubstituted aralkylsulfonyl group, substituted or unsubstituted heteroaralkyloxy group, substituted or unsubstituted heteroaralkylcarbonyl group, substituted or unsubstituted heteroaralkyloxy group Cicarbonyl group, substituted or unsubstituted heteroaralkylsulfonyl group, substituted or unsubstituted saturated or unsaturated aliphatic heterocyclic group, substituted or unsubstituted saturated or unsaturated aliphatic heterocyclic carbonyl group, substituted or unsubstituted Represents a substituted saturated or unsaturated aliphatic heterocyclic sulfonyl group, a substituted or unsubstituted carbamoyl group, or a substituted or unsubstituted sulfamoyl group;
^{-W 4 = W 5 -W 6 =} W 7 - has the following formula (a) ~ (h):
^{(A) -CR 4 = CR 5} -CR 6 = CR 7 -;
^{(B) -N = CR 5 -CR} 6 = CR 7 -;
^{(C) -CR 4 = N-} CR 6 = CR 7 -;
^{(D) -CR 4 = CR 5} -N = CR 7 -;
^{(E) -CR 4 = CR 5} -CR 6 = N-;
^{(F) -N = CR 5 -N} = CR 7 -;
^{(G) -CR 4 = N-} CR 6 = N-;
^{(H) -CR 4 = N-} N = CR 7 -
[Wherein, R ⁴ , R ⁵ , R ⁶ and R ⁷ are each independently the same or different and represent the formula: -EA, wherein E is a single bond or the following formula 1 )~14):
1) -C (R ¹⁶ ) R ^17- ,
2) -O-,
3) -S (= O) m-,
4) -S (= O) ₂ NR ^16- ,
5) -C (= O)-,
6) -C (= O) O-,
7) -C (= O) NR ^16- ,
8) −C (= NR ¹⁶ ) NR ¹⁷ −,
9) -NR ^16- ,
^{10) -N (R 16) C} (= O) -,
11) -N (R ¹⁶ ) S (= O) _2- ,
^{12) -N (R 16) C} (= O) N (R 17) -,
^{13) -N (R 16) S} (= O) 2 N (R 17) -,
14) -P (= O) (OR ¹⁶ ) _2-
(Wherein R ¹⁶ and R ¹⁷ each independently represents a hydrogen atom, an alkyl group having 1 to 3 carbon atoms, or an alkoxy group having 1 to 3 carbon atoms, or formula 8). In 12) and 13), R ¹⁶ and R ¹⁷ may be bonded to each other to represent an alkylene group having 2 to 4 carbon atoms, and m represents 0, 1 or 2. ) Represents a group selected from
When E is a single bond, A is a hydrogen atom, halogen atom, cyano group, nitro group, hydroxyl group, carboxyl group, substituted or unsubstituted alkyl group, substituted or unsubstituted alkenyl group, substituted or unsubstituted alkynyl. Group, substituted or unsubstituted cycloalkyl group, substituted or unsubstituted cycloalkenyl group, substituted or unsubstituted aryl group, substituted or unsubstituted heteroaryl group, substituted or unsubstituted aralkyl group, substituted or unsubstituted Represents a heteroaralkyl group, or a substituted or unsubstituted saturated or unsaturated aliphatic heterocyclic group,
When E represents a group selected from the above formulas 1) to 14), A represents a hydrogen atom, a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkenyl group, a substituted or unsubstituted alkynyl group, substituted or An unsubstituted cycloalkyl group, a substituted or unsubstituted cycloalkenyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted heteroaryl group, a substituted or unsubstituted aralkyl group, a substituted or unsubstituted heteroaralkyl group, Or a substituted or unsubstituted saturated or unsaturated aliphatic heterocyclic group. ]
Represents a group selected from
R ⁸ represents a group represented by the formula: —OR ¹¹ or —N (R ¹¹ ) R ¹² (wherein R ¹¹ and R ¹² are each independently a hydrogen atom, or substituted or unsubstituted) Represents an alkyl group having 1 to 5 carbon atoms),
R ⁹ represents an alkyl group substituted with one or more halogen atoms, or a cycloalkyl group substituted with one or more halogen atoms;
R ¹⁰ represents a group represented by the formula: — [C (R ¹³ ) R ¹⁴ ] n—R ¹⁵ (wherein R ¹³ and R ¹⁴ are each independently a hydrogen atom, an alkyl group or a halogen atom). R ¹³ and R ¹⁴ together represent an oxo group, or R ¹³ and R ¹⁴ may be bonded together to form a cycloalkane together with the carbon atom to which they are bonded, One or two —CH ₂ — groups in the cycloalkane are —NH—, —S—, —S (═O) —, —S (═O) ₂ —, —C (═O) — and —O. May be the same or different and replaced by a group selected from:
n represents an integer of 1 to 10, and when n is an integer of 2 to 10, C (R ¹³ ) R ¹⁴ may be the same or different;
R ¹⁵ represents a hydroxyl group, a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkenyl group, a substituted or unsubstituted alkynyl group, a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted cycloalkenyl group, substituted or Unsubstituted aryl group, substituted or unsubstituted heteroaryl group, substituted or unsubstituted alkoxy group, substituted or unsubstituted alkylthio group, substituted or unsubstituted alkylsulfinyl group, substituted or unsubstituted alkylsulfonyl group, substituted Or an unsubstituted cycloalkyloxy group, a substituted or unsubstituted cycloalkylthio group, a substituted or unsubstituted cycloalkylsulfinyl group, a substituted or unsubstituted cycloalkylsulfonyl group, a substituted or unsubstituted aryloxy group, a substituted or unsubstituted Replacement ants Ruthio group, substituted or unsubstituted arylsulfinyl group, substituted or unsubstituted arylsulfonyl group, substituted or unsubstituted heteroaryloxy group, substituted or unsubstituted heteroarylthio group, substituted or unsubstituted heteroarylsulfinyl group Substituted or unsubstituted heteroarylsulfonyl group, substituted or unsubstituted carbamoyl group, substituted or unsubstituted sulfamoyl group, substituted or unsubstituted thiocarbamoyl group, substituted or unsubstituted saturated or unsaturated aliphatic heterocycle Group, substituted or unsubstituted saturated or unsaturated aliphatic heterocyclic oxy group, substituted or unsubstituted saturated or unsaturated aliphatic heterocyclic thio group, substituted or unsubstituted saturated or unsaturated aliphatic heterocyclic ring Sulfinyl group, substituted or unsubstituted Saturated or aliphatic heterocyclic sulfonyl group unsaturated, or formula: N (R ¹⁸⁾ group (wherein represented by R ^19, R ¹⁸ and R ¹⁹ are independently hydrogen atom, a substituted or unsubstituted Alkyl group, substituted or unsubstituted alkenyl group, substituted or unsubstituted alkynyl group, substituted or unsubstituted cycloalkyl group, substituted or unsubstituted cycloalkenyl group, substituted or unsubstituted aryl group, substituted or unsubstituted Heteroaryl group, substituted or unsubstituted aralkyl group, substituted or unsubstituted heteroaralkyl group, substituted or unsubstituted alkanoyl group, substituted or unsubstituted alkoxycarbonyl group, substituted or unsubstituted alkylsulfonyl group, substituted or Unsubstituted cycloalkylcarbonyl group, substituted or unsubstituted cycloalkyloxy Nyl group, substituted or unsubstituted cycloalkylsulfonyl group, substituted or unsubstituted aroyl group, substituted or unsubstituted aryloxycarbonyl group, substituted or unsubstituted arylsulfonyl group, substituted or unsubstituted heteroarylcarbonyl group, Substituted or unsubstituted heteroaryloxycarbonyl group, substituted or unsubstituted heteroarylsulfonyl group, substituted or unsubstituted aralkylcarbonyl group, substituted or unsubstituted aralkyloxycarbonyl group, substituted or unsubstituted aralkylsulfonyl group, substituted Or an unsubstituted heteroaralkylcarbonyl group, a substituted or unsubstituted heteroaralkyloxycarbonyl group, a substituted or unsubstituted heteroaralkylsulfonyl group, a substituted or unsubstituted carbamoyl group, substituted Or an unsubstituted sulfamoyl group, a substituted or unsubstituted thiocarbamoyl group, a substituted or unsubstituted saturated or unsaturated aliphatic heterocyclic group, a substituted or unsubstituted saturated or unsaturated aliphatic heterocyclic carbonyl group, Represents a substituted or unsubstituted saturated or unsaturated aliphatic heterocyclic sulfonyl group, or R ¹⁸ and R ¹⁹ are bonded together with the nitrogen atom to which they are bonded, together with a substituted or unsubstituted, saturated or unsaturated A monocyclic, bicyclic or tricyclic nitrogen-containing heterocycle containing 1 to 4 heteroatoms selected from 0 to 2 oxygen atoms, 0 to 2 sulfur atoms and 1 to 4 nitrogen atoms May be formed. ). ]
Or a prodrug thereof, or a pharmaceutically acceptable salt thereof;
[2] The 5-membered ring Cy with R ¹ is represented by the formula (2):

で表される環を表す、〔１〕に記載の化合物もしくはそのプロドラッグ、又はそれらの薬学上許容される塩；
〔３〕 −Ｗ⁴＝Ｗ⁵−Ｗ⁶＝Ｗ⁷−が、式（ａ）：−ＣＲ⁴＝ＣＲ⁵−ＣＲ⁶＝ＣＲ⁷−（式中、Ｒ⁴、Ｒ⁵、Ｒ⁶及びＲ⁷は〔１〕と同義である）を表す、〔１〕又は〔２〕に記載の化合物もしくはそのプロドラッグ、又はそれらの薬学上許容される塩；
〔４〕 −Ｗ⁴＝Ｗ⁵−Ｗ⁶＝Ｗ⁷−が、式（ｄ）：−ＣＲ⁴＝ＣＲ⁵−Ｎ＝ＣＲ⁷−（式中、Ｒ⁴、Ｒ⁵及びＲ⁷は〔１〕と同義である）を表す、〔１〕又は〔２〕に記載の化合物もしくはそのプロドラッグ、又はそれらの薬学上許容される塩；
〔５〕 Ｒ¹が、置換もしくは無置換のアラルキル基、置換もしくは無置換のヘテロアラルキル基、置換もしくは無置換のアリール基、置換もしくは無置換のヘテロアリール基、置換もしくは無置換のシクロアルキル基、置換もしくは無置換のシクロアルキル基で置換されたアルキル基、又は置換もしくは無置換の飽和もしくは不飽和の脂肪族ヘテロ環で置換されたアルキル基を表す、〔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、又はそれらの薬学上許容される塩；
〔６〕 Ｒ⁸が、式：−ＯＲ¹¹で表される基を表す（式中、Ｒ¹¹は〔１〕と同義である）、〔１〕〜〔５〕のいずれかに記載の化合物もしくはそのプロドラッグ、又はそれらの薬学上許容される塩；
〔７〕 Ｒ¹¹が、水素原子を表す、〔６〕に記載の化合物もしくはそのプロドラッグ、又はそれらの薬学上許容される塩；
〔８〕 Ｒ⁹が、１〜７個のフッ素原子又は塩素原子で置換された炭素原子数が１〜６のアルキル基を表す、〔１〕〜〔７〕のいずれかに記載の化合物もしくはそのプロドラッグ、又はそれらの薬学上許容される塩；
〔９〕 Ｒ⁹が、トリフルオロメチル基を表す、〔８〕に記載の化合物もしくはそのプロドラッグ、又はそれらの薬学上許容される塩；
〔１０〕 Ｒ¹⁰の式：−［Ｃ（Ｒ¹³）Ｒ¹⁴］ｎ−Ｒ¹⁵において、Ｒ¹³及びＲ¹⁴が水素原子を表し、ｎが１又は２を表し、Ｒ¹⁵が式：Ｎ（Ｒ¹⁸）Ｒ¹⁹で表される基（式中、Ｒ¹⁸及びＲ¹⁹は〔１〕と同義である）を表す、〔１〕〜〔９〕のいずれかに記載の化合物もしくはそのプロドラッグ、又はそれらの薬学上許容される塩；
〔１１〕 Ｒ¹⁸及びＲ¹⁹が結合して、それらが結合する窒素原子と共に、置換されている飽和もしくは不飽和で単環もしくは二環の含窒素ヘテロ環を表す、〔１０〕に記載の化合物もしくはそのプロドラッグ、又はそれらの薬学上許容される塩；
〔１２〕 〔１〕〜〔１１〕のいずれかに記載の化合物もしくはそのプロドラッグ、又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グルココルチコイド受容体機能調節剤；
〔１３〕 〔１〕〜〔１１〕のいずれかに記載の化合物もしくはそのプロドラッグ、又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、炎症性疾患もしくは糖尿病の治療薬又は予防薬；
に関する。

Or a prodrug thereof, or a pharmaceutically acceptable salt thereof, which represents a ring represented by:
[3] ^{-W 4 = W 5 -W 6 =} W 7 - is of the formula ^{(a): - CR 4 =} CR 5 -CR 6 = CR 7 - ( wherein, R ^4, R ^5, R ⁶ and R ⁷ represents the same as [1]), the compound according to [1] or [2] or a prodrug thereof, or a pharmaceutically acceptable salt thereof;
[4] ^{-W 4 = W 5 -W 6 =} W 7 - is of formula ^{(d): - CR 4 =} CR 5 -N = CR 7 - ( wherein, the R ^4, R ⁵ and R ⁷ [1 Or a prodrug thereof, or a pharmaceutically acceptable salt thereof, which represents the same as
[5] R ¹ represents a substituted or unsubstituted aralkyl group, a substituted or unsubstituted heteroaralkyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted heteroaryl group, a substituted or unsubstituted cycloalkyl group, Any one of [1] to [4], which represents an alkyl group substituted with a substituted or unsubstituted cycloalkyl group, or an alkyl group substituted with a substituted or unsubstituted saturated or unsaturated aliphatic heterocycle The described compound or a prodrug thereof, or a pharmaceutically acceptable salt thereof;
[6] R ⁸ has the formula: represents a group represented by -OR ¹¹ (wherein, R ¹¹ has the same meaning as in [1]), compound according to any one of [1] to [5] or Their prodrugs, or pharmaceutically acceptable salts thereof;
[7] The compound according to [6] or a prodrug thereof, or a pharmaceutically acceptable salt thereof, wherein R ¹¹ represents a hydrogen atom;
[8] The compound according to any one of [1] to [7] or a compound thereof, wherein R ⁹ represents an alkyl group having 1 to 6 carbon atoms substituted with 1 to 7 fluorine atoms or chlorine atoms. Prodrugs, or pharmaceutically acceptable salts thereof;
[9] The compound according to [8] or a prodrug thereof, or a pharmaceutically acceptable salt thereof, wherein R ⁹ represents a trifluoromethyl group;
[10] In the formula of R ¹⁰ : — [C (R ¹³ ) R ¹⁴ ] n—R ¹⁵ , R ¹³ and R ¹⁴ represent a hydrogen atom, n represents 1 or 2, and R ¹⁵ represents the formula: N ( R ¹⁸ ) A compound represented by any one of [1] to [9] or a prodrug thereof, which represents a group represented by R ¹⁹ (wherein R ¹⁸ and R ¹⁹ have the same meanings as [1]), Or a pharmaceutically acceptable salt thereof;
[11] The compound according to [10], wherein R ¹⁸ and R ¹⁹ are bonded to each other to represent a substituted saturated or unsaturated monocyclic or bicyclic nitrogen-containing heterocycle together with the nitrogen atom to which they are bonded. Or a prodrug thereof, or a pharmaceutically acceptable salt thereof;
[12] A glucocorticoid receptor function regulator comprising the compound according to any one of [1] to [11] or a prodrug thereof, or a pharmaceutically acceptable salt thereof as an active ingredient;
[13] A therapeutic or prophylactic agent for inflammatory diseases or diabetes comprising the compound according to any one of [1] to [11] or a prodrug thereof, or a pharmaceutically acceptable salt thereof as an active ingredient;
About.

According to the present invention, a glucocorticoid function modulator (modulator), that is, a compound having a novel condensed pyrazole skeleton, a prodrug thereof, or a pharmaceutically acceptable compound thereof, useful as a therapeutic or prophylactic agent for inflammatory diseases or diabetes. It has become possible to provide the salt to be made.

Hereinafter, the present invention will be described more specifically.
The description of each group in the present invention also applies to the case where the group is a part of another group, unless otherwise specified.
The number of substituents in the present specification is not particularly limited as long as substitution is possible, and is 1 or more, preferably 1 to 5.

  In the present specification, 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 10 carbon atoms, specifically, methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl group. , Sec-butyl group, tert-butyl group, pentyl group, isopentyl group, neopentyl group, tert-pentyl group, 1-methylbutyl group, hexyl group, heptyl group, octyl group, nonyl group, decyl group, etc. it can. Among them, preferred is an alkyl group having 1 to 6 carbon atoms.

  Examples of the “alkenyl group” include linear or branched alkenyl groups having 2 to 6 carbon atoms, specifically, vinyl group, 1-propenyl group, allyl group (2-propenyl group), Isopropenyl group (1-methylvinyl group), 1-butenyl group, 2-butenyl group, 3-butenyl group, 1-methyl-1-propenyl group, 1-methyl-2-propenyl group, 2-methylallyl group, 1 -An ethyl vinyl group, 1-pentenyl group, 1-hexenyl group, etc. can be mentioned. Among them, preferred is an alkenyl group having 2 to 4 carbon atoms.

  Examples of the “alkynyl group” include linear or branched alkynyl groups having 2 to 6 carbon atoms, and specifically include an ethynyl group, a 1-propynyl group, a 2-propynyl group, and a 1-butynyl group. 1-methyl-2-propynyl group, 2-butynyl group, 3-butynyl group, 1-pentynyl group, or 1-hexynyl group. Among them, preferred is an alkynyl group having 2 to 4 carbon atoms.

  Examples of the “cycloalkyl group” include 3- to 10-membered saturated monocyclic to tricyclic aliphatic hydrocarbon ring groups, and specifically include a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, and a cyclohexyl group. A cycloheptyl group, a cyclooctyl group, a bicyclo [3,2,1] octyl group, a bicyclo [2,2,2] octyl group, or an adamantyl group. Of these, a 4- to 6-membered saturated cycloalkyl group is preferable.

  Examples of the “cycloalkenyl group” include a 4- to 10-membered monocyclic to tricyclic aliphatic hydrocarbon group containing 1 or 2 double bonds in the ring, specifically, a cyclobutenyl group. , Cyclopentenyl group, cyclohexenyl group, cycloheptenyl group, or cyclooctenyl group, and the bonding position is not particularly limited. Among them, a 4- to 6-membered cycloalkenyl group is preferable.

  Examples of the “aryl group” include an aryl group having 6 to 10 carbon atoms, and specific examples include a phenyl group, a 1-naphthyl group, and a 2-naphthyl group.

  The “heteroaryl group” is a monocyclic 5-membered member containing 1 to 4 heteroatoms selected from 0 to 4 nitrogen atoms, 0 to 2 oxygen atoms and 0 to 2 sulfur atoms. Alternatively, a 6-membered heteroaryl group or a bicyclic 9-membered or 10-membered heteroaryl group can be mentioned, and the bonding position is not particularly limited as long as it is chemically stable. Specifically, furyl group, thienyl group, pyrrolyl group, oxazolyl group, isoxazolyl group, thiazolyl group, imidazolyl group, pyrazolyl group, furazanyl group, triazolyl group, pyridyl group, pyrimidinyl group, pyrazinyl group, tetrazolyl group, indolyl group, Examples thereof include a benzoxazolyl group, a benzisoxazolyl group, a benzothiazolyl group, a benzimidazolyl group, a quinolyl group, an isoquinolyl group, a quinazolinyl group, an imidazopyridinyl group, and a purinyl group.

  The “aralkyl group” is also referred to as an arylalkyl group, and examples of the “aralkyl group” include a linear or branched alkyl group having 1 to 6 carbon atoms substituted with an aryl group. Examples of the aryl group and the alkyl group are the same as described above. Specific examples of the aralkyl group include benzyl group (phenylmethyl group), phenethyl group (2-phenylethyl group), 3-phenylpropyl group, 2-phenyl-2-methylethyl group, 1-phenylethyl group, 1 -Naphthylmethyl, 2-naphthylmethyl, etc. can be mentioned.

  The “heteroaralkyl group” is also called a heteroarylalkyl group, and examples of the “heteroaralkyl group” include a linear or branched alkyl group having 1 to 6 carbon atoms substituted with a heteroaryl group. It is done. Examples of the heteroaryl group and the alkyl group include those described above, and the bonding position between the heteroaryl group and the alkyl group is not particularly limited as long as it is chemically stable. Specific examples of the heteroaralkyl group include 2-pyridylmethyl group, 3-pyridylmethyl group, 4-pyridylmethyl group, 2-furylmethyl (furfuryl group), 3-furylmethyl group, 2-thienylmethyl group, 3- A thienylmethyl group, a 2-pyridylethyl group, a 3-pyridylethyl group, a 4-pyridylethyl group, and the like can be given.

  Examples of the “alkoxy group” include linear or branched alkoxy groups having 1 to 10 carbon atoms, and specifically include methoxy group, ethoxy group, propoxy group, isopropoxy group, butoxy group, isobutoxy group. Group, sec-butoxy group, tert-butoxy group, pentyloxy group, isopentyloxy group, neopentyloxy group, tert-pentyloxy group, 1-methylbutoxy group, hexyloxy group, heptyloxy group, octyloxy group, Nonyloxy group, decyloxy group, etc. can be mentioned. Among them, preferred is an alkoxy group having 1 to 6 carbon atoms.

  The “alkanoyl group” is also referred to as an acyl group, and the “alkanoyl group” includes a straight-chain or branched alkanoyl group having 2 to 10 carbon atoms, specifically, an acetyl group, propionyl group, and the like. Group, butyryl group, isobutyryl group, valeryl group, isovaleryl group, pivaloyl group, hexanoyl group, heptanoyl group, octanoyl group, nonanoyl group, decanoyl group and the like. Among them, preferred is an alkanoyl group having 2 to 6 carbon atoms.

  The “alkanoyl” in the “alkanoyloxy group” has the same meaning as the “alkanoyl group”.

  Examples of the “alkoxycarbonyl group” include linear or branched alkoxycarbonyl groups having 2 to 11 carbon atoms, and specifically include methoxycarbonyl group, ethoxycarbonyl group, propoxycarbonyl group, isopropoxycarbonyl group. Group, butoxycarbonyl group, isobutoxycarbonyl group, sec-butoxycarbonyl group, tert-butoxycarbonyl group, pentyloxycarbonyl group, isopentyloxycarbonyl group, neopentyloxycarbonyl group, tert-pentyloxycarbonyl group, 1-methyl A butoxycarbonyl group, a hexyloxycarbonyl group, a heptyloxycarbonyl group, an octyloxycarbonyl group, a nonyloxycarbonyl group, a decyloxycarbonyl group, and the like can be given. Among them, preferred is an alkoxycarbonyl group having 2 to 7 carbon atoms.

  Examples of the “alkylthio group” include linear or branched alkylthio groups having 1 to 10 carbon atoms, and specifically include methylthio group, ethylthio group, propylthio group, isopropylthio group, butylthio group, isobutyl group. Thio group, sec-butylthio group, tert-butylthio group, pentylthio group, isopentylthio group, neopentylthio group, tert-pentylthio group, 1-methylbutylthio group, hexylthio group, heptylthio group, octylthio group, nonylthio group, Or a decylthio group can be mentioned. Among them, preferred is an alkylthio group having 1 to 6 carbon atoms.

  Examples of the “alkylsulfinyl group” include linear or branched alkylsulfinyl groups having 1 to 10 carbon atoms, specifically, methylsulfinyl group, ethylsulfinyl group, propylsulfinyl group, isopropylsulfinyl group. Butylsulfinyl group, isobutylsulfinyl group, sec-butylsulfinyl group, tert-butylsulfinyl group, pentylsulfinyl group, isopentylsulfinyl group, neopentylsulfinyl group, tert-pentylsulfinyl group, 1-methylbutylsulfinyl group, hexylsulfinyl group A group, heptylsulfinyl group, octylsulfinyl group, nonylsulfinyl group, or decylsulfinyl group. Among them, preferred is an alkylsulfinyl group having 1 to 6 carbon atoms.

  Examples of the “alkylsulfonyl group” include linear or branched alkylsulfonyl groups having 1 to 10 carbon atoms, specifically, methylsulfonyl group, ethylsulfonyl group, propylsulfonyl group, isopropylsulfonyl group. Butylsulfonyl group, isobutylsulfonyl group, sec-butylsulfonyl group, tert-butylsulfonyl group, pentylsulfonyl group, isopentylsulfonyl group, neopentylsulfonyl group, tert-pentylsulfonyl group, 1-methylbutylsulfonyl group, hexylsulfonyl A group, a heptylsulfonyl group, an octylsulfonyl group, a nonylsulfonyl group, or a decylsulfonyl group. Among them, preferred is an alkylsulfonyl group having 1 to 6 carbon atoms.

  “Alkylene” includes linear or branched alkylene having 1 to 10 carbon atoms, specifically, methylene, ethylene, trimethylene, 1-methylmethylene, 1-methylethylene, tetramethylene, Examples include octamethylene and decamethylene. Among them, preferred is alkylene having 1 to 6 carbon atoms.

  The “saturated aliphatic heterocyclic group” includes 1 to 4 heteroatoms selected from 0 to 4 nitrogen atoms, 0 to 2 oxygen atoms and 0 to 2 sulfur atoms. A 10-membered monocyclic or bicyclic saturated aliphatic heterocyclic group is exemplified, and the bonding position is not particularly limited as long as it is chemically stable. Specifically, azetidinyl group, pyrrolidinyl group, piperidyl group, piperidino group, piperazinyl group, azepanyl group, azocanyl group, tetrahydrofuryl group, tetrahydrothienyl group, tetrahydropyranyl group, morpholinyl group, morpholino group, thiomorpholinyl group, 1- Oxothiomorpholinyl group, 1,1-dioxothiomorpholinyl group, thiomorpholino group, 1-oxothiomorpholino group, 1,1-dioxothiomorpholino group, 1,3-dioxolanyl group, 1,4 -A dioxanyl group, a decahydroquinolino group, a decahydroquinoxalino, a 1,4-diazabicyclo [4.4.0] decano group, or a decahydroisoquinolino can be mentioned.

