JP2013014548A - Acylsulfonamide derivative - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a compound useful as a therapeutic agent for diabetes.SOLUTION: There is disclosed a compound expressed by chemical formula or its pharmaceutical acceptable salt. In the formula, ring A represents a substituted or unsubstituted aromatic carbon ring or a substituted or unsubstituted aromatic heterocycle; Rrepresents hydrogen, substituted or unsubstituted alkyl or the like; Rand Reach independently represent hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, or the like; Rrepresents -CRR-, -O- or -S-; Reach independently represents halogen, hydroxy, cyano, nitro, carboxy or substituted or unsubstituted alkyl; Rand Reach independently represent hydrogen, halogen, hydroxy, cyano, nitro, carboxy or substituted or unsubstituted alkyl; m is an integer of 0 to 3; and n is an integer of 0 to 6.

Description

  The present invention relates to a pharmaceutical, particularly a novel acylsulfonamide derivative useful as a therapeutic agent for diabetes or a pharmaceutically acceptable salt thereof, and a pharmaceutical comprising an acylsulfonamide derivative as an active ingredient.

Diabetes mellitus is a disease whose main feature is chronic hyperglycemia and develops due to an absolute or relative lack of insulin action. In clinical practice, insulin-dependent diabetes (hereinafter referred to as “type 1 diabetes”) and non-insulin-dependent diabetes (hereinafter referred to as “type 2 diabetes”) are roughly classified. In type 2 diabetes, which accounts for about 90% of diabetic patients, a decrease in insulin secretion from pancreatic β cells is one of the main causes of onset, and postprandial hyperglycemia due to early insulin secretion disorder is particularly observed. Currently, sulfonylurea agents (SU agents) are the mainstream as insulin secretagogues, but they are prone to hypoglycemia and are known to cause secondary ineffectiveness due to pancreatic exhaustion in long-term administration. Moreover, although the SU agent is effective for blood glucose control between meals, it is difficult to suppress hyperglycemia after meals. Recently, it was confirmed by a large-scale clinical trial that correction of postprandial hyperglycemia is important for suppression of the onset and progression of diabetic complications (Non-patent Document 1). In addition, it has been reported that arteriosclerosis develops at the time of only postprandial hyperglycemia, and that the persistence of postprandial mild hyperglycemia increases mortality due to causes such as cardiovascular disease (Non-patent Documents 2 and 3). This indicates that postprandial hyperglycemia, even if mild, is an independent risk factor for cardiovascular death. From the above, the importance and necessity of pharmacotherapy for postprandial hyperglycemia has been recognized.
In type 2 diabetes, it is understood that chronic hyperglycemia causes a decrease in pancreatic β-cell function, that is, a decrease in pancreatic insulin content (Non-patent Document 4).
Therefore, a drug having a rapid onset of action and having a hypoglycemic action without causing hypoglycemia has a profile suitable for correcting postprandial hyperglycemia and / or fasting blood sugar, or enhancing pancreatic function, and type 1 diabetes It is considered useful for the treatment and prevention of type 2 diabetes.

特許文献２には、Ｃ型肝炎に有用な化合物として、以下のアシルスルホンアミド誘導体が記載されているが、血糖降下作用については記載されていない。

特許文献３には、痛風に有用な化合物として、以下のアシルスルホンアミド誘導体が記載されているが、血糖降下作用については記載されていない。

特許文献４には、利尿薬に有用な化合物として、以下のアシルスルホンアミド誘導体が記載されているが、血糖降下作用については記載されていない。

非特許文献５には、以下のアシルスルホンアミド誘導体が記載されているが、血糖降下作用については記載されていない。

非特許文献６には、以下のアシルスルホンアミド誘導体のＰＰＡＲγ活性について記載されているが、それらは単に予測に過ぎず、実際に以下の化合物を合成して確認したものではない。

非特許文献７には、以下のアシルスルホンアミド誘導体が記載されているが、血糖降下作用については記載されていない。

非特許文献８には、アンギオテンシンＩＩアンタゴニスト作用を有する化合物として、以下のアシルスルホンアミド誘導体が記載されているが、血糖降下作用については記載されていない。

非特許文献９には、以下のアシルスルホンアミド誘導体が記載されているが、血糖降下作用については記載されていない。

Patent Document 1 describes the following acylsulfonamide derivatives as compounds useful for diabetes.

Patent Document 2 describes the following acylsulfonamide derivatives as compounds useful for hepatitis C, but does not describe the hypoglycemic effect.

Patent Document 3 describes the following acylsulfonamide derivatives as compounds useful for gout, but does not describe the hypoglycemic effect.

Patent Document 4 describes the following acylsulfonamide derivatives as useful compounds for diuretics, but does not describe the hypoglycemic action.

Non-Patent Document 5 describes the following acylsulfonamide derivatives, but does not describe the hypoglycemic effect.

Non-Patent Document 6 describes the PPARγ activity of the following acylsulfonamide derivatives, but these are merely predictions and are not actually confirmed by synthesizing the following compounds.

Non-Patent Document 7 describes the following acylsulfonamide derivatives, but does not describe the hypoglycemic effect.

Non-Patent Document 8 describes the following acylsulfonamide derivatives as compounds having an angiotensin II antagonistic action, but does not describe the hypoglycemic action.

Non-Patent Document 9 describes the following acylsulfonamide derivatives, but does not describe the hypoglycemic effect.

International Publication No. 2005/108370 Pamphlet JP 2002-517508 A JP-A-51-021975 US Pat. No. 3,557,153

N. Engl. J. Med., 329: 977-986, 1993 Lancet, 354: 617, 1999 Brit. Med. J., 321: 405-413, 2000 Joslin ′s Diabetes Mellitus, Thirteenth Edition, Lea and Febiger, Philadelphia, PA, U.S.A, 1994 Organic Letters (2009), 11 (12), 2707-2710 Molecular Pharmacology (2007), 71 (2), 398-406 Angewandte Chemie, International Edition (2006), 45 (19), 3154-3157 Bioorganic & Medicinal Chemistry Letters (1995), 5 (22), 2605-10 Journal of the American Chemical Society (1955), 77, 4564-5

  An object of the present invention is to provide a novel compound having a hypoglycemic action and a medicament containing the same.

（式中、
環Ａは置換若しくは非置換の芳香族炭素環または置換若しくは非置換の芳香族複素環であり、
Ｒ^１は水素、置換若しくは非置換のアルキル、置換若しくは非置換のアルケニル、置換若しくは非置換のアルキニル、置換若しくは非置換のアリール、置換若しくは非置換のヘテロアリール、置換もしくは非置換のシクロアルキル、置換もしくは非置換のシクロアルケニルまたは置換若しくは非置換のヘテロサイクリルであり、
Ｒ^２及びＲ^３はそれぞれ独立して、水素、置換若しくは非置換のアルキル、置換若しくは非置換のアルケニル、置換若しくは非置換のアルキニル、置換若しくは非置換のヘテロアリール、置換もしくは非置換のシクロアルキル、置換もしくは非置換のシクロアルケニルまたは置換若しくは非置換のヘテロサイクリルであり、
Ｒ^４は−ＣＲ^５ａＲ^５ｂ−、−Ｏ−または−Ｓ−であり、
Ｒ^５はそれぞれ独立して、ハロゲン、ヒドロキシ、シアノ、ニトロ、カルボキシまたは置換若しくは非置換のアルキルであり、
Ｒ^５ａ及びＲ^５ｂはそれぞれ独立して、水素、ハロゲン、ヒドロキシ、シアノ、ニトロ、カルボキシまたは置換若しくは非置換のアルキルであり、
ｍは０〜３の整数であり、
ｎは０〜６の整数である。
但し、以下に示される化合物：

を除く。）で示される化合物またはその製薬上許容される塩。
（２）
環Ａが

（ここで、Ｒ^６、Ｒ^７、Ｒ^８、Ｒ^９及びＲ^１０はそれぞれ独立して、水素、ハロゲン、ヒドロキシ、シアノ、ニトロ、カルボキシ、置換若しくは非置換のアルキル、置換若しくは非置換のアルケニル、置換若しくは非置換のアルキニル、置換若しくは非置換のアリール、置換若しくは非置換のヘテロアリール、置換もしくは非置換のシクロアルキル、置換もしくは非置換のシクロアルケニル、置換若しくは非置換のヘテロサイクリル、置換若しくは非置換のアルキルオキシ、置換若しくは非置換のアリールオキシ、置換若しくは非置換のヘテロアリールオキシ、置換若しくは非置換のシクロアルキルオキシ、置換若しくは非置換のシクロアルケニルオキシ、置換若しくは非置換のヘテロサイクリルオキシ、置換若しくは非置換のアリールアルキルオキシ、置換若しくは非置換のヘテロアリールアルキルオキシ、置換若しくは非置換のシクロアルキルアルキルオキシ、置換若しくは非置換のシクロアルケニルアルキルオキシ、置換若しくは非置換のヘテロサイクリルアルキルオキシ、置換若しくは非置換のアシル、置換若しくは非置換のカルバモイル、置換若しくは非置換のアミノまたは式：−（ＣＲ^１２Ｒ^１３）ｐ−ＮＲ^１４−（Ｃ＝Ｏ）−Ｒ^１５（式中、Ｒ^１２及びＲ^１３はそれぞれ独立して、水素、置換若しくは非置換のアルキル、置換若しくは非置換のアルケニル、置換若しくは非置換のアルキニル、置換若しくは非置換のアリール、置換若しくは非置換のヘテロアリール、置換もしくは非置換のシクロアルキル、置換もしくは非置換のシクロアルケニルまたは置換若しくは非置換のヘテロサイクリルであり、ｐは１〜３の整数であり、Ｒ^１４は水素、置換若しくは非置換のアルキル、置換若しくは非置換のアルケニル、置換若しくは非置換のアルキニル、置換若しくは非置換のアリール、置換若しくは非置換のヘテロアリール、置換もしくは非置換のシクロアルキル、置換もしくは非置換のシクロアルケニルまたは置換若しくは非置換のヘテロサイクリルであり、Ｒ^１５は置換若しくは非置換のアリール、置換若しくは非置換のヘテロアリール、置換もしくは非置換のシクロアルキル、置換もしくは非置換のシクロアルケニルまたは置換若しくは非置換のヘテロサイクリルである。）で示される基である。）で示される基である、前記（１）記載の化合物またはその製薬上許容される塩。
（３）
Ｒ^８がハロゲン、ヒドロキシ、シアノ、ニトロ、カルボキシ、置換若しくは非置換のアルキル、置換若しくは非置換のアルケニル、置換若しくは非置換のアルキニル、置換若しくは非置換のアリール、置換若しくは非置換のヘテロアリール、置換もしくは非置換のシクロアルキル、置換もしくは非置換のシクロアルケニル、置換若しくは非置換のヘテロサイクリル、置換若しくは非置換のアルキルオキシ、置換若しくは非置換のアリールオキシ、置換若しくは非置換のヘテロアリールオキシ、置換若しくは非置換のシクロアルキルオキシ、置換若しくは非置換のシクロアルケニルオキシ、置換若しくは非置換のヘテロサイクリルオキシ、置換若しくは非置換のアリールアルキルオキシ、置換若しくは非置換のヘテロアリールアルキルオキシ、置換若しくは非置換のシクロアルキルアルキルオキシ、置換若しくは非置換のシクロアルケニルアルキルオキシ、置換若しくは非置換のヘテロサイクリルアルキルオキシ、置換若しくは非置換のアシル、置換若しくは非置換のカルバモイル、置換若しくは非置換のアミノまたは式：−（ＣＲ^１２Ｒ^１３）ｐ−ＮＲ^１４−（Ｃ＝Ｏ）−Ｒ^１５（式中、Ｒ^１２、Ｒ^１３、ｐ、Ｒ^１４及びＲ^１５は前記（２）と同意義である。）で示される基である、前記（２）記載の化合物またはその製薬上許容される塩。
（４）
Ｒ^８が置換若しくは非置換のヘテロアリールアルキルオキシ、置換若しくは非置換のアシルまたは式：−（ＣＲ^１２Ｒ^１３）ｐ−ＮＲ^１４−（Ｃ＝Ｏ）−Ｒ^１５（式中、Ｒ^１２、Ｒ^１３、ｐ、Ｒ^１４及びＲ^１５は前記（２）と同意義である。）で示される基である、前記（２）または（３）記載の化合物またはその製薬上許容される塩。
（５）
Ｒ^６、Ｒ^７、Ｒ^９及びＲ^１０が水素である、前記（３）または（４）記載の化合物またはその製薬上許容される塩。
（６）
ｍが１である、前記（１）〜（５）のいずれかに記載の化合物またはその製薬上許容される塩。
（７）
Ｒ^４が−ＣＲ^５ａＲ^５ｂ−である、前記（１）〜（６）のいずれかに記載の化合物またはその製薬上許容される塩。
（８）
Ｒ^５ａ及びＲ^５ｂが水素であり、ｍが１であり、ｎが０である、前記（７）記載の化合物またはその製薬上許容される塩。
（９）
式（Ｉ）中、

で示される部分が

（ここで、Ｒ^５ａ及びＲ^５ｂは前記（１）と同意義であり、Ｒ^１１は水素、ハロゲン、ヒドロキシ、シアノ、ニトロ、カルボキシまたは置換若しくは非置換のアルキルである。）である、前記（１）〜（５）のいずれかに記載の化合物またはその製薬上許容される塩。
（１０）
Ｒ^１が水素である、前記（１）〜（９）のいずれかに記載の化合物またはその製薬上許容される塩。
（１１）
Ｒ^２及びＲ^３が水素である、前記（１）〜（１０）のいずれかに記載の化合物またはその製薬上許容される塩。
（１２）
前記（１）〜（１１）のいずれかに記載の化合物またはその製薬上許容される塩を含有する医薬組成物。
（１３）
式（ＩＩ）：

（式中、
環Ａは置換若しくは非置換の芳香族炭素環または置換若しくは非置換の芳香族複素環であり、
環Ｂは置換若しくは非置換の非芳香族炭素環または置換若しくは非置換の非芳香族複素環であり、
Ｒ^１は水素、置換若しくは非置換のアルキル、置換若しくは非置換のアルケニル、置換若しくは非置換のアルキニル、置換若しくは非置換のアリール、置換若しくは非置換のヘテロアリール、置換もしくは非置換のシクロアルキル、置換もしくは非置換のシクロアルケニルまたは置換若しくは非置換のヘテロサイクリルであり、
Ｒ^２及びＲ^３はそれぞれ独立して、水素、置換若しくは非置換のアルキル、置換若しくは非置換のアルケニル、置換若しくは非置換のアルキニル、置換若しくは非置換のアリール、置換若しくは非置換のヘテロアリール、置換もしくは非置換のシクロアルキル、置換もしくは非置換のシクロアルケニルまたは置換若しくは非置換のヘテロサイクリルである。但し、以下に示される化合物：

