HK1221220B

HK1221220B - Cyclopentylacrylic acid amide derivative

Info

Publication number: HK1221220B
Application number: HK16109335.7A
Authority: HK
Inventors: 福田保路; 朝比奈由和; 高土居雅法; 山本真则
Original assignee: 杏林制药株式会社; 帝人制药株式会社
Priority date: 2008-04-28
Filing date: 2016-08-05
Publication date: 2018-10-05

Description

Cyclopentyl acrylamide derivative

The present application is a divisional application of chinese patent application having an application number of 200980125629.6, an application date of 2009, 27 th month, and an invention name of "cyclopentyl acrylamide derivative".

Technical Field

The present invention relates to a substance that activates glucokinase (hereinafter sometimes abbreviated as GK). The present invention also relates to a pharmaceutical composition for treating or preventing diabetes, obesity, and the like, which contains a GK activator as an active ingredient.

Background

According to the investigation of patients in 2002 (in 14 years), the number of diabetic patients in japan is 228 ten thousand, and according to the actual condition of diabetes in the same year, the total of "people with a high possibility of diabetes" and "people who cannot exclude the possibility of diabetes" has increased to 1620 thousand, which is a big problem.

Since japanese has a genetic factor of weak insulin secretion ability, insulin hyposecretion is a center in the domestic market of japan. However, the number of patients with insulin resistance is increasing in recent years because of the westernization of dietary life. Therefore, it is desired to develop a drug which is expected to be effective both against insulin hyposecretion and against insulin resistance.

Glucokinase (GK), which catalyzes phosphorylation of glucose, functions as an in vivo glucose receptor, and promotes insulin secretion and insulin utilization in the liver at high glucose levels. Since the glucose concentration of a diabetic patient is not kept constant in vivo, activation of GK promotes glucose concentration-dependent insulin secretion in the liver, which leads to increased glucose utilization and suppressed glucose release in the liver, and lowers blood glucose (non-patent documents 1 to 3). Therefore, it is desired to provide a GK activator which exhibits effects on both insulin hyposecretion (pancreatic action) and insulin resistance (liver action) as a therapeutic agent for diabetes.

As the GK activating substance, various amide compounds (patent documents 11 to 21) such as arylcycloalkylpropionamides (patent document 1), 2, 3-disubstituted trans-olefinic N-aromatic heterocycles or ureidopropionamides (patent document 2), alkynylphenylheteroaromatic carboxamides (patent document 3), hydantoins (patent document 4), substituted phenylacetamides (patent document 5), p-alkyl-, allyl-, cycloheteroalkyl-, or heteroaryl (carbonyl or sulfonyl) amine-substituted phenylamides (patent document 6), α -acyl-, and α -heteroatom-substituted phenylacetamides (patent document 7), tetrazolylphenylacetamides (patent document 8), fused ring heteroaromatic compounds (patent document 9), and phenylacetamides having 1 substituted cycloalkane among heterocycles or carbon atoms (patent document 10) are known, but acrylamide compounds having a structure in which cyclopentyl groups are substituted with 2 fluorine atoms are not disclosed.

Documents of the prior art

Patent document

Patent document 1: WO2000/058293 pamphlet

Patent document 2: WO2001/044216 pamphlet

Patent document 3: WO2001/083465 pamphlet

Patent document 4: WO2001/083478 pamphlet

Patent document 5: WO2001/085706 pamphlet

Patent document 6: WO2001/085707 pamphlet

Patent document 7: WO2002/008209 booklet

Patent document 8: WO2002/014312 pamphlet

Patent document 9: WO2002/046173 pamphlet

Patent document 10: WO2003/095438 booklet

Patent document 11: WO2004/052869 pamphlet

Patent document 12: WO2004/072031 pamphlet

Patent document 13: WO2004/072066 pamphlet

Patent document 14: WO2005/103021 pamphlet

Patent document 15: WO2006/016174 brochure

Patent document 16: WO2006/016178 pamphlet

Patent document 17: WO2006/016194 booklet

Patent document 18: WO2006/059163 pamphlet

Patent document 19: specification of U.S. Pat. No. 6911545

Patent document 20: WO2007/026761 booklet

Patent document 21: WO2008/012227 pamphlet

Non-patent document

Non-patent document 1: diabetes 45, 223-

Non-patent document 2: diabetes 41, 792-806(1992)

Non-patent document 3: FASEB J.10, 1213-

Disclosure of Invention

An object of the present invention is to provide a compound having an excellent GK activating effect or hypoglycemic effect for the treatment or prevention of diabetes, obesity and the like.

The present inventors have conducted extensive studies to solve the above problems, and as a result, have found that a compound having a specific steric structure among compounds having a 3, 4-difluorocyclopentyl group at the 3-position of an acrylamide compound exhibits excellent GK-activating action and hypoglycemic action, thereby completing the present invention.

That is, the present invention relates to the following technical matters.

1) Is represented by the general formula (1)

A compound represented by the formula (I) or a pharmaceutically acceptable salt thereof, wherein R is¹And R²The same or different represent a hydrogen atom or halogenAn element atom, amino group, hydroxyl group, hydroxyamino group, nitro group, cyano group, sulfamoyl group, C₁～C₆Alkyl of (C)₁～C₆Alkoxy group of (C)₁～C₆Alkyl sulfanyl (mercapto), C₁～C₆Alkylsulfinyl group of (1), C₁～C₆Alkylsulfonyl or C₁～C₆alkoxy-C₁～C₆An alkylsulfonyl group, and A represents an optionally substituted heteroaryl group).

2) The compound according to 1) or a pharmaceutically acceptable salt thereof, wherein R is¹And R²Same or different and is hydrogen atom, halogen atom or C¹～C₆An alkylsulfonyl group of (a).

3) The compound according to 1) or a pharmaceutically acceptable salt thereof, wherein R is¹Is a hydrogen atom or a halogen atom, R²Is C₁～C₆An alkylsulfonyl group of (a).

4) The compound according to 1) or a pharmaceutically acceptable salt thereof, wherein R is¹Is a hydrogen atom, R²Is C₁～C₆An alkylsulfonyl group of (a).

5) The compound according to 1) or a pharmaceutically acceptable salt thereof, wherein R is¹Is a hydrogen atom, R²Is cyclopropylsulfonyl.

6) The compound according to 1) or a pharmaceutically acceptable salt thereof, wherein R is¹Is a hydrogen atom, R²Is methylsulfonyl.

7)1) to 6) or a pharmaceutically acceptable salt thereof, represented by general formula (1 a):

is represented by (wherein R is¹、R²And a are as defined above).

8)1) to 6) or a pharmaceutically acceptable salt thereof, represented by general formula (1 b):

is represented by (wherein R is¹、R²And a are as defined above).

9)1) to 8), or a pharmaceutically acceptable salt thereof, wherein a is an unsubstituted heteroaryl or a heteroaryl monosubstituted with: halogen atom, C optionally substituted by halogen atom or hydroxy group₁～C₆Alkyl group of (2), C optionally substituted by halogen atom or hydroxyl group₁～C₆Alkoxy, nitro, cyano, or a compound of the formula

-(O)_p(CH₂)_mC(O)OR³

(in the formula, R³Represents a hydrogen atom or C₁～C₆M represents an integer of 0 to 2, and p represents 0 or 1).

10)1) to 8) or a pharmaceutically acceptable salt thereof, wherein A is a halogen atom or C₁～C₆Alkyl or C₁～C₆The hydroxyalkyl-monosubstituted heteroaryl of (a).

11)1) to 8), or a pharmaceutically acceptable salt thereof, wherein a is a heteroaryl group monosubstituted with: c optionally substituted by halogen atoms or hydroxy groups₁～C₆Alkoxy of, or C₁～C₃alkoxy-C₁～C₃An alkoxy group.

12)1) to 8), or a pharmaceutically acceptable salt thereof, wherein a is a heteroaryl group monosubstituted with: c optionally substituted by halogen atoms or hydroxy groups₁～C₆An alkylsulfanyl group of (1).

13)9) to 12), wherein a is an unsubstituted or monosubstituted five-or six-membered aromatic heterocyclic ring containing 1 to 3 hetero atoms selected from a sulfur atom, an oxygen atom and a nitrogen atom, wherein 1 hetero atom is a nitrogen atom adjacent to a bonding ring atom (a bonding ring atom), or a pharmaceutically acceptable salt thereof.

14)9) to 12), wherein a is an unsubstituted or monosubstituted condensed hetero ring having a five-or six-membered aromatic hetero ring containing 1 to 3 hetero atoms selected from a sulfur atom, an oxygen atom and a nitrogen atom, wherein 1 hetero atom is a nitrogen atom adjacent to a bonding ring atom, or a pharmaceutically acceptable salt thereof.

15)9) to 12), wherein a is an unsubstituted or substituted aromatic heterocycle selected from the group consisting of the following groups, or a pharmaceutically acceptable salt thereof.

16)1) or a pharmaceutically acceptable salt thereof, which is selected from the group consisting of (E) -3- [ (1 α,3 α,4 α) -3, 4-difluorocyclopentyl]-N- (5-fluorothiazol-2-yl) -2- (4- (methylsulfonyl) phenyl) acrylamide, (E) -N- (5-chlorothiazol-2-yl) -3- [ (1 α,3 α,4 α) -3, 4-difluorocyclopentyl]-2- (4- (methylsulfonyl) phenyl) acrylamide, (E) -3- [ (1 α,3 α,4 α) -3, 4-difluorocyclopentyl]-2- (4- (methylsulfonyl) phenyl) -N- (4-methylthiazol-2-yl) acrylamide, (E) -3- [ (1 α,3 α,4 α) -3, 4-difluorocyclopentyl]-2- (4- (methylsulfonyl) phenyl) -N- (5-methylthiazol-2-yl) acrylamide, (+) - (E) -3- [ (1 α,3 α,4 α) -3, 4-difluorocyclopentyl]-N- [4- (2, 2-dimethyl-1, 3-dioxolan-4-yl) thiazol-2-yl]-2- (4- (methylsulfonyl) phenyl) acrylamide, (-) - (E) -3- [ (1 α,3 α,4 α) -3, 4-difluorocyclopentyl]-N- [4- (2, 2-dimethyl-1, 3-dioxolan-4-yl) thiazol-2-yl]-2- (4- (methylsulfonyl) phenyl) acrylamide,(+) - (E) -3- [ (1 α,3 α,4 α) -3, 4-difluorocyclopentyl]-N- [4- (1, 2-dihydroxyethyl) thiazol-2-yl]-2- (4- (methylsulfonyl) phenyl) acrylamide, (-) - (E) -3- [ (1 α,3 α,4 α) -3, 4-difluorocyclopentyl]-N- [4- (1, 2-dihydroxyethyl) thiazol-2-yl]-2- (4- (methylsulfonyl) phenyl) acrylamide, (E) -N- (4-tert-butylthiazol-2-yl) -3- [ (1 α,3 α,4 α) -3, 4-difluorocyclopentyl]-2- (4- (methylsulfonyl) phenyl) acrylamide, (E) -3- [ (1 α,3 α,4 α) -3, 4-difluorocyclopentyl]-2- (4- (methylsulfonyl) phenyl) -N- {4- [2- (tetrahydro-2H-pyran-2-yloxy) ethyl]Thiazol-2-yl acrylamide, (E) -3- [ (1 α,3 α,4 α) -3, 4-difluorocyclopentyl]-N- [4- (2-hydroxyethyl) thiazol-2-yl]-2- (4- (methylsulfonyl) phenyl) acrylamide, (E) -3- [ (1 α,3 α,4 α) -3, 4-difluorocyclopentyl]-N- [5- (N, N-dimethylsulfamoyl) thiazol-2-yl]-2- (4- (methylsulfonyl) phenyl) acrylamide, (E) -3- [ (1 α,3 α,4 α) -3, 4-difluorocyclopentyl]-N- [5- (4-methylpiperazin-1-ylsulfonyl) thiazol-2-yl]-2- (4- (methylsulfonyl) phenyl) acrylamide, (E) -3- [ (1 α,3 α,4 α) -3, 4-difluorocyclopentyl]-2- (4- (methylsulfonyl) phenyl) -N- (1,2, 4-thiadiazol-5-yl) acrylamide, (E) -3- [ (1 α,3 α,4 α) -3, 4-difluorocyclopentyl]-2- (4- (methylsulfonyl) phenyl) -N- (3-methyl-1, 2, 4-thiadiazol-5-yl) acrylamide, (E) -3- [ (1 α,3 α,4 α) -3, 4-difluorocyclopentyl 1-N- (3-ethyl-1, 2, 4-thiadiazol-5-yl) -2- (4- (methylsulfonyl) phenyl) acrylamide, (E) -3- [ (1 α,3 α,4 α) -3, 4-difluorocyclopentyl]-N- (3-methoxy-1, 2, 4-thiadiazol-5-yl) -2- (4- (methylsulfonyl) phenyl) acrylamide, (E) -3- [ (1 α,3 α,4 α) -3, 4-difluorocyclopentyl]-2- (4- (methylsulfonyl) phenyl) -N- (pyridin-2-yl) acrylamide, (E) -3- [ (1 α,3 α,4 α) -3, 4-difluorocyclopentyl]-N- (5-fluoropyridin-2-yl) -2- (4- (methylsulfonyl) phenyl) acrylamide, (E) -N- (5-chloropyridin-2-yl) -3- [ (1 α,3 α,4 α) -3, 4-difluorocyclopentyl]-2- (4- (methylsulfonyl) phenyl) acrylamide, (E) -3- [ (1 α,3 α,4 α) -3, 4-difluorocyclopentyl]-2- (4- (methylsulfonyl) phenyl) -N- [5- (methylthio) pyridin-2-yl]Acrylamide, (E) -N- (5-cyclopropylpyridin-2-yl) -3- [ (1 α,3 α,4 α) -3, 4-difluorocyclopentyl]-2- (4- (methylsulfonyl) phenyl) acrylamideAnd (E) -3- [ (1 α,3 α,4 α) -3, 4-difluorocyclopentyl]-N- [5- (hydroxymethyl) pyridin-2-yl]-2- (4- (methylsulfonyl) phenyl) acrylamide, (E) -3- [ (1 α,3 α,4 α) -3, 4-difluorocyclopentyl]-N- [5- (N, N-dimethylsulfamoyl) pyridin-2-yl]-2- (4- (methylsulfonyl) phenyl) acrylamide, (E) -3- [ (1 α,3 α,4 α) -3, 4-difluorocyclopentyl]-2- (4- (methylsulfonyl) phenyl) -N- (pyrazin-2-yl) acrylamide, (E) -3- [ (1 α,3 α,4 α) -3, 4-difluorocyclopentyl]-N- (5-methylpyrazin-2-yl) -2- (4- (methylsulfonyl) phenyl) acrylamide, (E) -3- [ (1 α,3 α,4 α) -3, 4-difluorocyclopentyl]-N- (5-ethylpyrazin-2-yl) -2- (4- (methylsulfonyl) phenyl) acrylamide, (E) -3- [ (1 α,3 α,4 α) -3, 4-difluorocyclopentyl]-N- (5-methoxypyrazin-2-yl) -2- (4- (methylsulfonyl) phenyl) acrylamide, (E) -3- [ (1 α,3 α,4 α) -3, 4-difluorocyclopentyl]-N- [5- (2-methylethoxy) pyrazin-2-yl]-2- (4- (methylsulfonyl) phenyl) acrylamide, (E) -3- [ (1 α,3 α,4 α) -3, 4-difluorocyclopentyl]-N- [5- (2-methoxyethoxy) pyrazin-2-yl]-2- (4- (methylsulfonyl) phenyl) acrylamide, (E) -3- [ (1 α,3 α,4 α) -3, 4-difluorocyclopentyl]-N- [5- (3-methoxypropoxy) pyrazin-2-yl]-2- (4- (methylsulfonyl) phenyl) acrylamide, (E) -3- [ (1 α,3 α,4 α) -3, 4-difluorocyclopentyl]-N- [5- (2-ethoxyethoxy) pyrazin-2-yl]-2- (4- (methylsulfonyl) phenyl) acrylamide, (E) -3- [ (1 α,3 α,4 α) -3, 4-difluorocyclopentyl]-2- (4- (methylsulfonyl) phenyl) -N- {5- [2- (methylthio) ethoxy]Pyrazin-2-yl } acrylamide, (E) -2- (4- (methylsulfonyl) phenyl) -3- [ (1 α,3 α,4 α) -3, 4-difluorocyclopentyl]-N- [5- (2-hydroxyethylthio) pyrazin-2-yl]Acrylamide, (E) -3- [ (1 α,3 αα,4 α) -3, 4-difluorocyclopentyl]-2- (4- (methylsulfonyl) phenyl) -N- {5- [2- (tetrahydro-2H-pyran-2-yloxy) ethoxy]Pyrazin-2-yl } acrylamide, (E) -3- [ (1 α,3 α,4 α) -3, 4-difluorocyclopentyl]-N- [5- (2-hydroxyethoxy) pyrazin-2-yl]-2- (4- (methylsulfonyl) phenyl) acrylamide, (E) -3- [ (1 α,3 α,4 α) -3, 4-difluorocyclopentyl]-N- {5- [ (4R) -2, 2-dimethyl-1, 3-dioxolan-4-yl]Pyrazin-2-yl } -2- (4- (methylsulfonyl) phenyl) acrylamide, (E) -3- [ (1 α,3 α,4 α) -3, 4-difluorocyclopentyl]-N- {5- [ (4S) -2, 2-dimethyl-1, 3-bisOxocyn-4-yl]Pyrazin-2-yl } -2- (4- (methylsulfonyl) phenyl) acrylamide, (E) -3- [ (1 α,3 α,4 α) -3, 4-difluorocyclopentyl]-N- {5- [ (2R) -1, 2-dihydroxyethyl]Pyrazin-2-yl } -2- (4- (methylsulfonyl) phenyl) acrylamide, (E) -3- [ (1 α,3 α,4 α) -3, 4-difluorocyclopentyl]-N- {5- [ (2S) -1, 2-dihydroxyethyl]Pyrazin-2-yl } -2- (4- (methylsulfonyl) phenyl) acrylamide, 5- { (E) -3- [ (1 α,3 α,4 α) -3, 4-difluorocyclopentyl-2- (4- (methylsulfonyl) phenyl)]Acrylamide } pyrazin-2-ylphosphonic acid diethyl ester, (5- { (E) -3- [ (1 α,3 α,4 α) -3, 4-difluorocyclopentyl-2- (4- (methylsulfonyl) phenyl)]Acrylamide } pyrazin-2-yl) methylphosphonic acid diethyl ester, (E) -3- [ (1 α,3 α,4 α) -3, 4-difluorocyclopentyl]-N- [ 1-methyl-1H-pyrazol-3-yl]-2- (4- (methylsulfonyl) phenyl) acrylamide, (E) -3- [ (1 α,3 α,4 α) -3, 4-difluorocyclopentyl]-N- [ 1-ethyl-1H-pyrazol-3-yl]-2- (4- (methylsulfonyl) phenyl) acrylamide, (E) -3- [ (1 α,3 α,4 αα) -3, 4-difluorocyclopentyl]-N- [1- (difluoromethyl) -1H-pyrazol-3-yl]-2- (4- (methylsulfonyl) phenyl) acrylamide, (E) -3- [ (1 α,3 α,4 α) -3, 4-difluorocyclopentyl]-N- [1- (2-fluoroethyl) -1H-pyrazol-3-yl]-2- (4- (methylsulfonyl) phenyl) acrylamide, (E) -3- [ (1 α,3 α,4 α) -3, 4-difluorocyclopentyl]-2- (4- (methylsulfonyl) phenyl) -N- [1- (2,2, 2-trifluoroethyl) -1H-pyrazol-3-yl]Acrylamide, (E) -3- [ (1 α,3 α,4 α) -3, 4-difluorocyclopentyl]-N- [1- (2-hydroxyethyl) -1H-pyrazol-3-yl]-2- (4- (methylsulfonyl) phenyl) acrylamide, (E) -3- [ (1 α,3 α,4 α) -3, 4-difluorocyclopentyl]-N- [1- (2-hydroxy-2-methylpropyl) -1H-pyrazol-3-yl]-2- (4- (methylsulfonyl) phenyl) acrylamide, (E) -3- [ (1 α,3 α,4 α) -3, 4-difluorocyclopentyl]-N- (1- { [ (4R) -2, 2-dimethyl-1, 3-dioxolan-4-yl]Methyl } -1H-pyrazol-3-yl) -2- (4- (methylsulfonyl) phenyl) acrylamide, (E) -3- [ (1 α,3 α,4 α) -3, 4-difluorocyclopentyl]-N- (1- { [ (4S) -2, 2-dimethyl-1, 3-dioxolan-4-yl]Methyl } -1H-pyrazol-3-yl) -2- (4- (methylsulfonyl) phenyl) acrylamide, (E) -3- [ (1 α,3 α,4 α) -3, 4-difluorocyclopentyl]-N- {1- [ (2R) -2, 3-dihydroxypropyl]-1H-pyrazol-3-yl } -2- (4- (methylsulfonyl) phenyl) acrylamide, (E) -3- [ (1 α,3 α,4 α) -3, 4-difluorocyclopentyl]-N- {1- [ (2S) -2, 3-dihydroxypropyl group]-1H-pyrazol-3-yl } -2- (4- (methylsulfonyl) phenyl) acrylamide, (E) -3- [ (1 α,3 α,4 α) -3, 4-difluorocyclopentyl]-N- (iso)Oxazol-3-yl) -2- (4- (methylsulfonyl) phenyl) acrylamide, (E) -3- [ (1 α,3 α,4 α) -3, 4-difluorocyclopentyl]-N- (6-methoxybenzo [ d ]]Thiazol-2-yl) -2- (4- (methylsulfonyl) phenyl) acrylamide, (E) -3- [ (1 α,3 α,4 α) -3, 4-difluorocyclopentyl]-N- [6- (difluoromethoxy) benzo [ d ]]Thiazol-2-yl]-2- (4- (methylsulfonyl) phenyl) acrylamide, (E) -3- [ (1 α,3 α,4 α) -3, 4-difluorocyclopentyl]-N- [5- (2-methoxyethoxy) thiazolo [5,4-b]Pyridin-2-yl]-2- (4- (methylsulfonyl) phenyl) acrylamide, and (E) -2- {2- [ (R) -2- (4- (methylsulfonyl) phenyl) -3- [ (1 α,3 α,4 α) -3, 4-difluorocyclopentyl]Acrylamide]Thiazolo [5,4-b ]]Pyridin-5-yloxy } acetic acid ethyl ester.