  The “unsaturated aliphatic heterocyclic group” includes 1 to 4 heteroatoms selected from 0 to 4 nitrogen atoms, 0 to 2 oxygen atoms and 0 to 2 sulfur atoms, Examples thereof include a 5- to 10-membered monocyclic or bicyclic unsaturated aliphatic heterocyclic group having no aromatic attribute and containing one or two double bonds, and the bonding position is not particularly limited as long as it is chemically stable. Specific examples include a 2-pyrrolinyl group, a 3-pyrrolinyl group, a 2-imidazolinyl group, a 3-imidazolinyl group, a 2-pyrazolinyl group, a 3-pyrazolinyl group, and an octahydroquinolinyl group.

  “Saturated or unsaturated aliphatic heterocyclic oxy group” means a group in which an oxygen atom is bonded to any carbon atom of the above “saturated aliphatic heterocyclic group” or “unsaturated aliphatic heterocyclic group”. Represents.

  “Saturated or unsaturated aliphatic heterocyclic carbonyl group” means a group in which a carbonyl group is bonded to any carbon atom of the above “saturated aliphatic heterocyclic group” or “unsaturated aliphatic heterocyclic group”. Represents.

“Saturated or unsaturated aliphatic heterocyclic sulfonyl group” means that sulfonyl (SO ₂ ) is present on any carbon atom of the above “saturated aliphatic heterocyclic group” or “unsaturated aliphatic heterocyclic group”. Represents a bonded group.

  “Saturated or unsaturated aliphatic heterocyclic sulfinyl group” means that sulfinyl (SO) is bonded to any carbon atom of the above “saturated aliphatic heterocyclic group” or “unsaturated aliphatic heterocyclic group”. Represents the group.

  “Saturated or unsaturated aliphatic heterocyclic thio group” means that thio (S) is bonded to any carbon atom of the above “saturated aliphatic heterocyclic group” or “unsaturated aliphatic heterocyclic group”. Represents the group.

  “Saturated or unsaturated aliphatic heterocyclic oxycarbonyl group” means a carbonyl on the oxygen atom outside the ring of the above “saturated aliphatic heterocyclic oxy group” or “unsaturated aliphatic heterocyclic oxy group”. A group to which a group is bonded is represented.

  The “aroyl group” is also referred to as an arylcarbonyl group, and the “aroyl group” includes a carbonyl group having an aryl group having 6 to 10 carbon atoms, specifically, a benzoyl group or a 1-naphthoyl group. Or a 2-naphthoyl group.

  The cycloalkyl part in the “cycloalkyloxy group”, “cycloalkylcarbonyl group”, “cycloalkyloxycarbonyl group”, “cycloalkylthio group”, “cycloalkylsulfinyl group”, and “cycloalkylsulfonyl group” is as defined above. It is.

  The cycloalkenyl moiety in the “cycloalkenyloxy group”, “cycloalkenylcarbonyl group”, “cycloalkenyloxycarbonyl group”, “cycloalkenylthio group”, “cycloalkenylsulfinyl group”, and “cycloalkenylsulfonyl group” is as defined above. It is synonymous.

  The aryl moiety in the “aryloxy group”, “aryloxycarbonyl group”, “arylthio group”, “arylsulfinyl group”, and “arylsulfonyl group” has the same meaning as described above.

  The heteroaryl moiety in the “heteroaryloxy group”, “heteroarylcarbonyl group”, “heteroaryloxycarbonyl group”, “heteroarylthio group”, “heteroarylsulfinyl group”, and “heteroarylsulfonyl group” is as defined above. It is the same.

  The aralkyl moiety in the “aralkyloxy group”, “aralkylcarbonyl group”, “aralkyloxycarbonyl group”, “aralkylthio group”, “aralkylsulfinyl group”, and “aralkylsulfonyl group” is as defined above.

The heteroaralkyl moiety in the “heteroaralkyloxy group”, “heteroaralkylcarbonyl group”, “heteroaralkyloxycarbonyl group”, “heteroaralkylthio group”, “heteroaralkylsulfinyl group”, and “heteroaralkylsulfonyl group” It is synonymous.

“Alkyl group”, “alkenyl group”, “alkynyl group”, “alkoxy group”, “alkanoyl group”, “alkoxycarbonyl group”, “alkylthio group”, “alkylsulfinyl group” or “alkylsulfonyl group” substituted In this case, the substituent is selected from the following groups (i) to (v), and 1 to 6 identical or different substituents may be substituted:
(I) halogen atom, hydroxyl group, carboxyl group, cyano group, formyl group, oxo group, sulfo group (—SO ₂ OH), phosphono group (—PO (OH) ₂ );
(Ii) a substituted or unsubstituted amino group, a substituted or unsubstituted carbamoyl group, a substituted or unsubstituted sulfamoyl group, a substituted or unsubstituted thiocarbamoyl group;
(Iii) alkoxy group, alkanoyl group, alkanoyloxy group, alkoxycarbonyl group, alkylthio group, alkylsulfinyl group, alkylsulfonyl group;
[These groups are selected from a halogen atom, a hydroxyl group, a carboxyl group, a substituted or unsubstituted amino group, a substituted or unsubstituted carbamoyl group, a substituted or unsubstituted sulfamoyl group, and a substituted or unsubstituted thiocarbamoyl group. It may be substituted with a substituent. ];
(Iv) a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted cycloalkyloxy group, a substituted or unsubstituted cycloalkylcarbonyl group, a substituted or unsubstituted cycloalkyloxycarbonyl group, a substituted or unsubstituted cycloalkylthio Group, substituted or unsubstituted cycloalkylsulfonyl group, substituted or unsubstituted cycloalkylsulfinyl group, substituted or unsubstituted cycloalkenyl group, substituted or unsubstituted saturated or unsaturated aliphatic heterocyclic group, substituted or unsubstituted A substituted saturated or unsaturated aliphatic heterocyclic oxy group, a substituted or unsubstituted saturated or unsaturated aliphatic heterocyclic sulfonyl group, a substituted or unsubstituted saturated or unsaturated aliphatic heterocyclic carbonyl group, substituted or Unsubstituted saturated or unsaturated aliphatic heterocyclic thio , Substituted or unsubstituted, saturated or unsaturated aliphatic heterocyclic sulfinyl group, a substituted or unsubstituted, saturated or unsaturated aliphatic heterocyclic oxycarbonyl group;
(V) a substituted or unsubstituted aryl group, a substituted or unsubstituted heteroaryl group, a substituted or unsubstituted aroyl group, a substituted or unsubstituted heteroarylcarbonyl group, a substituted or unsubstituted aryloxy group, substituted or unsubstituted Substituted heteroaryloxy group, substituted or unsubstituted aryloxycarbonyl group, substituted or unsubstituted heteroaryloxycarbonyl group, substituted or unsubstituted arylthio group, substituted or unsubstituted heteroarylthio group, substituted or unsubstituted Arylsulfonyl group, substituted or unsubstituted heteroarylsulfonyl group, substituted or unsubstituted arylsulfinyl group, substituted or unsubstituted heteroarylsulfinyl group, substituted or unsubstituted aralkyloxy group, substituted or unsubstituted arral Kill carbonyl group, substituted or unsubstituted aralkyloxycarbonyl group, substituted or unsubstituted aralkylthio group, substituted or unsubstituted aralkylsulfinyl group, substituted or unsubstituted aralkylsulfonyl group, substituted or unsubstituted heteroaralkyloxy group , Substituted or unsubstituted heteroaralkylcarbonyl group, substituted or unsubstituted heteroaralkyloxycarbonyl group, substituted or unsubstituted heteroaralkylthio group, substituted or unsubstituted heteroaralkylsulfinyl group, substituted or unsubstituted heteroaralkylsulfonyl Group.

“Cycloalkyl group”, “cycloalkenyl group”, “cycloalkyloxy group”, “cycloalkylcarbonyl group”, “cycloalkyloxycarbonyl group”, “cycloalkylthio group”, “cycloalkylsulfinyl group”, “cycloalkyl” “Sulfonyl group”, “saturated or unsaturated aliphatic heterocyclic group”, “saturated or unsaturated aliphatic heterocyclic oxy group”, “saturated or unsaturated aliphatic heterocyclic carbonyl group”, “saturated or unsaturated” An aliphatic heterocyclic oxycarbonyl group ”,“ saturated or unsaturated aliphatic heterocyclic sulfonyl group ”,“ saturated or unsaturated aliphatic heterocyclic sulfinyl group ”, or“ saturated or unsaturated aliphatic heterocyclic thio ” When the “group” is substituted, the substituent is selected from the following groups (vi) to (ix) One or five different substituents may be substituted:
(Vi) halogen atom, hydroxyl group, carboxyl group, cyano group, nitro group, oxo group, thioxo group, formyl group, sulfo group (—SO ₂ OH), phosphono group (—PO (OH) ₂ );
(Vii) A substituted or unsubstituted amino group, a substituted or unsubstituted carbamoyl group, a substituted or unsubstituted sulfamoyl group, a substituted or unsubstituted thiocarbamoyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted hetero group An aryl group, a substituted or unsubstituted aryloxy group, a substituted or unsubstituted heteroaryloxy group, a substituted or unsubstituted aroyl group, a substituted or unsubstituted heteroarylcarbonyl group, a substituted or unsubstituted aryloxycarbonyl group, Substituted or unsubstituted heteroaryloxycarbonyl group, substituted or unsubstituted arylthio group, substituted or unsubstituted heteroarylthio group, substituted or unsubstituted arylsulfonyl group, substituted or unsubstituted heteroarylsulfonyl group, substituted or Nothing Substituted arylsulfinyl group, substituted or unsubstituted heteroarylsulfinyl group, substituted or unsubstituted aralkyl group, substituted or unsubstituted aralkyloxy group, substituted or unsubstituted aralkylcarbonyl group, substituted or unsubstituted aralkyloxycarbonyl Group, substituted or unsubstituted aralkylthio group, aralkylsulfinyl group, substituted or unsubstituted aralkylsulfonyl group, substituted or unsubstituted heteroaralkyl group, substituted or unsubstituted heteroaralkyloxy group, substituted or unsubstituted heteroaralkyl A carbonyl group, a substituted or unsubstituted heteroaralkyloxycarbonyl group, a substituted or unsubstituted heteroaralkylthio group, a substituted or unsubstituted heteroaralkylsulfinyl group, a substituted or unsubstituted B aralkyl sulfonyl group;
(Viii) an alkyl group, an alkenyl group, an alkynyl group, an alkoxy group, an alkanoyl group, an alkanoyloxy group, an alkoxycarbonyl group, an alkylthio group, an alkylsulfinyl group, an alkylsulfonyl group [these groups are represented by the following (1) to (3 ):
(1) a halogen atom, a hydroxyl group, a carboxyl group, a formyl group, a sulfo group (—SO ₂ OH), a phosphono group (—PO (OH) ₂ ), a substituted or unsubstituted amino group, a substituted or unsubstituted carbamoyl group, A substituted or unsubstituted sulfamoyl group, a substituted or unsubstituted thiocarbamoyl group;
(2) an alkoxy group, an alkanoyl group, an alkoxycarbonyl group, an alkanoyloxy group, an alkylthio group, an alkylsulfinyl group, an alkylsulfonyl group (groups of this group are halogen atoms, hydroxyl groups, carboxyl groups, alkoxy groups, substituted or unsubstituted groups) An amino group, a substituted or unsubstituted carbamoyl group, or a substituted or unsubstituted sulfamoyl group).
(3) Cycloalkyl group, cycloalkyloxy group, cycloalkylsulfonyl group, cycloalkylcarbonyl group, cycloalkyloxycarbonyl group, cycloalkylthio group, cycloalkylsulfinyl group, cycloalkenyl group, cycloalkenyloxy group, cycloalkenylsulfonyl group , Cycloalkenylthio group, cycloalkenylcarbonyl group, cycloalkenyloxycarbonyl group, cycloalkenylsulfinyl group, saturated or unsaturated aliphatic heterocyclic group, saturated or unsaturated aliphatic heterocyclic oxy group, saturated or unsaturated Aliphatic heterocyclic sulfonyl group, saturated or unsaturated aliphatic heterocyclic thio group, saturated or unsaturated aliphatic heterocyclic carbonyl group, saturated or unsaturated aliphatic heterocyclic oxycarbonyl group, saturated or unsaturated fat Heterocycle Finyl group, aryl group, aryloxy group, arylthio group, arylsulfonyl group, aroyl group, aryloxycarbonyl group, arylsulfinyl group, heteroaryl group, heteroaryloxy group, heteroarylthio group, heteroarylsulfonyl group, heteroaryl Carbonyl group, heteroaryloxycarbonyl group, heteroarylsulfinyl group (groups of this group are halogen atom, hydroxyl group, carboxyl group, formyl group, cyano group, sulfo group (—SO ₂ OH), phosphono group (—PO (OH ) _2), a carboxyl group or an alkoxycarbonyl alkyl group which may be substituted with a group, a carboxyl group or alkoxycarbonyl alkenyl group which may be substituted with a group, an alkoxy group, an alkanoyl group, an alkoxycarbonyl group, also substituted Ku may be substituted by unsubstituted amino group, a substituted or unsubstituted carbamoyl group, or a substituted or unsubstituted sulfamoyl group)
May be substituted with the same or different 1 to 5 substituents selected from ];
(Ix) a cycloalkyl group, a cycloalkenyl group, a cycloalkoxy group, a cycloalkylcarbonyl group, a cycloalkoxycarbonyl group, a cycloalkylthio group, a cycloalkylsulfonyl group, a cycloalkylsulfinyl group, a saturated or unsaturated aliphatic heterocyclic group, Saturated or unsaturated aliphatic heterocyclic oxy group, saturated or unsaturated aliphatic heterocyclic carbonyl group, saturated or unsaturated aliphatic heterocyclic sulfonyl group, saturated or unsaturated aliphatic heterocyclic thio group, saturated or Unsaturated aliphatic heterocyclic oxycarbonyl group, saturated or unsaturated aliphatic heterocyclic sulfinyl group [These groups are the following (1) to (3):
(1) Halogen atom, hydroxyl group, carboxyl group, formyl group, cyano group, nitro group, sulfo group (—SO ₂ OH), phosphono group (—PO (OH) ₂ ), substituted or unsubstituted amino group, substituted or An unsubstituted carbamoyl group, a substituted or unsubstituted sulfamoyl group, a substituted or unsubstituted thiocarbamoyl group;
(2) an alkyl group, an alkoxy group, an alkanoyl group, an alkoxycarbonyl group, an alkanoyloxy group, an alkylthio group, an alkylsulfinyl group, an alkylsulfonyl group (groups of this group are halogen atoms, hydroxyl groups, carboxyl groups, alkoxy groups, substituted or An optionally substituted amino group, a substituted or unsubstituted carbamoyl group, or a substituted or unsubstituted sulfamoyl group);
(3) Cycloalkyl group, cycloalkyloxy group, cycloalkylsulfonyl group, cycloalkylcarbonyl group, cycloalkyloxycarbonyl group, cycloalkylthio group, cycloalkylsulfinyl group, cycloalkenyl group, saturated or unsaturated aliphatic heterocycle Group, saturated or unsaturated aliphatic heterocyclic oxy group, saturated or unsaturated aliphatic heterocyclic sulfonyl group, saturated or unsaturated aliphatic heterocyclic thio group, saturated or unsaturated aliphatic heterocyclic carbonyl group, Saturated or unsaturated aliphatic heterocyclic oxycarbonyl group, saturated or unsaturated aliphatic heterocyclic sulfinyl group, aryl group, aryloxy group, arylthio group, arylsulfonyl group, aroyl group, aryloxycarbonyl group, arylsulfinyl group , Heteroaryl group, heteroaryl Xyl group, heteroarylthio group, heteroarylsulfonyl group, heteroarylcarbonyl group, heteroaryloxycarbonyl group, heteroarylsulfinyl group, aralkyl group, aralkyloxy group, aralkylcarbonyl group, aralkyloxycarbonyl group, aralkylthio group, aralkyl Sulfinyl group, aralkylsulfonyl group, heteroaralkyl group, heteroaralkyloxy group, heteroaralkylcarbonyl group, heteroaralkyloxycarbonyl group, heteroaralkylthio group, heteroaralkylsulfinyl group, heteroaralkylsulfonyl group (the group in this group is a halogen atom) , a hydroxyl group, a carboxyl group, a formyl group, a cyano group, a sulfo group (-SO ₂ OH), a phosphono group (-PO (OH) _2), a carboxyl group or alkoxycarbonyl Alkyl group which may be substituted with, alkenyl group which may be substituted with carboxyl group or alkoxycarbonyl group, alkoxy group, alkanoyl group, alkoxycarbonyl group, substituted or unsubstituted amino group, substituted or unsubstituted carbamoyl Group or a substituted or unsubstituted sulfamoyl group)
May be substituted with the same or different 1 to 5 substituents selected from ].

“Aryl group”, “aryloxy group”, “aroyl group”, “aryloxycarbonyl group”, “arylthio group”, “arylsulfinyl group”, “arylsulfonyl group”, “heteroaryl group”, “heteroaryloxy” Group, heteroarylcarbonyl group, heteroaryloxycarbonyl group, heteroarylthio group, heteroarylsulfinyl group, heteroarylsulfonyl group, aralkyl group, aralkyloxy group, "Aralkylcarbonyl group", "Aralkyloxycarbonyl group", "Aralkylthio group", "Aralkylsulfinyl group", "Aralkylsulfonyl group", "Heteroaralkyl group", "Heteroaralkyloxy group", "Heteroaralkylcarbonyl group" , "Hetero Aralkyl Oki The substituent when the “carbonyl group”, “heteroaralkylthio group”, “heteroaralkylsulfinyl group” or “heteroaralkylsulfonyl group” is substituted is selected from the following groups (x) to (xiv) 1 to 5 of the same or different substituents may be substituted:
(X) halogen atom, hydroxyl group, carboxyl group, cyano group, nitro group, formyl group, sulfo group (—SO ₂ OH), phosphono group (—PO (OH) ₂ );
(Xi) a substituted or unsubstituted amino group, a substituted or unsubstituted carbamoyl group, a substituted or unsubstituted sulfamoyl group, a substituted or unsubstituted thiocarbamoyl group;
(Xii) an alkyl group, an alkenyl group, an alkynyl group, an alkoxy group, an alkanoyl group, an alkanoyloxy group, an alkoxycarbonyl group, an alkylthio group, an alkylsulfinyl group, an alkylsulfonyl group [these groups are represented by the following (1) to (4 ):
(1) Halogen atom, hydroxyl group, carboxyl group, formyl group, oxo group, cyano group, sulfo group (—SO ₂ OH), phosphono group (—PO (OH) ₂ );
(2) a substituted or unsubstituted amino group, a substituted or unsubstituted carbamoyl group, a substituted or unsubstituted sulfamoyl group, a substituted or unsubstituted thiocarbamoyl group;
(3) alkoxy group, alkoxycarbonyl group, alkylthio group, alkylsulfinyl group, alkylsulfonyl group
[This group is based on the following (a) or (b):
(a) a halogen atom, a hydroxyl group, a carboxyl group, an alkoxy group, a substituted or unsubstituted amino group, a substituted or unsubstituted carbamoyl group, a substituted or unsubstituted sulfamoyl group, a substituted or unsubstituted thiocarbamoyl group;
(b) Cycloalkyl group, cycloalkyloxy group, cycloalkylthio group, cycloalkylsulfinyl group, cycloalkylsulfonyl group, cycloalkenyl group, cycloalkenyloxy group, saturated or unsaturated aliphatic heterocyclic group, saturated or unsaturated Aliphatic heterocyclic oxy group, saturated or unsaturated aliphatic heterocyclic thio group, saturated or unsaturated aliphatic heterocyclic sulfinyl group, saturated or unsaturated aliphatic heterocyclic sulfonyl group, aryl group, aryloxy group An arylthio group, an arylsulfonyl group, an arylsulfinyl group, a heteroaryl group, a heteroaryloxy group, a heteroarylthio group, a heteroarylsulfonyl group, a heteroarylsulfinyl group (groups of this group include a halogen atom, a hydroxyl group, a carboxyl group, Formyl group, cyano group, sulfo (-SO ₂ OH), a phosphono group (-PO (OH) _2), an alkyl group which may be substituted with a carboxyl group, an alkenyl group which may be substituted with a carboxyl group, optionally substituted by a carboxyl group Substituted by good alkoxy group, alkanoyl group, alkoxycarbonyl group, alkylsulfonyl group optionally substituted by carboxyl group, substituted or unsubstituted amino group, substituted or unsubstituted carbamoyl group, or substituted or unsubstituted sulfamoyl group May be)
Optionally substituted with a substituent selected from:
(4) Cycloalkyl group, cycloalkyloxy group, cycloalkylthio group, cycloalkylsulfinyl group, cycloalkylsulfonyl group, cycloalkenyl group, cycloalkenyloxy group, saturated or unsaturated aliphatic heterocyclic group, saturated or unsaturated Aliphatic heterocyclic oxy group, saturated or unsaturated aliphatic heterocyclic thio group, saturated or unsaturated aliphatic heterocyclic sulfinyl group, saturated or unsaturated aliphatic heterocyclic sulfonyl group, aryl group, aryloxy group An arylthio group, an arylsulfonyl group, an arylsulfinyl group, a heteroaryl group, a heteroaryloxy group, a heteroarylthio group, a heteroarylsulfonyl group, a heteroarylsulfinyl group (groups of this group include a halogen atom, a hydroxyl group, a carboxyl group, Formyl group, cyano group, sulfo (-SO ₂ OH), a phosphono group (-PO (OH) _2), an alkyl group which may be substituted with a carboxyl group, an alkenyl group which may be substituted with a carboxyl group, an alkoxy group, an alkanoyl group, an alkoxycarbonyl A group, a substituted or unsubstituted amino group, a substituted or unsubstituted carbamoyl group, or a substituted or unsubstituted sulfamoyl group)
May be substituted with the same or different 1 to 5 substituents selected from ];
(Xiii) cycloalkyl group, cycloalkenyl group, cycloalkyloxy group, cycloalkylcarbonyl group, cycloalkylthio group, cycloalkylsulfinyl group, cycloalkylsulfonyl group, cycloalkenyl group, cycloalkenyloxy group, saturated or unsaturated fat Aromatic heterocyclic group, saturated or unsaturated aliphatic heterocyclic oxy group, saturated or unsaturated aliphatic heterocyclic carbonyl group, saturated or unsaturated aliphatic heterocyclic thio group, saturated or unsaturated aliphatic heterocyclic ring A sulfinyl group, a saturated or unsaturated aliphatic heterocyclic sulfonyl group [groups of this group are the following (1) to (3):
(1) Halogen atom, hydroxyl group, carboxyl group, formyl group, oxo group, thioxo group, sulfo group (—SO ₂ OH), phosphono group (—PO (OH) ₂ );
(2) an alkoxy group, an alkoxycarbonyl group, an alkylthio group, an alkylsulfinyl group, an alkylsulfonyl group, an amino group optionally substituted with the same or different 1 or 2 alkyl groups, and the same or different 1 or 2 alkyls A carbamoyl group which may be substituted with a group, a sulfamoyl group which may be substituted with one or two alkyl groups which are the same or different (groups in this group are a halogen atom, a hydroxyl group, a carboxyl group, an alkoxy group, an alkoxycarbonyl group) A group, an amino group optionally substituted with the same or different 1 or 2 alkyl groups, and an optionally substituted carbamoyl group optionally substituted with 1 or 2 alkyl groups);
(3) Cycloalkyl group, cycloalkyloxy group, cycloalkenyl group, cycloalkenyloxy group, saturated or unsaturated aliphatic heterocyclic group, saturated or unsaturated aliphatic heterocyclic oxy group, aryl group, aryloxy group , Arylthio group, arylsulfonyl group, heteroaryl group, heteroaryloxy group, heteroarylthio group, heteroarylsulfonyl group (groups in this group are halogen atom, hydroxyl group, carboxyl group, alkyl group, alkoxy group, the same or different An amino group which may be substituted with 1 or 2 alkyl groups, a carbamoyl group which may be substituted with the same or different 1 or 2 alkyl groups, a substituted with 1 or 2 alkyl groups which are the same or different Optionally substituted with a sulfamoyl group);
May be substituted with the same or different 1 to 5 substituents selected from ];
(Xiv) aryl group, aryloxy group, arylthio group, arylsulfonyl group, aroyl group, aryloxycarbonyl group, arylsulfinyl group, heteroaryl group, heteroaryloxy group, heteroarylthio group, heteroarylsulfonyl group, heteroaryl A carbonyl group, a heteroaryloxycarbonyl group, a heteroarylsulfinyl group [these groups are represented by the following (1) to (3):
(1) Halogen atom, hydroxyl group, carboxyl group, cyano group, nitro group, formyl group, sulfo group (—SO ₂ OH), phosphono group (—PO (OH) ₂ );
(2) an alkyl group, an alkoxy group, an alkylthio group, an alkylsulfonyl group, an alkylsulfinyl group, an alkoxycarbonyl group, an amino group which may be substituted with the same or different 1 or 2 alkyl groups, the same or different 1 or 2 A carbamoyl group which may be substituted with one alkyl group, a sulfamoyl group which may be substituted with the same or different one or two alkyl groups (groups of this group are halogen atoms, hydroxyl groups, carboxyl groups, alkoxy groups, An alkoxycarbonyl group, an amino group optionally substituted with the same or different 1 or 2 alkyl groups, an optionally substituted carbamoyl group optionally substituted with 1 or 2 alkyl groups );
(3) Cycloalkyl group, cycloalkenyl group, cycloalkenyloxy group, saturated or unsaturated aliphatic heterocyclic group, saturated or unsaturated aliphatic heterocyclic oxy group, aryl group, aryloxy group, arylthio group, aryl Sulfonyl group, heteroaryl group, heteroaryloxy group, heteroarylthio group, heteroarylsulfonyl group (groups in this group are halogen atom, hydroxyl group, carboxyl group, carbamoyl group, alkyl group, alkoxy group, alkylsulfonyl group, the same Or an amino group which may be substituted with different 1 or 2 alkyl groups, a carbamoyl group which may be substituted with the same or different 1 or 2 alkyl groups, or 1 or 2 alkyl groups which are the same or different Optionally substituted with an optionally substituted sulfamoyl group )
May be substituted with the same or different 1 to 5 substituents selected from ].

