Pharmaceutical composition containing an ABHD6 antagonist

Abstract

To provide a pharmaceutical composition containing a compound having ABHD6 inhibitory activity, in the prevention and / or treatment of ABHD6-associated disease.SOLUTION: A compound represented by general formula (I-A) (where, all symbols have the same meanings as those described in the specifications) or a pharmaceutically acceptable salt thereof has ABHD6 inhibitory activity. Therefore, a pharmaceutical composition containing the compound represented by general formula (I-A) or the pharmaceutically acceptable salt thereof is suitable as an agent for the prevention and / or treatment of ABHD6-associated disease.SELECTED DRAWING: None

Description

[Technical Field]

[0001] This disclosure relates to pharmaceutical compositions, etc., containing a compound having ABHD6 inhibitory activity or a pharmaceutically acceptable salt thereof. For details, see General Formula (IA): [ka] This invention relates to a pharmaceutical composition, etc., containing a compound represented by (wherein all symbols have the same meaning as described below) or a pharmaceutically acceptable salt thereof (hereinafter referred to as the disclosed compound). [Background technology]

[0002] ABHD6 (alpha / beta-Hydrolase domain containing 6) is a serine hydrolase and one of the metabolic enzymes for the endogenous cannabinoid 2-arachidonoylglycerol (2-AG). Because 2-AG acts as an important lipid precursor in the eicosanoid signaling pathway and also functions as an endogenous signaling lipid for the activation of cannabinoid receptors 1 and 2 (CB1 and CB2, respectively), ABHD6 and 2-AG are known to be involved in the regulation of various physiological processes, including pain, neurotransmission, inflammation, insulin secretion, lipotanning, feeding, autoimmune disorders, neurological diseases, and metabolic diseases (Non-Patent Literature 1).

[0003] Furthermore, inhibiting ABHD6 is known to significantly reduce neuroinflammation and exert neuroprotective effects in animal models of traumatic brain injury and multiple sclerosis. Therefore, inhibiting ABHD6 is considered useful for the prevention and / or treatment of various inflammatory and neurological diseases without causing central nervous system side effects (Non-Patent Literature 2).

[0004] On the other hand, Patent Document 1 states that the compound represented by the following general formula (A) is a compound that has mAChR receptor antagonistic activity. General formula (A) is, [ka] (In the formula, ring A A represents a 5- or 6-membered heteroaryl ring having 1 to 3 heteroatoms selected from N, O, and S, Q A represents NR aA or O, mA represents 0, 1, or 2, R 1A is selected from heteroaryl, aryl, heterocyclyl, cycloalkyl, halogen, -OR bA , -NR cA R dA and NHCOR eA and, nA represents 1 or 2, R 2A is selected from hydrogen, a C1-4 alkyl group, halogen, and -OR fA and, R 3A is selected from hydrogen and a C1-4 alkyl group, R 4A is -(CR gA R hA ) pA -Y A ', and is selected from hydrogen, a C1-8 alkyl group, and a C1-8 alkenyl group, R 5A is selected from hydrogen, a C1-4 alkyl group, halogen, a C1-4 haloalkyl group, a C1-4 alkoxy group, and a C1-4 haloalkoxy group, Y A ' is selected from cycloalkyl, cycloalkenyl, heterocycle, aryl, and heteroaryl, p A represents an integer from 0 to 4. (A partial excerpt of the definition of the group is shown.))

[0005] Also, it is described that the compound represented by the following general formula (B) in Patent Document 2 is a compound having an FAAH inhibitory action. General formula (B) is

Chemical formula

[0006] Furthermore, Patent Document 3 states that the compound represented by the following general formula (C) is a compound that has Ca channel inhibitory activity. General formula (C) is, [ka] (In the formula, L 1C C(O), S(O)2, SO2N(R) 4 ), C(O)O or -(CR aC R bC ) mC -and, R 1C is alkyl, G 1C ,-CH(G 1C )2, -(CR aC R bC ) mC -G 1C ,-(CR aC R bC ) mC -CH(G 1C )2, -(CR eC R fC ) nC -N(R 5C )2, -(CR eC R fC ) nC -N(R 5C )-C(O)O(alkyl),-(CR eC R fC ) nC -N(R 5C )-C(O)(alkyl) or -(CR eC R fC ) nC -N(R 5C )-SO2R 6C and; or L 1C -R 1C These combine to form hydrogen, alkyl, hydroxyalkyl, G 1C or -CH(G 1C )2, L 2C is, -(CR cC R dC ) pC -, C(O), C(O)N(R) 4C ), S(O)2, SO2N(R5C ) or C(O)O, R 2C is alkyl, G 2C , -C(R cC )(G 2C )(G 3C ), -(CR cC R dC ) pC -G 2C , -(CR cC R dC ) pC -CH(G 2C )(G 3C ), -(CR gC R hC ) qC -N(R 5C )-C(O)O(alkyl), -(CR gC R hC ) y qC -N(R 5C )-C(O)O-G 2C , -(CR gC R hC ) qC -N(R 5C )-C(O)(alkyl), -(CR gC R hC ) qC -N(R 5C )-SO2R 6C , -(CR gC R hC ) qC -N(R 4C )(R 5C ), -(CR gC R hC ) qC -N(R 5C )-C(O)N(R 5C )-(alkyl) or -(CR gC R hC ) qC -N(R 5C )-C(O)N(R 5C )-G 2C ; or L 2C -R 2C is combined to be alkyl, G 2C or -C(R cC )(G 2C )(G 3C ), G 1C , G 2C and G 3C Each of these is independently an aryl, cycloalkyl, cycloalkenyl, heteroaryl, or heterocycle; G 1C , G 2C and G 3C Each of them is independently either unsubstituted or substituted with 1, 2, 3, 4, or 5 substituents; G 1C is anything other than quinoline, quinazolindione, or pyridopyrimidinedione; R 3C This represents hydrogen, alkyl, haloalkyl, cycloalkyl, or cycloalkylalkyl. (Partial definition of the group.) However, none of the prior art documents describe or suggest that the disclosed compound has ABHD6 inhibitory activity. [Prior art documents] [Patent Documents]

[0007] [Patent Document 1] International Publication No. 2019 / 089676 brochure [Patent Document 2] International Publication No. 2010 / 130944 Pamphlet [Patent Document 3] International Publication No. 2010 / 062927 Pamphlet [Non-patent literature]

[0008] [Non-Patent Document 1] European Journal of Medicinal Chemistry, Vol. 198, Article No. 112353, 2020. [Non-Patent Document 2] Journal of Neuroinflammation (2018) 15:9 [Overview of the Initiative] [Problems that the invention aims to solve]

[0009] The object of the present invention is to provide a pharmaceutical composition containing a compound having inhibitory activity against ABHD6. [Means for solving the problem]

[0010] As a result of diligent research to solve the above problems, the inventors have found that a pharmaceutical composition containing the compound represented by the general formula (IA) described below has potent inhibitory activity against ABHD6. In other words, this disclosure is, in one manner, [1] General formula (IA): [ka] (In the formula, X 1 , X 2 These are (1) CH and (2) CR, respectively, independently. X , or (3) N, where X 1 and X 2 At least one of them represents N, R 1 This represents a halogen atom, R X This represents (1) a halogen atom, (2) a C1-6 alkyl group, (3) a C2-6 alkenyl group, (4) a C2-6 alkynyl group, (5) a C1-6 alkoxy group, (6) a C1-6 haloalkyl group, (7) a C2-6 haloalkenyl group, (8) a C2-6 haloalkynyl group, (9) a C1-6 haloalkoxy group, or (10) a cyano group. R 2 This represents (1) a halogen atom, (2) a C1-6 alkyl group, (3) a C2-6 alkenyl group, (4) a C2-6 alkynyl group, (5) a C1-6 alkoxy group, (6) a C1-6 haloalkyl group, (7) a C2-6 haloalkenyl group, (8) a C2-6 haloalkynyl group, (9) a C1-6 haloalkoxy group, or (10) a cyano group. When m is 2 or greater, multiple R 2 They may be the same or different. R 3 This represents (1) a hydrogen atom, (2) a C1-6 alkyl group, (3) a C1-6 haloalkyl group, (4) a 3-10 membered cyclic group, (5)-(C1-6 alkylene)-(3-10 membered cyclic group), and (6)-(C1-6 haloalkylene)-(3-10 membered cyclic group), wherein one or two carbon atoms in the C1-6 alkyl group, C1-6 haloalkyl group, C1-6 alkylene, and C1-6 haloalkylene may be replaced by an oxygen atom or an oxidized sulfur atom. R 3 The 3-10 membered cyclic group inside contains 1-5 R 301 It may also be replaced with R 301 (1) halogen atom, (2) C1-4 alkyl group, (3) C1-4 alkoxy group, (4) C1-4 haloalkyl group, (5) C1-4 haloalkoxy group, (6) COOR 302 (7) CONR 303 R 304 (8) C3-6 cycloalkyl group, (9) hydroxyl group, (10) nitro group, (11) cyano group, (12)-NR 305 R 306 (13)-SR 307 (14)-SOR 308 (15)-SO2R 309 , or (16) representing an oxo group, R 301 When two or more substitutions occur, multiple R 301 They may be the same or different. R 302 , R 303 , R 304 , R 305 , R 306 , R 307 , R 308 , or R 309 Each of these independently represents either (1) a hydrogen atom or (2) a C1-4 alkyl group. R 2 R 2 This represents (2) to (9) inside, R 3 When R represents a C1-6 alkyl group, 2and R 3 It may also form a 5-6 membered cyclic group together with the atom to which it is bonded. R 4 This represents (1) a halogen atom, (2) a C1-6 alkyl group, (3) a C2-6 alkenyl group, (4) a C2-6 alkynyl group, (5) a C1-6 alkoxy group, (6) a C1-6 haloalkyl group, (7) a C2-6 haloalkenyl group, (8) a C2-6 haloalkynyl group, or (9) a C1-6 haloalkoxy group. When n is 2 or greater, multiple R 4 They may be the same or different. Two R atoms located on the same carbon atom 4 When represents a C1-6 alkyl group, it may form a C3-6 cycloalkyl group together with the bonded carbon atom. ring1 represents a 3-15 membered cyclic group, R 5-A (1) halogen atom, (2) C1-6 alkyl group, (3) C2-6 alkenyl group, (4) C2-6 alkynyl group, (5) C1-6 alkoxy group, (6) C1-6 alkylthio group, (7) C1-6 alkylsulfinyl group, (8) C1-6 alkylsulfonyl group, (9) C2-6 acyl group, (10) 3-6 membered cyclic group, (11)-L R5 -(3-6 membered cyclic group), (12) hydroxyl group, (13) nitro group, (14) cyano group, (15) oxo group, (16)-NR 501 R 502 (17)-COOR 503 (18)-CONR 504 R 505 , or (19)-SO2NR 506 R 507 The C1-6 alkyl group, C2-6 alkenyl group, C2-6 alkynyl group, C1-6 alkoxy group, C1-6 alkylthio group, C1-6 alkylsulfinyl group, C1-6 alkylsulfonyl group, and C2-6 acyl group may have 1-2 carbon atoms replaced by oxygen atoms or sulfur atoms that may be oxidized. When p is 2 or greater, multiple R 5-A They may be the same or different. R 5-AOf these, the bases (2) to (11) have 1 to 9 R 508 It may also be replaced with R 508 (1) halogen atom, (2) C1-4 alkyl group, (3) C1-4 alkoxy group, (4) C2-6 acyl group, (5) C3-6 cycloalkyl group, (6) hydroxyl group, or (7)-NR 509 R 510 This represents, R 508 When two or more substitutions occur, multiple R 508 They may be the same or different. L R5 (1)-O-, (2)-(C1-4 alkylene)-, (3)-O-(C1-4 alkylene)-, (4)-(C1-4 alkylene)-O-, (5)-NR 511 -, or (6)-SO 0-2 - represents, R 501 , R 502 , R 503 , R 504 , R 505 , R 506 , R 507 , R 509 , R 510 , or R 511 Each of these independently represents (1) a hydrogen atom, (2) a C1-6 alkyl group, (3) a C2-6 acyl group, or (4) a C1-6 alkylsulfonyl group. m represents an integer between 0 and 2. n represents an integer from 0 to 5. p represents an integer from 0 to 5.) A pharmaceutical composition containing a compound represented by ) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, [2] General formula (I): [ka] (In the formula, R 5(1) halogen atom, (2) C1-6 alkyl group, (3) C2-6 alkenyl group, (4) C2-6 alkynyl group, (5) C1-6 alkoxy group, (6) C1-6 alkylthio group, (7) C1-6 alkylsulfinyl group, (8) C1-6 alkylsulfonyl group, (9) C2-6 acyl group, (10) 3-6 membered cyclic group, (11)-L R5 -(3-6 membered cyclic group), (12) hydroxyl group, (13) nitro group, (14) cyano group, (15) oxo group, (16)-NR 501 R 502 (17)-COOR 503 (18)-CONR 504 R 505 , or (19)-SO2NR 506 R 507 This represents, When p is 2 or greater, multiple R 5 They may be the same or different. R 5 Of these, the bases (2) to (11) have 1 to 9 R 508 It may also be replaced with Other symbols have the same meaning as the symbols described in [1] above. A pharmaceutical composition containing a compound represented by ) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, [3] The present invention provides embodiments of the pharmaceutical composition described in [1] or [2] above, which is an ABHD6 inhibitor. [Effects of the Invention]

[0011] Since the disclosed compound has inhibitory activity against ABHD6, a pharmaceutical composition containing the disclosed compound is useful as a preventive and / or therapeutic agent for diseases related to ABHD6. [Brief explanation of the drawing]

[0012] [Figure 1]Figure 1 shows the powder X-ray diffraction spectrum chart of the crystalline [(3aS,4R,6aR)-4-[(6-bromo-3-pyridazinyl)amino]hexahydrocyclopenta[c]pyrrole-2(1H)-yl](5-methyl-2-thienyl)methanone (the vertical axis represents intensity (counts), and the horizontal axis represents 2θ (degrees)). [Figure 2] Figure 2 shows a differential scanning calorimetry (DSC) chart of the crystals of [(3aS,4R,6aR)-4-[(6-bromo-3-pyridazinyl)amino]hexahydrocyclopenta[c]pyrrole-2(1H)-yl](5-methyl-2-thienyl)methanone (the vertical axis represents heat flux (W / g) and the horizontal axis represents temperature (°C)). [Modes for carrying out the invention]

[0013] The details of this disclosure are described below. In this specification, examples of halogen atoms include fluorine, chlorine, bromine, and iodine atoms.

[0014] In this specification, examples of C1-4 alkyl groups include methyl, ethyl, propyl, butyl groups, and their isomers. In this specification, examples of C1-6 alkyl groups include methyl, ethyl, propyl, butyl, pentyl, hexyl groups, and their isomers.

[0015] In this specification, examples of C2-6 alkenyl groups include ethenyl, propenyl, butenyl, butadienyl, pentenyl, pentadienyl, hexenyl, hexadienyl groups, and their isomers.

[0016] In this specification, examples of C2-6 alkynyl groups include ethynyl, propynyl, butynyl, butadiinyl, pentynyl, pentadinyl, hexynyl, hexadinyl groups, and their isomers.

[0017] In this specification, examples of C1-4 alkylenes include methylene, ethylene, propylene, butylene, and their isomers. In this specification, examples of C1-6 alkylenes include methylene, ethylene, propylene, butylene, pentylene, hexylene, and their isomers.

[0018] In this specification, C1-4 haloalkyl groups mean alkyl groups substituted with one or more halogen atoms, specifically including fluoromethyl, chloromethyl, bromomethyl, iodomethyl, difluoromethyl, trifluoromethyl, 1-fluoroethyl, 2-fluoroethyl, 2-chloroethyl, pentafluoroethyl, 1-fluoropropyl, 2-chloropropyl, 3-fluoropropyl, 3-chloropropyl, 4,4,4-trifluorobutyl, 4-bromobutyl, and their isomers. In this specification, C1-6 haloalkyl groups mean, for example, alkyl groups substituted with one or more halogen atoms, specifically including fluoromethyl group, chloromethyl group, bromomethyl group, iodomethyl group, difluoromethyl group, trifluoromethyl group, 1-fluoroethyl group, 2-fluoroethyl group, 2-chloroethyl group, pentafluoroethyl group, 1-fluoropropyl group, 2-chloropropyl group, 3-fluoropropyl group, 3-chloropropyl group, 4,4,4-trifluorobutyl group, 4-bromobutyl group, 5,5,5-trifluoropentyl group, 6,6,6-trifluorohexyl group, and their isomers.

[0019] In this specification, C1-6 haloalkylene means, for example, alkylene substituted with one or more halogen atoms, specifically including fluoromethylene, chloromethylene, bromomethylene, iodomethylene, difluoromethylene, 1-fluoroethylene, 2-fluoroethylene, 2-chloroethylene, pentafluoroethylene, 1-fluoropropylene, 2-chloropropylene, 3-fluoropropylene, 3-chloropropylene, 4-bromobutylene, 5-fluoropentylene, 6-fluorohexylene, and their isomers.

[0020] In this specification, a C2-6 haloalkenyl group means, for example, an alkenyl group substituted with one or more halogen atoms, specifically including 1-fluoroethenyl group, 2-fluoroethenyl group, 2-chloroethenyl group, 1-fluoropropenyl group, 2-chloropropenyl group, 3-fluoropropenyl group, 3-chloropropenyl group, 4-bromobutenyl group, 5,5,5-trifluoropentenyl group, 6,6,6-trifluorohexenyl group, and their isomers.

[0021] In this specification, a C2-6 haloalkynyl group means, for example, an alkynyl group substituted with one or more halogen atoms, specifically including 2-fluoroethynyl group, 2-chloroethynyl group, 3-fluoropropynyl group, 3-chloropropynyl group, 4-bromobutynyl group, 5,5,5-trifluoropentynyl group, 6,6,6-trifluorohexynyl group, and their isomers.

[0022] In this specification, examples of C1-4 alkoxy groups include methoxy, ethoxy, propoxy, butoxy groups, and their isomers. In this specification, examples of C1-6 alkoxy groups include methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy groups, and their isomers.

[0023] In this specification, a C1-4 haloalkoxy group means, for example, an alkoxy group substituted with one or more halogen atoms, specifically including fluoromethoxy, chloromethoxy, bromomethoxy, iodomethoxy, difluoromethoxy, trifluoromethoxy, 1-fluoroethoxy, 2-fluoroethoxy, 2-chloroethoxy, pentafluoroethoxy, 1-fluoropropoxy, 2-chloropropoxy, 3-fluoropropoxy, 3-chloropropoxy, 4,4,4-trifluorobutoxy, 4-bromobutoxy, and their isomers. In this specification, a C1-6 haloalkoxy group means, for example, an alkoxy group substituted with one or more halogen atoms, specifically including fluoromethoxy, chloromethoxy, bromomethoxy, iodomethoxy, difluoromethoxy, trifluoromethoxy, 1-fluoroethoxy, 2-fluoroethoxy, 2-chloroethoxy, pentafluoroethoxy, 1-fluoropropoxy, 2-chloropropoxy, 3-fluoropropoxy, 3-chloropropoxy, 4,4,4-trifluorobutoxy, 4-bromobutoxy, 5,5,5-trifluoropentyloxy, 6,6,6-trifluorohexyloxy, and their isomers.

[0024] In this specification, examples of C1-6 alkylthio groups include methylthio, ethylthio, propylthio, butylthio, pentylthio, hexylthio, and their isomers.

[0025] In this specification, examples of C1-6 alkylsulfinyl groups include methylsulfinyl, ethylsulfinyl, propylsulfinyl, butylsulfinyl, pentylsulfinyl, hexylsulfinyl groups, and their isomers.

[0026] In this specification, examples of C1-6 alkylsulfonyl groups include methylsulfonyl, ethylsulfonyl, propylsulfonyl, butylsulfonyl, pentylsulfonyl, hexylsulfonyl groups, and their isomers.

[0027] In this specification, examples of C3-6 cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl groups. In this specification, examples of C2-6 acyl groups include ethanol, propanoyl, butanoyl, pentanolyl, hexanoyl groups, and their isomers.

[0028] In this specification, a 3-6 membered cyclic group refers to a C3-6 carbon ring and a 3-6 membered heterocycle. In this specification, examples of C3-6 carbon rings include cyclopropane, cyclobutane, cyclopentane, cyclohexane, cyclobutene, cyclopentene, cyclohexene, cyclobutadiene, cyclopentadiene, cyclohexadiene, and benzene rings. In this specification, 3-6 membered heterocycles include, for example, aziridine, azetidine, oxirane, oxetane, thiirane, thietan, pyrrole, imidazole, triazole, tetrazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, furan, pyran, thiophene, thiopyran, oxazole, isoxazole, thiazole, isothiazole, furazan, oxadiazole, oxazine, oxadiazine, thiadiazole, thiadin, thiadiazine, pyrroline, pyrrolidine, imidazoline, imidazolidine, triazoline, triazolidine, tetrazoline, tetrazolidine, pyrazolidine, dihydropyridine, tetrahydropyridine, piperidine, dihydropyrazine, tetrahydropyrazine, piperazine, dihydropyrimidine, tetrahydropyrimidine, perhydropyrimidine, dihydropyridazine, tetrahydropyridazine, perhydropyridazine, dihydrofuran, tetrahydrofuran, tetrahydropyran Examples include lan, dihydrothiophene, tetrahydrothiophene, dihydrothiopyran, tetrahydrothiopyran, dihydroxazole, tetrahydroxazole (oxazolidine), dihydroisoxazole, tetrahydroisoxazole (isoxazolidine), dihydrothiazole, tetrahydrothiazole (thiazolidine), dihydroisothiazole, tetrahydroisothiazole (isothiazolidine), dihydrofurazan, tetrahydrofurazan, dihydroxadiazole, tetrahydroxadiazole (oxadiazolidine), dihydroxazine, tetrahydroxazine, dihydroxadiazine, tetrahydroxadiazine, dihydrothiadiazole, tetrahydrothiadiazole (thiadiazolidine), dihydrothiadin, tetrahydrothiadin, dihydrothiadiazine, tetrahydrothiadin, morpholine, thiomorpholine, oxatian, dioxolane, dioxane, dithiolane, and dithiane rings.

[0029] In this specification, a 5-6 membered cyclic group refers to a C5-6 carbon ring and a 5-6 membered heterocycle. In this specification, examples of C5-6 carbon rings include cyclopentane, cyclohexane, cyclopentene, cyclohexene, cyclopentadiene, cyclohexadiene, and benzene rings. In this specification, 5-6 membered heterocycles include, for example, pyrrole, imidazole, triazole, tetrazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, furan, pyran, thiophene, thiopyran, oxazole, isoxazole, thiazole, isothiazole, furazan, oxadiazole, oxazine, oxadiazine, thiadiazole, thiadin, thiadiazine, pyrroline, pyrrolidine, imidazoline, imidazolidine, triazoline, triazolidine, tetrazoline, tetrazolidine, pyrazoline, pyrazolidine, dihydropyridine, tetrahydropyridine, piperidine, dihydropyrazine, tetrahydropyrazine, piperazine, dihydropyrimidine, tetrahydropyrimidine, perhydropyrimidine, dihydropyridazine, tetrahydropyridazine, perhydropyridazine, dihydrofuran, tetrahydrofuran, dihydropyran, tetrahydropyran, dihydrothiophene, tetrahydro Examples include dorothiophene, dihydrothiopyran, tetrahydrothiopyran, dihydroxazole, tetrahydroxazole (oxazolidine), dihydroisoxazole, tetrahydroisoxazole (isoxazolidine), dihydrothiazole, tetrahydrothiazole (thiazolidine), dihydroisothiazole, tetrahydroisothiazole (isothiazolidine), dihydrofurazan, tetrahydrofurazan, dihydroxadiazole, tetrahydroxadiazole (oxadiazolidine), dihydroxazine, tetrahydroxazine, dihydroxadiazine, tetrahydrothiadiazole (thiadiazolidine), dihydrothiadin, tetrahydrothiadin, dihydrothiadiazine, tetrahydrothiadin, tetrahydrothiadin, morpholine, thiomorpholine, oxatian, dioxolane, dioxane, dithiolane, and dithiane rings.

[0030] In this specification, a 3-10 membered cyclic group refers to a C3-10 carbon ring and a 3-10 membered heterocycle. In this specification, the C3-10 carbon ring is, for example, cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, cyclooctane, cyclononane, cyclodecane, cyclobutene, cyclopentene, cyclohexene, cycloheptene, cyclooctene, cyclononene, cyclodecene, cyclobutadiene, cyclopentadiene, cyclohexadiene, cycloheptadiene, cyclooctadiene, benzene, pentalene, perhydropentalene, azulene, perhydroazulene, indene, perhydro Examples include ndene, indan, naphthalene, dihydronaphthalene, tetrahydronaphthalene, perhydronaphthalene, bicyclo[1.1.1]pentane, bicyclo[2.1.1]hexane, bicyclo[2.1.1]hexene, bicyclo[2.2.1]heptane, bicyclo[2.2.1]heptene, bicyclo[3.1.1]heptane, bicyclo[3.1.1]heptene, bicyclo[2.2.2]octane, bicyclo[2.2.2]octane, bicyclo[3.2.1]octane, and bicyclo[3.2.1]octene rings. In this specification, the 3-10 membered heterocycle is, for example, the 3-6 membered heterocycle and azepine, diazepine, oxepine, thiepine, oxazepine, oxadiazepine, thiazepine, thiadiazepine, indole, isoindole, indidine, benzofuran, isobenzofuran, benzothiophene, isobenzothiophene, dithianaphthalene, indazole, quinoline, isoquinoline, quinoridine, purine, phthalazine, pteridine, naphthyridine, quinoxaline, quinazoline, cinnoline, benzoxazole, benzothiazole, benzimidazole, Clomen, benzoflazan, benzothiadiazole, benzotriazole, dihydroazepine, tetrahydroazepine, perhydroazepine, dihydrodiazepine, tetrahydrodiazepine, perhydrodiazepine, dihydrooxepine, tetrahydrooxepine, perhydrooxepine, dihydrothiepine, tetrahydrothiepine, perhydrothiepine, dihydrooxazepine, tetrahydrooxazepine, perhydrooxazepine, dihydrooxadiazepine, tetrahydrooxadiazepine, perhydrooxadiazepine, dihydrothiazepine, tetrahydrooxadiazepine, perhydrooxadiazepine, dihydrothiepine, tetra Lahydrothiazepine, perhydrothiazepine, dihydrothiadiazepine, tetrahydrothiadiazepine, perhydrothiadiazepine, indoline, isoindoline, dihydrobenzofuran, perhydrobenzofuran, dihydroisobenzofuran, perhydroisobenzofuran, dihydrobenzothiophene, perhydrobenzothiophene, dihydroisobenzothiophene, perhydroisobenzothiophene, dihydroindazole, perhydroindazole, dihydroquinoline, tetrahydroquinoline, perhydroquinoline, dihydroisoquinoline, tetrahydro Diisoquinoline, perhydroisoquinoline, dihydrophthalazine, tetrahydrophthalazine, perhydrophthalazine, dihydronaphthyridine, tetrahydronaphthyridine, perhydronaphthyridine, dihydroquinoxaline, tetrahydroquinoxaline, perhydroquinoxaline, dihydroquinazoline, tetrahydroquinazoline, perhydroquinazoline, dihydrosinnoline, tetrahydrosinnoline, perhydrosinnoline, benzoxatian, dihydrobenzoxazine, dihydrobenzothiazine, pyrazinomorpholine, dihydrobenzoxazole,Perhydrobenzoxazole, dihydrobenzothiazole, perhydrobenzothiazole, dihydrobenzimidazole, perhydrobenzimidazole, dioxaindan, benzodioxane, chroman, benzodithiolane, benzodithiane, azaspiro[4.4]nonane, oxazaspiro[4.4]nonane, dioxaspiro[4.4]nonane, azaspiro[4.5]decane, thiaspiro[4.5]decane, dithiaspiro[4.5]decane, dioxaspiro[4.5]decane, oxazaspiro[4.5]decane, azabicyclo[3.2.1]octane, ox Examples include sabicyclo[3.2.1]octane, thieno[3,2-c]pyrazole, thieno[2,3-c]pyrazole, thieno[2,3-d]thiazole, thieno[2,3-d][1.2.3]triazole, dihydropyrano[3,4-d]thiazole, dihydrothieno[2,3-b]pyran, dihydrothieno[3,2-c]pyran, dihydrothieno[3,2-b]pyran, dihydrothieno[3,2-c]thiopyran, tetrahydrothieno[3,2-b]pyridine, tetrahydrothieno[3,2-c]pyridine, and thieno[3,2-c]pyridine rings.

[0031] In this specification, a 3-15 membered cyclic group refers to a C3-15 carbon ring and a 3-15 membered heterocycle. In this specification, examples of C3-15 carbon rings include the aforementioned C3-10 carbon rings and heptalene, biphenylene, as-indacene, s-indacene, acenaphthylene, acenaphthene, fluorene, phenalene, phenanthrene, and anthracene rings. In this specification, the 3-15 membered heterocycle is, for example, the 3-10 membered heterocycle and benzoxadiazepine, benzothiadiazepine, benzoxazepine, benzothiazepine, benzodiazepine, dihydrobenzodiazepine, tetrahydrobenzodiazepine, benzodioxepane, dihydrobenzoxazepine, tetrahydrobenzoxazepine, benzooxepane, benzothiepine, benzazepine, dihydrobenzazepine, tetrahydrobenzazepine, perimidine, β-carbolin, dihydrocarbazepine Examples include tetrahydrocarbazole, dihydrodibenzofuran, dihydrodibenzothiophene, tetrahydrodibenzofuran, tetrahydrodibenzothiophene, carbazole, dibenzofuran, dibenzothiophene, phenothiazine, phenoxazine, phenoxatiin, thianthrene, phenazine, phenanthroline, xanthene, dihydroacridine, tetrahydroacridine, acridine, phenanthridine, and dihydropyrrolo[1,2-b]thieno[2,3-d]pyrazole rings.