を除く。）で示される化合物またはその製薬上許容される塩を有効成分とする、糖尿病治療剤。
また、本発明には、
（１４）
糖尿病の治療および／または予防のための、前記（１２）または（１３）記載の医薬組成物、
（１５）
前記（１）〜（１１）のいずれかに記載の化合物またはその製薬上許容される塩を投与することを特徴とする、糖尿病の予防または治療方法、
（１６）
糖尿病の治療および／または予防のための、前記（１）〜（１１）のいずれかに記載の化合物またはその製薬上許容される塩、
（１７）
前記式（Ｉ）で示される化合物またはその製薬上許容される塩による治療を受けている糖尿病患者に、他の糖尿病治療薬を投与することを特徴とする糖尿病の治療方法、
（１８）
前記式（Ｉ）で示される化合物またはその製薬上許容される塩と併用して他の糖尿病治療薬を投与することを特徴とする糖尿病の治療方法
も包含される。 The present invention relates to the following.
(1)
Formula (I):

(Where
Ring A is a substituted or unsubstituted aromatic carbocyclic ring or a substituted or unsubstituted aromatic heterocyclic ring,
R ¹ is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted Or unsubstituted cycloalkenyl or substituted or unsubstituted heterocyclyl,
R ² and R ³ are each independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, Substituted or unsubstituted cycloalkenyl or substituted or unsubstituted heterocyclyl,
R ⁴ is —CR ^5a R ^5b —, —O— or —S—;
Each R ⁵ is independently halogen, hydroxy, cyano, nitro, carboxy or substituted or unsubstituted alkyl;
R ^5a and R ^5b are each independently hydrogen, halogen, hydroxy, cyano, nitro, carboxy or substituted or unsubstituted alkyl;
m is an integer from 0 to 3,
n is an integer of 0-6.
However, the compounds shown below:

except for. Or a pharmaceutically acceptable salt thereof.
(2)
Ring A is

(Wherein R ⁶ , R ⁷ , R ⁸ , R ⁹ and R ¹⁰ are each independently hydrogen, halogen, hydroxy, cyano, nitro, carboxy, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, Substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted Substituted alkyloxy, substituted or unsubstituted aryloxy, substituted or unsubstituted heteroaryloxy, substituted or unsubstituted cycloalkyloxy, substituted or unsubstituted cycloalkenyloxy, substituted or unsubstituted heterocyclyloxy, Substituted or unsubstituted allies Alkyloxy, substituted or unsubstituted heteroarylalkyloxy, substituted or unsubstituted cycloalkylalkyloxy, substituted or unsubstituted cycloalkenylalkyloxy, substituted or unsubstituted heterocyclylalkyloxy, substituted or unsubstituted acyl , substituted or unsubstituted carbamoyl, substituted or unsubstituted amino or formula ^{:-( CR 12 R 13) p-} NR 14 - (C = O) -R 15 ( ^{wherein, R 12} and ^{R 13} are each independently Hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or Unsubstituted cycloalkenyl or A heterocyclyl substituted or unsubstituted, p is an integer from 1 to 3, R ¹⁴ is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted Substituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, or substituted or unsubstituted heterocyclyl, R ¹⁵ is substituted or unsubstituted aryl, substituted Or a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted cycloalkenyl, or a substituted or unsubstituted heterocyclyl)). The compound according to (1) or a pharmaceutically acceptable salt thereof.
(3)
R ⁸ is halogen, hydroxy, cyano, nitro, carboxy, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted Or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted aryloxy, substituted or unsubstituted heteroaryloxy, substituted Or unsubstituted cycloalkyloxy, substituted or unsubstituted cycloalkenyloxy, substituted or unsubstituted heterocyclyloxy, substituted or unsubstituted arylalkyloxy, substituted or unsubstituted heteroarylalkyloxy, Substituted or unsubstituted cycloalkylalkyloxy, substituted or unsubstituted cycloalkenylalkyloxy, substituted or unsubstituted heterocyclylalkyloxy, substituted or unsubstituted acyl, substituted or unsubstituted carbamoyl, substituted or unsubstituted Amino or formula: — (CR ¹² R ¹³ ) p—NR ¹⁴ — (C═O) —R ¹⁵ (wherein R ¹² , R ¹³ , p, R ¹⁴ and R ¹⁵ are the same as defined in (2) above) Or a pharmaceutically acceptable salt thereof.
(4)
R ⁸ is substituted or unsubstituted heteroarylalkyloxy, substituted or unsubstituted acyl or a formula: — (CR ¹² R ¹³ ) p—NR ¹⁴ — (C═O) —R ¹⁵ (wherein R ¹² , R ¹³ , p, R ¹⁴ and R ¹⁵ are the same as defined in (2) above), or a pharmaceutically acceptable salt thereof.
(5)
The compound according to (3) or (4) or a pharmaceutically acceptable salt thereof, wherein R ⁶ , R ⁷ , R ⁹ and R ¹⁰ are hydrogen.
(6)
The compound or a pharmaceutically acceptable salt thereof according to any one of (1) to (5), wherein m is 1.
(7)
The compound or a pharmaceutically acceptable salt thereof according to any one of (1) to (6), wherein R ⁴ is —CR ^5a R ^5b —.
(8)
The compound according to (7) or a pharmaceutically acceptable salt thereof, wherein R ^5a and R ^5b are hydrogen, m is 1, and n is 0.
(9)
In formula (I),

The part indicated by

Wherein R ^5a and R ^5b are as defined in (1) above, and R ¹¹ is hydrogen, halogen, hydroxy, cyano, nitro, carboxy, or substituted or unsubstituted alkyl. The compound according to any one of 1) to (5) or a pharmaceutically acceptable salt thereof.
(10)
The compound or a pharmaceutically acceptable salt thereof according to any one of (1) to (9), wherein R ¹ is hydrogen.
(11)
The compound or a pharmaceutically acceptable salt thereof according to any one of (1) to (10), wherein R ² and R ³ are hydrogen.
(12)
A pharmaceutical composition comprising the compound according to any one of (1) to (11) or a pharmaceutically acceptable salt thereof.
(13)
Formula (II):

(Where
Ring A is a substituted or unsubstituted aromatic carbocyclic ring or a substituted or unsubstituted aromatic heterocyclic ring,
Ring B is a substituted or unsubstituted non-aromatic carbocyclic ring or a substituted or unsubstituted non-aromatic heterocyclic ring,
R ¹ is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted Or unsubstituted cycloalkenyl or substituted or unsubstituted heterocyclyl,
R ² and R ³ are each independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted Or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl or substituted or unsubstituted heterocyclyl. However, the compounds shown below:

except for. ) Or a pharmaceutically acceptable salt thereof as an active ingredient.
In the present invention,
(14)
The pharmaceutical composition according to the above (12) or (13) for the treatment and / or prevention of diabetes,
(15)
A method for preventing or treating diabetes, comprising administering the compound according to any one of (1) to (11) or a pharmaceutically acceptable salt thereof,
(16)
The compound or a pharmaceutically acceptable salt thereof according to any one of the above (1) to (11) for the treatment and / or prevention of diabetes,
(17)
A method for treating diabetes, comprising administering another therapeutic agent for diabetes to a diabetic patient undergoing treatment with the compound represented by the formula (I) or a pharmaceutically acceptable salt thereof,
(18)
A method for treating diabetes, which comprises administering another therapeutic agent for diabetes in combination with the compound represented by the formula (I) or a pharmaceutically acceptable salt thereof, is also included.

  The compound according to the present invention is useful as a therapeutic and / or prophylactic agent for diabetes, particularly type 2 diabetes, because it exhibits rapid action and exhibits hypoglycemic action without causing hypoglycemia.

It is a figure which shows the hypoglycemic effect of the compound (I-1) using a GK rat. The vertical axis represents blood glucose level and the horizontal axis represents elapsed time. Example 4 It is a figure which shows the hypoglycemic effect of the compound (I-1) using a Wistar rat. The vertical axis represents blood glucose level and the horizontal axis represents elapsed time. (Example 5) It is a figure which shows the plasma insulin level using a Wistar rat. The vertical axis represents plasma insulin levels. (Example 5)

  The terms used in this specification will be described below. In the present specification, each term has the same meaning whether used alone or in combination with other terms.

  “Halogen” includes fluorine, chlorine, bromine and iodine.

  “Alkyl” means a linear or branched alkyl group having 1 to 10 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert -Butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, isohexyl, n-heptyl, n-octyl, n-nonyl, n-decyl and the like. Preferred is alkyl having 1 to 6 or 1 to 4 carbon atoms, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, iso Examples include pentyl, neopentyl, n-hexyl, and isohexyl.

  “Alkenyl” means a linear or branched alkenyl having 2 to 8 carbon atoms having one or more double bonds to the above “alkyl”, and examples thereof include vinyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 1,3-butadienyl, 3-methyl-2-butenyl and the like can be mentioned.

  “Alkynyl” means a linear or branched alkynyl having 2 to 8 carbon atoms having one or more triple bonds to the above “alkyl”, and examples thereof include ethynyl, propynyl, butynyl and the like. Can be mentioned. Furthermore, you may have a double bond.

  “Cycloalkyl” means a cyclic saturated hydrocarbon group having 3 to 15 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, bridged cyclic hydrocarbon group, spiro hydrocarbon. Group and the like. Preferably, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and a bridged cyclic hydrocarbon group are used.

  “Bridged cyclic hydrocarbon group” includes a group formed by removing one hydrogen from an aliphatic ring having 5 to 8 carbon atoms in which two or more rings share two or more atoms. To do. Specifically, bicyclo [2.1.0] pentyl, bicyclo [2.2.1] heptyl, bicyclo [2.2.2] octyl and bicyclo [3.2.1] octyl, tricyclo [2.2. 1.0] heptyl and the like.

  The “spiro hydrocarbon group” includes a group formed by removing one hydrogen from a ring in which two hydrocarbon rings are configured to share one carbon atom. Specific examples include spiro [3.4] octyl.

  “Cycloalkenyl” means a cyclic unsaturated aliphatic hydrocarbon group having 3 to 10 carbon atoms, such as cyclopropenyl (eg, 1-cyclopropenyl), cyclobutenyl (eg, 1-cyclobutenyl), cyclopentenyl. (Eg 1-cyclopenten-1-yl, 2-cyclopenten-1-yl, 3-cyclopenten-1-yl), cyclohexenyl (eg 1-cyclohexen-1-yl, 2-cyclohexen-1-yl, 3 -Cyclohexen-1-yl), cycloheptenyl (eg 1-cycloheptenyl), cyclooctenyl (eg 1-cyclooctenyl) and the like. Cyclopropenyl, cyclobutenyl, cyclopentenyl, and cyclohexenyl are preferable. Cycloalkenyl also includes bridged cyclic hydrocarbon groups and spiro hydrocarbon groups having an unsaturated bond in the ring.

  “Aryl” means a monocyclic aromatic hydrocarbon group (eg, phenyl) and a polycyclic aromatic hydrocarbon group (eg, 1-naphthyl, 2-naphthyl, 1-anthryl, 2-anthryl, 9-anthryl, 1 -Phenanthryl, 2-phenanthryl, 3-phenanthryl, 4-phenanthryl, 9-phenanthryl and the like). Preferably, phenyl or naphthyl (1-naphthyl, 2-naphthyl) is used.

“Heteroaryl” refers to monocyclic aromatic heterocyclic groups and fused aromatic heterocyclic groups.
The “monocyclic aromatic heterocyclic group” is a substitution derived from a 5- to 8-membered aromatic ring which may contain 1 to 4 oxygen atoms, sulfur atoms and / or nitrogen atoms in the ring. It means a group which may have a bond at any possible position.
The “fused aromatic heterocyclic group” has 1 to 4 5 to 8 membered aromatic rings which may contain 1 to 4 oxygen atoms, sulfur atoms and / or nitrogen atoms in the ring. It means a group which may have a bond at any substitutable position which is condensed with a ˜8-membered aromatic carbocycle or other 5- to 8-membered aromatic heterocycle.

  Examples of the “heteroaryl” include furyl (eg, 2-furyl, 3-furyl), thienyl (eg, 2-thienyl, 3-thienyl), pyrrolyl (eg, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl). ), Imidazolyl (eg: 1-imidazolyl, 2-imidazolyl, 4-imidazolyl), pyrazolyl (eg: 1-pyrazolyl, 3-pyrazolyl, 4-pyrazolyl), triazolyl (eg: 1,2,4-triazole-1-) Yl, 1,2,4-triazol-3-yl, 1,2,4-triazol-4-yl), tetrazolyl (eg 1-tetrazolyl, 2-tetrazolyl, 5-tetrazolyl), oxazolyl (eg 2- Oxazolyl, 4-oxazolyl, 5-oxazolyl), isoxazolyl (eg 3-isoxazolyl, 4-isoxazolyl, 5-i Xazolyl), thiazolyl (eg: 2-thiazolyl, 4-thiazolyl, 5-thiazolyl), thiadiazolyl, isothiazolyl (eg: 3-isothiazolyl, 4-isothiazolyl, 5-isothiazolyl), pyridyl (eg: 2-pyridyl, 3-pyridyl) 4-pyridyl), pyridazinyl (eg: 3-pyridazinyl, 4-pyridazinyl), pyrimidinyl (eg: 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl), furazanil (eg: 3-furazanyl), pyrazinyl (eg: 2 -Pyrazinyl), oxadiazolyl (eg 1,3,4-oxadiazol-2-yl), benzofuryl (eg 2-benzo [b] furyl, 3-benzo [b] furyl, 4-benzo [b] furyl 5-benzo [b] furyl, 6-benzo [b] furyl, 7-benzo [b] furyl), Zothienyl (eg 2-benzo [b] thienyl, 3-benzo [b] thienyl, 4-benzo [b] thienyl, 5-benzo [b] thienyl, 6-benzo [b] thienyl, 7-benzo [b] Thienyl), benzimidazolyl (eg, 1-benzimidazolyl, 2-benzimidazolyl, 4-benzoimidazolyl, 5-benzoimidazolyl), dibenzofuryl, benzoxazolyl, benzothiazolyl, quinoxalyl (eg, 2-quinoxalinyl, 5-quinoxalinyl, 6-quinoxalinyl) Cinnolinyl (eg: 3-cinnolinyl, 4-cinnolinyl, 5-cinnolinyl, 6-cinnolinyl, 7-cinnolinyl, 8-cinnolinyl), quinazolyl (eg: 2-quinazolinyl, 4-quinazolinyl, 5-quinazolinyl, 6-quinazolinyl, 7-quinazolinyl, 8 -Quinazolinyl), quinolyl (eg: 2-quinolyl, 3-quinolyl, 4-quinolyl, 5-quinolyl, 6-quinolyl, 7-quinolyl, 8-quinolyl), phthalazinyl (eg: 1-phthalazinyl, 5-phthalazinyl, 6 -Phthalazinyl), isoquinolyl (eg: 1-isoquinolyl, 3-isoquinolyl, 4-isoquinolyl, 5-isoquinolyl, 6-isoquinolyl, 7-isoquinolyl, 8-isoquinolyl), prill, pteridinyl (eg: 2-pteridinyl, 4-pteridinyl) , 6-pteridinyl, 7-pteridinyl), carbazolyl, phenanthridinyl, acridinyl (eg 1-acridinyl, 2-acridinyl, 3-acridinyl, 4-acridinyl, 9-acridinyl), indolyl (eg 1-indolyl), 2-indolyl, 3-indolyl, 4-i Drill, 5-indolyl, 6-indolyl, 7-indolyl), isoindolyl, fanadinyl (eg 1-phenazinyl, 2-phenazinyl) or phenothiazinyl (eg 1-phenothiazinyl, 2-phenothiazinyl, 3-phenothiazinyl, 4-phenothiazinyl) and the like.