  Or, “aryl group”, “heteroaryl group”, “aralkyl group”, “heteroaralkyl group”, “aryloxy group”, “aroyl group”, “aryloxycarbonyl group”, “arylthio group”, “arylsulfinyl” Group "," arylsulfonyl group "," heteroaryloxy group "," heteroarylcarbonyl group "," heteroaryloxycarbonyl group "," heteroarylthio group "," heteroarylsulfinyl group "," heteroarylsulfonyl group " ”,“ Aralkyloxy group ”,“ aralkylcarbonyl group ”,“ aralkyloxycarbonyl group ”,“ aralkylsulfonyl group ”,“ heteroaralkyloxy group ”,“ heteroaralkylcarbonyl group ”,“ heteroaralkyloxycarbonyl group ”, or "Hetero Aralkyl Kills By bonding two adjacent substituents of group ", the following formulas (T1) ~ (T18):

〔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、以下の(1)〜(3)：
(1)ハロゲン原子、水酸基、オキソ基、カルボキシ基、同一もしくは異なる１又は２個の置換基で置換されていてもよいカルバモイル基、飽和の脂肪族ヘテロ環オキシカルボニル基；
(2)アルキル基、アルコキシカルボニル基、アルコキシ基
（この群の基は、ハロゲン原子、カルボキシル基又はアルコキシ基で置換されていてもよい）；
(3)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場合；
のいずれかを表し、Ｒ^xは水素原子またはアルキル基を表す。〕
で表わされる二価基を表していてもよい。
ここで、前記「飽和の脂肪族ヘテロ環オキシカルボニル基」における「飽和の脂肪族ヘテロ環」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または２個有する、５又は６員の飽和の脂肪族ヘテロ環が挙げられる。飽和の脂肪族ヘテロ環オキシカルボニル基として、例えばテトラヒドロフラニルオキシカルボニル基、テトラヒドロピラニルオキシカルボニル基、ジヒドロフラニルオキシカルボニル基、テトラヒドロチオピラニルオキシカルボニル基、テトラヒドロジオキソチオピラニルオキシカルボニル基、ピロリジニルオキシカルボニル基、ピペリジルオキシカルボニル基、ピペラジルオキシカルボニル基、イミダゾリジニルオキシカルボニル基、オキサゾリジニルオキシカルボニル基、又はチアゾリジニルオキシカルボニル基が挙げられる。

[In the formula, R ^T does not exist, or one or a plurality thereof exist, and each independently represents the following (1) to (3):
(1) a halogen atom, a hydroxyl group, an oxo group, a carboxy group, a carbamoyl group which may be substituted with the same or different one or two substituents, a saturated aliphatic heterocyclic oxycarbonyl group;
(2) an alkyl group, an alkoxycarbonyl group, an alkoxy group (a group in this group may be substituted with a halogen atom, a carboxyl group or an alkoxy group);
(3) When 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;
^Rx represents a hydrogen atom or an alkyl group. ]
The divalent group represented by may be represented.
Here, as the “saturated aliphatic heterocycle” in the “saturated aliphatic heterocycle oxycarbonyl group”, for example, 5 or 6-membered having 1 or 2 oxygen atom, nitrogen atom and / or sulfur atom And a saturated aliphatic heterocycle. As saturated aliphatic heterocyclic oxycarbonyl group, for example, tetrahydrofuranyloxycarbonyl group, tetrahydropyranyloxycarbonyl group, dihydrofuranyloxycarbonyl group, tetrahydrothiopyranyloxycarbonyl group, tetrahydrodioxothiopyranyloxycarbonyl group, Examples include pyrrolidinyloxycarbonyl group, piperidyloxycarbonyl group, piperazyloxycarbonyl group, imidazolidinyloxycarbonyl group, oxazolidinyloxycarbonyl group, and thiazolidinyloxycarbonyl group.

Examples of the substituent in the substituted amino group, substituted carbamoyl group, substituted thiocarbamoyl group, and substituted sulfamoyl group include the following (1) to (3):
(1) alkyl group, alkylcarbonyl group, alkoxycarbonyl group, alkylsulfonyl group, alkenyl group
[This group is based on the following (a) or (b):
(a) Halogen atom, hydroxyl group, carboxyl group, oxo group, alkoxy group, alkoxycarbonyl group, alkylthio group, alkylsulfinyl group, alkylsulfonyl group, sulfo group (—SO ₂ OH), phosphono group (—PO (OH) ₂ ), An amino group optionally substituted with the same or different 1 or 2 alkyl groups, and a carbamoyl group optionally substituted with the same or different 1 or 2 alkyl groups;
(b) a cycloalkyl group, a cycloalkyloxy group, a cycloalkylthio group, a cycloalkylsulfonyl group, a cycloalkenyl group, a cycloalkenyloxy group, a saturated or unsaturated aliphatic heterocyclic group, and a saturated or unsaturated aliphatic heterocyclic ring Oxy group, saturated or unsaturated aliphatic heterocyclic thio group, saturated or unsaturated aliphatic heterocyclic sulfonyl group, aryl group, aryloxy group, arylthio group, arylsulfonyl group, aralkyl group, heteroaryl group, heteroaryl An oxy group, a heteroarylthio group, a heteroarylsulfonyl group, a heteroaralkyl group (a group in this group is substituted with a halogen atom, a hydroxyl group, a carboxyl group, a cyano group, an alkyl group which may be substituted with a carboxyl group, or a carboxyl group) An optionally substituted alkoxy group, the same or different 1 or An amino group which may be substituted with one alkyl group, a carbamoyl group which may be substituted with the same or different 1 or 2 alkyl groups, a substituent which may be substituted with 1 or 2 alkyl groups which are the same or different May be substituted with a good sulfamoyl group)
Optionally substituted with a group selected from
(2) Aryl group, heteroaryl group, aralkyl group, heteroaralkyl group, cycloalkyl group, aroyl group, heteroarylcarbonyl group, aralkylcarbonyl group, heteroaralkylcarbonyl group, cycloalkylcarbonyl group, aryloxycarbonyl group, heteroaryl Oxycarbonyl group, aralkyloxycarbonyl group, heteroaralkyloxycarbonyl group, cycloalkyloxycarbonyl group, arylsulfonyl group, heteroarylsulfonyl group, aralkylsulfonyl group, heteroaralkylsulfonyl group, cycloalkylsulfonyl group, saturated or unsaturated fat Aromatic heterocyclic group, saturated or unsaturated aliphatic heterocyclic carbonyl group, saturated or unsaturated aliphatic heterocyclic oxycarbonyl group, saturated or unsaturated aliphatic heterocyclic sulfonyl group Group [group this group, the following (a) or (b):
(a) a halogen atom, a hydroxyl group, a carboxyl group, a cyano group, a nitro group;
(b) an alkyl group, an alkoxy group, an alkoxycarbonyl group, an alkylsulfonyl group, an amino group which may be substituted with the same or different 1 or 2 substituents, and a substituted with the same or different 1 or 2 alkyl groups A carbamoyl group which may be substituted and a sulfamoyl group which may be substituted with the same or different 1 or 2 alkyl groups (groups of this group are halogen atom, hydroxyl group, carboxyl group, alkoxy group, alkoxycarbonyl group, alkylsulfonyl group) A group, an aryl group, an amino group optionally substituted with the same or different 1 or 2 alkyl groups, or a carbamoyl group optionally substituted with the same or different 1 or 2 alkyl groups Also good)
May be substituted with the same or different 1 to 5 substituents selected from ];
(3) Two substituents are bonded to form an alkylene having 2 to 6 carbon atoms which may be substituted with a carboxy group, a hydroxyl group, an alkyl group, an alkoxy group or an alkoxycarbonyl group, Any —CH ₂ — may be replaced by a divalent group selected from —O—, —NR ²⁰ —, —SO—, —SO ₂ —, —S— and —CO—, wherein R ²⁰ is the following (a) or (b):
(a) a hydrogen atom,
(b) an alkyl group, an alkoxycarbonyl group, an alkylcarbonyl group or an alkylsulfonyl group (the group in this group is a hydroxyl group, an alkoxy group, a carboxyl group, an amino group optionally substituted with one or two different alkyl groups, And optionally substituted with the same or different carbamoyl group optionally substituted with 1 or 2 alkyl groups)
Represents];
And may be substituted with the same or different 1 or 2 substituents.

“Saturated or unsaturated monocyclic, bicyclic or tricyclic nitrogen-containing heterocycle formed by combining R ¹⁸ and R ¹⁹ together with the nitrogen atom to which they are bonded” includes substituted or unsubstituted, 0 4 to 14 membered saturated or unsaturated nitrogen-containing heterocycle containing 1 to 4 heteroatoms selected from ˜2 oxygen atoms, 0 to 2 sulfur atoms and 1 to 4 nitrogen atoms Represents. “Unsaturated nitrogen-containing heterocycle” represents a non-aromatic unsaturated nitrogen-containing heterocycle having 1 or 2 double bonds in the ring. Specifically, azetidine, pyrrolidine, piperidine, piperazine, azepan, morpholine, thiazolidine, isothiazolidine, thiomorpholine, tetrahydropyrimidine, tetrahydroquinoline, tetrahydroisoquinoline, tetrahydrothienopyridine, tetrahydrothiazolopyridine, tetrahydropyrazolopyridine, tetrahydroimidazopyrazine , Tetrahydrotriazolopyrazine, tetrahydropyrazolopyrazine, dihydropyrrolopyrimidine, dihydropyrrolopyridazine, dihydropyrrolopyridine, tetrahydropyrrolopyridine, tetrahydrofuropyridine, tetrahydroimidazopyridine, tetrahydrooxazolopyridine, tetrahydroisothiazolopyridine, tetrahydroisoxazolopyridine Tetrahydroimidazopi Midine, Tetrahydrotriazolopyrimidine, Tetrahydropyrazolopyrimidine, Tetrahydronaphthylidine, Tetrahydropyridopyrimidine, Tetrahydropyridopyrazine, Tetrahydropyridopyridazine, Tetrahydroimidazodiazepine, Tetrahydrotriazolodiazepine, Tetrahydropyrazodiazepine, Tetrahydrotriazolo Diazepine, Tetrahydrothienoazepine, Hexahydropyrroloazepine, Tetrahydrofloorzepine, Tetrahydrothiazoloazepine, Hexahydroimidazoazepine, Tetrahydrooxazoazepine, Tetrahydroisothiazoloazepine, Hexahydropyrazoloazepine, Tetrahydroisoxazoloazepine, Hexahydro Triazoloazepine, dihydroimidazoimidazole, dihydro Midazotriazole, dihydroimidazopyrazole, dihydroimidazotriazole, dihydrothienopyrrole, tetrahydropyrrolopyrrole, dihydrofuropyrrole, dihydropyrrolothiazole, tetrahydropyrroloimidazole, dihydropyrrolooxazole, dihydropyrroloisothiazole, tetrahydropyrrolopyrazole, dihydropyrroloisoxazole, Examples thereof include tetrahydropyrrolotriazole, isoindoline, azabicyclohexane, azabicyclooctane, azabicycloheptane, azabicyclononane, and tetrahydrocarboline. Further, such a nitrogen-containing heterocyclic group may form a spiro ring together with an aryl group or a saturated or unsaturated aliphatic heterocyclic group condensed with a heteroaryl group. Specifically, the nitrogen-containing heterocyclic group may have the formula (S1) To (S7):

等を挙げることができる。
「Ｒ¹⁸およびＲ¹⁹が結合して、それらが結合する窒素原子と共に形成する、飽和もしくは不飽和の単環、二環もしくは三環の含窒素ヘテロ環」が置換されている場合の置換基としては、上述の「飽和もしくは不飽和の脂肪族ヘテロ環基」が置換されている場合の置換基と同じものが挙げられ、同一もしくは異なる置換基が１〜５個置換していてもよい。置換基の結合位置は特に限定は無く、化学的に安定であれば炭素原子上又は窒素原子と結合している。：
当該置換基が炭素原子に結合している場合、好ましくは以下の(1)〜(4)のいずれかに記載の置換基が挙げられる：
（1）ハロゲン原子、水酸基、カルボキシル基、シアノ基、ニトロ基；
（2）アルキル基、アルケニル基、アルキニル基、アルコキシ基、アルカノイル基、アルカノイルオキシ基、アルコキシカルボニル基、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、同一もしくは異なる１又は２個のアルキル基で置換されていてもよいアミノ基、同一もしくは異なる１又は２個のアルキル基で置換されていてもよいカルバモイル基、同一もしくは異なる１又は２個のアルキル基で置換されていてもよいスルファモイル基
（この群の基は、ハロゲン原子、水酸基、カルボキシル基、
アルコキシ基、アルコキシカルボニル基、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、同一もしくは異なる１又は２個のアルキル基で置換されていてもよいアミノ基、同一もしくは異なる１又は２個のアルキル基で置換されていてもよいカルバモイル基、及び同一もしくは異なる１又は２個のアルキル基で置換されていてもよいスルファモイル基より選択される基で置換されていてもよい）；
(3)置換もしくは無置換のアリール基、置換もしくは無置換のアラルキル基、置換もしくは無置換のアリールオキシ基、置換もしくは無置換のアロイル基、置換もしくは無置換のアリールチオ基、置換もしくは無置換のアリールスルフィニル基、置換もしくは無置換のアリールスルホニル基、置換もしくは無置換のヘテロアリール基、置換もしくは無置換のヘテロアラルキル基、置換もしくは無置換のヘテロアリールオキシ基、置換もしくは無置換のヘテロアリールカルボニル基、置換もしくは無置換のヘテロアリールチオ基、置換もしくは無置換のヘテロアリールスルフィニル基、置換もしくは無置換のヘテロアリールスルホニル基；
(4)シクロアルキルオキシ基、シクロアルキルオキシカルボニル基、シクロアルキルチオ基、シクロアルキルスルフィニル基、シクロアルキルスルホニル基、飽和もしくは不飽和の脂肪族ヘテロ環基、飽和もしくは不飽和の脂肪族ヘテロ環オキシ基、飽和もしくは不飽和の脂肪族ヘテロ環オキシカルボニル基、飽和もしくは不飽和の脂肪族ヘテロ環チオ基、飽和もしくは不飽和の脂肪族ヘテロ環スルフィニル基、飽和もしくは不飽和の脂肪族ヘテロ環スルホニル基
（この群の基は、ハロゲン原子、水酸基、カルボキシル基、ホルミル基、シアノ基、スルホ基（−SO₂OH）、ホスホノ基（−PO(OH)₂）、カルボキシル基もしくはアルコキシカルボニル基で置換されていてもよいアルキル基、カルボキシル基もしくはアルコキシカルボニル基で置換されていてもよいアルケニル基、アルコキシ基、アルカノイル基、アルコキシカルボニル基、置換もしくは無置換のアミノ基、置換もしくは無置換のカルバモイル基、又は置換もしくは無置換のスルファモイル基で置換されていてもよい）。
当該置換基が窒素原子に結合している場合、当該置換基としては、以下の(5)又は(6)に記載の置換基が挙げられる。
(5)アルキル基、アルコキシカルボニル基、アルキルカルボニル基又はアルキルスルホニル基及び同一もしくは異なる１又は２のアルキル基で置換されていてもよいカルバモイル基
（この群の基は、水酸基、アルコキシ基、カルボキシル基、同一もしくは異なる１又は２個のアルキル基で置換されていてもよいアミノ基、及び同一もしくは異なる１又は２個のアルキル基で置換されていてもよいカルバモイル基から選択される置換基で置換されていてもよい）；
(6)前記(3)及び(4)に記載の任意の基。

Etc.
As a substituent when “saturated or unsaturated monocyclic, bicyclic or tricyclic nitrogen-containing heterocycle formed by combining R ¹⁸ and R ¹⁹ with the nitrogen atom to which they are bonded” is substituted Includes the same substituents as those in the case where the above-mentioned “saturated or unsaturated aliphatic heterocyclic group” is substituted, and 1 to 5 of the same or different substituents may be substituted. The bonding position of the substituent is not particularly limited, and is bonded to a carbon atom or a nitrogen atom as long as it is chemically stable. :
In the case where the substituent is bonded to a carbon atom, the substituent described in any of the following (1) to (4) is preferable:
(1) halogen atom, hydroxyl group, carboxyl group, cyano group, nitro group;
(2) Alkyl group, alkenyl group, alkynyl group, alkoxy group, alkanoyl group, alkanoyloxy group, alkoxycarbonyl group, alkylthio group, alkylsulfinyl group, alkylsulfonyl group, substituted with the same or different 1 or 2 alkyl groups An optionally substituted amino group, a carbamoyl group optionally substituted with the same or different 1 or 2 alkyl groups, a sulfamoyl group optionally substituted with the same or different 1 or 2 alkyl groups (of this group The group is a halogen atom, a hydroxyl group, a carboxyl group,
Alkoxy group, alkoxycarbonyl group, alkylthio group, alkylsulfinyl group, alkylsulfonyl group, amino group optionally substituted by the same or different 1 or 2 alkyl groups, substituted by the same or different 1 or 2 alkyl groups An optionally substituted carbamoyl group, and a group selected from the same or different sulfamoyl groups optionally substituted with one or two alkyl groups);
(3) Substituted or unsubstituted aryl group, substituted or unsubstituted aralkyl group, substituted or unsubstituted aryloxy group, substituted or unsubstituted aroyl group, substituted or unsubstituted arylthio group, substituted or unsubstituted aryl A sulfinyl group, a substituted or unsubstituted arylsulfonyl group, a substituted or unsubstituted heteroaryl group, a substituted or unsubstituted heteroaralkyl group, a substituted or unsubstituted heteroaryloxy group, a substituted or unsubstituted heteroarylcarbonyl group, A substituted or unsubstituted heteroarylthio group, a substituted or unsubstituted heteroarylsulfinyl group, a substituted or unsubstituted heteroarylsulfonyl group;
(4) Cycloalkyloxy group, cycloalkyloxycarbonyl group, cycloalkylthio group, cycloalkylsulfinyl group, cycloalkylsulfonyl group, saturated or unsaturated aliphatic heterocyclic group, saturated or unsaturated aliphatic heterocyclic oxy group Saturated or unsaturated aliphatic heterocyclic oxycarbonyl group, saturated or unsaturated aliphatic heterocyclic thio group, saturated or unsaturated aliphatic heterocyclic sulfinyl group, saturated or unsaturated aliphatic heterocyclic sulfonyl group ( Groups in this group are substituted with halogen atoms, hydroxyl groups, carboxyl groups, formyl groups, cyano groups, sulfo groups (—SO ₂ OH), phosphono groups (—PO (OH) ₂ ), carboxyl groups or alkoxycarbonyl groups. Optionally substituted with an alkyl group, carboxyl group or alkoxycarbonyl group Optionally substituted alkenyl group, alkoxy group, alkanoyl group, alkoxycarbonyl group, substituted or unsubstituted amino group, substituted or unsubstituted carbamoyl group, or substituted or unsubstituted sulfamoyl group).
When the substituent is bonded to a nitrogen atom, examples of the substituent include the substituents described in the following (5) or (6).
(5) an alkyl group, an alkoxycarbonyl group, an alkylcarbonyl group or an alkylsulfonyl group and a carbamoyl group which may be substituted with the same or different 1 or 2 alkyl groups (the groups in this group are a hydroxyl group, an alkoxy group, a carboxyl group) Substituted with a substituent selected from an amino group optionally substituted with the same or different 1 or 2 alkyl groups, and a carbamoyl group optionally substituted with the same or different 1 or 2 alkyl groups May be);
(6) The arbitrary group as described in the above (3) and (4).

In the formula (1), the 5-membered ring Cy with R ¹ is represented by the formula (2):

で表される環、又は式（３）：

Or a ring represented by formula (3):

で表される環を表す。すなわち、式（１）の化合物としては、式（１−Ｃｙ２）：

Represents a ring represented by That is, as a compound of Formula (1), Formula (1-Cy2):

で表される化合物、又は式（１−Ｃｙ３）：

Or a compound represented by the formula (1-Cy3):

が挙げられる。Ｒ¹を伴う５員環Ｃｙとして好ましくは、式（２）：

Is mentioned. As the 5-membered ring Cy with R ¹ , preferably the formula (2):

で表される環が挙げられ、すなわち、式（１）の化合物の好ましい態様として、式（１−Ｃｙ２）：

In other words, as a preferable embodiment of the compound of the formula (1), a ring represented by the formula (1-Cy2):

で表される化合物を挙げることができる。

The compound represented by these can be mentioned.

R ^{1 in} formula (1) is preferably a substituted or unsubstituted aryl group, a substituted or unsubstituted heteroaryl group, a substituted or unsubstituted aralkyl group, a substituted or unsubstituted heteroaralkyl group, a substituted or unsubstituted group Examples include a cycloalkyl group, a substituted or unsubstituted cycloalkenyl group, an alkyl group substituted with a substituted or unsubstituted cycloalkyl group, and an alkyl group substituted with a substituted or unsubstituted cycloalkenyl group. A substituted benzyl group, an alkyl group of carbon chain 1 substituted with a substituted or unsubstituted cycloalkyl group, that is, a methyl group substituted with a substituted or unsubstituted cycloalkyl group is particularly preferred. In addition, the substituted aryl group, the substituted heteroaryl group, the substituted aralkyl group, the substituted heteroaralkyl group, the substituted cycloalkyl group, the substituted cycloalkenyl group, the alkyl group substituted with the substituted cycloalkyl group, and the substituted cycloalkenyl group are substituted. Preferred examples of the substituent for the alkyl group include a halogen atom, an alkyl group, and an alkoxy group.

In the formula ^{(1), -W 4 = W} 5 -W 6 = W 7 - as preferably, formula ^{(a): - CR 4 =} CR 5 -CR 6 = CR 7 - ( wherein, R ^4, R ⁵ , R ⁶ and R ⁷ are independently the same or different and each represents a group represented by the formula: -EA, and formula (d): -CR ⁴ = CR ⁵ -N = CR ⁷ -(In formula, R < ⁴ >, R < ⁵ > and R < ⁷ > are respectively independently the same or different and represent group | formula: -EA).
In the formula: -EA, E represents the following formulas 1) to 14):
1) -C (R ¹⁶ ) R ^17- ,
2) -O-,
3) -S (= O) m-,
4) -S (= O) ₂ NR ^16- ,
5) -C (= O)-,
6) -C (= O) O-,
7) -C (= O) NR ^16- ,
8) −C (= NR ¹⁶ ) NR ¹⁷ −,
9) -NR ^16- ,
^{10) -N (R 16) C} (= O) -,
11) -N (R ¹⁶ ) S (= O) _2- ,
^{12) -N (R 16) C} (= O) N (R 17) -,
^{13) -N (R 16) S} (= O) 2 N (R 17) -,
14) -P (= O) (OR ¹⁶ ) _2-
(Wherein, R ¹⁶ and R ¹⁷ are each independently either hydrogen atom, or a number of carbon atoms represents 1-3 alkyl group, or Formula 8), 12) in and 13), and R ¹⁶ R ¹⁷ may be bonded to represent an alkylene group having 2 to 4 carbon atoms. m represents 0, 1, or 2. )
Is bonded to the right side of the divalent group represented by formulas 1) to 14).
In this specification, when a divalent group is a different compound depending on in which direction it is bonded, it means that it is bonded in the direction represented by the structural formula unless otherwise specified.
In the formulas 1), 4) and 7) to 14), the “alkyl group having 1 to 3 carbon atoms” in R ¹⁶ and R ¹⁷ is a linear or branched carbon group having 1 to 3 carbon atoms. Represents an alkyl group, and specifically includes a methyl group, an ethyl group, a propyl group, or an isopropyl group.
In the formulas 8), 12) and 13), when R ¹⁶ and R ¹⁷ are bonded to represent an alkylene group having 2 to 4 carbon atoms, the divalent groups in formulas 8), 12) and 13) are Specifically, formulas (R1) to (R9):

を挙げることができる。

Can be mentioned.

^{-W 4 = W 5 -W 6 =} W 7 - in the formula ^{(a): - CR 4 =} CR 5 -CR 6 = CR 7 - as preferably a group represented by the formula: -CH = CH-C ( -E-A) = CH- groups represented by and among them the formula: -CH = CH-C (NO 2) = CH-, or formula: -CH = CH-C (CN ) = CH- in The groups represented are particularly preferred. The group represented by the formula (d): -CR ⁴ = CR ⁵ -N = CR ⁷ -in -W ⁴ = W ⁵ -W ⁶ = W ⁷ -is preferably the formula: -CH = CR ^5-. A group represented by N═CR ⁷ — may be mentioned. That is, as a preferable embodiment of the compound of the formula (1), the formula (1-Cy2-a), the formula (1-Cy2-b), or the formula (1-Cy2-c):

で表される化合物を挙げることができる。式（１−Ｃｙ２−ｃ）において、Ｒ⁵及びＲ⁷としては、各々独立して同一又は異なってハロゲン原子が特に好ましい。

The compound represented by these can be mentioned. In the formula (1-Cy2-c), R ⁵ and R ⁷ are independently the same or different and a halogen atom is particularly preferable.

In the formula (1), R ⁸ is preferably a group represented by the formula: —OR ¹¹ , and among them, a hydroxyl group is particularly preferable.
The “alkyl group having 1 to 5 carbon atoms” in R ¹¹ and R ¹² represents a linear or branched alkyl group having 1 to 5 carbon atoms, specifically, methyl group, ethyl A group, a propyl group, an isopropyl group, a butyl group, or a pentyl group. Examples of the substituent for the alkyl group include a halogen atom, a hydroxyl group, and an alkoxy group having 1 to 3 carbon atoms.

As the “alkyl group having 1 to 6 carbon atoms substituted with one or more halogen atoms” in R ^9, linear or branched carbon substituted with 1 to 7 identical or different halogen atoms An alkyl group having 1 to 6 atoms (specifically, methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl group, sec-butyl group, tert-butyl group, pentyl group, isopentyl group, neopentyl group) , Tert-pentyl group, 1-methylbutyl group, or hexyl group). Preferred examples of the halogen atom include a fluorine atom or a chlorine atom.
The “cycloalkyl group having 3 to 6 carbon atoms substituted with one or more halogen atoms” in R ⁹ is a 3 to 6-membered saturated cyclohexane substituted with 1 to 5 identical or different halogen atoms. An alkyl group (specifically, a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, or a cyclohexyl group can be given). The halogen atom is preferably a fluorine atom or a chlorine atom.
R ⁹ is preferably an alkyl group having 1 to 3 carbon atoms substituted with 1 to 5 identical or different halogen atoms, and particularly preferably a trifluoromethyl group.