[0032] In this specification, "one or two carbon atoms may be replaced by oxygen atoms or oxidized sulfur atoms" means that one or two carbon atoms (-CH2-) in the substituent at structurally possible positions may be replaced by oxygen atoms (-O-) or oxidized sulfur atoms (-S-, -SO-, or -SO2-). Specifically, in the case of C1-6 alkyl groups, examples include CH3-O-CH2- groups, CH3-CH2-O-CH2- groups, CH3-O-CH2-CH2- groups, CH3-O-CH2-CH2-CH2- groups, and CH3-CH2-O-CH2-CH2- groups.

[0033] In this disclosure, X 1 , X 2 It is preferably N. In this disclosure, R 1 Preferably, this is a chlorine atom or a bromine atom. In this disclosure, R 2is preferably a halogen atom, a C1-6 alkyl group, a C1-6 alkoxy group, a C1-6 haloalkyl group, or a cyano group, more preferably a chlorine atom, a methoxy group, a trifluoromethyl group, or a cyano group. In the present disclosure, R X is preferably a halogen atom, a C1-6 alkyl group, a C1-6 alkoxy group, a C1-6 haloalkyl group, or a cyano group, more preferably a chlorine atom, a methoxy group, a trifluoromethyl group, or a cyano group. In the present disclosure, R 3 is preferably a hydrogen atom, a C1-6 alkyl group, a C1-6 haloalkyl group, a 3-10 membered cyclic group, or -CH2-(3-10 membered cyclic group), more preferably a hydrogen atom, a C1-6 alkyl group, a C1-6 haloalkyl group, a cyclopropyl group, -CH2-benzene, -CH2-pyridine, or -CH2-imidazo[2,1-b]thiazole. In the present disclosure, R 4 is preferably a halogen atom or a C1-6 alkyl group and more preferably a fluorine atom or a methyl group.

[0034] In the present disclosure, ring1 is preferably a 3-10 membered cyclic group or

Chemical formula

Chemical formula

Chemical formula

[0035] In the present disclosure, R 5-A is preferably a halogen atom, a C1-6 alkyl group, a C1-6 alkoxy group, a C1-6 haloalkyl group, a C1-6 haloalkoxy group, a 3-6 membered cyclic group, an oxo group, -NR 501 R 502 , or -COOR 503 , and more preferably a C1-6 alkyl group, a C1-6 alkoxy group, a C1-6 haloalkyl group, a C1-6 haloalkoxy group, a cyclopropyl group, a furan ring, an N-methylpyrazole ring, an oxo group, a dimethylamino group, or -COOCH3, and even more preferably a C1-6 alkyl group, a C1-6 haloalkyl group, a C1-6 haloalkoxy group, or a cyclopropyl group.

[0036] In the present disclosure, m is preferably 0 or 1. In the present disclosure, n is preferably 0, 1, or 2. In the present disclosure, p is preferably 0, 1, or 2.

[0037] In the present disclosure, the compound represented by the general formula (I-A) or the general formula (I) is preferably the general formula (I-1): [ka] (In the formula, R 3-a This represents (1) a hydrogen atom, (2) a C1-6 alkyl group, (3) a C1-6 haloalkyl group, (4) a cyclopropyl group, or (5) -CH2-Q. Q represents (1) benzene, (2) pyridine, or (3) imidazo[2,1-b]thiazole. ring1-a has the following ring structure; [ka] (In the formula, the * indicates the bond position with the carbonyl group, and the hydrogen atom represented by NH is R) 5-a It may be replaced by ). Represents a ring structure selected from the group consisting of ) R 5-a This represents (1) a C1-6 alkyl group, (2) a C1-6 alkoxy group, (3) a C1-6 haloalkyl group, (4) a C1-6 haloalkoxy group, (5) a cyclopropyl group, (6) a furan ring, (7) an N-methylpyrazole ring, (8) an oxo group, (9) a dimethylamino group, or (10)-COOCH3. Other symbols have the same meaning as the symbols mentioned above. ) This is a compound represented by ).

[0038] In this disclosure, the compound represented by general formula (IA) is preferably the X mentioned above. 1 , X 2 , R 1 , R 2 , R 3 , R 4 , R 5-A This is a combination of preferred definitions for ring1, n, m, and p.

[0039] In this disclosure, the compound represented by general formula (I) is preferably the X mentioned above. 1 , X 2 , R 1 , R 2 , R 3 , R 4 , R 5 This is a combination of preferred definitions for ring1, n, m, and p.

[0040] In this disclosure, the most preferred alternative embodiment of the compound represented by general formula (IA) or general formula (I) is the example compound described in the following examples, or a pharmaceutically acceptable salt thereof.

[0041] In this disclosure, isomers are encompassed unless otherwise specified. For example, alkyl groups, alkoxy groups, and alkylene groups include both linear and branched forms. Furthermore, isomers at double bonds, rings, and fused rings (E, Z, cis, and trans isomers), isomers due to the presence of chiral carbons (R, S, α, β, enantiomers, and diastereomers), optically active isomers with optical activity (D, L, d, and l isomers), polar isomers separated by chromatography (highly polar and low polar isomers), equilibrium compounds, rotational isomers, mixtures of these in any proportion, and racemic mixtures are all included in this disclosure. In addition, isomers resulting from tautomerism are also encompassed in this disclosure.

[0042] In this specification, compounds with "rel-" in their name indicate that the stereochemistry of multiple chiral centers is relative.

[0043] In this disclosure, unless otherwise specified, symbols are used in a manner that would be obvious to those skilled in the art. [ka] This indicates that it is coupled to the other side of the paper (i.e., in an α-configuration). [ka] This indicates that it is bonded to the front side of the paper (i.e., in a β-configuration). [ka] This indicates any mixture of α-configuration and β-configuration.

[0044] In the present disclosure, the crystal forms of the example compounds are identified by the physicochemical data described herein. However, since each spectral data may vary somewhat in nature, it should not be interpreted strictly. For example, in powder X-ray diffraction spectral data, in the identification of crystal identity, the diffraction angle (2θ) and the overall pattern are important, and the relative intensity may vary somewhat depending on the crystal growth direction, particle size, and measurement conditions. Also, in DSC data, in the identification of crystal identity, the overall pattern is important and may vary somewhat depending on the measurement conditions. Therefore, in each crystal form of the compounds of the present disclosure, those with powder X-ray diffraction spectra or DSC patterns that are overall similar to each other are included in the crystal form. In the present disclosure, the description of the diffraction angle (2θ (degrees)) in the powder X-ray diffraction pattern and the onset temperature (°C) and peak temperature (°C) of the endothermic peak in DSC analysis means that it includes the error range normally allowed in the data measurement method, and means that it is approximately the diffraction angle and the onset temperature and peak temperature of the endothermic peak. For example, "about" the diffraction angle (2θ (degrees)) in the powder X-ray diffraction pattern is, in one aspect, ±0.2 degrees, and in another aspect, ±0.1 degrees. "About" the onset temperature (°C) or peak temperature (°C) of the endothermic peak in DSC analysis is, in one aspect, ±2 °C, and in another aspect, ±1 °C.

[0045] [Salt] The compound represented by the general formula (I-A) is converted into a salt by a known method. The salt is a pharmaceutically acceptable salt. The salt is preferably water-soluble. Examples of pharmaceutically acceptable salts include acid addition salts, alkali metal salts, alkaline earth metal salts, ammonium salts, or amine salts, etc. Examples of acid addition salts include inorganic salts such as hydrochloride, hydrobromide, hydroiodide, sulfate, phosphate, and nitrate, or organic salts such as acetate, lactate, tartrate, benzoate, citrate, methanesulfonate, ethanesulfonate, trifluoroacetate, benzenesulfonate, toluenesulfonate, isethionate, glucuronate, or gluconate. Examples of alkali metal salts include potassium salts and sodium salts. Examples of alkaline earth metal salts include calcium salts and magnesium salts. Examples of ammonium salts include tetramethylammonium salt. Examples of amine salts include triethylamine salt, methylamine salt, dimethylamine salt, cyclopentylamine salt, benzylamine salt, phenethylamine salt, piperidine salt, monoethanolamine salt, diethanolamine salt, tris(hydroxymethyl)aminomethane salt, lysine salt, arginine salt, and N-methyl-D-glucamine salt.

[0046] Furthermore, the disclosed compounds can be converted into N-oxide compounds by any method. An N-oxide compound refers to a compound in which the nitrogen atom of the compound represented by general formula (IA) has been oxidized.

[0047] Compounds represented by general formula (IA) and their pharmaceutically acceptable salts may exist in an unsolvated form or in a solvated form with a pharmaceutically acceptable solvent such as water or ethanol. Hydrates are preferred as solvates. Compounds represented by general formula (IA) and their pharmaceutically acceptable salts can be converted to solvates.

[0048] Compounds represented by general formula (IA) can form cocrystals with suitable cocrystal-forming agents. Preferably, the cocrystals are pharmaceutically acceptable and formed with pharmaceutically acceptable cocrystal-forming agents. A cocrystal is typically defined as a crystal formed by two or more different molecules through intermolecular interactions other than ionic bonding. A cocrystal may also be a complex of a neutral molecule and a salt. Cocrystals can be prepared by known methods, such as by melt crystallization, recrystallization from a solvent, or by physically grinding the components together. Suitable cocrystal-forming agents include those described in WO2006 / 007448.

[0049] In this disclosure, all references to the disclosed compounds include the compound represented by general formula (IA), its pharmaceutically acceptable salt, its N-oxide, its solvate (e.g., hydrate), or its cocrystal, or the N-oxide, solvate (e.g., hydrate), or cocrystal of a pharmaceutically acceptable salt of the compound represented by general formula (IA).

[0050] [Prodrug] A prodrug of a compound represented by general formula (IA) is a compound that is converted into a compound represented by general formula (IA) in the body by reactions involving enzymes or gastric acid. Examples of prodrugs of compounds represented by general formula (IA) include, if the compound represented by general formula (IA) has an amino group, a compound in which the amino group has been acylated, alkylated, or phosphorylated (for example, a compound in which the amino group of the compound represented by general formula (IA) has been eicosanoylated, alanylated, pentylaminocarbonylated, (5-methyl-2-oxo-1,3-dioxolene-4-yl)methoxycarbonylated, tetrahydrofuranylated, pyrrolidylmethylated, pivaloyloxymethylated, acetoxymethylated, or tert-butylated); if the compound represented by general formula (IA) has a hydroxyl group, a compound in which the hydroxyl group has been acylated, alkylated, phosphorylated, or borated (for example, a compound in which the hydroxyl group of the compound represented by general formula (IA) has been acetylated, palmitoylated, or propano Examples include compounds that have been ylated, pivaloylated, succinylated, fumalylated, alanylated, or dimethylaminomethylcarbonylated; and if the compound represented by general formula (IA) has a carboxyl group, examples include compounds in which the carboxyl group has been esterified or amidated (for example, compounds in which the carboxyl group of the compound represented by general formula (IA) has been ethyl esterified, phenyl esterified, carboxymethyl esterified, dimethylaminomethyl esterified, pivaloyloxymethyl esterified, 1-{(ethoxycarbonyl)oxy}ethyl esterified, phthalidyl esterified, (5-methyl-2-oxo-1,3-dioxolenn-4-yl)methyl esterified, 1-{[(cyclohexyloxy)carbonyl]oxy}ethyl esterified, or methylamidated). These compounds can be produced by known methods. Furthermore, the prodrug of the compound represented by general formula (IA) may be either a hydrate or an unhydrated form. Furthermore, the prodrug of the compound represented by general formula (IA) may be one that transforms into the compound represented by general formula (IA) under physiological conditions, as described on pages 163-198 of "Molecular Design," Volume 7 of "Pharmaceutical Development," published by Hirokawa Shoten in 1990.

[0051] Furthermore, each atom constituting the compound represented by general formula (IA) is its isotope (for example, 2 H, 3 H, 11 C, 13 C, 14 C, 15 N, 16 N, 17 O, 18 O, 18 F, 35 S, 36 Cl, 77 Br, 125 It may be replaced with something like I.

[0052] [Method for producing the disclosed compound] The compounds disclosed herein can be produced by appropriately modifying and combining known methods, such as the methods shown below, similar methods, methods described in Comprehensive Organic Transformations: A Guide to Functional Group Preparations, 3rd Edition (Richard C. Larock, John Wiley & Sons Inc, 2018), or methods shown in the examples. Salts may be used as starting materials. The order of each reaction can be appropriately changed depending on the protecting groups introduced and the reaction conditions.

[0053] Furthermore, compounds having an amino group, a carboxyl group, or a hydroxyl group can be prepared by using a commonly used protecting group for these groups, for example, a compound protected with a protecting group described in TW Greene, Protective Groups in Organic Synthesis, Wiley, New York, 5th Edition, 2014, and then performing a known deprotection reaction after an appropriate reaction step. Examples of protecting groups for carboxyl groups include methyl, ethyl, tert-butyl, trichloroethyl, benzyl (Bn), phenacyl, p-methoxybenzyl, trityl, and 2-chlorotrityl. Examples of protecting groups for amino groups or tetrazolyl groups include benzyloxycarbonyl group, tert-butoxycarbonyl group, allyloxycarbonyl (Alloc) group, 1-methyl-1-(4-biphenyl)ethoxycarbonyl (Bpoc) group, trifluoroacetyl group, 9-fluorenylmethoxycarbonyl group, benzyl (Bn) group, p-methoxybenzyl group, benzyloxymethyl (BOM) group, and 2-(trimethylsilyl)ethoxymethyl (SEM) group. Examples of protecting groups for hydroxyl groups or hydroxamic acids include methyl, trityl, methoxymethyl (MOM), 1-ethoxyethyl (EE), methoxyethoxymethyl (MEM), 2-tetrahydropyranyl (THP), trimethylsilyl (TMS), triethylsilyl (TES), tert-butyldimethylsilyl (TBDMS), tert-butyldiphenylsilyl (TBDPS), acetyl (Ac), pivaloyl, benzoyl, benzyl (Bn), p-methoxybenzyl, allyloxycarbonyl (Alloc), and 2,2,2-trichloroethoxycarbonyl (Troc).

[0054] Deprotection reactions are well known and can be carried out by the following methods. For example, (1) Deprotection reaction by alkaline hydrolysis, (2) Deprotection reaction under acidic conditions, (3) Deprotection reaction by hydrolysis, (4) Deprotection reaction of silyl group, (5) Deprotection reactions using metals, (6) Examples include deprotection reactions using metal complexes.

[0055] To explain these methods in detail, (1) Deprotection reactions by alkaline hydrolysis are carried out at 0 to 40°C in an organic solvent (e.g., methanol, tetrahydrofuran (hereinafter referred to as THF), dioxane, etc.) using alkali metal hydroxides (e.g., sodium hydroxide, potassium hydroxide, lithium hydroxide, etc.), alkaline earth metal hydroxides (e.g., barium hydroxide, calcium hydroxide, etc.), or carbonates (e.g., sodium carbonate, potassium carbonate, etc.), or aqueous solutions thereof, or mixtures thereof. (2) The deprotection reaction under acidic conditions is carried out at 0 to 100°C in an organic solvent (e.g., dichloromethane, chloroform, dioxane, ethyl acetate, methanol, isopropyl alcohol, THF, anisole, etc.), an organic acid (e.g., acetic acid, trifluoroacetic acid, methanesulfonic acid, p-tosylic acid, etc.), or an inorganic acid (e.g., hydrochloric acid, sulfuric acid, etc.) or a mixture thereof (e.g., hydrogen bromide / acetic acid, etc.), with or without 2,2,2-trifluoroethanol. (3) The deprotection reaction by hydrolysis is carried out at 0 to 200°C in a solvent (e.g., ether-based solvents (e.g., THF, dioxane, dimethoxyethane, diethyl ether, etc.), alcohol-based solvents (e.g., methanol, ethanol, etc.), benzene-based solvents (e.g., benzene, toluene, etc.), ketone-based solvents (e.g., acetone, methyl ethyl ketone, etc.), nitrile-based solvents (e.g., acetonitrile, etc.), amide-based solvents (e.g., N,N-dimethylformamide (hereinafter DMF), etc.), water, ethyl acetate, acetic acid, or a mixture of two or more of these solvents, etc.) in the presence of a catalyst (e.g., palladium-carbon, palladium black, palladium-carbon hydroxide, platinum oxide, Raney nickel, etc.), under atmospheric pressure or under a pressurized hydrogen atmosphere, or in the presence of ammonium formate. (4) The deprotection reaction of the silyl group is carried out at 0 to 40°C using tetrabutylammonium fluoride in an organic solvent that is miscible with water (e.g., THF, acetonitrile, etc.). Alternatively, it may be carried out at -10 to 100°C in an organic acid (e.g., acetic acid, trifluoroacetic acid, methanesulfonic acid, p-tosylic acid, etc.), or an inorganic acid (e.g., hydrochloric acid, sulfuric acid, etc.) or a mixture thereof (e.g., hydrogen bromide / acetic acid, etc.). (5) Deprotection reactions using metals are carried out at 0 to 40°C in the presence of powdered zinc in an acidic solvent (e.g., acetic acid, a buffer solution with a pH of 4.2 to 7.2, or a mixture of these solutions with an organic solvent such as THF), while sonication is applied if necessary. (6) Deprotection reactions using metal complexes are carried out at 0 to 40°C in an organic solvent (e.g., dichloromethane, DMF, THF, ethyl acetate, acetonitrile, dioxane, ethanol, etc.), water, or a mixture thereof, in the presence of a trap reagent (e.g., tributyltin hydride, triethylsilane, dimedone, morpholine, diethylamine, pyrrolidine, etc.), an organic acid (e.g., acetic acid, formic acid, 2-ethylhexanoic acid, etc.) and / or an organic acid salt (e.g., sodium 2-ethylhexanoate, potassium 2-ethylhexanoate, etc.), in the presence or absence of a phosphine reagent (e.g., triphenylphosphine, etc.), using a metal complex (e.g., tetrakistriphenylphosphine palladium(0), bis(triphenylphosphine)palladium(II) dichloride, palladium(II) acetate, tris(triphenylphosphine)rhodium(I) chloride, etc.).

[0056] The compound represented by general formula (IA) can be produced by reaction step 1. [ka] (In reaction equation 1, PG represents an amino group protecting group, Y represents a halogen atom, Z represents a halogen atom, and the other symbols have the same meanings as above.)

[0057] In reaction step formula 1, reaction 1-1 is a halogen substitution reaction or a cross-coupling reaction. Halogen substitution reactions are well known and are carried out, for example, by reacting in an organic solvent (DMF, dimethyl sulfoxide, chloroform, dichloromethane, diethyl ether, THF, methyl t-butyl ether, etc.) in the presence of a base (sodium ethylate, sodium hydroxide, potassium hydroxide, triethylamine, diisopropylethylamine, sodium carbonate, sodium bicarbonate, potassium carbonate, cesium carbonate, tripotassium phosphate, cesium fluoride, barium hydroxide, tetrabutylammonium fluoride, etc.) or an aqueous solution thereof or a mixture thereof at 0 to 200°C.

[0058] Cross-coupling reactions are well known, for example, in an organic solvent (benzene, toluene, DMF, dioxane, THF, methanol, acetonitrile, dimethoxyethane, acetone, etc.), a base (sodium ethylate, sodium hydroxide, potassium hydroxide, triethylamine, sodium carbonate, sodium bicarbonate, potassium carbonate, cesium carbonate, thallium carbonate, tripotassium phosphate, cesium fluoride, barium hydroxide, tetrabutylammonium fluoride, etc.) or an aqueous solution thereof, or a mixture thereof, and a catalyst (tetrabutylammonium fluoride). The reaction is carried out at room temperature to 120°C in the presence of palladium (Pd(PPh3)4), bis(triphenylphosphine)palladium dichloride (PdCl2(PPh3)2), palladium acetate (Pd(OAc)2), palladium black, 1,1'-bis(diphenylphosphinoferrocene)dichloropalladium (PdCl2(dppf)2), diallylpalladium dichloride (PdCl2(allyl)2), phenylbis(triphenylphosphine)palladium iodide (PhPdI(PPh3)2), etc. In reaction step formula 1, reaction 1-2 is an N-alkylation reaction. N-alkylation reactions are well known and are carried out, for example, by reacting in an organic solvent (DMF, dimethyl sulfoxide, chloroform, dichloromethane, diethyl ether, THF, methyl t-butyl ether, etc.) at 0-100°C in the presence of alkali metal hydroxides (sodium hydroxide, potassium hydroxide, lithium hydroxide, etc.), alkaline earth metal hydroxides (barium hydroxide, calcium hydroxide, etc.), or carbonates (sodium carbonate, potassium carbonate, etc.) or aqueous solutions thereof, or mixtures thereof.

[0059] In reaction step formula 1, reactions 1-3 are deprotection reactions and can be carried out in the same manner as described above.

[0060] In reaction equation 1, reactions 1-4 are amidation reactions. Amidation reactions are well known, for example, (1) Method using acid halides, (2) Method using mixed acid anhydrides, (3) Method using a condensing agent, These are some examples. To explain these methods in detail, (1) The method using acid halides is carried out by, for example, reacting a carboxylic acid with an acid halide agent (oxalyl chloride, thionyl chloride, etc.) in an organic solvent (chloroform, dichloromethane, diethyl ether, THF, etc.) or without a solvent at -20°C to reflux temperature, and then reacting the resulting acid halide with an amine in an organic solvent (chloroform, dichloromethane, diethyl ether, THF, etc.) in the presence of a base (pyridine, triethylamine, dimethylaniline, dimethylaminopyridine, diisopropylethylamine, etc.) at a temperature of 0 to 40°C. Alternatively, the method can also be carried out by reacting the resulting acid halide with an amine in an organic solvent (dioxane, THF, etc.) using an alkaline aqueous solution (such as sodium bicarbonate solution or sodium hydroxide solution) at 0 to 40°C. (2) The method using mixed acid anhydrides is carried out, for example, by reacting a carboxylic acid with an acid halide (pivaloyl chloride, tosyl chloride, mesyl chloride, etc.) or an acid derivative (ethyl chloroformate, isobutyl chloroformate, etc.) in an organic solvent (chloroform, dichloromethane, diethyl ether, THF, etc.) or without a solvent in the presence of a base (pyridine, triethylamine, dimethylaniline, dimethylaminopyridine, diisopropylethylamine, etc.) at 0 to 40°C, and then reacting the resulting mixed acid anhydride with an amine in an organic solvent (chloroform, dichloromethane, diethyl ether, THF, etc.) at 0 to 40°C. (3) Methods using a coupling agent include, for example, condensing a carboxylic acid and an amine in an organic solvent (chloroform, dichloromethane, DMF, diethyl ether, THF, etc.) or without a solvent, in or without a base (pyridine, triethylamine, dimethylaniline, dimethylaminopyridine, etc.), using a coupling agent (1,3-dicyclohexylcarbodiimide (DCC), 1-ethyl-3-[3-(dimethylamino)propyl]carbodiimide (EDC), 1,1'-carbonyldiimidazole (CDI), 2-chloro-1-methylpyridinium iodine, 1-propanephosphonic acid cyclic anhydride) This reaction is carried out using anhydride (e.g., PPA) or O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU) in the presence or absence of 1-hydroxybenztriazole (HOBt) at 0-40°C. The reactions (1), (2), and (3) should all be carried out under anhydrous conditions in an inert gas atmosphere (argon, nitrogen, etc.).

[0061] The compound represented by general formula 1a can be produced by reaction step formula 2. [ka] (In reaction equation 2, all symbols have the same meaning as above.)

[0062] In reaction step 2, reaction 2-1 is a cyclization reaction, which is carried out at a temperature of 0 to 100°C in the presence of an acid (such as trifluoroacetic acid) in an organic solvent (such as DMF, dimethyl sulfoxide, chloroform, dichloromethane, diethyl ether, THF, or methyl t-butyl ether).

[0063] In reaction step 2, reaction 2-2 is a reduction reaction of the carbonyl group, which is carried out in an organic solvent (such as dichloroethane, dichloromethane, DMF, THF, and mixtures thereof) in the presence of a reducing agent (such as sodium borohydride) at a temperature of 0 to 40°C.

[0064] In reaction step 2, reactions 2-3 are tosylation reactions, which can be carried out by reacting p-toluenesulfonyl chloride in an organic solvent (e.g., dichloromethane, diethyl ether, THF, acetonitrile, benzene, toluene) in the presence of a base (e.g., pyridine, triethylamine, dimethylaniline, dimethylaminopyridine, diisopropylethylamine, etc.) at a temperature of 0 to 100°C.

[0065] In reaction step 2, reactions 2-4 are azide reactions, which can be carried out by reacting sodium azide in an organic solvent (DMF, dimethyl sulfoxide, chloroform, dichloromethane, diethyl ether, THF, methyl t-butyl ether, etc.) at a temperature of 0 to 100°C.

[0066] In reaction step 2, reactions 2-5 are reduction reactions of azide groups, carried out in an organic solvent (e.g., THF, dioxane, dimethoxyethane, diethyl ether, methanol, ethanol, benzene, toluene, acetone, methyl ethyl ketone, acetonitrile, DMF, ethyl acetate, acetic acid, or a mixture of two or more of these solvents) in the presence of a hydrogenation catalyst (palladium-carbon, palladium black, palladium, palladium hydroxide, platinum dioxide, platinum-carbon, nickel, Raney nickel, ruthenium chloride, etc.), in or without an acid (hydrochloric acid, sulfuric acid, hypochlorous acid, boric acid, tetrafluoroboric acid, acetic acid, p-toluenesulfonic acid, oxalic acid, trifluoroacetic acid, formic acid, etc.), under atmospheric pressure or a pressurized hydrogen atmosphere, at 0-200°C.

[0067] In each reaction described herein, the compounds represented by general formulas 1b, 1d, 1g, 2a, and 2b, used as starting materials, are either known or can be easily produced by combining known methods, such as those described in Comprehensive Organic Transformations: A Guide to Functional Group Preparations, 3rd Edition (Richard C. Larock, John Wiley & Sons Inc, 2018), or by modifying known methods.

[0068] Among the disclosed compounds, those having optical activity can be produced by using optically active starting materials or reagents, by optically resolving a racemic intermediate and then proceeding to the disclosed compound, or by optically resolving a racemic compound of the disclosed compound. This optical resolution is well known, and examples include forming salts or complexes with other optically active compounds, recrystallizing them, and then isolating the target compound, or separating it directly using a chiral column or the like.

[0069] In each of the reactions described herein, reactions involving heating can be carried out using a water bath, an oil bath, a sand bath, or a microwave, as will be obvious to those skilled in the art. In each reaction described herein, a solid-phase supported reagent supported on a polymer (e.g., polystyrene, polyacrylamide, polypropylene, polyethylene glycol, etc.) may be used as appropriate.

[0070] In each reaction described herein, the reaction product can be purified by conventional purification methods, such as distillation under atmospheric or reduced pressure, high-performance liquid chromatography using silica gel or magnesium silicate, thin-layer chromatography, ion exchange resin, scavenger resin, or column chromatography, or by washing and recrystallization. Purification may be performed after each reaction or after several reactions have been completed. When recrystallization, seed crystals may or may not be used.

[0071] [toxicity] Since the toxicity of the disclosed compound is low, pharmaceutical compositions containing the disclosed compound can be used safely.

[0072] [Pharmaceutical composition] Because the disclosed compound has inhibitory activity against ABHD6, pharmaceutical compositions containing the disclosed compound are useful as preventive and / or therapeutic agents for diseases related to ABHD6, such as pain, neurological disorders, inflammatory diseases, autoimmune diseases, metabolic diseases, and malignant tumors.

[0073] More specifically, examples of pain include pain associated with osteoarthritis, cancer pain, pain associated with chemotherapy, chronic lower back pain, lower back pain associated with osteoporosis, fracture pain, pain associated with rheumatoid arthritis, neuropathic pain, postherpetic pain, pain associated with diabetic neuropathy, fibromyalgia, pain associated with pancreatitis, pain associated with interstitial cystitis / bladder pain syndrome, pain associated with endometriosis, pain associated with irritable bowel syndrome, migraines, and pain associated with pulpitis. Neurological disorders include, for example, tremors, dyskinesia, dystonia, spasticity, compulsive and obsessive behaviors, depression, mental disorders including anxiety disorders (e.g., panic disorder, acute stress reaction, post-traumatic stress disorder, obsessive-compulsive disorder, agoraphobia, social phobia), mood disorders, epilepsy, traumatic brain injury, spinal cord injury, multiple sclerosis, encephalomyelitis, Parkinson's disease, Huntington's disease, Alzheimer's disease, and sleep disorders.

[0074] Examples of inflammatory diseases include arthritis, rheumatoid arthritis, osteoarthritis, spondylitis, gout, vasculitis, Crohn's disease, and irritable bowel syndrome.

[0075] Examples of autoimmune diseases include psoriasis, amyotrophic lateral sclerosis (ALS), multiple sclerosis, Sjögren's syndrome, systemic lupus erythematosus, and AIDS.