  “Heterocyclyl” means a ring having at least one nitrogen atom, oxygen atom or sulfur atom in the ring, or cycloalkane (preferably 5 to 6 member), benzene ring and / or such ring. A non-aromatic heterocyclic group which may have a bond at any substitutable position on a ring condensed with a ring having at least one nitrogen atom, oxygen atom or sulfur atom in the ring. . The “non-aromatic heterocyclic group” may be saturated or unsaturated as long as it is non-aromatic. Preferably it is a 5-8 membered ring. For example, 1-pyrrolinyl, 2-pyrrolinyl, 3-pyrrolinyl, 1-pyrrolidinyl, 2-pyrrolidinyl, 3-pyrrolidinyl, 1-imidazolinyl, 2-imidazolinyl, 4-imidazolinyl, 1-imidazolidinyl, 2-imidazolidinyl, 4-imidazolidinyl, 1-pyrazolinyl, 3-pyrazolinyl, 4-pyrazolinyl, 1-pyrazolidinyl, 3-pyrazolidinyl, 4-pyrazolidinyl, piperidino, 2-piperidinyl, 3-piperidinyl, 4-piperidinyl, 1-piperazinyl, 2-piperazinyl, 2-morpholinyl, 3-morpholinyl, morpholino, tetrahydropyranyl and the like can be mentioned.

  “Acyl” refers to formyl, substituted or unsubstituted alkylcarbonyl, substituted or unsubstituted alkenylcarbonyl, substituted or unsubstituted cycloalkylcarbonyl, substituted or unsubstituted cycloalkenylcarbonyl, substituted or unsubstituted arylcarbonyl, It means substituted or unsubstituted heteroarylcarbonyl, substituted or unsubstituted heterocyclylcarbonyl. “Alkylcarbonyl”, “alkenylcarbonyl”, “cycloalkylcarbonyl”, “cycloalkenylcarbonyl”, “arylcarbonyl”, “heteroarylcarbonyl”, “heterocyclylcarbonyl” “alkyl” moiety, “alkenyl” moiety, The “cycloalkyl” moiety, “cycloalkenyl” moiety, “aryl” moiety, “heteroaryl” moiety, and “heterocyclyl” moiety are the above “alkyl”, “alkenyl”, “cycloalkyl”, “cycloalkenyl”, respectively. ”,“ Aryl ”,“ heteroaryl ”,“ heterocyclyl ”.

The alkyl part of “alkyloxy”, “arylalkyloxy”, “heteroarylalkyloxy”, “cycloalkylalkyloxy”, “cycloalkenylalkyloxy” and “heterocyclylalkyloxy” means the above “alkyl” To do.
The aryl part of “aryloxy” and “arylalkyloxy” means the above “aryl”.
The heteroaryl part of “heteroaryloxy” and “heteroarylalkyloxy” means the above “heteroaryl”.
The cycloalkyl part of “cycloalkyloxy” and “cycloalkylalkyloxy” means the above “cycloalkyl”.
The cycloalkenyl part of “cycloalkenyloxy” and “cycloalkenylalkyloxy” means the above “cycloalkenyl”.
The heterocyclyl part of “heterocyclyloxy” and “heterocyclylalkyloxy” means the above “heterocyclyl”.

“Substituted alkyl”, “substituted alkenyl”, “substituted alkynyl”, “substituted aryl”, “substituted heteroaryl”, “substituted cycloalkyl”, “substituted cycloalkenyl”, “substituted heterocyclyl”, “substituted alkyloxy” , “Substituted aryloxy”, “substituted heteroaryloxy”, “substituted cycloalkyloxy”, “substituted cycloalkenyloxy”, “substituted heterocyclyloxy”, “substituted arylalkyloxy”, “substituted heteroarylalkyloxy” , “Substituted cycloalkylalkyloxy”, “substituted cycloalkenylalkyloxy”, “substituted heterocyclylalkyloxy”, “substituted acyl”, “substituted carbamoyl” or “substituted amino” include, for example,
Halogen, hydroxy, carboxy, nitro, cyano,
Substituted or unsubstituted alkyl (substituents are halogen, hydroxy, carboxy, nitro, cyano, alkyl, aryl, cycloalkyl, cycloalkenyl, heteroaryl, heterocyclyl. Examples: methyl, ethyl, isopropyl, tert-butyl , CF ₃ , CHF ₂ ),
Substituted or unsubstituted alkenyl (substituents include halogen, hydroxy, carboxy, nitro, cyano, alkyl, aryl, cycloalkyl, cycloalkenyl, heteroaryl, heterocyclyl, eg, vinyl),
Substituted or unsubstituted alkynyl (substituents are halogen, hydroxy, carboxy, nitro, cyano, alkyl, aryl, cycloalkyl, cycloalkenyl, heteroaryl, heterocyclyl, eg ethynyl),
Substituted or unsubstituted aryl (substituents include halogen, hydroxy, carboxy, nitro, cyano, alkyl, aryl, cycloalkyl, cycloalkenyl, heteroaryl, heterocyclyl, alkyloxy, alkylsulfonyl, sulfamoyl, carbamoyl, amino , -SCHF ₂ cases:. phenyl, naphthyl),
Substituted or unsubstituted cycloalkyl (substituents include halogen, hydroxy, carboxy, nitro, cyano, alkyl, aryl, cycloalkyl, cycloalkenyl, heteroaryl, heterocyclyl, alkyloxy, alkylsulfonyl, sulfamoyl, carbamoyl, Amino, eg cyclopropyl, cyclobutyl),
Substituted or unsubstituted cycloalkenyl (substituents include halogen, hydroxy, carboxy, nitro, cyano, alkyl, aryl, cycloalkyl, cycloalkenyl, heteroaryl, heterocyclyl, alkyloxy, alkylsulfonyl, sulfamoyl, carbamoyl, Amino, eg cyclopropenyl),
Substituted or unsubstituted heteroaryl (substituents include halogen, hydroxy, carboxy, nitro, cyano, alkyl, aryl, cycloalkyl, cycloalkenyl, heteroaryl, heterocyclyl, alkyloxy, alkylsulfonyl, sulfamoyl, carbamoyl, Amino, eg tetrazolyl, indolyl, pyrazolyl),
Substituted or unsubstituted heterocyclyl (substituents include halogen, hydroxy, carboxy, nitro, cyano, alkyl, aryl, cycloalkyl, cycloalkenyl, heteroaryl, heterocyclyl, alkyloxy, alkylsulfonyl, sulfamoyl, carbamoyl Amino, eg pyrrolidinyl, morpholinyl, piperazinyl, piperidyl),
Substituted or unsubstituted alkyloxy (substituents are halogen, hydroxy, carboxy, nitro, cyano, alkyl, aryl, cycloalkyl, cycloalkenyl, heteroaryl, heterocyclyl. Examples: methoxy, ethoxy, propoxy, butoxy, OCF ₃ ),
Substituted or unsubstituted alkenyloxy (substituents are halogen, hydroxy, carboxy, nitro, cyano, alkyl, aryl, cycloalkyl, cycloalkenyl, heteroaryl, heterocyclyl, for example, vinyloxy, allyloxy),
Substituted or unsubstituted aryloxy (substituents are halogen, hydroxy, carboxy, nitro, cyano, alkyl, aryl, cycloalkyl, cycloalkenyl, heteroaryl, heterocyclyl, eg, phenyloxy),
Substituted or unsubstituted heteroaryloxy (substituents are halogen, hydroxy, carboxy, nitro, cyano, alkyl, aryl, cycloalkyl, cycloalkenyl, heteroaryl, heterocyclyl),
Substituted or unsubstituted cycloalkyloxy (substituents are halogen, hydroxy, carboxy, nitro, cyano, alkyl, aryl, cycloalkyl, cycloalkenyl, heteroaryl, heterocyclyl),
Substituted or unsubstituted cycloalkenyloxy (substituents are halogen, hydroxy, carboxy, nitro, cyano, alkyl, aryl, cycloalkyl, cycloalkenyl, heteroaryl, heterocyclyl),
Substituted or unsubstituted heterocyclyloxy (substituents are halogen, hydroxy, carboxy, nitro, cyano, alkyl, aryl, cycloalkyl, cycloalkenyl, heteroaryl, heterocyclyl),
Substituted or unsubstituted amino (eg, alkylamino (eg, methylamino, ethylamino, dimethylamino), acylamino (eg, acetylamino, benzoylamino), arylalkylamino (eg, benzylamino, tritylamino), hydroxyamino Alkyloxycarbonylamino, alkylsulfonylamino, arylsulfonylamino, heteroarylsulfonylamino, cycloalkylsulfonylamino, cycloalkenylsulfonylamino, heterocyclylsulfonylamino, carbamoylamino, sulfamoylamino),
Substituted or unsubstituted carbamoyl (substituents are alkyl, aryl, cycloalkyl, cycloalkenyl, heteroaryl, heterocyclyl. Examples: alkylcarbamoyl (eg, methylcarbamoyl, ethylcarbamoyl, dimethylcarbamoyl), alkylsulfonylcarbamoyl, Alkyloxycarbamoyl.),
Substituted or unsubstituted carbamoyloxy (the substituent is alkyl, aryl, cycloalkyl, cycloalkenyl, heteroaryl, heterocyclyl),
Substituted or unsubstituted acyl (substituents include halogen, hydroxy, carboxy, nitro, cyano, alkyl, aryl, cycloalkyl, cycloalkenyl, heteroaryl, heterocyclyl. Examples: alkylcarbonyl, arylcarbonyl, heteroarylcarbonyl , Heterocyclylcarbonyl, formyl, acetyl.),
Substituted or unsubstituted alkylsulfonyl (substituents are halogen, hydroxy, carboxy, nitro, cyano, alkyl, aryl, cycloalkyl, cycloalkenyl, heteroaryl, heterocyclyl, such as methanesulfonyl, ethanesulfonyl),
Substituted or unsubstituted arylsulfonyl (substituents are halogen, hydroxy, carboxy, nitro, cyano, alkyl, aryl, cycloalkyl, cycloalkenyl, heteroaryl, heterocyclyl),
Substituted or unsubstituted heteroarylsulfonyl (substituents are halogen, hydroxy, carboxy, nitro, cyano, alkyl, aryl, cycloalkyl, cycloalkenyl, heteroaryl, heterocyclyl),
Substituted or unsubstituted cycloalkylsulfonyl (substituents include halogen, hydroxy, carboxy, nitro, cyano, alkyl, aryl, cycloalkyl, cycloalkenyl, heteroaryl, heterocyclyl),
Substituted or unsubstituted cycloalkenylsulfonyl (substituents include halogen, hydroxy, carboxy, nitro, cyano, alkyl, aryl, cycloalkyl, cycloalkenyl, heteroaryl, heterocyclyl),
Substituted or unsubstituted heterocyclylsulfonyl (substituents are halogen, hydroxy, carboxy, nitro, cyano, alkyl, aryl, cycloalkyl, cycloalkenyl, heteroaryl, heterocyclyl),
Substituted or unsubstituted sulfamoyl (substituents are alkyl, aryl, cycloalkyl, cycloalkenyl, heteroaryl, heterocyclyl),
Substituted or unsubstituted alkyloxycarbonyl (substituents include halogen, hydroxy, carboxy, nitro, cyano, alkyl, aryl, cycloalkyl, cycloalkenyl, heteroaryl, heterocyclyl. Examples: methoxycarbonyl, ethoxycarbonyl, tert -Butoxycarbonyl),
Aryloxycarbonyl, heteroaryloxycarbonyl, cycloalkyloxycarbonyl, cycloalkenyloxycarbonyl, heterocyclyloxycarbonyl,
Alkylsulfinyl, arylsulfinyl, heteroarylsulfinyl, cycloalkylsulfinyl, cycloalkenylsulfinyl, heterocyclylsulfinyl,
Arylalkyloxy (eg benzyloxy), heteroarylalkyloxy, cycloalkylalkyloxy, cycloalkenylalkyloxy, heterocyclylalkyloxy,
Alkylthio (eg, methylthio), alkenylthio, arylthio, heteroarylthio, cycloalkylthio, cycloalkenylthio, heterocyclylthio,
Substituted or unsubstituted silyloxy,
Nitroso, azide, isocyano, isocyanato, thiocyanato, isothiocyanato, mercapto, formyloxy, haloformyl, oxalo, thioformyl, thiocarboxy, dithiocarboxy, thiocarbamoyl, sulfino, sulfo, sulfoamino, hydrazino, ureido, amidino, guanidino, phthalimide, oxo, etc. A group selected from the group consisting of: It may be substituted with 1 to 4 such substituents.

  The substituent of “substituted carbamoyl” or “substituted amino” is preferably hydroxy, substituted or unsubstituted alkyl (substituents include halogen, hydroxy, carboxy, nitro, cyano, alkyl, aryl, cycloalkyl, cyclo Alkenyl, heteroaryl, heterocyclyl.), Substituted or unsubstituted alkenyl (substituents are halogen, hydroxy, carboxy, nitro, cyano, alkyl, aryl, cycloalkyl, cycloalkenyl, heteroaryl, heterocyclyl. ), Substituted or unsubstituted aryl (substituents include halogen, hydroxy, carboxy, nitro, cyano, alkyl, aryl, cycloalkyl, cycloalkenyl, heteroaryl, heterocyclyl), substituted or unsubstituted Cycloalkyl (substituents are halogen, hydroxy, carboxy, nitro, cyano, alkyl, aryl, cycloalkyl, cycloalkenyl, heteroaryl, heterocyclyl), substituted or unsubstituted heteroaryl (substituents are Halogen, hydroxy, carboxy, nitro, cyano, alkyl, aryl, cycloalkyl, cycloalkenyl, heteroaryl, heterocyclyl), substituted or unsubstituted heterocyclyl (substituents include halogen, hydroxy, carboxy, nitro , Cyano, alkyl, aryl, cycloalkyl, cycloalkenyl, heteroaryl, heterocyclyl.), Alkyloxycarbonyl, aryloxycarbonyl, cycloalkyloxycarbonyl, cycloalkenyl Xyloxycarbonyl, heteroaryloxycarbonyl, heterocyclyloxycarbonyl, alkylsulfonyl, arylsulfonyl, cycloalkylsulfonyl, cycloalkenylsulfonyl, heteroarylsulfonyl, heterocyclylsulfonyl, carbamoyl, sulfamoyl, acyl, alkylsulfinyl, arylsulfinyl, cyclo Examples thereof include alkylsulfinyl, cycloalkenylsulfinyl, heteroarylsulfinyl, heterocyclylsulfinyl, amino and the like.