Examples of the “alkyl group” for R ¹³ and R ¹⁴ include linear or branched alkyl groups having 1 to 3 carbon atoms. Specific examples include a methyl group, an ethyl group, a propyl group, and an isopropyl group.
Examples of the cycloalkane formed by combining R ¹³ and R ¹⁴ together with the carbon atom to which they are bonded include 3- to 7-membered cycloalkane, specifically cyclopropane, cyclobutane, cyclopentane, cyclohexane or cycloheptane. Is mentioned. Preferably, cyclobutane, cyclopentane or cyclohexane is used.
In the formula (1), R ¹⁰ is preferably represented by the formula: — [C (R ¹³ ) R ¹⁴ ] n—R ¹⁵ , preferably an integer of 1 to 6, particularly preferably an integer of 1 or 2.
The formula:-[C (R ¹³ ) R ¹⁴ ] n-R ¹⁵ in R ¹⁰ in formula (1) is preferably formula: -CH ₂ -R ¹⁵ , formula:-(CH ₂ ) ₂ -R ¹⁵ , The formula: — (CH ₂ ) ₃ —R ¹⁵ , the formula: —CH ₂ C (═O) —R ¹⁵ , or the formula: —C (═O) —R ¹⁵ can be mentioned, among which the formula: —CH ₂ —R ¹⁵ is particularly preferred.
R ¹⁵ is preferably a substituted or unsubstituted alkenyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted heteroaryl group, a substituted or unsubstituted saturated or unsaturated aliphatic heterocyclic group, substituted or unsubstituted Substituted alkylthio group, substituted or unsubstituted alkylsulfonyl group, substituted or unsubstituted arylthio group, substituted or unsubstituted heteroarylthio group, substituted or unsubstituted saturated or unsaturated aliphatic heterocyclic thio group, substituted Or an unsubstituted arylsulfonyl group, a substituted or unsubstituted heteroarylsulfonyl group, a substituted or unsubstituted saturated or unsaturated aliphatic heterocyclic sulfonyl group, or a group represented by the formula: N (R ¹⁸ ) R ¹⁹ Is mentioned. Among these, a substituted or unsubstituted heteroaryl group or a group represented by the formula: N (R ¹⁸ ) R ¹⁹ is particularly preferable.
Preferably the R ¹⁸ and R ^19, bonded R ¹⁸ and R ¹⁹ is a monocyclic saturated or unsaturated and they are replaced with the nitrogen atom to which they are attached or which forms a nitrogen-containing heterocycle of the bicyclic Among them, the formula: N (R ¹⁸ ) R ¹⁹ substituted piperidino group, substituted tetrahydroquinolinyl group, substituted tetrahydroisoquinolinyl group, substituted tetrahydrothienopyridyl group Particularly preferred is the group, a substituted tetrahydrothiazolopyridyl group, a substituted tetrahydropyrazolopyridyl group, a substituted piperazinyl group, or a substituted tetrahydroimidazopyrazinyl group. The tetrahydrothienopyridyl group is more preferably a tetrahydrothieno [3,2-c] pyridyl group, and the tetrahydrothiazolopyridyl group is more preferably a tetrahydro [1,3] thiazolo [5,4-c] pyridyl group. As the pyrazolopyridyl group, a 4,5,6,7-tetrahydro-2H-pyrazolo [4,3-c] pyridyl group is more preferable. The substituent is preferably a substituted or unsubstituted aryl group, a substituted or unsubstituted aralkyl group, a substituted or unsubstituted aryloxy group, a substituted or unsubstituted aroyl group, a substituted or unsubstituted arylthio group, substituted or Unsubstituted arylsulfinyl group, substituted or unsubstituted arylsulfonyl group, substituted or unsubstituted heteroaryl group, substituted or unsubstituted heteroaralkyl group, substituted or unsubstituted heteroaryloxy group, substituted or unsubstituted heteroaryl Arylcarbonyl group, substituted or unsubstituted heteroarylthio group, substituted or unsubstituted heteroarylsulfinyl group, substituted or unsubstituted heteroarylsulfonyl group, substituted or unsubstituted cycloalkyloxy group, substituted or unsubstituted cycloaryl Alkyloxycarbonyl group, substituted or unsubstituted cycloalkylthio group, substituted or unsubstituted cycloalkylsulfinyl group, substituted or unsubstituted cycloalkylsulfonyl group, substituted or unsubstituted saturated or unsaturated aliphatic heterocyclic group, Substituted or unsubstituted saturated or unsaturated aliphatic heterocyclic oxy group, substituted or unsubstituted saturated or unsaturated aliphatic heterocyclic oxycarbonyl group, substituted or unsubstituted saturated or unsaturated aliphatic heterocyclic thio Group, a substituted or unsubstituted saturated or unsaturated aliphatic heterocyclic sulfinyl group, and a substituted or unsubstituted saturated or unsaturated aliphatic heterocyclic sulfonyl group.

The compound of the present invention represented by the formula (1) is appropriately combined from known compounds by the method shown in the following production method 1-11, a method similar to the following production method, or a synthesis method well known to those skilled in the art. Can be manufactured. In this specification, the following abbreviations may be used for simplification of description.
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: tert-butyl group Ph: phenyl group Bn: benzyl group Ms: methanesulfonyl group TFA: trifluoroacetic acid Alloc: allyloxycarbonyl Base

[Production Method 1]
Among the compounds represented by the formula (1), the compound represented by the formula (1-11) or a salt thereof is produced, for example, by the method shown below.

[式中、Ｒ¹を伴う５員環Ｃｙ、Ｒ¹、−Ｗ⁴＝Ｗ⁵−Ｗ⁶＝Ｗ⁷−、Ｒ⁹、及びＲ¹⁵は、前記と同義である。Ｍ¹は、ヘテロ元素（好ましくは、アルカリ金属、アルカリ土類金属、典型金属、珪素原子等）を表す。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、ｐ−トルエンスルホニルオキシ等）を表す。]
１）工程１
化合物（１−２）は、酸性溶媒中、公知または公知の合成法により得られる化合物（１−１）を亜硝酸ナトリウム等と反応させることにより製造することができる（例えば、J. Med. Chem. 2001, 44, 1021-1024、またはJ. Med. Chem. 1990, 33, 1781-1790 等を参照）。亜硝酸ナトリウムの使用量としては、化合物（１−１）に対して通常１〜５０当量の範囲から選択される。酸性溶媒としては、塩酸、硫酸、硝酸、臭酸等が挙げられ、好適には、塩酸が挙げられる。更にこれら酸性溶媒は、Ｎ，Ｎ−ジメチルホルムアミド、ジメチルスルホキシド、ジエチルエーテル、テトラヒドロフラン、アセトン等との混合溶媒として用いることもできる。反応温度としては、約−２０℃〜約５０℃の範囲から選択することができる。
２）工程２
化合物（１−４）は、工程１で得られた化合物（１−２）と化合物（１−３）を、不活性溶媒中、塩基と反応させることにより製造される。化合物（１−３）の使用量としては、化合物（１−２）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、エーテル系溶媒（テトラヒドロフラン、ジエチルエーテル、１，２−ジメトキシエタン、１，４−ジオキサン等）、非プロトン性極性溶媒（Ｎ，Ｎ−ジメチルホルムアミド、Ｎ，Ｎ−ジメチルアセトアミド、ジメチルスルホキシド、アセトニトリル等）、ケトン類（アセトン等）、またはこれらの混合溶媒等が挙げられる。
塩基としては、例えば、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、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、水素化カリウム等）、水酸化アルカリ(水酸化カリウム、水酸化ナトリウム等)、アルカリアルコキシド（ナトリウムエトキシド、ナトリウムtert-ブトキシド、カリウムtert-ブトキシド等）、有機塩基（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、ピリジン等）が挙げられ、好適には、炭酸カリウム、カリウムtert-ブトキシド、トリエチルアミン等が挙げられる。塩基の使用量としては、化合物（１−２）に対して通常１〜５当量の範囲から選択される。反応温度としては、約−７８℃〜約１５０℃の範囲から選択することができる。
３）工程３
化合物（１−６）は、不活性溶媒中、塩基の存在下または非存在下に、工程２で得られた化合物（１−４）を化合物（１−５）と反応させることにより製造することができる（例えば、Tetrahedron. 56, 7613 (2000)、またはChemistry Letters. 34, 88(2005) 等参照）。化合物（１−５）の使用量としては、化合物（１−４）に対して通常１〜１０当量の範囲から選択される。塩基としては、例えばフッ化物(フッ化カリウム、フッ化ナトリウム、フッ化セシウム、テトラブチルアンモニウム フロリド等)、酢酸アルカリ（酢酸リチウム、酢酸ナトリウム、酢酸カリウム等）等が挙げられ、好適には、酢酸リチウム等が挙げられる。塩基の使用量としては、化合物（１−４）に対して通常０．１〜３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、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、１，４−ジオキサン等)、ハロゲン化炭化水素類（ジクロロメタン、クロロホルム、１，２−ジクロロエタン、クロロベンゼン等）、炭化水素類（トルエン、ベンゼン等）、またはこれらの混合溶媒等が挙げられ、好適には、ジメチルスルホキシド、テトラヒドロフランが挙げられる。反応温度としては、約−７８℃〜約１５０℃の範囲から選択することができる。
４）工程４
化合物（１−７）は、不活性溶媒中、工程３で得られた化合物（１−６）を酸化反応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、ハロゲン系溶媒（ジクロロメタン、ジクロロエタン、クロロホルム）、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、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、ジクロロメタン等が挙げられる。反応温度としては、約−７８℃〜約１８０℃の範囲から選択することができる。酸化反応としては、ｓｗｅｒｎ酸化、Ｄｅｓｓ−Ｍａｒｔｉｎ酸化、クロム酸酸化、活性二酸化マンガン酸化が望ましく、文献（例えばComprehensive Organic transformation, R. C. ラロック著, VCH publisher Inc., 1989、実験化学講座（日本化学会編、丸善等参照）記載の方法に従って行うことができる。
５）工程５
化合物（１−８）は、不活性溶媒中、塩基の存在下、工程４で得られた化合物（１−７）とトリメチルスルホニウム ヨージドもしくはトリメチルスルフォキソニウム ヨージド等と反応させることにより製造することができる（例えば、Bull. Chem. Soc. Jpn., 68, 3591 (1995)、またはJ. Am. Chem. Soc. 86, 1899 (1964) 等を参照）。トリメチルスルホニウム ヨージドもしくはトリメチルスルフォキソニウム ヨージドの使用量としては、化合物（１−7）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、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、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、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（１−7）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、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、1,4-ジオキサン等)、ハロゲン化炭化水素類（ジクロロメタン、クロロホルム、１，２−ジクロロエタン、クロロベンゼン等）、ケトン(アセトン等)、炭化水素類（トルエン、ベンゼン等）、またはこれらの混合溶媒が挙げられ、更にはこれらの不活性溶媒と水との混合溶媒も挙げられ、好適には、ジメチルスルホキシド、またはジクロロメタン−水混合溶媒等が挙げられる。反応温度としては、約−７８℃〜約５０℃の範囲から選択することができる。
６）工程６
化合物（１−１１）は、不活性溶媒中、工程５で得られた化合物（１−８）と化合物（１−１０）をルイス酸、ルイス塩基もしくは塩基いずれか一方の存在下または非存在下に反応させることにより製造することができる。
工程６の反応が炭素−ヘテロ原子（酸素原子、硫黄原子もしくは窒素原子）結合形成反応である場合、すなわち化合物（１−１０）がアルコール類、フェノール類、チオール類、チオフェノール類、アミン類またはアニリン類である場合には、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、ピコリン等）、または炭酸アルカリ(炭酸カリウム、炭酸ナトリウム、炭酸水素カリウム、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、水素化カリウム等）もしくは水酸化アルカリ(水酸化カリウムまたは水酸化ナトリウム等)等の無機塩基が挙げられ、好適には、トリエチルアミン、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、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、１,４−ジオキサン等)、アルコール系溶媒(エタノール、メタノール、２−プロパノール、ヘキサフルオロ２−プロパノール等)、またはこれらの混合溶媒等が挙げられ、好適には、２−プロパノール等が挙げられる。反応温度としては、約−７８℃〜約１８０℃の範囲から選択することができる。
工程６の反応が炭素−炭素結合形成反応の場合には、通常は化合物（１−１０）を不活性溶媒中で塩基と反応させた後に、化合物（１−８）との縮合反応を行う。塩基としては、アルカリ金属、有機銅試薬等が望ましく、文献（例えばComprehensive Organic transformation, R. C. ラロック著, VCH publisher Inc., 1989、実験化学講座（日本化学会編、丸善等参照）等）記載の方法により調製することができる。
７）工程７
化合物（１−９）は、不活性溶媒中、工程４で得られた化合物（１−７）から製造することができる。例えばWittig反応、Tebbe反応もしくはPetersonオレフィン化反応等の反応を、文献（例えばComprehensive Organic transformation, R. C. ラロック著, VCH publisher Inc., 1989等参照）記載の方法で行うことにより、製造することができる。好ましくはWittig反応が挙げられ、塩基としては、強塩基が好ましく、例えば、水素化アルカリ（水素化ナトリウム、水素化カリウム等）、アルカリアルコキシド（ナトリウムエトキシド、ナトリウムtert-ブトキシド、カリウムtert-ブトキシド等）、アルカリ金属（ｎ−ブチルリチウム、メチルリチウム、イソプロピルマグネシウムブロミド等）が挙げられ、好適には、カリウムtert-ブトキシド、ｎ−ブチルリチウム等が挙げられる。塩基の使用量としては、メチルトリフェニルホスホニウム ブロミド等のホスホニウムハライドに対して、通常１当量〜３等量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、１,４−ジオキサン等)、非プロトン性溶媒(Ｎ，Ｎ−ジメチルホルムアミド、Ｎ，Ｎ−ジメチルアセトアミド)、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−７８℃〜約１００℃の範囲から選択される。
８）工程８
化合物（１−８）は、溶媒中、工程７で得られた化合物（１−９）を、文献（例えばJ. Am. Chem. Soc., 112, 2801 (1990)、J. Am. Chem. Soc., 119, 6189 (1997)、J. Am. Chem. Soc., 122, 3220 (2000)、J. Am. Chem. Soc., 123, 2933 (2001)等参照）記載の方法に従いエポキシ化することで、製造することができる。

Wherein 5-membered ring Cy with ^{R 1, R 1, -W 4} = W 5 -W 6 = W 7 -, R 9, and R ¹⁵ are as defined above. M ¹ represents a hetero element (preferably an alkali metal, an alkaline earth metal, a typical metal, a silicon atom, or the like). X represents a leaving group (for example, iodine atom, bromine atom, chlorine atom, methanesulfonyloxy, trifluoromethanesulfonyloxy, p-toluenesulfonyloxy, etc.). ]
1) Step 1
Compound (1-2) can be produced by reacting compound (1-1) obtained by a known or known synthesis method with sodium nitrite or the like in an acidic solvent (for example, J. Med. Chem). 2001, 44, 1021-1024, or J. Med. Chem. 1990, 33, 1781-1790 etc.). The amount of sodium nitrite used is usually selected from the range of 1 to 50 equivalents relative to compound (1-1). Examples of the acidic solvent include hydrochloric acid, sulfuric acid, nitric acid, odorous acid and the like, and preferably hydrochloric acid. Furthermore, these acidic solvents can also be used as a mixed solvent with N, N-dimethylformamide, dimethyl sulfoxide, diethyl ether, tetrahydrofuran, acetone or the like. The reaction temperature can be selected from the range of about -20 ° C to about 50 ° C.
2) Step 2
Compound (1-4) is produced by reacting compound (1-2) obtained in step 1 and compound (1-3) with a base in an inert solvent. The amount of compound (1-3) to be used is generally selected from the range of 1 equivalent to excess with respect to compound (1-2). Examples of the inert solvent include ether solvents (tetrahydrofuran, diethyl ether, 1,2-dimethoxyethane, 1,4-dioxane, etc.), aprotic polar solvents (N, N-dimethylformamide, N, N-dimethyl). Acetamide, dimethyl sulfoxide, acetonitrile, etc.), ketones (acetone, etc.), or a mixed solvent thereof.
Examples of the base include alkali carbonates (cesium carbonate, potassium carbonate, sodium carbonate, potassium hydrogen carbonate, sodium hydrogen carbonate, etc.), alkali hydrides (sodium hydride, potassium hydride, etc.), alkali hydroxides (potassium hydroxide, Sodium hydroxide, alkali alkoxide (sodium ethoxide, sodium tert-butoxide, potassium tert-butoxide, etc.), organic base (N-methylmorpholine, triethylamine, diisopropylethylamine, tributylamine, 1,8-diazabicyclo [5.4 0.0] undec-7-ene, 1,5-diazabicyclo [4.3.0] non-5-ene, 1,4-diazabicyclo [5.4.0] undec-7-ene, pyridine, etc.) Preferable examples include potassium carbonate, potassium tert-butoxide, triethylamine and the like. The usage-amount of a base is normally selected from the range of 1-5 equivalent with respect to a compound (1-2). The reaction temperature can be selected from the range of about −78 ° C. to about 150 ° C.
3) Step 3
Compound (1-6) is produced by reacting compound (1-4) obtained in Step 2 with compound (1-5) in an inert solvent in the presence or absence of a base. (See, for example, Tetrahedron. 56, 7613 (2000) or Chemistry Letters. 34, 88 (2005)). The amount of compound (1-5) to be used is generally selected from the range of 1 to 10 equivalents relative to compound (1-4). Examples of the base include fluorides (potassium fluoride, sodium fluoride, cesium fluoride, tetrabutylammonium fluoride, etc.), alkali acetates (lithium acetate, sodium acetate, potassium acetate, etc.), and preferably acetic acid. Lithium etc. are mentioned. The amount of the base used is usually selected from the range of 0.1 to 3 equivalents relative to the compound (1-4). Examples of the inert solvent include aprotic solvents (N, N-dimethylformamide, dimethyl sulfoxide, etc.), ether solvents (diethyl ether, tetrahydrofuran, 1,4-dioxane, etc.), halogenated hydrocarbons (dichloromethane, chloroform, 1,2-dichloroethane, chlorobenzene, etc.), hydrocarbons (toluene, benzene, etc.), or a mixed solvent thereof, preferably dimethyl sulfoxide, tetrahydrofuran. The reaction temperature can be selected from the range of about −78 ° C. to about 150 ° C.
4) Step 4
Compound (1-7) can be produced by subjecting compound (1-6) obtained in Step 3 to an oxidation reaction in an inert solvent. Examples of the inert solvent include halogen solvents (dichloromethane, dichloroethane, chloroform), N, N-dimethylformamide, ether solvents (diethyl ether, tetrahydrofuran, 1,4-dioxane, etc.), or mixed solvents thereof. Preferable examples include dichloromethane and the like. The reaction temperature can be selected from the range of about -78 ° C to about 180 ° C. As the oxidation reaction, swern oxidation, des-martin oxidation, chromic acid oxidation, and active manganese dioxide oxidation are desirable, and literature (for example, Comprehensive Organic transformation, RC Laroc, VCH publisher Inc., 1989, Experimental Chemistry Course (edited by the Chemical Society of Japan) , See Maruzen et al.).
5) Step 5
Compound (1-8) is produced by reacting Compound (1-7) obtained in Step 4 with trimethylsulfonium iodide or trimethylsulfoxonium iodide in the presence of a base in an inert solvent. (See, for example, Bull. Chem. Soc. Jpn., 68, 3591 (1995), or J. Am. Chem. Soc. 86, 1899 (1964), etc.). The amount of trimethylsulfonium iodide or trimethylsulfoxonium iodide to be used is usually selected from the range of 1 to 5 equivalents relative to compound (1-7). Examples of the base include alkali carbonate (potassium carbonate, sodium carbonate, potassium bicarbonate, sodium bicarbonate, 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 the base used is usually selected from the range of 1 to 3 equivalents relative to the compound (1-7). Examples of the inert solvent include aprotic solvents (N, N-dimethylformamide, dimethyl sulfoxide, etc.), ether solvents (diethyl ether, tetrahydrofuran, 1,4-dioxane, etc.), halogenated hydrocarbons (dichloromethane, chloroform, 1,2-dichloroethane, chlorobenzene, etc.), ketones (acetone, etc.), hydrocarbons (toluene, benzene, etc.), or a mixed solvent thereof, and also a mixed solvent of these inert solvent and water. Preferably, dimethyl sulfoxide, a dichloromethane-water mixed solvent, or the like is used. The reaction temperature can be selected from the range of about −78 ° C. to about 50 ° C.
6) Step 6
Compound (1-11) is compounded with Compound (1-8) and Compound (1-10) obtained in Step 5 in an inert solvent in the presence or absence of either Lewis acid, Lewis base or base. It can manufacture by making it react.
When the reaction in Step 6 is a carbon-heteroatom (oxygen atom, sulfur atom or nitrogen atom) bond formation reaction, that is, the compound (1-10) is an alcohol, phenol, thiol, thiophenol, amine or In the case of anilines, examples of the base include organic bases (1-hydroxybenztriazole, N-methylmorpholine, triethylamine, diisopropylethylamine, tributylamine, 1,8-diazabicyclo [5.4.0] undeca- 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 alkali carbonate (potassium carbonate, sodium carbonate, potassium bicarbonate, sodium bicarbonate, etc.), alkali hydride ( Sodium hydride, inorganic bases can be mentioned, such as potassium hydride, etc.) or an alkali hydroxide (potassium hydroxide or sodium hydroxide, etc.), preferably, triethylamine, potassium carbonate, and the like. The amount of base used is usually selected from the range of 1 to 3 equivalents relative to compound (1-10). Examples of the inert solvent include N, N-dimethylformamide, ether solvents (diethyl ether, tetrahydrofuran, 1,4-dioxane, etc.), alcohol solvents (ethanol, methanol, 2-propanol, hexafluoro-2-propanol, etc.), Or these mixed solvents etc. are mentioned, 2-propanol etc. are mentioned suitably. The reaction temperature can be selected from the range of about -78 ° C to about 180 ° C.
When the reaction in Step 6 is a carbon-carbon bond forming reaction, the compound (1-10) is usually reacted with a base in an inert solvent and then subjected to a condensation reaction with the compound (1-8). The base is preferably an alkali metal, an organic copper reagent or the like, and the method described in the literature (for example, Comprehensive Organic transformation, RC Larroque, VCH publisher Inc., 1989, Experimental Chemistry Course (edited by the Chemical Society of Japan, Maruzen, etc.)) Can be prepared.
7) Step 7
Compound (1-9) can be produced from compound (1-7) obtained in Step 4 in an inert solvent. For example, it can be produced by carrying out a reaction such as Wittig reaction, Tebbe reaction or Peterson olefination reaction by the method described in the literature (for example, see Comprehensive Organic transformation, RC Laroc, VCH publisher Inc., 1989). Preferably, a Wittig reaction is used, and the base is preferably a strong base. For example, an alkali hydride (sodium hydride, potassium hydride, etc.), an alkali alkoxide (sodium ethoxide, sodium tert-butoxide, potassium tert-butoxide, etc.) ) And alkali metals (n-butyllithium, methyllithium, isopropylmagnesium bromide, etc.), preferably potassium tert-butoxide, n-butyllithium and the like. The amount of the base used is usually selected from the range of 1 equivalent to 3 equivalents with respect to the phosphonium halide such as methyltriphenylphosphonium bromide. Examples of the inert solvent include ether solvents (diethyl ether, tetrahydrofuran, 1,4-dioxane, etc.), aprotic solvents (N, N-dimethylformamide, N, N-dimethylacetamide), or a mixed solvent thereof. Etc. The reaction temperature is selected from the range of about -78 ° C to about 100 ° C.
8) Step 8
Compound (1-8) is compound (1-9) obtained in Step 7 in a solvent in the literature (for example, J. Am. Chem. Soc., 112, 2801 (1990), J. Am. Chem. Soc., 119, 6189 (1997), J. Am. Chem. Soc., 122, 3220 (2000), J. Am. Chem. Soc., 123, 2933 (2001), etc.) By doing so, it can be manufactured.

[Production method 2]
Among the compounds represented by formula (1), the compound represented by formula (1-11) or formula (2-8) or a salt thereof is produced, for example, by the method shown below.