[0076] Examples of metabolic diseases include obesity, metabolic syndrome, dyslipidemia, diabetes, and fatty liver disease.

[0077] Malignant tumors include, for example, breast cancer, ovarian cancer, colorectal cancer (e.g., colon cancer), lung cancer (e.g., non-small cell lung cancer), prostate cancer, head and neck cancer (e.g., oral squamous cell carcinoma, head and neck squamous cell carcinoma, pharyngeal cancer, laryngeal cancer, tongue cancer, thyroid cancer, acoustic neuroma, etc.), lymphoma (e.g., B-cell lymphoma, T-cell lymphoma, etc.), uveal melanoma, thymoma, mesothelioma, esophageal cancer, gastric cancer, and duodenal cancer. Examples include cancer, hepatocellular carcinoma, bile duct cancer, gallbladder cancer, pancreatic cancer, renal cell carcinoma, renal pelvis and ureteral cancer, bladder cancer, penile cancer, testicular cancer, uterine cancer, vaginal cancer, vulvar cancer, skin cancer (e.g., malignant melanoma), malignant bone tumors, soft tissue sarcomas, chondrosarcomas, leukemia (e.g., acute myeloid leukemia, acute lymphoblastic leukemia, chronic myeloid leukemia, chronic lymphocytic leukemia), myelodysplastic syndromes, brain tumors, or multiple myeloma.

[0078] In this specification, the prevention and / or treatment of malignant tumors includes, for example, treatments performed to (a) reduce the proliferation of cancer cells, (b) reduce cancer-related symptoms, improve the quality of life of cancer patients, (c) reduce the dose of other anticancer drugs or adjuvant cancer treatments already administered, (d) inhibit cancer progression, (e) inhibit cancer recurrence, and / or (f) extend the survival time of cancer patients. "Inhibiting cancer progression" means slowing the progression of cancer, stabilizing cancer-related symptoms, and reversing the progression of symptoms. "Inhibiting recurrence" means prophylactically preventing cancer recurrence in patients whose cancerous lesions have been completely or substantially eliminated or removed by cancer treatment or surgical resection of cancer.

[0079] Pharmaceutical compositions containing the disclosed compound typically include a pharmaceutically acceptable carrier. For use in the prevention and / or treatment of the above-mentioned diseases, the disclosed compound, which is the active ingredient, is typically formulated with a pharmaceutically acceptable carrier, such as various additives or solvents, and then administered systemically or topically, orally or parenterally. Here, a pharmaceutically acceptable carrier generally refers to a substance other than the active ingredient used in the formulation of pharmaceuticals. A pharmaceutically acceptable carrier is preferably one that does not exhibit pharmacological effects at the dosage of the formulation, is harmless, and does not interfere with the therapeutic effect of the active ingredient. Furthermore, a pharmaceutically acceptable carrier may be used to enhance the usefulness of the active ingredient and formulation, facilitate formulation, stabilize quality, or improve usability. Specifically, substances such as those listed in the "Dictionary of Pharmaceutical Additives" (edited by the Japan Pharmaceutical Additives Association), published by Yakuji Nippo Co., Ltd. in 2000, can be appropriately selected according to the purpose.

[0080] A pharmaceutical composition containing the disclosed compound may be a pharmaceutical composition administered to a subject (preferably a mammal, more preferably a human, and even more preferably a human patient) in a pharmaceutically effective amount of the disclosed compound. The dosage of the disclosed compound will inevitably vary depending on age, weight, symptoms, desired therapeutic effect, route of administration, and duration of treatment. Generally, it is administered orally to each patient in doses ranging from 0.1 ng to 1000 mg, or parenterally to each patient in doses ranging from 0.01 ng to 100 mg, or by continuous intravenous infusion. Of course, as mentioned above, the dosage of the disclosed compound will vary depending on various conditions, so in some cases a smaller amount than the above dosage may be sufficient, while in other cases an amount exceeding the range may be necessary.

[0081] Pharmaceutical compositions containing the disclosed compound can be in the form of various formulations, including, for example, oral formulations (e.g., tablets, capsules, granules, powders, oral liquids, syrups, oral jellies, etc.), oral formulations (e.g., oral tablets, oral sprays, semi-solid oral preparations, gargles, etc.), injectable formulations (e.g., injectables, etc.), dialysis formulations (e.g., dialysis preparations, etc.), inhalation formulations (e.g., inhalants, etc.), ophthalmic formulations (e.g., eye drops, eye ointments, etc.), otological formulations (e.g., ear drops, etc.), nasal formulations (e.g., nasal sprays, etc.), rectal formulations (e.g., suppositories, semi-solid rectal preparations, enema preparations, etc.), vaginal formulations (e.g., vaginal tablets, vaginal suppositories, etc.), and dermatological formulations (e.g., external solid preparations, external liquid preparations, sprays, ointments, creams, gels, patches, etc.).

[0082] [Oral administration formulation] Orally administered formulations include, for example, tablets, capsules, granules, powders, oral solutions, syrups, and oral jellies. Orally administered formulations also include rapidly disintegrating formulations, which do not have any particular control over the release of the active ingredient from the formulation, and release-controlled formulations, such as enteric-coated formulations and sustained-release formulations, in which the release is adjusted for a specific purpose through unique formulation design and manufacturing methods. Enteric-coated formulations are formulations designed to prevent the breakdown of the active ingredient in the stomach or to reduce the irritating effect of the active ingredient on the stomach, by not releasing the active ingredient in the stomach and instead releasing it mainly in the small intestine. They can usually be manufactured by coating the formulation with an acid-insoluble enteric-coated base. Sustained-release formulations are formulations in which the release rate, release time, and release site of the active ingredient from the formulation are adjusted for purposes such as reducing the number of administrations or reducing side effects. They can usually be manufactured by using an appropriate sustained-release agent. For oral formulations such as capsules, granules, and tablets, a suitable coating agent such as sugars, sugar alcohols, or high-molecular-weight compounds may be applied to facilitate administration or prevent the breakdown of the active ingredient.

[0083] (1) Tablets Tablets are solid preparations with a specific shape that are administered orally. These include not only commonly referred to tablets such as uncoated tablets, film-coated tablets, sugar-coated tablets, multilayer tablets, and core tablets, but also orally disintegrating tablets, chewable tablets, effervescent tablets, dispersible tablets, and dissolvable tablets. When manufacturing uncoated tablets, the following methods (a), (b), or (c) are typically used: (a) Add excipients such as excipients, binders, and disintegrants to the active ingredient and mix until homogenized. Then, using water or a binder-containing solution, form granules by an appropriate method, add lubricants and other additives, mix, and compress and mold. (b) The active ingredient is mixed with additives such as excipients, binders, and disintegrants to form a homogenous mixture, which is then directly compressed and molded, or granules prepared in advance with additives are mixed with the active ingredient and lubricants to form a homogenous mixture, which is then compressed and molded; (c) Additives such as excipients and binders to the active ingredient and mix until homogenized, then pour the mixture moistened with a solvent into a mold and shape it, and then dry it using an appropriate method; These are used. Film-coated tablets can usually be manufactured by applying a thin coating to an uncoated tablet with a suitable coating agent such as a polymer compound. Sugar-coated tablets can usually be manufactured by applying a coating to an uncoated tablet with a coating agent containing sugars or sugar alcohols. Multilayer tablets can be manufactured by stacking powders and granules of different compositions in layers using an appropriate method and then compressing them. Core tablets can be manufactured by covering an inner core tablet with outer layers of different compositions. Tablets can also be made into enteric-coated or sustained-release tablets using known appropriate methods. Orally disintegrating tablets, chewable tablets, effervescent tablets, dispersible tablets, and dissolving tablets are tablets that have been given unique functions by the appropriate selection of additives, and can be manufactured in accordance with the manufacturing methods of the tablets described above. Orally disintegrating tablets are tablets that can be quickly dissolved or disintegrated in the mouth for administration; chewable tablets are tablets that are chewed before administration; effervescent tablets are tablets that dissolve or disperse rapidly in water while effervescent; dispersible tablets are tablets that are dispersed in water for administration; and dissolvable tablets are tablets that are dissolved in water for administration. Effervescent tablets can be manufactured by using appropriate acidic substances, carbonates, bicarbonates, etc., as additives.

[0084] (2) Capsules Capsules are preparations in which a substance is filled into a capsule or encapsulated in a capsule base, and include hard capsules, soft capsules, etc. Hard capsules can be manufactured by mixing an active ingredient with excipients and other additives to make a homogeneous mixture, or by forming the mixture into granules or molded products using an appropriate method, and then filling the capsule as is or after light molding. Soft capsules can be manufactured by encapsulating an active ingredient with additives in a suitable capsule base such as gelatin with increased plasticity due to the addition of glycerin, D-sorbitol, etc., into a specific shape. Capsules can also be made into enteric-coated capsules or sustained-release capsules using known appropriate methods, and colorants or preservatives can be added to the capsule base.

[0085] (3) Granules Granules are formulations that have been granulated into granular form, and include not only those commonly referred to as granules, but also effervescent granules, etc. When manufacturing granules, the following methods (a), (b), or (c) are usually used: (a) After mixing the active ingredient in powder form with excipients, binders, disintegrants, or other additives to make it homogenized, it is formed into granules by an appropriate method; (b) Add excipients and other additives to the active ingredient which has been prepared in granular form in advance, and mix until homogenized; (c) Add excipients and other additives to the active ingredient that has been prepared in granular form in advance, mix, and form granules by an appropriate method; These are used. The granules may be coated as needed, and can also be made into enteric-coated or sustained-release granules using known appropriate methods. Effervescent granules can be manufactured by using appropriate acidic substances, carbonates, bicarbonates, etc. as additives. Effervescent granules refer to granules that dissolve or disperse rapidly in water while effervescent. Granules can also be made into fine granules by adjusting the particle size.

[0086] (4) Powder Powdered preparations are powdered formulations that can usually be manufactured by mixing an active ingredient with excipients or other additives to create a homogeneous mixture.

[0087] (5) Oral liquid preparations Oral solutions are liquid or fluid, viscous gel-like preparations, and generally include not only those referred to as oral solutions, but also elixirs, suspensions, emulsions, and lemonades. Oral solutions can usually be manufactured by adding an active ingredient, an additive, and purified water, mixing and dissolving them homogeneously, or emulsifying or suspending them, and filtering as necessary. An elixir is a clear, liquid oral solution containing ethanol with a sweet taste and aroma, and can usually be manufactured by dissolving a solid active ingredient or its extract with ethanol, purified water, a flavoring agent, and sucrose, other sugars, or a sweetener, and then filtering or otherwise obtaining a clear liquid. A suspension is an oral solution in which the active ingredient is finely and homogeneously suspended, and can usually be manufactured by adding a suspending agent or other additive and purified water or oil to a solid active ingredient, suspending it in an appropriate manner, and making the whole mixture homogeneous. An emulsion is an oral liquid preparation in which the active ingredient is emulsified into a fine, homogeneous form. It can usually be manufactured by adding an emulsifier and purified water to a liquid active ingredient, emulsifying it using an appropriate method, and ensuring the entire mixture is homogeneous. A limonade, on the other hand, is a clear, liquid oral preparation with a sweet and sour taste.

[0088] (6) Syrup Syrups are viscous liquid or solid preparations containing sugars or sweeteners, and include syrup preparations. Syrups can usually be manufactured by adding an active ingredient to a solution of sucrose, other sugars, or sweeteners, or to a simple syrup, dissolving, mixing, suspending, or emulsifying it, boiling the mixture as needed, and then filtering it while hot. Syrup preparations are granular or powdered preparations that become syrups when water is added, and are sometimes called dry syrup preparations. Syrup preparations can usually be manufactured using sugars or sweeteners as additives, in accordance with the manufacturing methods of the granular or powdered preparations described above.

[0089] (7) Oral jelly Oral jelly preparations are non-flowing, molded gel-like formulations that can usually be manufactured by mixing an active ingredient with additives and a polymer gel base, gelling it using an appropriate method, and then molding it into a specific shape.

[0090] [Injectable preparation] (1) Injectable Injectable preparations are sterile formulations, solutions, suspensions, emulsions, or solid preparations that are administered directly to body tissues or organs such as subcutaneously, intramuscularly, or intravascularly. These include not only what are commonly referred to as injectable preparations, but also lyophilized injectable preparations, powder injectable preparations, pre-filled syringes, cartridges, infusions, implantable injectable preparations, and sustained-release injectable preparations. When manufacturing injectable preparations, the following methods (a) or (b) are typically used: (a) The active ingredient, either as is or with additives added, is dissolved, suspended, or emulsified in sterile water for injection, other aqueous solvents, or non-aqueous solvents to form a homogeneous mixture, which is then filled into a container for injection, sealed, and sterilized; (b) The active ingredient, either as is or with additives added, is dissolved, suspended, or emulsified in water for injection, another aqueous solvent, or a non-aqueous solvent, and the resulting mixture is aseptically filtered, or the mixture is aseptically prepared and homogenized, and then filled into a container for injection and sealed; These are used. Lyophilized injectable preparations can usually be manufactured by dissolving the active ingredient as is, or the active ingredient and excipients in sterile water for injection, aseptically filtering it, filling it into an injectable container, and then lyophilizing it, or by lyophilizing it in a dedicated container and then filling it directly into a container. Powdered injectable preparations can usually be manufactured by processing them by aseptic filtration, then adding the powder obtained by crystallization or the powder to which sterilized additives have been added, and then filling it into an injectable container. Pre-filled syringe preparations can usually be manufactured by preparing a solution, suspension, or emulsion using the active ingredient as is, or using the active ingredient and additives, and then filling it into a syringe. Cartridge preparations refer to injectable preparations in which a cartridge filled with drug solution is placed in a dedicated syringe, and cartridges filled with drug solution can usually be manufactured by preparing a solution, suspension, or emulsion using the active ingredient as is, or using the active ingredient and additives, and then filling it into a cartridge. Infusion preparations refer to injectable preparations that are administered intravenously, usually in quantities of 100 mL or more. Implantable injectable drugs refer to solid or gel-type injectable drugs that are administered subcutaneously, intramuscularly, or via implantation devices or surgery, with the aim of releasing active ingredients over a long period of time. Implantable injectable drugs can usually be manufactured using biodegradable polymer compounds in the form of pellets, microspheres, or gels. Sustained-release injectable drugs refer to injectable drugs administered intramuscularly or via other means, with the aim of releasing active ingredients over a long period of time. They can usually be manufactured by dissolving or suspending the active ingredient in vegetable oil or other substances, or by creating a suspension of microspheres using biodegradable polymer compounds.

[0091] A pharmaceutical composition containing the disclosed compound is 1) Complementing and / or enhancing the preventive and / or therapeutic effects of the compounds disclosed herein, 2) Improvement of the kinetics and absorption of the disclosed compounds, reduction of dosage, and / or 3) Reduction of side effects of the disclosed compound It may be a pharmaceutical composition (or combination agent) administered in combination with other drugs for the purpose of achieving the desired effect.

[0092] The aforementioned pharmaceutical composition (or combination agent) may be administered in the form of a combination preparation containing both components in a single formulation, or it may be administered as separate formulations. When administered as separate formulations, this includes simultaneous administration and administration with a time difference. Furthermore, in the case of administration with a time difference, the disclosed compound may be administered first and the other drug afterward, or the other drug may be administered first and the disclosed compound afterward. Each of these administration methods may be the same or different.

[0093] The diseases for which the above-mentioned pharmaceutical composition (or combination agent) provides preventive and / or therapeutic effects are not particularly limited, and any disease that complements and / or enhances the preventive and / or therapeutic effects of the disclosed compound is acceptable.

[0094] Other agents for complementing and / or enhancing the pain-preventive and / or therapeutic effects of the disclosed compounds include, for example, acetaminophen, nonsteroidal anti-inflammatory drugs, opioids, antidepressants, antiepileptic drugs, N-methyl-D-aspartate antagonists, muscle relaxants, antiarrhythmics, steroids, and bisphosphonates.

[0095] Nonsteroidal anti-inflammatory drugs include, for example, aspirin preparations such as sazapyrin, sodium salicylate, aspirin, aspirin-dialuminate combination, diflunisal, indomethacin, suprofen, ufenamate, dimethylisopropylazulene, bufexamac, felbinac, diclofenac, tolmetin sodium, clinol, fenbufen, nabumetone, proglummetacin, indomethacin farnesil, acemetacin, proglummetacin maleate, amfenac sodium, mofezolac, etodolac, ibuprofen, ibuprofen piconol, naproxen, flurbiprofen, flurbiprofen axetil, ketoprofen, and fenoprofen calcium. Examples include tiaprofen, oxaprozin, pranoprofen, loxoprofen sodium, aluminoprofen, zaltoprofen, mefenamic acid, aluminum mefenamate, tolfenamic acid, phloxataphenin, ketophenylbutazone, oxyfenbutazone, piroxicam, tenoxicam, ampiroxicam, napagel ointment, epirizole, tiaramide hydrochloride, tinoridine hydrochloride, emorphazon, sulpyrine, migrenin, saridon, Sedes G, Amipiro-N, Sorbon, pyrine-based cold medicines, acetaminophen, phenacetin, dimethothiazine mesylate, meloxicam, celecoxib, lofecoxib, vardecoxib, simetride combination preparations, and non-pyrine cold medicines.

[0096] Examples of opioid drugs include codeine, fentanyl, hydromorphone, levorphanol, meperidine, methadone, morphine, oxycodone, oxymorphone, propoxyfen, and tramadol.

[0097] Examples of antidepressants include tricyclic antidepressants (e.g., amitriptyline hydrochloride, imipramine hydrochloride, clomipramine hydrochloride, dosurepin hydrochloride, nortriptyline hydrochloride, lofepramine hydrochloride, trimipramine maleate, amoxapine, etc.), tetracyclic antidepressants (e.g., maprotiline hydrochloride, mianserin hydrochloride, setiptiline maleate, etc.), monoamine oxidase (MAO) inhibitors (safrazine hydrochloride), serotonin and norepinephrine reuptake inhibitors (SNRIs) (e.g., milnacipran hydrochloride, venlafaxine hydrochloride, etc.), selective serotonin reuptake inhibitors (SSRIs) (e.g., fluvoxamine maleate, paroxetine hydrochloride, fluoxetine hydrochloride, citalopram hydrochloride, etc.), and serotonin reuptake inhibitors (e.g., trazodone hydrochloride, etc.).

[0098] Examples of antiepileptic drugs include phenobarbital, primidone, phenytoin, ethosuximide, zonisamide, nitrazepam, clonazepam, carbamazepine, sodium valproate, acetazolamide, and sultiam.

[0099] Examples of N-methyl-D-aspartate antagonists include ketamine hydrochloride, amantadine hydrochloride, memantine hydrochloride, dextromethorphan, and methadone.

[0100] Examples of muscle relaxants include succinylcholine, succinylcholine, vecuronium bromide, pancuronium bromide, and dantrolene sodium.

[0101] Examples of antiarrhythmic drugs include procainamide, disopyramide, cibenzoline, pirmenol, lidocaine, mexiletine, aprindine, pilsicainide, flecainide, propafenone, propranolol, atenolol, bisoprolol, amiodarone, sotalol, verapamil, diltiazem, and bepridil.

[0102] Examples of steroid medications include topical medications such as clobetasol propionate, diflorasone acetate, fluocinonide, mometasone furoate, betamethasone dipropionate, betamethasone propionate butyrate, betamethasone valerate, difluprednate, budesonide, diflucortolone valerate, amcinonide, halcinonide, dexamethasone, dexamethasone propionate, dexamethasone valerate, and dexamethasone acetate. Examples include tazone, hydrocortisone acetate, hydrocortisone butyrate, hydrocortisone propionate butyrate, deprodone propionate, prednisolone acetate valerate, fluocinolone acetonide, beclomethasone propionate, triamcinolone acetonide, flumethasone pivalate, alclomethasone propionate, clobetazone butyrate, prednisolone, beclomethasone propionate, and fludroxycortide. Oral or injectable medications include cortisone acetate, hydrocortisone, sodium hydrocortisone phosphate, sodium hydrocortisone succinate, fludrocortisone acetate, prednisolone, prednisolone acetate, sodium prednisolone succinate, prednisolone butylacetate, sodium prednisolone phosphate, halopredone acetate, methylprednisolone, methylprednisolone acetate, sodium methylprednisolone succinate, triamcinolone, triamcinolone acetate, triamcinolone acetonide, dexamethasone, dexamethasone acetate, sodium dexamethasone phosphate, dexamethasone palmitate, paramethasone acetate, and betamethasone.

[0103] Examples of inhaled medications include beclomethasone propionate, fluticasone propionate, budesonide, flunisolide, triamcinolone, ST-126P, ciclesonide, dexamethasone paromithionate, mometasone furacarbonate, prasterone sulfonate, deflazacort, methylprednisolone sleptanate, and methylprednisolone sodium succinate.

[0104] Examples of bisphosphonate drugs include etidronate, pamidronate, alendronate, risedronate, zoledronate, and minodronate.

[0105] Other medications may be administered in any combination of two or more types.

[0106] Furthermore, other agents that complement and / or enhance the preventive and / or therapeutic effects of the disclosed compounds include those already discovered, as well as those yet to be discovered, based on the mechanisms described above. Unless otherwise defined, all technical and scientific terms and abbreviations used herein have the same meanings as those commonly understood by those skilled in the art. Furthermore, all patent and non-patent documents or references explicitly cited herein may be incorporated herein by reference as part of this specification.

[0107] This disclosure provides, in one embodiment, the following embodiments. [1] General formula (IA): [ka] (In the formula, X 1 , X 2 These are (1) CH and (2) CR, respectively, independently. X , or (3) N, where X 1 and X 2 At least one of them represents N, R 1 This represents a halogen atom, R X This represents (1) a halogen atom, (2) a C1-6 alkyl group, (3) a C2-6 alkenyl group, (4) a C2-6 alkynyl group, (5) a C1-6 alkoxy group, (6) a C1-6 haloalkyl group, (7) a C2-6 haloalkenyl group, (8) a C2-6 haloalkynyl group, (9) a C1-6 haloalkoxy group, or (10) a cyano group. R 2This represents (1) a halogen atom, (2) a C1-6 alkyl group, (3) a C2-6 alkenyl group, (4) a C2-6 alkynyl group, (5) a C1-6 alkoxy group, (6) a C1-6 haloalkyl group, (7) a C2-6 haloalkenyl group, (8) a C2-6 haloalkynyl group, (9) a C1-6 haloalkoxy group, or (10) a cyano group. When m is 2 or greater, multiple R 2 They may be the same or different. R 3 This represents (1) a hydrogen atom, (2) a C1-6 alkyl group, (3) a C1-6 haloalkyl group, (4) a 3-10 membered cyclic group, (5)-(C1-6 alkylene)-(3-10 membered cyclic group), and (6)-(C1-6 haloalkylene)-(3-10 membered cyclic group), wherein one or two carbon atoms in the C1-6 alkyl group, C1-6 haloalkyl group, C1-6 alkylene, and C1-6 haloalkylene may be replaced by an oxygen atom or an oxidized sulfur atom. R 3 The 3-10 membered cyclic group inside contains 1-5 R 301 It may also be replaced with R 301 (1) halogen atom, (2) C1-4 alkyl group, (3) C1-4 alkoxy group, (4) C1-4 haloalkyl group, (5) C1-4 haloalkoxy group, (6) COOR 302 (7) CONR 303 R 304 (8) C3-6 cycloalkyl group, (9) hydroxyl group, (10) nitro group, (11) cyano group, (12)-NR 305 R 306 (13)-SR 307 (14)-SOR 308 (15)-SO2R 309 , or (16) representing an oxo group, R 301 When two or more substitutions occur, multiple R 301 They may be the same or different. R 302 , R 303 , R 304 , R 305 , R 306 , R 307 , R308 , or R 309 Each of these independently represents either (1) a hydrogen atom or (2) a C1-4 alkyl group. R 2 R 2 This represents (2) to (9) inside, R 3 When R represents a C1-6 alkyl group, 2 and R 3 It may also form a 5-6 membered cyclic group together with the atom to which it is bonded. R 4 This represents (1) a halogen atom, (2) a C1-6 alkyl group, (3) a C2-6 alkenyl group, (4) a C2-6 alkynyl group, (5) a C1-6 alkoxy group, (6) a C1-6 haloalkyl group, (7) a C2-6 haloalkenyl group, (8) a C2-6 haloalkynyl group, or (9) a C1-6 haloalkoxy group. When n is 2 or greater, multiple R 4 They may be the same or different. Two R atoms located on the same carbon atom 4 When represents a C1-6 alkyl group, it may form a C3-6 cycloalkyl group together with the bonded carbon atom. ring1 represents a 3-15 membered cyclic group, R 5-A (1) halogen atom, (2) C1-6 alkyl group, (3) C2-6 alkenyl group, (4) C2-6 alkynyl group, (5) C1-6 alkoxy group, (6) C1-6 alkylthio group, (7) C1-6 alkylsulfinyl group, (8) C1-6 alkylsulfonyl group, (9) C2-6 acyl group, (10) 3-6 membered cyclic group, (11)-L R5 -(3-6 membered cyclic group), (12) hydroxyl group, (13) nitro group, (14) cyano group, (15) oxo group, (16)-NR 501 R 502 (17)-COOR 503 (18)-CONR 504 R 505 , or (19)-SO2NR 506 R 507The C1-6 alkyl group, C2-6 alkenyl group, C2-6 alkynyl group, C1-6 alkoxy group, C1-6 alkylthio group, C1-6 alkylsulfinyl group, C1-6 alkylsulfonyl group, and C2-6 acyl group may have 1-2 carbon atoms replaced by oxygen atoms or sulfur atoms that may be oxidized. When p is 2 or greater, multiple R 5-A They may be the same or different. R 5-A Of these, the bases (2) to (11) have 1 to 9 R 508 It may also be replaced with R 508 (1) halogen atom, (2) C1-4 alkyl group, (3) C1-4 alkoxy group, (4) C2-6 acyl group, (5) C3-6 cycloalkyl group, (6) hydroxyl group, or (7)-NR 509 R 510 This represents, R 508 When two or more substitutions occur, multiple R 508 They may be the same or different. L R5 (1)-O-, (2)-(C1-4 alkylene)-, (3)-O-(C1-4 alkylene)-, (4)-(C1-4 alkylene)-O-, (5)-NR 511 -, or (6)-SO 0-2 - represents, R 501 , R 502 , R 503 , R 504 , R 505 , R 506 , R 507 , R 509 , R 510 , or R 511 Each of these independently represents (1) a hydrogen atom, (2) a C1-6 alkyl group, (3) a C2-6 acyl group, or (4) a C1-6 alkylsulfonyl group. m represents an integer between 0 and 2. n represents an integer from 0 to 5. A pharmaceutical composition containing a compound represented by (where p is an integer from 0 to 5), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. [2] General formula (I): [ka] (In the formula, X 1 , X 2 These are (1) CH and (2) CR, respectively, independently. X , or (3) N, where X 1 and X 2 At least one of them represents N, R 1 This represents a halogen atom, R X This represents (1) a halogen atom, (2) a C1-6 alkyl group, (3) a C2-6 alkenyl group, (4) a C2-6 alkynyl group, (5) a C1-6 alkoxy group, (6) a C1-6 haloalkyl group, (7) a C2-6 haloalkenyl group, (8) a C2-6 haloalkynyl group, (9) a C1-6 haloalkoxy group, or (10) a cyano group. R 2 This represents (1) a halogen atom, (2) a C1-6 alkyl group, (3) a C2-6 alkenyl group, (4) a C2-6 alkynyl group, (5) a C1-6 alkoxy group, (6) a C1-6 haloalkyl group, (7) a C2-6 haloalkenyl group, (8) a C2-6 haloalkynyl group, (9) a C1-6 haloalkoxy group, or (10) a cyano group. When m is 2 or greater, multiple R 2 They may be the same or different. R 3 This represents (1) a hydrogen atom, (2) a C1-6 alkyl group, (3) a C1-6 haloalkyl group, (4) a 3-10 membered cyclic group, (5)-(C1-6 alkylene)-(3-10 membered cyclic group), and (6)-(C1-6 haloalkylene)-(3-10 membered cyclic group), wherein one or two carbon atoms in the C1-6 alkyl group, C1-6 haloalkyl group, C1-6 alkylene, and C1-6 haloalkylene may be replaced by an oxygen atom or an oxidized sulfur atom. R 3 The 3-10 membered cyclic group inside contains 1-5 R 301 It may also be replaced with R 301(1) halogen atom, (2) C1-4 alkyl group, (3) C1-4 alkoxy group, (4) C1-4 haloalkyl group, (5) C1-4 haloalkoxy group, (6) COOR 302 (7) CONR 303 R 304 (8) C3-6 cycloalkyl group, (9) hydroxyl group, (10) nitro group, (11) cyano group, (12)-NR 305 R 306 (13)-SR 307 (14)-SOR 308 (15)-SO2R 309 , or (16) representing an oxo group, R 301 When two or more substitutions occur, multiple R 301 They may be the same or different. R 302 , R 303 , R 304 , R 305 , R 306 , R 307 , R 308 , or R 309 Each of these independently represents either (1) a hydrogen atom or (2) a C1-4 alkyl group. R 2 R 2 This represents (2) to (9) inside, R 3 When R represents a C1-6 alkyl group, 2 and R 3 It may also form a 5-6 membered cyclic group together with the atom to which it is bonded. R 4 This represents (1) a halogen atom, (2) a C1-6 alkyl group, (3) a C2-6 alkenyl group, (4) a C2-6 alkynyl group, (5) a C1-6 alkoxy group, (6) a C1-6 haloalkyl group, (7) a C2-6 haloalkenyl group, (8) a C2-6 haloalkynyl group, or (9) a C1-6 haloalkoxy group. When n is 2 or greater, multiple R 4 They may be the same or different. Two R atoms located on the same carbon atom 4 When represents a C1-6 alkyl group, it may form a C3-6 cycloalkyl group together with the bonded carbon atom. ring1 represents a 3-15 membered cyclic group, R 5 (1) halogen atom, (2) C1-6 alkyl group, (3) C2-6 alkenyl group, (4) C2-6 alkynyl group, (5) C1-6 alkoxy group, (6) C1-6 alkylthio group, (7) C1-6 alkylsulfinyl group, (8) C1-6 alkylsulfonyl group, (9) C2-6 acyl group, (10) 3-6 membered cyclic group, (11)-L R5 -(3-6 membered cyclic group), (12) hydroxyl group, (13) nitro group, (14) cyano group, (15) oxo group, (16)-NR 501 R 502 (17)-COOR 503 (18)-CONR 504 R 505 , or (19)-SO2NR 506 R 507 This represents, When p is 2 or greater, multiple R 5 They may be the same or different. R 5 Of these, the bases (2) to (11) have 1 to 9 R 508 It may also be replaced with R 508 (1) halogen atom, (2) C1-4 alkyl group, (3) C1-4 alkoxy group, (4) C2-6 acyl group, (5) C3-6 cycloalkyl group, (6) hydroxyl group, or (7)-NR 509 R 510 This represents, R 508 When two or more substitutions occur, multiple R 508 They may be the same or different. L R5 (1)-O-, (2)-(C1-4 alkylene)-, (3)-O-(C1-4 alkylene)-, (4)-(C1-4 alkylene)-O-, (5)-NR 511 -, or (6)-SO 0-2 - represents, R 501 , R 502 , R 503 , R 504 , R 505 , R 506 , R507 , R 509 , R 510 , or R 511 Each of these independently represents (1) a hydrogen atom, (2) a C1-6 alkyl group, (3) a C2-6 acyl group, or (4) a C1-6 alkylsulfonyl group. m represents an integer between 0 and 2. n represents an integer from 0 to 5. A pharmaceutical composition containing a compound represented by (where p is an integer from 0 to 5), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. [3] ring1 is a 3-10 membered cyclic group or [ka] The pharmaceutical composition according to [1] or [2] above, wherein (wherein the formula, the * indicates the bond position with the carbonyl group.) [4] ring1 has the following ring structure; [ka] (In the formula, the * indicates the bond position with the carbonyl group, and the hydrogen atom represented by NH is R) 5-A The pharmaceutical composition according to [1] or [3] above, wherein the ring structure is selected from the group consisting of (which may be replaced by ). [5] ring1 has the following ring structure; [ka] (In the formula, the * indicates the bond position with the carbonyl group, and the hydrogen atom represented by NH is R) 5 The pharmaceutical composition according to [2] or [3], wherein the ring structure is selected from the group consisting of (which may be replaced by ). [6] ring1 has the following ring structure; [ka] (In the formula, the * indicates the bond position with the carbonyl group, and the hydrogen atom represented by NH is R) 5-A or R 5A pharmaceutical composition according to any one of the above [1] to [5], wherein the ring structure is selected from the group consisting of (which may be replaced by ). [7] R 5-A or R 5 However, (1) halogen atom, (2) C1-6 alkyl group, (3) C1-6 alkoxy group, (4) C1-6 haloalkyl group, (5) C1-6 haloalkoxy group, (6) 3-6 membered cyclic group, (7) oxo group, (8)-NR 501 R 502 , or (9)-COOR 503 A pharmaceutical composition according to any one of the above items [1] to [6]. [8] R 5-A or R 5 The pharmaceutical composition according to any one of the above [1] to [7], wherein the (1) C1-6 alkyl group, (2) C1-6 alkoxy group, (3) C1-6 haloalkyl group, (4) C1-6 haloalkoxy group, (5) cyclopropyl group, (6) furan ring, (7) N-methylpyrazole ring, (8) oxo group, (9) dimethylamino group, or (10)-COOCH3. [9] R 3 The pharmaceutical composition according to any one of the above [1] to [8], wherein the member is (1) a hydrogen atom, (2) a C1-6 alkyl group, (3) a C1-6 haloalkyl group, (4) a 3-10 membered cyclic group, or (5) a CH2-(3-10 membered cyclic group).

