ABHD6 antagonists

Abstract

To provide a drug which contains, as an active ingredient, a compound having ABHD6 inhibitory activity in the prevention and / or treatment of a disease associated with ABHD6.SOLUTION: A compound represented by general formula (I-A) (where, all symbols represent the same meaning as those described in the specification) or a pharmaceutically acceptable salt thereof exhibits ABHD6 inhibitory activity and is, therefore, useful as a pharmaceutical ingredient having potent ABHD6 inhibitory activity in the prevention and / or treatment of a disease associated with ABHD6.SELECTED DRAWING: None

Description

[Technical Field]

[0001] The present disclosure relates to a compound having ABHD6 inhibitory activity or a pharmaceutically acceptable salt thereof, and a pharmaceutical containing the compound or a salt thereof as an active ingredient. [ka] (wherein all symbols have the same meaning as defined below), or a pharmaceutically acceptable salt thereof (hereinafter referred to as the disclosed compound), and pharmaceutical compositions containing them as an active ingredient, etc. [Background technology]

[0002] ABHD6 (alpha / beta-Hydrolase domain containing 6) is a serine hydrolase and one of the metabolic enzymes of the endocannabinoid 2-arachidonoylglycerol (2-AG). 2-AG serves 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). Therefore, ABHD6 and 2-AG are known to be involved in the regulation of various physiological processes, including pain sensation, neurotransmission, inflammation, insulin secretion, adipose tissue browning, food intake, autoimmune disorders, neurological disorders, and metabolic diseases (Non-Patent Document 1).

[0003] Furthermore, it is known that ABHD6 inhibition significantly reduces neuroinflammation and exerts neuroprotection in animal models of traumatic brain injury and multiple sclerosis. Therefore, ABHD6 inhibition is thought to be useful for the prevention and / or treatment of various inflammatory and neurological diseases without causing central side effects caused by the cannabinoid system (Non-Patent Document 2).

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

[0005] Furthermore, Patent Document 2 describes that the compound represented by the following general formula (B) is a compound that has FAAH inhibitory activity. The general formula (B) is [ka] (In the formula, R 2B is hydrogen, fluorine, hydroxyl, cyano, trifluoromethyl, a C1-6 alkyl group, a C1-6 alkoxy group, or NR 8B R 9B represents a group, m B , n B , o B and p B are, independently of one another, numbers ranging from 0 to 3, and m B +o B and n B +p B represents a number such that each of the is less than or equal to 4, A B is a covalent bond, an oxygen atom, a C1-6 alkylene group or an -O-C1-6 alkylene group (in this case the terminus represented by the oxygen atom is replaced by a group R 1B and the terminus represented by the alkylene group is attached to a carbon of the bicycle. R 1B is unsubstituted or contains one or more R 6B and / or R 7B is substituted with R 5B represents R 5B represents a group selected from phenyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, naphthyl, quinolyl, isoquinolyl, phthalazinyl, quinazolinyl, quinoxalinyl, cinnolinyl, naphthyridinyl, benzothiazolyl, benzoxazolyl, benzimidazolyl, benzisothiazolyl, benzisoxazolyl, indazolyl and bentriazolyl, R 3B represents a hydrogen atom, a fluorine atom, a C1-6 alkyl group, or a trifluoromethyl group, R 4B represents a 5-membered heterocycle selected from furyl, pyrrolyl, thienyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyrazolyl, oxadiazolyl, thiadiazolyl, imidazole, triazolyl, and tetrazolyl (the definitions of the groups are partially excerpted).

[0006] Furthermore, Patent Document 3 discloses that the compound represented by the following general formula (C) is a compound that has a Ca channel inhibitory effect. The general formula (C) is [ka] (In the formula, L 1C are 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 are combined 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(R4C ), S(O)2, SO2N(R 5C ) 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 ) qC -N(R 5C )-C(O)OG 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 and; or L 2C -R 2C together to form alkyl, G 2C or -C(R cC )(G 2C )(G3C ) and G 1C , G 2C and G 3C are each independently an aryl, cycloalkyl, cycloalkenyl, heteroaryl, or heterocycle; G 1C , G 2C and G 3C are each independently unsubstituted or substituted with 1, 2, 3, 4, or 5 substituents; G 1C is other than a quinoline, quinazolinedione or pyridopyrimidinedione; R 3C represents hydrogen, alkyl, haloalkyl, cycloalkyl, or cycloalkylalkyl. (Some definitions of groups are excerpted.)

[0007] However, none of the prior art documents describes or suggests that the compounds disclosed herein have ABHD6 inhibitory activity. [Prior art documents] [Patent documents]

[0008] [Patent Document 1] International Publication No. 2019 / 089676 Brochure [Patent Document 2] International Publication No. 2010 / 130944 Brochure [Patent Document 3] International Publication No. 2010 / 062927 Brochure [Non-patent literature]

[0009] [Non-Patent Document 1] European Journal of Medicinal Chemistry, Volume 198, Article No. 112353, 2020 (European Journal of Medicinal Chemistry 198 (2020) 112353) [Non-patent document 2] Journal of Neuroinflammation, Volume 15, Article No. 9, 2018 (Journal of Neuroinflammation (2018) 15:9) Summary of the Invention [Problem to be solved by the invention]

[0010] An object of the present invention is to provide a compound having inhibitory activity against ABHD6. [Means for solving the problem]