17) The compound according to 1) or a pharmaceutically acceptable salt thereof, which is selected from the group consisting of (E) -2- (4- (cyclopropylsulfonyl) phenyl) -3- [ (1 α,3 α,4 α) -3, 4-difluorocyclopentyl]-N- (5-fluorothiazol-2-yl) acrylamide, (E) -N- (5-bromothiazol-2-yl) -2- (4- (cyclopropylsulfonyl) phenyl) -3- [ (1 α,3 α,4 α) -3, 4-difluorocyclopentyl]Acrylamide, (E) -2- (4- (cyclopropylsulfonyl) phenyl) -3- [ (1 α,3 α,4 α) -3, 4-difluorocyclopentyl]-N- (4-methylthiazol-2-yl) acrylamide, (E) -2- (4- (cyclopropylsulfonyl) phenyl) -3- [ (1 α,3 α,4 α) -3, 4-difluorocyclopentyl]-N- (5-methylthiazol-2-yl) acrylamide, (+) - (E) -2- (4- (cyclopropylsulfonyl) phenyl) -3- [ (1 α,3 α,4 α) -3, 4-difluorocyclopentyl]-N- [4- (2, 2-dimethyl-1, 3-dioxolan-4-yl) thiazol-2-yl]Acrylamide, (-) - (E) -2- (4- (cyclopropylsulfonyl) phenyl) -3- [ (1 α,3 α,4 α) -3, 4-difluorocyclopentyl]-N- [4- (2, 2-dimethyl-1, 3-dioxolan-4-yl) thiazol-2-yl]Acrylamide, (E) -N- (4-tert-butylthiazol-2-yl) -2- (4- (cyclopropylsulfonyl) phenyl) -3- [ (1 α,3 α,4 α) -3, 4-difluorocyclopentyl]Acrylamide, (E) -2- (4- (cyclopropylsulfonyl) phenyl) -3- [ (1 α,3 α,4 α) -3, 4-difluorocyclopentyl]-N- [5- (4-methyl)Piperazin-1-ylsulfonyl) thiazol-2-yl]Acrylamide, 3- {2- [ (E) -2- (4- (cyclopropylsulfonyl) phenyl) -3- [ (1 α,3 α,4 α) -3, 4-difluorocyclopentyl]Acrylamide]Thiazol-4-yl } propanoic acid methyl ester, (E) -2- (4- (cyclopropylsulfonyl) phenyl) -3- [ (1 α,3 α,4 α) -3, 4-difluorocyclopentyl]-N- (1,2, 4-thiadiazol-5-yl) acrylamide, (E) -2- (4- (cyclopropylsulfonyl) phenyl) -3- [ (1 α,3 α,4 α) -3, 4-difluorocyclopentyl]-N- (3-methyl-1, 2, 4-thiadiazol-5-yl) acrylamide, (E) -2- (4- (cyclopropylsulfonyl) phenyl) -3- [ (1 α,3 α,4 α) -3, 4-difluorocyclopentyl]-N- (3-ethyl-1, 2, 4-thiadiazol-5-yl) acrylamide, (E) -2- (4- (cyclopropylsulfonyl) phenyl) -3- [ (1 α,3 α,4 α) -3, 4-difluorocyclopentyl]-N- (3-phenyl-1, 2, 4-thiadiazol-5-yl) acrylamide, (E) -2- (4- (cyclopropylsulfonyl) phenyl) -3- [ (1 α,3 α,4 α) -3, 4-difluorocyclopentyl]-N- (pyridin-2-yl) acrylamide, (E) -2- (4- (cyclopropylsulfonyl) phenyl) -3- [ (1 α,3 α,4 α) -3, 4-difluorocyclopentyl]-N- [5- (methylthio) pyridin-2-yl]Acrylamide, (E) -N- (5-cyclopropylpyridin-2-yl) -2- (4- (cyclopropylsulfonyl) phenyl) -3- [ (1 α,3 α,4 α) -3, 4-difluorocyclopentyl]Acrylamide, (E) -2- (4- (cyclopropylsulfonyl) phenyl) -3- [ (1 α,3 α,4 α) -3, 4-difluorocyclopentyl]-N- [5- (hydroxymethyl) pyridin-2-yl]Acrylamide, (E) -2- (4- (cyclopropylsulfonyl) phenyl) -3- [ (1 α,3 α,4 α) -3, 4-difluorocyclopentyl]-N- [5- (N, N-dimethylsulfamoyl) pyridin-2-yl]Acrylamide, (E) -2- (4- (cyclopropylsulfonyl) phenyl) -3- [ (1 α,3 α,4 α) -3, 4-difluorocyclopentyl]-N- (pyrazin-2-yl) acrylamide, (E) -2- (4- (cyclopropylsulfonyl) phenyl) -3- [ (1 α,3 α,4 α) -3, 4-difluorocyclopentyl]-N- (5-methylpyrazin-2-yl) acrylamide, (E) -2- (4- (cyclopropylsulfonyl) phenyl) -3- [ (1 α,3 α,4 α) -3, 4-difluorocyclopentyl]-N- (5-ethylpyrazin-2-yl) acrylamide, (E) -2- (4- (cyclopropylsulfonyl) phenyl) -3- [ (1 α,3 α,4 α) -3, 4-difluorocyclopentyl]-N- (5-methoxypyrazin-2-yl) acrylamide, (E) -2- (4- (cyclopropylsulfonyl) phenyl) -3- [ (1 α,3 α,4 α) -3, 4-difluorocyclopentyl]-N- [5- (methylthio) pyrazin-2-yl]Acrylamide, (E) -2- (4- (cyclopropylsulfonyl) phenyl) -3- [ (1 α,3 α,4 α) -3, 4-difluorocyclopentyl]-N- [5- (2-methylethoxy) pyrazine-2-radical]Acrylamide, (E) -2- (4- (cyclopropylsulfonyl) phenyl) -3- [ (1 α,3 α,4 α) -3, 4-difluorocyclopentyl]-N- [5- (2-methoxyethoxy) pyrazin-2-yl]Acrylamide, (E) -2- (4- (cyclopropylsulfonyl) phenyl) -3- [ (1 α,3 α,4 α) -3, 4-difluorocyclopentyl]-N- [5- (3-methoxypropoxy) pyrazin-2-yl]Acrylamide, (E) -2- (4- (cyclopropylsulfonyl) phenyl) -3- [ (1 α,3 α,4 α) -3, 4-difluorocyclopentyl]-N- [5- (2-ethoxyethoxy) pyrazin-2-yl]Acrylamide, (E) -2- (4- (cyclopropylsulfonyl) phenyl) -3- [ (1 α,3 α,4 α) -3, 4-difluorocyclopentyl]-N- {5- [2- (methylthio) ethoxy]Pyrazin-2-yl } acrylamide, (E) -2- (4- (cyclopropylsulfonyl) phenyl) -3- [ (1 α,3 α,4 α) -3, 4-difluorocyclopentyl]-N- {5- [2- (tetrahydro-2H-pyran-2-yloxy) ethoxy]Pyrazin-2-yl } acrylamide, (E) -2- (4- (cyclopropylsulfonyl) phenyl) -3- [ (1 α,3 α,4 α) -3, 4-difluorocyclopentyl]-N- [5- (2-hydroxyethoxy) pyrazin-2-yl]Acrylamide, (E) -2- (4- (cyclopropylsulfonyl) phenyl) -3- [ (1 α,3 α,4 α) -3, 4-difluorocyclopentyl]-N- {5- [ (4R) -2, 2-dimethyl-1, 3-dioxolan-4-yl]Pyrazin-2-yl } acrylamide, (E) -2- (4- (cyclopropylsulfonyl) phenyl) -3- [ (1 α,3 α,4 α) -3, 4-difluorocyclopentyl]-N- {5- [ (4S) -2, 2-dimethyl-1, 3-dioxolan-4-yl]Pyrazin-2-yl } acrylamide, (E) -2- (4- (cyclopropylsulfonyl) phenyl) -3- [ (1 α,3 α,4 α) -3, 4-difluorocyclopentyl]-N- {5- [ (2R) -1, 2-dihydroxyethyl]Pyrazin-2-yl } acrylamide, (E) -2- (4- (cyclopropylsulfonyl) phenyl) -3- [ (1 α,3 α,4 α) -3, 4-difluorocyclopentyl]-N- {5- [ (2S) -1, 2-dihydroxyethyl]Pyrazin-2-yl } acrylamide, 5- ((E) -2- (4- (cyclopropylsulfonyl) phenyl) -3- [ (1 α,3 α,4 α) -3, 4-difluorocyclopentyl]Acrylamide } pyrazin-2-ylphosphonic acid diethyl ester, (5- { (E) -2- (4- (cyclopropylsulfonyl) phenyl) -3- [ (1 α,3 α,4 α) -3, 4-difluorocyclopentyl]Acrylamide } pyrazin-2-yl) methylphosphonic acid diethyl ester, (E) -2- (4- (cyclopropylsulfonyl) phenyl) -3- [ (1 α,3 α,4 α) -3, 4-difluorocyclopentyl]-N- [ 1-methyl-1H-pyrazol-3-yl]Acrylamide, (E) -2- (4- (cyclopropylsulfonyl) phenyl) -3- [ (1 α,3 α,4 α) -3, 4-difluorocyclopentyl]-N- [ 1-ethyl-1H-pyrazol-3-yl]Acrylamide, (E) -2- (4- (cyclopropylsulfonyl) phenyl) -3- [ (1 α,3 α,4 α) -3, 4-difluorocyclopentyl]-N- [1- (2-fluoroethyl) -1H-pyrazol-3-yl]Acrylamide, (E) -2- (4- (cyclopropylsulfonyl) phenyl) -3- [ (1 α,3 α,4 α) -3, 4-difluorocyclopentyl]-N- [1- (2-hydroxyethyl) -1H-pyrazol-3-yl]Acrylamide, (E) -2- (4- (cyclopropylsulfonyl) phenyl) -3- [ (1 α,3 α,4 α) -3, 4-difluorocyclopentyl]-N- [1- (2-hydroxy-2-methylpropyl) -1H-pyrazol-3-yl]Acrylamide, (E) -2- (4- (cyclopropylsulfonyl) phenyl) -3- [ (1 α,3 α,4 α) -3, 4-difluorocyclopentyl]-N- (1- { [ (4R) -2, 2-dimethyl-1, 3-dioxolan-4-yl]Methyl } -1H-pyrazol-3-yl) acrylamide, (E) -2- (4- (cyclopropylsulfonyl) phenyl) -3- [ (1 α,3 α,4 α) -3, 4-difluorocyclopentyl]-N- (1- { [ (4S) -2, 2-dimethyl-1, 3-dioxolan-4-yl]Methyl } -1H-pyrazol-3-yl) acrylamide, (E) -2- (4- (cyclopropylsulfonyl) phenyl) -3- [ (1 α,3 α,4 α) -3, 4-difluorocyclopentyl]-N- {1- [ (2R) -2, 3-dihydroxypropyl]-1H-pyrazol-3-yl } acrylamide, (E) -2- (4- (cyclopropylsulfonyl) phenyl) -3- [ (1 α,3 α,4 α) -3, 4-difluorocyclopentyl]-N- (1- { [ (4S) -2, 2-dimethyl-1, 3-dioxolan-4-yl]Methyl } -1H-pyrazol-3-yl) acrylamide, (E) -2- (4- (cyclopropylsulfonyl) phenyl) -3- [ (1 α,3 α,4 α) -3, 4-difluorocyclopentyl]-N- (iso)Oxazol-3-yl) acrylamide, (E) -N- (benzo [ d ]]Thiazol-2-yl) -2- (4- (cyclopropylsulfonyl) phenyl) -3- [ (1 α,3 α,4 α) -3, 4-difluorocyclopentyl]Acrylamide, (E) -2- (4- (cyclopropylsulfonyl) phenyl) -3- [ (1 α,3 α,4 α) -3, 4-difluorocyclopentyl]-N- (6-methoxybenzo [ d ]]Thiazol-2-yl) acrylamide, (E) -2- (4- (cyclopropylsulfonyl) phenyl) -3- [ (1 α,3 α,4 α) -3, 4-difluorocyclopentyl]-N- [6- (difluoromethoxy) benzo [ d ]]Thiazol-2-yl]Acrylamide, (E) -2- (4- (cyclopropylsulfonyl) phenyl) -3- [ (1 α,3 α,4 α) -3, 4-difluorocyclopentyl]-N- (6-fluorobenzo [ d ]]Thiazol-2-yl) acrylamide, 2- { (E) -2- (4- (cyclopropylsulfonyl) phenyl) -3- [ (1 α,3 α,4 α) -3, 4-difluorocyclopentyl]Acrylamide } benzo [ d]Thiazole-6-carboxylic acid 2-methylethyl ester, (E) -2- (4- (cyclopropylsulfonyl) phenyl) -3- [ (1 α,3 α,4 α) -3, 4-difluorocyclopentyl]-N- (thiazolo [5,4-b ]]Pyridin-2-yl) acrylamide, (E) -N- (5-butoxythiazolo[5，4-b]Pyridin-2-yl) -2- (4- (cyclopropylsulfonyl) phenyl) -3- [ (1 α,3 α,4 α) -3, 4-difluorocyclopentyl]Acrylamide, (E) -2- (4- (cyclopropylsulfonyl) phenyl) -3- [ (1 α,3 α,4 α) -3, 4-difluorocyclopentyl]-N- [5- (2-methoxyethoxy) thiazolo [5,4-b]Pyridin-2-yl]Acrylamide, and 2- {2- [ (R) -2- (4- (cyclopropylsulfonyl) phenyl) -3- [ (1 α,3 α,4 α) -3, 4-difluorocyclopentyl]Acrylamide]Thiazolo [5,4-b ]]Pyridin-5-yloxy } acetic acid ethyl ester.

18) A compound described in 1) or a pharmaceutically acceptable salt thereof, which is selected from the group consisting of (E) -3- [ (1 α,3 α,4 α) -3, 4-difluorocyclopentyl ] -2- [4- (ethylsulfonyl) phenyl ] -N- (thiazol-2-yl) acrylamide, (E) -3- [ (1 α,3 α,4 α) -3, 4-difluorocyclopentyl ] -2- [4- (ethylsulfonyl) phenyl ] -N- (5-methylpyrazin-2-yl) acrylamide, and (E) -3- [ (1 α,3 α,4 α) -3, 4-difluorocyclopentyl ] -2- [4- (ethylsulfonyl) phenyl ] -N- (1-methyl-1H-pyrazol-3-yl) acrylamide.

19) A compound described in 1) or a pharmaceutically acceptable salt thereof, which is selected from the group consisting of (E) -3- [ (1 α,3 α,4 α) -3, 4-difluorocyclopentyl ] -2- [4- (2-methoxyethylsulfonyl) phenyl ] -N- (thiazol-2-yl) acrylamide, (E) -3- [ (1 α,3 α,4 α) -3, 4-difluorocyclopentyl ] -2- [4- (2-methoxyethylsulfonyl) phenyl ] -N- (5-methylpyrazin-2-yl) acrylamide, and (E) -3- [ (1 α,3 α,4 α) -3, 4-difluorocyclopentyl ] -2- [4- (2-methoxyethylsulfonyl) phenyl ] -N- (1-methyl-1H-pyrazol-3-yl) acrylamide.

20) A method for treating or preventing diabetes, which comprises administering the compound according to any one of 1) to 19) or a pharmaceutically acceptable salt thereof.

21)1) to 19) or a pharmaceutically acceptable salt thereof for use in the production of a therapeutic or prophylactic drug for diabetes.

22) A pharmaceutical composition comprising the compound according to any one of 1) to 19) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

23) A compound represented by the general formula (2),

(in the formula, R¹And R²The same or different represents a hydrogen atom, a halogen atom, an amino group, a hydroxyl group, a hydroxyamino group, a nitro group, a cyano group, a sulfamoyl group, C₁～C₆Alkyl of (C)₁～C₆Alkoxy group of (C)₁～C₆Alkyl sulfanyl, C₁～C₆Alkylsulfinyl group of (1), C₁～C₆Alkylsulfonyl or C₁～C₆alkoxy-C₁～C₆An alkylsulfonyl group. ).

24)23) the compound according to (1), wherein R is¹Is a hydrogen atom, R²Is cyclopropylsulfonyl.

25)23) the compound according to (1), wherein R is¹Is a hydrogen atom, R²Is methylsulfonyl.

The present invention provides a compound having an excellent GK-activating effect or hypoglycemic effect and small side effects (for example, QT interval prolongation (related to hERG current suppression), insulin-induced hypoglycemia, and the like), and a pharmaceutical product excellent in the treatment or prevention of diabetes, obesity, and the like.

Detailed Description

The halogen atom means a fluorine atom, a chlorine atom, a bromine atom or an iodine atom.

C₁～C₆The alkyl group (C) is a linear or branched alkyl group having 1 to 6 carbon atoms or a cyclic alkyl group having 3 to 6 carbon atoms, and examples thereof include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, cyclopropyl, cyclobutyl and the like.

C₁～C₆The alkoxy group (b) is a linear or branched alkoxy group having 1 to 6 carbon atoms or a cyclic alkoxy group having 3 to 6 carbon atoms, and examples thereof include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, cyclopropyloxy, cyclobutoxy and the like.

C₁～C₆The alkylsulfanyl group in (1) is a linear or branched alkylsulfanyl group having 1 to 6 carbon atoms or a cyclic alkylsulfanyl group having 3 to 6 carbon atoms, and examples thereof include methylsulfanyl, ethylsulfanyl, propylsulfanyl, isopropylsulfanyl, butylsulfanyl, isobutylsulfanyl, sec-butylsulfanyl, tert-butylsulfanyl, cyclopropylsulfanyl, cyclobutylsulfanyl, and cyclopentylsulfanyl.

C₁～C₆The alkylsulfinyl group in (b) is a linear or branched alkylsulfinyl group having 1 to 6 carbon atoms or a cyclic alkylsulfinyl group having 3 to 6 carbon atoms, and examples thereof include methylsulfinyl, ethylsulfinyl, propylsulfinyl, isopropylsulfinyl, butylsulfinyl, isobutylsulfinyl, sec-butylsulfinyl, tert-butylsulfinyl, cyclopropylsulfinyl, cyclobutylsulfinyl and cyclopentylsulfinyl.

C₁～C₆The alkylsulfonyl group (b) is a linear or branched alkylsulfonyl group having 1 to 6 carbon atoms or a cyclic alkylsulfonyl group having 3 to 6 carbon atoms, and examples thereof include methylsulfonyl group, ethylsulfonyl group, propylsulfonyl group, isopropylsulfonyl group, butylsulfonyl group, isobutylsulfonyl group, sec-butylsulfonyl group, tert-butylsulfonyl group, cyclopropylsulfonyl group, cyclobutylsulfonyl group and cyclopentylsulfonyl group.

C₁～C₆alkoxy-C₁～C₆The alkylsulfonyl group is a linear or branched alkylsulfonyl group of 1 to 6 carbon atoms substituted with a linear or branched alkoxy group of 1 to 6 carbon atoms or a cyclic alkoxy group of 3 to 6 carbon atoms, and may, for example, be a methoxymethylsulfonyl group, a methoxyethylsulfonyl group, a propargyl,Methoxypropylsulfonyl, isopropoxymethylsulfonyl, cyclopropyloxymethylsulfonyl and the like.

The heteroaryl group is a five-or six-membered aromatic heterocyclic ring containing 1 to 3 heteroatoms selected from a sulfur atom, an oxygen atom and a nitrogen atom as constituent atoms of the ring, and the aromatic heterocyclic ring may optionally form a condensed ring with a benzene ring or the five-or six-membered aromatic heterocyclic ring. As a preferred heteroaryl group, the following groups may be mentioned: the aromatic heterocyclic ring contains 1-3 heteroatoms selected from sulfur atom, oxygen atom, nitrogen atom, wherein 1 heteroatom is a nitrogen atom adjacent to a bonding ring atom. The bonding ring atom is a ring-inside atom that participates in bonding with the nitrogen atom of the amide group, and as such a bonding ring atom, a carbon atom is preferable.

Preferred heteroaryl groups include thiazolyl, thiadiazolyl, pyrazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, and the like,Azolyl radical, isoAzolyl, imidazolyl, triazinyl, benzothiazolyl, benzoOxazolyl, benzimidazolyl, pyridothiazolyl, quinolinyl, and the like. More preferably thiazolyl, pyrazolyl, pyrazinyl, pyridyl, thiazolo [5,4-b ]]Pyridyl, thiadiazolyl or pyridothiazolyl.

As A "heteroaryl group optionally having substituent(s)" is preferred an unsubstituted or mono-substituted heteroaryl group, and as the substituent(s), there may be mentioned halogen atom, C optionally substituted by halogen atom or hydroxy group₁～C₆Alkyl (methyl, t-butyl, cyclopropyl, fluoroethyl, difluoromethyl, 1, 2-dihydroxyethyl, etc.), C optionally substituted with a halogen atom or a hydroxyl group₁～C₆Alkoxy group of (C)₁～C₃alkoxy-C₁～C₃Alkoxy radical, C₁～C₃alkoxycarbonyl-C₁～C₃Alkoxy radical, C₁～C₃alkoxycarbonyl-C₁～C₆Alkylsulfanyl group, C₁～C₆Alkylsulfanyl group of (a), optionally substituted by C₁～C₃Alkyl substituted C₁～C₆Aminoalkylsulfanyl, C₁～C₆alkylsulfanyl-C₁～C₆Alkoxy, aryl (phenyl, etc.), heteroaryl, optionally substituted with C₁～C₆Alkyl-substituted aliphatic heterocyclic group (morpholino group, dioxolyl group, etc.), aliphatic heterocyclic carbonyl group, aliphatic heterocyclic sulfonyl group, aliphatic heterocyclic group-C₁～C₃Alkyl, aliphatic heterocyclyl-C₁～C₃Alkoxy, aliphatic heterocyclyloxy-C₁～C₃Alkoxy, optionally substituted by C₁～C₃Alkyl-substituted aminosulfonyl, C₁～C₆Hydroxyalkyl sulfanyl, nitro, cyano, of the formula

-(O)_p(CH₂)_mC(O)OR³

(in the formula, R³Represents a hydrogen atom, C₁～C₆Alkyl or C₁～C₃alkoxy-C₁～C₃An alkyl group, m represents an integer of 0 to 2, p represents a group represented by 0 or 1), a group represented by the formula

-(CH₂)_mP(O)R⁴R⁵

(in the formula, R⁴And R⁵The same or different represent hydroxy, C₁～C₃Alkyl or C₁～C₃M represents an integer of 0 to 2).

The pharmaceutically acceptable salt refers to any salt with an inorganic acid or an organic acid such as hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, citric acid, formic acid, maleic acid, acetic acid, succinic acid, or tartaric acid.

Specific examples of the compound of the present invention include the following compounds and pharmaceutically acceptable salts thereof.