[式中、Ｒ¹を伴う５員環Ｃｙ、Ｒ¹、−Ｗ⁴＝Ｗ⁵−Ｗ⁶＝Ｗ⁷−、Ｒ⁹、Ｒ¹⁵、及びＸは、前記と同義である。Ｐrot¹及びProt²は、水酸基の保護基（Protective Groups in Organic Synthesis 3rd Edition (John Wiley & Sons, Inc.等参照)又はＲ¹¹を表す。]
１）工程１
化合物（２−１）は、製造法１の工程７で得られた化合物（１−９）を原料に用い、溶媒中、酸化剤の存在下、四酸化オスミウム等と反応させることにより製造することができる（例えば、J. Org. Chem. 56, 4585 (1991)、Tetrahedron: Asymmetry. 14, 503 (2003) 等参照）。
２）工程２
化合物（２−２）は、不活性溶媒中、塩基の存在下、工程１で得られた化合物（２−１）を反応させることにより製造することができる。例えば、文献（Protective Groups in Organic Synthesis 3rd Edition (John Wiley & Sons, Inc.) 、Tetrahedron: Asymmetry. 14, 503 (2003) 等）記載の方法により製造することができる。
３）工程３
文献（Protective Groups in Organic Synthesis 3rd Edition (John Wiley & Sons, Inc.) 、Tetrahedron: Asymmetry. 14, 503 (2003) 等）に記載されている方法等と同様の方法によって、工程２で得られた化合物（２−２）から化合物（２−３）を製造することができる。この際用いる保護基は、工程２で用いた保護基とは異なる方法で脱保護可能な保護基を適宜選択することができる。
４）工程４
文献（Protective Groups in Organic Synthesis 3rd Edition (John Wiley & Sons, Inc.)）に記載されている方法等によって一級水酸基の保護基（Prot¹）のみを選択的に脱保護することで、工程３で得られた化合物（２−３）から化合物（２−４）を製造することができる。
５）工程５
文献（例えばComprehensive Organic transformation, R. C. ラロック著, VCH publisher Inc., 1989等参照）に記載されている方法等によって、工程４で得られた化合物（２−４）から化合物（２−５）を製造することができる。
６）工程６
ステップ１）の縮合反応は、製造法１記載の工程６と同様の方法によって行われる。得られる化合物の水酸基の保護基を文献（Protective Groups in Organic Synthesis 3rd Edition (John Wiley & Sons, Inc.)に記載されている方法等によって、ステップ２）の脱保護を行うことにより、化合物（１−１１）を得ることができる。
７）工程７
文献（例えばComprehensive Organic transformation, R. C. ラロック著, VCH publisher Inc., 1989、Tetrahedron Lett., 40, 7879 (1999)等参照）に記載されている方法等と同様の方法によって、化合物（２−９）から化合物（１−８）を製造することができる。
８）工程８
文献（例えばTetrahedron: Asymmetry. 14, 503 (2003)、Tetrahedron Lett., 40, 7879 (1999)等参照）に記載されている方法等と同様の方法によって、工程４で得られた化合物（２−４）から化合物（２−６）を製造することができる。
９）工程９
文献（例えばComprehensive Organic transformation, R. C. ラロック著, VCH publisher Inc., 1989等参照）に記載されている方法等と同様の方法によって、工程８で得られた化合物（２−６）から化合物（２−７）を製造することができる。
１０）工程１０
文献（Protective Groups in Organic Synthesis 3rd Edition (John Wiley & Sons, Inc.)に記載されている方法等と同様の方法によって、工程９で得られた化合物（２−７）から化合物（２−８）を製造することができる。
１１）工程１１
工程５と同様の方法によって行われる。
１２）工程１２
文献（例えばTetrahedron. 52, 12761 (1996), Synthesis. 11, 1584 (1998), Synthesis. 1, 45 (2003), Comprehensive Organic transformation, R. C. ラロック著, VCH publisher Inc., 1989等参照）に記載されている方法等と同様の方法によって、製造法１の工程７で得られた化合物（１−９）から化合物（２−９）を製造することができる。
１３）工程１３
製造法１記載の工程６と同様の方法によって行われる。

Wherein 5-membered ring Cy with ^{R 1, R 1, -W 4} = W 5 -W 6 = W 7 -, R 9, R 15, and X have the same meanings as defined above. Prot ¹ and Prot ² represent a protecting group for a hydroxyl group (Protective Groups in Organic Synthesis 3rd Edition (see John Wiley & Sons, Inc., etc.) or R ¹¹ ]
1) Step 1
Compound (2-1) is produced by using compound (1-9) obtained in Step 7 of Production Method 1 as a raw material and reacting with osmium tetroxide or the like in a solvent in the presence of an oxidizing agent. (See, for example, J. Org. Chem. 56, 4585 (1991), Tetrahedron: Asymmetry. 14, 503 (2003), etc.).
2) Step 2
Compound (2-2) can be produced by reacting compound (2-1) obtained in Step 1 in the presence of a base in an inert solvent. For example, it can be produced by the method described in literature (Protective Groups in Organic Synthesis 3rd Edition (John Wiley & Sons, Inc.), Tetrahedron: Asymmetry. 14, 503 (2003), etc.).
3) Step 3
It was obtained in Step 2 by a method similar to that described in the literature (Protective Groups in Organic Synthesis 3rd Edition (John Wiley & Sons, Inc.), Tetrahedron: Asymmetry. 14, 503 (2003), etc.) Compound (2-3) can be produced from compound (2-2). As the protective group used in this case, a protective group that can be deprotected by a method different from the protective group used in Step 2 can be appropriately selected.
4) Step 4
By selectively deprotecting only the primary hydroxyl protecting group (Prot ¹ ) by the method described in the literature (Protective Groups in Organic Synthesis 3rd Edition (John Wiley & Sons, Inc.)) A compound (2-4) can be manufactured from the obtained compound (2-3).
5) Step 5
The compound (2-5) is produced from the compound (2-4) obtained in step 4 by the method described in the literature (for example, see Comprehensive Organic transformation, RC Larro, VCH publisher Inc., 1989). can do.
6) Step 6
The condensation reaction in Step 1) is performed by the same method as in Step 6 described in Production Method 1. By deprotecting the protecting group of the hydroxyl group of the obtained compound by the method described in the literature (Protective Groups in Organic Synthesis 3rd Edition (John Wiley & Sons, Inc.)), the compound (1 -11) can be obtained.
7) Step 7
Compound (2-9) by a method similar to the method described in the literature (for example, Comprehensive Organic transformation, RC Larro, VCH publisher Inc., 1989, Tetrahedron Lett., 40, 7879 (1999)). From this, the compound (1-8) can be produced.
8) Step 8
The compound obtained in Step 4 by the method similar to the method described in the literature (for example, Tetrahedron: Asymmetry. 14, 503 (2003), Tetrahedron Lett., 40, 7879 (1999) etc.) (2- The compound (2-6) can be produced from 4).
9) Step 9
The compound (2-6) obtained in Step 8 is converted into the compound (2-) by a method similar to the method described in the literature (for example, see Comprehensive Organic transformation, RC Larro, VCH publisher Inc., 1989). 7) can be manufactured.
10) Step 10
From the compound (2-7) obtained in Step 9 to the compound (2-8) by a method similar to the method described in the literature (Protective Groups in Organic Synthesis 3rd Edition (John Wiley & Sons, Inc.)) Can be manufactured.
11) Step 11
The same method as in step 5 is performed.
12) Step 12
(See, for example, Tetrahedron. 52, 12761 (1996), Synthesis. 11, 1584 (1998), Synthesis. 1, 45 (2003), Comprehensive Organic transformation, RC Larock, VCH publisher Inc., 1989, etc.) Compound (2-9) can be produced from compound (1-9) obtained in Step 7 of Production Method 1 by the same method as described above.
13) Step 13
This is carried out by the same method as in Step 6 described in Production Method 1.

Production method 3
Among the compounds represented by the formula (1), the compound represented by the formula (3-4) or a salt thereof is produced, for example, by the method shown below.

[式中、Ｒ¹を伴う５員環Ｃｙ、Ｒ¹、−Ｗ⁴＝Ｗ⁵−Ｗ⁶＝Ｗ⁷−、Ｒ⁹、Ｒ¹⁰、及びＭ¹は、前記と同義である。]
１）工程１
化合物（１−２）を原料に用い、製造法１記載の工程２と同様の方法によって行われる。
２）工程２
製造法１記載の工程３と同様の方法によって行われる。
３）工程３
製造法１記載の工程４と同様の方法によって行われる。
４）工程４
製造法１記載の工程３と同様の方法によって行われる。
５）工程５
製造法１記載の工程３と同様の方法によって行われる。
６）工程６
製造法１記載の工程２と同様の方法によって行われる。

Wherein 5-membered ring Cy with ^{R 1, R 1, -W 4} = W 5 -W 6 = W 7 -, R 9, R 10, and M ¹ are as defined above. ]
1) Step 1
The reaction is performed in the same manner as in step 2 described in production method 1, using compound (1-2) as a raw material.
2) Step 2
This is carried out by the same method as in step 3 described in production method 1.
3) Step 3
This is carried out by the same method as in Step 4 described in Production Method 1.
4) Step 4
This is carried out by the same method as in step 3 described in production method 1.
5) Step 5
This is carried out by the same method as in step 3 described in production method 1.
6) Step 6
This is carried out by the same method as in step 2 described in production method 1.

Manufacturing method 4
Among the compounds represented by the formula (1), the compound represented by the formula (4-3) or a salt thereof is produced, for example, by the method shown below.

[式中、Ｒ¹を伴う５員環Ｃｙ、Ｒ¹、−Ｗ⁴＝Ｗ⁵−Ｗ⁶＝Ｗ⁷−、Ｒ⁹、Ｒ¹³、Ｒ¹⁴、Ｒ¹⁵Ｘは、前記と同義である。Ｍ²は、金属元素（好ましくは、アルカリ金属、アルカリ土類金属、典型金属等）を表す。]
１）工程１
化合物（４−１）は、溶媒中、製造法１の工程４で得られた化合物（１−７）と化合物（４−４）とを反応させることにより製造することができる（例えば、実験化学講座（日本化学会編、丸善）、Tetrahedron Lett., 40, 9333 (1999)等参照）。化合物（４−４）の使用量としては、化合物（１−７）に対して通常１〜１０当量の範囲から選択される。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、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、１,４−ジオキサン等)、ハロゲン化炭化水素類（ジクロロメタン、クロロホルム、１，２−ジクロロエタン、クロロベンゼン等）、炭化水素類（トルエン、ベンゼン等）、またはこれらの混合溶媒、もしくはこれらと水との混合溶媒等が挙げられ、好適には、エーテル系溶媒が挙げられる。反応温度としては、約−７８℃〜約１５０℃の範囲から選択することができる。
２）工程２
化合物（４−２）は、溶媒中、工程１で得られた化合物（４−１）と化合物（４−５）を触媒存在下、ヘック反応を用いて縮合させることにより製造することができる（例えば、Palladium Reagents and Catalysts, Jiro Tsuji著, John Wiley & Sons Ltd, 2004、J. Am. Chem. Soc. 123, 6989 (2001) 等参照）。尚、化合物（４−５）におけるＲ¹⁵としては、アリール基、ヘテロアリール基が望ましい。
３）工程３
文献（例えばComprehensive Organic transformation, R. C. ラロック著, VCH publisher Inc., 1989等参照）に記載されている方法等と同様の方法によって、工程２で得られた化合物（４−２）の還元反応を行うことにより、化合物（４−３）を製造することができる。

Wherein 5-membered ring Cy with ^{R 1, R 1, -W 4} = W 5 -W 6 = W 7 -, R 9, R 13, R 14, R 15 X has the same meaning as defined above. M ² represents a metal element (preferably an alkali metal, an alkaline earth metal, a typical metal, or the like). ]
1) Step 1
Compound (4-1) can be produced by reacting compound (1-7) obtained in Step 4 of Production Method 1 with compound (4-4) in a solvent (for example, experimental chemistry). Lecture (Chemical Society of Japan, Maruzen), Tetrahedron Lett., 40, 9333 (1999) etc.). The amount of compound (4-4) to be used is generally selected from the range of 1 to 10 equivalents relative to compound (1-7). Examples of the solvent include aprotic solvents (N, N-dimethylformamide, dimethyl sulfoxide, etc.), ether solvents (diethyl ether, tetrahydrofuran, 1,4-dioxane, etc.), halogenated hydrocarbons (dichloromethane, chloroform, 1, 2-dichloroethane, chlorobenzene, etc.), hydrocarbons (toluene, benzene, etc.), a mixed solvent thereof, a mixed solvent of these with water, and the like, and preferably an ether solvent. The reaction temperature can be selected from the range of about −78 ° C. to about 150 ° C.
2) Step 2
Compound (4-2) can be produced by condensing Compound (4-1) obtained in Step 1 and Compound (4-5) in a solvent using a Heck reaction in the presence of a catalyst ( For example, see Palladium Reagents and Catalysts, Jiro Tsuji, John Wiley & Sons Ltd, 2004, J. Am. Chem. Soc. 123, 6989 (2001)). In addition, as R < ¹⁵ > in a compound (4-5), an aryl group and heteroaryl group are desirable.
3) Step 3
The reduction reaction of the compound (4-2) obtained in step 2 is carried out by a method similar to the method described in the literature (for example, see Comprehensive Organic transformation, RC Larroc, VCH publisher Inc., 1989). Thus, compound (4-3) can be produced.

Manufacturing method 5
Among the compounds represented by the formula (1), the compound represented by the formula (5-1) or a salt thereof is produced, for example, by the method shown below.

[式中、Ｒ¹を伴う５員環Ｃｙ、Ｒ¹、−Ｗ⁴＝Ｗ⁵−Ｗ⁶＝Ｗ⁷−、Ｒ⁹、Ｒ¹³、Ｒ¹⁴、及びＲ¹⁵は、前記と同義である。]
１）工程１
化合物（５−１）は、溶媒中、製造法１の工程４で得られた化合物（１−７）と化合物（５−２）をアルドール反応させることにより製造することができる（例えば、Modern aldol reactions, Rainer Mahrwald著, John Wiley & Sons linc., 2004、Tetrahedron. 58, 8269 (2002)等参照）。

Wherein 5-membered ring Cy with ^{R 1, R 1, -W 4} = W 5 -W 6 = W 7 -, R 9, R 13, R 14, and R ¹⁵ are as defined above. ]
1) Step 1
Compound (5-1) can be produced by subjecting compound (1-7) obtained in Step 4 of Production Method 1 and compound (5-2) to an aldol reaction in a solvent (for example, Modern aldol reactions, Rainer Mahrwald, John Wiley & Sons linc., 2004, Tetrahedron. 58, 8269 (2002)).

Manufacturing method 6
Among the compounds represented by the formula (1), the compound (6-2), the compound (6-3) or a salt thereof is produced, for example, by the method shown below.

[式中、Ｒ¹を伴う５員環Ｃｙ、Ｒ¹、−Ｗ⁴＝Ｗ⁵−Ｗ⁶＝Ｗ⁷−、Ｒ⁹、及びＲ¹⁰は、前記と同義である。Ｒ^11h及びＲ^12hは、各々独立して、置換もしくは無置換の炭素原子数が１〜５のアルキル基を表す]
１）工程１
文献（例えばSynth Commun. 24, 2419 (1999)、Tetrahedron Lett., 28, 6513 (1987)等参照）に記載されている方法等と同様の方法によって、製造法３の工程４で得られた化合物（３−４）から化合物（６−１）を製造することができる。
２）工程２
文献（Protective Groups in Organic Synthesis 3rd Edition (John Wiley & Sons, Inc.)に記載されている方法等と同様な方法によって、工程１で得られた化合物（６−１）とアミン類とを反応させることによって、化合物（６−２）を製造することができる。
３）工程３
文献（Protective Groups in Organic Synthesis 3rd Edition (John Wiley & Sons, Inc.)； Comprehensive Organic transformation, R. C. ラロック著, VCH publisher Inc., 1989) に記載されている方法等によって、工程２で得られた化合物（６−２）のアミノ基のアルキル化化合物（６−３）を製造することができる。

Wherein 5-membered ring Cy with ^{R 1, R 1, -W 4} = W 5 -W 6 = W 7 -, R 9, and R ¹⁰ are as defined above. R ^11h and R ^12h each independently represents a substituted or unsubstituted alkyl group having 1 to 5 carbon atoms.
1) Step 1
Compound obtained in Step 4 of Production Method 3 by a method similar to that described in the literature (for example, see Synth Commun. 24, 2419 (1999), Tetrahedron Lett., 28, 6513 (1987), etc.) Compound (6-1) can be produced from (3-4).
2) Step 2
The compound (6-1) obtained in Step 1 is reacted with amines by a method similar to that described in the literature (Protective Groups in Organic Synthesis 3rd Edition (John Wiley & Sons, Inc.)). Thus, compound (6-2) can be produced.
3) Step 3
Compound obtained in Step 2 by the method described in the literature (Protective Groups in Organic Synthesis 3rd Edition (John Wiley & Sons, Inc.); Comprehensive Organic transformation, RC Larroque, VCH publisher Inc., 1989) The alkylated compound (6-3) of the amino group of (6-2) can be produced.

Manufacturing method 7
Among the compounds represented by the formula (1), the compound represented by the compound (7-4), the compound (7-5), the compound (7-6) or a salt thereof is, for example, by the method shown below. Manufactured.

[式中、Ｒ¹を伴う５員環Ｃｙ、Ｒ¹、−Ｗ⁴＝Ｗ⁵−Ｗ⁶＝Ｗ⁷−、Ｒ⁹、Ｒ¹¹、Ｒ¹²、及びＲ¹⁵は、前記と同義である。Ｐrotは、アミノ基の保護基（Protective Groups in Organic Synthesis 3rd Edition (John Wiley & Sons, Inc.)）もしくはＲ¹¹をあらわす。]
１）工程１
文献（例えばJ. Org. Chem. 43, 4271 (1978)、Tetrahedron: Asymmetry. 8, 903 (1997)、J. Heterocycl. Chem. 28, 473 (1991)等参照）に記載されている方法等と同様な方法によって、製造法１の工程５もしくは工程８で得られた化合物（１−８）から化合物（７−１）を製造することができる。
２）工程２
文献（例えばTetrahedron. 51, 11515 (1995)、Synthesis. 15, 2254 (2002)等参照）に記載されている方法等と同様の方法によって、工程１で得られた化合物（７−１）から化合物（７−２）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等参照）に記載されている方法等と同様な方法によって、工程２で得られた化合物（７−２）から化合物（７−３）を製造することができる。
４）工程４
文献（Protective Groups in Organic Synthesis 3rd Edition (John Wiley & Sons, Inc.)に記載されている方法等と同様な方法によって、工程３で得られた化合物（７−３）から化合物（７−４）を製造することができる。
５）工程５
文献（例えばComprehensive Organic transformation, R. C. ラロック著, VCH publisher Inc., 1989等参照）に記載されている方法等と同様な方法によって、工程４で得られた化合物（７−４）から化合物（７−５）を製造することができる。
６）工程６
文献（Protective Groups in Organic Synthesis 3rd Edition (John Wiley & Sons, Inc.)に記載されている方法等と同様な方法によって、工程２で得られた化合物（７−２）の脱保護をおこなうことにより化合物（７−６）を製造することができる。

Wherein 5-membered ring Cy with ^{R 1, R 1, -W 4} = W 5 -W 6 = W 7 -, R 9, R 11, R 12, and R ¹⁵ are as defined above. Prot represents protecting group of amino group (Protective Groups in Organic Synthesis 3rd Edition (John Wiley & Sons, Inc.)) or R ¹¹ . ]
1) Step 1
Methods described in literature (for example, see J. Org. Chem. 43, 4271 (1978), Tetrahedron: Asymmetry. 8, 903 (1997), J. Heterocycl. Chem. 28, 473 (1991), etc.) By a similar method, compound (7-1) can be produced from compound (1-8) obtained in step 5 or step 8 of production method 1.
2) Step 2
Compound from compound (7-1) obtained in step 1 by a method similar to that described in the literature (for example, see Tetrahedron. 51, 11515 (1995), Synthesis. 15, 2254 (2002), etc.) (7-2) can be manufactured.
3) Step 3
The compound (7-2) from the compound (7-2) obtained in Step 2 was prepared by a method similar to that described in the literature (for example, see Comprehensive Organic transformation, RC Larro, VCH publisher Inc., 1989). 3) can be manufactured.
4) Step 4
From the compound (7-3) obtained in Step 3 to the compound (7-4) by a method similar to the method described in the literature (Protective Groups in Organic Synthesis 3rd Edition (John Wiley & Sons, Inc.)) Can be manufactured.
5) Step 5
From the compound (7-4) obtained in step 4 to the compound (7-) by a method similar to the method described in the literature (for example, see Comprehensive Organic transformation, RC Larro, VCH publisher Inc., 1989). 5) can be manufactured.
6) Step 6
By deprotecting the compound (7-2) obtained in Step 2 by a method similar to that described in the literature (Protective Groups in Organic Synthesis 3rd Edition (John Wiley & Sons, Inc.)) Compound (7-6) can be produced.

Manufacturing method 8
Among the compounds represented by the formula (1), the compound represented by the compound (8-2) or the compound (8-4) or a salt thereof is produced, for example, by the method shown below.

[式中、Ｒ¹を伴う５員環Ｃｙ、Ｒ¹、−Ｗ⁴＝Ｗ⁵−Ｗ⁶＝Ｗ⁷−、Ｒ⁹、Ｒ¹³、Ｒ¹⁴、Ｒ¹⁸、及びＲ¹⁹は、前記と同義である。]
１）工程１
文献（例えばComprehensive Organic transformation, R. C. ラロック著, VCH publisher Inc., 1989等参照）に記載されている方法等と同様の方法によって、製造法４の工程１で得られた化合物（４−１）から化合物（８−１）を製造することができる。好ましくは、オゾン分解を用いる方法が挙げられる。
２）工程２
文献（例えばJ. Org. Chem. 61, 3849 (1996)等参照）に記載されている方法等と同様の方法によって、工程１で得られた化合物（８−１）とアミン化合物（８−５）との還元的アミノ化を行うことにより、化合物（８−２）を製造することができる。
３）工程３
文献（例えばJ. Am. Chem. Soc. 119, 12386 (1997)、Tetrahedron Lett., 40, 7879 (1999) 等参照等参照）に記載されている方法等と同様の方法によって、工程１で得られた化合物（８−１）から化合物（８−３）を製造することができる。
４）工程４
文献（例えばComprehensive Organic transformation, R. C. ラロック著, VCH publisher Inc., 1989等参照）に記載されている方法等と同様の方法によって、工程３で得られた化合物（８−３）から化合物（８−４）を製造することができる。

Wherein 5-membered ring Cy with ^{R 1, R 1, -W 4} = W 5 -W 6 = W 7 -, R 9, R 13, R 14, R 18, and R ¹⁹ are as defined above It is. ]
1) Step 1
From the compound (4-1) obtained in Step 1 of Production Method 4 by a method similar to that described in the literature (for example, see Comprehensive Organic transformation, RC Larro, VCH publisher Inc., 1989). Compound (8-1) can be produced. Preferably, a method using ozonolysis is used.
2) Step 2
The compound (8-1) obtained in Step 1 and the amine compound (8-5) by a method similar to the method described in the literature (for example, see J. Org. Chem. 61, 3849 (1996), etc.) Compound (8-2) can be produced by performing reductive amination with
3) Step 3
Obtained in step 1 by a method similar to that described in the literature (see, for example, J. Am. Chem. Soc. 119, 12386 (1997), Tetrahedron Lett., 40, 7879 (1999), etc.). The compound (8-3) can be produced from the obtained compound (8-1).
4) Step 4
From the compound (8-3) obtained in Step 3 by the same method as described in the literature (for example, see Comprehensive Organic transformation, RC Larro, VCH publisher Inc., 1989), the compound (8- 4) can be manufactured.

Manufacturing method 9
Among the compounds represented by the formula (1), the compound represented by the compound (9-3) or a salt thereof is produced, for example, by the method shown below.

［式中、Ｒ¹を伴う５員環Ｃｙ、Ｒ¹、−Ｗ⁴＝Ｗ⁵−Ｗ⁶＝Ｗ⁷−、Ｒ⁹、Ｒ¹³、Ｒ¹⁴、Ｒ¹⁵、及びＸは、前記と同義である。］
１）工程１
文献（例えばComprehensive Organic transformation, R. C. ラロック著, VCH publisher Inc., 1989等参照）に記載されている方法等と同様な方法によって、製造法８の工程１で得られた化合物（８−１）を還元することにより、化合物（９−１）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等参照）に記載されている方法等と同様な方法によって、工程１で得られた化合物（９−１）から化合物（９−２）を製造することができる。
３）工程３
文献（例えばComprehensive Organic transformation, R. C. ラロック著, VCH publisher Inc., 1989等参照）に記載されている方法等と同様な方法によって、工程２で得られた化合物（９−２）から化合物（９−３）を製造することができる。

Wherein 5-membered ring Cy with ^{R 1, R 1, -W 4} = W 5 -W 6 = W 7 -, R 9, R 13, R 14, R 15, and X is a as defined above is there. ]
1) Step 1
The compound (8-1) obtained in Step 1 of Production Method 8 was prepared by a method similar to that described in the literature (for example, see Comprehensive Organic transformation, RC Larroc, VCH publisher Inc., 1989). The compound (9-1) can be produced by reduction.
2) Step 2
The compound (9-1) is obtained from the compound (9-1) obtained in step 1 by a method similar to the method described in the literature (for example, see Comprehensive Organic transformation, RC Larro, VCH publisher Inc., 1989). 2) can be produced.
3) Step 3
By a method similar to the method described in the literature (for example, Comprehensive Organic transformation, RC Larro, VCH publisher Inc., 1989, etc.), the compound (9- 3) can be manufactured.

Manufacturing method 10
Among the compounds represented by the formula (1), the compound represented by the compound (10-1) or a salt thereof is produced, for example, by the method shown below.

［式中、Ｒ¹を伴う５員環Ｃｙ、Ｒ¹、−Ｗ⁴＝Ｗ⁵−Ｗ⁶＝Ｗ⁷−、Ｒ⁹、Ｒ¹⁰、及びＲ¹¹は、前記と同義である。］
１）工程１
文献（Protective Groups in Organic Synthesis 3rd Edition (John Wiley & Sons, Inc.)； Comprehensive Organic transformation, R. C. ラロック著, VCH publisher Inc., 1989) に記載されている方法等によって、化合物（３−４）から化合物（１０−１）を製造することができる。例えば、塩基の存在下に化合物（３−４）をハロゲン化アルキル化合物等と反応させることができる。

Wherein 5-membered ring Cy with ^{R 1, R 1, -W 4} = W 5 -W 6 = W 7 -, R 9, R 10, and R ¹¹ are as defined above. ]
1) Step 1
From the compound (3-4) by the method described in the literature (Protective Groups in Organic Synthesis 3rd Edition (John Wiley & Sons, Inc.); Comprehensive Organic transformation, RC Larroque, VCH publisher Inc., 1989) Compound (10-1) can be produced. For example, compound (3-4) can be reacted with a halogenated alkyl compound or the like in the presence of a base.

Manufacturing method 11
Among the compounds represented by the formula (1), the compound represented by the compound (11-3) or the compound (11-5) or a salt thereof is produced, for example, by the method shown below.