[0011] As a result of intensive research aimed at solving the above problems, the present inventors have found that a compound represented by the general formula (IA) described below has a strong inhibitory activity against ABHD6. That is, in one aspect, the present disclosure provides: [1] General formula (IA): [ka] (In the formula, X 1 , X 2 are independently (1) CH, (2) CR X , or (3) represents N, where X 1 and X 2 At least one of represents N, R 1 represents a halogen atom, R X represents (1) a halogen atom, (2) a C alkyl group, (3) a C alkenyl group, (4) a C alkynyl group, (5) a C alkoxy group, (6) a C haloalkyl group, (7) a C haloalkenyl group, (8) a C haloalkynyl group, (9) a C haloalkoxy group, or (10) a cyano group; R 2represents (1) a halogen atom, (2) a C alkyl group, (3) a C alkenyl group, (4) a C alkynyl group, (5) a C alkoxy group, (6) a C haloalkyl group, (7) a C haloalkenyl group, (8) a C haloalkynyl group, (9) a C haloalkoxy group, or (10) a cyano group; When m is 2 or more, multiple R 2 may be the same or different, R 3 represents (1) a hydrogen atom, (2) a C1-6 alkyl group, (3) a C1-6 haloalkyl group, (4) a 3- to 10-membered cyclic group, (5) -(C1-6 alkylene)-(3- to 10-membered cyclic group), (6) -(C1-6 haloalkylene)-(3- to 10-membered cyclic group), in which 1 to 2 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 optionally oxidized sulfur atom, R 3 The 3-10 membered cyclic group in 301 may be substituted with R 301 is (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, or (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) an oxo group; R 301 When there are two or more substitutions, multiple R 301 may be the same or different, R 302 , R 303 , R 304 , R 305 , R 306 , R 307, R 308 , or R 309 each independently represents (1) a hydrogen atom or (2) a C1-4 alkyl group; R 2 R 2 Represents (2) to (9) in the 3 represents a C1-6 alkyl group, R 2 and R 3 may form a 5- or 6-membered cyclic group together with the atom to which it is attached, R 4 represents (1) a halogen atom, (2) a C alkyl group, (3) a C alkenyl group, (4) a C alkynyl group, (5) a C alkoxy group, (6) a C haloalkyl group, (7) a C haloalkenyl group, (8) a C haloalkynyl group, or (9) a C haloalkoxy group; When n is 2 or more, multiple R 4 may be the same or different, Two R's on the same carbon atom 4 represents a C alkyl group, it may be taken together with the carbon atom to which it is attached to form a C cycloalkyl group; ring1 represents a 3- to 15-membered cyclic group; R 5-A is (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 alkylthio group, (7) a C1-6 alkylsulfinyl group, (8) a C1-6 alkylsulfonyl group, (9) a C2-6 acyl group, (10) a 3- to 6-membered cyclic group, (11) -L R5 -(3- to 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 507wherein 1 to 2 carbon atoms in 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 or C2-6 acyl group may be replaced by an oxygen atom or an optionally oxidized sulfur atom, When p is 2 or more, multiple R 5-A may be the same or different, R 5-A Among these, groups (2) to (11) are each a group having 1 to 9 R 508 may be substituted with R 508 (1) Halogen atoms 、 (2) a C1-4 alkyl group, (3) a C1-4 alkoxy group, (4) a C2-6 acyl group, (5) a C3-6 cycloalkyl group, (6) a hydroxyl group, or (7) -NR 509 R 510 represents R 508 When there are two or more substitutions, multiple R 508 may be the same or different, L R5 are (1) -O-, (2) -(C1-4 alkylene)-, (3) -O-(C1-4 alkylene)-, (4) -(C1-4 alkylene)-O-, and (5) -NR 511 -, (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 independently represents (1) a hydrogen atom, (2) a C alkyl group, (3) a C acyl group, or (4) a C alkylsulfonyl group; m represents an integer of 0 to 2; n represents an integer of 0 to 5, and p represents an integer of 0 to 5, or a pharmaceutically acceptable salt thereof. [2] General formula (I): [ka] (In the formula, R 5 is (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 alkylthio group, (7) a C1-6 alkylsulfinyl group, (8) a C1-6 alkylsulfonyl group, (9) a C2-6 acyl group, (10) a 3- to 6-membered cyclic group, (11) -L R5 -(3- to 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 represents When p is 2 or more, multiple R 5 may be the same or different, R 5 Among these, groups (2) to (11) are each a group having 1 to 9 R 508 may be substituted with Other symbols have the same meanings as those described in the above [1].) or a pharmaceutically acceptable salt thereof, [3] A pharmaceutical composition comprising the compound according to [1] or [2] above or a pharmaceutically acceptable salt thereof as an active ingredient, and further comprising a pharmaceutically acceptable carrier. [4] An embodiment of the pharmaceutical composition etc. described in [3] above is provided, which is an ABHD6 inhibitor. [Effects of the Invention]

[0012] The compounds of the present disclosure have inhibitory activity against ABHD6 and can therefore be used as active ingredients in preventive and / or therapeutic agents for diseases associated with ABHD6. DETAILED DESCRIPTION OF THE INVENTION

[0013] The present disclosure will be described in detail below. As used herein, halogen atoms include fluorine, chlorine, bromine, and iodine atoms.

[0014] In the present specification, C1-4 alkyl groups include methyl, ethyl, propyl, butyl groups and isomers thereof. In this specification, C1-6 alkyl groups include methyl, ethyl, propyl, butyl, pentyl, hexyl groups, and isomers thereof.

[0015] In the present specification, C2-6 alkenyl groups include ethenyl, propenyl, butenyl, butadienyl, pentenyl, pentadienyl, hexenyl, hexadienyl groups, and isomers thereof.

[0016] In the present specification, C2-6 alkynyl groups include ethynyl, propynyl, butynyl, butadiynyl, pentynyl, pentadiynyl, hexynyl, hexadiynyl groups, and isomers thereof.

[0017] In this specification, C1-4 alkylene includes methylene, ethylene, propylene, butylene and isomers thereof. In this specification, C1-6 alkylene includes methylene, ethylene, propylene, butylene, pentylene, hexylene and isomers thereof.