[10] R 3 However, (1) a hydrogen atom, (2) a C1-6 alkyl group, (3) a C1-6 haloalkyl group, (4) a cyclopropyl group, or (5)-CH2-Q, A pharmaceutical composition according to any one of the above [1] to [9], wherein Q is (1) benzene, (2) pyridine, or (3) imidazo[2,1-b]thiazole.

[11] X 1 , X 2 A pharmaceutical composition according to any one of the above items [1] to

[10] , wherein all of the above are N.

[12] A compound represented by general formula (IA) or general formula (I), or a pharmaceutically acceptable salt thereof, is classified as general formula (I-1): [ka] (In the formula, R 3-a This represents (1) a hydrogen atom, (2) a C1-6 alkyl group, (3) a C1-6 haloalkyl group, (4) a cyclopropyl group, or (5) -CH2-Q. ring1-a has the following ring structure; [ka] (In the formula, the * indicates the bond position with the carbonyl group, and the hydrogen atom represented by NH is R) 5-a It may be replaced by ). Represents a ring structure selected from the group consisting of ) R 5-a This represents (1) a C1-6 alkyl group, (2) a C1-6 alkoxy group, (3) a C1-6 haloalkyl group, (4) a C1-6 haloalkoxy group, (5) a cyclopropyl group, (6) a furan ring, (7) an N-methylpyrazole ring, (8) an oxo group, (9) a dimethylamino group, or (10)-COOCH3. Other symbols have the same meaning as the symbols described in [1], [2], or

[10] above.) A pharmaceutical composition according to any one of [1] to

[11] above, which is a compound represented by ) or a pharmaceutically acceptable salt thereof.

[13] ring1-a has the following ring structure; [ka] (In the formula, the * indicates the bond position with the carbonyl group, and the hydrogen atom represented by NH is R) 5ーa The pharmaceutical composition according to

[12] above, wherein the ring structure is selected from the group consisting of (which may be replaced by ).

[14] A compound represented by general formula (IA) or general formula (I), or a pharmaceutically acceptable salt thereof, (1) {(3aS,4R,6aR)-4-[(6-chloro-3-pyridazinyl)amino]hexahydrocyclopenta[c]pyrrole-2(1H)-yl}[5-(difluoromethyl)-2-thienyl]methanone, (2) {(3aS,4R,6aR)-4-[(6-chloro-3-pyridazinyl)amino]hexahydrocyclopenta[c]pyrrole-2(1H)-yl}(5-methyl-2-thienyl)methanone, (3)[(3aS,4R,6aR)-4-[(6-chloro-3-pyridazinyl)amino]hexahydrocyclopenta[c]pyrrole-2(1H)-yl](6,7-dihydro-4H-thieno[3,2-c]pyran-2-yl)methanone, (4)[(3aS,4R,6aR)-4-[(6-bromo-3-pyridazinyl)amino]hexahydrocyclopenta[c]pyrrole-2(1H)-yl](5-methyl-2-thienyl)methanone, (5)[(3aS,4R,6aR)-4-[(6-bromo-3-pyridazinyl)amino]hexahydrocyclopenta[c]pyrrole-2(1H)-yl](6,7-dihydro-4H-thieno[3,2-c]pyran-2-yl)methanone, (6)[(3aS,4R,6aR)-4-[(6-bromo-3-pyridazinyl)amino]hexahydrocyclopenta[c]pyrrole-2(1H)-yl](2-methyl-2H-thieno[3,2-c]pyrazole-5-yl)methanone, (7)[(3aS,4R,6aR)-4-[benzyl(6-bromo-3-pyridazinyl)amino]hexahydrocyclopenta[c]pyrrole-2(1H)-yl](5-methyl-2-thienyl)methanone, (8)rel-6-chloro-3-({(3aS,4R,6aR)-2-[(5-methyl-2-thienyl)carbonyl]octahydrocyclopenta[c]pyrrole-4-yl}amino)-4-pyridazinecarbonitride, (9){(3aR,4R,6aS)-4-[(6-chloro-3-pyridazinyl)amino]-3a-fluorohexahydrocyclopenta[c]pyrrole-2(1H)-yl}(6,7-dihydro-4H-thieno[3,2-c]pyran-2-yl)methanone, and (10) A compound selected from the group consisting of [(3aR,6R,6aS)-6-[(6-bromo-3-pyridazinyl)amino]-4,4-difluorohexahydrocyclopenta[c]pyrrole-2(1H)-yl](6,7-dihydro-4H-thieno[3,2-c]pyran-2-yl)methanone, or a pharmaceutically acceptable salt thereof, according to [1] or [2] above.

[15] A compound represented by general formula (IA) or general formula (I), or a pharmaceutically acceptable salt thereof, (1)[(3aS,4R,6aR)-4-[(6-bromo-3-pyridazinyl)(methyl)amino]hexahydrocyclopenta[c]pyrrole-2(1H)-yl](5-methyl-2-thienyl)methanone, (2)[(3aS,4R,6aR)-4-[(6-bromo-3-pyridazinyl)(methyl)amino]hexahydrocyclopenta[c]pyrrole-2(1H)-yl]{5-[2-(2-fluoroethoxy)ethyl]-2-thienyl}methanone, (3)[(3aS,4R,6aR)-4-[(6-bromo-3-pyridazinyl)(methyl)amino]hexahydrocyclopenta[c]pyrrole-2(1H)-yl][5-(2-fluoroethoxy)-2-thienyl]methanone, and (4) A compound selected from the group consisting of [(3aS,4R,6aR)-4-{(6-bromo-3-pyridazinyl)[2-(2-fluoroethoxy)ethyl]amino}hexahydrocyclopenta[c]pyrrole-2(1H)-yl](5-methyl-2-thienyl)methanone, or a pharmaceutically acceptable salt thereof, according to [1] or [2] above.

[16] A pharmaceutical composition according to any one of the above items [1] to

[15] , which is an ABHD6 inhibitor.

[17] A pharmaceutical composition according to any one of the above [1] to

[16] , which is a treatment and / or prophylactic agent for diseases related to ABHD6.

[18] The pharmaceutical composition according to

[17] , wherein the disease associated with ABHD6 is pain, neurological disease, inflammatory disease, autoimmune disease, metabolic disease, or malignant tumor.

[19] The pharmaceutical composition according to

[17] or

[18] above, wherein the disease associated with ABHD6 is pain, and the pain is pain associated with osteoarthritis, cancer pain, pain associated with chemotherapy, chronic low back pain, low back pain associated with osteoporosis, fracture pain, pain associated with rheumatoid arthritis, neuropathic pain, postherpetic pain, pain associated with diabetic neuropathy, fibromyalgia, pain associated with pancreatitis, pain associated with interstitial cystitis / bladder pain syndrome, pain associated with endometriosis, pain associated with irritable bowel syndrome, migraine, or pain associated with pulpitis.

[20] The pharmaceutical composition according to

[17] or

[18] , wherein the disorder associated with ABHD6 is a neurological disorder, and the neurological disorder is tremor, dyskinesia, dystonia, spasticity, compulsive and obsessive behavior, depression, anxiety disorder, panic disorder, acute stress reaction, post-traumatic stress disorder, obsessive-compulsive disorder, agoraphobia, social phobia, mood disorder, epilepsy, traumatic brain injury, spinal cord injury, multiple sclerosis, encephalomyelitis, Parkinson's disease, Huntington's disease, Alzheimer's disease, or sleep disorder.

[21] The pharmaceutical composition according to any one of the above

[16] to

[20] , characterized in that it is administered in combination with at least one selected from the group consisting of acetaminophen, nonsteroidal anti-inflammatory drugs, opioid drugs, antidepressants, antiepileptic drugs, N-methyl-D-aspartate antagonists, muscle relaxants, antiarrhythmic drugs, steroids, and bisphosphonate drugs.

[22] A therapeutic and / or prophylactic agent for diseases associated with ABHD6, comprising any one of the compounds described in [1] to

[15] above, or a pharmaceutically acceptable salt thereof.

[23] A method for preventing and / or treating a disease related to ABHD6, characterized by administering a pharmaceutical composition containing a compound described in any one of the above items [1] to

[15] , or a pharmaceutically acceptable salt thereof, to a patient who is in need of prevention and / or treatment of a disease related to ABHD6.

[24] A pharmaceutical composition containing one of the compounds described in any one of the preceding paragraphs [1] to

[15] , or a pharmaceutically acceptable salt thereof, for use in the prevention and / or treatment of diseases associated with ABHD6.

[25] Use of any compound described in any one of the preceding paragraphs [1] to

[15] , or a pharmaceutically acceptable salt thereof, for the manufacture of a prophylactic and / or therapeutic agent for diseases associated with ABHD6.

[0108] [Synthesis Examples] The solvents in parentheses in the chromatographic separation section and the TLC section indicate the elution or developing solvent used, and the percentages represent volume ratios. The solvent indicated in parentheses next to the NMR section is the solvent used for the measurement. The compound names used herein are generally named using the computer program ACD / Name®, which names compounds according to IUPAC rules, or using Chemdraw Ultra (version 12.0, Cambridge Soft), or according to IUPAC nomenclature. LC-MS / ELSD was performed under the following TFA or formic acid conditions. TFA conditions; Column: YMC Triart C 18 (Particle size: 1.9x10) -6 m; Column length: 30 x 2.0 mm ID); Flow rate: 1.0 mL / min; Column temperature: 30°C; Mobile phase (A): 0.1% trifluoroacetic acid aqueous solution; Mobile phase (B): 0.1% trifluoroacetic acid-acetonitrile solution; Gradient (Ratio of mobile phase (A): mobile phase (B) indicated): [0 min] 95:5; [0.1 min] 95:5; [1.2 min] 5:95; [1.6 min] 5:95; Detector: UV (PDA), ELSD, MS. Formic acid conditions; Column: YMC Triart C 18 (Particle size: 1.9x10) -6 m; Column length: 30 x 2.0 mm ID); Flow rate: 1.0 mL / min; Column temperature: 30°C; Mobile phase (A): 0.1% formic acid aqueous solution; Mobile phase (B): 0.1% formic acid-acetonitrile solution; Gradient (Ratio of mobile phase (A): mobile phase (B) indicated): [0 min] 95:5; [0.1 min] 95:5; [1.2 min] 5:95; [1.6 min] 5:95; Detector: UV (PDA), ELSD, MS. Unless otherwise specified, the HPLC retention time refers to the retention time under the conditions described in the LC-MS / ELSD section above. The information in parentheses next to the HPLC retention time indicates the measurement conditions.

[0109] Reference Example 1: 2-benzylhexahydrocyclopenta[c]pyrrole-4(1H)-one 50 g of N-benzyl-N-(methoxymethyl)-N-trimethylsilylmethylamine (CAS No. 93102-05-7) was dissolved in dichloromethane (600 mL), to which 2-cyclopentenone (CAS No. 930-30-3, 17 g) and trifluoroacetic acid (CAS No. 76-05-1, 240 mg) were added, and the mixture was stirred at room temperature for 16 hours. Triethylamine (430 mg) was added to the reaction mixture, and the mixture was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound (30 g). HPLC retention time (min): 0.65 (TFA); MS(ESI, Pos.):226(M+H) + .

[0110] Reference Example 2: (R)-N-((3aS,6aR,E)-2-benzylhexahydrocyclopenta[c]pyrrole-4(1H)-ylidene)-2-methylpropane-2-sulfinamide To a solution of the compound (20 g) prepared in Reference Example 1 in THF (300 mL), titanium(IV) ethoxide (CAS No.: 3037-36-3, 46.6 g) and (R)-(+)-2-methyl-2-propanesulfinamide (CAS No.: 196929-78-9, 11.8 g) were added and the mixture was stirred at 60°C for 15 hours. The reaction mixture was slowly poured into saturated sodium bicarbonate aqueous solution and dichloromethane and filtered. The mixture was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound (12.4 g). HPLC retention time (min): 0.80 (TFA); MS(ESI, Pos.):319(M+H) + .

[0111] Reference Example 3: (3aS,6aR)-2-benzylhexahydrocyclopenta[c]pyrrole-4(1H)-one To a solution of the compound (20 g) prepared in Reference Example 2 in THF (60 mL), 2N hydrochloric acid (60 mL) was added and the mixture was stirred at room temperature for 1 hour. The reaction mixture was neutralized with 2N sodium hydroxide and extracted with dichloromethane. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting title compound was used in the next reaction without purification.

[0112] Reference Example 4: 2-Methyl-2-propanyl (3aS,6aR)-4-oxohexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate Di-tert-butyl dicarbonate (CAS No.: 24424-99-5, 9.4 g) and 20% palladium hydroxide (CAS No.: 12135-22-7, 700 mg) were added to a THF (60 mL) solution of the compound prepared in Reference Example 3, and the mixture was stirred at room temperature under a hydrogen atmosphere for 15 hours. The reaction mixture was filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound (7.0 g). 1 H-NMR (CD3OD): δ3.66-3.53, 3.14, 3.06-2.98, 2.76-2.71, 2.39-2.35, 2.21-2.12, 1.87 1.45.

[0113] Reference Example 5: 2-Methyl-2-propanyl (3aS,4S,6aR)-4-hydroxyhexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate To a THF (200 mL) solution of the compound (7.3 g) prepared in Reference Example 4, 1 M lithium tri-sec-butylbohydride THF solution (CAS number: 38721-52-7, 49 mL) was added at -78°C and the mixture was stirred at -78°C for 1 hour. A 35% aqueous hydrogen peroxide solution was slowly added to the reaction mixture at 0°C until the foaming subsided, and the mixture was extracted with dichloromethane. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound (6.5 g). 1 H-NMR(CDCl3): δ4.30-4.25, 3.63-3.50, 3.38-3.30, 3.17-3.15, 2.67, 1.90-1.73, 1.73-1.54, 1.47.

[0114] Reference Example 6: 2-Methyl-2-propanyl (3aS,4S,6aR)-4-{[(4-methylphenyl)sulfonyl]oxy}hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate To a solution of the compound (6.5 g) prepared in Reference Example 5 in dichloromethane (100 mL), triethylamine (12 mL), p-toluenesulfonyl chloride (CAS No.: 98-59-9, 8.2 g), and trimethylamine hydrochloride (CAS No.: 75-50-3, 820 mg) were added and the mixture was stirred at room temperature for 6 hours. Saturated sodium bicarbonate aqueous solution was added to the reaction mixture and extracted with dichloromethane. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound (9.3 g). HPLC retention time (min): 1.2 (TFA); MS(ESI, Pos.):382(M+H) + .

[0115] Reference Example 7: 2-Methyl-2-propanyl (3aS,4R,6aR)-4-azidohexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate To a solution of the compound (9.3 g) prepared in Reference Example 6 in dimethyl sulfoxide (72 mL), sodium azide (CAS number: 26628-22-8, 3.2 g) was added and the mixture was stirred at 60°C for 6 hours. Water was added to the reaction mixture and extracted with dichloromethane. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and used in the next reaction without purification.

[0116] Reference Example 8: 2-Methyl-2-propanyl (3aS,4R,6aR)-4-aminohexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate To a solution of the compound (6.5 g) prepared in Reference Example 7 in ethanol (240 mL), 20% palladium hydroxide (930 mg) was added, and the mixture was stirred at room temperature under a hydrogen atmosphere for 15 hours. The reaction mixture was filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound (4.5 g). HPLC retention time (min): 0.77 (TFA); MS(ESI, Pos.):227(M+H) + .

[0117] Reference Example 9: 2-Methyl-2-propanyl (3aS,4R,6aR)-4-[(6-chloro-3-pyridazinyl)amino]hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate To a solution of the compound (1.5 g) prepared in Reference Example 8 in N,N-dimethylacetamide (DMA) (25 mL), N,N-diisopropylethylamine (DIPEA) (6.9 mL) and 3,6-dichloropyridazine (CAS number: 141-30-0, 1.5 g) were added, and the mixture was stirred at 160°C for 1 hour. Water was added to the reaction mixture, and it was extracted with dichloromethane. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound (1.5 g). HPLC retention time (minutes): 0.89 (formic acid); MS(ESI, Pos.):339(M+H) + .

[0118] Reference Example 10: (3aS,4R,6aR)-N-(6-chloro-3-pyridazinyl)octahydrocyclopenta[c]pyrrole-4-amine dihydrochloride 1.2 g of the compound prepared in Reference Example 9 was mixed with 4N hydrochloric acid (1,4-dioxane solution, 12 mL) and stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure to obtain the title compound (1.0 g). HPLC retention time (minutes): 0.59 (formic acid); MS(ESI, Pos.):239(M+H) + .

[0119] Reference Example 10-1: rel-(3aS,4R,6aR)-N-(6-chloro-3-pyridazinyl)octahydrocyclopenta[c]pyrrole-4-amine dihydrochloride racemic mixture The title compound was obtained by using the compound prepared in Reference Example 1 instead of the compound prepared in Reference Example 3, and performing the same procedure as in Reference Example 4 → Reference Example 5 → Reference Example 6 → Reference Example 7 → Reference Example 8 → Reference Example 9 → Reference Example 10.

[0120] Example 1: {(3aS,4R,6aR)-4-[(6-chloro-3-pyridazinyl)amino]hexahydrocyclopenta[c]pyrrole-2(1H)-yl}[5-(difluoromethyl)-2-thienyl]methanone [ka] To a DMA (0.5 mL) solution of the compound (30 mg) prepared in Reference Example 10, DIPEA (0.083 mL), 5-(difluoromethyl)thiophene-2-carboxylic acid (CAS No.: 189330-23-2, 19 mg), and O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (hereinafter referred to as HATU) (CAS No.: 148893-10-1, 38 mg) were added, and the mixture was stirred at room temperature for 3 hours. Water was added to the reaction mixture, and it was extracted with dichloromethane. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound (32 mg). HPLC retention time (min): 0.88 (TFA); MS(ESI, Pos.):399(M+H) + ; 1 H-NMR(CDCl3): δ7.43, 7.18, 6.83, 6.63, 4.78-4.52, 4.12, 3.88, 3.67, 3.49, 2.99-2.80, 2.79-2.61, 2.36, 2.13, 1.69-1.57.

[0121] Examples 1-1 to 1-6 The title compound was obtained by performing the same procedure as in Example 1, using the compound prepared in Reference Example 10 or the compound prepared in Reference Example 10-1 instead of the compound prepared in Reference Example 10, using the corresponding carboxylic acid compound instead of 5-(difluoromethyl)thiophene-2-carboxylic acid.

[0122] Example 1-1: rel-1,3-benzothiazole-2-yl{(3aS,4R,6aR)-4-[(6-chloro-3-pyridazinyl)amino]hexahydrocyclopenta[c]pyrrole-2(1H)-yl}methanone racemic mixture [ka] HPLC retention time (minutes): 1.10 (formic acid); MS(ESI, Pos.):400(M+H) + ; 1H-NMR(DMSO-d6): δ8.23-8.14, 7.64-7.55, 7.42-7.30, 6.92, 4.44-4.27, 4.14-4.07, 4.24-4.03, 3.93-3.81, 3.78-3.66, 3.55-3.47, 3.35-3.24, 3.23-3.05, 3.00-2.70, 2.61-2.54, 2.26-2.16, 2.13-1.97, 1.66-1.49.

[0123] Examples 1-2: {(3aS,4R,6aR)-4-[(6-chloro-3-pyridazinyl)amino]hexahydrocyclopenta[c]pyrrole-2(1H)-yl}(5-methyl-2-thienyl)methanone

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[0124] Examples 1-3: [(3aS,4R,6aR)-4-[(6-chloro-3-pyridazinyl)amino]hexahydrocyclopenta[c]pyrrole-2(1H)-yl](thieno[3,2-c]pyridine-2-yl)methanone

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[0125] Examples 1-4: [(3aS,4R,6aR)-4-[(6-chloro-3-pyridazinyl)amino]hexahydrocyclopenta[c]pyrrole-2(1H)-yl](6,7-dihydro-4H-thieno[3,2-c]pyran-2-yl)methanone

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[0126] Examples 1-5: [(3aS,4R,6aR)-4-[(6-chloro-3-pyridazinyl)amino]hexahydrocyclopenta[c]pyrrole-2(1H)-yl][4-(2-furyl)phenyl]methanone

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[0127] Examples 1-6: 1-Benzofran-2-yl[(3aS,4R,6aR)-4-[(6-chloro-3-pyridazinyl)amino]hexahydrocyclopenta[c]pyrrole-2(1H)-yl]methanone

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[0128] Reference Example 11: 2-Methyl-2-propanyl (3aS,4R,6aR)-4-[(6-bromo-3-pyridazinyl)amino]hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate To a DMA (25 mL) solution of the compound (4.0 g) prepared in Reference Example 8, DIPEA (18 mL) and 3,6-dibromopyridazine (CAS No.: 17973-86-3, 6.3 g) were added and the mixture was stirred at 160°C for 15 hours. Water was added to the reaction mixture and extracted with dichloromethane. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound (4.0 g). HPLC retention time (minutes): 0.91 (formic acid); MS(ESI, Pos.):383(M+H) + .

[0129] Reference Example 12: (3aS,4R,6aR)-N-(6-bromo-3-pyridazinyl)octahydrocyclopenta[c]pyrrole-4-amine dihydrochloride 4.0 g of the compound prepared in Reference Example 11 was mixed with 4N hydrochloric acid (1,4-dioxane solution, 12 mL) and stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure to obtain the title compound (3.7 g). HPLC retention time (minutes): 0.59 (formic acid); MS(ESI, Pos.):283(M+H) + .

[0130] Reference Example 12-1: rel-(3aS,4R,6aR)-N-(6-bromo-3-pyridazinyl)octahydrocyclopenta[c]pyrrole-4-amine dihydrochloride racemic mixture The title compound was obtained by using the compound prepared in Reference Example 1 instead of the compound prepared in Reference Example 3, and performing the same procedure as in Reference Example 4 → Reference Example 5 → Reference Example 6 → Reference Example 7 → Reference Example 8 → Reference Example 11 → Reference Example 12.

[0131] Example 2: [(3aS,4R,6aR)-4-[(6-bromo-3-pyridazinyl)amino]hexahydrocyclopenta[c]pyrrole-2(1H)-yl](5-methyl-2-thienyl)methanone [ka] To a DMA (20 mL) solution of the compound (3.0 g) prepared in Reference Example 12, DIPEA (2.9 mL), 5-methyl-2-thiophenecarboxylic acid (CAS No.: 1918-79-2, 6.6 g), and HATU (3.8 g) were added and the mixture was stirred at room temperature for 3 hours. Water was added to the reaction mixture and extracted with dichloromethane. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound (1.8 g) as a crystalline solid. HPLC retention time (min): 0.87 (TFA); MS(ESI, Pos.):407(M+H) + ; 1 H-NMR(CDCl3):δ7.33-7.27, 6.75-6.72, 6.54, 5.00, 4.15-3.99, 3.98-3.78, 3.66, 2.88, 2.68, 2.50, 2.39-2.29, 2.14-2.03, 1.68-1.59.

[0132] Figure 1 shows the powder X-ray diffraction spectrum chart of the crystal measured under the following conditions, and Figure 2 shows the DSC chart. (1) Powder X-ray diffraction spectrum Measurement conditions Device: Rigaku SmartLab Target: Cu Voltage: 45kV Current: 200mA Scanning speed: 30 degrees / min Table 1 shows the diffraction angle (2θ) (degrees) and relative intensity (%) obtained by powder X-ray diffraction spectroscopy using Cu-Kα rays. [Table 1] (2) Differential scanning calorimetry (DSC) Measurement conditions Equipment: Discovery DSC manufactured by T.A. Instruments Sample cell: Aluminum pan Nitrogen gas flow rate: 40 mL / min Sample amount: 1.05 mg Heating rate: 10℃ / min Endothermic peak: Onset temperature approximately 132°C, peak temperature approximately 134°C

[0133] Examples 2-1 to 2-14 The title compound was obtained by using the corresponding carboxylic acid compound instead of 5-methyl-2-thiophenecarboxylic acid and performing the same procedure as in Example 2.

[0134] Example 2-1: [(3aS,4R,6aR)-4-[(6-bromo-3-pyridazinyl)amino]hexahydrocyclopenta[c]pyrrole-2(1H)-yl](6,7-dihydro-4H-thieno[3,2-c]pyran-2-yl)methanone [ka] HPLC retention time (min): 0.93 (TFA); MS(ESI, Pos.):451(M+H) + ; 1 H-NMR(CDCl3):δ7.32-7.27, 7.17, 6.54, 4.77-4.63, 4.10, 4.04-3.93, 3.87, 3.65, 2.89, 2.69, 2.40-2.29, 2.17-2.07, 1.68-1.57.

[0135] Example 2-2: [(3aS,4R,6aR)-4-[(6-bromo-3-pyridazinyl)amino]hexahydrocyclopenta[c]pyrrole-2(1H)-yl][5-(difluoromethyl)-2-thienyl]methanone [ka] HPLC retention time (minutes): 1.00 (formic acid); MS(ESI, Pos.):443(M+H) + ; 1 H-NMR(DMSO-d6):δ7.63-7.56, 7.50-7.47, 7.46-7.43, 7.34-7.27, 7.32, 6.86-6.73, 4.11-3.87, 3.87-3.70, 3.71-3.54, 2.96-2.72, 2.71-2.56, 2.23-2.11, 2.09-1.95, 1.59, 1.51.