“Alkylsulfonyl”, “alkylamino”, “arylalkylamino”, “alkyloxycarbonylamino”, “alkylsulfonylamino”, “alkylcarbamoyl”, “alkylsulfonylcarbamoyl”, “alkyloxycarbamoyl”, “alkyloxycarbonyl” , “Alkylsulfinyl” and “alkylthio” means the above “alkyl”.
The alkenyl part of “alkenyloxy” and “alkenylthio” means the above “alkenyl”.
The aryl part of “arylalkylamino”, “arylsulfonylamino”, “arylsulfonyl”, “aryloxycarbonyl”, “arylsulfinyl” and “arylthio” means the above “aryl”.
The cycloalkyl part of “cycloalkylsulfonylamino”, “cycloalkylsulfonyl”, “cycloalkyloxycarbonyl”, “cycloalkylsulfinyl” and “cycloalkylthio” means the above “cycloalkyl”.
The cycloalkenyl moiety of “cycloalkenylsulfonylamino”, “cycloalkenylsulfonyl”, “cycloalkenyloxycarbonyl”, “cycloalkenylsulfinyl” and “cycloalkenylthio” means the above “cycloalkenyl”.
The heteroaryl part of “heteroarylsulfonylamino”, “heteroarylsulfonyl”, “heteroaryloxycarbonyl”, “heteroarylsulfinyl” and “heteroarylthio” means the above “heteroaryl”.
The heterocyclyl part of “heterocyclylsulfonylamino”, “heterocyclylsulfonyl”, “heterocyclyloxycarbonyl”, “heterocyclylsulfinyl” and “heterocyclylthio” means the above “heterocyclyl”. To do.

環Ａとして、好ましくは、以下の環が挙げられる。

環Ａとして、さらに好ましくは、以下の環が挙げられる。

環Ａとして、特に好ましくは、以下の環が挙げられる。

なお、環Ａは、置換可能な任意の位置の原子が次の置換基から選択される１以上の基で置換されていてもよい。
置換基：ハロゲン、ヒドロキシ、シアノ、ニトロ、カルボキシ、置換若しくは非置換のアルキル、置換若しくは非置換のアルケニル、置換若しくは非置換のアルキニル、置換若しくは非置換のアリール、置換若しくは非置換のヘテロアリール、置換もしくは非置換のシクロアルキル、置換もしくは非置換のシクロアルケニル、置換若しくは非置換のヘテロサイクリル、置換若しくは非置換のアルキルオキシ、置換若しくは非置換のアリールオキシ、置換若しくは非置換のヘテロアリールオキシ、置換若しくは非置換のシクロアルキルオキシ、置換若しくは非置換のシクロアルケニルオキシ、置換若しくは非置換のヘテロサイクリルオキシ、置換若しくは非置換のアリールアルキルオキシ、置換若しくは非置換のヘテロアリールアルキルオキシ、置換若しくは非置換のシクロアルキルアルキルオキシ、置換若しくは非置換のシクロアルケニルアルキルオキシ、置換若しくは非置換のヘテロサイクリルアルキルオキシ、置換若しくは非置換のアシル、置換若しくは非置換のカルバモイル、置換若しくは非置換のアミノおよび式：−（ＣＲ^１２Ｒ^１３）ｐ−ＮＲ^１４−（Ｃ＝Ｏ）−Ｒ^１５（式中、Ｒ^１２、Ｒ^１３、ｐ、Ｒ^１４およびＲ^１５は前記と同意義である。）で示される基。 Of the compounds of the present invention, the compounds of the following embodiments are preferred.
Ring A is a substituted or unsubstituted aromatic carbocyclic ring or a substituted or unsubstituted aromatic heterocyclic ring. Ring A includes not only a single ring but also a condensed ring (2 to 3 condensed rings), and a single ring is particularly preferable.
Examples of the ring A include the following rings.

The ring A is preferably the following ring.

More preferably, ring A includes the following rings.

As the ring A, the following rings are particularly preferable.

In ring A, an atom at any substitutable position may be substituted with one or more groups selected from the following substituents.
Substituents: halogen, hydroxy, cyano, nitro, carboxy, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted Or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted aryloxy, substituted or unsubstituted heteroaryloxy, substituted Or unsubstituted cycloalkyloxy, substituted or unsubstituted cycloalkenyloxy, substituted or unsubstituted heterocyclyloxy, substituted or unsubstituted arylalkyloxy, substituted or unsubstituted heteroarylalkyloxy Substituted or unsubstituted cycloalkylalkyloxy, substituted or unsubstituted cycloalkenylalkyloxy, substituted or unsubstituted heterocyclylalkyloxy, substituted or unsubstituted acyl, substituted or unsubstituted carbamoyl, substituted or unsubstituted in (C = O) ^{-R 15 (wherein, R 12, R 13, p} , R 14 and ^{R 15} are as defined above) - amino and formula ^{:-( CR 12 R 13) p-} NR 14. A group represented by

R ¹ is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted Or unsubstituted cycloalkenyl or substituted or unsubstituted heterocyclyl.
R ¹ is more preferably hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl or substituted or unsubstituted alkynyl.
R ¹ is more preferably hydrogen.

R ² and R ³ are each independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted Or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl or substituted or unsubstituted heterocyclyl.
Preferred is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, or substituted or unsubstituted alkynyl.
More preferably, it is hydrogen.

R ⁴ is —CR ^5a R ^5b —, —O— or —S—.
R ⁴ is more preferably —CR ^5a R ^5b — or —O—.

R ^5a and R ^5b are each independently hydrogen, halogen, hydroxy, cyano, nitro, carboxy or substituted or unsubstituted alkyl.
Preferably, it is hydrogen.

Each R ⁵ is independently halogen, hydroxy, cyano, nitro, carboxy or substituted or unsubstituted alkyl.

m is an integer of 0-3.
Preferably, it is 0 or 1. More preferably, it is 1.

  n is an integer of 0-6.

R ⁶ , R ⁷ , R ⁸ , R ⁹ and R ¹⁰ are each independently hydrogen, halogen, hydroxy, cyano, nitro, carboxy, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted Alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted alkyloxy Substituted or unsubstituted aryloxy, substituted or unsubstituted heteroaryloxy, substituted or unsubstituted cycloalkyloxy, substituted or unsubstituted cycloalkenyloxy, substituted or unsubstituted heterocyclyloxy, substituted or unsubstituted Arylalkyl Xy, substituted or unsubstituted heteroarylalkyloxy, substituted or unsubstituted cycloalkylalkyloxy, substituted or unsubstituted cycloalkenylalkyloxy, substituted or unsubstituted heterocyclylalkyloxy, substituted or unsubstituted acyl, a substituted or unsubstituted carbamoyl, substituted or unsubstituted amino or formula ^{:-( CR 12 R 13) p-} NR 14 - is (C = O) a group represented by ^{-R 15.}

R ⁸ is preferably halogen, hydroxy, cyano, nitro, carboxy, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted Heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted aryloxy, substituted or unsubstituted hetero Aryloxy, substituted or unsubstituted cycloalkyloxy, substituted or unsubstituted cycloalkenyloxy, substituted or unsubstituted heterocyclyloxy, substituted or unsubstituted arylalkyloxy, substituted or unsubstituted heteroaryl Alkyloxy, substituted or unsubstituted cycloalkylalkyloxy, substituted or unsubstituted cycloalkenylalkyloxy, substituted or unsubstituted heterocyclylalkyloxy, substituted or unsubstituted acyl, substituted or unsubstituted carbamoyl, substituted or unsubstituted substituted amino or formula ^{:-( CR 12 R 13) p-} NR 14 - ( a group represented by C = O) ^{-R 15.}
More preferably, substituted or unsubstituted heteroaryl alkyloxy, substituted or unsubstituted acyl or formula ^{:-( CR 12 R 13) p-} NR 14 - is a group represented by (C = O) ^{-R 15.}
Particularly preferred is substituted or unsubstituted acyl.

R ¹² and R ¹³ are each independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted Or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl or substituted or unsubstituted heterocyclyl.
Preferred is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, or substituted or unsubstituted alkynyl.
More preferably, it is hydrogen.

p is an integer of 1 to 3.
Preferably, it is 1 or 2. More preferably, it is 2.

R ¹⁴ is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted Or unsubstituted cycloalkenyl or substituted or unsubstituted heterocyclyl.
Preferred is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, or substituted or unsubstituted alkynyl.
More preferably, it is hydrogen.

R ¹⁵ is substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, or substituted or unsubstituted heterocyclyl.
Preferred is substituted or unsubstituted heterocyclyl.

で示される部分は、好ましくは、

（ここで、Ｒ^５ａ、Ｒ^５ｂ及びＲ^１１は前記と同意義である。）である。 In formula (I),

The portion represented by

Where R ^5a , R ^5b and R ¹¹ are as defined above.

R ¹¹ is hydrogen, halogen, hydroxy, cyano, nitro, carboxy or substituted or unsubstituted alkyl.
R ¹¹ is preferably hydrogen.

環Ｂとして、好ましくは、以下の環が挙げられる。

環Ｂとして、さらに好ましくは、以下の環が挙げられる。

環Ｂとして、特に好ましくは、以下の環が挙げられる。

なお、環Ｂは、置換可能な任意の位置の原子が次の置換基から選択される１以上の基で置換されていてもよい。
置換基：ハロゲン、ヒドロキシ、シアノ、ニトロ、カルボキシおよび置換若しくは非置換のアルキル。 Ring B is a substituted or unsubstituted non-aromatic carbocyclic ring or a substituted or unsubstituted non-aromatic heterocyclic ring. Ring B includes not only a single ring but also a condensed ring (2 to 3 condensed rings), and a single ring is particularly preferable.
Examples of the ring B include the following rings.

The ring B is preferably the following ring.

More preferably, ring B includes the following rings.

As the ring B, particularly preferred are the following rings.

Ring B may be substituted at one or more groups selected from the following substituents at any substitutable atom.
Substituents: halogen, hydroxy, cyano, nitro, carboxy and substituted or unsubstituted alkyl.

As preferable combinations of substituents of the compound represented by the formula (I), the following 1) to 2) may be mentioned.
1) Ring A is a substituted or unsubstituted aromatic carbocycle, R ¹ is hydrogen, R ² and R ³ are hydrogen, R ⁴ is —CR ^5a R ^5b —, R ^5a and R ^A compound wherein ^5b is hydrogen, m is 1 and n is 0;
2) Ring A is a substituted or unsubstituted aromatic carbocycle, R ¹ is hydrogen, R ² and R ³ are hydrogen, R ⁴ is —O—, and R ⁵ is independently , Hydroxy or substituted or unsubstituted alkyl, wherein m is 1 and n is 4.

  The compounds of formula (I) or formula (II) are not limited to specific isomers, but all possible isomers (eg keto-enol isomers, imine-enamine isomers, diastereoisomers). Isomers, optical isomers, rotational isomers, etc.), racemates or mixtures thereof.

One or more hydrogen, carbon and / or other atoms of the compounds of the present invention may be replaced with hydrogen, carbon and / or isotopes of other atoms, respectively. Examples of such isotopes are ² H, ³ H, ¹¹ C, ¹³ C, ¹⁴ C, ¹⁵ N, ¹⁸ O, ¹⁷ O, ³¹ P, ³² P, ³⁵ S, ¹⁸ F, ¹²³ I and ^{Like 36} Cl, hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine and chlorine are included. The compounds of the present invention also include compounds substituted with such isotopes. The compound substituted with the isotope is useful as a pharmaceutical and includes all radiolabeled compounds of the present invention. A “radiolabeling method” for producing the “radiolabeled product” is also encompassed in the present invention, and is useful as a metabolic pharmacokinetic study, a study in a binding assay, and / or a diagnostic tool.

The radioactive label of the compound of the present invention can be prepared by a method well known in the art. For example, the tritium-labeled compound represented by the formula (I) can be prepared by introducing tritium into the specific compound represented by the formula (I) by, for example, catalytic dehalogenation reaction using tritium. This method reacts a tritium gas with a precursor in which the compound of formula (I) is appropriately halogen-substituted in the presence of a suitable catalyst such as Pd / C, in the presence or absence of a base. Including that. Suitable methods for preparing other tritium labeled compounds include the document Isotopes in the Physical and Biomedical Sciences, Vol. 1, Labeled Compounds (Part A), Chapter 6 (1987). ^{The 14} C-labeled compound can be prepared by using a raw material having ¹⁴ C carbon.

  Examples of the pharmaceutically acceptable salt of the compound of the present invention include, for example, the compound of the present invention, an alkali metal (for example, lithium, sodium, potassium, etc.), an alkaline earth metal (for example, calcium, barium, etc.), magnesium, and a transition metal. (Eg, zinc, iron, etc.), ammonia, organic bases (eg, trimethylamine, triethylamine, dicyclohexylamine, ethanolamine, diethanolamine, triethanolamine, meglumine, diethanolamine, ethylenediamine, pyridine, picoline, quinoline, etc.) and salts with amino acids Or inorganic acids (eg, hydrochloric acid, sulfuric acid, nitric acid, carbonic acid, hydrobromic acid, phosphoric acid, hydroiodic acid, etc.) and organic acids (eg, formic acid, acetic acid, propionic acid, trifluoroacetic acid, citric acid, Lactic acid, tartaric acid, oxalic acid, male Acid, fumaric acid, mandelic acid, glutaric acid, malic acid, benzoic acid, phthalic acid, ascorbic acid, benzenesulfonic acid, p- toluenesulfonic acid, methanesulfonic acid, and salts with ethanesulfonic acid, etc.). Particularly, salts with hydrochloric acid, sulfuric acid, phosphoric acid, tartaric acid, methanesulfonic acid and the like can be mentioned. These salts can be formed by a commonly performed method.

The compound of the present invention or a pharmaceutically acceptable salt thereof may form a solvate (for example, hydrate etc.) and / or a crystal polymorph, and the present invention includes such various solvates and crystals. Also includes polymorphs.
For example, the “solvate” may be coordinated with any number of solvent molecules (for example, water molecules) with respect to the compound represented by the formula (I). When the compound represented by the formula (I) or a pharmaceutically acceptable salt thereof is left in the air, it may absorb moisture and adsorbed water may adhere or form a hydrate. In some cases, the compound represented by formula (I) or a pharmaceutically acceptable salt thereof may be recrystallized to form a crystalline polymorph thereof.