[0018] In the present specification, the term "C1-4 haloalkyl group" refers to, for example, an alkyl group substituted with one or more halogen atoms, and specific examples thereof include a fluoromethyl group, a chloromethyl group, a bromomethyl group, an iodomethyl group, a difluoromethyl group, a trifluoromethyl group, a 1-fluoroethyl group, a 2-fluoroethyl group, a 2-chloroethyl group, a pentafluoroethyl group, a 1-fluoropropyl group, a 2-chloropropyl group, a 3-fluoropropyl group, a 3-chloropropyl group, a 4,4,4-trifluorobutyl group, a 4-bromobutyl group, and isomers thereof. In the present specification, the term "C1-6 haloalkyl group" refers to, for example, an alkyl group substituted by one or more halogen atoms, and specific examples thereof include a fluoromethyl group, a chloromethyl group, a bromomethyl group, an iodomethyl group, a difluoromethyl group, a trifluoromethyl group, a 1-fluoroethyl group, a 2-fluoroethyl group, a 2-chloroethyl group, a pentafluoroethyl group, a 1-fluoropropyl group, a 2-chloropropyl group, a 3-fluoropropyl group, a 3-chloropropyl group, a 4,4,4-trifluorobutyl group, a 4-bromobutyl group, a 5,5,5-trifluoropentyl group, a 6,6,6-trifluorohexyl group, and isomers thereof.

[0019] In the present specification, C1-6 haloalkylene means, for example, an alkylene substituted by one or more halogen atoms, and specific examples include 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 isomers thereof.

[0020] In the present specification, the term "C2-6 haloalkenyl group" refers to an alkenyl group substituted by one or more halogen atoms, and specific examples include a 1-fluoroethenyl group, a 2-fluoroethenyl group, a 2-chloroethenyl group, a 1-fluoropropenyl group, a 2-chloropropenyl group, a 3-fluoropropenyl group, a 3-chloropropenyl group, a 4-bromobutenyl group, a 5,5,5-trifluoropentenyl group, a 6,6,6-trifluorohexenyl group, and isomers thereof.

[0021] In the present specification, the term "C2-6 haloalkynyl group" refers to an alkynyl group substituted by one or more halogen atoms, and specific examples include a 2-fluoroethynyl group, a 2-chloroethynyl group, a 3-fluoropropynyl group, a 3-chloropropynyl group, a 4-bromobutynyl group, a 5,5,5-trifluoropentynyl group, a 6,6,6-trifluorohexynyl group, and isomers thereof.

[0022] In the present specification, C1-4 alkoxy groups include methoxy, ethoxy, propoxy, butoxy groups and isomers thereof. In the present specification, C1-6 alkoxy groups include methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy groups, and isomers thereof.

[0023] In the present specification, the term "C1-4 haloalkoxy group" means, for example, an alkoxy group substituted with one or more halogen atoms, and specific examples thereof include a fluoromethoxy group, a chloromethoxy group, a bromomethoxy group, an iodomethoxy group, a difluoromethoxy group, a trifluoromethoxy group, a 1-fluoroethoxy group, a 2-fluoroethoxy group, a 2-chloroethoxy group, a pentafluoroethoxy group, a 1-fluoropropoxy group, a 2-chloropropoxy group, a 3-fluoropropoxy group, a 3-chloropropoxy group, a 4,4,4-trifluorobutoxy group, a 4-bromobutoxy group, and isomers thereof. In the present specification, the term "C1-6 haloalkoxy group" means, for example, an alkoxy group substituted by one or more halogen atoms, and specific examples include a fluoromethoxy group, a chloromethoxy group, a bromomethoxy group, an iodomethoxy group, a difluoromethoxy group, a trifluoromethoxy group, a 1-fluoroethoxy group, a 2-fluoroethoxy group, a 2-chloroethoxy group, a pentafluoroethoxy group, a 1-fluoropropoxy group, a 2-chloropropoxy group, a 3-fluoropropoxy group, a 3-chloropropoxy group, a 4,4,4-trifluorobutoxy group, a 4-bromobutoxy group, a 5,5,5-trifluoropentyloxy group, a 6,6,6-trifluorohexyloxy group, and isomers thereof.

[0024] In the present specification, C1-6 alkylthio groups include methylthio, ethylthio, propylthio, butylthio, pentylthio, hexylthio groups, and isomers thereof.

[0025] In the present specification, C1-6 alkylsulfinyl groups include methylsulfinyl, ethylsulfinyl, propylsulfinyl, butylsulfinyl, pentylsulfinyl, hexylsulfinyl groups, and isomers thereof.

[0026] In the present specification, C1-6 alkylsulfonyl groups include methylsulfonyl, ethylsulfonyl, propylsulfonyl, butylsulfonyl, pentylsulfonyl, hexylsulfonyl groups, and isomers thereof.

[0027] In this specification, C3-6 cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl groups.

[0028] In the present specification, C2-6 acyl includes ethanoyl, propanoyl, butanoyl, pentanoyl, hexanoyl and isomers thereof.

[0029] In the present specification, the term "3- to 6-membered cyclic group" refers to a C3-6 carbocyclic ring and a 3- to 6-membered heterocyclic ring. In the present specification, examples of the C3-6 carbocyclic ring include cyclopropane, cyclobutane, cyclopentane, cyclohexane, cyclobutene, cyclopentene, cyclohexene, cyclobutadiene, cyclopentadiene, cyclohexadiene, and a benzene ring. In the present specification, examples of the 3- to 6-membered heterocycle include aziridine, azetidine, oxirane, oxetane, thiirane, thietane, pyrrole, imidazole, triazole, tetrazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, furan, pyran, thiophene, thiopyran, oxazole, isoxazole, thiazole, isothiazole, furazan, oxadiazole, oxazine, oxadiazine, thiadiazole, thiazine, 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, tetrahydropyrazine, Examples of the dihydrothiophene include lan, dihydrothiophene, tetrahydrothiophene, dihydrothiopyran, tetrahydrothiopyran, dihydrooxazole, tetrahydrooxazole (oxazolidine), dihydroisoxazole, tetrahydroisoxazole (isoxazolidine), dihydrothiazole, tetrahydrothiazole (thiazolidine), dihydroisothiazole, tetrahydroisothiazole (isothiazolidine), dihydrofurazan, tetrahydrofurazan, dihydrooxadiazole, tetrahydrooxadiazole (oxadiazolidine), dihydrooxazine, tetrahydrooxazine, dihydrooxadiazine, tetrahydrooxadiazine, dihydrothiadiazole, tetrahydrothiadiazole (thiadiazolidine), dihydrothiazine, tetrahydrothiazine, dihydrothiadiazine, tetrahydrothiadiazine, morpholine, thiomorpholine, oxathiane, dioxolane, dioxane, dithiolane, and dithiane rings.