[0136] Examples 2-3: [(3aS,4R,6aR)-4-[(6-bromo-3-pyridazinyl)amino]hexahydrocyclopenta[c]pyrrole-2(1H)-yl](5-methyl-1,3-thiazole-2-yl)methanone

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[0137] Examples 2-4: [(3aS,4R,6aR)-4-[(6-bromo-3-pyridazinyl)amino]hexahydrocyclopenta[c]pyrrole-2(1H)-yl](thieno[3,2-c]pyridine-2-yl)methanone

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[0138] Examples 2-5: [(3aS,4R,6aR)-4-[(6-bromo-3-pyridazinyl)amino]hexahydrocyclopenta[c]pyrrole-2(1H)-yl](6,7-dihydro-4H-pyrano[3,4-d][1,3]thiazole-2-yl)methanone

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[0139] Examples 2-6: [(3aS,4R,6aR)-4-[(6-bromo-3-pyridazinyl)amino]hexahydrocyclopenta[c]pyrrole-2(1H)-yl][2-(dimethylamino)-1,3-thiazole-5-yl]methanone

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[0140] Example 2-7: [(3aS,4R,6aR)-4-[(6-bromo-3-pyridazinyl)amino]hexahydrocyclopenta[c]pyrrole-2(1H)-yl](5,5-dioxide-6,7-dihydro-4H-thieno[3,2-c]thiopyran-2-yl)methanone

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[0141] Example 2-8: [(3aS,4R,6aR)-4-[(6-bromo-3-pyridazinyl)amino]hexahydrocyclopenta[c]pyrrole-2(1H)-yl](6,7-dihydro-4H-thieno[3,2-c]thiopyran-2-yl)methanone

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[0142] Example 2-9: [(3aS,4R,6aR)-4-[(6-bromo-3-pyridazinyl)amino]hexahydrocyclopenta[c]pyrrole-2(1H)-yl](1-methyl-1H-thieno[2,3-c]pyrazole-5-yl)methanone

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[0143] Example 2-10: [(3aS,4R,6aR)-4-[(6-bromo-3-pyridazinyl)amino]hexahydrocyclopenta[c]pyrrole-2(1H)-yl][2-(dimethylamino)thieno[2,3-d][1,3]thiazole-5-yl]methanone

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[0144] Example 2-11: [(3aS,4R,6aR)-4-[(6-bromo-3-pyridazinyl)amino]hexahydrocyclopenta[c]pyrrole-2(1H)-yl](3-methyl-3H-thieno[2,3-d][1,2,3]triazole-5-yl)methanone

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[0145] Example 2-12: [(3aS,4R,6aR)-4-[(6-bromo-3-pyridazinyl)amino]hexahydrocyclopenta[c]pyrrole-2(1H)-yl](5-methoxy-2-furyl)methanone

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[0146] Example 2-13: [(3aS,4R,6aR)-4-[(6-bromo-3-pyridazinyl)amino]hexahydrocyclopenta[c]pyrrole-2(1H)-yl](1,3-dimethyl-1H-thieno[2,3-c]pyrazole-5-yl)methanone

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[0147] Example 2-14: Bicyclo[2.2.2]octo-2-yl[(3aS,4R,6aR)-4-[(6-bromo-3-pyridazinyl)amino]hexahydrocyclopenta[c]pyrrole-2(1H)-yl]methanone [ka] HPLC retention time (minutes): 1.10 (formic acid); MS(ESI, Pos.):419(M+H) + ; 1 H-NMR (DMSO-d6): δ7.51-7.39, 7.38-7.25, 6.85-6.74, 4.07-3.85, 3.73-3.51, 3.29-3.16, 2.87-2.59, 2.18-1.82, 1.72-1.14.

[0148] Reference Example 13: Methyl 5-[(1E)-3-ethoxy-3-oxo-1-propen-1-yl]-4-nitro-2-thiophenecarboxylate To a solution of methyl 5-bromo-4-nitrothiophene-2-carboxylate (CAS No.: 38239-32-6, 120 mg) in 1,2-dimethoxyethane (3 mL), DIPEA (0.083 mL), tripotassium phosphate (CAS No.: 7778-53-2, 1730 mg), (E)-ethyl 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)acrylate (CAS No.: 1009307-13-4, 300 mg), and bis(triphenylphosphine)palladium(II) chloride (CAS No.: 13965-03-2, 63 mg) were added, and the mixture was stirred at 55°C for 3 hours. Water was added to the reaction mixture, and it was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound (97 mg). HPLC retention time (minutes): 1.20 (formic acid); MS(ESI, Pos.):286(M+H) + .

[0149] Reference Example 14: Methyl 4-amino-5-(3-ethoxy-3-oxopropyl)-2-thiophenecarboxylate To a methanol (2 mL) solution of the compound (50 mg) prepared in Reference Example 13, 20% palladium hydroxide (100 mg) was added and the mixture was stirred at room temperature under a hydrogen atmosphere for 1 hour. The reaction mixture was filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound (30 mg). HPLC retention time (minutes): 0.80 (formic acid); MS(ESI, Pos.):258(M+H) + .

[0150] Reference Example 15: Methyl 5-oxo-4,5,6,7-tetrahydrothieno[3,2-b]pyridine-2-carboxylate To a methanol (1 mL) solution of the compound (20 mg) prepared in Reference Example 14, p-toluenesulfonic acid monohydrate (CAS number: 6192-52-5, 1.5 mg) was added and the mixture was stirred at 60°C for 15 hours. Saturated sodium bicarbonate solution was added to the reaction mixture and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound (5 mg). HPLC retention time (minutes): 0.81 (formic acid); MS(ESI, Pos.):212(M+H) + .

[0151] Reference Example 16: Methyl 4-methyl-5-oxo-4,5,6,7-tetrahydrothieno[3,2-b]pyridine-2-carboxylate Sodium hydride (CAS number: 7646-69-7, 2.9 mg) and iodomethane (CAS number: 74-88-4, 22 mg) were added to a solution of the compound (5 mg) prepared in Reference Example 15 in DMF (0.25 mL), and the mixture was stirred at room temperature for 3 hours. 2N hydrochloric acid was added to the reaction mixture, and it was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound (7 mg). HPLC retention time (minutes): 0.88 (formic acid); MS(ESI, Pos.):225(M+H) + .

[0152] Reference Example 17: 4-methyl-5-oxo-4,5,6,7-tetrahydrothieno[3,2-b]pyridine-2-carboxylic acid A methanol solution (1 mL) of the compound (7 mg) prepared in Reference Example 16 was mixed with a 2 N sodium hydroxide aqueous solution (0.5 mL) and stirred at 60°C for 1 hour. 1 N hydrochloric acid was added to the reaction mixture, and the precipitate was filtered to obtain the title compound (5.0 mg).

[0153] Reference example 18: 5-chloro-3,4-dihydro-2H-pyran-6-carbaldehyde To a solution of phosphoryl chloride (CAS number: 10025-87-3, 1400 mg) in dichloromethane (5 mL), DMF (0.70 mL) was added at 0°C and the mixture was stirred at 0°C for 1 hour. Dihydro-2H-pyran-3(4H)-one (CAS number: 23462-75-1, 900 mg) was added to the mixture and the mixture was stirred at room temperature for 2 hours. Saturated sodium bicarbonate aqueous solution was added to the reaction mixture and extracted with dichloromethane. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting title compound was used in the next reaction without purification.

[0154] Reference Example 19: Methyl [(6-formyl-3,4-dihydro-2H-pyran-5-yl)thio]acetate To a 20 mL solution of the compound prepared in Reference Example 18 in dichloroethane, triethylamine (2.5 mL) and methyl thioglycolate (CAS No.: 2365-48-2, 1100 mg) were added, and the mixture was stirred at 70°C for 15 hours. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography to obtain the title compound (300 mg).

[0155] Reference Example 20: Methyl 6,7-dihydro-5H-thieno[3,2-b]pyran-2-carboxylate To a methanol (10 mL) solution of the compound prepared in Reference Example 19, 28% sodium methoxide (CAS number: 124-41-4, 0.85 mL) was added and the mixture was stirred at 70°C for 1 hour. The reaction mixture was concentrated under reduced pressure, 2N hydrochloric acid was added, and the mixture was extracted with dichloromethane. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound (220 mg).

[0156] Reference Example 21: 6,7-dihydro-5H-thieno[3,2-b]pyran-2-carboxylic acid A 2N sodium hydroxide aqueous solution (0.5 mL) was added to a methanol (1 mL) solution of the compound (20 mg) prepared in Reference Example 20, and the mixture was stirred at 60°C for 1 hour. 1N hydrochloric acid was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The resulting title compound was used in the next reaction without purification. HPLC retention time (minutes): 1.00 (formic acid); MS(ESI, Pos.):449(M+H) + ; 1 H-NMR(DMSO-d6):δ7.55-7.43, 7.10, 6.89-6.60, 4.67-4.62, 4.17-4.07, 4.05-3.87, 3.73, 3.67, 3.42-3.40, 3.37-3.33, 3.30, 3.22-3.04, 2.79-2.70, 2.58-2.53, 2.17, 2.09-1.85, 1.71-1.37.

[0157] Reference Example 22: Dimethyl 6,7-dihydrothieno[3,2-c]pyridine-2,5(4H)-dicarboxylate To a solution of methyl 4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxylate (CAS No.: 221316-61-6, 50 mg) in dichloromethane (1 mL), triethylamine (0.11 mL) and methyl chloroformate (CAS No.: 79-22-1, 72 mg) were added at 0°C and the mixture was stirred at room temperature for 15 hours. 2N hydrochloric acid was added to the reaction mixture and extracted with dichloromethane. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting title compound was used in the next reaction without purification.

[0158] Reference Example 23: 5-(methoxycarbonyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxylic acid A methanol solution (1 mL) of the compound (20 mg) prepared in Reference Example 22 was mixed with a 2 N sodium hydroxide aqueous solution (0.5 mL) and stirred at 50°C for 1 hour. 1 N hydrochloric acid was added to the reaction mixture, the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The resulting title compound was used in the next reaction without purification.

[0159] Reference example 24: 4,4-dimethyl-6,7-dihydrothieno[3,2-c]pyran 2,2-Dimethoxypropane (CAS No. 77-76-9, 0.38 mL) and iron(III) trifluoromethanesulfonate (CAS No. 63295-48-7, 15.7 mg) were added to a solution of 2-(2-thienyl)ethanol (CAS No. 160774-13-8, 400 mg) in toluene (4 mL), and the mixture was stirred at 70°C for 17 hours. Triethylamine (0.22 mL) was added to the reaction mixture, and the mixture was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound (284 mg). TLC: Rf 0.50 (ethyl acetate:n-hexane = 1:9); HPLC retention time (min): 1.07 (TFA); MS(ESI, Pos.):169(M+H) + .

[0160] Reference example 25: 4,4-dimethyl-6,7-dihydrothieno[3,2-c]pyran-2-carboxylic acid To a THF (10 mL) solution of the compound (284 mg) prepared in Reference Example 24, a 1.6 M n-butyllithium hexane solution (CAS number: 109-72-8, 1.2 mL) was added at -78°C and the mixture was stirred at -78°C for 2 hours. Then, dry ice (1 g) was added to the reaction mixture and the mixture was stirred at room temperature for 2 hours. Water and 1 N sodium hydroxide aqueous solution were added to the reaction mixture, and the aqueous layer was washed with methyl tert-butyl ether. After adding 1 N hydrochloric acid aqueous solution to the aqueous layer to adjust the pH to 1, the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the title compound (306 mg). HPLC retention time (min): 0.89 (TFA); MS(ESI, Pos.):213(M+H) + .

[0161] Reference example 26: 4H-pyrano[3,4-d]thiazole-7-one 2-amino-4H-pyrano[3,4-d]thiazole-7-one (CAS No.: 1253281-38-7, 873 mg) was dissolved in THF (17.5 mL) and n-pentyl nitrite (CAS No.: 463-04-7, 0.97 mL) was added, and the mixture was stirred at 60°C for 15 hours. Water was added to the reaction mixture, and it was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound (568 mg). TLC: Rf 0.28 (ethyl acetate:n-hexane = 1:2).

[0162] Reference example 27: 7-methylene-4H-pyrano[3,4-d]thiazole A solution of methyltriphenylphosphonium bromide (CAS number: 1779-49-3, 253 mg) in THF (1.5 mL) was mixed with a 1.3 N lithium bis(trimethylsilyl)amide THF solution (CAS number: 4039-32-1, 0.55 mL) at 0°C and stirred at 0°C for 1 hour. Then, the compound prepared in Reference Example 26 (100 mg) was added and stirred at 0°C for 40 minutes. Saturated ammonium chloride aqueous solution was added to the reaction mixture, and the aqueous layer was extracted with dichloromethane. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound (90 mg). TLC: Rf 0.5 (ethyl acetate:n-hexane = 1:2).

[0163] Reference example 28: 7-methyl-6,7-dihydro-4H-pyrano[3,4-d][1,3]thiazole A methanol (1.8 mL) solution of the compound prepared in Reference Example 27 was mixed with 20% palladium hydroxide (10 mg) and stirred at room temperature under a hydrogen atmosphere for 7 hours. The reaction mixture was filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound (40 mg).

[0164] Reference example 29: 7-methyl-6,7-dihydro-4H-pyrano[3,4-d][1,3]thiazole-2-carboxylic acid To a solution of the compound (40 mg) prepared in Reference Example 28 in THF (2 mL), 0.16 mL of 1.6 M n-butyllithium hexane solution was added at -78 °C, and the mixture was stirred at -78 °C for 1 hour. Then, 300 mg of dry ice was added to the reaction mixture, and the mixture was stirred at room temperature for 1 hour. Water and 1 N sodium hydroxide aqueous solution were added to the reaction mixture, and the aqueous layer was washed with methyl tert-butyl ether. After adding 1 N hydrochloric acid aqueous solution to the aqueous layer to adjust the pH to 1, the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the title compound (20 mg). HPLC retention time (min): 0.76 (TFA); MS(ESI, Pos.):200(M+H) + .

[0165] Reference Example 30: Methyl 5-hydroxy-2-thiophenecarboxylate To a solution of thiophene-2-carboxylate methyl ester-5-boronic acid (CAS No.: 876189-21-8, 120 mg) in polyethylene glycol 200 (CAS No.: 25322-68-3, 0.64 mL), 30% aqueous hydrogen peroxide solution (CAS No.: 7722-84-1, 0.11 mL) was added and the mixture was stirred at room temperature for 2 hours. Water was added to the reaction mixture and extracted with methyl tert-butyl ether. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound (23 mg). HPLC retention time (min): 0.84 (TFA); MS(ESI, Pos.):171(M+Na) + .

[0166] Reference Example 31: Methyl 5-(difluoromethoxy)-2-thiophenecarboxylate To a solution of the compound (23 mg) prepared in Reference Example 30 in DMF (0.2 mL), chlorodifluoroacetic acid (CAS No.: 76-04-0, 0.027 mL) and cesium carbonate (CAS No.: 534-17-8, 142 mg) were added, and the mixture was stirred at 100°C for 10 minutes. Water was added to the reaction mixture, and it was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound (31 mg). HPLC retention time (min): 1.06 (TFA); MS(ESI, Pos.):209(M+H) + .

[0167] Reference Example 32: 5-(difluoromethoxy)-2-thiophenecarboxylic acid To a solution of the compound (31 mg) prepared in Reference Example 31 in THF (0.2 mL), methanol (0.1 mL) and 1N lithium hydroxide aqueous solution (CAS number: 1310-65-2, 0.2 mL) were added and the mixture was stirred at room temperature for 16 hours. 1N hydrochloric acid aqueous solution was added to the reaction mixture to adjust the pH of the aqueous layer to 1, and then extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the title compound (21 mg). HPLC retention time (min): 0.91 (TFA); MS(ESI, Pos.):195(M+H) + .

[0168] Reference Example 33: Methyl 3-iodo-1H-thieno[3,2-c]pyrazole-5-carboxylate To a solution of methyl 1H-thieno[3,2-c]pyrazole-5-carboxylate (CAS No.: 1246552-43-1, 185 mg) in DMF (2 mL), potassium hydroxide (CAS No.: 1310-58-3, 140 mg) and iodine (CAS No.: 7553-56-2, 570 mg) were added, and the mixture was stirred at 0°C for 1 hour. 2N hydrochloric acid was added to the reaction mixture, and saturated sodium thiosulfate aqueous solution was added, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was washed with hexane and ethyl acetate to obtain the title compound (180 mg).

[0169] Reference Example 34: Methyl 3-(3-hydroxy-1-propyne-1-yl)-1H-thieno[3,2-c]pyrazole-5-carboxylate To a solution of the compound (40 mg) prepared in Reference Example 33 in THF (1 mL), propargyl alcohol (CAS No.: 107-19-7, 11 mg), copper(I) iodide (CAS No.: 7681-65-4, 2.5 mg), tetrakis(triphenylphosphine)palladium(O) (CAS No.: 14221-01-3, 15 mg), and triethylamine (0.09 mL) were added, and the mixture was stirred at 60°C for 1 hour. Water was added to the reaction mixture, and it was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound (23 mg). HPLC retention time (minutes): 0.84 (formic acid); MS(ESI, Pos.):237(M+H) + .

[0170] Reference Example 35: Methyl 3-(3-hydroxypropyl)-1H-thieno[3,2-c]pyrazole-5-carboxylate To a methanol (1 mL) solution of the compound (23 mg) prepared in Reference Example 34, 20% palladium hydroxide (25 mg) was added and the mixture was stirred at room temperature under a hydrogen atmosphere for 6 hours. The reaction mixture was filtered, concentrated under reduced pressure, and the resulting title compound was used in the next reaction without purification.

[0171] Reference Example 36: Methyl 7,8-dihydro-6H-pyrrolo[1,2-b]thieno[2,3-d]pyrazole-2-carboxylate To a solution of the compound prepared in Reference Example 35 (18 mg) in toluene (0.5 mL), cyanomethylenetributylphosphoran (CAS number: 157141-27-0, 27 mg) was added and the mixture was stirred at 60°C for 1 hour. The title compound (10 mg) was obtained by purification by silica gel column chromatography. 1 H-NMR (CDCl3): δ7.85, 4.38, 3.83, 3.10, 2.73.

[0172] Reference example 37: 7,8-dihydro-6H-pyrrolo[1,2-b]thieno[2,3-d]pyrazole-2-carboxylic acid To a methanol (1 mL) solution of the compound (20 mg) prepared in Reference Example 36, 0.5 mL of 2 N sodium hydroxide aqueous solution was added and the mixture was stirred at 60°C for 1 hour. 1 N hydrochloric acid was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The resulting title compound was used in the next reaction without purification.

[0173] Reference Example 38: Methyl 5-methyl-4-(1-methyl-1H-pyrazole-4-yl)-2-thiophenecarboxylate To a solution of methyl 4-bromo-5-methylthiophene-2-carboxylate (CAS No.: 237385-15-8, 30 mg) in toluene (0.75 mL), water (0.37 mL), 1-methyl-1H-pyrazole-4-boronic acid (CAS No.: 847818-55-7, 48 mg), cesium carbonate (124 mg), and tetrakis(triphenylphosphine)palladium (0) (15 mg) were added, and the mixture was stirred at 80°C for 13 hours. The reaction mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound (10 mg). HPLC retention time (minutes): 1.00 (formic acid); MS(ESI, Pos.):237(M+H) + .

[0174] Reference example 39: 5-methyl-4-(1-methyl-1H-pyrazole-4-yl)-2-thiophenecarboxylic acid To a methanol (1 mL) solution of the compound (20 mg) prepared in Reference Example 38, 0.5 mL of 2 N sodium hydroxide aqueous solution was added and the mixture was stirred at 60°C for 1 hour. 1 N hydrochloric acid was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The resulting title compound was used in the next reaction without purification.

[0175] Reference Example 40: Methyl 2,3-dimethyl-2H-thieno[2,3-c]pyrazole-5-carboxylate To a solution of methyl 3-methyl-1H-thieno[2,3-c]pyrazole-5-carboxylate (CAS number: 873072-42-5, 20 mg) in DMF (1.0 mL), sodium hydride (2.9 mg) and iodomethane (22 mg) were added, and the mixture was stirred at room temperature for 3 hours. 2N hydrochloric acid was added to the reaction mixture, and it was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound (10 mg). 1 H-NMR (CDCl3): δ7.69, 3.95, 3.89, 2.52.

[0176] Reference Example 41: 2,3-dimethyl-2H-thieno[2,3-c]pyrazole-5-carboxylic acid A methanol solution (1 mL) of the compound (20 mg) prepared in Reference Example 40 was mixed with a 2 N sodium hydroxide aqueous solution (0.5 mL) and stirred at 60°C for 1 hour. 1 N hydrochloric acid was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting title compound was used in the next reaction without purification.

[0177] Reference Example 42: Methyl 2-methyl-2H-thieno[3,2-c]pyrazole-5-carboxylate To a solution of methyl 1H-thieno[3,2-c]pyrazole-5-carboxylate (2.0 g) in THF (40 mL), cesium carbonate (7.2 g) and iodomethane (1.6 g) were added and the mixture was stirred at room temperature for 3 hours. 2N hydrochloric acid was added to the reaction mixture and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound (1.05 g). 1 H-NMR (CDCl3): δ7.70, 7.66, 4.06, 3.93.

[0178] Reference Example 43: 2-methyl-2H-thieno[3,2-c]pyrazole-5-carboxylic acid To a methanol (1 mL) solution of the compound (20 mg) prepared in Reference Example 42, 0.5 mL of 2 N sodium hydroxide aqueous solution was added and the mixture was stirred at 60°C for 1 hour. 1 N hydrochloric acid was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The resulting title compound was used in the next reaction without purification.

[0179] Reference Example 44: Methyl 2-cyclopropyl-2H-thieno[3,2-c]pyrazole-5-carboxylate To a solution of methyl 1H-thieno[3,2-c]pyrazole-5-carboxylate (1.0 g) in dichloroethane (20 mL), cyclopropylboronic acid (CAS No.: 873072-42-5, 940 mg), sodium carbonate (CAS No.: 497-19-8, 1200 mg), copper(II) acetate (CAS No.: 142-71-2, 1.1 g), and 1,10-phenanthroline (CAS No.: 66-71-7, 1.1 g) were added, and the mixture was stirred at 70°C for 15 hours. 1N hydrochloric acid was added to the reaction mixture, and it was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound (200 mg). HPLC retention time (minutes): 1.00 (formic acid); MS(ESI, Pos.):223(M+H) + .

[0180] Reference Example 45: 2-Cyclopropyl-2H-thieno[3,2-c]pyrazole-5-carboxylic acid To a methanol (1 mL) solution of the compound (20 mg) prepared in Reference Example 44, 0.5 mL of 2 N sodium hydroxide aqueous solution was added and the mixture was stirred at 60°C for 1 hour. 1 N hydrochloric acid was added to the reaction mixture, extracted with ethyl acetate, washed the organic layer with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting title compound was used in the next reaction without purification.

[0181] Reference Example 46: Methyl 2-(difluoromethyl)-2H-thieno[3,2-c]pyrazole-5-carboxylate To a solution of methyl 1H-thieno[3,2-c]pyrazole-5-carboxylate (500 mg) in DMF (10 mL), sodium chlorodifluoroacetate (CAS number: 1895-39-2, 2100 mg) and potassium carbonate (1900 mg) were added, and the mixture was stirred at 100°C for 20 hours. Water was added to the reaction mixture, and it was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound (85 mg).

[0182] Reference Example 47: 2-(difluoromethyl)-2H-thieno[3,2-c]pyrazole-5-carboxylic acid To a methanol (1 mL) solution of the compound (20 mg) prepared in Reference Example 46, 0.5 mL of 2 N sodium hydroxide aqueous solution was added and the mixture was stirred at 60°C for 1 hour. 1 N hydrochloric acid was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The resulting title compound was used in the next reaction without purification.

[0183] Reference example 48: (1) Methyl 2-(2,2,2-trifluoroethyl)-2H-thieno[3,2-c]pyrazole-5-carboxylate, and (2) Methyl 1-(2,2,2-trifluoroethyl)-2H-thieno[3,2-c]pyrazole-5-carboxylate To a solution of methyl 1H-thieno[3,2-c]pyrazole-5-carboxylate (200 mg) in DMF (5 mL), cesium carbonate (720 mg) and 2,2,2-trifluoroethyl trifluoromethanesulfonic acid (CAS number: 6226-25-1, 510 mg) were added and the mixture was stirred at room temperature for 15 hours. Water was added to the reaction mixture and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain (1) 61 mg and (2) 71 mg of the title compound, respectively. (1) TLC: Rf 0.31 (ethyl acetate:n-hexane = 1:3); (2) TLC: Rf 0.34 (ethyl acetate:n-hexane = 1:3).

[0184] Reference Example 49: 2-(2,2,2-trifluoroethyl)-2H-thieno[3,2-c]pyrazole-5-carboxylic acid A methanol solution (1 mL) of the compound (60 mg) prepared in Reference Example 48(1) was mixed with 2 N sodium hydroxide aqueous solution (0.5 mL) and stirred at 60°C for 1 hour. 1 N hydrochloric acid was added to the reaction mixture, extracted with ethyl acetate, washed the organic layer with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting title compound was used in the next reaction without purification.

[0185] Reference Example 50: 1-(2,2,2-trifluoroethyl)-1H-thieno[3,2-c]pyrazole-5-carboxylic acid A methanol solution (1 mL) of the compound (60 mg) prepared in Reference Example 48(2) was mixed with 2 N sodium hydroxide aqueous solution (0.5 mL) and stirred at 60°C for 1 hour. 1 N hydrochloric acid was added to the reaction mixture, extracted with ethyl acetate, washed the organic layer with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting title compound was used in the next reaction without purification.

[0186] Reference Example 51: 2,3-dimethyl-2H-thieno[3,2-c]pyrazole-5-carboxylic acid The title compound was obtained by performing the same procedure as in Reference Example 40 → Reference Example 41 using methyl 3-methyl-1H-thieno[3,2-c]pyrazole-5-carboxylate (CAS number: 1379258-29-3) instead of methyl 3-methyl-1H-thieno[2,3-c]pyrazole-5-carboxylate.

[0187] Example 3: 2-{[(3aS,4R,6aR)-4-[(6-bromo-3-pyridazinyl)amino]hexahydrocyclopenta[c]pyrrole-2(1H)-yl]carbonyl}-4-methyl-6,7-dihydrothieno[3,2-b]pyridine-5(4H)-one [ka] To a DMA (0.25 mL) solution of the compound prepared in Reference Example 12 (5 mg) and the compound prepared in Reference Example 17 (9.2 mg), DIPEA (0.016 mL) and HATU (10 mg) were added, and the mixture was stirred at room temperature for 3 hours. Water was added to the reaction mixture, and it was extracted with dichloromethane. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound (4.7 mg). HPLC retention time (minutes): 0.89 (formic acid); MS(ESI, Pos.):476(M+H) + ; 1H-NMR(DMSO-d6):δ7.44, 7.38, 7.28, 6.80, 4.10-3.96, 3.24, 3.18-3.03, 3.01-2.87, 2.85, 2.71-2.57, 2.25-2.10, 2.10-1.96, 1.62-1.45.

[0188] Examples 3-1 to 3-14 The title compound was obtained by performing the same procedure as in Example 3, using the compound prepared in Reference Example 21, Reference Example 23, Reference Example 25, Reference Example 29, Reference Example 32, Reference Example 37, Reference Example 39, Reference Example 41, Reference Example 43, Reference Example 45, Reference Example 47, Reference Example 49, Reference Example 50, or Reference Example 51 instead of the compound prepared in Reference Example 17, and using the compound prepared in Reference Example 10 instead of the compound prepared in Reference Example 12.

[0189] Example 3-1: [(3aS,4R,6aR)-4-[(6-bromo-3-pyridazinyl)amino]hexahydrocyclopenta[c]pyrrole-2(1H)-yl](6,7-dihydro-5H-thieno[3,2-b]pyran-2-yl)methanone [ka] HPLC retention time (minutes): 0.74 (formic acid); MS(ESI, Pos.):400(M+H) + ; 1 H-NMR(DMSO-d6):δ9.46-9.25, 8.63-8.43, 8.40-8.30, 8.29-8.14, 7.43-7.30, 6.97-6.83, 4.20-4.00, 3.99-3.65, 3.15-3.04, 3.04-2.79, 2.77-2.57, 2.27-2.15, 2.14-1.98, 1.70-1.58, 1.58-1.48.

[0190] Example 3-2: Methyl 2-{[(3aS,4R,6aR)-4-[(6-bromo-3-pyridazinyl)amino]hexahydrocyclopenta[c]pyrrole-2(1H)-yl]carbonyl}-6,7-dihydrothieno[3,2-c]pyridine-5(4H)-carboxylate [ka] HPLC retention time (minutes): 0.97 (formic acid); MS(ESI, Pos.):506(M+H) + ; 1H-NMR(DMSO-d6): δ7.49-7.44, 7.44-7.31, 6.86-6.78, 4.57-4.41, 4.07-4.00, 3.67, 3.64, 3.20-3.05, 2.81, 2.71-2.45, 2.27-2.12, 2.09-1.95, 1.64-1.54, 1.54-1.42.