The compound of the present invention or a pharmaceutically acceptable salt thereof may form a prodrug, and the present invention also includes such various prodrugs. A prodrug is a derivative of a compound of the present invention having a group that can be chemically or metabolically degraded, and is a compound that becomes a pharmaceutically active compound of the present invention by solvolysis or under physiological conditions in vivo.
For example, a prodrug is hydrolyzed by a compound converted to the compound represented by the formula (I) by enzymatically oxidizing, reducing, hydrolyzing, etc. under physiological conditions in vivo, gastric acid, etc. The compound etc. which are converted into the compound shown by these are included. Methods for selecting and producing suitable prodrug derivatives are described, for example, in Design of Prodrugs, Elsevier, Amsterdam 1985. Prodrugs may themselves have activity.

When the compound of the present invention or a pharmaceutically acceptable salt thereof has a hydroxyl group, for example, the compound having a hydroxyl group and an appropriate acyl halide, an appropriate acid anhydride, an appropriate sulfonyl chloride, an appropriate sulfonyl anhydride, and a mix Examples thereof include prodrugs such as acyloxy derivatives and sulfonyloxy derivatives produced by reacting with doan hydride or reacting with a condensing agent. For _{example, CH 3 COO-, C 2 H} 5 COO-, t-BuCOO-, C 15 H 31 COO-, PhCOO -, (m-NaOOCPh) COO-, NaOOCCH 2 CH 2 COO-, CH 3 CH (NH 2 _{) COO-, CH 2 N (CH} 3) 2 COO-, CH 3 SO 3 -, CH 3 CH 2 SO 3 -, CF 3 SO 3 -, CH 2 FSO 3 -, CF 3 CH 2 SO 3 -, p _{-CH 3 -O-PhSO 3 -,} PhSO 3 -, p-CH 3 PhSO 3 - and the like.

(Method for producing the compound of the present invention)
The general production method of the compound of the present invention is exemplified below. Extraction, purification, and the like may be performed in a normal organic chemistry experiment.
The synthesis of the compound of the present invention can be carried out in consideration of techniques known in the art.

（式中、各記号は前記と同意義であり、式（Ｉ−１）で示される化合物は公知の化合物を用いてもよく、公知の化合物から常法により誘導された化合物を用いてもよい。「Ｈａｌ」はハロゲンを意味する。） The compound represented by the formula (I) can be synthesized as follows.

(In the formula, each symbol is as defined above, and the compound represented by the formula (I-1) may be a known compound or a compound derived from a known compound by a conventional method. “Hal” means halogen.)

First Step In this step, the compound represented by the formula (I-1) is reacted with the compound represented by the formula (I-2) to produce the compound represented by the formula (I).
Reaction solvents include N, N-dimethylformamide, dimethyl sulfoxide, aromatic hydrocarbons (eg, toluene, benzene, xylene, etc.), saturated hydrocarbons (eg, cyclohexane, hexane, etc.), halogenated hydrocarbons ( Examples, dichloromethane, chloroform, 1,2-dichloroethane, etc.), ethers (eg, tetrahydrofuran, diethyl ether, dioxane, 1,2-dimethoxyethane, etc.), esters (eg, methyl acetate, ethyl acetate, etc.), ketones (Eg, acetone, methyl ethyl ketone, etc.), nitriles (eg, acetonitrile, etc.), alcohols (eg, methanol, ethanol, t-butanol, etc.), water and mixed solvents thereof.
Preferably, N, N-dimethylformamide, aromatic hydrocarbons (eg, toluene, benzene, xylene, etc.), halogenated hydrocarbons (eg, dichloromethane, chloroform, 1,2-dichloroethane, etc.), ethers (eg, , Tetrahydrofuran, diethyl ether, dioxane, 1,2-dimethoxyethane, etc.), ketones (eg, acetone, methyl ethyl ketone, etc.) or nitriles (eg, acetonitrile, etc.) may be used.
In particular, ketones (eg, acetone, methyl ethyl ketone, etc.) or nitriles (eg, acetonitrile, etc.) are preferred.
Examples of the base include metal hydrides (eg, sodium hydride), metal hydroxides (eg, sodium hydroxide, potassium hydroxide, lithium hydroxide, barium hydroxide), metal carbonates (eg, sodium carbonate) , Calcium carbonate, cesium carbonate, etc.), metal alkoxide (eg, sodium methoxide, sodium ethoxide, potassium t-butoxide, etc.), sodium bicarbonate, metal sodium, metal amide, organic amine (eg, triethylamine, diisopropylethylamine, DBU) 2,6-lutidine, etc.), pyridine, alkyl lithium (n-BuLi, sec-BuLi, tert-BuLi) and the like.
Preferably, metal hydride (eg, sodium hydride), metal hydroxide (eg, sodium hydroxide, potassium hydroxide, lithium hydroxide, barium hydroxide), metal carbonate (eg, sodium carbonate, carbonate) Calcium, cesium carbonate, etc.), sodium hydrogen carbonate, or organic amines (eg, triethylamine, diisopropylethylamine, DBU, 2,6-lutidine, etc.) may be used.
In particular, organic amines (eg, triethylamine, diisopropylethylamine, DBU, 2,6-lutidine, etc.) are preferable.
The reaction temperature is -20 ° C to the temperature at which the solvent used is refluxed, preferably -10 ° C to room temperature.
The reaction time is 0.5 to 24 hours, preferably 0.5 to 12 hours.

（式中、各記号は前記と同意義であり、式（Ｉ−１）で示される化合物は公知の化合物を用いてもよく、公知の化合物から常法により誘導された化合物を用いてもよい。「Ｈａｌ」はハロゲンを意味する。） The compound represented by the formula (II) can also be synthesized as follows in the same manner as in the above scheme.

(In the formula, each symbol is as defined above, and the compound represented by the formula (I-1) may be a known compound or a compound derived from a known compound by a conventional method. “Hal” means halogen.)

The compound according to the present invention is useful as a therapeutic and / or prophylactic agent for diabetes, particularly type 2 diabetes, because it exhibits rapid action and exhibits hypoglycemic action without causing hypoglycemia.
The compound of the present invention has not only a hypoglycemic action but also a usefulness as a medicine, and has any or all of the following excellent features.
a) The inhibitory effect on CYP enzymes (for example, CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP3A4, etc.) is weak.
b) Good pharmacokinetics such as high bioavailability and moderate clearance.
c) High metabolic stability.
d) Does not show irreversible inhibitory action on CYP enzymes (eg CYP3A4) within the concentration range of the measurement conditions described herein.
e) Not mutagenic.
f) Low cardiovascular risk.
g) High solubility.

  When the pharmaceutical composition of the present invention is administered, it can be administered either orally or parenterally. Oral administration may be prepared and administered in a commonly used dosage form such as tablets, granules, powders, capsules and the like according to conventional methods. For parenteral administration, any commonly used dosage form such as an injection can be suitably administered. Since the compound according to the present invention has high oral absorbability, it can be suitably used as an oral preparation.

  Various pharmaceutical additives such as excipients, binders, disintegrants, lubricants and the like suitable for the dosage form can be mixed with the effective amount of the compound of the present invention as necessary to obtain a pharmaceutical composition.

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

  The compound of the present invention is an insulin secretagogue (for example, a sulfonylurea (SU) drug), a fast-acting insulin secretagogue (for example, a phenylalanine derivative) for the purpose of enhancing the action of the compound or reducing the dose of the compound. Drugs), glucose absorption inhibitors (for example, α-glucosidase inhibitors (αGI drugs)), insulin sensitizers (for example, biguanide drugs (BG drugs), thiazolidine derivatives (TZD drugs)), insulin preparations, peptidyl peptidases IV (DPP-IV) inhibitors, GLP-1 receptor agonists, type 1 sodium-dependent glucose transporter (SGLT1) inhibitors, type 2 sodium-dependent glucose transporter (SGLT2) inhibitors, etc. (Abbreviated). In this case, the administration time of the compound of the present invention and the concomitant drug is not limited, and these may be administered to the administration subject at the same time or may be administered with a time difference. Furthermore, the compound of the present invention and the concomitant drug may be administered as two types of preparations containing each active ingredient, or may be administered as a single preparation containing both active ingredients.

  The dose of the concomitant drug can be appropriately selected based on the clinically used dose. The compounding ratio of the compound of the present invention and the concomitant drug can be appropriately selected depending on the administration subject, administration route, target disease, symptom, combination and the like. For example, when the administration subject is a human, the concomitant drug may be used in an amount of 0.01 to 100 parts by weight per 1 part by weight of the compound of the present invention.

  EXAMPLES The present invention will be described in more detail below with reference to examples and test examples of the present invention, but the present invention is not limited thereto.

Moreover, the abbreviation used in this specification represents the following meaning.
Et ₃ N: triethylamine DEAD: diethyl azodicarboxylate PPh ₃ : triphenylphosphine DMAP: 4-dimethylaminopyridine THF: tetrahydrofuran DPPA: diphenyl phosphate azide DMSO: dimethyl sulfoxide PPTS: pyridinium p-toluenesulfonate

The NMR analysis obtained in each example was performed at 300 or 400 MHz and measured using CDCl _3, acetone-d ₆ , DMSO-d ₆ .

化合物１(1.00 g、5.02 mmol)にアセトン(50 mL)、トリエチルアミン(1.40 mL、10.10 mmol)を加え、氷冷下、撹拌しながら化合物２(0.77 mL、5.02 mmol)を滴下した。その後、反応液を室温で２時間撹拌し、水を加え反応を停止した。この混合液に飽和塩化アンモニウム水溶液、酢酸エチルを加えて抽出し、有機層を無水硫酸ナトリウムで乾燥した。減圧下、溶媒を留去し、残渣をシリカゲルカラムクロマトグラフィー、再結晶にて精製し、化合物（Ｉ−１）(1.15 g、71 %)を得た。
化合物（Ｉ−１）；1H-NMR (CDCl3) δ: 0.94 (m, 2H), 1.04 - 1.26 (m, 3H), 1.59 - 1.67 (m, 5H), 1.67 - 1.76 (m, 1H), 2.11 (d, J = 7.0 Hz, 2H), 2.67 (s, 3H), 8.10 (dt, J = 8.8, 1.9 Hz, 2H), 8.17 (dt, J = 8.8, 1.9 Hz, 2H), 8.28 (br s, 1H).

Acetone (50 mL) and triethylamine (1.40 mL, 10.10 mmol) were added to compound 1 (1.00 g, 5.02 mmol), and compound 2 (0.77 mL, 5.02 mmol) was added dropwise with stirring under ice cooling. Thereafter, the reaction solution was stirred at room temperature for 2 hours, and water was added to stop the reaction. A saturated aqueous ammonium chloride solution and ethyl acetate were added to the mixed solution for extraction, and the organic layer was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography and recrystallization to obtain compound (I-1) (1.15 g, 71%).
Compound (I-1); 1H-NMR (CDCl3) δ: 0.94 (m, 2H), 1.04-1.26 (m, 3H), 1.59-1.67 (m, 5H), 1.67-1.76 (m, 1H), 2.11 (d, J = 7.0 Hz, 2H), 2.67 (s, 3H), 8.10 (dt, J = 8.8, 1.9 Hz, 2H), 8.17 (dt, J = 8.8, 1.9 Hz, 2H), 8.28 (br s , 1H).

化合物３(2.02 g、16.14 mmol)、トルエン (50 mL)、化合物４(2.30 mL、16.61 mmol)の混合液を４時間加熱還流した。反応後、減圧下、溶媒を留去し、再結晶にて精製して化合物５(2.29 g、52 %)を得た。
化合物５；1H NMR (CDCl3) δ: 1.06 (t, J = 7.7 Hz, 3H), 2.04 (s, 3H), 2.27 (q, J = 7.7 Hz, 2H), 2.88 (t, J = 7.7 Hz, 2H), 3.58 (dt, J = 7.7, 6.5 Hz, 2H), 4.18 (s, 2H), 7.18 - 7.34 (m, 5H), 8.45 (br t, 1H).
Chlorosulfonic acid (3.0 mL)に氷冷下、撹拌しながら化合物５(1.54 g、5.70 mmol)を加えた後、反応液を室温に戻して１時間撹拌した。この反応液に氷冷しながら水を加え、析出した固体を濾取し、化合物６を得た。
化合物６；1H NMR (CDCl3) δ: 1.06 (t, J = 7.8 Hz, 3H), 2.05 (s, 3H), 2.28 (q, J = 7.8 Hz, 2H), 3.01 (t, J = 7.6 Hz, 2H), 3.63 (dt, J = 7.6, 5.4 Hz, 2H), 4.18 (s, 2H), 7.49 (d, J = 8.6 Hz, 2H), 7.97 (d, J = 8.6 Hz, 2H), 8.52 (br t, 1H).
化合物６のメタノール(5 mL)溶液に、28% アンモニア水(5 mL)を加え、この混合液を70℃で2.5時間撹拌した。この混合液に水、酢酸エチルを加えて抽出し、有機層を無水硫酸ナトリウムで乾燥した。減圧下、溶媒を留去し、化合物７(1.70 g、85 %)を得た。
化合物７；1H NMR (CDCl3) δ: 1.06 (t, J = 8.0 Hz, 3H), 2.05 (s, 3H), 2.26 (q, J = 8.0 Hz, 2H), 2.95 (t, J = 7.6 Hz, 2H), 3.60 (dt, J = 7.6, 6.3 Hz, 2H), 4.18 (s, 2H), 7.37 (d, J = 8.6 Hz, 2H), 7.85 (d, J = 8.6 Hz, 2H), 8.49 (t, J = 6.3 Hz, 1H).
化合物７(1.11g、3.16mmol)にアセトン(60mL)、トリエチルアミン(0.90 mL、6.49 mmol)を加えて、氷冷下、撹拌しながら化合物２(0.50 mL、3.26 mmol)を滴下し、反応液を室温で8時間撹拌した後、水を加えて反応を停止した。この混合液に酢酸エチルを加えて抽出し、有機層を無水硫酸ナトリウムで乾燥した。減圧下、溶媒を留去し、残渣をシリカゲルカラムクロマトグラフィー、再結晶にて精製し、化合物（Ｉ−２）(0.56 g、37 %)を得た。
化合物（Ｉ−２）；1H NMR (CDCl3) δ: 0.93 - 0.83 (m, 2H), 1.07 (t, J = 7.6 Hz, 3H), 1.26 - 1.01 (m, 2H), 1.64 - 1.59 (m, 5H), 1.78 - 1.68 (m, 1H), 1.90 - 1.86 (m, 1H), 2.06 (s, 3H), 2.12 (d, J = 7.0 Hz, 2H), 2.28 (q, J = 7.6 Hz, 2H), 2.98 (t, J = 7.6 Hz, 2H), 3.61 (dt, J = 7.6, 6.3 Hz, 2H), 4.21 (s, 2H), 7.40 (d, J = 8.4 Hz, 2H), 7.98 (d, J = 8.4 Hz, 2H), 8.56 (t, J = 5.8 Hz, 1H), 9.18 - 9.10 (m, 1H).