[0030] In the present specification, the term "5-6 membered cyclic group" refers to a C5-6 carbocyclic ring and a 5-6 membered heterocyclic ring. In the present specification, examples of the C5-6 carbocyclic ring include cyclopentane, cyclohexane, cyclopentene, cyclohexene, cyclopentadiene, cyclohexadiene, and a benzene ring. In the present specification, examples of the 5- or 6-membered heterocycle include pyrrole, imidazole, triazole, tetrazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, furan, pyran, thiophene, thiopyran, oxazole, isoxazole, thiazole, isothiazole, furazan, oxadiazole, oxazine, oxadiazine, thiadiazole, thiazine, 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, tetrahydrofuran, tetrahydrofuran, dihydropyran, dihydrothiophene, tetrahydrofuran, tetrahydrofuran, dihydrothiophene, tetrahydrofuran, dihydrofuran, dihydrothiophene, tetrahydrofuran, dihydrofuran, dihydrothiophene, di ... dihydrothiophene, dihydrothiopyran, tetrahydrothiopyran, dihydrooxazole, tetrahydrooxazole (oxazolidine), dihydroisoxazole, tetrahydroisoxazole (isoxazolidine), dihydrothiazole, tetrahydrothiazole (thiazolidine), dihydroisothiazole, tetrahydroisothiazole (isothiazolidine), dihydrofurazan, tetrahydrofurazan, dihydrooxadiazole, tetrahydrooxadiazole (oxadiazolidine), dihydrooxazine, tetrahydrooxazine, dihydrooxadiazine, tetrahydrooxadiazine, dihydrothiadiazole, tetrahydrothiadiazole (thiadiazolidine), dihydrothiazine, tetrahydrothiazine, dihydrothiadiazine, tetrahydrothiadiazine, morpholine, thiomorpholine, oxathiane, dioxolane, dioxane, dithiolane, and dithiane rings.

[0031] In this specification, the term "3-10 membered cyclic group" refers to a C3-10 carbocyclic ring and a 3-10 membered heterocyclic ring. In the present specification, examples of C3-10 carbocyclic rings include 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, and perhydroisopropyl. Examples include indene, indane, 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]octene, bicyclo[3.2.1]octane and bicyclo[3.2.1]octene rings. In the present specification, examples of the 3- to 10-membered heterocycle include the above-mentioned 3- to 6-membered heterocycle, as well as azepine, diazepine, oxepin, thiepine, oxazepine, oxadiazepine, thiazepine, thiadiazepine, indole, isoindole, indolizine, benzofuran, isobenzofuran, benzothiophene, isobenzothiophene, dithianaphthalene, indazole, quinoline, isoquinoline, quinolizine, purine, phthalazine, pteridine, naphthyridine, quinoxaline, quinazoline, cinnoline, benzoxazole, benzothiazole, benzimidazole, Chromene, benzofurazan, benzothiadiazole, benzotriazole, dihydroazepine, tetrahydroazepine, perhydroazepine, dihydrodiazepine, tetrahydrodiazepine, perhydrodiazepine, dihydrooxepine, tetrahydrooxepine, perhydrooxepine, dihydrothiepine, tetrahydrothiepine, perhydrothiepine, dihydrooxazepine, tetrahydrooxazepine, perhydrooxazepine, dihydrooxadiazepine, tetrahydrooxadiazepine, perhydrooxadiazepine, dihydrothiazepine, tet perhydrothiazepine, perhydrothiazepine, dihydrothiadiazepine, tetrahydrothiadiazepine, perhydrothiadiazepine, indoline, isoindoline, dihydrobenzofuran, perhydrobenzofuran, dihydroisobenzofuran, perhydroisobenzofuran, dihydrobenzothiophene, perhydrobenzothiophene, dihydroisobenzothiophene, perhydroisobenzothiophene, dihydroindazole, perhydroindazole, dihydroquinoline, tetrahydroquinoline, perhydroquinoline, dihydroisoquinoline, tetrahydro dihydroisoquinoline, perhydroisoquinoline, dihydrophthalazine, tetrahydrophthalazine, perhydrophthalazine, dihydronaphthyridine, tetrahydronaphthyridine, perhydronaphthyridine, dihydroquinoxaline, tetrahydroquinoxaline, perhydroquinoxaline, dihydroquinazoline, tetrahydroquinazoline, perhydroquinazoline, dihydrocinnoline, tetrahydrocinnoline, perhydrocinnoline, benzoxathiane, dihydrobenzoxazine, dihydrobenzothiazine, pyrazinomorpholine, dihydrobenzoxazole,Perhydrobenzoxazole, dihydrobenzothiazole, perhydrobenzothiazole, dihydrobenzimidazole, perhydrobenzimidazole, dioxindan, 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, oxa 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.