[0191] Example 3-3: [(3aS,4R,6aR)-4-[(6-chloro-3-pyridazinyl)amino]hexahydrocyclopenta[c]pyrrole-2(1H)-yl](4,4-dimethyl-6,7-dihydro-4H-thieno[3,2-c]pyran-2-yl)methanone

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[0192] Examples 3-4: [(3aS,4R,6aR)-4-[(6-chloro-3-pyridazinyl)amino]hexahydrocyclopenta[c]pyrrole-2(1H)-yl](7-methyl-6,7-dihydro-4H-pyrano[3,4-d][1,3]thiazole-2-yl)methanone

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[0193] Examples 3-5: [(3aS,4R,6aR)-4-[(6-chloro-3-pyridazinyl)amino]hexahydrocyclopenta[c]pyrrole-2(1H)-yl][5-(difluoromethoxy)-2-thienyl]methanone

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[0194] Examples 3-6: [(3aS,4R,6aR)-4-[(6-bromo-3-pyridazinyl)amino]hexahydrocyclopenta[c]pyrrole-2(1H)-yl](7,8-dihydro-6H-pyrrolo[1,2-b]thieno[2,3-d]pyrazole-2-yl)methanone

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[0195] Examples 3-7: [(3aS,4R,6aR)-4-[(6-bromo-3-pyridazinyl)amino]hexahydrocyclopenta[c]pyrrole-2(1H)-yl][5-methyl-4-(1-methyl-1H-pyrazole-4-yl)-2-thienyl]methanone

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[0196] Examples 3-8: [(3aS,4R,6aR)-4-[(6-bromo-3-pyridazinyl)amino]hexahydrocyclopenta[c]pyrrole-2(1H)-yl](2,3-dimethyl-2H-thieno[2,3-c]pyrazole-5-yl)methanone

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[0197] Examples 3-9: [(3aS,4R,6aR)-4-[(6-bromo-3-pyridazinyl)amino]hexahydrocyclopenta[c]pyrrole-2(1H)-yl](2-methyl-2H-thieno[3,2-c]pyrazole-5-yl)methanone

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[0198] Example 3-10: [(3aS,4R,6aR)-4-[(6-bromo-3-pyridazinyl)amino]hexahydrocyclopenta[c]pyrrole-2(1H)-yl](2-cyclopropyl-2H-thieno[3,2-c]pyrazole-5-yl)methanone

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[0199] Example 3-11: [(3aS,4R,6aR)-4-[(6-bromo-3-pyridazinyl)amino]hexahydrocyclopenta[c]pyrrole-2(1H)-yl][2-(difluoromethyl)-2H-thieno[3,2-c]pyrazole-5-yl]methanone

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[0200] Example 3-12: [(3aS,4R,6aR)-4-[(6-bromo-3-pyridazinyl)amino]hexahydrocyclopenta[c]pyrrole-2(1H)-yl][1-(2,2,2-trifluoroethyl)-1H-thieno[3,2-c]pyrazole-5-yl]methanone

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[0201] Example 3-13: [(3aS,4R,6aR)-4-[(6-bromo-3-pyridazinyl)amino]hexahydrocyclopenta[c]pyrrole-2(1H)-yl][2-(2,2,2-trifluoroethyl)-2H-thieno[3,2-c]pyrazole-5-yl]methanone

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[0202] Example 3-14: [(3aS,4R,6aR)-4-[(6-bromo-3-pyridazinyl)amino]hexahydrocyclopenta[c]pyrrole-2(1H)-yl](2,3-dimethyl-2H-thieno[3,2-c]pyrazole-5-yl)methanone [ka] HPLC retention time (minutes): 0.91 (formic acid); MS(ESI, Pos.):461(M+H) + .

[0203] Reference example 52: 1-(5-((3aS,4R,6aR)-4-((6-bromopyridazine-3-yl)amino)octahydrocyclopenta[c]pyrrole-2-carbonyl)thiophen-2-yl)ethane-1-one To a solution of the compound (10 mg) prepared in Reference Example 12 in DMA (0.25 mL), 5-acetylthiophene-2-carboxylic acid (CAS: 4066-41-5, 6.0 mg), DIPEA (0.030 mL), and HATU (20 mg) were added, and the mixture was stirred at room temperature for 3 hours. Water was added to the reaction mixture, and it was extracted with dichloromethane. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound (15 mg).

[0204] Example 4: [(3aS,4R,6aR)-4-[(6-bromo-3-pyridazinyl)amino]hexahydrocyclopenta[c]pyrrole-2(1H)-yl][5-(2-hydroxy-2-propanyl)-2-thienyl]methanone [ka] To a solution of the compound (5 mg) prepared in Reference Example 52 in THF (0.3 mL), 3 M methylmagnesium bromide (CAS: 75-16-1, 0.03 mL) was added and the mixture was stirred at room temperature for 3 hours. Water was added to the reaction mixture and extracted with dichloromethane. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound (1.3 mg). HPLC retention time (minutes): 0.89 (formic acid); MS(ESI, Pos.):451(M+H) + .

[0205] Example 5: [(3aS,4R,6aR)-4-[(6-iodo-3-pyridazinyl)amino]hexahydrocyclopenta[c]pyrrole-2(1H)-yl](5-methyl-2-thienyl)methanone [ka] To a solution of the compound prepared in Example 2 (10 mg) in 1,4-dioxane (0.1 mL), copper(I) iodide (3.0 mg), sodium iodide (CAS: 7681-82-5, 7.4 mg), and N,N'-dimethylethylenediamine (CAS: 110-70-3, 2.8 mg) were added, and the mixture was stirred at 110°C for 18 hours. Aqueous ammonia solution was added to the reaction mixture, and it was extracted with dichloromethane. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound (7.6 mg). HPLC retention time (min): 0.88 (TFA); MS(ESI, Pos.):455(M+H) + .

[0206] Example 6: rel-{(3aS,4R,6aR)-4-[(6-bromo-3-pyridazinyl)(methyl)amino]hexahydrocyclopenta[c]pyrrole-2(1H)-yl}(5-methyl-2-thienyl)methanone racemic mixture [ka] The title compound was obtained by using the compound prepared in Reference Example 12-1 instead of the compound prepared in Reference Example 12, and performing the same procedure as in Example 2 → Reference Example 16. HPLC retention time (minutes): 1.10 (formic acid); MS(ESI, Pos.):421(M+H) + ; 1 H-NMR(DMSO-d6):δ7.55, 7.38, 7.19-7.10, 6.83, 4.86, 3.62, 3.27, 3.22-3.05, 2.93, 2.81, 2.49-2.43, 2.06-1.96, 1.90-1.75, 1.58-1.45.

[0207] Examples 6-1 to 6-9 Using iodomethane or a corresponding halogen compound instead of iodomethane, and using 5-methyl-2-thiophenecarboxylic acid or a corresponding carboxylic acid instead of 5-methyl-2-thiophenecarboxylic acid, the same procedure as in Example 2 to Reference Example 16 was performed to obtain the title compound using the compound prepared in Reference Example 12, or the compound prepared in Reference Example 10-1 or Reference Example 12-1 instead of the compound prepared in Reference Example 12.

[0208] Example 6-1: rel-{(3aS,4R,6aR)-4-[(6-bromo-3-pyridazinyl)(butyl)amino]hexahydrocyclopenta[c]pyrrole-2(1H)-yl}(5-methyl-2-thienyl)methanone racemic mixture [ka] HPLC retention time (minutes): 1.30 (formic acid); MS(ESI, Pos.):463(M+H) + ; 1 H-NMR(DMSO-d6):δ7.51, 7.38, 7.12-7.05, 6.83, 4.66-4.58, 3.62, 3.47, 3.45-3.43, 3.35-3.25, 3.22-3.05, 2.84, 2.45, 2.06-1.91, 1.83-1.75, 1.54-1.40, 1.38-1.23, 1.18, 0.92.

[0209] Example 6-2: [(3aS,4R,6aR)-4-[benzyl(6-bromo-3-pyridazinyl)amino]hexahydrocyclopenta[c]pyrrole-2(1H)-yl](5-methyl-2-thienyl)methanone [ka] HPLC retention time (min): 1.20 (TFA); MS(ESI, Pos.):497(M+H) + ; 1 H-NMR(CDCl3):δ7.36-7.27, 7.21-7.16, 6.73, 6.48, 5.09, 4.60, 3.92-3.73, 3.62, 2.82, 2.50, 2.29-2.21, 2.14-2.03, 1.89, 1.62-1.56.

[0210] Example 6-3: [(3aS,4R,6aR)-4-[(6-bromo-3-pyridazinyl)(methyl)amino]hexahydrocyclopenta[c]pyrrole-2(1H)-yl](6,7-dihydro-4H-thieno[3,2-c]pyran-2-yl)methanone

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[0211] Example 6-4: rel-{(3aS,4R,6aR)-4-[(6-chloro-3-pyridazinyl)(3-methoxypropyl)amino]hexahydrocyclopenta[c]pyrrole-2(1H)-yl}[5-(difluoromethyl)-2-thienyl]methanone racemic mixture

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[0212] Example 6-5: rel-{(3aS,4R,6aR)-4-[(6-chloro-3-pyridazinyl)(imidazo[2,1-b][1,3]thiazole-6-ylmethyl)amino]hexahydrocyclopenta[c]pyrrole-2(1H)-yl}[5-(difluoromethyl)-2-thienyl]methanone racemic mixture

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[0213] Example 6-6: rel-{(3aS,4R,6aR)-4-[(6-chloro-3-pyridazinyl)(4-pyridinylmethyl)amino]hexahydrocyclopenta[c]pyrrole-2(1H)-yl}[5-(difluoromethyl)-2-thienyl]methanone racemic mixture

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[0214] Examples 6-7: rel-2-{[(6-chloro-3-pyridazinyl)((3aS,4R,6aR)-2-{[5-(difluoromethyl)-2-thienyl]carbonyl}octahydrocyclopenta[c]pyrrole-4-yl)amino]methyl}benzonitrile racemic mixture

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[0215] Examples 6-8: [(3aS,4R,6aR)-4-[(6-bromo-3-pyridazinyl)(3-fluoropropyl)amino]hexahydrocyclopenta[c]pyrrole-2(1H)-yl](5-methyl-2-thienyl)methanone [ka] HPLC retention time (min): 1.10 (TFA); MS(ESI, Pos.):467(M+H) + ; 1 H-NMR(CDCl3):δ7.32-7.28, 6.79-6.72, 4.60, 4.48, 3.82, 3.71-3.52, 2.91, 2.51, 2.20-2.02, 1.98, 1.66-1.58, 1.50, 1.33-1.19, 0.82.

[0216] Examples 6-9: [(3aS,4R,6aR)-4-[(6-bromo-3-pyridazinyl)(methyl)amino]hexahydrocyclopenta[c]pyrrole-2(1H)-yl](5-methyl-2-thienyl)methanone [ka] HPLC retention time (min): 0.93 (TFA); MS(ESI,Pos.):421(M+H) + ; 1 H-NMR(CDCl3):δ7.32-7.23, 6.78-6.65, 4.92-4.75, 4.01-3.85, 3.85-3.77, 3.64, 2.98, 2.92-2.77, 2.50, 2.17-2.05, 1.91-1.79, 1.61-1.52.

[0217] Reference Example 53: rel-(3aS,6aR)-hexahydrocyclopenta[c]pyrrole-4(1H)-one hydrochloride, racemic mixture The title compound was obtained by using the compound prepared in Reference Example 1 instead of the compound prepared in Reference Example 3, and performing the same procedure as in Reference Example 4 → Reference Example 10.

[0218] Reference Example 53-1: (3aS,6aR)-Hexahydrocyclopenta[c]pyrrole-4(1H)-one hydrochloride The title compound was obtained by using the compound prepared in Reference Example 3 instead of the compound prepared in Reference Example 9, and performing the same procedure as in Reference Example 10.

[0219] Reference Example 54: rel-(3aS,6aR)-2-(5-methylthiophen-2-carbonyl)hexahydrocyclopenta[c]pyrrole-4(1H)-one racemic mixture The compound prepared in Reference Example 53 (5.0 g) and 5-methyl-2-thiophenecarboxylic acid (6.6 g) were dissolved in DMA (100 mL), to which DIPEA (22 mL) and HATU (17.6 g) were added, and the mixture was stirred at room temperature for 3 hours. 2N hydrochloric acid was added to the reaction mixture, and it was extracted with dichloromethane. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound (7.0 g). HPLC retention time (minutes): 0.88 (formic acid); MS(ESI, Pos.):250(M+H) + .

[0220] Reference Example 54-1: (3aS,6aR)-2-(5-methylthiophen-2-carbonyl)hexahydrocyclopenta[c]pyrrole-4(1H)-one The title compound was obtained by performing the same procedure as in Reference Example 54, using the compound prepared in Reference Example 53-1 instead of the compound prepared in Reference Example 53.

[0221] Reference Example 55: (rel-(3aS,4R,6aR)-4-(cyclopropylamino)hexahydrocyclopenta[c]pyrrole-2(1H)-yl)(5-methylthiophen-2-yl)methanone racemic mixture To a solution of the compound (300 mg) prepared in Reference Example 54 in dichloromethane (10 mL), cyclopropylamine (CAS: 765-30-0, 0.25 mL) and acetic acid (0.34 mL) were added and the mixture was stirred at room temperature for 10 minutes. Sodium triacetoxyborohydride (CAS: 56553-60-7, 760 mg) was added and the mixture was stirred at 40°C for 3 hours. 2N sodium hydroxide was added to the reaction mixture and extracted with dichloromethane. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound (22 mg). HPLC retention time (minutes): 0.78 (formic acid); MS(ESI, Pos.):291(M+H) + .

[0222] Example 7: rel-{(3aS,4R,6aR)-4-[(6-bromo-3-pyridazinyl)(cyclopropyl)amino]hexahydrocyclopenta[c]pyrrole-2(1H)-yl}(5-methyl-2-thienyl)methanone racemic mixture [ka] To a solution of the compound (20 mg) prepared in Reference Example 55 in tert-amyl alcohol (CAS: 75-85-4, 0.3 mL), 3-bromo-6-fluoropyridazine (CAS: 1353854-35-9, 39 mg) and DIPEA (0.083 mL) were added, and the mixture was stirred in a sealed tube at 180°C for 1 hour. After concentrating the reaction mixture under reduced pressure, the resulting residue was purified by silica gel column chromatography to obtain the title compound (1.0 mg). HPLC retention time (minutes): 1.20 (formic acid); MS(ESI, Pos.):447(M+H) + .

[0223] Reference Example 56: (rel-(3aS,4S,6aR)-4-hydroxyhexahydrocyclopenta[c]pyrrole-2(1H)-yl)(5-methylthiophen-2-yl)methanone racemic mixture To a THF (42 mL) solution of the compound (1.4 g) prepared in Reference Example 54, 8.5 mL of 1 M lithium tri-sec-butylbohydride THF solution was added at -78°C and the mixture was stirred at -78°C for 1 hour. A 35% aqueous hydrogen peroxide solution was slowly added to the reaction mixture at 0°C until the foaming subsided, and the mixture was extracted with dichloromethane. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound (600 mg). HPLC retention time (min): 0.86 (TFA); MS(ESI, Pos.):252(M+H) + .

[0224] Reference Example 57: rel-(3aS,4S,6aR)-2-(5-methylthiophen-2-carbonyl)octahydrocyclopenta[c]pyrrole-4-yl 4-methylbenzenesulfonate racemic mixture To a solution of the compound (3.6 g) prepared in Reference Example 56 in dichloromethane (70 mL), triethylamine (4 mL), p-toluenesulfonyl chloride (4.1 g), and trimethylamine hydrochloride (280 mg) were added and the mixture was stirred at room temperature. Saturated sodium bicarbonate aqueous solution was added to the reaction mixture and extracted with dichloromethane. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound (3.6 g). HPLC retention time (min): 1.16 (TFA); MS(ESI, Pos.):406(M+H) + .

[0225] Example 8: rel-[(3aS,4R,6aR)-4-(3-chloro-5,6-dihydro-7H-pyrrolo[2,3-c]pyridazin-7-yl)hexahydrocyclopenta[c]pyrrole-2(1H)-yl](5-methyl-2-thienyl)methanone racemic mixture [ka] To a solution of the compound (10 mg) prepared in Reference Example 57 in THF (1 mL), 60% sodium hydride (3 mg) and 3-chloro-6,7-dihydro-5H-pyrrolo[2,3-c]pyridazine (CAS number: 2089649-63-6, 7.7 mg) were added and the mixture was stirred at 50°C for 20 hours. After adding water to the reaction mixture, the title compound (1.3 mg) was obtained by purification using reverse-phase column chromatography. HPLC retention time (minutes): 0.90 (formic acid); MS(ESI, Pos.):389(M+H) + ; 1 H-NMR(DMSO-d6):δ7.45-7.38, 7.21-7.17, 6.88-6.80, 4.33-4.23, 3.67-3.59, 3.54-3.44, 3.08-2.99, 2.92-2.77, 2.29-2.14, 2.08-1.94, 1.94-1.76, 1.68-1.54, 1.57-1.42.

[0226] Examples 8-1 to 8-4 The title compound was obtained by using the corresponding amine compound instead of 3-chloro-6,7-dihydro-5H-pyrrolo[2,3-c]pyridazine and performing the same procedure as in Example 8.

[0227] Example 8-1: rel-[(3aS,4R,6aR)-4-(3-chloro-7H-pyrrolo[2,3-c]pyridazin-7-yl)hexahydrocyclopenta[c]pyrrole-2(1H)-yl](5-methyl-2-thienyl)methanone racemic mixture [ka] HPLC retention time (min): 1.10 (TFA); MS(ESI, Pos.):387(M+H) + ; 1H-NMR(CDCl3): δ7.69, 7.55, 7.33, 6.74, 6.46, 5.14-4.96, 4.01-3.86, 3.73, 3.35-3.25, 3.13, 2.62, 2.51, 2.48-2.29, 1.80-1.65.

[0228] Example 8-2: rel-{(3aS,4R,6aR)-4-[(6-chloro-4-methoxy-3-pyridazinyl)amino]hexahydrocyclopenta[c]pyrrole-2(1H)-yl}(5-methyl-2-thienyl)methanone racemic mixture

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[0229] Example 8-3: rel-((3aS,4R,6aR)-4-((6-chloropyridine-3-yl)amino)hexahydrocyclopenta[c]pyrrole-2(1H)-yl)(5-methylthiophen-2-yl)methanone racemic mixture

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[0230] Example 8-4: rel-((3aS,4R,6aR)-4-((4,6-dichloropyridine-3-yl)amino)hexahydrocyclopenta[c]pyrrole-2(1H)-yl)(5-methylthiophen-2-yl)methanone racemic mixture

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[0231] Reference Example 58: rel-tert-butyl (3aS,4R,6aR)-4-((6-chloro-4-cyanopyridazine-3-yl)amino)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate racemic mixture The title compound was obtained by using the compound prepared in Reference Example 1 instead of the compound prepared in Reference Example 3, and 3,6-dichloropyridazine-4-carbonitride (CAS number: 35857-93-3, 45 mg) instead of 3,6-dichloropyridazine, and performing the same procedure as in Reference Example 4 → Reference Example 5 → Reference Example 6 → Reference Example 7 → Reference Example 8 → Reference Example 9.

[0232] Reference Example 59: rel-6-chloro-3-(((3aS,4R,6aR)-octahydrocyclopenta[c]pyrrole-4-yl)amino)pyridazine-4-carbonitriel racemic mixture 100 mg of the compound prepared in Reference Example 58 was mixed with 4N hydrochloric acid (1,4-dioxane solution, 3 mL) and stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure to obtain the title compound (5 mg).

[0233] Example 9: rel-6-chloro-3-({(3aS,4R,6aR)-2-[(5-methyl-2-thienyl)carbonyl]octahydrocyclopenta[c]pyrrole-4-yl}amino)-4-pyridazine carbonitride racemic mixture [ka] The title compound was obtained by performing the same procedure as in Example 2, using the compound prepared in Reference Example 59 instead of the compound prepared in Reference Example 12. HPLC retention time (min): 1.10 (TFA); MS(ESI, Pos.):388(M+H) + ; 1 H-NMR(CDCl3):δ7.42, 7.37-7.27, 6.75, 5.11, 4.47-4.39, 4.05, 3.99-3.82, 3.68, 2.91, 2.74, 2.53-2.50, 2.50-2.42, 2.21-1.98, 1.78-1.54.

[0234] Example 9-1 The title compound was obtained by performing the same procedure as in Reference Example 9 → Reference Example 10 → Example 1, using the corresponding halogen compound instead of 3,6-dichloropyridazine and the corresponding carboxylic acid instead of 5-(difluoromethyl)thiophene-2-carboxylic acid.

[0235] Example 9-1: [(3aS,4R,6aR)-4-{[6-chloro-4-(trifluoromethyl)-3-pyridazinyl]amino}hexahydrocyclopenta[c]pyrrole-2(1H)-yl](6,7-dihydro-4H-thieno[3,2-c]pyran-2-yl)methanone [ka] HPLC retention time (minutes): 1.10 (formic acid); MS(ESI, Pos.):473(M+H) + ; 1 H-NMR(DMSO-d6):δ7.94-7.83, 7.37-7.24, 6.85-6.70, 4.60, 4.48-4.37, 3.88, 3.82-3.63, 2.84-2.78, 2.97-2.67, 2.29-2.12, 2.10-1.98, 1.83-1.70, 1.58-1.43.

[0236] Reference example 60: (1)[(R)-4-[tert-butyl(dimethyl)silyl]oxy-3,5,6,6a-tetrahydro-1H-cyclopenta[c]pyrrole-2-yl]-(5-methyl-2-thienyl)methanone, and (2)[(3aR,6aS)-6-{[dimethyl(2-methyl-2-propanyl)silyl]oxy}-3,3a,4,6a-tetrahydrocyclopenta[c]pyrrole-2(1H)-yl](5-methyl-2-thienyl)methanone To a solution of the compound (4.3 g) prepared in Reference Example 54-1 in dichloromethane (86 mL), triethylamine (2.4 mL) and tert-butyldimethylsilyl trifluoromethanesulfonic acid (CAS No.: 69739-34-0, 2.0 mL) were added and the mixture was stirred at 40°C for 2 hours. Saturated sodium bicarbonate aqueous solution was added to the reaction mixture and extracted with dichloromethane. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compounds (1) (1.9 g) and (2) (1.0 g), respectively.

[0237] Reference Example 61: (3aR,6aS)-3a-fluoro-2-(5-methylthiophen-2-carbonyl)-3,5,6,6a-tetrahydro-1H-cyclopenta[c]pyrrole-4-one To a solution of the compound (1.9 g) prepared in Reference Example 60(1) in acetonitrile (38 mL), 1-chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate) (CAS number: 140681-55-6, 2.2 g) was added and the mixture was stirred at room temperature for 20 minutes. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography to obtain the title compound (540 mg). HPLC retention time (min): 0.95 (TFA); MS(ESI, Pos.):268(M+H) + .

[0238] Reference Example 62: [(3aR,4S,6aS)-3a-fluoro-4-hydroxy-1,3,4,5,6,6a-hexahydrocyclopenta[c]pyrrole-2-yl]-(5-methyl-2-thienyl)methanone To a solution of the compound (1.9 g) prepared in Reference Example 61 in methanol (19 mL) and THF (19 mL), sodium borohydride (CAS number: 16940-66-2, 405 mg) was added at 0°C and the mixture was stirred at 0°C for 1 hour. Water was added to the reaction mixture and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound (872 mg). HPLC retention time (min): 0.88 (TFA); MS(ESI, Pos.):270(M+H) + .

[0239] Reference Example 63: [(3aR,4R,6aS)-3a-fluoro-2-(5-methylthiophen-2-carbonyl)-1,3,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-4-yl] 4-methylbenzenesulfonate To a solution of the compound (872 mg) prepared in Reference Example 62 in dichloromethane (13 mL), triethylamine (1.4 mL), p-toluenesulfonyl chloride (1.2 g), and trimethylamine hydrochloride (154 mg) were added and the mixture was stirred at room temperature for 23 hours. Water was added to the reaction mixture and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound (1.0 g). HPLC retention time (min): 1.16 (TFA); MS(ESI, Pos.):424(M+H) + .

[0240] Reference Example 64: [(3aR,4R,6aS)-4-azido-3a-fluoro-1,3,4,5,6,6a-hexahydrocyclopenta[c]pyrrole-2-yl]-(5-methyl-2-thienyl)methanone To a solution of the compound (1.4 g) prepared in Reference Example 63 in dimethyl sulfoxide (13 mL), sodium azide (560 mg) was added and the mixture was stirred at 100°C for 90 hours. Water was added to the reaction mixture and extracted with dichloromethane. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting title compound was used in the next reaction without purification. HPLC retention time (min): 1.08 (TFA); MS(ESI, Pos.):295(M+H) + .

[0241] Reference Example 65: [(3aR,4R,6aS)-4-amino-3a-fluoro-1,3,4,5,6,6a-hexahydrocyclopenta[c]pyrrole-2-yl]-(5-methyl-2-thienyl)methanone To a solution of the compound (892 mg) prepared in Reference Example 64 in ethanol (18 mL), 20% palladium hydroxide (1.8 g) was added and the mixture was stirred at room temperature under a hydrogen atmosphere for 15 hours. The reaction mixture was filtered, concentrated under reduced pressure, and the resulting title compound was used in the next reaction without purification. HPLC retention time (min): 0.72 (TFA); MS(ESI, Pos.):269(M+H) + .

[0242] Example 10: [(3aR,4R,6aS)-4-[(6-bromopyridazin-3-yl)amino]-3a-fluoro-1,3,4,5,6,6a-hexahydrocyclopenta[c]pyrrole-2-yl]-(5-methyl-2-thienyl)methanone [ka] To a solution of the compound (470 mg) prepared in Reference Example 65 in 2-methyl-2-butanol (9.4 mL), DIPEA (0.91 mL) and 3-bromo-6-fluoropyridazine (619 mg) were added, and the mixture was stirred at 180°C for 3 hours. Water was added to the reaction mixture, and it was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound (141 mg). HPLC retention time (min): 1.00 (TFA); MS(ESI, Pos.):427(M+H) + .

[0243] Reference example 66: (3aR,4R,6aS)-N-(6-bromo-3-pyridazinyl)-3a-fluorooctahydrocyclopenta[c]pyrrole-4-amine To a solution of the compound prepared in Example 10 (40 mg) in THF (2 mL), methanol (1 mL) and 5N sodium hydroxide aqueous solution (1 mL) were added and the mixture was stirred at 50°C for 16 hours. Water was added to the reaction mixture and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting title compound was used in the next reaction without purification.

[0244] Example 11: [(3aR,4R,6aS)-4-[(6-bromo-3-pyridazinyl)amino]-3a-fluorohexahydrocyclopenta[c]pyrrole-2(1H)-yl](6,7-dihydro-4H-thieno[3,2-c]pyran-2-yl)methanone [ka] To a solution of the compound prepared in Reference Example 66 and 6,7-dihydro-4H-thieno[3,2-c]pyran-2-carboxylic acid (14 mg) in DMA (0.22 mL), DIPEA (0.02 mL) and HATU (31 mg) were added, and the mixture was stirred at room temperature for 3 hours. 2N hydrochloric acid was added to the reaction mixture, and it was extracted with dichloromethane. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound (22 mg). HPLC retention time (min): 0.89 (TFA); MS(ESI, Pos.):467(M+H) + ; 1 H-NMR(CDCl3):δ7.29, 7.24-7.16, 6.59, 4.78, 4.75-4.67, 4.56, 4.28, 4.22-4.08, 4.01-3.89, 3.61, 2.89, 2.51-2.40, 2.26-2.17, 1.86-1.75, 1.60, 1.52-1.34.

[0245] Examples 11-1 to 11-3 The title compound was obtained by using the corresponding carboxylic acid compound instead of 6,7-dihydro-4H-thieno[3,2-c]pyran-2-carboxylic acid and performing the same procedure as in Example 11.

[0246] Example 11-1: [(3aR,4R,6aS)-4-[(6-bromo-3-pyridazinyl)amino]-3a-fluorohexahydrocyclopenta[c]pyrrole-2(1H)-yl](2-cyclopropyl-2H-thieno[3,2-c]pyrazole-5-yl)methanone [ka] HPLC retention time (min): 0.91 (TFA); MS(ESI, Pos.):491(M+H) + ; 1 H-NMR(DMSO-d6):δ8.17, 7.64, 7.47, 7.30, 6.92, 4.55-4.41, 4.00, 2.89, 2.73-2.68, 2.56-2.53, 2.29-2.16, 2.14-2.01, 1.87-1.72, 1.47-1.35, 1.28-1.12, 1.12-1.01.

[0247] Example 11-2: [(3aR,4R,6aS)-4-[(6-bromo-3-pyridazinyl)amino]-3a-fluorohexahydrocyclopenta[c]pyrrole-2(1H)-yl][5-(fluoromethyl)-2-thienyl]methanone [ka] HPLC retention time (min): 0.92 (TFA); MS(ESI, Pos.):443(M+H) + ; 1 H-NMR(CDCl3):δ7.40, 7.31, 7.28, 7.10, 6.60, 5.54, 5.42, 4.84-4.74, 4.62-4.48, 4.27-4.13, 4.01-3.93, 3.87, 3.61, 3.49, 3.00-2.83, 2.50, 2.19, 2.28-2.14, 1.61-1.58, 1.53-1.36.