(E) -3- [ (1 α,3 α,4 α) -3, 4-difluorocyclopentyl]-N- (5-fluorothiazol-2-yl) -2- (4- (methylsulfonyl) phenyl) acrylamide, (E) -N- (5-chlorothiazol-2-yl) -3- [ (1 α,3 α,4 α) -3, 4-difluorocyclopentyl]-2- (4- (methylsulfonyl) phenyl) acrylamide, (E) -3- [ (1 α,3 α,4 α) -3, 4-difluorocyclopentyl]-2- (4- (methylsulfonyl) phenyl) -N- (4-methylthiazol-2-yl) acrylamide, (E) -3- [ (1 α,3 α,4 α) -3, 4-difluorocyclopentyl]-2- (4- (methylsulfonyl) phenyl) -N- (5-methylthiazol-2-yl) acrylamide, (+) - (E) -3- [ (1 α,3 α,4 α) -3, 4-difluorocyclopentyl]-N- [4- (2, 2-dimethyl-1, 3-dioxolan-4-yl) thiazol-2-yl]-2- (4- (methylsulfonyl) phenyl) acrylamide, (-) - (E) -3- [ (1 α,3 α,4 α) -3, 4-difluorocyclopentyl]-N- [4- (2, 2-dimethyl-1, 3-dioxolan-4-yl) thiazol-2-yl]-2- (4- (methylsulfonyl) phenyl) acrylamide, (+) - (E) -3- [ (1 α,3 α,4 α) -3, 4-difluorocyclopentyl]-N- [4- (1, 2-dihydroxyethyl) thiazol-2-yl]-2- (4- (methylsulfonyl) phenyl) acrylamide, (-) - (E) -3- [ (1 α,3 α,4 α) -3, 4-difluorocyclopentyl]-N- [4- (1, 2-dihydroxyethyl) thiazol-2-yl]-2- (4- (methylsulfonyl) phenyl) acrylamide, (E) -N- (4-tert-butylthiazol-2-yl) -3- [ (1 α,3 α,4 α) -3, 4-difluorocyclopentyl]-2- (4- (methylsulfonyl) phenyl) acrylamide, (E) -3- [ (1 α,3 α,4 α) -3, 4-difluorocyclopentyl]-2- (4- (methylsulfonyl) phenyl) -N- {4- [2- (tetrahydro-2H-pyran-2-yloxy) ethyl]Thiazol-2-yl acrylamide, (E) -3- [ (1 α,3 α,4 α) -3, 4-difluorocyclopentyl]-N- [4- (2-hydroxyethyl) thiazol-2-yl]-2- (4- (methylsulfonyl) phenyl) acrylamide, (E) -3- [ (1 α,3 α,4 α) -3, 4-difluorocyclopentyl]-N- [5- (N, N-dimethylsulfamoyl) thiazol-2-yl]-2- (4- (methylsulfonyl) phenyl) acrylamide, (E) -3- [ (1 α,3 α,4 α) -3, 4-difluorocyclopentyl]-N- [5- (4-methylpiperazin-1-ylsulfonyl) thiazol-2-yl]-2- (4- (methylsulfonyl) phenyl) acrylamide, (E) -3- [ (1 α,3 α,4 α) -3, 4-difluorocyclopentyl]-2- (4- (methylsulfonyl) phenyl) -N- (1,2, 4-thiadiazol-5-yl) acrylamide, (E) -3- [ (1 α,3 α,4 α) -34-difluoro cyclopentyl group]-2- (4- (methylsulfonyl) phenyl) -N- (3-methyl-1, 2, 4-thiadiazol-5-yl) acrylamide, (E) -3- [ (1 α,3 α,4 α) -3, 4-difluorocyclopentyl]-N- (3-ethyl-1, 2, 4-thiadiazol-5-yl) -2- (4- (methylsulfonyl) phenyl) acrylamide, (E) -3- [ (1 α,3 α,4 α) -3, 4-difluorocyclopentyl]-N- (3-methoxy-1, 2, 4-thiadiazol-5-yl) -2- (4- (methylsulfonyl) phenyl) acrylamide, (E) -3- [ (1 α,3 α,4 α) -3, 4-difluorocyclopentyl]-2- (4- (methylsulfonyl) phenyl) -N- (pyridin-2-yl) acrylamide, (E) -3- [ (1 α,3 α,4 α) -3, 4-difluorocyclopentyl]-N- (5-fluoropyridin-2-yl) -2- (4- (methylsulfonyl) phenyl) acrylamide, (E) -N- (5-chloropyridin-2-yl) -3- [ (1 α,3 α,4 α) -3, 4-difluorocyclopentyl]-2- (4- (methylsulfonyl) phenyl) acrylamide, (E) -3- [ (1 α,3 α,4 α) -3, 4-difluorocyclopentyl]-2- (4- (methylsulfonyl) phenyl) -N- [5- (methylthio) pyridin-2-yl]Acrylamide, (E) -N- (5-cyclopropylpyridin-2-yl) -3- [ (1 α,3 α,4 α) -3, 4-difluorocyclopentyl]-2- (4- (methylsulfonyl) phenyl) acrylamide, (E) -3- [ (1 α,3 α,4 α) -3, 4-difluorocyclopentyl]-N- [5- (hydroxymethyl) pyridin-2-yl]-2- (4- (methylsulfonyl) phenyl) acrylamide, (E) -3- [ (1 α,3 α,4 α) -3, 4-difluorocyclopentyl]-N- [5- (N, N-dimethylsulfamoyl) pyridin-2-yl]-2- (4- (methylsulfonyl) phenyl) acrylamide, (E) -3- [ (1 α,3 α,4 α) -3, 4-difluorocyclopentyl]-2- (4- (methylsulfonyl) phenyl) -N- (pyrazin-2-yl) acrylamide, (E) -3- [ (1 α,3 α,4 α) -3, 4-difluorocyclopentyl]-N- (5-methylpyrazin-2-yl) -2- (4- (methylsulfonyl) phenyl) acrylamide, (E) -3- [ (1 α,3 α,4 α) -3, 4-difluorocyclopentyl]-N- (5-ethylpyrazin-2-yl) -2- (4- (methylsulfonyl) phenyl) acrylamide, (E) -3- [ (1 α,3 α,4 α) -3, 4-difluorocyclopentyl]-N- (5-methoxypyrazin-2-yl) -2- (4- (methylsulfonyl) phenyl) acrylamide, (E) -3- [ (1 α,3 α,4 α) -3, 4-difluorocyclopentyl]-N- [5- (2-methylethoxy) pyrazin-2-yl]-2- (4- (methylsulfonyl) phenyl) acrylamide, (E) -3- [ (1 α,3 α,4 α) -3, 4-difluorocyclopentyl]-N- [5- (2-methoxyethoxy) pyrazin-2-yl]-2- (4- (methylsulfonyl) phenyl) acrylamide, (E) -3- [ (1 α,3 α,4 α) -3, 4-difluorocyclopentyl]-N- [5- (3-methoxypropoxy) pyrazin-2-yl]-2- (4- (methylsulfonyl)Phenyl) acrylamide, (E) -3- [ (1 α,3 α,4 α) -3, 4-difluorocyclopentyl]-N- [5- (2-ethoxyethoxy) pyrazin-2-yl]-2- (4- (methylsulfonyl) phenyl) acrylamide, (E) -3- [ (1 α,3 α,4 α) -3, 4-difluorocyclopentyl]-2- (4- (methylsulfonyl) phenyl) -N- {5- [2- (methylthio) ethoxy]Pyrazin-2-yl } acrylamide, (E) -2- (4- (methylsulfonyl) phenyl) -3- [ (1 α,3 α,4 α) -3, 4-difluorocyclopentyl]-N- [5- (2-hydroxyethylthio) pyrazin-2-yl]Acrylamide, (E) -3- [ (1 α,3 α,4 α) -3, 4-difluorocyclopentyl]-2- (4- (methylsulfonyl) phenyl) -N- {5- [2- (tetrahydro-2H-pyran-2-yloxy) ethoxy]Pyrazin-2-yl } acrylamide, (E) -3- [ (1 α,3 α,4 α) -3, 4-difluorocyclopentyl]-N- [5- (2-hydroxyethoxy) pyrazin-2-yl]-2- (4- (methylsulfonyl) phenyl) acrylamide, (E) -3- [ (1 α,3 α,4 α) -3, 4-difluorocyclopentyl]-N- {5- [ (4R) -2, 2-dimethyl-1, 3-dioxolan-4-yl]Pyrazin-2-yl } -2- (4- (methylsulfonyl) phenyl) acrylamide, (E) -3- [ (1 α,3 α,4 α) -3, 4-difluorocyclopentyl]-N- {5- [ (4S) -2, 2-dimethyl-1, 3-dioxolan-4-yl]Pyrazin-2-yl } -2- (4- (methylsulfonyl) phenyl) acrylamide, (E) -3- [ (1 α,3 α,4 α) -3, 4-difluorocyclopentyl]-N- {5- [ (2R) -1, 2-dihydroxyethyl]Pyrazin-2-yl } -2- (4- (methylsulfonyl) phenyl) acrylamide, (E) -3- [ (1 α,3 α,4 α) -3, 4-difluorocyclopentyl]-N- {5- [ (2S) -1, 2-dihydroxyethyl]Pyrazin-2-yl } -2- (4- (methylsulfonyl) phenyl) acrylamide, 5- { (E) -3- [ (1 α,3 α,4 α) -3, 4-difluorocyclopentyl-2- (4- (methylsulfonyl) phenyl)]Acrylamide } pyrazin-2-ylphosphonic acid diethyl ester, (5- { (E) -3- [ (1 α,3 α,4 α) -3, 4-difluorocyclopentyl-2- (4- (methylsulfonyl) phenyl)]Acrylamide } pyrazin-2-yl) methylphosphonic acid diethyl ester, (E) -3- [ (1 α,3 α,4 α) -3, 4-difluorocyclopentyl]-N- [ 1-methyl-1H-pyrazol-3-yl]-2- (4- (methylsulfonyl) phenyl) acrylamide, (E) -3- [ (1 α,3 α,4 α) -3, 4-difluorocyclopentyl]-N- [ 1-ethyl-1H-pyrazol-3-yl]-2- (4- (methylsulfonyl) phenyl) acrylamide, (E) -3- [ (1 α,3 α,4 α) -3, 4-difluorocyclopentyl]-N- [1- (difluoromethyl) -1H-pyrazol-3-yl]-2- (4- (methylsulfonyl) phenyl) acrylamide, (E) -3- [ (1 α,3 α,4 α) -3, 4-difluorocyclopentyl]-N- [1- (2-fluoroethyl) -1H-pyrazol-3-yl]-2- (4- (methylsulfonyl) phenyl) acrylamideAnd (E) -3- [ (1 α,3 α,4 α) -3, 4-difluorocyclopentyl]-2- (4- (methylsulfonyl) phenyl) -N- [1- (2,2, 2-trifluoroethyl) -1H-pyrazol-3-yl]Acrylamide, (E) -3- [ (1 α,3 α,4 α) -3, 4-difluorocyclopentyl]-N- [1- (2-hydroxyethyl) -1H-pyrazol-3-yl]-2- (4- (methylsulfonyl) phenyl) acrylamide, (E) -3- [ (1 α,3 α,4 α) -3, 4-difluorocyclopentyl]-N- [1- (2-hydroxy-2-methylpropyl) -1H-pyrazol-3-yl]-2- (4- (methylsulfonyl) phenyl) acrylamide, (E) -3- [ (1 α,3 α,4 α) -3, 4-difluorocyclopentyl]-N- (1- { [ (4R) -2, 2-dimethyl-1, 3-dioxolan-4-yl]Methyl } -1H-pyrazol-3-yl) -2- (4- (methylsulfonyl) phenyl) acrylamide, (E) -3- [ (1 α,3 α,4 α) -3, 4-difluorocyclopentyl]-N- (1- { [ (4S) -2, 2-dimethyl-1, 3-dioxolan-4-yl]Methyl } -1H-pyrazol-3-yl) -2- (4- (methylsulfonyl) phenyl) acrylamide, (E) -3- [ (1 α,3 α,4 α) -3, 4-difluorocyclopentyl]-N- {1- [ (2R) -2, 3-dihydroxypropyl]-1H-pyrazol-3-yl } -2- (4- (methylsulfonyl) phenyl) acrylamide, (E) -3- [ (1 α,3 α,4 α) -3, 4-difluorocyclopentyl]-N- {1- [ (2S) -2, 3-dihydroxypropyl group]-1H-pyrazol-3-yl } -2- (4- (methylsulfonyl) phenyl) acrylamide, (E) -3- [ (1 α,3 α,4 α) -3, 4-difluorocyclopentyl]-N- (iso)Oxazol-3-yl) -2- (4- (methylsulfonyl) phenyl) acrylamide, (E) -3- [ (1 α,3 α,4 α) -3, 4-difluorocyclopentyl]-N- (6-methoxybenzo [ d ]]Thiazol-2-yl) -2- (4- (methylsulfonyl) phenyl) acrylamide, (E) -3- [ (1 α,3 α,4 α) -3, 4-difluorocyclopentyl]-N- [6- (difluoromethoxy) benzo [ d ]]Thiazol-2-yl]-2- (4- (methylsulfonyl) phenyl) acrylamide, (E) -3- [ (1 α,3 α,4 α) -3, 4-difluorocyclopentyl]-N- [5- (2-methoxyethoxy) thiazolo [5,4-b]Pyridin-2-yl]-2- (4- (methylsulfonyl) phenyl) acrylamide, (E) -2- {2- [ (R) -2- (4- (methylsulfonyl) phenyl) -3- [ (1 α,3 α,4 α) -3, 4-difluorocyclopentyl]Acrylamide]Thiazolo [5,4-b ]]Pyridin-5-yloxy } acetic acid ethyl ester, (E) -2- (4- (cyclopropylsulfonyl) phenyl) -3- [ (1 α,3 α,4 α) -3, 4-difluorocyclopentyl]-N- (5-fluorothiazol-2-yl) acrylamide, (E) -N- (5-bromothiazol-2-yl) -2- (4- (cyclopropylsulfonyl) phenyl) -3- [ (1 α,3 α,4 α) -3,4-Difluorocyclopentyl radical]Acrylamide, (E) -2- (4- (cyclopropylsulfonyl) phenyl) -3- [ (1 α,3 α,4 α) -3, 4-difluorocyclopentyl]-N- (4-methylthiazol-2-yl) acrylamide, (E) -2- (4- (cyclopropylsulfonyl) phenyl) -3- [ (1 α,3 α,4 α) -3, 4-difluorocyclopentyl]-N- (5-methylthiazol-2-yl) acrylamide, (+) - (E) -2- (4- (cyclopropylsulfonyl) phenyl) -3- [ (1 α,3 α,4 α) -3, 4-difluorocyclopentyl]-N- [4- (2, 2-dimethyl-1, 3-dioxolan-4-yl) thiazol-2-yl]Acrylamide, (-) - (E) -2- (4- (cyclopropylsulfonyl) phenyl) -3- [ (1 α,3 α,4 α) -3, 4-difluorocyclopentyl]-N- [4- (2, 2-dimethyl-1, 3-dioxolan-4-yl) thiazol-2-yl]Acrylamide, (E) -N- (4-tert-butylthiazol-2-yl) -2- (4- (cyclopropylsulfonyl) phenyl) -3- [ (1 α,3 α,4 α) -3, 4-difluorocyclopentyl]Acrylamide, (E) -2- (4- (cyclopropylsulfonyl) phenyl) -3- [ (1 α,3 α,4 α) -3, 4-difluorocyclopentyl]-N- [5- (4-methylpiperazin-1-ylsulfonyl) thiazol-2-yl]Acrylamide, 3- {2- [ (E) -2- (4- (cyclopropylsulfonyl) phenyl) -3- [ (1 α,3 α,4 α) -3, 4-difluorocyclopentyl]Acrylamide]Thiazol-4-yl } propanoic acid methyl ester, (E) -2- (4- (cyclopropylsulfonyl) phenyl) -3- [ (1 α,3 α,4 α) -3, 4-difluorocyclopentyl]-N- (1,2, 4-thiadiazol-5-yl) acrylamide, (E) -2- (4- (cyclopropylsulfonyl) phenyl) -3- [ (1 α,3 α,4 α) -3, 4-difluorocyclopentyl]-N- (3-methyl-1, 2, 4-thiadiazol-5-yl) acrylamide, (E) -2- (4- (cyclopropylsulfonyl) phenyl) -3- [ (1 α,3 α,4 α) -3, 4-difluorocyclopentyl]-N- (3-ethyl-1, 2, 4-thiadiazol-5-yl) acrylamide, (E) -2- (4- (cyclopropylsulfonyl) phenyl) -3- [ (1 α,3 α,4 α) -3, 4-difluorocyclopentyl]-N- (3-phenyl-1, 2, 4-thiadiazol-5-yl) acrylamide, (E) -2- (4- (cyclopropylsulfonyl) phenyl) -3- [ (1 α,3 α,4 α) -3, 4-difluorocyclopentyl]-N- (pyridin-2-yl) acrylamide, (E) -2- (4- (cyclopropylsulfonyl) phenyl) -3- [ (1 α,3 α,4 α) -3, 4-difluorocyclopentyl]-N- [5- (methylthio) pyridin-2-yl]Acrylamide, (E) -N- (5-cyclopropylpyridin-2-yl) -2- (4- (cyclopropylsulfonyl) phenyl) -3- [ (1 α,3 α,4 α) -3, 4-difluorocyclopentyl]Acrylamide, (E) -2- (4- (cyclopropylsulfonyl) phenyl) -3- [ (1 α,3 α,4 α) -3, 4-difluorocyclopentyl]-N- [5- (hydroxymethyl) pyridin-2-yl]Acrylamide, (E) -2- (4- (cyclopropylsulfonyl) phenyl) -3- [ (1 α, 3)α,4 α) -3, 4-difluorocyclopentyl]-N- [5- (N, N-dimethylsulfamoyl) pyridin-2-yl]Acrylamide, (E) -2- (4- (cyclopropylsulfonyl) phenyl) -3- [ (1 α,3 α,4 α) -3, 4-difluorocyclopentyl]-N- (pyrazin-2-yl) acrylamide, (E) -2- (4- (cyclopropylsulfonyl) phenyl) -3- [ (1 α,3 α,4 α) -3, 4-difluorocyclopentyl]-N- (5-methylpyrazin-2-yl) acrylamide, (E) -2- (4- (cyclopropylsulfonyl) phenyl) -3- [ (1 α,3 α,4 α) -3, 4-difluorocyclopentyl]-N- (5-ethylpyrazin-2-yl) acrylamide, (E) -2- (4- (cyclopropylsulfonyl) phenyl) -3- [ (1 α,3 α,4 α) -3, 4-difluorocyclopentyl]-N- (5-methoxypyrazin-2-yl) acrylamide, (E) -2- (4- (cyclopropylsulfonyl) phenyl) -3- [ (1 α,3 α,4 α) -3, 4-difluorocyclopentyl]-N- [5- (methylthio) pyrazin-2-yl]Acrylamide, (E) -2- (4- (cyclopropylsulfonyl) phenyl) -3- [ (1 α,3 α,4 α) -3, 4-difluorocyclopentyl]-N- [5- (2-methylethoxy) pyrazin-2-yl]Acrylamide, (E) -2- (4- (cyclopropylsulfonyl) phenyl) -3- [ (1 α,3 α,4 α) -3, 4-difluorocyclopentyl]-N- [5- (2-methoxyethoxy) pyrazin-2-yl]Acrylamide, (E) -2- (4- (cyclopropylsulfonyl) phenyl) -3- [ (1 α,3 α,4 α) -3, 4-difluorocyclopentyl]-N- [5- (3-methoxypropoxy) pyrazin-2-yl]Acrylamide, (E) -2- (4- (cyclopropylsulfonyl) phenyl) -3- [ (1 α,3 α,4 α) -3, 4-difluorocyclopentyl]-N- [5- (2-ethoxyethoxy) pyrazin-2-yl]Acrylamide, (E) -2- (4- (cyclopropylsulfonyl) phenyl) -3- [ (1 α,3 α,4 α) -3, 4-difluorocyclopentyl]-N- {5- [2- (methylthio) ethoxy]Pyrazin-2-yl } acrylamide, (E) -2- (4- (cyclopropylsulfonyl) phenyl) -3- [ (1 α,3 α,4 α) -3, 4-difluorocyclopentyl]-N- {5- [2- (tetrahydro-2H-pyran-2-yloxy) ethoxy]Pyrazin-2-yl } acrylamide, (E) -2- (4- (cyclopropylsulfonyl) phenyl) -3- [ (1 α,3 α,4 α) -3, 4-difluorocyclopentyl]-N- [5- (2-hydroxyethoxy) pyrazin-2-yl]Acrylamide, (E) -2- (4- (cyclopropylsulfonyl) phenyl) -3- [ (1 α,3 α,4 α) -3, 4-difluorocyclopentyl]-N- {5- [ (4R) -2, 2-dimethyl-1, 3-dioxolan-4-yl-1-pyrazin-2-yl } acrylamide, (E) -2- (4- (cyclopropylsulfonyl) phenyl) -3- [ (1 α,3 α,4 α) -3, 4-difluorocyclopentyl]-N- {5- [ (4S) -2, 2-dimethyl-1, 3-dioxolan-4-yl]Pyrazin-2-yl } acrylamide, (E) -2- (4- (cyclopropylsulfonyl) phenyl) -3- [ (1 α,3 α,4 α) -3,4-Difluorocyclopentyl radical]-N- {5- [ (2R) -1, 2-dihydroxyethyl]Pyrazin-2-yl } acrylamide, (E) -2- (4- (cyclopropylsulfonyl) phenyl) -3- [ (1 α,3 α,4 α) -3, 4-difluorocyclopentyl]-N- {5- [ (2S) -1, 2-dihydroxyethyl]Pyrazin-2-yl } acrylamide, 5- { (E) -2- (4- (cyclopropylsulfonyl) phenyl) -3- [ (1 α,3 α,4 α) -3, 4-difluorocyclopentyl]Acrylamide } pyrazin-2-ylphosphonic acid diethyl ester, (5- { (E) -2- (4- (cyclopropylsulfonyl) phenyl) -3- [ (1 α,3 α,4 αα) -3, 4-difluorocyclopentyl]Acrylamide } pyrazin-2-yl) methylphosphonic acid diethyl ester, (E) -2- (4- (cyclopropylsulfonyl) phenyl) -3- [ (1 α,3 α,4 α) -3, 4-difluorocyclopentyl]-N- [ 1-methyl-1H-pyrazol-3-yl]Acrylamide, (E) -2- (4- (cyclopropylsulfonyl) phenyl) -3- [ (1 α,3 α,4 α) -3, 4-difluorocyclopentyl]-N- [ 1-ethyl-1H-pyrazol-3-yl]Acrylamide, (E) -2- (4- (cyclopropylsulfonyl) phenyl) -3- [ (1 α,3 α,4 α) -3, 4-difluorocyclopentyl]-N- [1- (2-fluoroethyl) -1H-pyrazol-3-yl]Acrylamide, (E) -2- (4- (cyclopropylsulfonyl) phenyl) -3- [ (1 α,3 α,4 α) -3, 4-difluorocyclopentyl]-N- [1- (2-hydroxyethyl) -1H-pyrazol-3-yl]Acrylamide, (E) -2- (4- (cyclopropylsulfonyl) phenyl) -3- [ (1 α,3 α,4 α) -3, 4-difluorocyclopentyl]-N- [1- (2-hydroxy-2-methylpropyl) -1H-pyrazol-3-yl]Acrylamide, (E) -2- (4- (cyclopropylsulfonyl) phenyl) -3- [ (1 α,3 α,4 α) -3, 4-difluorocyclopentyl]-N- (1- { [ (4R) -2, 2-dimethyl-1, 3-dioxolan-4-yl]Methyl } -1H-pyrazol-3-yl) acrylamide, (E) -2- (4- (cyclopropylsulfonyl) phenyl) -3- [ (1 α,3 α,4 α) -3, 4-difluorocyclopentyl]-N- (1- { [ (4S) -2, 2-dimethyl-1, 3-dioxolan-4-yl]Methyl } -1H-pyrazol-3-yl) acrylamide, (E) -2- (4- (cyclopropylsulfonyl) phenyl) -3- [ (1 α,3 α,4 α) -3, 4-difluorocyclopentyl]-N- {1- [ (2R) -2, 3-dihydroxypropyl]-1H-pyrazol-3-yl } acrylamide, (E) -2- (4- (cyclopropylsulfonyl) phenyl) -3- [ (1 α,3 α,4 α) -3, 4-difluorocyclopentyl]-N- (1- { [ (4S) -2, 2-dimethyl-1, 3-dioxolan-4-yl]Methyl } -1H-pyrazol-3-yl) acrylamide, (E) -2- (4- (cyclopropylsulfonyl) phenyl) -3- [ (1 α,3 α,4 α) -3, 4-difluorocyclopentyl]-N- (iso)Azol-3-yl acrylamide, (b) and (c)E) -N- (benzo [ d ]]Thiazol-2-yl) -2- (4- (cyclopropylsulfonyl) phenyl) -3- [ (1 α,3 α,4 α) -3, 4-difluorocyclopentyl]Acrylamide, (E) -2- (4- (cyclopropylsulfonyl) phenyl) -3- [ (1 α,3 α,4 α) -3, 4-difluorocyclopentyl]-N- (6-methoxybenzo [ d ]]Thiazol-2-yl) acrylamide, (E) -2- (4- (cyclopropylsulfonyl) phenyl) -3- [ (1 α,3 α,4 α) -3, 4-difluorocyclopentyl]-N- [6- (difluoromethoxy) benzo [ d ]]Thiazol-2-yl]Acrylamide, (E) -2- (4- (cyclopropylsulfonyl) phenyl) -3- [ (1 α,3 α,4 α) -3, 4-difluorocyclopentyl]-N- (6-fluorobenzo [ d ]]Thiazol-2-yl) acrylamide, 2- { (E) -2- (4- (cyclopropylsulfonyl) phenyl) -3- [ (1 α,3 α,4 α) -3, 4-difluorocyclopentyl]Acrylamide } benzo [ d]Thiazole-6-carboxylic acid 2-methylethyl ester, (E) -2- (4- (cyclopropylsulfonyl) phenyl) -3- [ (1 α,3 α,4 α) -3, 4-difluorocyclopentyl]-N- (thiazolo [5,4-b ]]Pyridin-2-yl) acrylamide, (E) -N- (5-butoxythiazolo [5, 4-b)]Pyridin-2-yl) -2- (4- (cyclopropylsulfonyl) phenyl) -3- [ (1 α,3 α,4 α) -3, 4-difluorocyclopentyl]Acrylamide, (E) -2- (4- (cyclopropylsulfonyl) phenyl) -3- [ (1 α,3 α,4 α) -3, 4-difluorocyclopentyl]-N- [5- (2-methoxyethoxy) thiazolo [5,4-b]Pyridin-2-yl]Acrylamide, 2- {2- [ (R) -2- (4- (cyclopropylsulfonyl) phenyl) -3- [ (1 α,3 α,4 α) -3, 4-difluorocyclopentyl]Acrylamide]Thiazolo [5,4-b ]]Pyridin-5-yloxy } acetic acid ethyl ester, (E) -3- [ (1 α,3 α,4 α) -3, 4-difluorocyclopentyl]-2- [4- (ethylsulfonyl) phenyl]-N- (thiazol-2-yl) acrylamide, (E) -3- [ (1 α,3 α,4 α) -3, 4-difluorocyclopentyl]-2- [4- (ethylsulfonyl) phenyl]-N- (5-methylpyrazin-2-yl) acrylamide, (E) -3- [ (1 α,3 α,4 α) -3, 4-difluorocyclopentyl]-2- [4- (ethylsulfonyl) phenyl]-N- (1-methyl-1H-pyrazol-3-yl) acrylamide, (E) -3- [ (1 α,3 α,4 α) -3, 4-difluorocyclopentyl]-2- [4- (2-methoxyethylsulfonyl) phenyl]-N- (thiazol-2-yl) acrylamide, (E) -3- [ (1 α,3 α,4 α) -3, 4-difluorocyclopentyl]-2- [4- (2-methoxyethylsulfonyl) phenyl]-N- (5-methylpyrazin-2-yl) acrylamide, (E) -3- [ (1 α,3 α,4 α) -3, 4-difluorocyclopentyl]-2- [4- (2-methoxyethylsulfonyl) phenyl]-N- (1-methyl-1H-pyrazol-3-yl) acrylamide.

The compound represented by the general formula (1) of the present invention can be produced, for example, by the following production process using the compound represented by the general formula (2) as an intermediate.

(in the formula, R¹、R²And A is as defined above)

This step is a step of reacting the compound represented by the above general formula (2) with a heteroarylamine in the presence of an appropriate reagent to produce the compound represented by the above general formula (1).