A mixture of compound 3 (2.02 g, 16.14 mmol), toluene (50 mL) and compound 4 (2.30 mL, 16.61 mmol) was heated to reflux for 4 hours. After the reaction, the solvent was distilled off under reduced pressure, and purification by recrystallization gave Compound 5 (2.29 g, 52%).
Compound 5; 1H NMR (CDCl3) δ: 1.06 (t, J = 7.7 Hz, 3H), 2.04 (s, 3H), 2.27 (q, J = 7.7 Hz, 2H), 2.88 (t, J = 7.7 Hz, 2H), 3.58 (dt, J = 7.7, 6.5 Hz, 2H), 4.18 (s, 2H), 7.18-7.34 (m, 5H), 8.45 (br t, 1H).
Compound 5 (1.54 g, 5.70 mmol) was added to Chlorosulfonic acid (3.0 mL) with stirring under ice cooling, and then the reaction solution was returned to room temperature and stirred for 1 hour. Water was added to the reaction solution while cooling with ice, and the precipitated solid was collected by filtration to obtain Compound 6.
Compound 6; 1H NMR (CDCl3) δ: 1.06 (t, J = 7.8 Hz, 3H), 2.05 (s, 3H), 2.28 (q, J = 7.8 Hz, 2H), 3.01 (t, J = 7.6 Hz, 2H), 3.63 (dt, J = 7.6, 5.4 Hz, 2H), 4.18 (s, 2H), 7.49 (d, J = 8.6 Hz, 2H), 7.97 (d, J = 8.6 Hz, 2H), 8.52 ( br t, 1H).
To a solution of compound 6 in methanol (5 mL) was added 28% aqueous ammonia (5 mL), and the mixture was stirred at 70 ° C. for 2.5 hours. The mixture was extracted by adding water and ethyl acetate, and the organic layer was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain Compound 7 (1.70 g, 85%).
Compound 7; 1H NMR (CDCl3) δ: 1.06 (t, J = 8.0 Hz, 3H), 2.05 (s, 3H), 2.26 (q, J = 8.0 Hz, 2H), 2.95 (t, J = 7.6 Hz, 2H), 3.60 (dt, J = 7.6, 6.3 Hz, 2H), 4.18 (s, 2H), 7.37 (d, J = 8.6 Hz, 2H), 7.85 (d, J = 8.6 Hz, 2H), 8.49 ( t, J = 6.3 Hz, 1H).
Acetone (60 mL) and triethylamine (0.90 mL, 6.49 mmol) are added to compound 7 (1.11 g, 3.16 mmol), and compound 2 (0.50 mL, 3.26 mmol) is added dropwise with stirring under ice cooling. After stirring at room temperature for 8 hours, water was added to stop the reaction. The mixture was extracted with ethyl acetate, and the organic layer was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography and recrystallization to obtain compound (I-2) (0.56 g, 37%).
Compound (I-2); 1H NMR (CDCl3) δ: 0.93-0.83 (m, 2H), 1.07 (t, J = 7.6 Hz, 3H), 1.26-1.01 (m, 2H), 1.64-1.59 (m, 5H), 1.78-1.68 (m, 1H), 1.90-1.86 (m, 1H), 2.06 (s, 3H), 2.12 (d, J = 7.0 Hz, 2H), 2.28 (q, J = 7.6 Hz, 2H ), 2.98 (t, J = 7.6 Hz, 2H), 3.61 (dt, J = 7.6, 6.3 Hz, 2H), 4.21 (s, 2H), 7.40 (d, J = 8.4 Hz, 2H), 7.98 (d , J = 8.4 Hz, 2H), 8.56 (t, J = 5.8 Hz, 1H), 9.18-9.10 (m, 1H).

窒素気流中、化合物９(2.00 g、13.23 mmol)、化合物８(2.33 g, 13,47 mmol)、４−ジメチルアミノピリジン(0.16 g、1.30 mmol)、トリフェニルホスフィン(5.19 g、19.80 mmol)、THF (60 mL)の混合液に、氷冷下、撹拌しながら40% ジエチルアゾジカルボキシレート(DEAD)トルエン溶液(10.40 mL、23.89 mmol)を滴下した。この反応液を5時間撹拌し、室温で40時間静置した後、水を加えて反応を停止した。この混合液に飽和塩化アンモニウム水溶液、ジクロロメタンを加えて抽出し、有機層を無水硫酸ナトリウムで乾燥した。減圧下、溶媒を留去し、残渣を酢酸エチルで洗浄し、濾取して化合物１０(2.46 g、61%)を得た。
化合物１０；1H NMR (acetone-d6) δ: 1.22 (t, J = 7.7 Hz, 3H), 2.62 (q, J = 7.7 Hz, 2H), 3.22 (t, J = 6.5 Hz, 2H), 4.47 (t, J = 6.5 Hz, 2H), 6.43 (br s, 2H), 7.06 (d, J = 8.9 Hz, 2H), 7.27 (d, J = 8.9 Hz, 1H), 7.56 (dd, J = 8.9, 2.4 Hz, 1H), 7.79 (d, J = 8.9 Hz, 2H), 8.38 (d, J = 2.4 Hz, 1H).
化合物１０(0.78 g、2.56 mmol)にアセトン(20 mL)、トリエチルアミン(1.00 mL、7.21 mmol)を加えて、冷却下、撹拌しながら化合物２(0.80 mL、5.21 mmol)を滴下した。その後、反応液を60℃で12時間撹拌し、水を加えて反応を停止した。この混合液にジクロロメタンを加えて抽出し、有機層を無水硫酸ナトリウムで乾燥した。減圧下、溶媒を留去し、残渣をシリカゲルカラムクロマトグラフィーにて精製し、化合物（Ｉ−３）(0.83 g、75 %)を得た。
化合物（Ｉ−３）；1H NMR (CDCl3) δ: 0.82 - 0.92 (m, 2H), 1.25 (t, J = 7.6 Hz, 3H), 1.11 - 1.28 (m, 3H), 1.59 - 1.66 (m, 5H), 1.67 - 1.75 (m, 1H), 2.08 (d, J = 7.0 Hz, 2H), 2.64 (q, J = 7.6 Hz, 2H), 3.26 (t, J = 6.7 Hz, 2H), 4.42 (t, J = 6.7 Hz, 2H), 6.98 (d, J = 9.0 Hz, 2H), 7.18 (d, J = 7.8 Hz, 1H), 7.48 (dd, J = 7.8, 2.3 Hz, 1H), 7.96 (d, J = 9.0 Hz, 2H), 8.40 (d, J = 2.3 Hz, 1H).

In a nitrogen stream, compound 9 (2.00 g, 13.23 mmol), compound 8 (2.33 g, 13,47 mmol), 4-dimethylaminopyridine (0.16 g, 1.30 mmol), triphenylphosphine (5.19 g, 19.80 mmol), A 40% diethyl azodicarboxylate (DEAD) toluene solution (10.40 mL, 23.89 mmol) was added dropwise to a THF (60 mL) mixture with stirring under ice cooling. The reaction was stirred for 5 hours and allowed to stand at room temperature for 40 hours, after which water was added to stop the reaction. The mixture was extracted by adding a saturated aqueous ammonium chloride solution and dichloromethane, and the organic layer was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was washed with ethyl acetate and collected by filtration to obtain compound 10 (2.46 g, 61%).
Compound 10; 1H NMR (acetone-d6) δ: 1.22 (t, J = 7.7 Hz, 3H), 2.62 (q, J = 7.7 Hz, 2H), 3.22 (t, J = 6.5 Hz, 2H), 4.47 ( t, J = 6.5 Hz, 2H), 6.43 (br s, 2H), 7.06 (d, J = 8.9 Hz, 2H), 7.27 (d, J = 8.9 Hz, 1H), 7.56 (dd, J = 8.9, 2.4 Hz, 1H), 7.79 (d, J = 8.9 Hz, 2H), 8.38 (d, J = 2.4 Hz, 1H).
Acetone (20 mL) and triethylamine (1.00 mL, 7.21 mmol) were added to compound 10 (0.78 g, 2.56 mmol), and compound 2 (0.80 mL, 5.21 mmol) was added dropwise with stirring under cooling. Thereafter, the reaction solution was stirred at 60 ° C. for 12 hours, and water was added to stop the reaction. Dichloromethane was added to the mixture for extraction, and the organic layer was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography to obtain compound (I-3) (0.83 g, 75%).
Compound (I-3); 1H NMR (CDCl3) δ: 0.82-0.92 (m, 2H), 1.25 (t, J = 7.6 Hz, 3H), 1.11-1.28 (m, 3H), 1.59-1.66 (m, 5H), 1.67-1.75 (m, 1H), 2.08 (d, J = 7.0 Hz, 2H), 2.64 (q, J = 7.6 Hz, 2H), 3.26 (t, J = 6.7 Hz, 2H), 4.42 ( t, J = 6.7 Hz, 2H), 6.98 (d, J = 9.0 Hz, 2H), 7.18 (d, J = 7.8 Hz, 1H), 7.48 (dd, J = 7.8, 2.3 Hz, 1H), 7.96 ( d, J = 9.0 Hz, 2H), 8.40 (d, J = 2.3 Hz, 1H).

ここで、Ｒ^８としては、以下の基が挙げられる。

ここで、Ｒ^１１としては、水素、メチル、エチルまたはトリフルオロメチルが挙げられる。 In the same manner as in the above examples, for example, the following compounds can be synthesized as the compound of the present invention.

Here, examples of R ⁸ include the following groups.

Here, examples of R ¹¹ include hydrogen, methyl, ethyl, and trifluoromethyl.

ここで、Ｒ^８としては、以下の基が挙げられる。

ここで、環Ｂとしては、以下の環が挙げられる。

Furthermore, the following compounds can also be synthesized as the compounds of the present invention.

Here, examples of R ⁸ include the following groups.

Here, examples of the ring B include the following rings.

The following compounds were also synthesized.
(Reference Example 1)

化合物（Ｓ−１）(1.92 g、11.29 mmol)、トルエン(25 mL)、トリエチルアミン(3.20 mL、23.09 mmol)、ジフェニルリン酸アジド(3.30 ml、15.31 mmol)の混合液を3時間加熱還流した。その後60℃に冷却して、化合物１(1.50 g、7.53 mmol)を加えた。その後、１時間加熱還流し、室温にて13時間静置した。この反応液に飽和塩化アンモニウム水溶液、酢酸エチルを加えて抽出し、有機層を無水硫酸ナトリウムで乾燥した。減圧下、溶媒を留去し、残渣をシリカゲルカラムクロマトグラフィー、再結晶にて精製し、化合物（Ｓ−３）(1.29 g、47 %)を得た。
化合物（Ｓ−３）；1H-NMR (DMSO-d6) δ: 0.92 (d, J = 6.7 Hz, 6H), 1.01 - 1.31 (m, 5H), 1.40 - 1.55 (m, 1H), 1.73 - 1.87 (m, 4H), 2.76 (s, 3H), 3.23 - 3.36 (m, 1H), 6.53 (br d, J = 7.6 Hz, 1H), 8.13 (dt, J = 8.5, 1.8 Hz, 2H), 8.25 (dt, J = 8.5, 1.8 Hz, 2H).
（参考例２）

A mixture of compound (S-1) (1.92 g, 11.29 mmol), toluene (25 mL), triethylamine (3.20 mL, 23.09 mmol) and diphenylphosphoric acid azide (3.30 ml, 15.31 mmol) was heated to reflux for 3 hours. Then, it cooled to 60 degreeC and the compound 1 (1.50 g, 7.53 mmol) was added. Thereafter, the mixture was heated to reflux for 1 hour and allowed to stand at room temperature for 13 hours. A saturated aqueous ammonium chloride solution and ethyl acetate were added to the reaction solution for extraction, and the organic layer was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography and recrystallization to obtain compound (S-3) (1.29 g, 47%).
Compound (S-3): 1H-NMR (DMSO-d6) δ: 0.92 (d, J = 6.7 Hz, 6H), 1.01-1.31 (m, 5H), 1.40-1.55 (m, 1H), 1.73-1.87 (m, 4H), 2.76 (s, 3H), 3.23-3.36 (m, 1H), 6.53 (br d, J = 7.6 Hz, 1H), 8.13 (dt, J = 8.5, 1.8 Hz, 2H), 8.25 (dt, J = 8.5, 1.8 Hz, 2H).
(Reference Example 2)

化合物（Ｓ−４）(5.03 g、25.22 mmol)、2,2-dimethoxypropane (30 mL)、pyridinium p-toluenesulfonate (0.64 g、2.52 mmol) の混合液を7時間加熱還流した。この反応液を減圧下、濃縮し、残渣をシリカゲルカラムクロマトグラフィー、再結晶にて精製し、化合物（Ｓ−５）(4.50 g、73 %)を得た。続いて、化合物（Ｓ−５）(2.52 g、10.32 mmol)にDMSO (30 mL)、NaH (0.50 g、20.67 mmol)を加え、60℃で１時間撹拌した。この反応液に化合物（Ｓ−６）(1.58 mL、12.37 mmol)を加えて5時間撹拌した。この反応液に飽和塩化アンモニウム水溶液、酢酸エチルを加えて抽出し、有機層を無水硫酸ナトリウムで乾燥した。減圧下、溶媒を留去し、残渣をシリカゲルカラムクロマトグラフィー、再結晶にて精製し、化合物（Ｓ−７）(2.78 g、73%)を得た。続いて、化合物（Ｓ−７）(1.53 g、4.13 mmol)にTHF(15 mL)、6N HCl (2 mL)を加え、10分間撹拌した。この反応液に飽和塩化アンモニウム水溶液、メタノール、酢酸エチルを加えて抽出し、有機層を無水硫酸ナトリウムで乾燥した。減圧下、溶媒を留去し、残渣を酢酸エチルにて洗浄して化合物（Ｓ−８）(1.25 g、93%)を得た。
化合物（Ｓ−８）；1H-NMR (DMSO-d6) δ: 1.12 - 1.39 (m, 5H), 1.60 - 1.74 (m, 5H), 2.77 (s, 3H), 3.41 - 3.55 (m, 1H), 4.44 (s, 2H), 8.11 (d, J = 8.5 Hz, 2H), 8.24 (d, J = 8.9, 1H), 8.28 (d, J = 8.5 Hz, 2H).
（参考例３）