[0032] In this specification, the term "3-15 membered cyclic group" refers to a C3-15 carbocyclic ring and a 3-15 membered heterocyclic ring. In the present specification, examples of the C3-15 carbocyclic ring include the above-mentioned C3-10 carbocyclic ring, as well as heptalene, biphenylene, as-indacene, s-indacene, acenaphthylene, acenaphthene, fluorene, phenalene, phenanthrene, and anthracene rings. In the present specification, examples of the 3-15 membered heterocycle include the above-mentioned 3-10 membered heterocycle, as well as benzoxadiazepine, benzothiadiazepine, benzoxazepine, benzothiazepine, benzodiazepine, dihydrobenzodiazepine, tetrahydrobenzodiazepine, benzodioxepane, dihydrobenzoxazepine, tetrahydrobenzoxazepine, benzoxepine, benzothiepine, benzazepine, dihydrobenzazepine, tetrahydrobenzazepine, perimidine, β-carboline, dihydrocarbazole Examples of suitable aryls include tetrahydrocarbazole, dihydrodibenzofuran, dihydrodibenzothiophene, tetrahydrodibenzofuran, tetrahydrodibenzothiophene, carbazole, dibenzofuran, dibenzothiophene, phenothiazine, phenoxazine, phenoxathiin, thianthrene, phenazine, phenanthroline, xanthene, dihydroacridine, tetrahydroacridine, acridine, phenanthridine, and dihydropyrrolo[1,2-b]thieno[2,3-d]pyrazole rings.

[0033] In this specification, the phrase "one to two carbon atoms may be replaced by an oxygen atom or an optionally oxidized sulfur atom" means that one or two carbon atoms (-CH2-) in any structurally possible position in the substituent may be replaced by an oxygen atom (-O-) or an optionally oxidized sulfur atom (-S-, -SO-, or -SO2-). Specific examples of such groups in the case of a C1-6 alkyl group include CH3-O-CH2- group, CH3-CH2-O-CH2- group, CH3-O-CH2-CH2- group, CH3-O-CH2-CH2- group, CH3-CH2-O-CH2-CH2- group, and CH3-CH2-O-CH2-CH2- group.

[0034] In this disclosure, X 1 , X 2 is preferably N.

[0035] In this disclosure, R 1 is preferably a chlorine atom or a bromine atom.

[0036] In this disclosure, R2 is preferably a halogen atom, a C1-6 alkyl group, a C1-6 alkoxy group, a C1-6 haloalkyl group, or a cyano group, and more preferably a chlorine atom, a methoxy group, a trifluoromethyl group, or a cyano group.

[0037] In this 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, and more preferably a chlorine atom, a methoxy group, a trifluoromethyl group, or a cyano group.

[0038] In this disclosure, R 3 is preferably a hydrogen atom, a C1-6 alkyl group, a C1-6 haloalkyl group, a 3- to 10-membered cyclic group, or —CH2— (3- to 10-membered cyclic group), and more preferably a hydrogen atom, a C1-6 alkyl group, a C1-6 haloalkyl group, cyclopropyl group, —CH2-benzene, —CH2-pyridine, or —CH2-imidazo[2,1-b]thiazole.

[0039] In this disclosure, R 4 is preferably a halogen atom or a C1-6 alkyl group. and more preferably a fluorine atom or a methyl group.

[0040] In the present disclosure, ring 1 is preferably a 3- to 10-membered cyclic group or [ka] (wherein the * symbol indicates the bonding position with the carbonyl group), and more preferably [ka] (In the formula, the * symbol indicates the bond position with the carbonyl group, and the hydrogen atom represented by NH is R 5-A or R 5 and more preferably, [ka] (In the formula, the * symbol indicates the bond position with the carbonyl group, and the hydrogen atom represented by NH is R 5-A or R 5 and wherein R is a ring structure selected from the group consisting of: In this disclosure, R 5 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- to 6-membered cyclic group, an oxo group, or -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.

[0041] In this 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- to 6-membered cyclic group, an oxo group, or -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.

[0042] In the present disclosure, m is preferably 0 or 1.

[0043] In the present disclosure, n is preferably 0, 1, or 2.

[0044] In the present disclosure, p is preferably 0, 1, or 2.

[0045] In the present disclosure, the compound represented by general formula (IA) or general formula (I) is preferably a compound represented by general formula (I-1): [ka] (In the formula, R 3-a represents (1) a hydrogen atom, (2) a C alkyl group, (3) a C haloalkyl group, (4) a cyclopropyl group, or (5) -CH-Q; Q represents (1) benzene, (2) pyridine, or (3) imidazo[2,1-b]thiazole; ring1-a is the following ring structure: [ka] (In the formula, the * symbol indicates the bond position with the carbonyl group, and the hydrogen atom represented by NH is R 5-a and R 5-a 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; The other symbols have the same meanings as those defined above.

[0046] In the present disclosure, the compound represented by general formula (IA) is preferably a compound represented by the above-mentioned X 1 , X 2 , R 1 , R 2 , R 3 , R 4 , R 5-A , ring1, n, m, and p are each a combination of preferred definitions.

[0047] In the present disclosure, the compound represented by general formula (I) is preferably a compound represented by the above-mentioned X 1 , X 2 , R 1 , R 2 , R 3 , R 4 , R 5 , ring1, n, m, and p are each a combination of preferred definitions.

[0048] In the present disclosure, another embodiment of the compound represented by general formula (IA) or general formula (I) is most preferably an example compound described in the examples below, or a pharmaceutically acceptable salt thereof.

[0049] In this disclosure, all isomers are encompassed unless otherwise specified. For example, alkyl groups, alkoxy groups, and alkylene groups include both straight-chain and branched-chain isomers. Furthermore, isomers (E, Z, cis, trans) in double bonds, rings, and fused rings; isomers due to the presence of asymmetric carbons (R, S, α, β, enantiomers, diastereomers); optically active isomers with optical rotation (D, L, d, l); polar isomers (high polarity, low polarity) obtained by chromatographic separation; equilibrium compounds; rotational isomers; mixtures of these in any proportion; and racemic mixtures are all encompassed in this disclosure. Furthermore, all isomers due to tautomerism are also encompassed in this disclosure.

[0050] In this specification, a compound with the name "rel-" indicates that the configuration of multiple asymmetric centers is relative.