The reaction can be carried out by a method using a conventional condensing agent, or an active ester method, a mixed acid anhydride method, an acid halide method, a carbodiimide method, or the like as appropriate. Examples of the reagent used in the reaction include thionyl chloride, oxalyl chloride, N '-dicyclohexylcarbodiimide, N' -diisopropylcarbodiimide, 1-methyl-2-bromopyridinium iodide, N '-carbonyldiimidazole, diphenylphosphoryl chloride, diphenylphosphoryl azide, N-disuccinimidyl carbonate, N' -disuccinimidyl oxalate, 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride, ethyl chloroformate, isobutyl chloroformate, benzotriazol-1-yl-oxy-tris (dimethylamino) phosphonium hexafluorophosphate, N-bromosuccinimide/triphenylphosphine, and the like. In this step, a base and a condensation assistant may be used together with the above-mentioned reagents. As the base used in this case, any base may be used as long as it does not participate in the reaction, and examples thereof include alkali metal alkoxides such as sodium methoxide and sodium ethoxide; alkali metal hydrides such as sodium hydride and potassium hydride; alkali metal organic bases such as n-butyllithium, lithium bis (trimethylsilyl) amide, sodium bis (trimethylsilyl) amide, and potassium bis (trimethylsilyl) amide; triethylamine, diisopropylethylamine, pyridine, N-methylmorpholine, imidazole, N-methylpyrrolidine, N-methylpiperidine 1, 5-diazabicyclo [4.3.0]]Non-5-ene, 1, 8-diazabicyclo [5.4.0]Tertiary organic bases such as undec-7-ene; the reaction is carried out in the presence of an inorganic base such as potassium carbonate or sodium hydrogencarbonate. As a condensation aidExamples of the agent include N-hydroxybenzotriazole hydrate, N-hydroxysuccinimide, N-hydroxy-5-norbornene-2, 3-dicarboximide (carboxyimide), 3-hydroxy-3, 4-dihydro-4-oxo-1, 2, 3-benzotriazole, pentafluorophenol and the like. As the reaction solvent, any solvent can be used as long as it does not participate in the reaction, and hydrocarbon solvents such as pentane, hexane, cyclohexane, benzene, toluene, xylene, and the like; halogenated hydrocarbon solvents such as dichloromethane, 1, 2-dichloroethane, chloroform, carbon tetrachloride and the like; diethyl ether, tetrahydrofuran, 1, 4-bisEther solvents such as alkanes; aprotic polar solvents such as acetonitrile, propionitrile, nitromethane, nitroethane, N-dimethylformamide, N-methylpyrrolidone, sulfolane, and dimethylsulfoxide. The reaction is usually carried out smoothly at-78 ℃ to 200 ℃.

The compounds represented by the general formulae (1) and (2) of the present invention can also be produced by the following production steps.

(in the formula, R⁶Represents an optionally substituted alkoxy group or an optionally substituted amino group, R⁷Represents a boric acid derivative, a halogen atom or a trifluoromethanesulfonyloxy group, and X represents a halogen atom; r¹And R²As defined above).

(first step)

This step is a step of reacting (3) with glyoxal in the presence of a base to produce an acrylic acid derivative (4). Examples of the base used in the reaction include alkali metal amides such as lithium diisopropylamide, lithium bis (trimethylsilyl) amide, sodium bis (trimethylsilyl) amide and potassium bis (trimethylsilyl) amide, metal hydrides such as lithium hydride, sodium hydride and potassium hydride, potassium carbonate, potassium tert-butoxide and n-butyllithium, and lithium bis (trimethylsilyl) amide is preferable in the reaction.

The solvent used in the reaction may be any solvent as long as it does not participate in the reaction, and examples thereof include hydrocarbon solvents such as pentane, hexane, cyclohexane, benzene, toluene and xylene, halogenated hydrocarbon solvents such as dichloromethane, 1, 2-dichloroethane, chloroform and carbon tetrachloride, diethyl ether, tetrahydrofuran and 1, 4-bis (methylene chloride), and the likeEther solvents such as alkanes. The reaction proceeds smoothly at-80 ℃ to 80 ℃.

(second Process)

This step is a step of halogenating the 3- (3, 4-difluorocyclopentyl) acrylic acid derivative represented by the above formula (4) obtained in the above first step with a molecular halogen and then reacting the resultant with a base to obtain a 3- (3, 4-difluorocyclopentyl) -2-haloacrylic acid derivative.

Examples of the base used in the reaction include carbonates such as sodium carbonate, potassium carbonate, calcium carbonate, cesium carbonate and barium carbonate, and organic bases such as triethylamine, diisopropylethylamine, N, N, N-tetramethylethylenediamine, diazabicyclo [5.4.0] -7-undecene, diazabicyclo [4.3.0] -5-nonene, phosphazene base and pentaisopropylguanidine, and triethylamine is preferable in the reaction.

(third Process)

The present step is a step of reacting a compound represented by the general formula (6) with the 3- (3, 4-difluorocyclopentyl) -2-halogenoacrylic acid derivative represented by the general formula (5) obtained in the second step in the presence of a catalyst and a base to obtain a 3- (3, 4-difluorocyclopentyl) -2- (substituted propyl) acrylic acid derivative.

In the general formula, R⁷In the case of a halogen atom or a trifluoromethanesulfonyloxy group, for example, boric acid or pinacol diboron may be reacted with a palladium complex such as 1, 1-bis (diphenylphosphino) ferrocene-palladium (II) dichloride in the presence of an acetate such as potassium acetate to convert it into a boric acid derivative. The boric acid derivative thus obtained is used after separation and purification, or is produced in a reaction system.

As the catalyst used in this reaction, a palladium complex such as tetrakis (triphenylphosphine) palladium, palladium acetate, 1-bis (diphenylphosphino) ferrocene-palladium (II) dichloride, or the like can be used.

As the base used in this reaction, carbonates such as sodium carbonate, potassium carbonate, calcium carbonate, cesium carbonate and barium carbonate, and acetates such as potassium acetate and sodium acetate can be used.

The solvent used in the reaction may be any solvent as long as it does not participate in the reaction, and may be used alone, for example, hydrocarbon solvents such as pentane, hexane, cyclohexane, benzene, toluene, xylene, halogenated hydrocarbon solvents such as dichloromethane, 1, 2-dichloroethane, chloroform, carbon tetrachloride, diethyl ether, tetrahydrofuran, 1, 4-bis (methylene chloride), and the likeAn ether solvent such as an alkane, an aprotic polar solvent such as acetonitrile, propionitrile, nitromethane, nitroethane, N-dimethylformamide, or dimethylsulfoxide, an alcohol solvent such as methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, 2-methyl-1-propanol, 2-methyl-2-propanol, or benzyl alcohol, and water, or 2 or 3 of these solvents may be used in combination. The reaction proceeds smoothly at-80 ℃ to 150 ℃.

In addition, one embodiment of the present invention relates to a pharmaceutical product containing a compound represented by formula (1) or a pharmaceutically acceptable salt thereof as an active ingredient. The drug of the present invention has a GK activating action or a hypoglycemic action, and therefore, is useful for the treatment or prevention of type 1 diabetes, type 2 diabetes, hyperlipidemia (high LDL cholesterolemia, high triglyceride cholesterolemia and low HDL cholesterolemia), obesity, insulin resistance, impaired glucose tolerance, metabolic syndrome and the like.

The medicine of the present invention may be orally taken or rectally, subcutaneously, intravenously, intramuscularly, transdermally and other parenterally taken.

The compound of the present invention or a pharmaceutically acceptable salt thereof can be used as a pharmaceutical product in the form of a solid composition, a liquid composition, or other compositions, and the most suitable form can be selected as needed. The pharmaceutical product of the present invention may be manufactured by incorporating a pharmaceutically acceptable carrier into the compound of the present invention. Specifically, it can be added with conventional excipient, bulking agent, binder, disintegrating agent, coating agent, sugar coating agent, pH regulator, solubilizer, or aqueous or non-aqueous solvent, and made into tablet, pill, capsule, granule, powder, liquid, emulsion, suspension, injection, etc. by conventional preparation technology.

The amount of the compound of the present invention or a pharmaceutically acceptable salt thereof to be administered varies depending on the disease, symptoms, body weight, age, sex, administration route and the like, and in the case of oral administration to an adult, it is preferably from about 0.01 to about 1000mg/kg body weight/day, more preferably from about 0.5 to about 200mg/kg body weight/day, and these amounts of the drug may be administered once or in several portions a day.

For example, a combination of 1 or more antidiabetic agents including sulfonylureas, biguanides, glucagon antagonists, α -glucosidase inhibitors, insulin secretion promoting substances, insulin sensitizers and the like, antihyperglycemic agents or antiobesity agents can be suitably used.

The sulfonylureas include glibenclamide, glimepiride, glyburide (glipiride), glipizide, chlorpropamide, gliclazide, glimepiride, acetohexamide, glibornuride, tolbutamide, tolazamide, gliquidone, glipizide, tolbutamide, and tolcyclamide, the biguanides include metformin, phenformin, and buformin, the glucagon antagonists include peptide or non-peptide glucagon antagonists, α -glucosidase inhibitors include acarbose, voglibose, miglitol, the insulin sensitizer includes troglitazone, rosiglitazone, pioglitazone, and ciglitazone, the antiobesity agent includes sibutramine, orlistat, and the compound of the present invention or a pharmaceutically acceptable salt thereof may be administered simultaneously, continuously, or in portions with other antidiabetic agents, antihyperglycemic agents, or antiobesity agents.

Example 1

3- [ (α,3 α,4 α) -3, 4-difluorocyclopentyl]-2- [4- (methylthio) phenyl]Acrylic acid ethyl ester

(1 α,3 α,4 α) - (3, 4-difluorocyclopentyl) methyltriphenylphosphonium iodide (2.67g) was suspended in tetrahydrofuran (10mL), and lithium bis (trimethylsilyl) amide (1mol/L tetrahydrofuran solution, 5.30mL) was added under an argon atmosphere at-40 ℃ and stirred at that temperature for 2 hours, then, while the reaction mixture was cooled at-40 ℃, a tetrahydrofuran (3.70mL) solution of ethyl 2- [ (4-methylthio) phenyl ] oxoacetate (1.12g) was added dropwise and stirred at that temperature for 2 hours, and then stirred at room temperature for 18 hours, water (10mL) was added to the reaction mixture, the pH was adjusted to 2 with 3mol/L hydrochloric acid, the tetrahydrofuran was distilled off under reduced pressure, the residue was extracted with ethyl acetate (20 mL. times.2.) the ethyl acetate extracts were combined, washed with saturated brine (10mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (elution solvent: ethyl acetate 4: 1,3, 4-difluorocyclopentyl) methyltriphenylphosphonium iodide (3.7 g-3- [ 3, 3- [ 3] propyl ] acrylic acid, 3- [ 5954).

¹H NMR(400MHz，CDCl₃)δ1.27(t，J＝7.3Hz，3H)，1.30(t，J＝7.3Hz，3H)，1.84-2.19(m，6H)，2.28-2.42(m，2H)，2.49(s，3H)，2.50(s，3H)，2.55-2.69(m，1H)，3.17-3.31(m，1H)，4.21(q，J＝7.3Hz，2H)，4.27(q，J＝7.3Hz，2H)，4.68-5.04(m，4H)，6.13(d，J＝9.8Hz，1H)，7.00(d，J＝10.4Hz，1H)，7.03-7.08(m，2H)，7.22-7.25(m，6H).

MS(ESI⁺)m/z：327(MH⁺).

Example 2

3- [ (1 α,3 α,4 α) -3, 4-difluorocyclopentyl]-2- [4- (methylsulfonyl) phenyl]Acrylic acid ethyl ester

Ethyl 3- [ (1 α,3 α,4 α) -3, 4-difluorocyclopentyl ] -2- [4- (methylthio) phenyl ] acrylate (3.00g) was dissolved in methylene chloride (31mL), and while cooling in an ice-water bath, m-chloroperbenzoic acid (5.37g) was added, and the mixture was stirred at that temperature for 0.5 hour, and then stirred at room temperature for 1.5 hours, insoluble matter in the reaction mixture was removed by filtration, and the filtrate was diluted with methylene chloride (42mL), and the methylene chloride solution was washed with a 10% aqueous sodium sulfite solution (20 mL. times.2), a saturated aqueous sodium bicarbonate solution (20 mL. times.2), and a saturated saline solution (20mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give ethyl 3- [ (1 α,3 α,4 α) -3, 4-difluorocyclopentyl ] -2- [4- (methylsulfonyl) phenyl ] acrylate (3.41 g).

¹H NMR(400MHz，CDCl₃)δ1.30(t，J＝7.3Hz，3H)，1.31(t，J＝7.3Hz，3H)，1.86-2.20(m，6H)，2.30-2.56(m，3H)，3.06(s，3H)，3.10(s，3H)，3.35-3.48(m，1H)，4.24(q，J＝7.3Hz，2H)，4.29(q，J＝7.3Hz，2H)，4.69-5.10(m，4H)，6.29(d，J＝9.8Hz，1H)，7.09(d，J＝10.4Hz，1H)，7.33-7.38(m，2H)，7.48-7.53(m，2H)，7.89-7.93(m，2H)，7.93-7.97(m，2H).

MS(EI)m/z：358(M⁺).

Example 3

(E) -3- [ (1 α,3 α,4 α) -3, 4-difluorocyclopentyl]-2- [4- (methylsulfonyl) phenyl]Acrylic acid methyl ester

Ethyl 3- [ (1 α,3 α,4 α) -3, 4-difluorocyclopentyl ] -2- [4- (methylsulfonyl) phenyl ] acrylate (5.00g) was suspended in methanol (26mL), a sodium methoxide solution prepared from 460mg of sodium and 20mL of methanol was added dropwise at room temperature, and the mixture was stirred at room temperature for 3 hours, the methanol was distilled off under reduced pressure, and the resulting residue was filtered off and washed with methanol (50mL) to give methyl (E) -3- [ (1 α,3 α,4 α) -3, 4-difluorocyclopentyl ] -2- [4- (methylsulfonyl) phenyl ] acrylate (3.98 g).

¹H NMR(400MHz，CDCl₃)δ1.87-2.20(m，4H)，2.43-2.58(m，1H)，3.10(s，3H)，3.78(s，3H)，4.69-4.95(m，2H)，7.12(d，J＝11.0Hz，1H)，7.34(d，J＝7.9Hz，2H)，7.96(d，J＝7.9Hz，2H).

MS(EI)m/z：344(M⁺).

Example 4

(E) -3- [ (1 α,3 α,4 α) -3, 4-difluorocyclopentyl]-2- [4- (methylsulfonyl) phenyl]Acrylic acid

To methyl (E) -3- [ (1 α,3 α,4 α) -3, 4-difluorocyclopentyl ] -2- [4- (methylsulfonyl) phenyl ] acrylate (3.95g) was added a mixture of concentrated sulfuric acid (6.89mL), acetic acid (37.1mL) and water (22.5mL), and the mixture was heated and stirred at 103 ℃ C (inner temperature) for 3 hours, the reaction mixture was allowed to cool and distilled off under reduced pressure, water (37mL) was added to the residue, the precipitate was collected by filtration, washed with water (100mL), the filtrate was dissolved in a saturated aqueous sodium bicarbonate solution, and methylene chloride extraction (15 mL. times.2) was performed, while the aqueous layer was cooled in an ice-water bath, concentrated hydrochloric acid was added to the aqueous layer to acidify the mixture, the precipitate was collected by filtration, and washed with water (100mL) to obtain (E) -3- [ (1 α,3 α,4 α) -3, 4-difluorocyclopentyl ] -2- [ 4-methylsulfonyl) phenyl ] acrylic acid (3.26 g).

¹H NMR(400MHz，CDCl₃)δ1.88-2.21(m，4H)，2.47-2.62(m，1H)，3.09(s，3H)，4.73-4.97(m，2H)，7.24(d，J＝10.4Hz，1H)，7.34-7.39(m，2H)，7.94-7.99(m，2H).MS(EI)m/z：330(M⁺).

Example 5

(E) -3- [ (1 α,3 α,4 α) -3, 4-difluorocyclopentyl]-2- [4- (methylsulfonyl) phenyl]-N- (thiazole-2-) Yl) acrylamide (inventive Compound 1A)

To (E) -3- [ (1 α,3 α,4 α) -3, 4-difluorocyclopentyl ] -2- [4- (methylsulfonyl) phenyl ] acrylic acid (343mg) was added thionyl chloride (3.43mL), and the mixture was refluxed for 45 minutes, cooled to room temperature, then distilled off thionyl chloride, toluene (3mL × 3) was added, and distillation under reduced pressure was performed, to the resulting residue was added a pyridine solution (1.37mL) of 2-aminothiazole (104mg) over a salt-ice water bath, the mixture was stirred at room temperature for 1 hour, the reaction mixture was washed with ethyl acetate (30mL), and the resulting residue was purified by silica gel column chromatography (elution solvent: chloroform: methanol ═ 50: 1) successively with 1mol/L hydrochloric acid (30mL × 2), a saturated aqueous sodium bicarbonate solution (30mL × 2), and a saturated saline solution (30mL), dried over anhydrous sodium sulfate, filtered, and the solvent was distilled off under reduced pressure, and the resulting residue was washed with ether to obtain (E) -3- [ (1 α,3 α,3, 4-difluorocyclopentyl ] -2- [4- (methylsulfonyl) acrylamide (154 mg).

MS(ESI⁺)m/z：413(MH⁺).

C₁₈H₁₉F₂N₂O₃S₂(MH⁺) HRMS (ESI)⁺): calculated value, 413.08051; found 413.08048.

¹H NMR(400MHz，CDCl₃)δ1.82-2.01(m，2H)，2.07-2.25(m，2H)，2.48-2.60(m，1H)，3.25(s，3H)，4.84-5.08(m，2H)，7.83(d，J＝10.4Hz，1H)，7.21(brs，1H)，7.47(d，J＝8.6Hz，2H)，7.51(d，J＝3.1Hz，1H)，7.94(d，J＝8.6Hz，2H)，12.4(brs，1H).

Example 6

Compounds 2A to 62A of the present invention were prepared by the same procedure as in example 5.

In the optical rotation in the table, the inventive compounds 7A, 8A, 40A, 41A, 53A and 54A were measured using methanol as a solvent, the inventive compounds 51A and 52A were measured using methylene chloride as a solvent, and the remaining compounds were measured using chloroform as a solvent.

[ Table 1]

[ Table 2]

[ Table 3]

[ Table 4]

[ Table 5]

[ Table 6]

[ Table 7]

[ Table 8]

[ Table 9]

[ Table 10]

[ Table 11]

[ Table 12]

Example 7

(E) -2- [4- (cyclopropylthio) phenyl]-3- [ (1 α,3 α,4 α) -3, 4-difluorocyclopentyl]Acrylic acid ethyl ester

(1 α,3 α,4 α) - (3, 4-difluorocyclopentyl) methyltriphenylphosphonium iodide (60.9g) was suspended in tetrahydrofuran (186mL), and while cooling in an ice-water bath, bis (trimethylsilyl) aminolithium (1mol/L tetrahydrofuran solution, 120mL) was added, followed by stirring at that temperature for 1 hour, and then while cooling the reaction mixture over an ice-water bath, a solution of ethyl [ (4-cyclopropylthio) phenyl ] oxoacetate (25.0g) in tetrahydrofuran (120mL) was added dropwise, followed by stirring at that temperature for 1 hour, and then stirring at room temperature for 5 hours, water (230mL) was added to the reaction mixture, after adjusting to pH6 with 1mol/L hydrochloric acid, tetrahydrofuran was distilled off under reduced pressure, the residue was extracted with ethyl acetate (2 × 540mL), the ethyl acetate extracts were combined, washed with saturated brine (180mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, the residue was purified by silica gel column chromatography (eluent: ethyl acetate: 4834, 3, 4-difluorocyclopentyl) methyltriphenylphosphonium iodide (60.9g) and the title compound was purified as the mixture of cyclopropyl-propyl-3- [ (3, 3- [ 3, 4] thioacrylate (3, 3-5-9 g) and the following procedures for 5 hours, 3- [ (369 g of the title compound, 3-5-9 g, 3- [ (3-9 g, 3-2, 3-9 g.

MS(EI)m/z：352(M⁺).

C₁₉H₂₂F₂N₂O₂S(M⁺) Hrms (ei): calculated value, 352.1309; found 352.1302.

¹HNMR(400MHz，CDCl₃)δ0.69-0.73(m，2H)，1.04-1.11(m，2H)，1.28(t，J＝7.3Hz，3H)，1.89-2.03(m，2H)，2.06-2.21(m，3H)，2.58-2.69(m，1H)，4.22(q，J＝7.3Hz，2H)，4.73-4.92(m，2H)，6.97(d，J＝10.4Hz，1H)，7.03-7.37(m，2H).

Example 8

(E) -2- [4- (cyclopropylsulfonyl) phenyl]-3- [ (1 α,3 α,4 α) -3, 4-difluorocyclopentyl]Acrylic acid ethyl ester

Ethyl (E) -2- [4- (cyclopropylthio) phenyl ] -3- [ (1 α,3 α,4 α) -3, 4-difluorocyclopentyl ] acrylate (8.81g) was dissolved in methylene chloride (90mL), and after adding m-chloroperbenzoic acid (14.6g) while cooling in an ice-water bath, the mixture was stirred at that temperature for 1 hour, and then stirred at room temperature for 1 hour, then insoluble matter was removed by filtration, the filtrate was diluted with methylene chloride (150mL), the methylene chloride solution was washed with a 10% aqueous sodium sulfite solution (2 × 35mL), a saturated aqueous sodium bicarbonate solution (2 × 35mL), and water (35mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent: hexane: ethyl acetate: 1) to give ethyl (E) -2- [4- (cyclopropylsulfonyl) phenyl ] -3- [ (1 α,3 α,4 α) -3, 4-difluorocyclopentyl ] acrylate (9.54 g).

MS(EI)m/z：384(M⁺).

C₁₉H₂₂F₂N₂O₄S(M⁺) Hrms (ei): calculated value, 384.1207; found 384.1163.

¹H NMR(400MHz，CDCl₃)δ1.03-1.10(m，2H)，1.30(t，J＝7.3Hz，3H)，1.34-1.41(m，2H)，1.91-2.17(m，4H)，2.47-2.58(m，2H)，4.24(q，J＝7.3Hz，2H)，4.74-4.94(m，2H)，7.08(d，J＝10.4Hz，1H)，7.32-7.35(m，2H)，7.87-7.92(m，2H).

Example 9

(E)-2-[4-(Cyclopropylsulfonyl) phenyl]-3- [ (1 α,3 α,4 α) -3, 4-difluorocyclopentyl]Acrylic acid

To ethyl (E) -2- [4- (cyclopropylsulfonyl) phenyl ] -3- [ (1 α,3 α,4 α) -3, 4-difluorocyclopentyl ] acrylate (9.54g) was added a mixture of concentrated sulfuric acid (15.0mL), acetic acid (80.0mL) and water (48.0mL), and the mixture was heated and stirred at 98 ℃ (internal temperature) for 6 hours, after cooling, the reaction mixture was distilled off under reduced pressure, and water (80mL) was added to the residue to collect the precipitate, followed by washing with water, dissolving the filtrate in a saturated aqueous sodium bicarbonate solution (200mL), washing with methylene chloride (50mL × 2), adjusting the aqueous layer to acidic properties (pH1) by adding concentrated hydrochloric acid while cooling the aqueous layer in an ice-water bath, and collecting the precipitate by filtration, and washing the filtrate with water (100mL) to obtain (E) -2- [4- (cyclopropylsulfonyl) phenyl ] -3- [ (1 α,3 α,4 α) -3, 4-difluorocyclopentyl ] acrylic acid (7.79 g).

MS(EI)m/z：356(M⁺).

C₁₇H₁₈F₂N₂O₄S(M⁺) Hrms (ei): calculated value, 356.0894; found 356.0870.

¹H NMR(400MHz，CDCl₃)δ1.05-1.10(m，2H)，1.30-1.41(m，2H)，1.91-2.19(m，4H)，2.46-2.62(m，2H)，4.76-4.94(m，2H)，7.24(d，J＝11.0Hz，1H)，7.34-7.36(m，2H)，7.91-7.93(m，2H).

Example 10

(E) -2- [4- (cyclopropylsulfonyl) phenyl 1-3- [ (1 α,3 α,4 α) -3, 4-difluorocyclopentyl]-N- (thiazole-2-) Yl) acrylamide (inventive Compound 1B)

To (E) -2- [4- (cyclopropylsulfonyl) phenyl ] -3- [ (1 α,3 α,4 α) -3, 4-difluorocyclopentyl ] acrylic acid (108mg) was added thionyl chloride (1.00mL), and the mixture was refluxed for 1.5 hours, then cooled to room temperature, then distilled off the thionyl chloride, toluene (0.5mL) was added, and distillation was performed under reduced pressure, the resulting residue was dissolved in dehydrated tetrahydrofuran (0.4mL), a pyridine solution (0.40mL) of 2-aminothiazole (30.3mg) was added to a salt-ice bath, and the mixture was stirred at room temperature for 1 hour, the reaction mixture was diluted with ethyl acetate (5mL), followed by 1mol/L hydrochloric acid (8mL × 2), a saturated aqueous sodium bicarbonate solution (3mL), and a saturated saline solution (3mL), drying was performed with anhydrous sodium sulfate, then filtration was performed, the solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (elution solvent: chloroform acetone ═ 20: 1), and then the resulting compound was washed with diethyl ether to obtain (E) -2- [4- (cyclopropylsulfonyl) phenyl ] -3- [ (3, 3-364-difluorocyclopentyl ] acrylic amide (α mg).

MS(ESI⁺)m/z：439.1(MH⁺).

C₂₀H₂₁F₂N₂O₃S₂(MH⁺) HRMS (ESI)⁺): calculated value, 439.09616; found 439.09701.

¹H NMR(400MHz，CDCl₃)δ1.17(ddd，J＝13.4，6.7，2.5Hz，2H)，1.45(ddd，J＝10.4，6.1，1.8Hz，2H)，1.93-2.17(m，4H)，2.37-2.17(m，1H)，2.57(tt，J＝8.0，4.9Hz，1H)，4.73-4.94(m，2H)，7.03(d，J＝3.7Hz，1H)，7.27(d，J＝9.4Hz，1H)，7.41(dJ＝3.67Hz，1H)，7.45(dt，J＝8.6，1.8Hz，2H)，8.03(dt，J＝8.5，1.8 Hz，2H)，8.51(brs，1H).