［式中、Ｒ¹を伴う５員環Ｃｙ、Ｒ¹、−Ｗ⁴＝Ｗ⁵−Ｗ⁶＝Ｗ⁷−、Ｒ⁹、及びＸは、前記と同義である。］
１）工程１
化合物（１１−２）は、公知または公知の合成法により得られる縮合ピラゾール化合物（１１−１）を、溶媒中、塩基存在下または非存在下にハロゲン化剤と反応させることにより製造される（例えばTetrahedron Letters. 43, 2695 (2002), Comprehensive Organic transformation, R. C. ラロック著, VCH publisher Inc., 1989等参照）。ハロゲン化剤としては、N-クロロスクシニルイミド、N-ブロモスクシニルイミド、もしくはN-ヨードスクシニルイミド等のN-ハロゲン化イミド類、塩素、臭素、またはヨウ素を挙げることが出来る。ハロゲン化剤の使用量としては、化合物（１１−１）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、エーテル系溶媒（テトラヒドロフラン、ジエチルエーテル、１，２−ジメトキシエタン、１，４−ジオキサン等）、非プロトン性極性溶媒（Ｎ，Ｎ−ジメチルホルムアミド、Ｎ，Ｎ−ジメチルアセトアミド、ジメチルスルホキシド、アセトニトリル等）、ケトン類（アセトン等）、またはこれらの混合溶媒等が挙げられる。
塩基としては、例えば炭酸アルカリ(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、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、水素化カリウム等）、水酸化アルカリ(水酸化カリウム、水酸化ナトリウム等)、アルカリアルコキシド（ナトリウムエトキシド、ナトリウムtert-ブトキシド、カリウムtert-ブトキシド等）、または有機塩基（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、ピリジン等）が挙げられ、好適には、炭酸カリウム、カリウムtert-ブトキシド、トリエチルアミン等が挙げられる。塩基の使用量としては、化合物（１１−１）に対して通常１〜５当量の範囲から選択される。反応温度としては、約−７８℃〜約１５０℃の範囲から選択することができる。
２）工程２
製造法１記載の工程２と同様の方法によって行われる。
３）工程３
化合物（１１−５）は、溶媒中、工程２で得られた化合物（１１−３）と化合物（１１−４）を触媒存在下、鈴木-宮浦反応を用いてカップリングさせることにより製造することができる（例えば、Palladium Reagents and Catalysts, Jiro Tsuji著, John Wiley & Sons Ltd, 2004、Tetrahedron Letters 42, 4083 (2001), Chemistry Letters Vol.33, No.9, 1207 (2004)等参照）。
４）工程４
化合物（１１−６）は、不活性溶媒中、工程２で得られた化合物（１１−３）をハロゲン-金属交換したのちに（１１−7）と反応させることにより製造することができる。ハロゲン-金属交換の方法としては、例えば、Angew. Chem. Int. Ed. 43, 3333 (2004), Angew. Chem. Int. Ed. 42, 4302 (2003), Angew. Chem. Int. Ed. 39, 4414 (2000)等の文献が挙げられる。

Wherein 5-membered ring Cy with ^{R 1, R 1, -W 4} = W 5 -W 6 = W 7 -, R 9, and X have the same meanings as defined above. ]
1) Step 1
Compound (11-2) is produced by reacting a condensed pyrazole compound (11-1) obtained by a known or known synthesis method with a halogenating agent in a solvent in the presence or absence of a base ( For example, see Tetrahedron Letters. 43, 2695 (2002), Comprehensive Organic transformation, RC Larroc, VCH publisher Inc., 1989). Examples of the halogenating agent include N-halogenated imides such as N-chlorosuccinimide, N-bromosuccinimide, or N-iodosuccinimide, chlorine, bromine, and iodine. The amount of the halogenating agent to be used is usually selected from the range of 1 equivalent to excess with respect to compound (11-1). Examples of the inert solvent include ether solvents (tetrahydrofuran, diethyl ether, 1,2-dimethoxyethane, 1,4-dioxane, etc.), aprotic polar solvents (N, N-dimethylformamide, N, N-dimethyl). Acetamide, dimethyl sulfoxide, acetonitrile, etc.), ketones (acetone, etc.), or a mixed solvent thereof.
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.), alkali hydroxide (potassium hydroxide, water, etc.) Sodium oxide, etc.), alkali alkoxides (sodium ethoxide, sodium tert-butoxide, potassium tert-butoxide, etc.), or organic bases (N-methylmorpholine, triethylamine, diisopropylethylamine, tributylamine, 1,8-diazabicyclo [5.4 0.0] undec-7-ene, 1,5-diazabicyclo [4.3.0] non-5-ene, 1,4-diazabicyclo [5.4.0] undec-7-ene, pyridine, etc.) Preferable examples include potassium carbonate, potassium tert-butoxide, triethylamine and the like. The amount of base used is usually selected from the range of 1 to 5 equivalents relative to compound (11-1). The reaction temperature can be selected from the range of about −78 ° C. to about 150 ° C.
2) Step 2
This is carried out by the same method as in step 2 described in production method 1.
3) Step 3
Compound (11-5) is produced by coupling compound (11-3) obtained in step 2 and compound (11-4) in a solvent using a Suzuki-Miyaura reaction in the presence of a catalyst. (See, for example, Palladium Reagents and Catalysts, Jiro Tsuji, John Wiley & Sons Ltd, 2004, Tetrahedron Letters 42, 4083 (2001), Chemistry Letters Vol. 33, No. 9, 1207 (2004)).
4) Step 4
Compound (11-6) can be produced by reacting compound (11-3) obtained in Step 2 with (11-7) after halogen-metal exchange in an inert solvent. As a method of halogen-metal exchange, for example, Angew. Chem. Int. Ed. 43, 3333 (2004), Angew. Chem. Int. Ed. 42, 4302 (2003), Angew. Chem. Int. Ed. 39 , 4414 (2000).

Unless otherwise specified, the raw materials and reagents used in the above are commercially available compounds, or can be produced from known compounds using known methods.
In each of the above production steps, when the raw material compound of each reaction has a reaction active group such as a hydroxyl group, an amino group or a carboxyl 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 carboxyl 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, 3rd edition, John Wiley & Sons, Inc. (1999)).
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 carboxyl 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, and in the case of ortho ester, for example, 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.
Moreover, among the above production methods, in the step of introducing the R ¹ group, a mixture of regioisomers, that is, the R ¹ group on the 1-position nitrogen atom represented by the formula (1-Cy2), for example And a mixture of a compound having an R ¹ group on the 2-position nitrogen atom as represented by the formula (1-Cy3) may be obtained. From this mixture, each positional isomer can be isolated and separated by a known method such as silica gel column chromatography or fractional crystallization, if necessary.

The compounds represented by the formula (1) include those having an optically active center, and therefore, these can be obtained as a racemate or in an optically active form when an optically active starting material is used. it can. If necessary, the racemates obtained can be physically or chemically resolved into their optical enantiomers by known methods. It can also be synthesized using known asymmetric reactions. 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.
In addition, the compound represented by the formula (1) includes those having a tautomer. Examples of tautomerism include formula (13-1) and formula (13-2).

The compound of the present invention and a prodrug thereof can be converted to a salt by mixing with a pharmaceutically acceptable acid or alkali in a solvent such as water, methanol, ethanol, acetone or the like. Examples of the pharmaceutically acceptable acid 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. Examples of the pharmaceutically acceptable alkali addition salt include ammonium salt, lithium salt, sodium salt, potassium salt, calcium salt, magnesium salt and the like.
The present invention also includes solvates such as a hydrate of the compound represented by the general formula (1) or a pharmaceutically acceptable salt thereof, and an ethanol solvate.

In the present invention, examples of the prodrug, that is, a compound that is metabolized by an enzyme in a living body and converted into an active ingredient includes a compound in which a carboxyl group is esterified. Specific examples of the ester include methyl ester, ethyl ester, benzyl ester, pivaloyloxymethyl ester, cilexetil, medoxomil, pivoxyl, proxetyl, and mofetil (see, for example, J. Med. Chem. 47, 2393 (2004)). Etc. These compounds can be produced according to a conventional method (for example, see J. Med. Chem. 35, 4727 (1992), WO 01/40180 etc.). Prodrugs are usually used as oral preparations. That is, when the compound of the present invention has a carboxy group or a hydroxyl group, compounds obtained by converting these groups into esters are also included in the category of the present invention.
In addition, when the compound of the present invention is metabolized by an in vivo enzyme and converted into a metabolite having a lower physiological activity, the compound can be used as an ante-drug. Ante-drug is usually used as a topical agent.

The novel condensed pyrazole derivative of the present invention, a prodrug thereof, or a pharmaceutically acceptable salt thereof functions as a glucocorticoid function regulator (GR modulator) and can be used as a therapeutic or prophylactic agent for all pathological conditions involving GR. .
The “glucocorticoid function regulator” in the present invention represents a substance that activates or suppresses the function of the glucocorticoid receptor (GR). For example, a GR agonist (including a partial agonist), a GR antagonist (including a partial antagonist). Etc. Specifically, “GR modulator” inhibits the binding of GR and known steroid (including natural and synthetic steroids) compounds such as dexamethasone and suppresses the activity of dexamethasone in vitro. / It is a substance showing an enhancing action.
Glucocorticoid function regulators can be applied to the treatment of the following various diseases in which existing steroidal anti-inflammatory drugs are clinically used. 1) Diseases that are improved by physiological hormonal effects, such as hormone deficiency in which blood cortisol levels are abnormally low due to pituitary gland failure, adrenal insufficiency, etc., adrenal enzyme deficiency or dexamethasone inhibitory hypertension via high ACTH levels; 2) Rheumatoid arthritis, juvenile rheumatoid arthritis, systemic lupus erythematosus, systemic sclerosis, polymyositis, dermatomyositis, mixed connective tissue disease, vasculitis syndrome, Behcet's disease, adult Still's disease, Sjogren's syndrome, etc. 3) Idiopathic thrombocytopenic purpura, autoimmune hemolytic anemia, aplastic anemia, erythroblastic fistula, blood phagocytic syndrome, Hodgkin disease, non-Hodgkin lymphoma, multiple myeloma, acute lymph Blood diseases such as primary leukemia, chronic lymphocytic leukemia, paroxysmal nocturnal hemoglobinuria, thrombotic thrombocytopenic purpura, retinoid syndrome, cytarabine syndrome; 4) Minimal change nephrotic syndrome, membranous nephropathy, focal glomerulosclerosis, IgA nephropathy, membranoproliferative glomerulonephritis, rapidly progressive nephritis syndrome, renal lesions associated with multiple myeloma, cloglobulinemia Nephropathy, acute interstitial nephritis, drug-induced nephropathy, etc. in infectious diseases; 5) Infectious diseases (carini pneumonia, mycoplasma pneumonia), chronic obstructive pulmonary disease, interstitial lung disease (idiopathic interstitial pneumonia) , Acute interstitial pneumonia, adult respiratory distress syndrome, nonspecific interstitial pneumonia, obstructive bronchiolitis organizing pneumonia), bronchial asthma, pulmonary eosinophilia syndrome (allergic bronchopulmonary aspergillosis, allergic) Granulomatous vasculitis, chronic eosinophilic pneumonia, acute eosinophilic pneumonia), hypersensitivity pneumonia, sarcoidosis, Goodpasture syndrome, drug-induced pneumonia, radioactive pneumonia, collagen disease, and other respiratory diseases; 6) Multiple Sclerosis, acute disseminated encephalomyelitis, severe Myasthenia gravis, chronic inflammatory demyelinating polyneuritis, Lambert-Eaton myasthenia syndrome, HTLV-1-related myelopathy, tuberculous meningitis, central nervous lupus, neuropathy associated with vasculitis, neurological symptoms associated with Sjogren's syndrome・ Tolosa-Hunt syndrome ・ Nerve sarcoidosis ・ Nerve Behcet's disease ・ Idiopathic peripheral facial palsy ・ Cerebral neuropathy such as brain edema and spinal cord injury associated with head injury or brain tumor; 7) Thyroid crisis ・ Graves' disease Thyroiditis, thyroid diseases such as drug-induced hyperthyroidism, myxedema coma; 8) Gastrointestinal diseases such as Crohn's disease, ulcerative colitis, primary intestinal malignant lymphoma, intestinal Behcet's disease; 9) Acute hepatitis, fulminant Liver diseases such as hepatitis and autoimmune hepatitis. ; 10) Ophthalmic diseases such as allergic conjunctivitis, hay fever, spring catarrh, rejection after corneal transplantation, iritis, iridocyclitis, Vogt-Koyanagi-Harada disease, optic neuritis, etc .; 11) autoimmune blistering ( Pemphigus, pemphigoid, linear IgA bullosa, acquired epidermolysis bullosa), skin disease associated with collagen disease, neutrophilic dermatosis (Sweet disease, pyoderma gangrenosum), Weber Christian disease, Steves Johnson syndrome, toxic epidermal necrosis, cutaneous vasculitis, eczema dermatitis group, drug eruption, urticaria, polymorphic exudative erythema, erythema nodosum, scleroderma, discoid lupus erythematosus, deep lupus erythematosus, cutaneous malignant lymphoma・ Skin sarcoidosis, alopecia areata, scab hemangioma, eruption group, palmoplantar pustulosis, psoriasis, insect bites, poisoning rash, gibber rose rash, squamous red lichen, erythroderma, hypertrophic scar, keloid, Granulomatosis / Amyloid lichen Skin diseases such as alopecia areata; 12) As a therapeutic or prophylactic agent for diseases such as osteoarthritis, gout, pseudogout, inflammation around tendons or tendons, strangulation neuropathy, orthopedics-related diseases such as disc herniation Useful.
In addition, the glucocorticoid function regulator is considered to be applied to the following disease treatments that are expected to suppress the action of glucocorticoid. 1) Cushing's syndrome and other diseases in which the blood cortisol level is high or GR is excessively activated; 2) a state of reduced immune capacity associated with HIV infection, etc .; 3) a neuropsychiatric disorder (anxiety) Disorder, mood disorder, schizophrenia, dementia, depression / anxiety symptoms associated with various diseases, premenstrual syndrome); 4) changes associated with excessive stress state; 5) useful as a therapeutic or preventive agent for diabetes, etc. .
Moreover, the glucocorticoid function regulator of this invention can be used as a therapeutic agent and a preventive agent with respect to an inflammatory disease as a GR partial agonist.

In addition, the compound of the present invention has an immunosuppressive agent, an anti-inflammatory agent, an anti-rheumatic agent, an antithrombotic agent, an antihistamine, an antiallergic agent, a β2-stimulating agent, an ST combination, a diabetes therapeutic agent, a diabetic agent for the purpose of enhancing its effect It can be used in combination with a drug (hereinafter abbreviated as a concomitant drug) such as a complication therapeutic agent, an antihyperlipidemic agent, an antihypertensive agent or an antiobesity agent.
As immunosuppressants, cyclophosphamide, methotrexate, cyclosporin A, etc., as anti-inflammatory agents, indomethacin, bucillamine, etc., as antirheumatic agents, leflunomide, sulfasalazine, limacarib, etc., as antithrombotic agents, warfarin, etc. Antihistamines such as olopatadine hydrochloride, fexofenadine hydrochloride, tranilast as antiallergic agents, salbutamol sulfate as probiotics such as β2 stimulants, procaterol hydrochloride as ST combinations, cotrimoxazole, etc. as antidiabetic agents Insulin resistance-improving agents (such as pioglitazone or its hydrochloride), diabetic complications, antihyperlipidemic agents, antihypertensives, anti-obesity agents such as central anti-obesity agents (such as phentermine) and pancreatic lipase Inhibitors (such as orlistat).
In anticipation of an anti-inflammatory action / immunomodulatory action, the combination drug preferably includes methotrexate, indomethacin, fexofenadine hydrochloride and the like, and the antidiabetic agent preferably includes an insulin resistance improving agent and the like.
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.

The compounds of the present invention, when used therapeutically, are used as pharmaceutical compositions as oral or parenteral (eg, intravenous, subcutaneous, intramuscular, topical, rectal, transdermal, or nasal, Pulmonary). Examples of dosage forms for oral administration include dosage forms such as tablets, capsules, pills, granules, powders, liquids, suspensions, etc. Examples of dosage forms for parenteral administration include , Preparations in the form of aqueous injections, oily injections, ointments, creams, lotions, aerosols, suppositories, patches and the like. These preparations can be prepared using a conventionally known technique, and can contain a nontoxic and inert carrier or excipient usually used in the pharmaceutical field.
The dose varies depending on the individual compound and the patient's disease, age, weight, sex, symptom, route of administration, etc., but usually for adults (50 kg body weight) The drug or a pharmaceutically acceptable salt thereof is administered at 0.1 to 1000 mg / day, preferably 1 to 300 mg / day once a day or divided into 2 to 3 times a day. It can also be administered once every few days to several weeks.
The compound of the present invention is an immunosuppressant, anti-inflammatory agent, anti-rheumatic agent, anti-thrombotic agent, anti-histamine agent, anti-allergic agent, β2 stimulant, ST combination, antidiabetic agent, diabetic complication Can be used in combination with drugs (concomitant drugs) such as anti-hyperlipidemic agents, antihyperlipidemic agents, antihypertensive agents, and anti-obesity agents. The administration timing of the compound of the present invention and the concomitant drug is not limited, and these may be administered simultaneously to the administration subject, 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.

  The present invention will be described in more detail below with reference to examples and test examples, but the technical scope of 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.

Reference example 1
6-nitro-1H-indazole-3-carbaldehyde

6-ニトロインドール(5.0g)の6N 塩酸(93ml)溶液に、亜硝酸ナトリウム(42.5ｇ)の水(1000ｍｌ)溶液を25℃にて1時間かけて滴下した。さらに20時間撹拌した。反応溶液を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、ろ過した。ろ液を減圧濃縮して得られた残渣にジエチルエーテルを加え、ろ過した。ろ液を乾燥させることにより表題の化合物(8.05g)を得た。（実施文献 J. Med. Chem. 2001, 44, 1021-1024.）

To a 6N hydrochloric acid (93 ml) solution of 6-nitroindole (5.0 g), a solution of sodium nitrite (42.5 g) in water (1000 ml) was added dropwise at 25 ° C. over 1 hour. The mixture was further stirred for 20 hours. The reaction solution was extracted with ethyl acetate, and the organic layer was washed with saturated brine, dried over sodium sulfate, and filtered. Diethyl ether was added to the residue obtained by concentrating the filtrate under reduced pressure, followed by filtration. The filtrate was dried to give the title compound (8.05g). (Reference document J. Med. Chem. 2001, 44, 1021-1024.)

Reference example 2
1-benzyl-6-nitro-1H-indazole-3-carbaldehyde 1-benzyl-6-nitro-1H-indazole-3-carbaldehyde

参考例１で得られた6-ニトロ-1H-インダゾール-3-カルボアルデヒド(955mg)のN,N-ジメチルホルムアミド(30ml)溶液に水酸化カリウム(337mg)、ベンジルブロミド(1.03g)、沃化カリウム(10mg)を加えて25℃で4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、ろ過した。ろ液を減圧濃縮後、得られた残渣をシリカゲルカラムクロマトグラフィーで精製することにより表題の化合物(6.94mg)を得た。
¹H-NMR (400 MHz, CDCl₃) δ 10.29 (s, 1H), 8.45 (d, J= 8.9 Hz, 1H), 8.38 (d, J= 1.8 Hz, 1H), 8.20 (dd, J= 8.9, 1.8 Hz, 1H), 7.41-7.34 (m, 3H), 7.34-7.28 (m, 2H), 5.78 (s, 2H).

To a solution of 6-nitro-1H-indazole-3-carbaldehyde (955 mg) obtained in Reference Example 1 in N, N-dimethylformamide (30 ml), potassium hydroxide (337 mg), benzyl bromide (1.03 g), iodide Potassium (10 mg) was added and stirred at 25 ° C. for 4 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 sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography to give the title compound (6.94 mg).
¹ H-NMR (400 MHz, CDCl ₃ ) δ 10.29 (s, 1H), 8.45 (d, J = 8.9 Hz, 1H), 8.38 (d, J = 1.8 Hz, 1H), 8.20 (dd, J = 8.9 , 1.8 Hz, 1H), 7.41-7.34 (m, 3H), 7.34-7.28 (m, 2H), 5.78 (s, 2H).

Reference example 3
1- (1-benzyl-6-nitro-1H-indazol-3-yl) -2,2,2-trifluoroethanol 1- (1-benzyl-6-nitro-1H-indazol-3-yl) -2 , 2,2-trifluoroethanol

参考例２で得られた1-ベンジル-6-ニトロ-1H-インダゾール-3-カルボアルデヒド(694mg)のN,N-ジメチルホルムアミド(20ml)溶液に（トリフルオロメチル）トリメチルシラン(739ul)、酢酸リチウム(16mg)を加えて0℃で1時間撹拌した。さらに25℃で1時間撹拌したのちに、反応溶液に1.0M テトラブチルアンモニウムフロリド(10ml)を加え25℃で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、ろ過した。ろ液を減圧濃縮後、得られた残渣をシリカゲルカラムクロマトグラフィーで精製することにより表題の化合物(762mg)を得た。
¹H-NMR (400 MHz, CDCl₃) δ 8.31 (d, J= 1.9 Hz, 1H), 8.06 (dd, J= 8.9, 1.9 Hz, 1H), 7.97 (d, J= 8.9 Hz, 1H), 7.39-7.29 (m, 3H), 7.25-7.20 (m, 2H), 5.68 (s, 2H), 5.58-5.49 (m, 1H), 3.45 (d, J= 6.3 Hz, 1H).

To a solution of 1-benzyl-6-nitro-1H-indazole-3-carbaldehyde (694 mg) obtained in Reference Example 2 in N, N-dimethylformamide (20 ml), (trifluoromethyl) trimethylsilane (739 ul), acetic acid Lithium (16 mg) was added and stirred at 0 ° C. for 1 hour. After further stirring at 25 ° C. for 1 hour, 1.0 M tetrabutylammonium fluoride (10 ml) was added to the reaction solution and stirred at 25 ° C. for 1 hour. 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, and filtered. The filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography to give the title compound (762 mg).
¹ H-NMR (400 MHz, CDCl ₃ ) δ 8.31 (d, J = 1.9 Hz, 1H), 8.06 (dd, J = 8.9, 1.9 Hz, 1H), 7.97 (d, J = 8.9 Hz, 1H), 7.39-7.29 (m, 3H), 7.25-7.20 (m, 2H), 5.68 (s, 2H), 5.58-5.49 (m, 1H), 3.45 (d, J = 6.3 Hz, 1H).

Reference example 4
1- (1-benzyl-6-nitro-1H-indazol-3-yl) -2,2,2-trifluoroethanone 1- (1-benzyl-6-nitro-1H-indazol-3-yl) -2 , 2,2-trifluoroethanone

参考例３で得られた1-(1-ベンジル-6-ニトロ-1H-インダゾール-3-イル)-2,2,2-トリフルオロエタノール(755mg)のeクロロホルム(40ml)溶液に、Ｄｅｓｓ−Ｍａｒｔｉｎ試薬(1.09g)を加えて25℃で1週間撹拌した。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、ろ過した。ろ液を減圧濃縮後、得られた残渣をシリカゲルカラムクロマトグラフィーで精製することにより表題の化合物(175mg)を得た。
¹H-NMR (400 MHz, CDCl₃) δ 8.48 (d, J= 8.9 Hz, 1H), 8.40 (d, J= 1.7 Hz, 1H), 8.25 (dd, J= 8.9, 1.7 Hz, 1H), 7.42-7.30 (m, 5H), 5.82 (s, 2H).
MS (ESI+) 350（M⁺+1）

To a solution of 1- (1-benzyl-6-nitro-1H-indazol-3-yl) -2,2,2-trifluoroethanol (755 mg) obtained in Reference Example 3 in e-chloroform (40 ml), Dess- Martin reagent (1.09 g) was added and stirred at 25 ° C. for 1 week. 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, and filtered. The filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography to give the title compound (175 mg).
¹ H-NMR (400 MHz, CDCl ₃ ) δ 8.48 (d, J = 8.9 Hz, 1H), 8.40 (d, J = 1.7 Hz, 1H), 8.25 (dd, J = 8.9, 1.7 Hz, 1H), 7.42-7.30 (m, 5H), 5.82 (s, 2H).
MS (ESI +) 350 (M ⁺ +1)

Reference Example 5
1-benzyl-6-nitro-3- [1- (trifluoromethyl) vinyl] -1H-indazole 1-benzyl-6-nitro-3- [1- (trifluoromethyl) vinyl] -1H-indazole

メチルトリフェニルホスホニウムブロミド(357g)のテトラヒドロフラン(10ml)溶液に、25℃にてカリウム tert-ブトキシド(112mg)を加えた。25℃にて30分間撹拌後、参考例４で得られた1-(1-ベンジル-6-ニトロ-1H-インダゾール-3-イル)-2,2,2-トリフルオロエタノン(175mg)を加え、25℃で1時間撹拌した。反応溶液に飽和食塩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、ろ過した。ろ液を減圧濃縮後、得られた残渣をシリカゲルカラムクロマトグラフィーで精製することにより表題の化合物(135mg)を得た。
¹H-NMR (400 MHz, CDCl₃) δ 8.30 (d, J= 1.9 Hz, 1H), 8.06 (dd, J= 9.0, 1.9 Hz, 1H), 7.94 (d, J= 9.0 Hz, 1H), 7.39-7.30 (m, 3H), 7.30-7.27 (m, 2H), 6.32-6.26 (m, 2H).
MS (ESI+) 348（M⁺+1）

To a solution of methyltriphenylphosphonium bromide (357 g) in tetrahydrofuran (10 ml) was added potassium tert-butoxide (112 mg) at 25 ° C. After stirring at 25 ° C. for 30 minutes, 1- (1-benzyl-6-nitro-1H-indazol-3-yl) -2,2,2-trifluoroethanone (175 mg) obtained in Reference Example 4 was added. And stirred at 25 ° C. for 1 hour. To the reaction solution was added saturated brine, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography to give the title compound (135 mg).
¹ H-NMR (400 MHz, CDCl ₃ ) δ 8.30 (d, J = 1.9 Hz, 1H), 8.06 (dd, J = 9.0, 1.9 Hz, 1H), 7.94 (d, J = 9.0 Hz, 1H), 7.39-7.30 (m, 3H), 7.30-7.27 (m, 2H), 6.32-6.26 (m, 2H).
MS (ESI +) 348 (M ⁺ +1)

Reference Example 6
2- (1-benzyl-6-nitro-1H-indazol-3-yl) -3-bromo-1,1,1-trifluoropropan-2-ol 2- (1-benzyl-6-nitro-1H- indazol-3-yl) -3-bromo-1,1,1-trifluoropropan-2-ol