[0051] In this disclosure, unless otherwise specified, symbols that will be apparent to those skilled in the art are used. [ka] indicates bonding to the other side of the paper (i.e., α-configuration), [ka] indicates that the molecule is bonded to the front side of the paper (i.e., β-configuration), [ka] represents any mixture of α- and β-configurations.

[0052] [salt] The compound represented by the general formula (IA) can be converted into a salt by a known method. The salt is a pharmaceutically acceptable salt. The salt is preferably water-soluble.

[0053] Pharmaceutically acceptable salts include, for example, acid addition salts, alkali metal salts, alkaline earth metal salts, ammonium salts, or amine salts. Acid addition salts include, for example, inorganic acid salts such as hydrochloride, hydrobromide, hydroiodide, sulfate, phosphate, nitrate, or organic acid 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. Alkaline earth metal salts include, for example, calcium salts and magnesium salts. Examples of ammonium salts include tetramethylammonium salts. Examples of amine salts include triethylamine salts, methylamine salts, dimethylamine salts, cyclopentylamine salts, benzylamine salts, phenethylamine salts, piperidine salts, monoethanolamine salts, diethanolamine salts, tris(hydroxymethyl)aminomethane salts, lysine salts, arginine salts, and N-methyl-D-glucamine salts.

[0054] The compounds of the present disclosure can be converted into N-oxides by any method. The N-oxides refer to compounds in which the nitrogen atom of the compound represented by general formula (IA) is oxidized.

[0055] The compound represented by general formula (IA) and its pharmaceutically acceptable salts may exist in a non-solvated form or in a solvated form with a pharmaceutically acceptable solvent such as water, ethanol, etc. The solvate is preferably a hydrate. The compound represented by general formula (IA) and its pharmaceutically acceptable salts may be converted into a solvate.

[0056] The compound of formula (IA) can form a co-crystal with a suitable co-crystal former. The co-crystal is preferably a pharmaceutically acceptable co-crystal former. A co-crystal is typically defined as a crystal formed by two or more different molecules through intermolecular interactions other than ionic bonding. A co-crystal may also be a complex of a neutral molecule and a salt. Co-crystals can be prepared by known methods, such as melt crystallization, recrystallization from a solvent, or by physically grinding the components together. Suitable co-crystal formers include those described in WO 2006 / 007448.

[0057] In this disclosure, all references to the disclosed compounds include a compound represented by general formula (IA), a pharmaceutically acceptable salt thereof, an N-oxide thereof, a solvate (e.g., hydrate) thereof, or a co-crystal thereof, or an N-oxide of a pharmaceutically acceptable salt of a compound represented by general formula (IA), a solvate (e.g., hydrate) thereof, or a co-crystal thereof.

[0058] [Prodrug] A prodrug of a compound represented by general formula (IA) refers to a compound that is converted into a compound represented by general formula (IA) in vivo by a reaction catalyzed by an enzyme, gastric acid, or the like. Examples of prodrugs of a compound represented by general formula (IA) include, when the compound represented by general formula (IA) has an amino group, compounds in which the amino group has been acylated, alkylated, or phosphorylated (for example, compounds in which the amino group of a compound represented by general formula (IA) has been eicosanoylated, alanylated, pentylaminocarbonylated, (5-methyl-2-oxo-1,3-dioxolen-4-yl)methoxycarbonylated, tetrahydrofuranylated, pyrrolidylmethylated, pivaloyloxymethylated, acetoxymethylated, or tert-butylated); when the compound represented by general formula (IA) has a hydroxyl group, compounds in which the hydroxyl group has been acylated, alkylated, phosphorylated, or borated (for example, compounds in which the hydroxyl group of a compound represented by general formula (IA) has been acetylated, palmitoylated, or propanolated). When the compound represented by general formula (IA) has a carboxy group, compounds in which the carboxy group is esterified or amidated (for example, compounds in which the carboxy group of the compound represented by general formula (IA) is ethyl esterified, phenyl esterified, carboxymethyl esterified, dimethylaminomethyl esterified, pivaloyloxymethyl esterified, 1-{(ethoxycarbonyl)oxy}ethyl esterified, phthalidyl esterified, (5-methyl-2-oxo-1,3-dioxolen-4-yl)methyl esterified, 1-{[(cyclohexyloxy)carbonyl]oxy}ethyl esterified, or methylamidized) are included. These compounds can be produced by known methods. In addition, the prodrug of the compound represented by general formula (IA) may be either a hydrate or an anhydrate. Furthermore, the prodrug of the compound represented by general formula (IA) may be one that is converted into the compound represented by general formula (IA) under physiological conditions, as described in "Drug Development," Vol. 7, "Molecular Design," pp. 163-198, Hirokawa Publishing, 1990.

[0059] Furthermore, each atom constituting the compound represented by the general formula (IA) may contain 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 I, etc.) may be substituted.

[0060] [Method of producing the disclosed compound] The compounds of the present disclosure can be produced by appropriately modifying and combining known methods, such as the methods described below, methods similar thereto, the method described in Comprehensive Organic Transformations: A Guide to Functional Group Preparations, 3rd Edition (Richard C. Larock, John Wiley & Sons Inc., 2018), or the methods described 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.

[0061] Furthermore, a compound having an amino group, a carboxyl group, or a hydroxyl group can be produced, if necessary, by using a compound protected with a protecting group commonly used for these groups, for example, a protecting group described in T.W. Greene, Protective Groups in Organic Synthesis, Wiley, New York, 5th Edition, 2014, and performing a known deprotection reaction after an appropriate reaction step.

[0062] Examples of the protective group for a carboxyl group include methyl, ethyl, tert-butyl, trichloroethyl, benzyl (Bn), phenacyl, p-methoxybenzyl, trityl, and 2-chlorotrityl.