Example 11

Compounds 2B to 109B of the present invention were prepared in the same manner as in example 10.

In the optical rotation in the table, inventive compounds 6B and 7B were measured using methanol as a solvent, and the remaining compounds were measured using chloroform as a solvent.

[ Table 13]

[ Table 14]

[ Table 15]

[ Table 16]

[ Table 17]

[ Table 18]

[ Table 19]

[ Table 20]

[ Table 21]

[ Table 22]

[ Table 23]

[ Table 24]

[ Table 25]

[ Table 26]

[ Table 27]

[ Table 28]

[ Table 29]

[ Table 30]

[ Table 31]

[ Table 32]

[ Table 33]

[ Table 34]

[ Table 35]

[ Table 36]

Example 12

(E) -3- [ (1 α,3 α,4 α) -3, 4-difluorocyclopentyl]-2- [4- (ethylthio) phenyl]Acrylic acid ethyl ester

From (1 α,3 α,4 α 0) - (3, 4-difluorocyclopentyl) methyltriphenylphosphonium iodide (3.00g) and ethyl 2- [ (4-ethylthio) phenyl ] oxoacetate (1.34g), ethyl (E) -3- [ (1 α 1,3 α,4 α) -3, 4-difluorocyclopentyl ] -2- [4- (ethylthio) phenyl ] acrylate (773mg), (z) -3- [ (1 α,3 α,4 α) -3, 4-difluorocyclopentyl ] -2- [4- (ethylthio) phenyl ] acrylate (498mg) and 3- [ (1 α,3 α,4 α) -3, 4-difluorocyclopentyl ] -2- [4- (ethylthio) phenyl ] acrylate as E, Z mixture (249mg) were obtained according to the method of example 1.

¹H NMR(400MHz，CDCl₃)δ1.28(t，J＝7.3Hz，3H)，1.35(t，J＝7.3Hz，3H)，1.88-2.18(m，4H)，2.55-2.68(m，1H)，2.97(q，J＝7.3Hz，2H)，4.22(q，J＝7.3Hz，2H)，4.70-4.96(m，2H)，6.97(d，J＝10.4Hz，1H)，7.05(d，J＝8.6Hz，2H)，7.29(d，J＝8.6Hz，2H).

MS(ESI⁺)m/z：341.1(MH⁺).

Example 13

(E) -3- [ (1 α,3 α,4 α) -3, 4-difluorocyclopentyl]-2- [4- (ethylsulfonyl) phenyl]Acrylic acid ethyl ester

From ethyl (E) -3- [ (1 α,3 α,4 α) -3, 4-difluorocyclopentyl ] -2- [4- (ethylthio) phenyl ] acrylate from example 12 (730mg) according to the procedure of example 2, (E) -3- [ (1 α,3 α,4 α) -3, 4-difluorocyclopentyl ] -2- [4- (ethylsulfonyl) phenyl ] acrylate (665mg) was obtained.

¹H NMR(400MHz，CDCl₃)δ1.18-1.40(m，6H)，1.90-2.20(m，4H)，2.45-2.58(m，1H)，3.16(q，J＝7.3Hz，2H)，4.24(q，J＝7.3Hz，2H)，4.71-4.95(m，2H)，7.09(d，J＝10.4Hz，1H)，7.35(d，J＝7.9Hz，2H)，7.92(d，J＝7.9Hz，2H).

MS(ESI⁺)m/z：373.1(MH⁺).

Example 14

(E) -3- [ (1 α,3 α,4 α) -3, 4-difluorocyclopentyl]-2- [4- (ethylsulfonyl) phenyl]Acrylic acid

From ethyl (E) -3- [ (1 α,3 α,4 α) -3, 4-difluorocyclopentyl ] -2- [4- (ethylsulfonyl) phenyl ] acrylate (634mg) obtained in example 13 according to the procedure of example 4, (E) -3- [ (1 α,3 α,4 α) -3, 4-difluorocyclopentyl ] -2- [4- (ethylsulfonyl) phenyl ] acrylate (420 mg).

¹H NMR(400MHz，CDCl₃)δ1.33(t，J＝7.3Hz，3H)，1.88-2.21(m，4H)，2.47-2.62(m，1H)，3.15(q，J＝7.3Hz，2H)，4.71-4.99(m，2H)，7.24(d，J＝10.4Hz，1H)，7.36(d，J＝7.9Hz，2H)，7.93(d，J＝7.9Hz，2H).

MS(ESI⁺)m/z：345.1(MH⁺).

Example 15

(E) -3- [ (1 α,3 α,4 α) -3, 4-difluorocyclopentyl]-2- [4- (ethylsulfonyl) phenyl]-N- (thiazole-2-) Yl) acrylamide (inventive Compound 1C)

From (E) -3- [ (1 α,3 α,4 α) -3, 4-difluorocyclopentyl ] -2- [4- (ethylsulfonyl) phenyl ] acrylic acid (100mg) and 2-aminothiazole (29.0mg) obtained in example 14 according to the procedure of example 5 was (E) -3- [ (1 α,3 α,4 α) -3, 4-difluorocyclopentyl ] -2- [4- (ethylsulfonyl) phenyl ] -N- (thiazol-2-yl) acrylamide (47.4 mg).

¹H NMR(400MHz，CDCl₃)δ1.42(t，J＝7.3Hz，3H)，1.90-2.19(m，4H)，2.31-2.45(m，1H)，3.23(q，J＝7.3Hz，2H)，4.69-4.97(m，2H)，7.02(d，J＝3.3Hz，1H)，7.26(d，J＝10.4Hz，1H)，7.42(d，J＝3.3Hz，1H)，7.47(d，J＝8.6Hz，2H)，8.04(d，J＝8.6Hz，2H)，8.54(brs，1H).

MS(ESI⁺)m/z：427.1(MH⁺).

C₁₉H₂₁F₂N₂O₃S₂(MH⁺) HRMS (ESI)⁺): calculated value, 427.09616; found 427.09624.

Example 16

Compounds 2C and 3C of the present invention were prepared by the same procedure as in example 15.

[ Table 37]

Example 17

2- [4- (2-methoxyethylthio) phenyl]-2-Oxoacetic acid ethyl ester

Ethyl chloroacetaldehyde (8.76mL) and then (2-methoxyethyl) diphenyl sulfide (phenyl sulfide) (12.0g) were added dropwise to a dichloromethane suspension (127mL) of aluminum chloride (pulverized) (13.2g) under ice-cooling stirring. After stirring at room temperature for 2 hours, the reaction mixture was poured into ice water (200mL) and stirred for 10 minutes. After separation, the organic layer was washed with a saturated aqueous sodium bicarbonate solution (40 mL. times.3), followed by a saturated brine solution (60 mL). After drying over anhydrous sodium sulfate, the filtrate was filtered and distilled under reduced pressure. The resulting residue was purified by column chromatography (silica gel, hexane: ethyl acetate 4: 1) to give ethyl 2- [4- (2-methoxyethylthio) phenyl ] -2-oxoacetate (1.98 g).

¹H NMR(400MHz，CDCl₃)δ1.42(t，J＝7.0Hz，3H)，3.23(t，J＝6.7Hz，2H)，3.39(s，3H)，3.65(t，J＝6.7Hz，2H)，4.44(q，J＝7.0Hz，2H)，7.36(d，J＝8.6Hz，2H)，7.92(d，J＝8.6Hz，2H).

MS(ESI⁺)m/z：269.1(MH⁺).

Example 18

(E) -3- [ (1 α,3 α,4 α) -3, 4-difluorocyclopentyl]-2- [4- (methoxyethylthio) phenyl]Acrylic acid ethyl ester

From (1 α,3 α,4 α 0) - (3, 4-difluorocyclopentyl) methylphosphonium iodide (3.00g) and ethyl 2- [4- (2-methoxyethylthio) phenyl ] -2-oxoacetate (1.51g) of example 17, ethyl (E) -3- [ (1 α 1,3 α,4 α) -3, 4-difluorocyclopentyl ] -2- [4- (methoxyethylthio) phenyl ] acrylate (639mg), (z) -3- [ (1 α,3 α,4 α) -3, 4-difluorocyclopentyl ] -2- [4- (methoxyethylthio) phenyl ] acrylate (67mg) and ethyl 3- [ (1 α,3 α,4 α) -3, 4-difluorocyclopentyl ] -2- [4- (methoxyethylthio) phenyl ] acrylate as E, Z mixture (1.01g) were obtained according to the method of example 1, only the title compound thereof was used in the subsequent procedures.

¹H NMR(400MHz，CDCl₃)δ1.28(t，J＝7.1Hz，3H)，1.86-2.19(m，4H)，2.54-2.67(m，1H)，3.14(t，J＝6.7Hz，2H)，3.38(s，3H)，3.61(t，J＝6.7Hz，2H)，4.22(q，J＝7.1Hz，2H)，4.71-4.94(m，2H)，6.97(d，J＝10.4Hz，1H)，7.06(d，J＝8.6Hz，2H)，7.34(d，J＝8.6Hz，2H).

MS(ESI⁺)m/z：339.1(MH⁺).

Example 19

(E) -3- [ (1 α,3 α,4 α) -3, 4-difluorocyclopentyl]-2- [4- (2-methoxyethylsulfonyl) phenyl]Propylene (PA) Acid ethyl ester

From ethyl (E) -3- [ (1 α,3 α,4 α) -3, 4-difluorocyclopentyl ] -2- [4- (methoxyethylthio) phenyl ] acrylate (600mg) of example 18 according to the procedure of example 2, ethyl (E) -3- [ (1 α,3 α,4 α) -3, 4-difluorocyclopentyl ] -2- [4- (2-methoxyethylsulfonyl) phenyl ] acrylate (573mg) was obtained.

¹H NMR(400MHz，CDCl₃)δ1.29(t，J＝7.1Hz，3H)，1.90-2.18(m，4H)，2.45-2.57(m，1H)，3.26(s，3H)，3.42(t，J＝6.4Hz，2H)，3.79(t，J＝6.4Hz，2H)，4.23(q，J＝7.1Hz，2H)，4.73-4.95(m，2H)，7.09(d，J＝10.4Hz，1H)，7.34(d，J＝8.6Hz，2H)，7.92(d，J＝8.6Hz，2H).

MS(CI⁺)m/z：403.1(MH⁺).

Example 20

(E) -3- [ (1 α,3 α,4 α) -3, 4-difluorocyclopentyl]-2- [4- (2-methoxyethylsulfonyl) phenyl]Propylene (PA) Acid(s)

From ethyl (E) -3- [ (1 α,3 α,4 α) -3, 4-difluorocyclopentyl ] -2- [4- (2-methoxyethylsulfonyl) phenyl ] acrylate (550mg) obtained in example 19 according to the procedure of example 4 to give (E) -3- [ (1 α,3 α,4 α) -3, 4-difluorocyclopentyl ] -2- [4- (2-methoxyethylsulfonyl) phenyl ] acrylic acid (428 mg).

¹H NMR(400MHz，CDCl₃)δ1.91-2.19(m，4H)，2.49-2.61(m，1H)，3.26(s，3H)，3.42(t，J＝6.1Hz，2H)，3.79(t，J＝6.1Hz，2H)，4.74-4.96(m，2H)，7.23(d，J＝10.4Hz，1H)，7.35(d，J＝7.9Hz，2H)，7.93(d，J＝7.9Hz，2H).

MS(CI⁺)m/z：375.1(MH⁺).

Example 21

(E) -3- [ (1 α,3 α,4 α) -3, 4-difluorocyclopentyl]-2- [4- (2-methoxyethylsulfonyl) phenyl]-N- (Thiazol-2-yl) acrylamides

From (E) -3- [ (1 α,3 α,4 α) -3, 4-difluorocyclopentyl ] -2- [4- (2-methoxyethylsulfonyl) phenyl ] acrylic acid (100mg) and 2-aminothiazole (26.7mg) obtained in example 20 according to the procedure of example 5 was (E) -3- [ (1 α,3 α,4 α) -3, 4-difluorocyclopentyl ] -2- [4- (2-methoxyethylsulfonyl) phenyl ] -N- (thiazol-2-yl) acrylamide (44.8 mg).

¹H NMR(400MHz，CDCl₃)δ1.90-2.20(m，4H)，2.38-2.52(m，1H)，3.31(s，3H)，3.48(t，J＝5.8Hz，2H)，3.87(t，J＝5.8Hz，2H)，4.72-4.95(m，2H)，7.01(d，J＝3.7Hz，1H)，7.26(d，J＝10.4Hz，1H)，7.40(d，J＝3.7Hz，1H)，7.45(d，J＝7.9Hz，2H)，8.05(d，J＝7.9Hz，2H)，8.63(brs，1H).

MS(ESI⁺)m/z：457.1(MH⁺).

C₂₀H₂₃F₂N₂O₄S₂(MH⁺) HRMS (ESI)⁺): calculated value, 457.10673; found 457.10653.

Example 22

Compounds 2D and 3D of the present invention were prepared by the same procedure as in example 21.

[ Table 38]

Example 23

2- (5- { (E) -2- [4- (cyclopropylsulfonyl) phenyl]-3- [ (1 α,3 α,4 α) -3, 4-difluorocyclopentyl]Propylene (PA) Amide } pyrazin-2-yloxy) acetic acid ethyl ester

First step of

5- (4-methoxybenzyloxy) pyrazin-2-amine

To 4-methoxybenzyl alcohol (2.14mL) was added sodium hydride (oily, 60%) (78.8mg) at room temperature under an argon atmosphere, and the mixture was stirred for 30 minutes under the conditions. Subsequently, the reaction mixture was transferred to a metal sealed tube, and copper powder (146mg) and 2-amino-5-bromopyrazine (300mg) were added thereto, followed by heating and stirring at 160 ℃ for about 6 hours. After cooling, 25% aqueous ammonia and water were added to the reaction mixture, and the mixture was stirred at room temperature for 1 hour, and the reaction mixture was filtered through celite. Water (20mL) was added to the filtrate, and extraction was performed with ethyl acetate (20 mL. times.3). The organic layer was washed with saturated brine (50mL), dried over anhydrous sodium sulfate, filtered, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (eluting solvent: hexane: ethyl acetate ═ 3: 1) to give 5- (4-methoxybenzyloxy) pyrazin-2-amine (104 mg).

¹H NMR(CHCl₃，400MHz)·3.81(s，3H)，4.12(brs，2H)，5.21(s，2H)，6.90(d，J＝8.5Hz，2H)，7.37(d，J＝8.5Hz，2H)，7.56(d，J＝1.2Hz，1H)，7.79(d，J＝1.2Hz，1H).

MS(EI)m/z：231.1(M⁺).

C₁₂H₁₃N₃O₂(M⁺) HRMS (EI)⁺): calculated value, 231.1008; found 231.0988.

Second step of

(E) -2- [4- (cyclopropylsulfonyl) phenyl]-3- [ (1 α,3 α,4 α) -3, 4-difluorocyclopentyl]-N- [5- (4-methyl) Oxybenzyloxy) pyrazin-2-yl]Acrylamide

To a solution of the acid chloride (146mg) of (E) -2- [4- (cyclopropylsulfonyl) phenyl ] -3- [ (1 α,3 α,4 α) -3, 4-difluorocyclopentyl ] acrylic acid obtained in example 10 in dehydrated tetrahydrofuran (0.49mL) was added dropwise a dehydrated pyridine solution (0.49mL) of 5- (4-methoxybenzyloxy) pyrazine-2-amine (90mg) at room temperature under an argon atmosphere, and the mixture was stirred at room temperature for about 2 hours, ethyl acetate was added to the reaction mixture, the mixture was washed with a 10% aqueous solution of citric acid, the organic layer was washed with a saturated aqueous solution of sodium bicarbonate (10mL × 2), the organic layer was washed with a saturated aqueous solution of sodium chloride (10mL), then dried over anhydrous sodium sulfate, and the solvent was removed by filtration and distillation under reduced pressure, and the residue was purified by silica gel column chromatography (eluting solvent: hexane: ethyl acetate: 1), whereby (E) -2- [4- (cyclopropylsulfonyl) phenyl ] -3- [ (1 α,3 α,4 α) -3, 4-difluorocyclopentyl ] -N- [5- (4-methoxybenzyloxy) pyrazine (160 mg-2-based) pyrazine was obtained.

¹H NMR(CHCl₃，400MHz)·1.10-1.17(m，2H)，1.40-1.48(m，2H)，1.94-2.20(m，4H)，2.36-2.49(m，1H)，2.51-2.59(m，1H)，3.81(s，3H)，4.72-4.94(m，2H)，5.32(s，2H)，6.90(d，J＝8.5Hz，2H)，7.15(d，J＝10.3Hz，1H)，7.38(d，J＝8.5Hz，2H)，7.44(brs，1H)，7.46(d，J＝8.5Hz，2H)，7.86(d，J＝1.2Hz，1H)，8.02(d，J＝8.5Hz，2H)，9.13(d，J＝1.2Hz，1H).

MS(ESI⁺)m/z：570.2(MH⁺).

C₂₉H₃₀F₂N₃O₅S(MH⁺) HRMS (ESI)⁺): calculated value, 570.18742; found 570.18681.

Third Process

(E) -2- [4- (cyclopropylsulfonyl) phenyl]-3- [ (1 α,3 α,4 α) -3, 4-difluorocyclopentyl]-N- (5-hydroxy) Pyrazin-2-yl) acrylamides

Trifluoroacetic acid (1mL) was added to a dehydrated dichloromethane solution (1mL) of (E) -2- [4- (cyclopropylsulfonyl) phenyl ] -3- [ (1 α,3 α,4 α) -3, 4-difluorocyclopentyl ] -N- [5- (4-methoxybenzyloxy) pyrazin-2-yl ] acrylamide (100mg) at room temperature under an argon atmosphere, followed by stirring for 5 minutes, a saturated aqueous sodium bicarbonate solution was added to the reaction mixture to adjust the pH to 8, chloroform extraction (20mL × 2) was performed, the organic layer was washed with saturated brine (20mL), dried over anhydrous sodium sulfate, filtered, and the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (eluting solvent: chloroform: acetone ═ 5: 1) to give (E) -2- [4- (cyclopropylsulfonyl) phenyl ] -3- [ (1 α,3 α,4 α) -3, 4-difluorocyclopentyl ] -N- (5-hydroxypyrazin-2-yl) acrylamide (41 mg).

¹H NMR(CHCl₃，400MHz)·1.11-1.18(m，2H)，1.41-1.48(m，2H)，1.92-2.18(m，4H)，2.36-2.49(m，1H)，2.52-2.60(m，1H)，4.74-4.95(m，2H)，7.11(d，J＝10.9Hz，1H)，7.28(brs，1H)，7.44(d，J＝8.5Hz，2H)，7.95(d，J＝1.2Hz，1H)，8.03(d，J＝8.5Hz，2H)，8.48(d，J＝1.2Hz，1H).

MS(ESI⁺)m/z：450.1(MH⁺).

C₂₁H₂₂F₂N₃O₄S(MH⁺) HRMS (ESI)⁺): calculated value, 450.12991; found 450.12959.

The fourth step

Ethyl bromoacetate (74 μ L) and silver oxide (92.9mg) were added to a dehydrated toluene solution (5mL) of (E) -2- [4- (cyclopropylsulfonyl) phenyl ] -3- [ (1 α,3 α,4 α) -3, 4-difluorocyclopentyl ] -N- (5-hydroxypyrazin-2-yl) acrylamide (150mg) at room temperature under an argon atmosphere, and the mixture was heated and stirred at 100 ℃ for about 22 hours under an argon atmosphere, then the reaction mixture was filtered with celite after cooling, and the solvent was removed by distillation under reduced pressure after filtration.

IR(ATR)3300，2983，1746，1666，1603，1519，1400，1375，1353，1316，1292，1208，1186，1140，1087，1044，1025，994，972cm^-1.

¹H NMR(CHCl₃，400MHz)·1.11-1.18(m，2H)，1.29(t，J＝7.3Hz，3H)，1.41-1.48(m，2H)，1.92-2.20(m，4H)，2.35-2.48(m，1H)，2.52-2.60(m，1H)，4.24(q，J＝7.3Hz，2H)，4.73-4.95(m，2H)，4.90(s，2H)，7.15(d，J＝10.3Hz，1H)，7.45(d，J＝8.5Hz，2H)，7.47(brs，1H)，7.98(d，J＝1.2Hz，1H)，8.03(d，J＝8.5Hz，2H)，9.08(d，J＝1.2Hz，1H).

MS(ESI⁺)m/z：536.2(MH⁺).

C₂₅H₂₈F₂N₃O₆S(MH⁺) HRMS (ESI)⁺): calculated value, 536.16696; found 536.16654.

Example 24

2- [5- { (E) -2- [4- [ cyclopropylsulfonyl) phenyl]-3- [ (1 α,3 α,4 α) -3, 4-difluorocyclopentyl]Propylene (PA) Amide } pyrazin-2-yloxy) acetic acid

IR(ATR)3304，2942，2535，1729，1665，1609，1520，1469，1437，1360，1314，1288，1239，1200，1177，1141，1071，1048，1028，994，973cm^-1.

¹H NMR(DMSO，400MHz)·1.00-1.18(m、4H)，1.81-2.00(m、2H)，2.06-2.25(m、2H)，2.45-2.60(m、1H)，2.85-2.92(m、1H)，4.83(s、2H)，4.83-5.06(m、2H)，6.69(d，J＝10.3Hz，1H)，7.47(d，J＝8.5Hz，2H)，7.89(d，J＝8.5Hz，2H)，8.21(d，J＝1.2Hz，1H)，8.72(d，J＝1.2Hz，1H)，10.7(s，1H)，13.0(brs，1H).

MS(ESI⁺)m/z：508.1(MH⁺).

C₂₃H₂₄F₂N₃O₆S(MH⁺) HRMS (ESI)⁺): calculated value, 508.13539; found 508.13523.

Reference example 1

(1 α,3 α,4 α) -3, 4-Difluorocyclopentyl methyltriphenylphosphonium iodide

First step of

Benzoic acid [ (1 α,3 β,4 β) -3, 4-dihydroxyl cyclopentyl group]Methyl ester

N-methylmorpholine N-oxide (50% aqueous solution, 22.0mL) and osmium tetroxide (2.5% tert-butanol solution, 1.90mL) were dissolved in acetone (190mL), and a solution of benzoic acid (3-cyclopenten-1-yl) methyl ester (WO93/18009, Japanese patent application publication Hei 7-506816) (20.2g) in acetone (125mL) was added dropwise over 105 minutes with stirring, followed by stirring at room temperature for 15 hours, chloroform (310mL) and water (190mL) were added to the reaction mixture, and the organic layer was separated, and the separated organic layer was washed with 1mol/L hydrochloric acid (2X 90mL), water (90mL) and a saturated aqueous sodium bicarbonate solution (60mL) in this order, dried over anhydrous sodium sulfate, concentrated under reduced pressure, toluene (120mL) was added to the residue, and crystals were collected by filtration to give [ (1 α,3 β,4 β) -3, 4-dihydroxycyclopentyl ] methyl ester (16.9 g).

¹H NMR(CDCl₃)δ1.71-1.78(m，2H)，1.95-2.02(m，2H)，2.27(br，2H)，2.75-2.87(m，1H)，4.19-4.23(m，4H)，7.43-7.47(m，2H)，7.55-7.59(m，1H)，8.01-8.04(m，2H).

Concentrating the filtrate under reduced pressure to obtain benzoic acid [ (1 α,3 β,4 β) -3, 4-dihydroxyl cyclopentyl group]Methyl ester and benzoic acid [ (1 β,3 β,4 β) -3, 4-dihydroxycyclopentyl [ ]]A mixture of methyl esters (4.23g,according to¹H NMR, in an integrated ratio of about 1: 2).

¹H NMR(CDCl₃)δ1.58-1.65(m，1.3H)，1.71-1.78(m，0.7H)，1.96-2.17(m，2H)，2.75-2.85(m，1H)，4.09-4.32(m，4H)，7.42-7.46(m，2H)，7.54-7.59(m，1H)，8.01-8.06(m，2H).

Second step of

Benzoic acid (3a α, 5 α, 6a α) - (tetrahydro-4H-cyclopenta-1, 3, 2-dioxathia-5-yl) methyl ester S, S-bis Oxide compound

((3aα，5α，6aα)-(tetrahydro-4H-cyclopenta-1，3，2-thioxathiol-5-yl)methylbenzoate S，S-dioxide)

After suspending benzoic acid [ (1 α,3 β,4 β) -3, 4-dihydroxycyclopentyl ] methyl ester (5.00g) in carbon tetrachloride (75mL), adding thionyl chloride (1.90mL), heating under reflux for 1.5 hours with stirring, adding thionyl chloride (0.50mL) to the reaction mixture, heating under reflux for another 1 hour with stirring, concentrating the reaction mixture under reduced pressure, adding toluene (25mL) to the residue, concentrating under reduced pressure, and drying under reduced pressure to obtain benzoic acid (3a β, 5 β 1, 6a α) - (tetrahydro-4H-cyclopenta-1, 3, 2-dioxathia-5-yl) methyl ester S-oxide (6.09g), mixing the obtained benzoic acid (3a α, 5 α, 6a α) - (tetrahydro-4H-cyclopenta-1, 3, 2-dioxathia-5-yl) methyl ester S-oxide (4.27g), acetonitrile (30mL) and ruthenium (30mL), adding sodium tetrachloride (6 x α) - (tetrahydro-4H-cyclopenta-1, 3, 2-dioxathia-thia-5-yl) methyl ester S-oxide (4.27g), washing the obtained mixture with water, removing water, filtering, and drying the organic sodium chloride (30mL), removing water insoluble), filtering, 3 a) and drying the organic extract (30mL), and concentrating the filtrate (30 mL).