A mixture of compound (S-4) (5.03 g, 25.22 mmol), 2,2-dimethoxypropane (30 mL) and pyridinium p-toluenesulfonate (0.64 g, 2.52 mmol) was heated to reflux for 7 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography and recrystallization to obtain compound (S-5) (4.50 g, 73%). Subsequently, DMSO (30 mL) and NaH (0.50 g, 20.67 mmol) were added to compound (S-5) (2.52 g, 10.32 mmol), and the mixture was stirred at 60 ° C. for 1 hour. Compound (S-6) (1.58 mL, 12.37 mmol) was added to the reaction solution, and the mixture was stirred for 5 hours. A saturated aqueous ammonium chloride solution and ethyl acetate were added to the reaction solution for extraction, and the organic layer was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography and recrystallization to obtain compound (S-7) (2.78 g, 73%). Subsequently, THF (15 mL) and 6N HCl (2 mL) were added to the compound (S-7) (1.53 g, 4.13 mmol), and the mixture was stirred for 10 minutes. Saturated aqueous ammonium chloride solution, methanol and ethyl acetate were added to the reaction solution for extraction, and the organic layer was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was washed with ethyl acetate to obtain compound (S-8) (1.25 g, 93%).
Compound (S-8); 1H-NMR (DMSO-d6) δ: 1.12-1.39 (m, 5H), 1.60-1.74 (m, 5H), 2.77 (s, 3H), 3.41-3.55 (m, 1H) , 4.44 (s, 2H), 8.11 (d, J = 8.5 Hz, 2H), 8.24 (d, J = 8.9, 1H), 8.28 (d, J = 8.5 Hz, 2H).
(Reference Example 3)

化合物（Ｓ−９）(3.96g、31.40 mmol)にメタノール(15 mL) を加え、氷冷下、撹拌しながら、臭素(5.01 g、31.37 mmol)を滴下した。その後、反応液を15℃で30分間撹拌し、水を加え、室温で3時間撹拌した。この混合液にヘキサン/酢酸エチル (1 : 3)を加えて抽出し、有機層を10% 炭酸カリウム水溶液で洗浄した後、無水硫酸ナトリウムで乾燥した。減圧下、溶媒を留去し、化合物（Ｓ−１０）と化合物（Ｓ−９）(10：1)の混合物(6.55g)を得た。続いて、化合物（Ｓ−１０）と化合物（Ｓ−９）(10：1)の混合物(1.00g、化合物（Ｓ−１０）換算4.39 mmol)にアセトン(20 mL)、炭酸カリウム(1.89g、13.65 mmol)、化合物１(0.87 g、4.39 mmol)を加え、60℃で7時間撹拌した。この反応液に水、酢酸エチルを加えて抽出し、有機層を無水硫酸ナトリウムで乾燥した後、減圧下、溶媒を留去し、残渣をシリカゲルカラムクロマトグラフィーにて精製し、化合物（Ｓ−１１）(0.74 g、52 %)を得た。
化合物（Ｓ−１１）；1H-NMR (DMSO-d6) δ: 1.21 - 1.37 (m, 5H), 1.71 - 1.79 (m, 5H), 2.51 - 2.56 (m, 1H), 2.75 (s, 3H), 4.00 (s, 2H), 8.03 (d, J = 8.5, 2H), 8.23 (d, J = 8.5 Hz, 2H), 8.24 - 8.26 (m, 1H).

Methanol (15 mL) was added to compound (S-9) (3.96 g, 31.40 mmol), and bromine (5.01 g, 31.37 mmol) was added dropwise with stirring under ice cooling. Thereafter, the reaction solution was stirred at 15 ° C. for 30 minutes, water was added, and the mixture was stirred at room temperature for 3 hours. The mixture was extracted with hexane / ethyl acetate (1: 3), and the organic layer was washed with 10% aqueous potassium carbonate solution and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain a mixture (6.55 g) of compound (S-10) and compound (S-9) (10: 1). Subsequently, acetone (20 mL), potassium carbonate (1.89 g, 1.39 g, compound (S-9) (10: 1) mixture (1.00 g, compound (S-10) equivalent 4.39 mmol)) were added. 13.65 mmol) and compound 1 (0.87 g, 4.39 mmol) were added, and the mixture was stirred at 60 ° C. for 7 hours. The reaction mixture was extracted with water and ethyl acetate, and the organic layer was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography to obtain the compound (S-11). ) (0.74 g, 52%).
Compound (S-11): 1H-NMR (DMSO-d6) δ: 1.21-1.37 (m, 5H), 1.71-1.79 (m, 5H), 2.51-2.56 (m, 1H), 2.75 (s, 3H) , 4.00 (s, 2H), 8.03 (d, J = 8.5, 2H), 8.23 (d, J = 8.5 Hz, 2H), 8.24-8.26 (m, 1H).

Evaluation method using GK rats
GK male rats aged 5 to 11 weeks were divided into 8 groups, fasted for 12 to 18 hours from the day before the test, and compound (I-1) (100 mg / kg, 1 mL / kg) as a test compound was 1.5% carboxy. A suspension of methylcellulose was forcibly administered into the stomach with an oral sonde. As a control, a 1.5% carboxymethylcellulose solution (1 mL / kg) of the vehicle was orally administered. In the control group, compound (S-8) (100 mg / kg, 1 mL / kg) and acetohexamide (100 mg / kg, 1 mL / kg), which is an existing diabetes drug (SU drug), were administered. Thirty minutes after administration, glucose solution (500 mg / kg, 2 mL / kg) was orally administered, blood was collected from the tail vein at regular intervals, and blood glucose level was measured using an Accucheck Active Stick (Rosch). The effect of the test compound was evaluated by comparing the control and administration groups, and a significant difference test was performed.
The results are shown in FIG.
In an experiment using GK male rats that are non-obese type 2 diabetes model rats, the blood glucose level of the control group could be lowered by administration of acetohexamide and compound (I-1). Compound (I-1) was found to be more effective than acetohexamide in rapidly rising and exhibiting a fast-acting aspect to suppress postprandial hyperglycemia. Moreover, since the compound (I-1) has a good medicinal effect, it was found that hypoglycemia can be prevented as compared with acetohexamide.
In Reference Example Compound (S-8), these effects were not observed.
The reference example compound (S-11) was not shown in FIG.

Evaluation method using Wistar male rats
Male Wistar rats are divided into groups of 4 to 8 animals, fasted for 12 to 18 hours from the day before the test, and the test compound (I-1) (50 to 100 mg / kg, 1 mL / kg) is suspended in 1.5% carboxymethylcellulose. The liquid was forcibly administered into the stomach with an oral sonde. As a control, a 1.5% carboxymethylcellulose solution (1 mL / kg) of the vehicle was orally administered. In the control group, acetohexamide, nateglinide and compound (S-8), which are existing diabetes drugs, were administered. Blood was collected from the tail vein at regular intervals after administration, and the blood glucose level was measured using an Accucheck Active Stick (Rosch) (FIG. 2). In addition, blood was collected from the tail vein 90 minutes after administration, and the plasma insulin level was measured with Levis insulin rat T (Shibagoat) (FIG. 3). The effect of the test compound was evaluated by comparing the control and administration groups, and a significant difference test was performed.
The results are shown in FIG. 2 and FIG.
In an experiment using Wistar male rats, which are normal model rats, blood glucose levels were lower in the acetohexamide and nateglinide administration groups than in the control group. On the other hand, it was not decreased in the compound (I-1) administration group. This is because compound (I-1) acts to lower blood glucose level in GK male rats, which are model rats of non-obese type 2 diabetes (Example 4), and blood glucose level is reduced in Wistar male rats, which are normal model rats. Indicates that there is no reduction. In addition, in the reference example compound (S-8), these effects were not seen. (Figure 2)
The plasma insulin level 90 minutes after administration was higher in the acetohexamide and nateglinide administration groups than in the control group, but such a tendency was not seen in the compound (I-1) administration group. I couldn't. From this, it was found that the compound (I-1) and acetohexamide and nateglinide show different actions.
In addition, acetohexamide and nateglinide have the following structures.

  Hereinafter, biological test examples of the compound of the present invention will be described.

Test Example 1: CYP Inhibition Test O-deethylation of 7-ethoxyresorufin as a typical substrate metabolic reaction of human major CYP5 molecular species (CYP1A2, 2C9, 2C19, 2D6, 3A4) using commercially available pooled human liver microsomes (CYP1A2), methyl-hydroxylation of tolbutamide (CYP2C9), 4′-hydroxylation of mephenytoin (CYP2C19), O-demethylation of dextromethorphan (CYP2D6), and hydroxylation of terfenadine (CYP3A4), respectively. The degree to which the amount of metabolite produced is inhibited by the compound of the present invention is evaluated.

  The reaction conditions are as follows: substrate, 0.5 μmol / L ethoxyresorufin (CYP1A2), 100 μmol / L tolbutamide (CYP2C9), 50 μmol / L S-mephenytoin (CYP2C19), 5 μmol / L dextromethorphan (CYP2D6), 1 μmol / L terfenadine (CYP3A4); reaction time, 15 minutes; reaction temperature, 37 ° C .; enzyme, pooled human liver microsome 0.2 mg protein / mL; compound concentration of the present invention 1, 5, 10, 20 μmol / L (4 points) .

  As a reaction solution in a 96-well plate, each of 5 types of substrate, human liver microsome, and the compound of the present invention are added in the above composition in a 50 mmol / L Hepes buffer solution, and NADPH as a coenzyme is added to make a metabolic reaction as an index. To start. After reacting at 37 ° C. for 15 minutes, the reaction is stopped by adding a methanol / acetonitrile = 1/1 (V / V) solution. After centrifuging at 3000 rpm for 15 minutes, resorufin (CYP1A2 metabolite) in the centrifugation supernatant was quantified with a fluorescent multi-label counter, tolbutamide hydroxide (CYP2C9 metabolite), mephenytoin 4 ′ hydroxide (CYP2C19 metabolite) , Dextrorphan (CYP2D6 metabolite) and terfenadine alcohol (CYP3A4 metabolite) are quantified by LC / MS / MS.

The control (100%) was obtained by adding only DMSO, which is a solvent in which the drug was dissolved, to the reaction system, the residual activity (%) was calculated, and the IC ₅₀ was calculated by inverse estimation using a logistic model using the concentration and the inhibition rate. calculate.

Test Example 2: Examination of BA test oral absorbability Experimental materials and methods (1) Animals used: Mice or SD rats are used.
(2) Breeding conditions: Mice or SD rats are allowed to freely take solid feed and sterilized tap water.
(3) Setting of dosage and grouping: oral administration and intravenous administration are administered at a predetermined dosage. Set the group as follows. (Dose may vary for each compound)
Oral administration 1-30 mg / kg (n = 2-3)
Intravenous administration 0.5-10 mg / kg (n = 2-3)
(4) Preparation of administration solution: Oral administration is administered as a solution or suspension. Intravenous administration is administered after solubilization.
(5) Administration method: Oral administration is forcibly administered into the stomach with an oral sonde. Intravenous administration is performed from the tail vein using a syringe with an injection needle.
(6) Evaluation items: Blood is collected over time, and the concentration of the compound of the present invention in plasma is measured using LC / MS / MS.
(7) Statistical analysis: The plasma concentration-time curve area (AUC) is calculated using the non-linear least squares program WinNonlin (Registered Trademark) for plasma compound concentration transition, and the oral administration group and intravenous administration The bioavailability (BA) of the compound of the present invention is calculated from the AUC of the group.

Test Example 3: Metabolic stability test A commercially available pooled human liver microsome is reacted with the compound of the present invention for a certain period of time, and the residual rate is calculated by comparing the reaction sample with the unreacted sample to evaluate the degree of metabolism of the compound of the present invention in the liver. To do.

  In 0.2 mL buffer (50 mmol / L Tris-HCl pH 7.4, 150 mmol / L potassium chloride, 10 mmol / L magnesium chloride) containing 0.5 mg protein / mL human liver microsomes in the presence of 1 mmol / L NADPH React at 37 ° C. for 0 or 30 minutes (oxidative reaction). After the reaction, 50 μL of the reaction solution is added to 100 μL of a methanol / acetonitrile = 1/1 (v / v) solution, mixed, and centrifuged at 3000 rpm for 15 minutes. The compound of the present invention in the centrifugal supernatant is quantified by LC / MS / MS, and the residual amount of the compound of the present invention after the reaction is calculated with the compound amount at 0 minute reaction as 100%. The hydrolysis reaction is carried out in the absence of NADPH, the glucuronic acid conjugation reaction is carried out in the presence of 5 mmol / L UDP-glucuronic acid instead of NADPH, and the same operation is carried out thereafter.

Test Example 4: CYP3A4 fluorescence MBI test The CYP3A4 fluorescence MBI test is a test for examining the enhancement of CYP3A4 inhibition of the compounds of the present invention by metabolic reaction. 7-Benzyloxytrifluoromethylcoumarin (7-BFC) is debenzylated by the CYP3A4 enzyme (E. coli expression enzyme) to produce a fluorescent metabolite 7-hydroxytrifluoromethylcoumarin (7-HFC). CYP3A4 inhibition is evaluated using 7-HFC production reaction as an index.

  The reaction conditions are as follows: substrate, 5.6 μmol / L 7-BFC; pre-reaction time, 0 or 30 minutes; reaction time, 15 minutes; reaction temperature, 25 ° C. (room temperature); CYP3A4 content (E. coli expression enzyme), Pre-reaction 62.5 pmol / mL, reaction 6.25 pmol / mL (10-fold dilution); compound concentration of the present invention, 0.625, 1.25, 2.5, 5, 10, 20 μmol / L (6 points) ).

  The enzyme and the compound solution of the present invention are added to the 96-well plate as a pre-reaction solution in K-Pi buffer (pH 7.4) in the above-mentioned pre-reaction composition, and the substrate and K-Pi buffer are added to another 96-well plate. A part of the solution was transferred so as to be diluted by 1/10, and a reaction using NADPH as a coenzyme was started as an indicator (no pre-reaction). After reaction for a predetermined time, acetonitrile / 0.5 mol / L The reaction is stopped by adding Tris (trishydroxyaminomethane) = 4/1 (V / V). In addition, NADPH is also added to the remaining pre-reaction solution to start the pre-reaction (pre-reaction is present), and after pre-reaction for a predetermined time, one plate is diluted to 1/10 with the substrate and K-Pi buffer. Start the reaction with the part as the indicator. After the reaction for a predetermined time, the reaction is stopped by adding acetonitrile / 0.5 mol / L Tris (trishydroxyaminomethane) = 4/1 (V / V). The fluorescence value of 7-HFC, which is a metabolite, is measured using a fluorescent plate reader on the plate on which each index reaction has been performed. (Ex = 420nm, Em = 535nm)

A control (100%) was obtained by adding only DMSO, which is a solvent in which the compound of the present invention was dissolved, to the reaction system, and the residual activity (%) when each concentration of the compound of the present invention was added was calculated. Is used to calculate IC ₅₀ by inverse estimation using a logistic model. A case where the difference in IC ₅₀ values is 5 μmol / L or more is (+), and a case where the difference is 3 μmol / L or less is (−).