[0248] Example 11-3: [(3aR,4R,6aS)-4-[(6-bromo-3-pyridazinyl)amino]-3a-fluorohexahydrocyclopenta[c]pyrrole-2(1H)-yl][5-(2-fluoroethyl)-2-thienyl]methanone [ka] HPLC retention time (min): 0.94 (TFA); MS(ESI, Pos.):457(M+H) + ; 1 H-NMR(CDCl3):δ7.36-7.27, 6.87, 6.59, 4.71, 4.59, 4.19, 4.01, 3.63, 3.49, 3.28-3.17, 2.98-2.79, 2.57-2.41, 2.28-2.14, 1.87-1.73, 1.61-1.57, 1.53-1.45.

[0249] Example 12: {(3aR,4R,6aS)-4-[(6-chloro-3-pyridazinyl)amino]-3a-fluorohexahydrocyclopenta[c]pyrrole-2(1H)-yl}(6,7-dihydro-4H-thieno[3,2-c]pyran-2-yl)methanone [ka] The title compound was obtained by using 3,6-dichloropyridazine instead of 3-bromo-6-fluoropyridazine and the corresponding carboxylic acid instead of 6,7-dihydro-4H-thieno[3,2-c]pyran-2-carboxylic acid, following the same procedure as in Example 10 → Reference Example 66 → Example 11. HPLC retention time (min): 0.89 (TFA); MS(ESI, Pos.):423(M+H) + ; 1 H-NMR(CDCl3):δ7.22-7.15, 6.70, 4.85, 4.71, 4.66-4.47, 4.27, 4.19-4.09, 4.03-3.90, 3.61, 2.96-2.82, 2.45, 2.27-2.15, 1.88-1.66, 1.58-1.37.

[0250] Reference example 67: (3aS,5R,6aR)-5-fluoro-2-(5-methylthiophen-2-carbonyl)-1,3,3a,5,6,6a-hexahydrocyclopenta[c]pyrrole-4-one To a solution of the compound (1.3 g) prepared in Reference Example 60(2) in acetonitrile (25 mL), 1-chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate) (1.5 g) was added and the mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure, and the resulting residue was diluted with water and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound (633 mg). HPLC retention time (min): 0.81 (TFA); MS(ESI, Pos.):304(M+H) + .

[0251] Reference Example 68: [(3aS,4R,5R,6aR)-5-fluoro-4-hydroxy-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-yl]-(5-methyl-2-thienyl)methanone To a methanol (10 mL) solution of the compound (500 mg) prepared in Reference Example 67, sodium borohydride (106 mg) was added at 0°C and the mixture was stirred at 0°C for 1 hour. Water was added to the reaction mixture and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound (200 mg).

[0252] Reference Example 69: [(3aS,4R,5R,6aR)-5-fluoro-2-(5-methylthiophen-2-carbonyl)-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-4-yl] 4-methylbenzenesulfonate To a solution of the compound (120 mg) prepared in Reference Example 68 in acetonitrile (1.2 mL), DIPEA (0.23 mL), p-toluenesulfonyl chloride (127 mg), and trimethylamine hydrochloride (21 mg) were added and the mixture was stirred at room temperature for 24 hours. Water was added to the reaction mixture and extracted with dichloromethane. After concentration, the resulting residue was purified by silica gel column chromatography to obtain the title compound (190 mg). HPLC retention time (min): 1.13 (TFA); MS(ESI, Pos.):424(M+H) + .

[0253] Reference Example 70: [(3aS,4S,5R,6aR)-4-azido-5-fluorohexahydrocyclopenta[c]pyrrole-2(1H)-yl](5-methyl-2-thienyl)methanone To a solution of the compound (190 mg) prepared in Reference Example 69 in dimethyl sulfoxide (0.8 mL), sodium azide (145 mg) was added and the mixture was stirred at 100°C for 17 hours. Water was added to the reaction mixture and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting title compound was used in the next reaction without purification. HPLC retention time (min): 1.05 (TFA); MS(ESI, Pos.):295(M+H) + .

[0254] Reference Example 71: [(3aS,4S,5R,6aR)-4-amino-5-fluoro-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-yl]-(5-methyl-2-thienyl)methanone To a 2 mL solution of the compound prepared in Reference Example 70 in ethanol, 50 mg of palladium hydroxide was added, and the mixture was stirred at room temperature under a hydrogen atmosphere for 2 hours. The reaction mixture was filtered, concentrated under reduced pressure, and the resulting title compound was used in the next reaction without purification. HPLC retention time (min): 0.75 (TFA); MS(ESI, Pos.):269(M+H) + .

[0255] Example 13: [(3aS,4S,5R,6aR)-4-[(6-bromopyridazine-3-yl)amino]-5-fluoro-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-yl]-(5-methyl-2-thienyl)methanone [ka] To a solution of the compound (50 mg) prepared in Reference Example 71 in 2-methyl-2-butanol (0.23 mL), DIPEA (0.19 mL) and 3-bromo-6-fluoropyridazine (132 mg) were added, and the mixture was stirred at 160°C for 1 hour. The reaction mixture was purified by reverse-phase column chromatography to obtain the title compound (8.9 mg). HPLC retention time (min): 0.94 (TFA); MS(ESI, Pos.):426(M+H) + ; 1 H-NMR(CDCl3):δ7.32, 7.28-7.26, 6.73, 6.62, 5.42-5.10, 4.89, 4.51-4.38, 4.13-3.88, 3.63, 3.09-2.99, 2.82-2.75, 2.50, 1.95-1.77.

[0256] Reference Example 72: (3aS,6aR)-2-(6,7-dihydro-4H-thieno[3,2-c]pyran-2-ylcarbonyl)hexahydrocyclopenta[c]pyrrole-4(1H)-one To a solution of the compound (2.8 g) prepared in Reference Example 53-1 in DMA (230 mL), 6,7-dihydro-4H-thieno[3,2-c]pyran-2-carboxylic acid (4.6 g), DIPEA (13 mL), and HATU (9.5 g) were added and the mixture was stirred at room temperature for 3 hours. Water was added to the reaction mixture and extracted with dichloromethane. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound (4.1 g).

[0257] Reference Example 73: [(3aS,6aR)-6-{[dimethyl(2-methyl-2-propanyl)silyl]oxy}-3,3a,4,6a-tetrahydrocyclopenta[c]pyrrole-2(1H)-yl](6,7-dihydro-4H-thieno[3,2-c]pyran-2-yl)methanone To a solution of the compound (2.0 g) prepared in Reference Example 72 in dichloromethane (40 mL), triethylamine (2.8 mL) and tert-butyldimethylsilyl trifluoromethanesulfonate (2.3 mL) were added at 0°C and the mixture was stirred at 50°C for 22 hours. Saturated sodium bicarbonate aqueous solution was added to the reaction mixture and extracted with dichloromethane. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting title compound was used in the next reaction without purification.

[0258] Reference Example 74: (3aS,5R,6aR)-2-(6,7-dihydro-4H-thieno[3,2-c]pyran-2-ylcarbonyl)-5-methylhexahydrocyclopenta[c]pyrrole-4(1H)-one To a 10 mL solution of the compound prepared in Reference Example 73 in DMF, 9.5 g of iodomethane and 1 M tetra-N-butylammonium fluoride (CAS number: 429-41-4, 0.74 mL, THF solution) were added and the mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure, and the resulting residue was diluted with water and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound (100 mg).

[0259] Example 14: [(3aS,4R,5R,6aR)-4-[(6-bromo-3-pyridazinyl)amino]-5-methylhexahydrocyclopenta[c]pyrrole-2(1H)-yl](6,7-dihydro-4H-thieno[3,2-c]pyran-2-yl)methanone [ka] Using the compound prepared in Reference Example 74 instead of the compound prepared in Reference Example 61, the same procedure as in Reference Example 62 → Reference Example 63 → Reference Example 64 → Reference Example 65 → Example 10 was followed to obtain the title compound. HPLC retention time (min): 0.86 (TFA); MS(ESI, Pos.):463(M+H) + ; 1 H-NMR(CDCl3): δ7.33-7.28, 7.13, 6.65-6.58, 5.21, 4.70, 4.04-3.83, 3.66, 2.93-2.85, 2.76, 2.55, 1.88-1.69, 0.95.

[0260] Reference example 75: (3aS,6aR)-2-(6,7-dihydro-4H-thieno[3,2-c]pyran-2-carbonyl)spiro[3,3a,6,6a-tetrahydro-1H-cyclopenta[c]pyrrole-5,1'-cyclopropane]-4-one To a solution of the compound (300 mg) prepared in Reference Example 72 in dimethyl sulfoxide (7.5 mL), 1,8-diazabicyclo[5.4.0]undeca-7-ene (CAS No.: 6674-22-2, 0.31 mL) and diphenylvinylsulfonium triflate (CAS No.: 247129-88-0, 410 mg) were added, and the mixture was stirred at room temperature for 1 hour. Water and 1N hydrochloric acid aqueous solution were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound (100 mg). HPLC retention time (min): 0.90 (TFA); MS(ESI, Pos.):318(M+H) + .

[0261] Reference Example 76: [(3aS,4R,6aR)-4-hydroxyspiro[1,3,3a,4,6,6a-hexahydrocyclopenta[c]pyrrole-5,1'-cyclopropane]-2-yl]-(6,7-dihydro-4H-thieno[3,2-c]pyran-2-yl)methanone To a methanol (2.8 mL) solution of the compound (138 mg) prepared in Reference Example 75, sodium borohydride (25 mg) was added at 0°C and the mixture was stirred at 0°C for 30 minutes. Water was added to the reaction mixture and extracted with dichloromethane. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound (95 mg). HPLC retention time (min): 0.91 (TFA); MS(ESI, Pos.):320(M+H) + .

[0262] Reference Example 77: [(3aS,4S,6aR)-4-azidospiro[1,3,3a,4,6,6a-hexahydrocyclopenta[c]pyrrole-5,1'-cyclopropane]-2-yl]-(6,7-dihydro-4H-thieno[3,2-c]pyran-2-yl)methanone To a solution of the compound (95 mg) prepared in Reference Example 76 in THF (0.2 mL), triphenylphosphine (CAS No.: 603-35-0, 102 mg), 2.2 M diethyl azodicarboxylate solution (CAS No.: 1972-28-7, 0.18 mL), and diphenylphosphoryl azide (CAS No.: 26386-88-9, 82 mg) were added, and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was purified by silica gel column chromatography to obtain the title compound (43 mg). HPLC retention time (min): 1.08 (TFA); MS(ESI, Pos.):345(M+H) + .

[0263] Reference example 78: [(3aS,4S,6aR)-4-aminospiro[1,3,3a,4,6,6a-hexahydrocyclopenta[c]pyrrole-5,1'-cyclopropane]-2-yl]-(6,7-dihydro-4H-thieno[3,2-c]pyran-2-yl)methanone To a methanol (1 mL) solution of the compound (43 mg) prepared in Reference Example 77, 20% palladium hydroxide (20 mg) was added and the mixture was stirred at room temperature for 30 minutes under a hydrogen atmosphere. The reaction mixture was filtered, concentrated under reduced pressure, and purified by silica gel column chromatography to obtain the title compound (20 mg). HPLC retention time (min): 0.73 (TFA); MS(ESI, Pos.):319(M+H) + .

[0264] Example 15: [(3aS,4S,6aR)-4-[(6-bromopyridazine-3-yl)amino]spiro[1,3,3a,4,6,6a-hexahydrocyclopenta[c]pyrrole-5,1'-cyclopropane]-2-yl]-(6,7-dihydro-4H-thieno[3,2-c]pyran-2-yl)methanone [ka] To a solution of the compound (17 mg) prepared in Reference Example 78 in 2-methyl-2-butanol (0.5 mL), DIPEA (0.92 mL) and 3-bromo-6-fluoropyridazine (18.9 mg) were added, and the mixture was stirred at 180°C for 4 hours. Water was added to the reaction mixture, and it was extracted with dichloromethane. The organic layer was purified by silica gel column chromatography to obtain the title compound (13 mg). HPLC retention time (min): 0.97 (TFA); MS(ESI, Pos.):477(M+H) + ; 1 H-NMR(CD3OD):δ7.37, 7.34-7.18, 6.84, 4.68, 4.12-3.91, 3.80, 2.97, 2.93-2.81, 2.36, 2.07-1.95, 1.50, 1.41-1.17, 0.74-0.65, 0.60, 0.53-0.35.

[0265] Reference Example 79: 2-methyl-2-propanyl rel-[(3aS,4R,6aR)-2-benzyl-6-oxooctahydrocyclopenta[c]pyrrole-4-yl]carbamate racemic mixture To a 20 mL solution of N-benzyl-N-(methoxymethyl)-N-trimethylsilylmethylamine (3.6 g) in dichloromethane, tert-butyl N-(4-oxocyclopenta-2-en-1-yl)carbamate (CAS No.: 657396-97-9, 17 g) and trifluoroacetic acid (58 mg) were added, and the mixture was stirred at room temperature for 16 hours. Triethylamine (430 mg) was added to the reaction mixture, and the mixture was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound (300 mg). HPLC retention time (min): 0.86 (TFA); MS(ESI, Pos.):331(M+H) + .

[0266] Reference Example 80: 2-methyl-2-propanyl rel-[(3aS,4R,6aR)-2-benzyl-6,6-difluorooctahydrocyclopenta[c]pyrrole-4-yl]carbamate racemic mixture To a solution of the compound (300 mg) prepared in Reference Example 79 in dichloromethane (5 mL), bis(2-methoxyethyl)aminosulfur trifluoride (CAS number: 202289-38-1, 1.2 g) was added at 0°C and the mixture was stirred at room temperature for 15 hours. Saturated sodium bicarbonate aqueous solution was added to the reaction mixture and extracted with dichloromethane. The mixture was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound (120 mg). HPLC retention time (min): 0.91 (TFA); MS(ESI, Pos.):353(M+H) + .

[0267] Reference Example 81: 2-methyl-2-propanyl rel-[(3aS,4R,6aR)-6,6-difluorooctahydrocyclopenta[c]pyrrole-4-yl]carbamate racemic mixture To a solution of the compound (120 mg) prepared in Reference Example 80 in ethanol (10 mL), 20% palladium hydroxide (120 mg) was added and the mixture was stirred at room temperature under a hydrogen atmosphere for 2 hours. The reaction mixture was filtered and concentrated under reduced pressure. The resulting residue was used in the next reaction without purification.

[0268] Reference Example 82: 2-methyl-2-propanyl rel-[(3aS,4R,6aR)-2-(6,7-dihydro-4H-thieno[3,2-c]pyran-2-ylcarbonyl)-6,6-difluorooctahydrocyclopenta[c]pyrrole-4-yl]carbamate racemic mixture To a DMA (3 mL) solution of the compound prepared in Reference Example 81, 6,7-dihydro-4H-thieno[3,2-c]pyran-2-carboxylic acid (112 mg), DIPEA (0.26 mL), and HATU (210 mg) were added and the mixture was stirred at room temperature for 3 hours. Water was added to the reaction mixture and extracted with dichloromethane. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound (100 mg). HPLC retention time (minutes): 1.00 (formic acid); MS(ESI, Pos.):429(M+H) + .

[0269] Reference Example 83: rel-[(3aR,6R,6aS)-6-amino-4,4-difluorohexahydrocyclopenta[c]pyrrole-2(1H)-yl](6,7-dihydro-4H-thieno[3,2-c]pyran-2-yl)methanone racemic mixture 100 mg of the compound prepared in Reference Example 82 was mixed with 4N hydrochloric acid (1,4-dioxane solution, 3 mL) and stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure to obtain the title compound (80 mg).

[0270] Example 16: [(3aR,6R,6aS)-6-[(6-bromo-3-pyridazinyl)amino]-4,4-difluorohexahydrocyclopenta[c]pyrrole-2(1H)-yl](6,7-dihydro-4H-thieno[3,2-c]pyran-2-yl)methanone [ka] To a DMA (1 mL) solution of the compound (80 mg) prepared in Reference Example 83, DIPEA (0.24 mL) and 3,6-dibromopyridazine (120 mg) were added and the mixture was stirred at 160°C for 1 hour. Water was added to the reaction mixture and extracted with dichloromethane. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography, and then the two diastereomers were separated using supercritical fluid chromatography (CHIRALPAK IC, CO2:methanol = 70:30) to obtain the low-polarity compound (19 mg). HPLC retention time (min): 1.00 (TFA); MS(ESI, Pos.):485(M+H) + ; 1 H-NMR(DMSO-d6):δ7.54-7.45, 7.36-7.35, 7.40-7.32, 6.85, 4.62, 4.23-4.15, 3.88, 3.57-3.50, 3.38-3.31, 3.31-3.16, 2.99-2.88, 2.83, 2.30-2.17.

[0271] Reference example 84: 2-bromo-5-[2-(2-fluoroethoxy)ethyl]thiophene To a solution of 2-(5-bromothiophen-2-yl)ethane-1-ol (CAS No.: 57070-78-7, 653 mg) in dimethylacetamide (15 mL), 1-iodo-2-fluoroethane (CAS No.: 762-51-6, 1.52 mL) and sodium hydride (757 mg) were added and the mixture was stirred at room temperature for 17 hours. Then, the mixture was stirred at 60°C for 24 hours. Water was added to the reaction mixture, and the mixture was extracted with a mixed solvent of ethyl acetate and n-hexane. The organic layer was washed with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound (396 mg). HPLC retention time (min): 0.828 (TFA); 1 H-NMR (CDCl3): δ6.86, 6.61, 4.66-4.61, 4.54-4.49, 3.77-3.66, 3.04.

[0272] Reference example 85: 5-[2-(2-fluoroethoxy)ethyl]-2-thiophenecarboxylic acid To a solution of the compound (396 mg) prepared in Reference Example 84 in THF (1 mL), water (0.135 mL) and transbisacetatobis[2-(di-O-tolylphosphino)benzyl]dipalladium(II) (CAS No.: 172418-32-5, 141 mg), DBU (0.673 mL), tri-TERT-butylphosphonium tetrafluoroborate (CAS No.: 131274-22-1, 43 mg), and molybdenum hexacarbonyl (CAS No.: 13939-06-5, 595 mg) were added. The reaction mixture was heated at 120 °C for 1 hour. 1 M aqueous hydrochloric acid and ethyl acetate were added to the reaction mixture, and it was filtered. The organic layer was washed with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound (190 mg). 1 H-NMR (CDCl3): δ7.72, 6.91, 4.72-4.61, 4.55-4.49, 3.84-3.68, 3.15, 2.50.

[0273] Reference Example 86: [(3aS,4R,6aR)-4-[(6-bromo-3-pyridazinyl)amino]hexahydrocyclopenta[c]pyrrole-2(1H)-yl]{5-[2-(2-fluoroethoxy)ethyl]-2-thienyl}methanone To a solution of the compound prepared in Reference Example 12 (10 mg) and the compound prepared in Reference Example 85 (9.2 mg) in DMF (1.0 mL), DIPEA (0.024 mL) and hexafluorophosphate 1H-benzotriazole-1-yloxytripyrrolidinophosphonium (hereinafter referred to as PyBOP, 22 mg, CAS number: 128625-52-5) were added and the mixture was stirred at room temperature for 1 hour. Water was added to the reaction mixture and extracted with dichloromethane. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound (5.0 mg). HPLC retention time (min): 0.88 (TFA); MS(ESI, Pos.):483(M+H) + .

[0274] Example 17: [(3aS,4R,6aR)-4-[(6-bromo-3-pyridazinyl)(methyl)amino]hexahydrocyclopenta[c]pyrrole-2(1H)-yl]{5-[2-(2-fluoroethoxy)ethyl]-2-thienyl}methanone [ka] Sodium hydride (4.1 mg) was added to a solution of the compound (5.0 mg) prepared in Reference Example 86 in DMF (1.0 mL). After stirring at room temperature for 15 minutes, iodomethane (0.003 mL) was added, and the mixture was stirred at room temperature for a further 1 hour. Water was added to the reaction mixture, and it was extracted with dichloromethane. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound (3.9 mg). HPLC retention time (min): 0.95 (TFA); MS(ESI, Pos.):497(M+H) + ; 1 H-NMR(CDCl3):δ7.34-7.27, 6.82, 6.70, 4.84, 4.64-4.61, 4.53-4.49, 3.91, 3.83, 3.80-3.63, 3.11, 2.98, 2.92-2.77, 2.17-2.08, 1.90-1.80.

[0275] Reference example 87: 5-(2-fluoroethoxy)-2-thiophenecarboxylic acid Sodium hydride (1313 mg) was added to a DMA (15 mL) solution of 2-fluoroethanol (CAS No.: 371-62-0, 1578 mg) at room temperature, followed by the addition of 5-fluorothiophene-2-carboxylic acid (CAS No.: 4377-58-6, 600 mg). The reaction mixture was stirred at 100°C for 2 days. Water was added to the reaction mixture, and it was extracted with a mixed solvent of ethyl acetate and n-hexane. The organic layer was washed with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was dissolved in methanol (4 mL), and trimethylsilyldiazomethane (CAS No.: 18107-18-1, 1 mL) was added, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was purified by silica gel column chromatography to obtain a methyl ester compound (60 mg). The obtained methyl ester compound (60 mg) was dissolved in methanol (4 mL), followed by the addition of 2 M aqueous sodium hydroxide solution (1.5 mL). The reaction mixture was stirred at 50°C for 18 hours. The reaction mixture was treated with 1M hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure to obtain the title compound (57 mg). HPLC retention time (min): 0.83 (TFA); MS(ESI, Pos.):191(M+H) + ; 1 H-NMR (CDCl3): δ7.53, 6.28, 4.84-4.79, 4.72-4.67, 4.38-4.27.

[0276] Reference Example 88: [(3aS,4R,6aR)-4-[(6-bromo-3-pyridazinyl)amino]hexahydrocyclopenta[c]pyrrole-2(1H)-yl][5-(2-fluoroethoxy)-2-thienyl]methanone To a solution of the compound prepared in Reference Example 12 (10 mg) and the compound prepared in Reference Example 87 (8.1 mg) in DMF (1.0 mL), DIPEA (0.024 mL) and PyBOP (22 mg) were added, and the mixture was stirred at room temperature for 1 hour. Water was added to the reaction mixture, and it was extracted with dichloromethane. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound (7.0 mg). HPLC retention time (min): 0.89 (TFA); MS(ESI, Pos.):455(M+H) + .

[0277] Example 18: [(3aS,4R,6aR)-4-[(6-bromo-3-pyridazinyl)(methyl)amino]hexahydrocyclopenta[c]pyrrole-2(1H)-yl][5-(2-fluoroethoxy)-2-thienyl]methanone [ka] Sodium hydride (6.1 mg) was added to a solution of the compound (7.0 mg) prepared in Reference Example 88 in DMF (1.0 mL), and the mixture was stirred at room temperature for 15 minutes. Then, iodomethane (0.005 mL) was added, and the mixture was stirred at room temperature for a further 1 hour. Water was added to the reaction mixture, and it was extracted with dichloromethane. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound (3.9 mg). HPLC retention time (min): 0.95 (TFA); MS(ESI, Pos.):469(M+H) + ; 1 H-NMR(CDCl3):δ7.28, 7.19, 6.71, 6.24, 4.91-4.78, 4.71-4.66, 4.37-4.33, 4.30-4.26, 3.95-3.78, 3.63, 2.98, 2.92-2.77, 2.17-2.09, 1.91-1.80, 1.60.

[0278] Reference example 89: 2-{2-[(6-bromo-3-pyridazinyl){(3aS,4R,6aR)-2-[(5-methyl-2-thienyl)carbonyl]octahydrocyclopenta[c]pyrrole-4-yl}amino]ethoxy}ethyl 4-methylbenzene sulfonate Sodium hydride (88 mg) was added to a solution of the compound prepared in Example 2 (300 mg) in DMF (7.4 mL) and the mixture was stirred at room temperature for 30 minutes. Then, diethylene glycol ditosilate (CAS number: 7460-82-4, 305 mg) was added and the mixture was stirred at room temperature for 4 hours. An aqueous solution of sodium bicarbonate was added to the reaction mixture and extracted with dichloromethane. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound (100 mg). HPLC retention time (min): 1.18 (TFA); MS(ESI,Pos.):649(M+H) + .

[0279] Example 19: [(3aS,4R,6aR)-4-{(6-bromo-3-pyridazinyl)[2-(2-fluoroethoxy)ethyl]amino}hexahydrocyclopenta[c]pyrrole-2(1H)-yl](5-methyl-2-thienyl)methanone [ka] To a solution of the compound (100 mg) prepared in Reference Example 89 in acetonitrile (1.5 mL), potassium fluoride (27 mg) and 4,7,13,16,21,24-hexaoxa-1,10-diazabicyclo[8.8.8]hexacosan (CAS number: 23978-09-8, 174 mg) were added and the mixture was stirred at 80°C for 40 minutes. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography to obtain the title compound (41.6 mg). HPLC retention time (min): 1.05 (TFA); MS(ESI,Pos.):497(M+H) + ; 1 H-NMR(CDCl3):δ7.37-7.30, 7.28-7.21, 6.85, 6.73, 4.60-4.53, 4.48-4.41, 4.32-4.23, 3.89, 3.87-3.79, 3.78-3.61, 3.04-2.83, 2.50, 2.20-2.01, 1.98-1.87.

[0280] Pharmacological Experiment Example 1: Evaluation of ABHD6 Enzyme Inhibitory Activity 1-Arachidonoyl Glycerol (Cayman), the substrate, was prepared to a final concentration of 10 μmol / L in an assay buffer containing 50 mM Tris-HCl (pH 7.4), 100 mM NaCl, and 0.05% BSA. The compound was then added to the mixture to final concentrations of 0.0003, 0.001, 0.003, 0.01, 0.03, 0.1, 0.3, 1, 3, or 10 μmol / L (DMSO was added to a final concentration of 0.3%). A mixture with DMSO added to a final concentration of 0.3% was designated as the compound-free group. The enzymatic reaction was initiated by adding recombinant human ABHD6 (33-337), prepared in the same assay buffer, to a final concentration of 300 μg / mL in the substrate-compound mixture. Recombinant human ABHD6 (33-337) was GST-tagged and expressed in E. coli, then purified and concentrated using glutathione-sepharose 4B resin. The enzymatic reaction was performed at room temperature using a 384-well polypropylene microplate, with the enzyme-free wells designated as the blank group. One hour after the start of the enzymatic reaction, the reaction was stopped by adding methanol containing arachidonic acid-d8 (Cayman) and 1% formic acid as internal standards. The top of the reaction plate was sealed with aluminum foil, and the plate was centrifuged at 560g for 5 minutes at room temperature. The enzymatic reaction product, arachidonic acid, and the internal standard, arachidonic acid-d8, were then quantified using a RapidFire®-Mass Spectrometry system. The ratio of each quantified value was taken, and the average value for the Blank group was taken as 100% inhibition, and the average value for the group without compound addition was taken as 0% inhibition. The inhibition rate of arachidonic acid production at each compound concentration was calculated, and IC50 was calculated. 50 The value was calculated. The above pharmacological experiments revealed that the disclosed compounds possess potent ABHD6 inhibitory activity. For example, IC of several disclosed compounds 50 The values ​​are shown in Table 2 below. [Table 2]

[0281] Pharmacological experiment example 2: Measurement of binding affinity to human ABHD6 Using HEK293 cells that forcibly express the NanoLuc-human ABHD6 fusion protein, the binding affinity of the test compound to human ABHD6 was measured by competitively activating a fluorescent probe molecule with the test compound, using the bioluminescence resonance energy transfer (BRET) induced by the proximity of the probe molecule and the NanoLuc-human ABHD6 fusion protein as an indicator. <Compound treatment> The test compound and the control compound described in Example 2 were dissolved in dimethyl sulfoxide (DMSO) to prepare a 10 mmol / L solution. The prepared 10 mmol / L solution was thawed before use, serially diluted with DMSO, and used in the experiment. <Cell culture> NanoLuc-human ABHD6 fusion protein-expressing HEK293 cells were cultured statically at 37°C in the presence of 5% CO2 using 9.8 vol% non-dialysis-FBS (containing 0.5 vol% GENETICIN and 1% penicillin-streptomycin) that had been inactivated (56°C, 30 min). Subculturing was performed using the following method. Remove the culture medium, Ca 2+ and Mg 2+ The cells were washed once with phosphate-buffered saline that did not contain trypsin. An appropriate amount of trypsin-EDTA was added, and the cells were incubated at room temperature. After detaching the cells, 10 times the volume of culture medium in trypsin-EDTA (0.05%) was added to stop the enzymatic reaction. The cells were collected in a centrifuge tube and centrifuged at 120 g for 3 minutes at room temperature, and the supernatant was removed. The cells were suspended in an appropriate amount of culture medium and seeded in a culture flask. After preparing HEK293 cells expressing NanoLuc-human ABHD6 fusion protein, 5.0x10⁶ cells were used in CELLBANKER2. 6 Cells were frozen and stored at a concentration of cells / mL / vial before being used in the experiment. Additionally, HBSS(+) containing 20 mmol / L HEPES (pH 7.3) and 0.1% BSA was prepared and used as the assay buffer. The cells were thawed, and 2 x 10⁶ samples were taken. 5The cells were suspended in assay buffer to a concentration of cells / mL. The cell suspension (25 μL) was added to a 384-well assay plate pre-added with the test compound to initiate the reaction. After standing for 30 minutes at 37°C in the presence of 5% CO2, the fluorophore-containing probe molecule (10 mmol / L in DMSO) was diluted in assay buffer to a final concentration of 100 nmol / L, and 15 μL was added to each assay plate. After standing for another 30 minutes at 37°C in the presence of 5% CO2, Nano-Glo® Vivazine® substrate (PROMEGA) was diluted in assay buffer according to the method described in the company's protocol, and 10 μL was added to each assay plate. After standing for 1 hour at room temperature, luminescence and fluorescence intensity were measured using the GloMax® Discover system. The ratio of the emission intensity through a 450nm bandpass filter to the fluorescence intensity through a 600nm longpass filter was used as the measurement value for each sample. The measurement values ​​for the group containing the control substance at a final concentration of 30 μmol / L were set as 100% inhibition, and the measurement values ​​for the group without the compound were set as 0% inhibition. The IC of the test compound was then calculated from the measurement values ​​at each test compound concentration. 50 The value was calculated. In the cell evaluation system described above, the disclosed compounds were found to possess potent ABHD6 binding activity. For example, several disclosed compounds were found to have IC50 activity. 50 The values ​​are shown in Table 3 below. [Table 3]

[0282] Pharmacological Experiment Example 3: Evaluation of ABHD6 Selectivity Using rat brain membrane fractions, fluorescent probe molecules were reacted with the test compound, and after protein separation by electrophoresis, the binding affinity of the test compound was measured using the fluorescence intensity of ABHD6, MAGL, and FAAH as indicators. <Compound treatment> The test compound was dissolved in dimethyl sulfoxide (DMSO) to prepare a 10 mmol / L solution. The prepared 10 mmol / L solution was thawed before use and serially diluted with DMSO to a concentration 50 times higher than the final concentration. <Preparation of rat meninges membrane fraction> After anesthetizing and bleeding rats, their brains were removed. 1 mL of ice-cold phosphate-buffered saline (PBS, pH 7.5) was added per 200 mg of brain weight, and the mixture was homogenized using a homogenizer. The homogenate solution was centrifuged at 1000 g, 4°C, for 10 minutes, and the supernatant was collected. The obtained supernatant was centrifuged at 100,000 g, 4°C, for 45 minutes, and the precipitate was resuspended in ice-cold PBS to obtain the membrane fraction. The protein concentration of the prepared brain membrane fraction solution was quantified, and the solution was stored in a -80°C freezer until use. <abpp> The brain membrane fraction solution was prepared to 3 mg / mL in PBS. 50 μL of the 3 mg / mL membrane fraction solution was mixed with 1 μL of DMSO or compound solution and reacted at 37°C for 30 minutes. Then, 1 μL of a probe molecule containing a fluorophore (ActivX (trade name) TAMRA-FP Serine Hydrolase Probe, final concentration 1 μmol / L, DMSO solution) was added and reacted at room temperature for 30 minutes. The reaction was stopped with 4x sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE) loading buffer. After heating the sample at 95°C for 5 minutes, protein separation was performed using SDS-PAGE on a 10% acrylamide gel. The fluorescence of the gel after SDS-PAGE was visualized using a chemiluminescence imaging system. For each of the ABHD6, MAGL, and FAAH bands, the fluorescence band intensity of the control group (DMSO-treated group) was set as 0% inhibition, and the IC of the test compound was determined from the fluorescence intensity at each concentration of the test compound. 50 The values ​​were determined. As a result, it was found that the disclosed compound has selective inhibitory activity against ABHD6, with respect to MAGL and FAAH.