MS(CI⁺)m/z：299(MH⁺).

C₁₃H₁₅O₆S(MH⁺) HRMS (CI)⁺): calculated value, 299.0589; found 299.0593.

Third Process

Benzoic acid [ (1 α,3 α,4 β) -3-fluoro-4-hydroxycyclopentyl group]Methyl ester

Tetrabutylammonium fluoride hydrate (571mg) was dissolved in dehydrated acetonitrile (5mL), concentrated under reduced pressure, the same operation was repeated 2 times, and then the residue was dried under reduced pressure at 40 ℃ for 45 minutes, the residue was dissolved in dehydrated acetonitrile (5mL), benzoic acid (3a α, 5 α, 6a α) - (tetrahydro-4H-cyclopenta-1, 3, 2-dioxathia-5-yl) methyl ester S, S-dioxide (500mg) was added, the reaction mixture was heated under reflux for 45 minutes with stirring, the residue was dissolved in ethanol (5mL), sulfuric acid (0.15mL) was added, the reaction mixture was heated under reflux for 10 minutes with stirring, the residue was concentrated under reduced pressure, the residue was dissolved in ethyl acetate (40mL), washed with a saturated aqueous sodium bicarbonate solution (5mL), then with a saturated brine (5mL), dried with anhydrous sodium sulfate, and concentrated under reduced pressure, and a silica gel column (elution solvent: hexane/ethyl acetate: 1) was purified to obtain benzoic acid [ (1: 3, 3-cyclopentyl) methyl ester (α, 3-364-cyclopentyl) using silicon fluoride (342 mg).

MS(EI)m/z：238(M⁺).

C₁₃H₁₅FO₃(M⁺) Hrms (ei): calculated value, 238.1005; found 238.1046.

The fourth step

Benzoic acid [ (1 α,3 α,4 α) -3, 4-difluoro-cyclopentyl]Methyl ester

Benzoic acid [ (1 α,3 α,4 β) -3-fluoro-4-hydroxycyclopentyl ] methyl ester (326mg) was dissolved in dehydrated tetrahydrofuran (5mL), a solution of bis (2-methoxyethyl) aminosulfur trifluoride (455mg) in dehydrated tetrahydrofuran (2mL) was added, and the mixture was refluxed under stirring for 1.5 hours, the reaction mixture was added to a saturated aqueous sodium bicarbonate solution (10mL), extracted with ethyl acetate (2 × 30mL), the ethyl acetate extracts were combined, washed with a saturated saline solution (2 × 10mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure, and the residue was purified with a silica gel column (elution solvent: hexane/ethyl acetate: 4: 1) to give benzoic acid [ (1 α,3 α,4 α) -3, 4-difluoro-cyclopentyl ] methyl ester (233 mg).

MS(CI⁺)m/z：241(MH⁺).

C₁₃H₁₅F₂O₂(MH⁺) HRMS (CI)⁺): calculated value, 241.1040; found 241.1043.

The fifth step

[ (1 α,3 α,4 α) -3, 4-difluorocyclopentyl]Methanol

After dissolving [ (1 α,3 α,4 α) -3, 4-difluorocyclopentyl ] methyl benzoate (221mg) in ethanol (3mL), adding a solution of potassium carbonate (191mg) in water (1mL), and heating under reflux with stirring for 4 hours, the reaction mixture was concentrated under reduced pressure, and the residue was purified by a silica gel column (elution solvent: hexane/ethyl acetate ═ 1: 2), to give [ (1 α,3 α,4 α) -3, 4-difluorocyclopentyl ] methanol (123 mg).

MS(CI⁺)m/z：137(MH⁺).

C₆H₁₁F₂O(MH⁺) HRMS (CI)⁺): calculated value, 137.0778; found 137.0801.

The sixth step

(1 α,3 α,4 α) -3,4- α difluorocyclopentylmethyl iodide

Iodine (120mg) was added to a dichloromethane solution (2.0mL) of imidazole (64.5mg) and triphenylphosphine (124mg) under ice-cooling, and after stirring at room temperature for 30 minutes, a dichloromethane solution (0.5mL) of [ (1 α,3 α,4 α) -3, 4-difluorocyclopentyl ] methanol (43.0mg) was added, and after stirring at room temperature for 4 hours, insoluble matter was removed by filtration, the filtrate was concentrated, and the resulting residue was purified by silica gel column chromatography to give (1 α,3 α,4 α) -3, 4-difluorocyclopentylmethyl iodide (28.0 mg).

MS(EI)m/z：246(M⁺).

C₆H₉F₂I(M⁺) Hrms (ei): calculated value, 245.9717; found 245.9741.

Seventh Process

(1 α,3 α,4 α) - (3, 4-difluorocyclopentyl) methyltriphenylphosphonium iodide

(1 α,3 α,4 α) - (3, 4-difluorocyclopentyl) methyl iodide (9.84g), triphenylphosphine (12.6g) and acetonitrile (3mL) were mixed, and the mixture was stirred at 90 to 95 ℃ for 4 hours, acetonitrile (2mL) was added to the reaction mixture, and the mixture was further stirred at 90 to 95 ℃ for 20 hours, after cooling, diethyl ether (50mL) was added to the reaction mixture, and the precipitated crystal was collected by filtration, suspended in diethyl ether (50mL), collected by filtration, washed with an appropriate amount of diethyl ether, and dried under reduced pressure to obtain the title compound (20 g).

¹H NMR(400MHz，CDCl₃)δ1.72-1.85(m，2H)，2.17-2.29(m，2H)，2.69-2.82(m，1H)，3.86(dd，J＝7.3，2.4Hz，1H)，3.89(dd，J＝7.3，2.4Hz，1H)，4.74-4.92(m，2H)，7.31-7.90(m，15H).

Reference example 2

2- (5-Aminopyrazin-2-ylthio) ethanol

2-hydroxy-1-ethanethiol (0.93mL) and tetrakis (triphenylphosphine) palladium (3.39g) were added to a solution of 2-amino-5-bromopyrazine (1.00g, 5.75mmoL) in N, N-dimethylformamide (15.1mL) by the method described in WO2004/052869, followed by heating and stirring at 120 ℃ for about 3 hours in a sealed tube. After cooling, the reaction mixture was diluted with water and extracted with a mixture (dichloromethane: ethanol ═ 5: 1) (100mL × 6). The organic layer was dried over anhydrous sodium sulfate, filtered, and the solvent was distilled off under reduced pressure. The residue was purified by column chromatography (hexane: ethyl acetate 1: 1, then ethyl acetate: methanol 10: 1), followed by recrystallization (chloroform) to give 470mg of the title compound as yellow needle crystals (yield 44%).

MS(EI⁺)m/z：171(M⁺).

C₆H₉N₃OS(M⁺) HRMS (EI)⁺): calculated value, 171.0466; found 171.0451.

Reference example 3

5- [2- (methylthio) ethoxy group]Pyrazin-2-amines

To methylthioethanol (7.88mL) was added sodium hydride (50% oil) (314mg) followed by copper (490mg) and 2-amino-5-bromopyrazine (1.00g) with ice-cold stirring, using the method described in WO2007007886 as a reference. The reaction mixture was charged into an autoclave and heated and stirred at 160 ℃ for about 5 hours. After cooling, the reaction mixture was diluted with water (50mL) and ethyl acetate (50mL), and then 25% aqueous ammonia (2mL) was added to make it basic. The reaction mixture was filtered through celite, and the layers were separated into an organic layer and an aqueous layer. The aqueous layer was extracted with ethyl acetate (50mL × 2), and the combined organic layers were dried over anhydrous sodium sulfate, filtered, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate 1: 1) followed by preparative thin layer chromatography (preparative TLC) (chloroform: methanol 10: 1, then NH silica gel, hexane: acetone 3: 1) to give 59.2mg of the title compound as white powdery crystals (yield 6%).

MS(EI⁺)m/z：185(M⁺).

C₇H₁₁N₃OS(M⁺) HRMS (EI)⁺): calculated value, 185.0623; found 185.0613.

Reference example 4

5- (2-ethoxyethoxy) pyrazin-2-amine

From 2-amino-5-bromopyrazine (3.48g) and ethoxyethanol (36.0g), 1.50g of the title compound was obtained as yellow crystals (yield 41%) according to the procedure of reference example 3.

MS(EI⁺)m/z：183(M⁺).

C₈H₁₃N₃O₂(M⁺) HRMS (EI)⁺): calculated value, 183.1008; found 183.0996.

Reference example 5

5- (3-methoxypropoxy) pyrazin-2-amine

The title compound was obtained as yellow crystals (yield 18%) 644mg from 2-amino-5-bromopyrazine (3.48g) and methoxypropanol (18.0g) according to the method of reference example 3.

MS(EI⁺)m/z：183(M⁺).

C₈H₁₃N₃O₂(M⁺) HRMS (EI)⁺): calculated value, 183.1008; found 183.1011.

Reference example 6

5- [2- (dimethylamino) ethoxy]Pyrazin-2-amines

From 2-amino-5-bromopyrazine (500mg) and 2-dimethylaminoethanol (2.56g), 121mg of the title compound was obtained as a yellow oil (yield 23%) according to the method of reference example 3.

MS(CI)m/z：183(MH⁺).

C₈H₁₅N₄O(MH⁺) Hrms (ci): calculated value, 183.1246; found 183.1242.

¹H NMR(400MHz，CDCl₃)δ2.33(s，6H)，2.70(t，J＝5.8Hz，2H)，4.12(brs，2H)，4.31(t，J＝5.8Hz，2H)，7.53(d，J＝1.2Hz，1H)，7.80(d，J＝1.2Hz，1H).

IR(ATR)：1280，1630，3330cm^-1.

Reference example 7

5- [ 2-methyl-2- (tetrahydro-2H-pyran-2-yloxy) propoxy]Pyrazin-2-amines

From 2-amino-5-bromopyrazine (299mg) and 2-methyl-2- [ (tetrahydro-2H-pyran-2-yl) oxy ] -1-propanol (1.50g) according to the process of reference example 3, 60mg of the title compound was obtained as crystals in the form of brown powder (yield 13%).

MS(CI)m/z：268(MH⁺).

C₁₃H₂₂N₃O₃(MH⁺) Hrms (ci): calculated value, 268.1661; found 268.1645.

¹H NMR(400MHz，CDCl₃)δ1.35(s，6H)，1.46-1.52(m，4H)，1.59-1.72(m，1H)，1.76-1.88(m，1H)，3.43(td，J＝8.3，4.3Hz，1H)，3.94(ddd，J＝11.6，5.2，3.7Hz，1H)，4.11(d，J＝10.4Hz，1H)，4.16(d，J＝10.4Hz，1H)，4.21(s，2H)，4.88(q，J＝2.9Hz，1H)，7.54(d，J＝1.8Hz，1H)，7.79(d，J＝1.8Hz，1H).

IR(ATR)：1620，1487，1379cm^-1.

Reference example 8

1- [2- (dimethylamino) -2-methylpropyl]-1H-pyrazol-3-amine

To a dehydrated DMF solution (2mL) of 3-nitro-1H-pyrazole (196mg) was added sodium hydride (156mg) under ice-cooling, and the mixture was stirred at room temperature for 15 minutes. Then, a DMF solution of 1-chloro-N, N, 2-trimethylpropane-2-amine (0.52mL) was added and the mixture was stirred at room temperature for about 24 hours. While the reaction mixture was cooled in ice, a saturated aqueous ammonium chloride solution (25mL) and ethyl acetate (25mL) were added thereto, and the mixture was stirred to separate layers. The organic layer was washed with saturated brine (100mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (silica gel, neutral sphere, ethyl acetate: hexane ═ 1: 1), to give 90.9mg of N, 2-trimethyl-1- (3-nitro-1H-pyrazol-1-yl) propan-2-amine as yellow powdery crystals (yield 2%).

MS(CI)m/z：213(MH⁺).

C₉H₁₇N₄O₂(MH⁺) Hrms (ci): calculated value, 213.1352; found 213.1314.

N, N, 2-trimethyl-1- (3-nitro-1H-pyrazol-1-yl) propan-2-amine (70.6mg) was dissolved in an ethanol-ethyl acetate mixture (4: 1, 5mL), and 10% palladium on carbon (7mg) was added to conduct catalytic reduction at 101kPa for about 2 hours. The reaction mixture was filtered through celite, the filtrate was removed by distillation under the reduced pressure, and the resulting residue was purified by silica gel column chromatography (silica gel NH, ethyl acetate: hexane ═ 1: 1) to give 56.8mg of the title compound as a yellow oil (yield 94%).

MS(CI)m/z：183(MH⁺).

C₉H₁₄N₄(MH⁺) Hrms (ci): calculated value, 183.1610; found 183.1615.

¹H NMR(400MHz，CDCl₃)δ1.50(s，6H)，2.03(s，6H)，2.53(s，2H)，3.59(s，2H)，5.56(d，J＝2.4Hz，1H)，7.28(d，J＝2.4Hz，1H).

IR(ATR)：1617，1541，1492cm^-1.

Reference example 9

5- (2-bromoethylthio) thiazol-2-amine

Triphenylphosphine (12.1g), imidazole (3.86g), and carbon tetrachloride (4.44g) were added to a suspension of 5- (2-hydroxyethylthio) thiazol-2-amine (2.00g) in dichloromethane (74.6mL) under ice-cooling, and the mixture was stirred under ice-cooling for 4 hours. Methylene chloride (200mL) and water (100mL) were added to the reaction mixture for extraction. The organic layer was washed with saturated brine (100mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (neutral spherical silica gel, ethyl acetate: hexane: 1: 10, then 1: 2) and washed with hexane to give 1.06g of the title compound as a white powder crystalline (yield 39%).

MS(EI)m/z：238(M⁺).

C₅H₇BrN₂S₂(M⁺) Hrms (ei): calculated value, 237.9234; found 237.9212.

Reference example 10

5- (3-Bromopropylthio) thiazol-2-amine

According to the method of reference example 9, 450mg of the title compound (yield 7%) was obtained as a yellow oil from 5- (3-hydroxypropylthio) thiazol-2-amine (5.00 g).

MS(ESI)m/z：253(MH⁺).

C₆H₁₀BrN₂S₂(M⁺) Hrms (esi): calculated value, 252.94688; found 252.94629.

Reference example 11

5- [2- (4-methylpiperazin-1-yl) ethylthio group]Thiazol-2-amines

To the compound (150mg) in reference example 9 was added 1-methylpiperazine (3.47mL), and the mixture was stirred at 60 ℃ for 2 hours. After cooling, the reaction mixture was concentrated under reduced pressure, and methylene chloride (10mL) and a saturated aqueous solution of sodium hydrogencarbonate (10mL) were added to the residue to conduct extraction. The mixture was extracted 2 times, and the combined organic layers were washed with saturated brine (7mL), dried over anhydrous sodium sulfate, filtered, and distilled under reduced pressure. The resulting amorphous was washed with diisopropyl ether to give 137mg of the title compound as crystals as a white powder (yield 84%).

The melting point is 106-108 DEG C

EIMSm/z：258(M⁺).

C₁₀H₁₈N₄S₂(M⁺) Hrms (ei): calculated value, 258.0973; found 258.0978.

¹H NMR(400MHz，CDCl₃)δ2.28(s，3H)，2.35-2.57(m，8H)，2.61(dd，J＝8.0，4.3Hz，2H)，2.77(dd，J＝8.0，4.3Hz，2H)，4.95(s，2H)，7.09(s，1H).

IR(ATR)：1653，1527，1485cm^-1.

Reference example 12

(S) -5- [2- (3-fluoropyrrolidin-1-yl) ethylthio group]Thiazol-2-amines

According to the method of reference example 11, 82.3mg of the title compound (yield 40%) as white powdery crystals were obtained from the compound of reference example 9 (200mg), (S) -3-fluoropyrrolidine hydrochloride (210mg) and triethylamine (0.50 mL).

The melting point is 144-145 DEG C

[α]_D ²⁴-4°(c0.41，DMSO)

EIMSm/z：247(M⁺).

C₉H₁₄FN₃S₂(M⁺) Hrms (ei): calculated value, 247.0613; found 247.0646.

¹H NMR(400MHz，CDCl₃)δ1.94-2.22(m，2H)，2.42-2.51(m，1H)，2.70-2.91(m，7H)，4.99(s，2H)，5.06-5.25(m，1H)，7.10(s，1H).

IR(ATR)：1649，1533，1491cm^-1.

Reference example 13

(R) -5- [2- (3-fluoropyrrolidin-1-yl) ethylthio]Thiazol-2-amines

From the compound (200mg), (R) -3-fluoropyrrolidine hydrochloride (210mg) and triethylamine (0.50mL) of reference example 9 according to the process of reference example 11, 98.8mg of the title compound (yield 48%) as white powdery crystals were obtained.

Melting Point 147 deg.C

[α]_D ²³+3°(c0.43，DMSO)

EIMSm/z：247(M⁺).

C₉H₁₄FN₃S₂(M⁺) Hrms (ei): calculated value, 247.0613; found 247.0622.

IR(ATR)：1649，1533，1491cm^-1.

Reference example 14

5- [2- (4, 4-Difluoropiperidin-1-yl) ethylthio]Thiazol-2-amines

From the compound (200mg) of referential example 9, 4-difluoropiperidine hydrochloride (263mg) and triethylamine (0.50mL) according to the process of referential example 11, 68.9mg of the title compound (yield 30%) were obtained as white powdery crystals.

Melting Point 127 deg.C

EIMSm/z：279(M⁺).

C₁₀H₁₅F₂N₃S₂(M⁺) Hrms (ei): calculated value, 279.0675; found 279.0679.

¹H NMR(400MHz，CDCl₃)δ1.93-2.06(m，4H)，2.56(t，J＝5.5Hz，4H)，2.64(dd，J＝8.9，5.8Hz，2H)，2.76(dd，J＝8.9，5.8Hz，2H)，5.21(s，2H)，7.08(s，1H).

IR(ATR)：1609，1519，1478cm^-1.

Reference example 15

1- [2- (2-Aminothiazol-5-ylthio) ethyl]Piperidine-4-carboxylic acid ethyl ester

The title compound was obtained as crystals as a white powder (150mg) from the compound (150mg) in referential example 9 and ethyl piperidine-4-carboxylate (4.83mL) according to the process of referential example 11 (yield 76%).

The melting point is 80-81 DEG C

MS(CI)m/z：316(MH⁺).

C₁₃H₂₂N₃O₂S₂(MH⁺) Hrms (ci): calculated value, 316.1153; found 316.1141.

¹H NMR(400MHz，CDCl₃)δ1.25(t，J＝7.1Hz，3H)，1.68-1.80(m，2H)，1.82-1.92(m，2H)，2.04-2.10(m，2H)，2.21-2.31(m，1H)，2.55-2.59(m，2H)，2.75-2.80(m，2H)，2.80-2.88(m，2H)，4.13(q，J＝7.1Hz，2H)，5.00(s，2H)，7.08(s，1H).

IR(ATR)：1707，1524，1448cm^-1.

Reference example 16

(S) - {1- [2- (2-Aminothiazol-5-ylthio) ethyl]Pyrrolidin-2-yl } methanol

According to the method of reference example 11, 130mg of the title compound (yield 80%) as white powdery crystals were obtained from the compound of reference example 9 (150mg) and (S) -pyrrolidin-2-ylmethanol (3.10 mL).

Melting point of 98-99 deg.C

[α]_D ²⁴-90°(c0.54，CHCl₃).

MS(CI)m/z：260(MH⁺).

C₁₀H₁₈N₃OS₂(MH⁺) Hrms (ci): calculated value, 260.0891; found 260.0892.

¹H NMR(400 MHz，CDCl₃)δ1.70-1.95(m，4H)，2.27(q，J＝8.6Hz，1H)，2.53-2.60(m，1H)，2.60-2.68(m，1H)，2.75-2.83(m，2H)，2.90-2.97(m，1H)，3.14-3.20(m，1H)，3.38(dd，J＝11.0，2.4Hz，1H)，3.62(dd，J＝11.0，3.7Hz，1H)，4.96(s，2H)，7.12(s，1H).

IR(ATR)：3161，1516，1498cm^-1.

Reference example 17

5- {2- [ cis-3, 4-difluoropyrrolidin-1-yl]Ethylthio } thiazol-2-amine

Using the compound (200mg) of referential example 9, cis-3, 4-difluoropyrrolidine hydrochloride (100mg) and diisopropylamine (141mg), a reaction was made according to the process of referential example 11, and potassium iodide (12mg) was added in the middle to give 35.0mg of the title compound as white powdery crystals (yield 19%).

MS(CI)m/z：266(MH⁺).

C₉H₁₄F₂N₃S₂(MH⁺) Hrms (ci): calculated value, 266.0597; found 266.0577.

¹H NMR(400MHz，CDCl₃)δ2.71-2.80(m，4H)，2.81-2.94(m，2H)，3.04-3.14(m，2H)，4.89-5.12(m，2H)，5.00(s，2H)，7.09(s，1H).

IR(ATR)：1645，1530，1490em^-1.

Reference example 18

5- {2- [ cis-2, 2-Dimethyltetrahydro-5H-1, 3-Dioxole (dioxolo) [4, 5-c ]]Pyrrole-5- Base of]Ethylthio } thiazol-2-amine

From the compound of referential example 9 (330mg), cis-2, 2-dimethyltetrahydro-5H-1, 3-dioxacyclopenta [4, 5-c ] pyrrole (280mg) according to the process of referential example 11, 127mg of the title compound (yield 30%) were obtained as white powdery crystals.

MS(ESI)m/z：302(MH⁺).

C₁₂H₂₀N₃O₂S₂(MH⁺) Hrms (esi): calculated value, 302.09969; found 302.09926.

¹H NMR(400MHz，CDCl₃)δ1.31(s，3H)，1.52(s，3H)，2.10-2.17(m，2H)，2.62-2.66(m，2H)，2.74-2.78(m，2H)3.06(d，J＝11.6Hz，2H)，4.62-4.65(m，2H)，4.96(s，2H)，7.08(s，1H).

IR(ATR)：1644，1513，1483cm^-1.

Reference example 19

(S) -1- [2- (2-aminothiazol-5-ylthio) ethyl]Pyrrolidine-2-carboxylic acid methyl ester

From the compound (200mg) of referential example 9, methyl (S) -pyrrolidine-2-carboxylate hydrochloride (277mg) and triethylamine (0.50mL) according to the process of referential example 11, 85.7mg of the title compound were obtained as a yellow oil (yield 36%).

[α]_D ²⁵-85°(c0.25，CHCl₃).

MS(CI)m/z：288(MH⁺).

C₁₁H₁₈N₃O₂S₂(MH⁺) Hrms (ci): calculated value, 288.0840; found 288.0837.

¹H NMR(400MHz，DMSO-d₆)δ1.74-1.87(m，1H)，1.87-2.00(m，2H)，2.04-2.18(m，1H)，2.41(q，J＝8.2Hz，1H)，2.66-2.72(m，1H)，2.77(dd，J＝7.9，6.7Hz，2H)，2.90-2.96(m，1H)，3.15(td，J＝8.3，3.1Hz，1H)，3.23(dd，J＝8.6，5.5Hz，1H)，3.71(s，3H)，5.00(s，2H)，7.10(s，1H).

IR(ATR)：3293，3124，2949，2815，1732，1517，1484cm^-1.

Reference example 20

(S) -1- [2- (2-aminothiazol-5-ylthio) ethyl]Pyrrolidine-2-carboxylic acid ethyl ester

From the compound (800mg) of referential example 9, ethyl (S) -pyrrolidine-2-carboxylate hydrochloride (15g) and isopropylamine (9.00g), 580mg of the title compound were obtained as a yellow oil (yield 58%) according to the process of referential example 11.

[α]_D ²⁵-61°(c0.28，CHCl₃).

MS(CI)m/z：302(MH⁺).

C₁₂H₂₀N₃O₂S₂(MH⁺) Hrms (ci): calculated value, 302.0997; found 302.1012.

¹H NMR(400MHz，DMSO-d₆)δ1.27(t，J＝6.7Hz，3H)，1.74-1.85(m，1H)，1.85-2.00(m，2H)，2.05-2.18(m，1H)，2.38-2.48(m，1H)，2.66-2.72(m，1H)，2.77(t，J＝7.3Hz，2H)，2.90-2.97(m，1H)，3.13-3.22(m，2H)，4.17(qd，J＝7.3，1.2Hz，2H)，5.35(s，2H)，7.07(s，1H).

IR(ATR)：1728，1619，1517 cm^-1.