[0063] Examples of protecting groups for amino groups or tetrazolyl groups include benzyloxycarbonyl groups, tert-butoxycarbonyl groups, allyloxycarbonyl (Alloc) groups, 1-methyl-1-(4-biphenyl)ethoxycarbonyl (Bpoc) groups, trifluoroacetyl groups, 9-fluorenylmethoxycarbonyl groups, benzyl (Bn) groups, p-methoxybenzyl groups, benzyloxymethyl (BOM) groups, and 2-(trimethylsilyl)ethoxymethyl (SEM) groups.

[0064] Examples of protecting groups for hydroxyl groups or hydroxamic acid 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).

[0065] The deprotection reaction is known and can be carried out by the following method. For example, (1) Deprotection reaction by alkaline hydrolysis, (2) Deprotection reaction under acidic conditions, (3) deprotection by hydrogenolysis, (4) deprotection reaction of the silyl group, (5) metal-mediated deprotection reaction, (6) Deprotection reaction using a metal complex, etc. To explain these methods in detail, (1) The deprotection reaction by alkaline hydrolysis is carried out, for example, in an organic solvent (e.g., methanol, tetrahydrofuran (hereinafter, THF), dioxane, etc.) using an alkali metal hydroxide (e.g., sodium hydroxide, potassium hydroxide, lithium hydroxide, etc.), an alkaline earth metal hydroxide (e.g., barium hydroxide, calcium hydroxide, etc.), or a carbonate (e.g., sodium carbonate, potassium carbonate, etc.), or an aqueous solution thereof, or a mixture thereof, at 0 to 40°C. (2) The deprotection reaction under acidic conditions is carried out, for example, in an organic solvent (e.g., dichloromethane, chloroform, dioxane, ethyl acetate, methanol, isopropyl alcohol, THF, anisole, etc.), in an organic acid (e.g., acetic acid, trifluoroacetic acid, methanesulfonic acid, p-tosylic acid, etc.), an inorganic acid (e.g., hydrochloric acid, sulfuric acid, etc.), or a mixture thereof (e.g., hydrogen bromide / acetic acid, etc.), in the presence or absence of 2,2,2-trifluoroethanol, at 0 to 100°C. (3) The deprotection reaction by hydrogenolysis is carried out, for example, in a solvent (e.g., ethers (e.g., THF, dioxane, dimethoxyethane, diethyl ether, etc.), alcohols (e.g., methanol, ethanol, etc.), benzenes (e.g., benzene, toluene, etc.), ketones (e.g., acetone, methyl ethyl ketone, etc.), nitriles (e.g., acetonitrile, etc.), amides (e.g., N,N-dimethylformamide (hereinafter, DMF)), water, ethyl acetate, acetic acid, or a mixed solvent of two or more thereof, etc.) in the presence of a catalyst (e.g., palladium-carbon, palladium black, palladium hydroxide-carbon, platinum oxide, Raney nickel, etc.) under a hydrogen atmosphere or ammonium formate at normal or elevated pressure, at 0 to 200°C. (4) The deprotection reaction of the silyl group is carried out, for example, using tetrabutylammonium fluoride in a water-miscible organic solvent (e.g., THF, acetonitrile, etc.) at 0 to 40° C. Alternatively, it is carried out, for example, in an organic acid (e.g., acetic acid, trifluoroacetic acid, methanesulfonic acid, p-tosylic acid, etc.), an inorganic acid (e.g., hydrochloric acid, sulfuric acid, etc.), or a mixture thereof (e.g., hydrogen bromide / acetic acid, etc.) at −10 to 100° C. (5) The deprotection reaction using a metal is carried out, for example, in an acidic solvent (e.g., acetic acid, a buffer solution of pH 4.2 to 7.2, or a mixture of such a solution with an organic solvent such as THF) in the presence of zinc powder at 0 to 40°C, if necessary, with ultrasonication. (6) The deprotection reaction using a metal complex is carried out in, for example, an organic solvent (e.g., dichloromethane, DMF, THF, ethyl acetate, acetonitrile, dioxane, ethanol, etc.), water, or a mixture thereof, in the presence of a trapping 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., tetrakistriphenylphosphinepalladium(0), bis(triphenylphosphine)palladium(II) dichloride, palladium(II) acetate, tris(triphenylphosphine)rhodium(I) chloride, etc.) at 0 to 40°C.

[0066] The compound of general formula (IA) can be prepared according to reaction scheme 1. [ka] (In reaction scheme 1, PG represents an amino-protecting group, Y represents a halogen atom, Z represents a halogen atom, and the other symbols have the same meanings as above.)

[0067] In Reaction Scheme 1, Reaction 1-1 is a halogen substitution reaction or a cross-coupling reaction. The halogen substitution reaction is known and can be carried out, for example, 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 hydrogencarbonate, potassium carbonate, cesium carbonate, tripotassium phosphate, cesium fluoride, barium hydroxide, tetrabutylammonium fluoride, etc.) or an aqueous solution or mixture thereof at 0 to 200°C.

[0068] Cross-coupling reactions are known. For example, a cross-coupling reaction can be carried out in an organic solvent (benzene, toluene, DMF, dioxane, THF, methanol, acetonitrile, dimethoxyethane, acetone, etc.) using a base (sodium ethylate, sodium hydroxide, potassium hydroxide, triethylamine, sodium carbonate, sodium hydrogencarbonate, 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 (tetrakis(t) The reaction is carried out at room temperature to 120°C in the presence of bis(triphenylphosphine)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.

[0069] In Reaction Scheme 1, Reaction 1-2 is an N-alkylation reaction. N-Alkylation reactions are known and can be carried out, for example, in an organic solvent (DMF, dimethyl sulfoxide, chloroform, dichloromethane, diethyl ether, THF, methyl t-butyl ether, etc.) in the presence of an alkali metal hydroxide (sodium hydroxide, potassium hydroxide, lithium hydroxide, etc.), an alkaline earth metal hydroxide (barium hydroxide, calcium hydroxide, etc.) or carbonate (sodium carbonate, potassium carbonate, etc.), an aqueous solution thereof, or a mixture thereof, at 0 to 100°C.