Test Example 5: Fluctuation Ames Test
The mutagenicity of the compound of the present invention is evaluated.
20 μL of Salmonella typhimurium TA98 strain, TA100 strain, which has been cryopreserved, is inoculated into 10 mL liquid nutrient medium (2.5% Oxoid nutritive broth No. 2) and cultured at 37 ° C. for 10 hours before shaking. For TA98 strain, 9 mL of the bacterial solution is centrifuged (2000 × g, 10 minutes) to remove the culture solution. 9 mL of Micro F buffer (K ₂ HPO ₄ : 3.5 g / L, KH ₂ PO ₄ : 1 g / L, (NH ₄ ) ₂ SO ₄ : 1 g / L, trisodium citrate dihydrate: 0. MicroF containing 110 mL Exposure medium (Biotin: 8 μg / mL, Histidine: 0.2 μg / mL, Glucose: 8 mg / mL) suspended in 25 g / L, MgSO ₄ · 7H ₂ 0: 0.1 g / L) Buffer). The TA100 strain is added to 120 mL of Exposure medium with respect to the 3.16 mL bacterial solution to prepare a test bacterial solution. Compound DMSO solution of the present invention (maximum dose of 50 mg / mL to several-fold dilution at 2-3 times common ratio), DMSO as negative control, and non-metabolic activation condition as a positive control. Nitroquinoline-1-oxide DMSO solution, 0.25 μg / mL 2- (2-furyl) -3- (5-nitro-2-furyl) acrylamide DMSO solution for TA100 strain, TA98 under metabolic activation conditions 40 μg / mL 2-aminoanthracene DMSO solution for the strain and 20 μg / mL 2-aminoanthracene DMSO solution for the TA100 strain, respectively, and 588 μL of the test bacterial solution (under metabolic activation conditions, 498 μL of the test bacterial solution and S9 mix 90 μL of the mixture) and incubate with shaking at 37 ° C. for 90 minutes. 2300 μL of 460 μL of the bacterial solution exposed to the compound of the present invention was added to Indicator Medium (BioF: 8 μg / mL, histidine: 0.2 μg / mL, glucose: 8 mg / mL, bromocresol purple: 37.5 μg / mL). 50 μL each and dispense into 48 wells / dose of the microplate, followed by static culture at 37 ° C. for 3 days. Since wells containing bacteria that have acquired growth ability by mutation of the amino acid (histidine) synthase gene change from purple to yellow due to pH change, the number of bacteria growth wells that changed to yellow in 48 wells per dose was counted. Evaluation is made in comparison with the negative control group. A negative mutagenicity is indicated as (−), and a positive mutagenicity is indicated as (+).

Test Example 6: hERG Test For the purpose of evaluating the risk of prolonging the electrocardiogram QT interval of the compound of the present invention, using HEK293 cells expressing human ether-a-go-related gene (hERG) channel, it is important for ventricular repolarization process Consider the action of the compounds of the present invention on the delayed rectifier K ⁺ current (I _Kr ) that plays a role.
Using a fully automatic patch clamp system (PatchXpress 7000A, Axon Instruments Inc.), the cells were held at a membrane potential of −80 mV by the whole cell patch clamp method, followed by a +40 mV depolarization stimulus for 2 seconds and a further −50 mV repolarization. Record the I _Kr elicited when the stimulus is applied for 2 seconds. After the generated current is stabilized, an extracellular fluid (NaCl: 135 mmol / L, KCl: 5.4 mmol / L, NaH ₂ PO ₄ : 0.3 mmol / L, in which the compound of the present invention is dissolved at a target concentration, CaCl ₂ · 2H ₂ O: 1.8 mmol / L, MgCl ₂ · 6H ₂ O: 1 mmol / L, glucose: 10 mmol / L, HEPES (4- (2-hydroxyethyl) -1-piperazine ethersulfonic acid, 4- (2- Hydroxyethyl) -1-piperazineethanesulfonic acid): 10 mmol / L, pH = 7.4) is applied to the cells for 10 minutes at room temperature. From the obtained I _Kr , the absolute value of the maximum tail current is measured based on the current value at the holding membrane potential using analysis software (DataXpress ver. 1, Molecular Devices Corporation). Furthermore, the inhibition rate with respect to the maximum tail current before application of the compound of the present invention is calculated, and compared with the vehicle application group (0.1% dimethyl sulfoxide solution), the effect of the compound of the present invention on I _Kr is evaluated.

Test Example 7: Solubility test The solubility of the compound of the present invention is determined under the condition of addition of 1% DMSO. Prepare a 10 mmol / L compound solution in DMSO, add 6 μL of the compound solution of the present invention to pH 6.8 artificial intestinal fluid (0.2 mol / L potassium dihydrogen phosphate test solution 250 mL, add 0.2 mol / L NaOH test solution 118 mL, water) Add to 594 μL. After allowing to stand at 25 ° C. for 16 hours, the mixed solution is subjected to suction filtration. The filtrate is diluted 2-fold with methanol / water = 1/1 (V / V), and the concentration in the filtrate is measured by HPLC or LC / MS / MS by the absolute calibration method.

Test Example 8: Powder solubility test An appropriate amount of the compound of the present invention is put in an appropriate container, and JP-1 solution (water is added to 2.0 g of sodium chloride and 7.0 mL of hydrochloric acid to make 1000 mL), JP-2 solution. (Add 500 mL of water to 500 mL of phosphate buffer solution at pH 6.8), 20 mmol / L sodium taurocholate (TCA) / JP-2 solution (JP-2 solution is added to 1.08 g of TCA to make 100 mL) 200 μL each Added. When the entire amount is dissolved after the addition of the test solution, the compound of the present invention is appropriately added. After sealing at 37 ° C. for 1 hour, the mixture is filtered, and 100 μL of methanol is added to 100 μL of each filtrate to perform 2-fold dilution. Change the dilution factor as necessary. Check for bubbles and deposits, seal and shake. The compound of the present invention is quantified using HPLC by the absolute calibration curve method.

The following formulation examples are merely illustrative and are not intended to limit the scope of the invention in any way.
(Formulation example 1)
Hard gelatin capsules are manufactured using the following ingredients:
dose
(Mg / capsule)
Active ingredient 250
Starch (dried) 200
Magnesium stearate 10
Total 460mg

(Formulation example 2)
Tablets are manufactured using the following ingredients:
dose
(Mg / tablet)
Active ingredient 250
Cellulose (microcrystal) 400
Silicon dioxide (fume) 10
Stearic acid 5
665mg total
The ingredients are mixed and compressed into tablets each weighing 665 mg.

(Formulation example 3)
An aerosol solution is prepared containing the following ingredients:
weight
Active ingredient 0.25
Ethanol 25.75
Propellant 22 (chlorodifluoromethane) 74.00
Total 100.00
The active ingredient and ethanol are mixed and this mixture is added to a portion of the propellant 22, cooled to -30 ° C and transferred to a filling device. The required amount is then fed into a stainless steel container and diluted with the remaining propellant. Attach the bubble unit to the container.

(Formulation example 4)
A tablet containing 60 mg of active ingredient is prepared as follows:
Active ingredient 60mg
45mg starch
Microcrystalline cellulose 35mg
Polyvinylpyrrolidone (10% solution in water) 4mg
Sodium carboxymethyl starch 4.5mg
Magnesium stearate 0.5mg
Talc 1mg
150mg total
The active ingredients, starch, and cellulose are no. 45 mesh U.V. S. And mix well. An aqueous solution containing polyvinylpyrrolidone was mixed with the obtained powder, and the mixture was 14 mesh U.S. S. Pass through a sieve. The granules thus obtained were dried at 50 ° C. 18 mesh U.F. S. Pass through a sieve. No. 60 mesh U.S. S. Sodium carboxymethyl starch, magnesium stearate, and talc passed through a sieve are added to the granules, mixed and then compressed on a tablet press to obtain tablets each weighing 150 mg.

(Formulation example 5)
Capsules containing 80 mg of active ingredient are prepared as follows:
Active ingredient 80mg
Starch 59mg
Microcrystalline cellulose 59mg
Magnesium stearate 2mg
Total 200mg
Mix the active ingredient, starch, cellulose and magnesium stearate; 45 mesh U.V. S. Through the sieve and filled into hard gelatin capsules 200 mg each.

(Formulation Example 6)
A suppository containing 225 mg of active ingredient is prepared as follows:
Active ingredient 225mg
Saturated fatty acid glyceride 2000mg
Total 2225mg
The active ingredient is No. 60 mesh U.S. S. And suspended in a saturated fatty acid glyceride that has been heated and melted to the minimum necessary. The mixture is then cooled in an apparent 2 g mold.

(Formulation example 7)
A suspension containing 50 mg of active ingredient is prepared as follows:
Active ingredient 50mg
Sodium carboxymethylcellulose 50mg
Syrup 1.25ml
Benzoic acid solution 0.10ml
Fragrance q. v.
Dye q. v.
5ml in total with purified water
The active ingredient is No. 45 mesh U.V. S. And is mixed with sodium carboxymethylcellulose and syrup to form a smooth paste. Add the benzoic acid solution and perfume diluted with a portion of the water and stir. Then add a sufficient amount of water to the required volume.

(Formulation Example 8)
The intravenous formulation is manufactured as follows:
Active ingredient 100mg
Saturated fatty acid glyceride 1000ml
Solutions of the above components are usually administered intravenously to the patient at a rate of 1 ml per minute.

  As is clear from the above test examples, the compound according to the present invention exhibits a hypoglycemic effect. Therefore, the compound according to the present invention is very useful as a therapeutic agent for diabetes.

Claims (13)

Formula (I):

(Where
Ring A is a substituted or unsubstituted aromatic carbocyclic ring or a substituted or unsubstituted aromatic heterocyclic ring,
R ¹ is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted Or unsubstituted cycloalkenyl or substituted or unsubstituted heterocyclyl,
R ² and R ³ are each independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, Substituted or unsubstituted cycloalkenyl or substituted or unsubstituted heterocyclyl,
R ⁴ is —CR ^5a R ^5b —, —O— or —S—;
Each R ⁵ is independently halogen, hydroxy, cyano, nitro, carboxy or substituted or unsubstituted alkyl;
R ^5a and R ^5b are each independently hydrogen, halogen, hydroxy, cyano, nitro, carboxy or substituted or unsubstituted alkyl;
m is an integer from 0 to 3,
n is an integer of 0-6.
However, the compounds shown below:

except for. Or a pharmaceutically acceptable salt thereof. Ring A is

(Wherein R ⁶ , R ⁷ , R ⁸ , R ⁹ and R ¹⁰ are each independently hydrogen, halogen, hydroxy, cyano, nitro, carboxy, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, Substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted Substituted alkyloxy, substituted or unsubstituted aryloxy, substituted or unsubstituted heteroaryloxy, substituted or unsubstituted cycloalkyloxy, substituted or unsubstituted cycloalkenyloxy, substituted or unsubstituted heterocyclyloxy, Substituted or unsubstituted allies Alkyloxy, substituted or unsubstituted heteroarylalkyloxy, substituted or unsubstituted cycloalkylalkyloxy, substituted or unsubstituted cycloalkenylalkyloxy, substituted or unsubstituted heterocyclylalkyloxy, substituted or unsubstituted acyl , substituted or unsubstituted carbamoyl, substituted or unsubstituted amino or formula ^{:-( CR 12 R 13) p-} NR 14 - (C = O) -R 15 ( ^{wherein, R 12} and ^{R 13} are each independently Hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or Unsubstituted cycloalkenyl or A heterocyclyl substituted or unsubstituted, p is an integer from 1 to 3, R ¹⁴ is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted Substituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, or substituted or unsubstituted heterocyclyl, R ¹⁵ is substituted or unsubstituted aryl, substituted Or a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted cycloalkenyl, or a substituted or unsubstituted heterocyclyl)). The compound according to claim 1 or a pharmaceutically acceptable salt thereof. R ⁸ is halogen, hydroxy, cyano, nitro, carboxy, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted Or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted aryloxy, substituted or unsubstituted heteroaryloxy, substituted Or unsubstituted cycloalkyloxy, substituted or unsubstituted cycloalkenyloxy, substituted or unsubstituted heterocyclyloxy, substituted or unsubstituted arylalkyloxy, substituted or unsubstituted heteroarylalkyloxy, Substituted or unsubstituted cycloalkylalkyloxy, substituted or unsubstituted cycloalkenylalkyloxy, substituted or unsubstituted heterocyclylalkyloxy, substituted or unsubstituted acyl, substituted or unsubstituted carbamoyl, substituted or unsubstituted Amino or formula: — (CR ¹² R ¹³ ) p—NR ¹⁴ — (C═O) —R ¹⁵ , wherein R ¹² , R ¹³ , p, R ¹⁴ and R ¹⁵ are as defined in claim 2. .) Or a pharmaceutically acceptable salt thereof. R ⁸ is substituted or unsubstituted heteroarylalkyloxy, substituted or unsubstituted acyl or a formula: — (CR ¹² R ¹³ ) p—NR ¹⁴ — (C═O) —R ¹⁵ (wherein R ¹² , R ¹³ , p, R ¹⁴ and R ¹⁵ are as defined in claim 2), or a pharmaceutically acceptable salt thereof. The compound according to claim 3 or 4, or a pharmaceutically acceptable salt thereof, wherein R ⁶ , R ⁷ , R ⁹ and R ¹⁰ are hydrogen. The compound according to any one of claims 1 to 5, wherein m is 1, or a pharmaceutically acceptable salt thereof. R ⁴ is ^-CR 5a ^{R 5b} - The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 6. The compound according to claim 7 or a pharmaceutically acceptable salt thereof, wherein R ^5a and R ^5b are hydrogen, m is 1, and n is 0. In formula (I),

The part indicated by

Wherein R ^5a and R ^5b are as defined in claim 1 and R ¹¹ is hydrogen, halogen, hydroxy, cyano, nitro, carboxy or substituted or unsubstituted alkyl. Or a pharmaceutically acceptable salt thereof. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 9, wherein R ¹ is hydrogen. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 10, wherein R ² and R ³ are hydrogen. A pharmaceutical composition comprising the compound according to any one of claims 1 to 11 or a pharmaceutically acceptable salt thereof. Formula (II):

(Where
Ring A is a substituted or unsubstituted aromatic carbocyclic ring or a substituted or unsubstituted aromatic heterocyclic ring,
Ring B is a substituted or unsubstituted non-aromatic carbocyclic ring or a substituted or unsubstituted non-aromatic heterocyclic ring,
R ¹ is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted Or unsubstituted cycloalkenyl or substituted or unsubstituted heterocyclyl,
R ² and R ³ are each independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted Or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl or substituted or unsubstituted heterocyclyl. However, the compounds shown below:

except for. ) Or a pharmaceutically acceptable salt thereof as an active ingredient.

Images