参考例５で得られた1-ベンジル-6-ニトロ-3-[1-(トリフルオロメチル)ビニル]-1H-インダゾゾール(69mg)のN,N-ジメチルホルムアミド(4ml)、水(1ml)の混合溶液に、N-ブロモスクシンイミド(178mg)を加えて90℃にて10時間撹拌した。その後、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、ろ過した。ろ液を減圧濃縮後、得られた残渣をシリカゲルカラムクロマトグラフィーで精製することにより表題の化合物(73mg)を得た。
MS (ESI+) 445（M⁺+1）

1-Benzyl-6-nitro-3- [1- (trifluoromethyl) vinyl] -1H-indazozole (69 mg) of N, N-dimethylformamide (4 ml) obtained in Reference Example 5 and water (1 ml) N-bromosuccinimide (178 mg) was added to the mixed solution and stirred at 90 ° C. for 10 hours. Thereafter, 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, and filtered. The filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography to give the title compound (73 mg).
MS (ESI +) 445 (M ⁺ +1)

Reference Example 7
1-benzyl-6-nitro-3- [2- (trifluoromethyl) oxirane-2-yl] -1H-indazole 1-benzyl-6-nitro-3- [2- (trifluoromethyl) oxiran-2-yl]- 1H-indazole

参考例６で得られた2-(1-ベンジル-6-ニトロ-1H-インダゾール-3-イル)-3-ブロモ-1,1,1-トリフルオロプロパン-2-オール(73mg)のメタノール(10ml)溶液を0℃に冷却後、炭酸カリウム(41mg)を加えて0℃にて30分間撹拌した。その後、25℃にて2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、ろ過した。ろ液を減圧濃縮後、得られた残渣をシリカゲルカラムクロマトグラフィーで精製することにより表題の化合物(49mg)を得た。
MS (ESI+) 364（M⁺+1）

2- (1-Benzyl-6-nitro-1H-indazol-3-yl) -3-bromo-1,1,1-trifluoropropan-2-ol (73 mg) methanol obtained in Reference Example 6 ( 10 ml) The solution was cooled to 0 ° C., potassium carbonate (41 mg) was added, and the mixture was stirred at 0 ° C. for 30 min. Then, it stirred at 25 degreeC for 2 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 sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography to give the title compound (49 mg).
MS (ESI +) 364 (M ⁺ +1)

Example 1
Ethyl 3- [4-({1- [2- (1-benzyl-6-nitro-1H-indazol-3-yl) -3,3,3-trifluoro-2-hydroxypropyl] piperidin-4-yl } Oxy) -3-methoxyphenyl] propanoate ethyl 3- [4-({1- [2- (1-benzyl-6-nitro-1H-indazol-3-yl) -3,3,3-trifluoro-2 -hydroxypropyl] piperidin-4-yl} oxy) -3-methoxyphenyl] propanoate

参考例７で得られた1-ベンジル-6-ニトロ-3-[2-(トリフルオロメチル)オキシラン2-イル]-1H-インダゾール(72mg)のイソプロピルアルコール(3ml)溶液に、エチル 3-[3-メトキシ-4-(ピペリジン-4-イルオキシ)フェニル]プロパノエート(61mg)を加えて90℃で8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、ろ過した。ろ液を減圧濃縮後、得られた残渣をシリカゲルカラムクロマトグラフィーで精製することにより表題の化合物(81mg)を得た。
¹H-NMR (400 MHz, CDCl₃) δ 8.30 (d, J= 9.0 Hz, 1H), 8.27 (d, J= 1.9 Hz, 1H), 8.01 (dd, J= 9.0, 1.9 Hz, 1H), 7.32-7.22 (m, 3H), 7.20-7.14 (m, 2H), 6.79 (d, J= 8.1 Hz, 1H), 6.73 (d, J= 2.0 Hz, 1H), 6.68 (dd, J= 8.1, 2.0 Hz, 1H), 5.65 (s, 2H), 4.24-4.16 (m, 1H), 4.12 (q, J= 7.1 Hz, 2H), 3.82 (s, 3H), 3.78 (d, J= 13.5 Hz, 1H), 3.16 (d, J= 13.5 Hz, 1H), 2.93-2.70 (m, 2H), 2.88 (t, J= 7.5 Hz, 2H), 2.59 (t, J= 7.5 Hz, 2H), 2.50-2.40 (m, 2H), 1.92-1.70 (m, 4H), 1.23 (t, J= 7.1 Hz, 3H).
MS (ESI+) 671（M⁺+1）

To a solution of 1-benzyl-6-nitro-3- [2- (trifluoromethyl) oxirane-2-yl] -1H-indazole (72 mg) obtained in Reference Example 7 in isopropyl alcohol (3 ml), ethyl 3- [ 3-Methoxy-4- (piperidin-4-yloxy) phenyl] propanoate (61 mg) was added and stirred at 90 ° C. for 8 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 sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography to give the title compound (81 mg).
¹ H-NMR (400 MHz, CDCl ₃ ) δ 8.30 (d, J = 9.0 Hz, 1H), 8.27 (d, J = 1.9 Hz, 1H), 8.01 (dd, J = 9.0, 1.9 Hz, 1H), 7.32-7.22 (m, 3H), 7.20-7.14 (m, 2H), 6.79 (d, J = 8.1 Hz, 1H), 6.73 (d, J = 2.0 Hz, 1H), 6.68 (dd, J = 8.1, 2.0 Hz, 1H), 5.65 (s, 2H), 4.24-4.16 (m, 1H), 4.12 (q, J = 7.1 Hz, 2H), 3.82 (s, 3H), 3.78 (d, J = 13.5 Hz, 1H), 3.16 (d, J = 13.5 Hz, 1H), 2.93-2.70 (m, 2H), 2.88 (t, J = 7.5 Hz, 2H), 2.59 (t, J = 7.5 Hz, 2H), 2.50- 2.40 (m, 2H), 1.92-1.70 (m, 4H), 1.23 (t, J = 7.1 Hz, 3H).
MS (ESI +) 671 (M ⁺ +1)

Example 2
3- [4-({1- [2- (1-Benzyl-6-nitro-1H-indazol-3-yl) -3,3,3-trifluoro-2-hydroxypropyl] piperidin-4-yl} Oxy) -3-methoxyphenyl] propanoic acid 3- [4-({1- [2- (1-benzyl-6-nitro-1H-indazol-3-yl) -3,3,3-trifluoro-2- hydroxypropyl] piperidin-4-yl} oxy) -3-methoxyphenyl] propanoic acid

実施例１で得られたエチル 3-[4-({1-[2-(1-ベンジル-6-ニトロ-1H-インダゾール-3-イル)-3,3,3-トリフルオロ-2-ヒドロキシプロピル]ピペリジン-4-イル}オキシ)-3-メトキシフェニル]プロパノエート(81mg)のテトラヒドロフラン(5ml)、メタノール(5ml)の混合溶液に1N 水素化ナトリウム水溶液(1ml)を加えて25℃で6時間撹拌した。反応溶液に飽和塩化アンモニウム水溶液を加えて酸性にした後に、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、ろ過した。ろ液を減圧濃縮後、残渣として表題の化合物(55mg)を得た。
¹H-NMR (400 MHz, CDCl₃) δ 8.30 (d, J= 1.9 Hz, 1H), 8.22 (d, J= 9.0 Hz, 1H), 8.07 (dd, J= 9.0, 1.9 Hz, 1H), 7.36-7.27 (m, 3H), 7.24-7.19 (m, 2H), 6.81-6.70 (m, 3H), 5.70 (d, J= 16.0 Hz, 1H), 5.59 (d, J= 16.0 Hz, 1H), 4.42 (bs, 1H), 4.33 (d, J= 13.0 Hz, 1H), 3.89-3.75 (m, 1H), 3.83 (s, 3H), 3.58 (d, J= 13.0 Hz, 1H), 3.54-3.43 (m, 1H), 3.39-3.24 (m, 2H), 2.92 (t, J= 7.5 Hz, 2H), 2.67 (t, J= 7.5 Hz, 2H), 2.25-1.75 (m, 4H).
MS (ESI+) 643（M⁺+1）

Ethyl 3- [4-({1- [2- (1-benzyl-6-nitro-1H-indazol-3-yl) -3,3,3-trifluoro-2-hydroxy] obtained in Example 1 1N sodium hydride aqueous solution (1 ml) was added to a mixed solution of (propyl) piperidin-4-yl} oxy) -3-methoxyphenyl] propanoate (81 mg) in tetrahydrofuran (5 ml) and methanol (5 ml) at 25 ° C. for 6 hours. Stir. The reaction solution was acidified by adding a saturated aqueous ammonium chloride solution, and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the title compound (55 mg) was obtained as a residue.
¹ H-NMR (400 MHz, CDCl ₃ ) δ 8.30 (d, J = 1.9 Hz, 1H), 8.22 (d, J = 9.0 Hz, 1H), 8.07 (dd, J = 9.0, 1.9 Hz, 1H), 7.36-7.27 (m, 3H), 7.24-7.19 (m, 2H), 6.81-6.70 (m, 3H), 5.70 (d, J = 16.0 Hz, 1H), 5.59 (d, J = 16.0 Hz, 1H) , 4.42 (bs, 1H), 4.33 (d, J = 13.0 Hz, 1H), 3.89-3.75 (m, 1H), 3.83 (s, 3H), 3.58 (d, J = 13.0 Hz, 1H), 3.54- 3.43 (m, 1H), 3.39-3.24 (m, 2H), 2.92 (t, J = 7.5 Hz, 2H), 2.67 (t, J = 7.5 Hz, 2H), 2.25-1.75 (m, 4H).
MS (ESI +) 643 (M ⁺ +1)

Similar to the compound of Example 1, the compounds of Examples 3 to 19 having structural formulas shown in Tables 1 to 2 were produced.

Example 3
Ethyl [4-({1- [2- (1-Benzyl-6-nitro-1H-indazol-3-yl) -3,3,3-trifluoro-2-hydroxypropyl] piperidin-4-yl} oxy ) -3-Methoxyphenyl] acetate ethyl [4-({1- [2- (1-benzyl-6-nitro-1H-indazol-3-yl) -3,3,3-trifluoro-2-hydroxypropyl] piperidin -4-yl} oxy) -3-methoxyphenyl] acetate
¹ H-NMR (400 MHz, CDCl ₃ ) δ 8.34 (s, 1H), 8.28 (d, J = 8.8 Hz, 1H), 8.09 (d, J = 8.8 Hz, 1H), 7.35-7.14 (m, 5H ), 6.90-6.85 (m, 3H), 5.73 (d, J = 15.3 Hz, 1H), 5.62 (d, J = 15.3 Hz, 1H), 4.50-4.35 (m, 2H), 4.16 (d, J = 7.2 Hz, 2H), 3.84 (s, 3H), 3.74-3.60 (m, 2H), 3.59-3.40 (m, 2H), 3.57 (s, 2H), 3.40-3.15 (m, 2H), 2.75-2.59 (m, 1H), 2.20-2.00 (m, 2H), 1.90-1.75 (m, 1H), 1.27 (t, J = 7.2 Hz, 3H).
MS (ESI +) 657 (M ⁺ +1)

Example 4
Ethyl 3- [4-({1- [2- (1-benzyl-6-nitro-1H-indazol-3-yl) -3,3,3-trifluoro-2-hydroxypropyl] piperidin-4-yl } Oxy) -3,5-dimethoxyphenyl] propanoate ethyl 3- [4-({1- [2- (1-benzyl-6-nitro-1H-indazol-3-yl) -3,3,3-trifluoro -2-hydroxypropyl] piperidin-4-yl} oxy) -3,5-dimethoxyphenyl] propanoate
¹ H-NMR (400 MHz, CDCl ₃ ) δ 8.31 (d, J = 9.0 Hz, 1H), 8.25 (d, J = 1.6 Hz, 1H), 8.01 (dd, J = 9.0, 1.6 Hz, 1H), 7.33-7.27 (m, 3H), 7.19-7.14 (m, 2H), 6.73, 6.39 (s, 2H), 5.65 (s, 2H), 4.13 (q, J = 7.1 Hz, 2H), 4.09-4.00 ( m, 1H), 3.83, 3.78 (s, 6H), 3.77 (d, J = 13.6 Hz, 1H), 3.17 (d, J = 13.6 Hz, 1H), 3.00-2.84 (m, 1H), 2.88 (t , J = 7.4 Hz, 2H), 2.85-2.75 (m, 1H), 2.60 (t, J = 7.4 Hz, 2H), 2.50-2.36 (m, 2H), 1.88-1.70 (m, 4H), 1.25 ( t, J = 7.1 Hz, 3H).
MS (ESI +) 701 (M ⁺ +1)

Example 5
Ethyl 3- [4-({1- [2- (1-benzyl-6-nitro-1H-indazol-3-yl) -3,3,3-trifluoro-2-hydroxypropyl] piperidin-4-yl } Sulphonyl) phenyl] propanoate ethyl 3- [4-({1- [2- (1-benzyl-6-nitro-1H-indazol-3-yl) -3,3,3-trifluoro-2-hydroxypropyl] piperidin -4-yl} sulfonyl) phenyl] propanoate
¹ H-NMR (400 MHz, CDCl ₃ ) δ 8.28 (d, J = 1.8 Hz, 1H), 8.25 (d, J = 9.0 Hz, 1H), 8.02 (dd, J = 9.0, 1.8 Hz, 1H), 7.74 (d, J = 8.2 Hz, 2H), 7.40 (d, J = 8.2 Hz, 2H), 7.34-7.27 (m, 3H), 7.18-7.13 (m, 2H), 5.65 (d, J = 15.8 Hz , 1H), 5.60 (d, J = 15.8 Hz, 1H), 5.54 (bs, 1H), 4.13 (q, J = 7.2 Hz, 2H), 3.71 (d, J = 13.7 Hz, 1H), 3.11 (d , J = 13.7 Hz, 1H), 3.05 (t, J = 7.6 Hz, 2H), 3.00 (bs, 1H), 2.90-2.80 (m, 1H), 2.66 (t, J = 7.6 Hz, 2H), 2.64 -2.56 (m, 1H), 2.54-2.45 (m, 1H), 2.23-2.12 (m, 1H), 2.00-1.92 (m, 1H), 1.84-1.69 (m, 2H), 1.60-1.48 (m, 1H), 1.23 (t, J = 7.2 Hz, 3H).
MS (ESI +) 689 (M ⁺ +1)

Example 6
Ethyl 3- {4-[(1- {2- [6-cyano-1- (3-methylbenzyl) -1H-indazol-3-yl] -3,3,3-trifluoro-2-hydroxypropyl} Piperidin-4-yl) oxy] -3,5-dimethoxyphenyl} propanoate ethyl 3- {4-[(1- {2- [6-cyano-1- (3-methylbenzyl) -1H-indazol-3-yl] ] -3,3,3-trifluoro-2-hydroxypropyl} piperidin-4-yl) oxy] -3,5-dimethoxyphenyl} propanoate
MS (ESI +) 695 (M ⁺ +1)

Example 7
Ethyl 3- {4-[(1- {2- [6-cyano-1- (tetrahydro-2H-pyran-2-yl) -1H-indazol-3-yl] -3,3,3-trifluoro- 2-Hydroxypropyl} piperidin-4-yl) oxy] -3,5-dimethoxyphenyl} propanoate ethyl 3- {4-[(1- {2- [6-cyano-1- (tetrahydro-2H-pyran-2 -yl) -1H-indazol-3-yl] -3,3,3-trifluoro-2-hydroxypropyl} piperidin-4-yl) oxy] -3,5-dimethoxyphenyl} propanoate
MS (ESI +) 675 (M ⁺ +1)

Example 8
1- (3-Methylbenzyl) -3- [2,2,2-trifluoro-1-hydroxy-1- (piperidin-1-ylmethyl) ethyl] -1H-indazole-6-carbonitrile 1- (3- methylbenzyl) -3- [2,2,2-trifluoro-1-hydroxy-1- (piperidin-1-ylmethyl) ethyl] -1H-indazole-6-carbonitrile
¹ H-NMR (400 MHz, CDCl ₃ ) δ 8.29 (d, J = 8.6 Hz, 1H), 7.65 (s, 1H), 7.35 (dd, J = 8.6, 1.3 Hz, 1H), 7.18 (dd, J = 7.5, 7.5 Hz, 1H), 7.09 (d, J = 7.5 Hz, 1H), 6.98-6.90 (m, 2H), 5.59 (d, J = 16.0 Hz, 1H), 5.53 (d, J = 16.0 Hz , 1H), 3.72 (d, J = 13.5 Hz, 1H), 3.10 (d, J = 13.5 Hz, 1H), 2.60-2.40 (m, 4H), 2.28 (s, 3H), 1.56-1.34 (m, 6H).
MS (ESI +) 443 (M ⁺ +1)

Example 9
1- (3-Methylbenzyl) -3- [2,2,2-trifluoro-1-hydroxy-1- (pyrrolidin-1-ylmethyl) ethyl] -1H-indazole-6-carbonitrile 1- (3- methylbenzyl) -3- [2,2,2-trifluoro-1-hydroxy-1- (pyrrolidin-1-ylmethyl) ethyl] -1H-indazole-6-carbonitrile
¹ H-NMR (400 MHz, CDCl ₃ ) δ 8.30 (d, J = 8.5 Hz, 1H), 7.66 (s, 1H), 7.35 (dd, J = 8.5, 1.2 Hz, 1H), 7.19 (dd, J = 7.5, 7.5 Hz, 1H), 7.10 (d, J = 7.5 Hz, 1H), 7.00-6.90 (m, 2H), 5.59 (d, J = 16.0 Hz, 1H), 5.54 (d, J = 16.0 Hz , 1H), 3.74 (d, J = 13.0 Hz, 1H), 3.40 (d, J = 13.0 Hz, 1H), 2.67-2.54 (m, 2H), 2.53-2.42 (m, 2H), 2.28 (s, 3H), 1.75-1.64 (m, 4H).
MS (ESI +) 429 (M ⁺ +1)

Example 10
1- (3-Methylbenzyl) -3- [2,2,2-trifluoro-1-hydroxy-1- (morpholin-4-ylmethyl) ethyl] -1H-indazole-6-carbonitrile 1- (3 -methylbenzyl) -3- [2,2,2-trifluoro-1-hydroxy-1- (morpholin-4-ylmethyl) ethyl] -1H-indazole-6-carbonitrile
¹ H-NMR (400 MHz, CDCl ₃ ) δ 8.26 (d, J = 8.6 Hz, 1H), 7.69 (s, 1H), 7.36 (dd, J = 8.6, 1.2 Hz, 1H), 7.19 (dd, J = 7.6, 7.6 Hz, 1H), 7.10 (d, J = 7.6 Hz, 1H), 6.97 (s, 1H), 6.94 (d, J = 7.6 Hz, 1H), 5.79 (br, 1H), 5.55 (s , 2H), 3.78 (d, J = 13.7 Hz, 1H), 3.65-3.54 (m, 4H), 3.12 (d, J = 13.7 Hz, 1H), 2.63-2.43 (m, 4H), 2.29 (s, 3H).
MS (ESI +) 445 (M ⁺ +1)

Example 11
1- (3-Methylbenzyl) -3- {2,2,2-trifluoro-1-hydroxy-1-[(4-hydroxypiperidin-1-yl) methyl] ethyl} -1H-indazole-6-carbo Nitrile 1- (3-methylbenzyl) -3- {2,2,2-trifluoro-1-hydroxy-1-[(4-hydroxypiperidin-1-yl) methyl] ethyl} -1H-indazole-6-carbonitrile
¹ H-NMR (400 MHz, CDCl ₃ ) δ 8.27 (d, J = 8.6 Hz, 1H), 7.66 (s, 1H), 7.36 (dd, J = 8.6, 1.2 Hz, 1H), 7.19 (dd, J = 7.6, 7.6 Hz, 1H), 7.09 (d, J = 7.6 Hz, 1H), 6.96 (s, 1H), 6.93 (d, J = 7.6 Hz, 1H), 5.55 (s, 2H), 3.77 (d , J = 13.6 Hz, 1H), 3.77-3.65 (m, 1H), 3.14 (d, J = 13.6 Hz, 1H), 2.88-2.76 (m, 1H), 2.68-2.57 (m, 1H), 2.53- 2.33 (m, 2H), 2.29 (s, 3H), 1.88-1.69 (m, 2H), 1.60-1.40 (m, 2H).
MS (ESI +) 459 (M ⁺ +1)

Example 12
3- {1-[(Dimethylamino) methyl] -2,2,2-trifluoro-1-hydroxyethyl} -1- (3-methylbenzyl) -1H-indazole-6-carbonitrile 3- {1- [(dimethylamino) methyl] -2,2,2-trifluoro-1-hydroxyethyl} -1- (3-methylbenzyl) -1H-indazole-6-carbonitrile
¹ H-NMR (400 MHz, CDCl ₃ ) δ 8.29 (d, J = 8.5 Hz, 1H), 7.65 (s, 1H), 7.35 (dd, J = 8.5, 1.2 Hz, 1H), 7.19 (dd, J = 7.6, 7.6 Hz, 1H), 7.09 (d, J = 7.6 Hz, 1H), 6.98-6.91 (m, 2H), 5.59 (d, J = 16.0 Hz, 1H), 5.54 (d, J = 16.0 Hz , 1H), 3.66 (d, J = 13.4 Hz, 1H), 3.13 (d, J = 13.4 Hz, 1H), 2.28 (s, 9H).
MS (ESI +) 403 (M ⁺ +1)

Example 13
1- (3-Methylbenzyl) -3- (2,2,2-trifluoro-1-hydroxy-1-{[4- (2-methylphenoxy) piperidin-1-yl] methyl} ethyl) -1H- Indazole-6-carbonitrile 1- (3-methylbenzyl) -3- (2,2,2-trifluoro-1-hydroxy-1-{[4- (2-methylphenoxy) piperidin-1-yl] methyl} ethyl) -1H-indazole-6-carbonitrile
¹ H-NMR (400 MHz, CDCl ₃ ) δ 8.28 (d, J = 8.3 Hz, 1H), 7.67 (s, 1H), 7.36 (d, J = 8.3 Hz, 1H), 7.18-7.07 (m, 3H ), 7.04 (d, J = 7.4 Hz, 1H), 6.98-6.90 (m, 2H), 6.84 (dd, J = 7.4, 7.4 Hz, 1H), 6.76 (d, J = 7.4 Hz, 1H), 5.55 (s, 2H), 4.36 (bs, 1H), 3.80 (d, J = 13.5 Hz, 1H), 3.16 (d, J = 13.5 Hz, 1H), 2.88-2.70 (m, 2H), 2.60-2.50 ( m, 1H), 2.47-2.35 (m, 1H), 2.24 (s, 3H), 2.22 (s, 3H), 1.95-1.67 (m, 4H).
MS (ESI +) 549 (M ⁺ +1)

Example 14
3- {1-[(6,7-dimethoxy-3,4-dihydroisoquinolin-2 (1H) -yl) methyl] -2,2,2-trifluoro-1-hydroxyethyl} -1- (3- Methylbenzyl) -1H-indazole-6-carbonitrile 3- {1-[(6,7-dimethoxy-3,4-dihydroisoquinolin-2 (1H) -yl) methyl] -2,2,2-trifluoro-1 -hydroxyethyl} -1- (3-methylbenzyl) -1H-indazole-6-carbonitrile
¹ H-NMR (400 MHz, CDCl ₃ ) δ 8.28 (d, J = 8.5 Hz, 1H), 7.69 (s, 1H), 7.36 (dd, J = 8.5, 1.3 Hz, 1H), 7.20 (dd, J = 7.5, 7.5 Hz, 1H), 7.11 (d, J = 7.5 Hz, 1H), 7.03 (s, 1H), 6.96 (d, J = 7.5 Hz, 1H), 6.56 (s, 1H), 6.25 (s , 1H), 5.61 (d, J = 16.0 Hz, 1H), 5.56 (d, J = 16.0 Hz, 1H), 3.92 (d, J = 13.7 Hz, 1H), 3.83 (s, 3H), 3.76 (s , 3H), 3.73 (d, J = 14.6 Hz, 1H), 3.61 (d, J = 14.6 Hz, 1H), 3.31 (d, J = 13.7 Hz, 1H), 2.91-2.82 (m, 2H), 2.82 -2.61 (m, 2H), 2.31 (s, 3H).
MS (ESI +) 551 (M ⁺ +1)

Example 15
3- [1- (4,7-Dihydrothieno [2,3-c] pyridin-6 (5H) -ylmethyl) -2,2,2-trifluoro-1-hydroxyethyl] -1- (3-methylbenzyl ) -1H-indazole-6-carbonitrile 3- [1- (4,7-dihydrothieno [2,3-c] pyridin-6 (5H) -ylmethyl) -2,2,2-trifluoro-1-hydroxyethyl] -1- (3-methylbenzyl) -1H-indazole-6-carbonitrile
¹ H-NMR (400 MHz, CDCl ₃ ) δ 8.28 (d, J = 8.5 Hz, 1H), 7.68 (s, 1H), 7.36 (dd, J = 8.5, 1.2 Hz, 1H), 7.22 (dd, J = 7.5, 7.5 Hz, 1H), 7.15-7.07 (m, 2H), 7.00 (s, 1H), 6.94 (d, J = 7.5 Hz, 1H), 6.76 (d, J = 5.1 Hz, 1H), 5.92 (bs, 1H), 5.57 (s, 2H), 3.98 (d, J = 13.6 Hz, 1H), 3.79 (dd, J = 13.6, 13.6 Hz, 1H), 3.72 (dd, J = 13.6, 13.6 Hz, 1H), 3.30 (d, J = 13.6 Hz, 1H), 2.98-2.83 (m, 2H), 2.77-2.57 (m, 2H), 2.32 (s, 3H).
MS (ESI +) 497 (M ⁺ +1)