[0283] Pharmacological Experiment Example 4: Analgesic effect on a rat model induced by sodium monoiodoacetate The analgesic effect of the disclosed compound was evaluated using a rat model induced by sodium monoiodoacetate (hereinafter abbreviated as MIA) (Sigma-Aldrich Japan). (1) Creation of a MIA-inducing model rat Under isoflurane anesthesia, the area around the right hind limb knee of rats was shaved, and 25 μL of 120 mg / mL MIA solution was administered into the right hind limb joint cavity using a syringe with a 29G needle (BD Lodose, Becton Dickinson Japan). 25 μL of physiological saline was administered to the normal control group. (2) Group composition and grouping The study was conducted with a group composition consisting of a normal control group, a disease-affected control group, a test substance administration group, and a tramadol administration group or a morphine administration group. Except for the normal control group, the right hind limb weight-bearing ratio (measurement method described below) was measured in model rats 13 or 14 days after MIA induction, prepared using the method described in (1) above, and the groups were divided so that there was no bias in the right hind limb weight-bearing ratio among the groups. (3) Administration of the test substance, tramadol, or morphine The test substance, the disclosed compound, was dissolved in a solubilizing medium (Colifor: PEG=7:3 solution) to prepare a 0.4 or 8 mg / mL solution. The prepared solutions were diluted four-fold with distilled water to prepare 0.1 or 2 mg / mL solutions (final concentration of solubilizing medium: 25%). Tramadol, the positive control drug, was dissolved in physiological saline to prepare a 2 mg / mL solution. Alternatively, morphine, the positive control drug, was dissolved in physiological saline to prepare a 0.6 mg / mL solution. The test substance was administered orally at a dose of 5 mL / kg 5 hours before evaluation, while tramadol and morphine were administered subcutaneously at a dose of 5 mL / kg 1 hour before evaluation. (4) Measurement of the load weight ratio of the right hind limb The load weight of the left and right hind limbs was measured using a Linton Incapacitance Tester (MJS Technology INC., UK). Specifically, rats were moved to a dedicated cage on the Linton Incapacitance Tester, and their posture was corrected so that the left and right hind limbs rested separately on two pairs of weight-measuring sensors. After confirming that the rat's posture was balanced both laterally and anteriorly, the load weight of the left and right hind limbs was measured for 3 seconds each. The load weight measurement was repeated three times per rat. To obtain stable measurements, rats were acclimatized in the dedicated cage for at least 20 minutes for at least 5 days between the day of MIA induction and 14 days after induction. Furthermore, they were acclimatized for approximately 10 minutes immediately before the load weight measurement. The load weight of the left and right hind limbs was measured before group division 14 days after MIA induction, and also 14 days after MIA induction in the normal control group, the diseased control group, the test substance administered group (5 hours after administration), the tramadol administered group (1 hour after administration), and the morphine administered group (1 hour after administration). Based on the average load weight of the left and right hind limbs, the ratio of the load weight of the right hind limb to the load weight of both hind limbs was calculated using Formula 1 below. Based on the ratio of the load weight of the right hind limb in each group 14 days after the induction of MIA, the improvement rate of the right hind limb load weight ratio upon administration of the disclosed compound was calculated using Formula 2 below, and the analgesic effect of the disclosed compound was evaluated.

number

number

[0284] Pharmacological Experiment Example 5: Antidepressant effect in forced swimming tests in rats The antidepressant effects of the disclosed compound were evaluated using a rat forced swimming test. (1) Group composition and grouping The study consisted of three groups: a vehicle administration group, a test substance administration group, and an imipramine administration group. Participants were assigned to one of the five groups using stratified randomization based on their body weight on the day of group assignment. (2) Administration of the test substance, imipramine The disclosed compound, the test substance, was dissolved in a solubilizing medium (Colifor: PEG=7:3 solution) to prepare a 4 mg / mL solution. The prepared solution was diluted fourfold with distilled water to prepare a 1 mg / mL solution (final concentration of solubilizing medium: 25%). Furthermore, the 1 mg / mL solution was diluted tenfold or 100fold with 25% solubilizing medium to prepare 0.1 mg / mL or 0.01 mg / mL solutions. As a positive control drug, imipramine was dissolved in physiological saline to prepare a 15 mg / mL solution. The test substance was administered orally at a dose of 5 mL / kg 5 hours before evaluation, and imipramine was administered intraperitoneally at a dose of 2 mL / kg 0.5 hours before evaluation. (3) Measurement of idle time The day before the measurement, rats were placed in a tank (water depth: 20 cm, water temperature: 24 ± 1 °C) and forced to swim for 15 minutes (measurement acclimatization). 24 hours later, the rats were again placed in the tank (water depth: 20 cm, water temperature: 24 ± 1 °C) and forced to swim for 5 minutes. The immobility time during this period was measured as depressive-like behavior. Immobility time was measured using a stopwatch, and the measured value was recorded as an integer rounded to one decimal place. As a result, it was found that the disclosed compound has an antidepressant effect comparable to that of the antidepressant imipramine.

[0285] Pharmacological Experiment Example 6: Anxiolytic Effect in Rat Social Interaction Tests The anxiolytic effect of the disclosed compound was evaluated using a rat social interaction study. (1) Group composition and grouping The study consisted of three groups: a vehicle administration group, a test substance administration group, and a diazepam administration group. Participants were assigned to one of the five groups using stratified randomization based on their body weight on the day of group assignment. (2) Administration of the test substance, diazepam The disclosed compound, the test substance, was dissolved in a solubilizing medium (Colifor: PEG=7:3 solution) to prepare a 4 mg / mL solution. The prepared solution was diluted fourfold with distilled water to prepare a 1 mg / mL solution (final concentration of solubilizing medium: 25%). Furthermore, the 1 mg / mL solution was diluted tenfold or 100fold with 25% solubilizing medium to prepare 0.1 mg / mL or 0.01 mg / mL solutions. As a positive control, diazepam was suspended in a 0.5% methylcellulose solution to prepare a 0.6 mg / mL suspension. The test substance was administered orally at a dose of 5 mL / kg two hours before evaluation, and diazepam was administered orally at a dose of 5 mL / kg one hour before evaluation. (3) Measurement of social interaction time Two rats (one pair) with a weight difference of no more than 20g were placed in an open-field apparatus two hours after administration of the test substance or one hour after administration of the positive control substance, and their behavior was video recorded for 10 minutes. From the 10 minutes of behavior, the time corresponding to the social behavior analysis items shown in Table 4 was measured. If these behavioral times were extended, it could be confirmed that the test substance exhibited an anxiolytic effect. [Table 4] As a result, it was found that the disclosed compound has an anxiolytic effect comparable to that of the anxiolytic drug diazepam.

[0286] [Examples of formulations] Examples of formulations After mixing the following components by conventional methods and compressing them into tablets, approximately 10,000 tablets containing 10 mg of the active ingredient per tablet are obtained. ·{(3aS,4R,6aR)-4-[(6-chloro-3-pyridazinyl)amino]hexahydrocyclopenta[c]pyrrole-2(1H)-yl}[5-(difluoromethyl)-2-thienyl]methanone ……100g • Carboxymethylcellulose calcium (disintegrant) …… 20g Magnesium stearate (lubricant) ... 10g Microcrystalline cellulose... 870g [Industrial applicability]

[0287] Because the disclosed compound has ABHD6 inhibitory activity, a pharmaceutical composition containing the disclosed compound as an active ingredient is useful as a preventive and / or therapeutic agent for diseases related to ABHD6.< / abpp>

Claims

1. General formula (IA): 【Chemistry 1】 (In the formula, X １ , X ２ These are (1) CH and (2) CR, respectively, independently. Ｘ , or (3) N, where X １ and X ２ At least one of them represents N, R １ This represents a halogen atom, R Ｘ This represents (1) a halogen atom, (2) a C1-6 alkyl group, (3) a C2-6 alkenyl group, (4) a C2-6 alkynyl group, (5) a C1-6 alkoxy group, (6) a C1-6 haloalkyl group, (7) a C2-6 haloalkenyl group, (8) a C2-6 haloalkynyl group, (9) a C1-6 haloalkoxy group, or (10) a cyano group. R ２ This represents (1) a halogen atom, (2) a C1-6 alkyl group, (3) a C2-6 alkenyl group, (4) a C2-6 alkynyl group, (5) a C1-6 alkoxy group, (6) a C1-6 haloalkyl group, (7) a C2-6 haloalkenyl group, (8) a C2-6 haloalkynyl group, (9) a C1-6 haloalkoxy group, or (10) a cyano group. When m is 2 or more, the plurality of Rs ２ may be the same or different from each other, R ３ (1) hydrogen atom, (2) C1-6 alkyl group, (3) C1-6 haloalkyl group, (4) 3-10 membered cyclic group, (5) -(C1-6 alkylene)-(3-10 membered cyclic group), (6) -(C1-6 haloalkylene)-(3-10 membered cyclic group), and one or two carbon atoms in the C1-6 alkyl group, C1-6 haloalkyl group, C1-6 alkylene and C1-6 haloalkylene may be replaced by oxygen atoms or sulfur atoms which may be oxidized. R ３ The 3-10 membered cyclic group inside contains 1 to 5 R ３０１ It may also be replaced with R ３０１ (1) halogen atom, (2) C1-4 alkyl group, (3) C1-4 alkoxy group, (4) C1-4 haloalkyl group, (5) C1-4 haloalkoxy group, (6) COOR ３０２ (7) CONR ３０３ R ３０４ (8) C3-6 cycloalkyl group, (9) hydroxyl group, (10) nitro group, (11) cyano group, (12) -NR ３０５ R ３０６ (13)-SR ３０７ (14)-SOR ３０８ (15)-SO ２ R ３０９ , or (16) representing an oxo group, R ３０１ When two or more substitutions occur, multiple R ３０１ They may be the same or different. R ３０２ , R ３０３ , R ３０４ , R ３０５ , R ３０６ , R ３０７ , R ３０８ , or R ３０９ Each of these independently represents either (1) a hydrogen atom or (2) a C1-4 alkyl group. R ２ R ２ Represents (2) to (9) inside, R ３ When R represents a C1-6 alkyl group, ２ and R ３ It may also form a 5-6 membered cyclic group together with the atom to which it is bonded. R ４ This represents (1) a halogen atom, (2) a C1-6 alkyl group, (3) a C2-6 alkenyl group, (4) a C2-6 alkynyl group, (5) a C1-6 alkoxy group, (6) a C1-6 haloalkyl group, (7) a C2-6 haloalkenyl group, (8) a C2-6 haloalkynyl group, or (9) a C1-6 haloalkoxy group. When n is 2 or greater, multiple R ４ They may be the same or different. Two R atoms located on the same carbon atom ４ When represents a C1-6 alkyl group, it may form a C3-6 cycloalkyl group together with the bonded carbon atom. Ring 1 has the following ring structure: 【Chemistry 2】 (In the formula, the asterisk indicates the bond position with the carbonyl group, and the hydrogen atom represented by NH may be replaced by R 5-A.) This represents a ring structure selected from the group consisting of these elements. R ５－Ａ (1) halogen atom, (2) C1-6 alkyl group, (3) C2-6 alkenyl group, (4) C2-6 alkynyl group, (5) C1-6 alkoxy group, (6) C1-6 alkylthio group, (7) C1-6 alkylsulfinyl group, (8) C1-6 alkylsulfonyl group, (9) C2-6 acyl group, (10) 3-6 membered cyclic group, (11)-L Ｒ５ - (3-6 membered cyclic group), (12) hydroxyl group, (13) nitro group, (14) cyano group, (15) oxo group, (16) - NR ５０１ R ５０２ , (17)-COOR ５０３ , (18)-CONR ５０４ R ５０５ , or (19)-SO ２ NR ５０６ R ５０７ The C1-6 alkyl group, C2-6 alkenyl group, C2-6 alkynyl group, C1-6 alkoxy group, C1-6 alkylthio group, C1-6 alkylsulfinyl group, C1-6 alkylsulfonyl group, and C2-6 acyl group may have one or two carbon atoms replaced by oxygen atoms or sulfur atoms that may be oxidized. When p is 2 or greater, multiple R ５－Ａ They may be the same or different. R ５－Ａ Of these, groups (2) to (11) have 1 to 9 R ５０８ It may also be replaced with R ５０８ (1) halogen atom, (2) C1-4 alkyl group, (3) C1-4 alkoxy group, (4) C2-6 acyl group, (5) C3-6 cycloalkyl group, (6) hydroxyl group, or (7) -NR ５０９ R ５１０ This represents, R ５０８ When two or more substitutions occur, multiple R ５０８ They may be the same or different. L Ｒ５ (1)-O-, (2)-(C1-4 alkylene)-, (3)-O-(C1-4 alkylene)-, (4)-(C1-4 alkylene)-O-, (5)-NR ５１１ - or (6)-SO ０－２ - represents, R ５０１ , R ５０２ , R ５０３ , R ５０４ , R ５０５ , R ５０６ , R ５０７ , R ５０９ , R ５１０ , or R ５１１ Each of these independently represents (1) a hydrogen atom, (2) a C1-6 alkyl group, (3) a C2-6 acyl group, or (4) a C1-6 alkylsulfonyl group. m represents an integer between 0 and 2. n represents an integer from 0 to 5. A pharmaceutical composition comprising a compound represented by (where p is an integer from 0 to 5), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

2. General formula (I): 【Transformation 3】 (In the formula, X １ , X ２ These are (1) CH and (2) CR, respectively, independently. Ｘ , or (3) N, where X １ and X ２ At least one of them represents N, R １ This represents a halogen atom, R Ｘ This represents (1) a halogen atom, (2) a C1-6 alkyl group, (3) a C2-6 alkenyl group, (4) a C2-6 alkynyl group, (5) a C1-6 alkoxy group, (6) a C1-6 haloalkyl group, (7) a C2-6 haloalkenyl group, (8) a C2-6 haloalkynyl group, (9) a C1-6 haloalkoxy group, or (10) a cyano group. R ２ This represents (1) a halogen atom, (2) a C1-6 alkyl group, (3) a C2-6 alkenyl group, (4) a C2-6 alkynyl group, (5) a C1-6 alkoxy group, (6) a C1-6 haloalkyl group, (7) a C2-6 haloalkenyl group, (8) a C2-6 haloalkynyl group, (9) a C1-6 haloalkoxy group, or (10) a cyano group. When m is 2 or more, multiple R ２ They may be the same or different. R ３ (1) hydrogen atom, (2) C1-6 alkyl group, (3) C1-6 haloalkyl group, (4) 3-10 membered cyclic group, (5) -(C1-6 alkylene)-(3-10 membered cyclic group), (6) -(C1-6 haloalkylene)-(3-10 membered cyclic group), and one or two carbon atoms in the C1-6 alkyl group, C1-6 haloalkyl group, C1-6 alkylene and C1-6 haloalkylene may be replaced by oxygen atoms or sulfur atoms which may be oxidized. R ３ The 3-10 membered cyclic group inside contains 1 to 5 R ３０１ It may also be replaced with R ３０１ represents (1) a halogen atom, (2) a C1-4 alkyl group, (3) a C1-4 alkoxy group, (4) a C1-4 haloalkyl group, (5) a C1-4 haloalkoxy group, (6) COOR ３０２ , (7) CONR ３０３ R ３０４ , (8) a C3-6 cycloalkyl group, (9) a hydroxyl group, (10) a nitro group, (11) a cyano group, (12) -NR ３０５ R ３０６ , (13) -SR ３０７ , (14) -SOR ３０８ , (15) -SO ２ R ３０９ , or (16) an oxo group, R ３０１ When two or more substitutions occur, multiple R ３０１ They may be the same or different. R ３０２ 、R ３０３ 、R ３０４ 、R ３０５ 、R ３０６ 、R ３０７ 、R ３０８ 、or R ３０９ represents, independently of each other, (1) a hydrogen atom, or (2) a C1-4 alkyl group, R ２ R ２ Represents (2) to (9) inside, R ３ When R represents a C1-6 alkyl group, ２ and R ３ It may also form a 5-6 membered cyclic group together with the atom to which it is bonded. R ４ This represents (1) a halogen atom, (2) a C1-6 alkyl group, (3) a C2-6 alkenyl group, (4) a C2-6 alkynyl group, (5) a C1-6 alkoxy group, (6) a C1-6 haloalkyl group, (7) a C2-6 haloalkenyl group, (8) a C2-6 haloalkynyl group, or (9) a C1-6 haloalkoxy group. When n is 2 or greater, multiple R ４ They may be the same or different. Two R atoms located on the same carbon atom ４ When represents a C1-6 alkyl group, it may form a C3-6 cycloalkyl group together with the bonded carbon atom. Ring 1 has the following ring structure: 【Chemistry 4】 (In the formula, the asterisk (*) indicates the bond position with the carbonyl group, and the hydrogen atom represented by NH may be replaced by R 5.) This represents a ring structure selected from the group consisting of these elements. R ５ (1) halogen atom, (2) C1-6 alkyl group, (3) C2-6 alkenyl group, (4) C2-6 alkynyl group, (5) C1-6 alkoxy group, (6) C1-6 alkylthio group, (7) C1-6 alkylsulfinyl group, (8) C1-6 alkylsulfonyl group, (9) C2-6 acyl group, (10) 3-6 membered cyclic group, (11)-L Ｒ５ - (3-6 membered cyclic group), (12) hydroxyl group, (13) nitro group, (14) cyano group, (15) oxo group, (16) - NR ５０１ R ５０２ , (17)-COOR ５０３ , (18)-CONR ５０４ R ５０５ , or (19)-SO ２ NR ５０６ R ５０７ This represents, When p is 2 or greater, multiple R ５ They may be the same or different. R ５ Of these, groups (2) to (11) have 1 to 9 R ５０８ It may also be replaced with R ５０８ (1) halogen atom, (2) C1-4 alkyl group, (3) C1-4 alkoxy group, (4) C2-6 acyl group, (5) C3-6 cycloalkyl group, (6) hydroxyl group, or (7) -NR ５０９ R ５１０ This represents, R ５０８ When two or more substitutions occur, multiple R ５０８ They may be the same or different. L Ｒ５ (1)-O-, (2)-(C1-4 alkylene)-, (3)-O-(C1-4 alkylene)-, (4)-(C1-4 alkylene)-O-, (5)-NR ５１１ - or (6)-SO ０－２ - represents, R ５０１ , R ５０２ , R ５０３ , R ５０４ , R ５０５ , R ５０６ , R ５０７ , R ５０９ , R ５１０ , or R ５１１ Each of these independently represents (1) a hydrogen atom, (2) a C1-6 alkyl group, (3) a C2-6 acyl group, or (4) a C1-6 alkylsulfonyl group. m represents an integer between 0 and 2. n represents an integer from 0 to 5. A pharmaceutical composition comprising a compound represented by (where p is an integer from 0 to 5), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

3. R ５－Ａ However, (1) C1-6 alkyl group, (2) C1-6 alkoxy group, (3) C1-6 haloalkyl group, (4) C1-6 haloalkoxy group, (5) cyclopropyl group, (6) furan ring, (7) N-methylpyrazole ring, (8) oxo group, (9) dimethylamino group, or (10)-COOCH ３ The pharmaceutical composition according to claim 1.

4. R ５ However, (1) C1-6 alkyl group, (2) C1-6 alkoxy group, (3) C1-6 haloalkyl group, (4) C1-6 haloalkoxy group, (5) cyclopropyl group, (6) furan ring, (7) N-methylpyrazole ring, (8) oxo group, (9) dimethylamino group, or (10)-COOCH ３ The pharmaceutical composition according to claim 2.

5. R ３ However, (1) a hydrogen atom, (2) a C1-6 alkyl group, (3) a C1-6 haloalkyl group, (4) a cyclopropyl group, or (5) -CH ２ - Q, A pharmaceutical composition according to any one of claims 1 to 4, wherein Q is (1) benzene, (2) pyridine, or (3) imidazo[2,1-b]thiazole.

6. X １ , X ２ A pharmaceutical composition according to any one of claims 1 to 4, wherein all of the elements are N.

7. A compound represented by general formula (I-A) or general formula (I), or a pharmaceutically acceptable salt thereof, is defined as general formula (I-1): 【Transformation 5】 (In the formula, R ３－ａ (1) a hydrogen atom, (2) a C1-6 alkyl group, (3) a C1-6 haloalkyl group, (4) a cyclopropyl group, or (5) -CH ２ - Represents Q, ring1-a has the following ring structure; 【Transformation 6】 (In the formula, the asterisk (*) indicates the bond position with the carbonyl group, and the hydrogen atom represented by NH is R) ５－ａ It may be replaced by ). Represents a ring structure selected from the group consisting of ) R ５－ａ (1) C1-6 alkyl group, (2) C1-6 alkoxy group, (3) C1-6 haloalkyl group, (4) C1-6 haloalkoxy group, (5) cyclopropyl group, (6) furan ring, (7) N-methylpyrazole ring, (8) oxo group, (9) dimethylamino group, or (10)-COOCH ３ This represents, The pharmaceutical composition according to claim 1 or 2, wherein the other symbols have the same meaning as the symbols described in claim 1 or 2, and the compound represented by ) or a pharmaceutically acceptable salt thereof.

8. (1) {(3aS,4R,6aR)-4-[(6-chloro-3-pyridazinyl)amino]hexahydrocyclopenta[c]pyrrole-2(1H)-yl}[5-(difluoromethyl)-2-thienyl]methanone, (2) {(3aS,4R,6aR)-4-[(6-chloro-3-pyridazinyl)amino]hexahydrocyclopenta[c]pyrrole-2(1H)-yl}(5-methyl-2-thienyl)methanone, (3) [(3aS,4R,6aR)-4-[(6-chloro-3-pyridazinyl)amino]hexahydrocyclopenta[c]pyrrole-2(1H)-yl](6,7-dihydro-4H-thieno[3,2-c]pyran-2-yl)methanone, (4) [(3aS,4R,6aR)-4-[(6-bromo-3-pyridazinyl)amino]hexahydrocyclopenta[c]pyrrole-2(1H)-yl](5-methyl-2-thienyl)methanone, (5) [(3aS,4R,6aR)-4-[(6-bromo-3-pyridazinyl)amino]hexahydrocyclopenta[c]pyrrole-2(1H)-yl](6,7-dihydro-4H-thieno[3,2-c]pyran-2-yl)methanone, (6) [(3aS,4R,6aR)-4-[(6-bromo-3-pyridazinyl)amino]hexahydrocyclopenta[c]pyrrole-2(1H)-yl](2-methyl-2H-thieno[3,2-c]pyrazole-5-yl)methanone, (7) [(3aS,4R,6aR)-4-[benzyl(6-bromo-3-pyridazinyl)amino]hexahydrocyclopenta[c]pyrrole-2(1H)-yl](5-methyl-2-thienyl)methanone, (8) rel-6-chloro-3-({(3aS,4R,6aR)-2-[(5-methyl-2-thienyl)carbonyl]octahydrocyclopenta[c]pyrrole-4-yl}amino)-4-pyridazinecarbonitrile, (9) {(3aR,4R,6aS)-4-[(6-chloro-3-pyridazinyl)amino]-3a-fluorohexahydrocyclopenta[c]pyrrole-2(1H)-yl}(6,7-dihydro-4H-thieno[3,2-c]pyran-2-yl)methanone, and (10) A pharmaceutical composition comprising a compound selected from the group consisting of [(3aR,6R,6aS)-6-[(6-bromo-3-pyridazinyl)amino]-4,4-difluorohexahydrocyclopenta[c]pyrrole-2(1H)-yl](6,7-dihydro-4H-thieno[3,2-c]pyran-2-yl)methanone, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

9. A pharmaceutical composition comprising [(3aS,4R,6aR)-4-[(6-bromo-3-pyridazinyl)amino]hexahydrocyclopenta[c]pyrrole-2(1H)-yl](5-methyl-2-thienyl)methanone, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

10. A pharmaceutical composition according to any one of claims 1 to 4, 8, and 9, which is an ABHD6 inhibitor.

11. A pharmaceutical composition according to any one of claims 1 to 4, 8 and 9, which is a therapeutic and / or prophylactic agent for diseases related to ABHD6.

12. The pharmaceutical composition according to claim 11, wherein the disease associated with ABHD6 is pain, neurological disease, inflammatory disease, autoimmune disease, metabolic disease, or malignant tumor.

13. The pharmaceutical composition according to claim 11, wherein the disease associated with ABHD6 is pain, and the pain is pain associated with osteoarthritis, cancer pain, pain associated with chemotherapy, chronic lower back pain, lower back pain associated with osteoporosis, fracture pain, pain associated with rheumatoid arthritis, neuropathic pain, postherpetic pain, pain associated with diabetic neuropathy, fibromyalgia, pain associated with pancreatitis, pain associated with interstitial cystitis / bladder pain syndrome, pain associated with endometriosis, pain associated with irritable bowel syndrome, migraine, or pain associated with pulpitis.

14. The pharmaceutical composition according to claim 11, wherein the disease associated with ABHD6 is a neurological disorder, and the neurological disorder is tremor, dyskinesia, dystonia, spasticity, compulsive and obsessive behavior, depression, anxiety disorder, panic disorder, acute stress reaction, post-traumatic stress disorder, obsessive-compulsive disorder, agoraphobia, social phobia, mood disorder, epilepsy, traumatic brain injury, spinal cord injury, multiple sclerosis, encephalomyelitis, Parkinson's disease, Huntington's disease, Alzheimer's disease, or sleep disorder.

15. The pharmaceutical composition according to claim 10, characterized in that it is administered in combination with at least one selected from the group consisting of acetaminophen, nonsteroidal anti-inflammatory drugs, opioid drugs, antidepressants, antiepileptic drugs, N-methyl-D-aspartate antagonists, muscle relaxants, antiarrhythmic drugs, steroids, and bisphosphonate drugs.

16. A therapeutic and / or prophylactic agent for diseases associated with ABHD6, comprising a compound according to any one of claims 1 to 4, 8, and 9, or a pharmaceutically acceptable salt thereof.

17. A pharmaceutical composition comprising a compound according to any one of claims 1 to 4, 8 and 9, or a pharmaceutically acceptable salt thereof, for use in the prevention and / or treatment of diseases associated with ABHD6.

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