Reference example 21

5- (3- (dimethylamino) propylthio) thiazol-2-amine

According to the method of reference example 11, 53.5mg of the title compound (yield 62%) as colorless powdery crystals were obtained from the compound of reference example 10 (100mg) and dimethylamine (2M methanol solution, 9.90 mL).

MS(APCI)m/z：216(MH⁺).

C₈H₁₄N₃S₂(MH⁺) Hrms (apci): calculated value, 216.06291; found 216.06354.

¹H NMR(400MHz，CDCl₃)δ1.72-1.79(m，2H)，2.20(s，6H)，2.35(t，J＝7.3Hz，2H)，2.68(t，J＝7.3Hz，2H)，5.26(s，2H)，7.07(s，1H).

IR(ATR)：1647，1514，1493cm^-1.

Reference example 22

(Z) -3- [ (1 α,3 α,4 α) -3, 4-difluorocyclopentyl]Acrylic acid ethyl ester

To a solution of [ (1 α,3 α,4 α) - (3, 4-difluorocyclopentyl) methyl ] triphenylphosphonium iodide (20.3g, 40mmol) synthesized in reference example 1 in anhydrous tetrahydrofuran (70mL) was added lithium bis (trimethylsilyl) amide (1mol/L tetrahydrofuran solution, 41.1mL, 41.1mmol) under an argon atmosphere at 4 ℃, followed by stirring at that temperature for 1 hour, then, a solution of ethyl glyoxylate (4.24g, 41.5mmol) in anhydrous tetrahydrofuran (50mL) was added at 4 ℃, followed by stirring at room temperature for 24 hours, then, water (20mL) was added at 4 ℃, followed by addition of 1mol/L aqueous hydrochloric acid, the organic layer was concentrated under reduced pressure, the residue was extracted with ethyl acetate, washed with saturated saline, dried with anhydrous sodium sulfate, and concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (ethyl acetate: hexane: 1: 4) to give 5.25g of the title compound as a pale yellow light yellow oil.

MS(EI⁺)m/z：204(M⁺).

C₁₀H₁₄F₂O₂(M⁺) HRMS (EI)⁺): calculated value, 204.0962; found 204.0942.

¹H NMR(400MHz，CDCl₃)δ1.29(t，J＝7.1Hz，3H)，1.74-1.90(m，2H)，2.26-2.42(m，2H)，3.84-3.98(m，1H)，4.16(q，J＝7.1Hz，2H)，4.80-4.90(m，1H)，4.92-5.02(m，1H)，5.74(dd，J＝11.6，1.2Hz，1H)，6.22(dd，J＝11.0，9.8Hz，1H).

Reference example 23

(Z) -2-bromo-3- [ (1 α,3 α,4 α) -3, 4-difluorocyclopentyl]Acrylic acid ethyl ester

To a solution of the compound (5.00g, 24.5mmol) obtained in reference example 22 in carbon tetrachloride (15mL) at-6 ℃ under an argon atmosphere was added bromine (1.19mL, 23.2 mmol 1), and the mixture was stirred at room temperature for 7 hours. The reaction mixture was concentrated under reduced pressure, and anhydrous dichloromethane (40mL) was added to the residue. Then, triethylamine (4.10mL, 29.4mmol) was added at 4 ℃ under an argon atmosphere, and the mixture was stirred at room temperature for 12 hours. After the reaction mixture was separated by adding water, the aqueous layer was extracted with dichloromethane, the organic layers were combined, washed with 1mol/L aqueous hydrochloric acid, then with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: hexane ═ 1: 5) to give 7.33g of the title compound as a colorless oil.

MS(EI⁺)m/z：282(M⁺).

C₁₀H₁₃BrF₂O₂(M⁺) HRMS (EI)⁺): calculated value, 282.0067, respectively; found 282.0081.

¹H NMR(400MHz，CDCl₃)δ1.34(t，J＝7.3Hz，3H)，1.86-2.02(m，2H)，2.28-2.44(m，2H)，3.08-3.20(m，1H)，4.29(q，J＝7.3Hz，2H)，4.84-4.94(m，1H)，4.96-5.06(m，1H)，7.29(d，J＝9.2Hz，1H).

Reference example 24

(E) -3- [ (1 α,3 α,4 α) -3, 4-difluorocyclopentyl]-2- [4- (methylsulfonyl) phenyl]Acrylic acid ethyl ester

To a solution of 4-bromomethylsulfonylbenzene (79.0mg, 0.33mmo1) in dimethylformamide (1mL) were added pinacol diboron (88.0mg, 0.35mmol), 1-bis (diphenylphosphino) ferrocene-palladium (II) dichloride (8mg) and potassium acetate (98.0mg, 1.00mmol), and stirred at 120 ℃ for 80 minutes under an argon atmosphere, then, (Z) -2-bromo-3- [ (1 α,3 α,4 α) -3, 4-difluorocyclopentyl ] acrylic acid ethyl ester (100.0mg, 0.33mmo1), 1-bis (diphenylphosphino) ferrocene-palladium (II) dichloride (10mg) and 2mol/L aqueous sodium carbonate solution (1mL) were added, stirred at 80 ℃ for 2 hours under an argon atmosphere, water was added to the reaction mixture, extraction was performed with ethyl acetate, the organic layer was washed with water and brine in this order, dried over anhydrous sodium sulfate, followed by reduced pressure concentration, silica gel column chromatography (ethyl acetate: 1mg, hexane) to separate the title compound.

Reference example 25

(E) -3- [ (1 β,3 α,4 α) -3, 4-difluorocyclopentyl]-2- [4- (methylsulfonyl) phenyl]-N- (thiazole-2-) Based) acrylamide(comparative Compound 1)

(1 β,3 α,4 α) - (3, 4-difluorocyclopentyl) methyltriphenylphosphonium iodide was synthesized by using [ (1 α,3 β,4 β) -3, 4-dihydroxycyclopentyl ] methyl benzoate obtained in the first step of reference example 1 and reacting in the same manner as in the second to seventh steps of reference example 1, and the title compound was obtained by carrying out the conversion of example 1 to example 5.

Reference example 26

(E) -3- [ (3 α,4 β) -3, 4-difluorocyclopentyl]-2- [4- (methylsulfonyl) phenyl]-N- (thiazol-2-yl) propan Alkeneamides(comparative Compound 2) and

(E) -3- [ (3 β,4 α) -3, 4-difluorocyclopentyl]-2- [4- (methylsulfonyl) phenyl]-N- (thiazol-2-yl) propan Alkeneamides(comparative Compound 3)

The benzoic acid [ (1 α,3 α,4 β) -3-fluoro-4-hydroxycyclopentyl ] obtained in the third step of reference example 1 was used]After the methyl ester is inverted in configuration by a Mitsunobu reaction (Mitsunobu reaction) of the hydroxyl group, it is fluorinated in the same manner as in the fourth step of reference example 1, and then converted into a carboxylic acid compound by hydrolysis of the ester group and oxidation of the hydroxymethyl group. Reacting it with (S) -4-phenylAfter the oxazolidinone condensation, the product was separated into diastereoisomers, the asymmetric auxiliary group was removed, and the resulting product was reduced to a methanol compound, and the sixth step and the subsequent reactions of reference example 1 were sequentially performed to obtain the title compound.

Test example 1 GK Activity measurement

The GK activity was examined not by directly measuring glucose-6-phosphate produced by the enzymatic reaction, but by measuring the amount of NADH produced by the coupling reaction of glucose-6-dehydrogenase.

(preparation of recombinant GK)

Cloning of human liver type and pancreas type GK and obtaining of recombinant protein

With the sequence Accession Number (Accession Number) of human hepatotype GK registered on GeneBank: NM — 033507, sequence accession number of human pancreatic GK: for reference, NM-000162 was PCR-cloned with Pyrobest DNA polymerase (TaKaRa) using human liver cDNA (Clontech) and human pancreas cDNA (Clontech) as templates, respectively. Then expressed as a soluble fraction in E.coli as a histidine-tagged fusion protein (tagged with 6 histidines (His) at the C-terminal side). The cells were ultrasonically crushed and then centrifuged to collect the supernatant. The recovered supernatant was purified by metal chelate affinity chromatography.

After purification, the enzyme was purified using 12.5mM HEPES (pH7.3), 75mM KCl, 0.5mM MgCl₂0.5mM DTT, 2.5mM glucose, 50% glycerol were stored at-80 ℃.

(GK Activity measurement)

The assay was performed at 25 ℃ using a flat bottom half-zone 96 well plate manufactured by Costar corporation. The culture mixture was adjusted to a final composition containing 25mM HEPES buffer (pH7.1) (Invitrogen), 25mM KCl (Wako pure chemical industries, Ltd.), and 2mM MgCl₂(Wako Junyaku Co., Ltd.), 5 mMD-glucose (Wako Junyaku Co., Ltd.), 1mM ATP (Roche Co., Ltd.), 1mM NAD (Sigma Co., Ltd.), 1mM dithiothreitol (Wako Junyaku K., Ltd.), 5 units/mL G6PDH (Sigma Co., Ltd.), 0.1% BSA (Sigma Co., Ltd.) test compound or 5% DMSO and GK.

Test compounds were pre-dissolved in DMSO, and 2. mu.L of the solution was added to the DMSO-containing solution containing HEPES buffer (pH7.1), KCl, MgCl₂D-glucose, ATP, NAD and dithiothreitol in 20. mu.L. Subsequently, 18. mu.L of a solution containing G6PDH, BSA and recombinant GK was added to start the reaction. The GK is added in a form that the increment of absorbance per minute in the presence of 5% DMSO is between 0.002 and 0.003. After the reaction started, the increase in absorbance at 340nm was measured with a SPECTRAmax190 microplate spectrophotometer (Molecular Device) over 15 minutes, and the increase was measured for the first 10 minutesTo evaluate the activity.

Compared with the wells containing no inventive compound, the inventive compounds 1A, 26A, 27A, 31A, 44A, 49A, 1B, 2B, 4B, 31B, 38B, 41B, 53B, 21B, and 26B exhibited a GK activation effect in human liver of 200% or more at a concentration of 10 μ M. Especially EC of inventive Compound 1A₅₀EC of comparative compounds 1 to 3 showing 1. mu.M or less as stereoisomers of inventive Compound 1A₅₀All of them are above 10. mu.M.

Test example 2 hypoglycemic test

The effect of the test compound on blood glucose levels was determined using ICR mice (male, 7-9 weeks old; Charles River, Japan). Each compound was dissolved in Gelucire44/14 (trade name, Gatefosse corporation): PEG400 was administered orally to mice (30mg/kg, 10mL/kg) after 2 hours fasting, as a 60: 40 mixture. Blood was collected through the tail vein using a blood collection tube coated with dipotassium ethylenediaminetetraacetate immediately before administration (Pre value) and at time points of 0.5 hour, 2 hours, and 4 hours after administration, and centrifuged (4 ℃, 3600 × g, 3 minutes) to obtain a plasma sample.

Each sample was diluted 5-fold with physiological saline, and the blood Glucose level was measured using Glucose CII-Test Wako (trade name, Wako pure chemical industries, Ltd.). Samples, physiological saline and 100mg/dL glucose standard solution (obtained by diluting 200mg/dL glucose standard solution 2-fold with physiological saline) were placed in 96-well plates at 10. mu.L/well, and a developing solution was added at 150. mu.L/well, followed by development by leaving to stand at 37 ℃ for 5 minutes. The measurement was carried out by using an En Vision2103 multi-labeled microplate reader (Multilabelreader) (trade name, Perkin Elmer) at OD505 nm. The glucose lowering rate (average of lowering rates of Pre value at each blood sampling time point) was calculated from lowering rates of Pre value at each blood sampling time point.

The compounds 1A, 26A, 27A, 31A, 44A, 1B, 2B, 11B, 12B, 21B, 26B, 62A, 31B, 79B, 103B, 108B, 4B, 38B, 53B, 46A, 58A, and 41B of the present invention showed a glucose reduction rate of 35% or more. In particular, the inventive compound 1A showed a reduction rate of 50% or more, whereas the comparative compounds 1 to 3, which are stereoisomers of the inventive compound 1A, all showed a reduction rate of less than 30%.

Test example 3 dose dependence of hypoglycemic and insulin secretion promoting tests

The effect of the test compounds on blood glucose levels and insulin secretion was determined using ICR mice (male, 7-9 weeks old; Chales river, Japan). Each compound was dissolved in Gelucire44/14 (trade name, manufactured by Gelucire Co.): PEG400 was administered orally to mice (30mg/kg, 10mL/kg) after 2 hours fasting, as a 60: 40 mixture. Blood was collected through the tail vein using a blood collection tube coated with dipotassium ethylenediaminetetraacetate at the time points of immediately before administration (Pre value) and 0.5 hour, 1 hour, 2 hours and 4 hours after administration, and centrifuged (4 ℃, 3600 × g, 3 minutes) to obtain a plasma sample.

Each sample was diluted 5-fold with physiological saline, and the blood Glucose level was measured using Glucose CII-Test Wako (trade name, Wako pure chemical industries, Ltd.). Samples, physiological saline and 100mg/dL glucose standard solution (obtained by diluting 200mg/dL glucose standard solution 2-fold with physiological saline) were placed in 96-well plates at 10. mu.L/well, and a developing solution was added at 150. mu.L/well, followed by development by leaving to stand at 37 ℃ for 5 minutes. The measurement was carried out by using an En Vision2103 multi-labeled microplate reader (Multilabelreader) (trade name, manufactured by Perkin Elmer) at OD505 nm. Calculating the area under the glucose curve from the blood glucose level at each blood sampling time point_0.5-4hr(Glucose AUC_0.5-4hr)。

The insulin concentration was measured using the stock solution of each sample using a Senyong insulin measurement kit (trade name, manufactured by Senyong Life science research). Calculating the area under the insulin curve according to the insulin value at each blood sampling time point_0.5-4hr(InsulinAUC_0.5-4hr)。

Test example 4 Effect on impaired glucose tolerance in diabetic db/db mice

The effect of a test compound on impaired glucose tolerance in critically ill diabetic db/db mice was tested by a method based on Fyfe et al (diabetologia.2007 Jun; 50 (6): 1277-87). The effect of the test compound on impaired glucose tolerance was determined using db/db mice (male, 7 weeks old; Chales river, Japan). The test compound was dissolved in Gelucire44/14 (trade name, manufactured by Gelucire Co.): the PEG400 was administered orally to mice after fasting for 16 to 20 hours in a 60: 40 mixed solution, and glucose loading (glucose load) was performed by administering a 5g/kg glucose solution 1 hour after the administration of the drug solution. Blood was collected through the tail vein using a blood collection tube coated with dipotassium ethylenediaminetetraacetate at time points of 1 hour before administration of the drug solution, 0.25 hour, 0.5 hour, 1 hour, 2 hours, and 4 hours after administration of the drug solution, and then centrifuged to obtain a plasma sample. Each sample was diluted 10-fold with physiological saline, and the blood glucose level was measured with a glucose C-II kit (trade name, manufactured by Wako pure chemical industries, Ltd.), and the blood glucose level AUC at 0.25 to 4 hours after sugar loading was calculated and used as "post sugar loading blood glucose".

EC was calculated from the blood test compound concentration (Cmax) and the dose of the test compound using the blood glucose lowering rate of each group when the data of the control group was 0 as an index of drug efficacy₅₀And ED₅₀。

Test example 5hERG Current suppression test

The hERG current through the whole cell membrane under the condition of fixed potential was recorded by whole cell patch clamp (clamp method) using HEK293 cells transfected with human ether-a-go-go related gene (hERG). To confirm the hERG current of the cells, the membrane potential was maintained at-80 mV and depolarization pulses were applied periodically. After the generated current was stabilized, a perfusion solution (application solution) in which the test substance was dissolved was perfused for 10 minutes. The effect of the test substance on the hERG channel was evaluated from the change in the tail current induced by the induction of a depolarization pulse of +20mV for 1.5 seconds followed by a repolarization pulse of-50 mV for 1.5 seconds. Stimulation was performed at a frequency of 1 time per 10 seconds. The experiment was carried out at 34 ℃. The absolute value of the maximum tail current was obtained with reference to the current value at the time of holding the membrane potential, and the rate of change (suppression rate) of the maximum tail current 10 minutes after application of the test substance to the maximum tail current before application of the test substance was calculated.

The hERG content was 50% or less when 30. mu.M of inventive compounds 1A, 12A, 44A, 18B, 31B, 41B, 71B, 103B, 4B, 31A, 38B and 68B were added.

INDUSTRIAL APPLICABILITY

The glucokinase-activating substance of the present invention has an excellent GK-activating effect or hypoglycemic effect and small side effects (e.g., QT interval prolongation (related to hERG current suppression), insulin-induced hypoglycemia, etc.), and thus is useful as a therapeutic or prophylactic drug for diabetes, obesity, etc.

Claims

1. A compound represented by the general formula (1) or a pharmaceutically acceptable salt thereof,

in the formula, R¹And R²The same or different represents a hydrogen atom, a halogen atom, an amino group, a hydroxyl group, a hydroxyamino group, a nitro group, a cyano group, a sulfamoyl group, C₁～C₆Alkyl of (C)₁～C₆Alkoxy group of (C)₁～C₆Alkyl sulfanyl, C₁～C₆Alkylsulfinyl group of (1), C₁～C₆Alkylsulfonyl or C₁～C₆alkoxy-C₁～C₆An alkyl sulfonyl group, a carboxyl group,

a is an unsubstituted or monosubstituted five-membered or six-membered aromatic heterocyclic ring, or an unsubstituted or monosubstituted condensed heterocyclic ring having a five-membered or six-membered aromatic heterocyclic ring, which contains 1 to 3 hetero atoms selected from a sulfur atom, an oxygen atom, and a nitrogen atom.

2. The compound or pharmaceutically acceptable salt thereof according to claim 1, wherein R is¹And R²Same or different and is hydrogen atom, halogen atom or C₁～C₆An alkylsulfonyl group of (a).

3. The compound or pharmaceutically acceptable salt thereof according to claim 1, wherein R is¹Is a hydrogen atom or a halogen atom, R²Is C₁～C₆An alkylsulfonyl group of (a).

4. The compound or pharmaceutically acceptable salt thereof according to claim 1, wherein R is¹Is a hydrogen atom, R²Is C₁～C₆An alkylsulfonyl group of (a).

5. The compound or pharmaceutically acceptable salt thereof according to claim 1, wherein R is¹Is a hydrogen atom, R²Is cyclopropylsulfonyl.

6. The compound or pharmaceutically acceptable salt thereof according to claim 1, wherein R is¹Is a hydrogen atom, R²Is methylsulfonyl.

7. The compound according to any one of claims 1 to 6, which is represented by the general formula (1a),

in the formula, R¹、R²And A is as defined above.

8. The compound according to any one of claims 1 to 6, which is represented by the general formula (1b),

in the formula, R¹、R²And A is as defined above.

9. The compound according to claim 1, wherein the aromatic heterocycle or fused heterocycle represented by a is unsubstituted or monosubstituted with a group selected from: halogen atom, C optionally substituted by halogen atom or hydroxy group₁～C₆Alkyl group of (2), C optionally substituted by halogen atom or hydroxyl group₁～C₆Alkoxy, nitro, cyano, or a compound of the formula- (O)_p(CH₂)_mC(O)OR³The group of the formula (I) is,

in the formula, R³Represents a hydrogen atom or C₁～C₆M represents an integer of 0 to 2, and p represents 0 or 1.

10. The compound according to claim 1, wherein the aromatic heterocycle or fused heterocycle represented by A is substituted with a halogen atom or C₁～C₆Alkyl or C₁～C₆Monosubstituted with hydroxyalkyl.

11. The compound according to claim 1, wherein the aromatic heterocycle or the condensed heterocycle represented by a is monosubstituted with a group represented by: c optionally substituted by halogen atoms or hydroxy groups₁～C₆Alkoxy of, or C₁～C₃alkoxy-C₁～C₃An alkoxy group.

12. The compound according to claim 1, wherein the aromatic heterocycle or the condensed heterocycle represented by a is monosubstituted with a group represented by: c optionally substituted by halogen atoms or hydroxy groups₁～C₆An alkylsulfanyl group of (1).

13. The compound according to any one of claims 9 to 12, wherein 1 of the hetero atoms contained in the aromatic heterocycle or fused heterocycle represented by a is a nitrogen atom adjacent to the bonding ring atom, or a pharmaceutically acceptable salt thereof.

14. The compound of any one of claims 9 to 12, or a pharmaceutically acceptable salt thereof, wherein a is an unsubstituted or substituted aromatic heterocycle selected from the group consisting of:

15. the compound of claim 1, or a pharmaceutically acceptable salt thereof, selected from the group consisting of (E) -3- [ (1 α,3 α,4 α) -3, 4-difluorocyclopentyl]-N- (5-fluorothiazol-2-yl) -2- (4- (methylsulfonyl) phenyl) acrylamide, (E) -N- (5-chlorothiazol-2-yl) -3- [ (1 α,3 α,4 α) -3, 4-difluorocyclopentyl]-2- (4- (methylsulfonyl) phenyl) acrylamide, (E) -3- [ (1 α,3 α,4 α) -3, 4-difluorocyclopentyl]-2- (4- (methylsulfonyl) phenyl) -N- (4-methylthiazol-2-yl) acrylamide, (E) -3- [ (1 α,3 α,4 α) -3, 4-difluorocyclopentyl]-2- (4- (methylsulfonyl) phenyl) -N- (5-methylthiazol-2-yl) acrylamide, (+) - (E) -3- [ (1 α,3 α,4 α) -3, 4-difluorocyclopentyl]-N- [4- (2, 2-dimethyl-1, 3-dioxolan-4-yl) thiazol-2-yl]-2- (4- (methylsulfonyl) phenyl) acrylamide, (-) - (E) -3- [ (1 α,3 α,4 α) -3, 4-difluorocyclopentyl]-N- [4- (2, 2-dimethyl-1, 3-dioxolan-4-yl) thiazol-2-yl]-2- (4- (methylsulfonyl) phenyl) acrylamide, (+) - (E) -3- [ (1 α,3 α,4 α) -3, 4-difluorocyclopentyl]-N- [4- (1, 2-dihydroxyethyl) thiazol-2-yl]-2- (4- (methylsulfonyl) phenyl) acrylamide, (-) - (E) -3- [ (1 α,3 α,4 α) -3, 4-difluorocyclopentyl]-N- [4- (1, 2-dihydroxyethyl) thiazol-2-yl]-2- (4- (methylsulfonyl) phenyl) acrylamide, (E) -N- (4-tert-butylthiazol-2-yl) -3- [ (1 α,3 α,4 α) -3, 4-difluorocyclopentyl]-2- (4- (methylsulfonyl) phenyl) acrylamide, (E) -3- [ (1 α,3 α,4 α) -3, 4-difluorocyclopentyl]-2- (4- (methylsulfonyl) phenyl) -N- {4- [2- (tetrahydro-2H-pyran-2-yloxy) ethyl]Thiazol-2-yl acrylamide, (E) -3- [ (1 α,3 α,4 α) -3, 4-difluorocyclopentyl]-N- [4- (2-hydroxyethyl) thiazol-2-yl]-2- (4- (methylsulfonyl) phenyl) acrylamide, (E) -3- [ (1 α,3 α,4 α) -3, 4-difluorocyclopentyl]-N- [5- (N, N-dimethylsulfamoyl) thiazol-2-yl]-2- (4- (methylsulfonyl) phenyl) acrylamide, (E) -3- [ (1 α,3 α,4 α) -3, 4-difluorocyclopentyl]-N- [5- (4-methylpiperazin-1-ylsulfonyl) thiazol-2-yl]-2- (4- (methylsulfonyl) phenyl) acrylamide, (E) -3- [ (1 α,3 α,4 α) -3, 4-difluorocyclopentyl]-2- (4- (methylsulfonyl) phenyl) -N- (1,2, 4-thiadiazol-5-yl) acrylamide, (E) -3- [ (1 α,3 α,4 α) -3, 4-difluorocyclopentyl]-2- (4- (methylsulfonyl) phenyl) -N- (3-methyl-1, 2, 4-thiadiazol-5-yl) acrylamide, (E) -3- [ (1 α,3 α,4 α) -3, 4-difluorocyclopentyl]-N- (3-ethyl-1, 2, 4-thiadiazol-5-yl) -2- (4- (methylsulfonyl) phenyl) acrylamide, (E) -3- [ (1 α,3 α,4 α) -3, 4-difluorocyclopentyl]-N- (3-methoxy-1, 2, 4-thiadiazol-5-yl) -2- (4- (methylsulfonyl) phenyl) acrylamide, (E) -3- [ (1 α,3 α,4 α) -3, 4-difluorocyclopentyl]-2- (4- (methylsulfonyl) phenyl) -N- (pyridin-2-yl) acrylamide, (E) -3- [ (1 α,3 α,4 α) -3, 4-difluorocyclopentyl]-N- (5-fluoropyridin-2-yl) -2- (4- (methylsulfonyl) phenyl) acrylamide, (E) -N- (5)-chloropyridin-2-yl) -3- [ (1 α,3 α,4 α) -3, 4-difluorocyclopentyl]-2- (4- (methylsulfonyl) phenyl) acrylamide, (E) -3- [ (1 α,3 α,4 α) -3, 4-difluorocyclopentyl]-2- (4- (methylsulfonyl) phenyl) -N- [5- (methylthio) pyridin-2-yl]Acrylamide, (E) -N- (5-cyclopropylpyridin-2-yl) -3- [ (1 α,3 α,4 α) -3, 4-difluorocyclopentyl]-2- (4- (methylsulfonyl) phenyl) acrylamide, (E) -3- [ (1 α,3 α,4 α) -3, 4-difluorocyclopentyl]-N- [5- (hydroxymethyl) pyridin-2-yl]-2- (4- (methylsulfonyl) phenyl) acrylamide, (E) -3- [ (1 α,3 α,4 α) -3, 4-difluorocyclopentyl]-N- [5- (N, N-dimethylsulfamoyl) pyridin-2-yl]-2- (4- (methylsulfonyl) phenyl) acrylamide, (E) -3- [ (1 α,3 α,4 α) -3, 4-difluorocyclopentyl]-2- (4- (methylsulfonyl) phenyl) -N- (pyrazin-2-yl) acrylamide, (E) -3- [ (1 α,3 α,4 α) -3, 4-difluorocyclopentyl]-N- (5-methylpyrazin-2-yl) -2- (4- (methylsulfonyl) phenyl) acrylamide, (E) -3- [ (1 α,3 α,4 α) -3, 4-difluorocyclopentyl]-N- (5-ethylpyrazin-2-yl) -2- (4- (methylsulfonyl) phenyl) acrylamide, (E) -3- [ (1 α,3 α,4 α) -3, 4-difluorocyclopentyl]-N- (5-methoxypyrazin-2-yl) -2- (4- (methylsulfonyl) phenyl) acrylamide, (E) -3- [ (1 α,3 α,4 α) -3, 4-difluorocyclopentyl]-N- [5- (2-methylethoxy) pyrazin-2-yl]-2- (4- (methylsulfonyl) phenyl) acrylamide, (E) -3- [ (1 α,3 α,4 α) -3, 4-difluorocyclopentyl]-N- [5- (2-methoxyethoxy) pyrazin-2-yl]-2- (4- (methylsulfonyl) phenyl) acrylamide, (E) -3- [ (1 α,3 α,4 α) -3, 4-difluorocyclopentyl]-N- [5- (3-methoxypropoxy) pyrazin-2-yl]-2- (4- (methylsulfonyl) phenyl) acrylamide, (E) -3- [ (1 α,3 α,4 α) -3, 4-difluorocyclopentyl]-N- [5- (2-ethoxyethoxy) pyrazin-2-yl]-2- (4- (methylsulfonyl) phenyl) acrylamide, (E) -3- [ (1 α,3 α,4 α) -3, 4-difluorocyclopentyl]-2- (4- (methylsulfonyl) phenyl) -N- {5- [2- (methylthio) ethoxy]Pyrazin-2-yl } acrylamide, (E) -2- (4- (methylsulfonyl) phenyl) -3- [ (1 α,3 α,4 α) -3, 4-difluorocyclopentyl]-N- [5- (2-hydroxyethylthio) pyrazin-2-yl]Acrylamide, (E) -3- [ (1 α,3 α,4 α) -3, 4-difluorocyclopentyl]-2- (4- (methylsulfonyl) phenyl) -N- {5- [2- (tetrahydro-2H-pyran-2-yloxy) ethoxy]Pyrazin-2-yl } acrylamide, (E) -3- [ (1 α,3 α,4 α) -3, 4-difluorocyclopentyl]-N- [5- (2-hydroxyethoxy) pyrazin-2-yl]-2- (4- (methylsulfonyl) phenyl) acrylamide (I), (II), (III), (IVE) -3- [ (1 α,3 α,4 α) -3, 4-difluorocyclopentyl]-N- {5- [ (4R) -2, 2-dimethyl-1, 3-dioxolan-4-yl]Pyrazin-2-yl } -2- (4- (methylsulfonyl) phenyl) acrylamide, (E) -3- [ (1 α,3 α,4 α) -3, 4-difluorocyclopentyl]-N- {5- [ (4S) -2, 2-dimethyl-1, 3-dioxolan-4-yl]Pyrazin-2-yl } -2- (4- (methylsulfonyl) phenyl) acrylamide, (E) -3- [ (1 α,3 α,4 α) -3, 4-difluorocyclopentyl]-N- {5- [ (2R) -1, 2-dihydroxyethyl]Pyrazin-2-yl } -2- (4- (methylsulfonyl) phenyl) acrylamide, (E) -3- [ (1 α,3 α,4 α) -3, 4-difluorocyclopentyl]-N- {5- [ (2S) -1, 2-dihydroxyethyl]Pyrazin-2-yl } -2- (4- (methylsulfonyl) phenyl) acrylamide, 5- { (E) -3- [ (1 α,3 α,4 α) -3, 4-difluorocyclopentyl-2- (4- (methylsulfonyl) phenyl)]Acrylamide } pyrazin-2-ylphosphonic acid diethyl ester, (5- { (E) -3- [ (1 α,3 α,4 α) -3, 4-difluorocyclopentyl-2- (4- (methylsulfonyl) phenyl)]Acrylamide } pyrazin-2-yl) methylphosphonic acid diethyl ester, (E) -3- [ (1 α,3 α,4 α) -3, 4-difluorocyclopentyl]-N- [ 1-methyl-1H-pyrazol-3-yl]-2- (4- (methylsulfonyl) phenyl) acrylamide, (E) -3- [ (1 α,3 α,4 α) -3, 4-difluorocyclopentyl]-N- [ 1-ethyl-1H-pyrazol-3-yl]-2- (4- (methylsulfonyl) phenyl) acrylamide, (E) -3- [ (1 α,3 α,4 α) -3, 4-difluorocyclopentyl]-N- [1- (difluoromethyl) -1H-pyrazol-3-yl]-2- (4- (methylsulfonyl) phenyl) acrylamide, (E) -3- [ (1 α,3 α,4 α) -3, 4-difluorocyclopentyl]-N- [1- (2-fluoroethyl) -1H-pyrazol-3-yl]-2- (4- (methylsulfonyl) phenyl) acrylamide, (E) -3- [ (1 α,3 α,4 α) -3, 4-difluorocyclopentyl]-2- (4- (methylsulfonyl) phenyl) -N- [1- (2,2, 2-trifluoroethyl) -1H-pyrazol-3-yl]Acrylamide, (E) -3- [ (1 α,3 α,4 α) -3, 4-difluorocyclopentyl]-N- [1- (2-hydroxyethyl) -1H-pyrazol-3-yl]-2- (4- (methylsulfonyl) phenyl) acrylamide, (E) -3- [ (1 α,3 α,4 α) -3, 4-difluorocyclopentyl]-N- [1- (2-hydroxy-2-methylpropyl) -1H-pyrazol-3-yl]-2- (4- (methylsulfonyl) phenyl) acrylamide, (E) -3- [ (1 α,3 α,4 α) -3, 4-difluorocyclopentyl]-N- (1- { [ (4R) -2, 2-dimethyl-1, 3-dioxolan-4-yl]Methyl } -1H-pyrazol-3-yl) -2- (4- (methylsulfonyl) phenyl) acrylamide, (E) -3- [ (1 α,3 α,4 α) -3, 4-difluorocyclopentyl]-N- (1- { [ (4S) -2, 2-dimethyl-1, 3-dioxolan-4-yl]Methyl } -1H-pyrazol-3-yl) -2- (4- (methylsulfonyl) phenyl) acrylamide, (E) -3- [ (1 α,3 α,4 α) -3, 4-difluorocyclopentyl]-N- {1- [ (2R) -2, 3-dihydroxyPropyl radical]-1H-pyrazol-3-yl } -2- (4- (methylsulfonyl) phenyl) acrylamide, (E) -3- [ (1 α,3 α,4 α) -3, 4-difluorocyclopentyl]-N- {1- [ (2S) -2, 3-dihydroxypropyl group]-1H-pyrazol-3-yl } -2- (4- (methylsulfonyl) phenyl) acrylamide, (E) -3- [ (1 α,3 α,4 α) -3, 4-difluorocyclopentyl]-N- (iso)Oxazol-3-yl) -2- (4- (methylsulfonyl) phenyl) acrylamide, (E) -3- [ (1 α,3 α,4 α) -3, 4-difluorocyclopentyl]-N- (6-methoxybenzo [ d ]]Thiazol-2-yl) -2- (4- (methylsulfonyl) phenyl) acrylamide, (E) -3- [ (1 α,3 α,4 α) -3, 4-difluorocyclopentyl]-N- [6- (difluoromethoxy) benzo [ d ]]Thiazol-2-yl]-2- (4- (methylsulfonyl) phenyl) acrylamide, (E) -3- [ (1 α,3 α,4 α) -3, 4-difluorocyclopentyl]-N- [5- (2-methoxyethoxy) thiazolo [5,4-b]Pyridin-2-yl]-2- (4- (methylsulfonyl) phenyl) acrylamide, and (E) -2- {2- [ (R) -2- (4- (methylsulfonyl) phenyl) -3- [ (1 α,3 α,4 α) -3, 4-difluorocyclopentyl]Acrylamide]Thiazolo [5,4-b ]]Pyridin-5-yloxy } acetic acid ethyl ester.

16. The compound of claim 1, or a pharmaceutically acceptable salt thereof, selected from the group consisting of (E) -2- (4- (cyclopropylsulfonyl) phenyl) -3- [ (1 α,3 α,4 α) -3, 4-difluorocyclopentyl]-N- (thiazol-2-yl) acrylamide, (E) -2- (4- (cyclopropylsulfonyl) phenyl) -3- [ (1 α,3 α,4 α) -3, 4-difluorocyclopentyl]-N- (5-fluorothiazol-2-yl) acrylamide, (E) -N- (5-bromothiazol-2-yl) -2- (4- (cyclopropylsulfonyl) phenyl) -3- [ (1 α,3 α,4 α) -3, 4-difluorocyclopentyl]Acrylamide, (E) -2- (4- (cyclopropylsulfonyl) phenyl) -3- [ (1 α,3 α,4 α) -3, 4-difluorocyclopentyl]-N- (4-methylthiazol-2-yl) acrylamide, (E) -2- (4- (cyclopropylsulfonyl) phenyl) -3- [ (1 α,3 α,4 α) -3, 4-difluorocyclopentyl]-N- (5-methylthiazol-2-yl) acrylamide, (+) - (E) -2- (4- (cyclopropylsulfonyl) phenyl) -3- [ (1 α,3 α,4 α) -3, 4-difluorocyclopentyl]-N- [4- (2, 2-dimethyl-1, 3-dioxolan-4-yl) thiazol-2-yl]Acrylamide, (-) - (E) -2- (4- (cyclopropylsulfonyl) phenyl) -3- [ (1 α,3 α,4 α) -3, 4-difluorocyclopentyl]-N- [4- (2, 2-dimethyl-1, 3-dioxolan-4-yl) thiazol-2-yl]Acryloyl groupAmine, (E) -N- (4-tert-butylthiazol-2-yl) -2- (4- (cyclopropylsulfonyl) phenyl) -3- [ (1 α,3 α,4 α) -3, 4-difluorocyclopentyl]Acrylamide, (E) -2- (4- (cyclopropylsulfonyl) phenyl) -3- [ (1 α,3 α,4 α) -3, 4-difluorocyclopentyl]-N- [5- (4-methylpiperazin-1-ylsulfonyl) thiazol-2-yl]Acrylamide, 3- {2- [ (E) -2- (4- (cyclopropylsulfonyl) phenyl) -3- [ (1 α,3 α,4 α) -3, 4-difluorocyclopentyl]Acrylamide]Thiazol-4-yl } propanoic acid methyl ester, (E) -2- (4- (cyclopropylsulfonyl) phenyl) -3- [ (1 α,3 α,4 α) -3, 4-difluorocyclopentyl]-N- (1,2, 4-thiadiazol-5-yl) acrylamide, (E) -2- (4- (cyclopropylsulfonyl) phenyl) -3- [ (1 α,3 α,4 α) -3, 4-difluorocyclopentyl]-N- (3-methyl-1, 2, 4-thiadiazol-5-yl) acrylamide, (E) -2- (4- (cyclopropylsulfonyl) phenyl) -3- [ (1 α,3 α,4 α) -3, 4-difluorocyclopentyl]-N- (3-ethyl-1, 2, 4-thiadiazol-5-yl) acrylamide, (E) -2- (4- (cyclopropylsulfonyl) phenyl) -3- [ (1 α,3 α,4 α) -3, 4-difluorocyclopentyl]-N- (3-phenyl-1, 2, 4-thiadiazol-5-yl) acrylamide, (E) -2- (4- (cyclopropylsulfonyl) phenyl) -3- [ (1 α,3 α,4 α) -3, 4-difluorocyclopentyl]-N- (pyridin-2-yl) acrylamide, (E) -2- (4- (cyclopropylsulfonyl) phenyl) -3- [ (1 α,3 α,4 α) -3, 4-difluorocyclopentyl]-N- [5- (methylthio) pyridin-2-yl]Acrylamide, (E) -N- (5-cyclopropylpyridin-2-yl) -2- (4- (cyclopropylsulfonyl) phenyl) -3- [ (1 α,3 α,4 α) -3, 4-difluorocyclopentyl]Acrylamide, (E) -2- (4- (cyclopropylsulfonyl) phenyl) -3- [ (1 α,3 α,4 α) -3, 4-difluorocyclopentyl]-N- [5- (hydroxymethyl) pyridin-2-yl]Acrylamide, (E) -2- (4- (cyclopropylsulfonyl) phenyl) -3- [ (1 α,3 α,4 α) -3, 4-difluorocyclopentyl]-N- [5- (N, N-dimethylsulfamoyl) pyridin-2-yl]Acrylamide, (E) -2- (4- (cyclopropylsulfonyl) phenyl) -3- [ (1 α,3 α,4 α) -3, 4-difluorocyclopentyl]-N- (pyrazin-2-yl) acrylamide, (E) -2- (4- (cyclopropylsulfonyl) phenyl) -3- [ (1 α,3 α,4 α) -3, 4-difluorocyclopentyl]-N- (5-methylpyrazin-2-yl) acrylamide, (E) -2- (4- (cyclopropylsulfonyl) phenyl) -3- [ (1 α,3 α,4 α) -3, 4-difluorocyclopentyl]-N- (5-ethylpyrazin-2-yl) acrylamide, (E) -2- (4- (cyclopropylsulfonyl) phenyl) -3- [ (1 α,3 α,4 α) -3, 4-difluorocyclopentyl]-N- (5-methoxypyrazin-2-yl) acrylamide, (E) -2- (4- (cyclopropylsulfonyl) phenyl) -3- [ (1 α,3 α,4 α) -3, 4-difluorocyclopentyl]-N- [5- (methylthio) pyrazin-2-yl]Acrylamide, (E) -2- (4- (cyclo)Propylsulfonyl) phenyl) -3- [ (1 α,3 α,4 α) -3, 4-difluorocyclopentyl]-N- [5- (2-methylethoxy) pyrazin-2-yl]Acrylamide, (E) -2- (4- (cyclopropylsulfonyl) phenyl) -3- [ (1 α,3 α,4 α) -3, 4-difluorocyclopentyl]-N- [5- (2-methoxyethoxy) pyrazin-2-yl]Acrylamide, (E) -2- (4- (cyclopropylsulfonyl) phenyl) -3- [ (1 α,3 α,4 α) -3, 4-difluorocyclopentyl]-N- [5- (3-methoxypropoxy) pyrazin-2-yl]Acrylamide, (E) -2- (4- (cyclopropylsulfonyl) phenyl) -3- [ (1 α,3 α,4 α) -3, 4-difluorocyclopentyl]-N- [5- (2-ethoxyethoxy) pyrazin-2-yl]Acrylamide, (E) -2- (4- (cyclopropylsulfonyl) phenyl) -3- [ (1 α,3 α,4 α) -3, 4-difluorocyclopentyl]-N- {5- [2- (methylthio) ethoxy]Pyrazin-2-yl } acrylamide, (E) -2- (4- (cyclopropylsulfonyl) phenyl) -3- [ (1 α,3 α,4 α) -3, 4-difluorocyclopentyl]-N- {5- [2- (tetrahydro-2H-pyran-2-yloxy) ethoxy]Pyrazin-2-yl } acrylamide, (E) -2- (4- (cyclopropylsulfonyl) phenyl) -3- [ (1 α,3 α,4 α) -3, 4-difluorocyclopentyl]-N- {5- [ (4R) -2, 2-dimethyl-1, 3-dioxolan-4-yl]Pyrazin-2-yl } acrylamide, (E) -2- (4- (cyclopropylsulfonyl) phenyl) -3- [ (1 α,3 α,4 α) -3, 4-difluorocyclopentyl]-N- {5- [ (4S) -2, 2-dimethyl-1, 3-dioxolan-4-yl]Pyrazin-2-yl } acrylamide, (E) -2- (4- (cyclopropylsulfonyl) phenyl) -3- [ (1 α,3 α,4 α) -3, 4-difluorocyclopentyl]-N- {5- [ (2R) -1, 2-dihydroxyethyl]Pyrazin-2-yl } acrylamide, (E) -2- (4- (cyclopropylsulfonyl) phenyl) -3- [ (1 α,3 α,4 α) -3, 4-difluorocyclopentyl]-N- {5- [ (2S) -1, 2-dihydroxyethyl]Pyrazin-2-yl } acrylamide, 5- { (E) -2- (4- (cyclopropylsulfonyl) phenyl) -3- [ (1 α,3 α,4 α) -3, 4-difluorocyclopentyl]Acrylamide } pyrazin-2-ylphosphonic acid diethyl ester, (5- { (E) -2- (4- (cyclopropylsulfonyl) phenyl) -3- [ (1 α,3 α,4 α) -3, 4-difluorocyclopentyl]Acrylamide } pyrazin-2-yl) methylphosphonic acid diethyl ester, (E) -2- (4- (cyclopropylsulfonyl) phenyl) -3- [ (1 α,3 α,4 α) -3, 4-difluorocyclopentyl]-N- [ 1-methyl-1H-pyrazol-3-yl]Acrylamide, (E) -2- (4- (cyclopropylsulfonyl) phenyl) -3- [ (1 α,3 α,4 α) -3, 4-difluorocyclopentyl]-N- [ 1-ethyl-1H-pyrazol-3-yl]Acrylamide, (E) -2- (4- (cyclopropylsulfonyl) phenyl) -3- [ (1 α,3 α,4 α) -3, 4-difluorocyclopentyl]-N- [1- (2-fluoroethyl) -1H-pyrazol-3-yl]Acrylamide, (E) -2- (4- (cyclopropylsulfonyl) phenyl) -3- [ (1 α,3 α,4 α) -3, 4-difluorocyclopentyl]-N-[1-(2-hydroxyethyl) -1H-pyrazol-3-yl]Acrylamide, (E) -2- (4- (cyclopropylsulfonyl) phenyl) -3- [ (1 α,3 α,4 α) -3, 4-difluorocyclopentyl]-N- [1- (2-hydroxy-2-methylpropyl) -1H-pyrazol-3-yl]Acrylamide, (E) -2- (4- (cyclopropylsulfonyl) phenyl) -3- [ (1 α,3 α,4 α) -3, 4-difluorocyclopentyl]-N- (1- { [ (4R) -2, 2-dimethyl-1, 3-dioxolan-4-yl]Methyl } -1H-pyrazol-3-yl) acrylamide, (E) -2- (4- (cyclopropylsulfonyl) phenyl) -3- [ (1 α,3 α,4 α) -3, 4-difluorocyclopentyl]-N- (1- { [ (4S) -2, 2-dimethyl-1, 3-dioxolan-4-yl]Methyl } -1H-pyrazol-3-yl) acrylamide, (E) -2- (4- (cyclopropylsulfonyl) phenyl) -3- [ (1 α,3 α,4 α) -3, 4-difluorocyclopentyl]-N- {1- [ (2R) -2, 3-dihydroxypropyl]-1H-pyrazol-3-yl } acrylamide, (E) -2- (4- (cyclopropylsulfonyl) phenyl) -3- [ (1 α,3 α,4 α) -3, 4-difluorocyclopentyl]-N- {1- [ (2S) -2, 3-dihydroxypropyl group]-1H-pyrazol-3-yl } acrylamide, (E) -2- (4- (cyclopropylsulfonyl) phenyl) -3- [ (1 α,3 α,4 α) -3, 4-difluorocyclopentyl]-N- (iso)Oxazol-3-yl) acrylamide, (E) -N- (benzo [ d ]]Thiazol-2-yl) -2- (4- (cyclopropylsulfonyl) phenyl) -3- [ (1 α,3 α,4 α) -3, 4-difluorocyclopentyl]Acrylamide, (E) -2- (4- (cyclopropylsulfonyl) phenyl) -3- [ (1 α,3 α,4 α) -3, 4-difluorocyclopentyl]-N- (6-methoxybenzo [ d ]]Thiazol-2-yl) acrylamide, (E) -2- (4- (cyclopropylsulfonyl) phenyl) -3- [ (1 α,3 α,4 α) -3, 4-difluorocyclopentyl]-N- [6- (difluoromethoxy) benzo [ d ]]Thiazol-2-yl]Acrylamide, (E) -2- (4- (cyclopropylsulfonyl) phenyl) -3- [ (1 α,3 α,4 α) -3, 4-difluorocyclopentyl]-N- (6-fluorobenzo [ d ]]Thiazol-2-yl) acrylamide, 2- { (E) -2- (4- (cyclopropylsulfonyl) phenyl) -3- [ (1 α,3 α,4 α) -3, 4-difluorocyclopentyl]Acrylamide } benzo [ d]Thiazole-6-carboxylic acid 1-methylethyl ester, (E) -2- (4- (cyclopropylsulfonyl) phenyl) -3- [ (1 α,3 α,4 α) -3, 4-difluorocyclopentyl]-N- (thiazolo [5,4-b ]]Pyridin-2-yl) acrylamide, (E) -N- (5-butoxythiazolo [5, 4-b)]Pyridin-2-yl) -2- (4- (cyclopropylsulfonyl) phenyl) -3- [ (1 α,3 α,4 α) -3, 4-difluorocyclopentyl]Acrylamide, (E) -2- (4- (cyclopropylsulfonyl) phenyl) -3- [ (1 α,3 α,4 α) -3, 4-difluorocyclopentyl]-N- [5- (2-methoxyethoxy) thiazolo [5,4-b]Pyridin-2-yl]Acrylamide, and 2- {2- [ (R) -2- (4- (cyclopropylsulfonyl) phenyl) -3- [ (1 α,3 α,4 α) -3, 4-difluorocyclopentyl]Acrylamide]Thiazolo [5,4-b ]]Pyridin-5-yloxy } acetic acid ethyl ester.

17. The compound of claim 1, or a pharmaceutically acceptable salt thereof, selected from the group consisting of (E) -3- [ (1 α,3 α,4 α) -3, 4-difluorocyclopentyl ] -2- [4- (ethylsulfonyl) phenyl ] -N- (thiazol-2-yl) acrylamide, (E) -3- [ (1 α,3 α,4 α) -3, 4-difluorocyclopentyl ] -2- [4- (ethylsulfonyl) phenyl ] -N- (5-methylpyrazin-2-yl) acrylamide, and (E) -3- [ (1 α,3 α,4 α) -3, 4-difluorocyclopentyl ] -2- [4- (ethylsulfonyl) phenyl ] -N- (1-methyl-1H-pyrazol-3-yl) acrylamide.

18. The compound of claim 1, or a pharmaceutically acceptable salt thereof, selected from the group consisting of (E) -3- [ (1 α,3 α,4 α) -3, 4-difluorocyclopentyl ] -2- [4- (2-methoxyethylsulfonyl) phenyl ] -N- (thiazol-2-yl) acrylamide, (E) -3- [ (1 α,3 α,4 α) -3, 4-difluorocyclopentyl ] -2- [4- (2-methoxyethylsulfonyl) phenyl ] -N- (5-methylpyrazin-2-yl) acrylamide, and (E) -3- [ (1 α,3 α,4 α) -3, 4-difluorocyclopentyl ] -2- [4- (2-methoxyethylsulfonyl) phenyl ] -N- (1-methyl-1H-pyrazol-3-yl) acrylamide.

19. Use of a compound according to any one of claims 1 to 18 or a pharmaceutically acceptable salt thereof for the preparation of a medicament for the treatment or prevention of diabetes.

20. A pharmaceutical composition comprising a compound according to any one of claims 1 to 18 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

21. A compound represented by the general formula (2),

in the formula, R¹And R²The same or different represents a hydrogen atom, a halogen atom, an amino group, a hydroxyl group, a hydroxyamino group, a nitro group, a cyano group, a sulfamoyl group, C₁～C₆Alkyl of (C)₁～C₆Alkoxy group of (C)₁～C₆Alkyl sulfanyl, C₁～C₆Alkylsulfinyl group of (1), C₁～C₆Alkylsulfonyl of, or C₁～C₆alkoxy-C₁～C₆An alkylsulfonyl group.

22. The compound of claim 21, wherein R is¹Is a hydrogen atom, R²Is cyclopropylsulfonyl.

23. The compound of claim 21, wherein R is¹Is a hydrogen atom, R²Is methylsulfonyl.