Example 16
1- (3-Methylbenzyl) -3- {2,2,2-trifluoro-1-hydroxy-1-[(4-phenylpiperazin-1-yl) methyl] ethyl} -1H-indazole-6-carbo Nitrile 1- (3-methylbenzyl) -3- {2,2,2-trifluoro-1-hydroxy-1-[(4-phenylpiperazin-1-yl) methyl] ethyl} -1H-indazole-6-carbonitrile
¹ H-NMR (400 MHz, CDCl ₃ ) δ 8.28 (d, J = 8.5 Hz, 1H), 7.69 (s, 1H), 7.37 (dd, J = 8.5, 1.2 Hz, 1H), 7.30-7.15 (m , 3H), 7.11 (d, J = 7.6 Hz, 1H), 6.99 (s, 1H), 6.96 (d, J = 7.6 Hz, 1H), 6.90-6.80 (m, 3H), 5.90 (bs, 1H) , 5.57 (s, 2H), 3.83 (d, J = 13.6 Hz, 1H), 3.21 (d, J = 13.6 Hz, 1H), 3.16-2.98 (m, 4H), 2.80-2.60 (m, 4H), 2.30 (s, 3H).
MS (ESI +) 520 (M ⁺ +1)

Example 17
1- (3-Methylbenzyl) -3- {2,2,2-trifluoro-1-hydroxy-1-[(methylamino) methyl] ethyl} -1H-indazole-6-carbonitrile 1- (3- methylbenzyl) -3- {2,2,2-trifluoro-1-hydroxy-1-[(methylamino) methyl] ethyl} -1H-indazole-6-carbonitrile
¹ H-NMR (400 MHz, CDCl ₃ ) δ 8.22 (d, J = 8.5 Hz, 1H), 7.63 (s, 1H), 7.35 (dd, J = 8.5, 1.2 Hz, 1H), 7.21 (dd, J = 7.6, 7.6 Hz, 1H), 7.11 (d, J = 7.6 Hz, 1H), 6.98 (s, 1H), 6.93 (d, J = 7.6 Hz, 1H), 5.56 (s, 2H), 3.65 (d , J = 12.8 Hz, 1H), 3.35 (d, J = 12.8 Hz, 1H), 2.50 (s, 3H), 2.31 (s, 3H).
MS (ESI +) 389 (M ⁺ +1)

Example 18
3- {1-[(Benzylamino) methyl] -2,2,2-trifluoro-1-hydroxyethyl} -1- (3-methylbenzyl) -1H-indazole-6-carbonitrile 3- {1- [(benzylamino) methyl] -2,2,2-trifluoro-1-hydroxyethyl} -1- (3-methylbenzyl) -1H-indazole-6-carbonitrile
¹ H-NMR (400 MHz, CDCl ₃ ) δ 8.17 (d, J = 8.5 Hz, 1H), 7.64 (s, 1H), 7.37-7.21 (m, 6H), 7.17 (dd, J = 7.6, 7.6 Hz , 1H), 7.09 (d, J = 7.6 Hz, 1H), 6.95 (s, 1H), 6.91 (d, J = 7.6 Hz, 1H), 5.54 (s, 2H), 3.87 (d, J = 13.2 Hz , 1H), 3.82 (d, J = 13.2 Hz, 1H), 3.76 (d, J = 12.7 Hz, 1H), 3.37 (d, J = 12.7 Hz, 1H), 2.27 (s, 3H).
MS (ESI +) 465 (M ⁺ +1)

Example 19
3- {1-[(Cyclohexylamino) methyl] -2,2,2-trifluoro-1-hydroxyethyl} -1- (3-methylbenzyl) -1H-indazole-6-carbonitrile 3- {1- [(cyclohexylamino) methyl] -2,2,2-trifluoro-1-hydroxyethyl} -1- (3-methylbenzyl) -1H-indazole-6-carbonitrile
¹ H-NMR (400 MHz, CDCl ₃ ) δ 8.24 (d, J = 8.6 Hz, 1H), 7.64 (s, 1H), 7.36 (dd, J = 8.6, 1.3 Hz, 1H), 7.20 (dd, J = 7.6, 7.6 Hz, 1H), 7.11 (d, J = 7.6 Hz, 1H), 6.97 (s, 1H), 6.93 (d, J = 7.6 Hz, 1H), 5.56 (s, 2H), 3.71 (d , J = 12.8 Hz, 1H), 3.37 (d, J = 12.8 Hz, 1H), 2.50-2.39 (m, 1H), 2.31 (s, 3H), 1.99-1.70 (m, 2H), 1.75-1.64 ( m, 2H), 1.64-1.54 (m, 1H), 1.33-0.97 (m, 6H).
MS (ESI +) 457 (M ⁺ +1)

Similar to the compound of Example 2, the compounds of Examples 20 to 23 whose structural formulas are shown in Table 3 were produced.

Example 20
[4-({1- [2- (1-Benzyl-6-nitro-1H-indazol-3-yl) -3,3,3-trifluoro-2-hydroxypropyl] piperidin-4-yl} oxy) -3-Methoxyphenyl] acetic acid [4-({1- [2- (1-benzyl-6-nitro-1H-indazol-3-yl) -3,3,3-trifluoro-2-hydroxypropyl] piperidin -4-yl} oxy) -3-methoxyphenyl] acetic acid
MS (ESI +) 629 (M ⁺ +1)

Example 21
3- [4-({1- [2- (1-Benzyl-6-nitro-1H-indazol-3-yl) -3,3,3-trifluoro-2-hydroxypropyl] piperidin-4-yl} Oxy) -3,5-dimethoxyphenyl] propanoic acid 3- [4-({1- [2- (1-benzyl-6-nitro-1H-indazol-3-yl) -3,3,3-trifluoro- 2-hydroxypropyl] piperidin-4-yl} oxy) -3,5-dimethoxyphenyl] propanoic acid
¹ H-NMR (400 MHz, CDCl ₃ ) δ 8.26 (d, J = 1.8 Hz, 1H), 8.21 (d, J = 9.0 Hz, 1H), 8.05 (dd, J = 9.0, 1.8 Hz, 1H), 7.38-7.19 (m, 5H), 6.75, 6.43 (s, 2H), 5.69 (d, J = 15.8 Hz, 1H), 5.59 (d, J = 15.8 Hz, 1H), 4.33-4.23 (m, 2H) , 3.94-3.75 (m, 1H), 3.86, 3.80 (s, 6H), 3.70-3.50 (m, 2H), 3.56 (d, J = 13.1 Hz, 1H), 3.35-3.24 (m, 1H), 2.91 (t, J = 7.5 Hz, 2H), 2.67 (t, J = 7.5 Hz, 2H), 2.06-1.79 (m, 4H).
MS (ESI +) 673 (M ⁺ +1)

Example 22
3- [4-({1- [2- (1-Benzyl-6-nitro-1H-indazol-3-yl) -3,3,3-trifluoro-2-hydroxypropyl] piperidin-4-yl} Sulphonyl) phenyl] propanoic acid 3- [4-({1- [2- (1-benzyl-6-nitro-1H-indazol-3-yl) -3,3,3-trifluoro-2-hydroxypropyl] piperidin- 4-yl} sulfonyl) phenyl] propanoic acid
¹ H-NMR (400 MHz, CDCl ₃ ) δ 8.34 (d, J = 1.6 Hz, 1H), 8.15 (d, J = 9.0 Hz, 1H), 8.04 (dd, J = 9.0, 1.6 Hz, 1H), 7.70 (d, J = 7.9 Hz, 2H), 7.42 (d, J = 7.9 Hz, 2H), 7.35-7.28 (m, 3H), 7.23-7.15 (m, 2H), 5.69 (d, J = 15.5 Hz , 1H), 5.51 (d, J = 15.5 Hz, 1H), 4.24 (d, J = 13.0 Hz, 1H), 3.90-3.70 (m, 1H), 3.60-3.30 (m, 2H), 3.53 (d, J = 13.0 Hz, 1H), 3.10-2.80 (m, 2H), 3.02 (t, J = 7.3 Hz, 2H), 2.96 (t, J = 7.3 Hz, 2H), 2.23-1.63 (m, 4H).
MS (ESI +) 661 (M ⁺ +1)

Example 23
3- {4-[(1- {2- [6-Cyano-1- (3-methylbenzyl) -1H-indazol-3-yl] -3,3,3-trifluoro-2-hydroxypropyl} piperidine -4-yl) oxy] -3,5-dimethoxyphenyl} propanoic acid 3- {4-[(1- {2- [6-cyano-1- (3-methylbenzyl) -1H-indazol-3-yl] -3,3,3-trifluoro-2-hydroxypropyl} piperidin-4-yl) oxy] -3,5-dimethoxyphenyl} propanoic acid
MS (ESI +) 667 (M ⁺ +1)

Test example 1
Binding inhibition test Insect cells infected with baculovirus to express human GRα protein were treated with approximately equal volume of binding buffer (10 mM Tris-Cl, 1.5 mM EDTA, 10% glycerol, 5 mM DTT, 20 mM sodium molybdate). , pH 7.6). The operation of rapidly freezing with liquid nitrogen and thawing at room temperature was performed twice to disrupt the cell membrane. Centrifugation was performed at 4 ° C. and 100,000 g for 1 hour in an ultracentrifuge, and the obtained supernatant was used as a cytoplasmic fraction containing human GRα protein.
A 96-well polypropylene plate (Coaster, etc.) was placed on ice, and 1 μL of DMSO or a test compound was placed in each well. Add 50 μL each of ³ H-Dex (tritiated dexamethasone; Amersham) / GR protein solution (diluted with binding buffer) diluted to 10 nM with binding buffer, and stir gently with a plate mixer And then allowed to stand at 4 ° C. for 16-20 hours (DMSO final concentration: 1%).
50 μL of dextran-coated activated carbon (Sigma) 5% solution suspended in a binding buffer was placed in each well and gently stirred for 30 seconds with a plate mixer. Then, it centrifuged at 4 degreeC and 2500 rotation for 5 minutes, and measured ³ H count of 50 microliters of supernatant liquids by the top count (made by Perkin Elmer). Each test compound was measured twice.
The binding activity was calculated as follows. The average value of ³ H count in the presence of 10 μM dexamethasone (Dex) was defined as NSB (non-specific binding), and the binding inhibition rate of each well was calculated by the following formula. Binding inhibition rate (%) = 100 × {1- (each well cpm value−NSB) / (DMSO well cpm value average−NSB)} (cpm is an abbreviation of count per minute) The average binding inhibition rate for each well was calculated and used as the binding inhibition rate for each test compound.
Test example 2
TAT (tyrosine aminotransferase) assay H4-III-E maintained in passage in α-MEM medium A (10% non-immobilized FBS, 50 μM 2-mercapto-ethanol) α-MEM medium A or α-MEM medium The suspension was suspended in B (phenol red-free, 10% non-immobilized FBS, 50 μM 2-mercapto-ethanol added), seeded in a 96-well plate at 2 × 10 ⁴ cells / 100 μL / well, and cultured overnight. The medium supernatant was removed, and 100 μL of the test compound (diluted with α-MEM medium A or α-MEM medium B) was added, followed by further overnight culture. When measuring agonist activity, add test compound alone, and when measuring antagonist activity, add dexamethasone at 0.005 μM simultaneously to determine how much the test compound suppresses TAT activity induction by dexamethasone. investigated.
The culture supernatant of the plate is removed by aspiration, and cell lysate (1% NP-40, 0.2% TritonX-100, 0.25% DOC, 0.1% SDS, 1 mM EGTA, 150 mM NaCl, Tris (pH 7.4), Protease inhibitor cocktail After adding 20 μL of [2.5 mg / ml aprotinin, 2.5 mg / ml leupeptin, 2.5 mg / ml soybean trypsin inhibitor]), TAT reaction reagent (10N KOH, 0.125M KH ₂ PO ₄ , 0.5M α-ketoglutarate, 5mM Pyridoxal- 150 μL of 5′phosphate, L-tyrosine) was added and allowed to react at 37 ° C. for 15 minutes. Furthermore, 20 μL of 10N KOH was added, reacted at 37 ° C. for 30 minutes, and absorbance at 331 nm was measured with a microplate reader (SPECTRA MAX250).
The value obtained by subtracting the average value of the absorbance of the non-drug-added group to which the drug and TAT reaction solution were not added from the average value of the absorbance of the well to which the test compound was added was compared with the Dex-treated group (0.5 nM to 5 μM) The agonist activity (%) was calculated based on the following calculation formula, assuming that the absorbance of the group exhibiting the maximum activity in the common ratio 10) was 100%. Agonist activity (%) = 100 × [(absorbance of drug-treated group) − (absorbance of TAT reaction reagent non-added group)] / [(absorbance of Dex-treated group showing maximum value) − (TAT reaction reagent non-added group) Absorbance of
On the other hand, antagonist activity was calculated as follows. Antagonist activity (%) = Inhibition rate of TAT activity increase by Dex (%) = 100−100 × [(absorbance of drug-treated group) − (absorbance of non-drug group)] / [(absorbance of Dex-treated group) − (Absorbance of the group without added drug)]
Tables 4 and 5 show the results of the binding inhibition test of Test Example 1. From the results of Tables 4 and 5, it can be seen that the compounds of the present invention have an action as a GR function regulator.

  The condensed pyrazole derivatives and their pharmaceutically acceptable salts according to the present invention can be used as non-steroidal anti-inflammatory drugs or anti-diabetic drugs with reduced side effects compared to steroidal anti-inflammatory drugs.

Claims (13)

Formula (1):

[Wherein the 5-membered Cy with R ¹ is represented by the formula (2):

Or a ring represented by formula (3):

Represents a ring represented by
R ¹ represents a substituted alkyl group, a substituted or unsubstituted alkenyl group, a substituted or unsubstituted alkynyl group, a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted cycloalkenyl group, a substituted or unsubstituted aryl group Substituted or unsubstituted heteroaryl group, substituted or unsubstituted aralkyl group, substituted or unsubstituted heteroaralkyl group, substituted or unsubstituted alkoxy group, substituted or unsubstituted alkanoyl group, substituted or unsubstituted alkoxycarbonyl Group, substituted or unsubstituted alkylsulfonyl group, substituted or unsubstituted cycloalkyloxy group, substituted or unsubstituted cycloalkylcarbonyl group, substituted or unsubstituted cycloalkyloxycarbonyl group, substituted or unsubstituted cycloalkylsulfonyl Group, Substituted or unsubstituted aryloxy group, substituted or unsubstituted aroyl group, substituted or unsubstituted aryloxycarbonyl group, substituted or unsubstituted arylsulfonyl group, substituted or unsubstituted heteroaryloxy group, substituted or unsubstituted Heteroarylcarbonyl group, substituted or unsubstituted heteroaryloxycarbonyl group, substituted or unsubstituted heteroarylsulfonyl group, substituted or unsubstituted aralkyloxy group, substituted or unsubstituted aralkylcarbonyl group, substituted or unsubstituted Aralkyloxycarbonyl group, substituted or unsubstituted aralkylsulfonyl group, substituted or unsubstituted heteroaralkyloxy group, substituted or unsubstituted heteroaralkylcarbonyl group, substituted or unsubstituted heteroaralkyloxy group Cicarbonyl group, substituted or unsubstituted heteroaralkylsulfonyl group, substituted or unsubstituted saturated or unsaturated aliphatic heterocyclic group, substituted or unsubstituted saturated or unsaturated aliphatic heterocyclic carbonyl group, substituted or unsubstituted Represents a substituted saturated or unsaturated aliphatic heterocyclic sulfonyl group, a substituted or unsubstituted carbamoyl group, or a substituted or unsubstituted sulfamoyl group;
^{-W 4 = W 5 -W 6 =} W 7 - has the following formula (a) ~ (h):
^{(A) -CR 4 = CR 5} -CR 6 = CR 7 -;
^{(B) -N = CR 5 -CR} 6 = CR 7 -;
^{(C) -CR 4 = N-} CR 6 = CR 7 -;
^{(D) -CR 4 = CR 5} -N = CR 7 -;
^{(E) -CR 4 = CR 5} -CR 6 = N-;
^{(F) -N = CR 5 -N} = CR 7 -;
^{(G) -CR 4 = N-} CR 6 = N-;
^{(H) -CR 4 = N-} N = CR 7 -
[Wherein, R ⁴ , R ⁵ , R ⁶ and R ⁷ are each independently the same or different and represent the formula: -EA, wherein E is a single bond or the following formula 1 )~14):
1) -C (R ¹⁶ ) R ^17- ,
2) -O-,
3) -S (= O) m-,
4) -S (= O) ₂ NR ^16- ,
5) -C (= O)-,
6) -C (= O) O-,
7) -C (= O) NR ^16- ,
8) −C (= NR ¹⁶ ) NR ¹⁷ −,
9) -NR ^16- ,
^{10) -N (R 16) C} (= O) -,
11) -N (R ¹⁶ ) S (= O) _2- ,
^{12) -N (R 16) C} (= O) N (R 17) -,
^{13) -N (R 16) S} (= O) 2 N (R 17) -,
14) -P (= O) (OR ¹⁶ ) _2-
(Wherein R ¹⁶ and R ¹⁷ each independently represents a hydrogen atom, an alkyl group having 1 to 3 carbon atoms, or an alkoxy group having 1 to 3 carbon atoms, or formula 8). In 12) and 13), R ¹⁶ and R ¹⁷ may be bonded to each other to represent an alkylene group having 2 to 4 carbon atoms, and m represents 0, 1 or 2. ) Represents a group selected from
When E is a single bond, A is a hydrogen atom, halogen atom, cyano group, nitro group, hydroxyl group, carboxyl group, substituted or unsubstituted alkyl group, substituted or unsubstituted alkenyl group, substituted or unsubstituted alkynyl. Group, substituted or unsubstituted cycloalkyl group, substituted or unsubstituted cycloalkenyl group, substituted or unsubstituted aryl group, substituted or unsubstituted heteroaryl group, substituted or unsubstituted aralkyl group, substituted or unsubstituted Represents a heteroaralkyl group, or a substituted or unsubstituted saturated or unsaturated aliphatic heterocyclic group,
When E represents a group selected from the above formulas 1) to 14), A represents a hydrogen atom, a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkenyl group, a substituted or unsubstituted alkynyl group, substituted or An unsubstituted cycloalkyl group, a substituted or unsubstituted cycloalkenyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted heteroaryl group, a substituted or unsubstituted aralkyl group, a substituted or unsubstituted heteroaralkyl group, Or a substituted or unsubstituted saturated or unsaturated aliphatic heterocyclic group. ]
Represents a group selected from
R ⁸ represents a group represented by the formula: —OR ¹¹ or —N (R ¹¹ ) R ¹² (wherein R ¹¹ and R ¹² are each independently a hydrogen atom, or substituted or unsubstituted) Represents an alkyl group having 1 to 5 carbon atoms),
R ⁹ represents an alkyl group substituted with one or more halogen atoms, or a cycloalkyl group substituted with one or more halogen atoms;
R ¹⁰ represents a group represented by the formula: — [C (R ¹³ ) R ¹⁴ ] n—R ¹⁵ (wherein R ¹³ and R ¹⁴ are each independently a hydrogen atom, an alkyl group or a halogen atom). R ¹³ and R ¹⁴ together represent an oxo group, or R ¹³ and R ¹⁴ may be bonded together to form a cycloalkane together with the carbon atom to which they are bonded, One or two —CH ₂ — groups in the cycloalkane are —NH—, —S—, —S (═O) —, —S (═O) ₂ —, —C (═O) — and —O. May be the same or different and replaced by a group selected from:
n represents an integer of 1 to 10, and when n is an integer of 2 to 10, C (R ¹³ ) R ¹⁴ may be the same or different;
R ¹⁵ represents a hydroxyl group, a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkenyl group, a substituted or unsubstituted alkynyl group, a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted cycloalkenyl group, substituted or Unsubstituted aryl group, substituted or unsubstituted heteroaryl group, substituted or unsubstituted alkoxy group, substituted or unsubstituted alkylthio group, substituted or unsubstituted alkylsulfinyl group, substituted or unsubstituted alkylsulfonyl group, substituted Or an unsubstituted cycloalkyloxy group, a substituted or unsubstituted cycloalkylthio group, a substituted or unsubstituted cycloalkylsulfinyl group, a substituted or unsubstituted cycloalkylsulfonyl group, a substituted or unsubstituted aryloxy group, a substituted or unsubstituted Replacement ants Ruthio group, substituted or unsubstituted arylsulfinyl group, substituted or unsubstituted arylsulfonyl group, substituted or unsubstituted heteroaryloxy group, substituted or unsubstituted heteroarylthio group, substituted or unsubstituted heteroarylsulfinyl group Substituted or unsubstituted heteroarylsulfonyl group, substituted or unsubstituted carbamoyl group, substituted or unsubstituted sulfamoyl group, substituted or unsubstituted thiocarbamoyl group, substituted or unsubstituted saturated or unsaturated aliphatic heterocycle Group, substituted or unsubstituted saturated or unsaturated aliphatic heterocyclic oxy group, substituted or unsubstituted saturated or unsaturated aliphatic heterocyclic thio group, substituted or unsubstituted saturated or unsaturated aliphatic heterocyclic ring Sulfinyl group, substituted or unsubstituted Saturated or aliphatic heterocyclic sulfonyl group unsaturated, or formula: N (R ¹⁸⁾ group (wherein represented by R ^19, R ¹⁸ and R ¹⁹ are independently hydrogen atom, a substituted or unsubstituted Alkyl group, substituted or unsubstituted alkenyl group, substituted or unsubstituted alkynyl group, substituted or unsubstituted cycloalkyl group, substituted or unsubstituted cycloalkenyl group, substituted or unsubstituted aryl group, substituted or unsubstituted Heteroaryl group, substituted or unsubstituted aralkyl group, substituted or unsubstituted heteroaralkyl group, substituted or unsubstituted alkanoyl group, substituted or unsubstituted alkoxycarbonyl group, substituted or unsubstituted alkylsulfonyl group, substituted or Unsubstituted cycloalkylcarbonyl group, substituted or unsubstituted cycloalkyloxy Nyl group, substituted or unsubstituted cycloalkylsulfonyl group, substituted or unsubstituted aroyl group, substituted or unsubstituted aryloxycarbonyl group, substituted or unsubstituted arylsulfonyl group, substituted or unsubstituted heteroarylcarbonyl group, Substituted or unsubstituted heteroaryloxycarbonyl group, substituted or unsubstituted heteroarylsulfonyl group, substituted or unsubstituted aralkylcarbonyl group, substituted or unsubstituted aralkyloxycarbonyl group, substituted or unsubstituted aralkylsulfonyl group, substituted Or an unsubstituted heteroaralkylcarbonyl group, a substituted or unsubstituted heteroaralkyloxycarbonyl group, a substituted or unsubstituted heteroaralkylsulfonyl group, a substituted or unsubstituted carbamoyl group, substituted Or an unsubstituted sulfamoyl group, a substituted or unsubstituted thiocarbamoyl group, a substituted or unsubstituted saturated or unsaturated aliphatic heterocyclic group, a substituted or unsubstituted saturated or unsaturated aliphatic heterocyclic carbonyl group, Represents a substituted or unsubstituted saturated or unsaturated aliphatic heterocyclic sulfonyl group, or R ¹⁸ and R ¹⁹ are bonded together with the nitrogen atom to which they are bonded, together with a substituted or unsubstituted, saturated or unsaturated A monocyclic, bicyclic or tricyclic nitrogen-containing heterocycle containing 1 to 4 heteroatoms selected from 0 to 2 oxygen atoms, 0 to 2 sulfur atoms and 1 to 4 nitrogen atoms May be formed. ). ]
Or a prodrug thereof, or a pharmaceutically acceptable salt thereof. A 5-membered ring Cy with R ¹ is represented by formula (2):

The compound of Claim 1 which represents the ring represented by this, its prodrug, or those pharmacologically acceptable salts. ^{-W 4 = W 5 -W 6 =} W 7 - is of the formula ^{(a): - CR 4 =} CR 5 -CR 6 = CR 7 - ( ^{wherein, R 4, R 5, R} 6 and R ⁷ wherein The compound according to claim 1 or 2 or a prodrug thereof, or a pharmaceutically acceptable salt thereof, which represents the same as defined in item 1. ^{-W 4 = W 5 -W 6 =} W 7 - is of formula ^{(d): - CR 4 =} CR 5 -N = CR 7 - ( wherein, R ^4, R ⁵ and R ⁷ claim 1 as defined Or a prodrug thereof, or a pharmaceutically acceptable salt thereof. R ¹ represents a substituted or unsubstituted aralkyl group, a substituted or unsubstituted heteroaralkyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted heteroaryl group, a substituted or unsubstituted cycloalkyl group, substituted or unsubstituted The compound according to any one of claims 1 to 4, which represents an alkyl group substituted with a substituted cycloalkyl group, or an alkyl group substituted with a substituted or unsubstituted saturated or unsaturated aliphatic heterocycle. Or a prodrug thereof, or a pharmaceutically acceptable salt thereof. R ⁸ represents a group represented by the formula: -OR ¹¹ (wherein R ¹¹ has the same meaning as in claim 1), or a compound or prodrug thereof according to any one of claims 1 to 5 Or a pharmaceutically acceptable salt thereof. The compound according to claim 6 or a prodrug thereof, or a pharmaceutically acceptable salt thereof, wherein R ¹¹ represents a hydrogen atom. The compound according to any one of claims 1 to 7 or a prodrug thereof, wherein R ⁹ represents an alkyl group having 1 to 6 carbon atoms substituted with 1 to 7 fluorine atoms or chlorine atoms, Or a pharmaceutically acceptable salt thereof. The compound according to claim 8, or a prodrug thereof, or a pharmaceutically acceptable salt thereof, wherein R ⁹ represents a trifluoromethyl group. In the formula of R ¹⁰ : — [C (R ¹³ ) R ¹⁴ ] n—R ¹⁵ , R ¹³ and R ¹⁴ represent a hydrogen atom, n represents 1 or 2, and R ¹⁵ represents the formula: N (R ¹⁸ ) The compound or prodrug thereof according to any one of claims 1 to 9, which represents a group represented by R ¹⁹ (wherein R ¹⁸ and R ¹⁹ have the same meaning as in claim 1), or a prodrug thereof A pharmaceutically acceptable salt. Attached R ¹⁸ and R ^19, together with the nitrogen atom to which they are attached, a saturated or unsaturated and is substituted represents a nitrogen-containing heterocyclic monocyclic or bicyclic compound or a professional according to claim 10 Drugs or pharmaceutically acceptable salts thereof.   The glucocorticoid receptor function regulator which contains the compound as described in any one of Claims 1-11, its prodrug, or those pharmacologically acceptable salts as an active ingredient.   The therapeutic agent or preventive agent of an inflammatory disease or diabetes which contains the compound as described in any one of Claims 1-11, its prodrug, or those pharmacologically acceptable salts as an active ingredient.