[0070] In reaction scheme 1, reactions 1-3 are deprotection reactions, which can be carried out in the same manner as described above.

[0071] In Reaction Scheme 1, Reactions 1-4 are amidation reactions. Amidation reactions are known and can be carried out, for example, (1) A method using an acid halide (2) A method using a mixed acid anhydride, (3) A method using a condensing agent, These methods are specifically described as follows: (1) The method using an acid halide is carried out, for example, by 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 the presence of a base (pyridine, triethylamine, dimethylaniline, dimethylaminopyridine, diisopropylethylamine, etc.) in an organic solvent (chloroform, dichloromethane, diethyl ether, THF, etc.) at a temperature of 0 to 40° C. Alternatively, the resulting acid halide can be reacted with an amine in an organic solvent (dioxane, THF, etc.) using an aqueous alkali solution (sodium bicarbonate solution, sodium hydroxide solution, etc.) at 0 to 40° C. (2) The method using a mixed acid anhydride is carried out by, for example, 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 the presence of a base (pyridine, triethylamine, dimethylaniline, dimethylaminopyridine, diisopropylethylamine, etc.) in an organic solvent (chloroform, dichloromethane, diethyl ether, THF, etc.) or without a solvent 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) The method using a condensing agent is, for example, a method in which a carboxylic acid and an amine are reacted in an organic solvent (chloroform, dichloromethane, DMF, diethyl ether, THF, etc.) or without a solvent, in the presence or absence of a base (pyridine, triethylamine, dimethylaniline, dimethylaminopyridine, etc.), with a condensing agent (1,3-dicyclohexylcarbodiimide (DCC), 1-ethyl-3-[3-(dimethylamino)propyl]carbodiimide (EDC), 1,1'-carbonyldiimidazole (CDI), 2-chloro-1-methylpyridinium iodide, 1-propylphosphonic acid cyclic anhydride (1-propanephosphonic acid cyclic anhydride), anhydride, PPA, etc.), O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU), in the presence or absence of 1-hydroxybenztriazole (HOBt), at 0 to 40°C. It is desirable that the reactions (1), (2) and (3) are all carried out under an inert gas (argon, nitrogen, etc.) atmosphere and under anhydrous conditions.

[0072] Compounds of general formula 1a can be prepared according to reaction scheme 2. [ka] (In reaction scheme 2, all symbols have the same meanings as above.)

[0073] In Reaction Scheme 2, Reaction 2-1 is a cyclization reaction, which is carried out, for example, in an organic solvent (DMF, dimethyl sulfoxide, chloroform, dichloromethane, diethyl ether, THF, methyl t-butyl ether, etc.) in the presence of an acid (trifluoroacetic acid, etc.) at a temperature of 0 to 100°C.

[0074] In Reaction Scheme 2, Reaction 2-2 is a reduction reaction of a carbonyl group, which is carried out in an organic solvent (dichloroethane, dichloromethane, DMF, THF, a mixture thereof, etc.) in the presence of a reducing agent (sodium borohydride, etc.) at a temperature of 0 to 40°C.

[0075] In Reaction Scheme 2, Reaction 2-3 is a tosylation reaction, 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.

[0076] In Reaction Scheme 2, Reaction 2-4 is an azidation reaction, which can be carried out, for example, 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.

[0077] In Reaction Scheme 2, Reaction 2-5 is a reduction reaction of an azide group, which is 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 thereof, etc.) in the presence of a hydrogenation catalyst (e.g., palladium-carbon, palladium black, palladium, palladium hydroxide, platinum dioxide, platinum-carbon, nickel, Raney nickel, ruthenium chloride, etc.) in the presence or absence of an acid (e.g., hydrochloric acid, sulfuric acid, hypochlorous acid, boric acid, tetrafluoroboric acid, acetic acid, p-toluenesulfonic acid, oxalic acid, trifluoroacetic acid, formic acid, etc.) under a hydrogen atmosphere at atmospheric or elevated pressure, at 0 to 200°C.

[0078] In each reaction in the present specification, the compounds used as starting materials and represented by general formula 1b, general formula 1d, general formula 1g, formula 2a, and general formula 2b are either known compounds or can be easily produced by a combination of 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 methods in which known methods are partially modified.

[0079] Among the compounds disclosed herein, optically active compounds can be produced using optically active starting materials or reagents, or by optically resolving a racemic production intermediate and then leading to the compound disclosed herein, or by optically resolving a racemic compound disclosed herein. This optical resolution is well known, and examples of such methods include forming a salt or complex with another optically active compound, recrystallizing it, and then isolating the target compound, or directly separating it using a chiral column.

[0080] In each reaction herein, reactions involving heating can be carried out using a water bath, oil bath, sand bath or microwave, as will be apparent to those skilled in the art.

[0081] In each reaction herein, a solid-phase-supported reagent supported on a high molecular weight polymer (for example, polystyrene, polyacrylamide, polypropylene, polyethylene glycol, etc.) may be used as appropriate.

[0082] In each reaction in this specification, the reaction product can be purified by a conventional purification method, for example, distillation under atmospheric pressure or reduced pressure, high performance liquid chromatography using silica gel or magnesium silicate, thin layer chromatography, ion exchange resin, scavenger resin, or column chromatography, washing, recrystallization, etc. Purification may be carried out for each reaction or after completion of several reactions.

[0083] [toxicity] The compounds of the present disclosure have low toxicity and can therefore be safely used as pharmaceuticals.

[0084] [Application to pharmaceuticals] The compounds of the present disclosure have inhibitory activity against ABHD6 and are therefore useful as prophylactic and / or therapeutic agents for diseases associated with ABHD6, such as pain, neurological diseases, inflammatory diseases, autoimmune diseases, metabolic diseases, and malignant tumors.

[0085] More specifically, examples of pain include pain associated with osteoarthritis, cancer pain, pain associated with chemotherapy, chronic low back pain, low back pain associated with osteoporosis, pain from fractures, pain associated with rheumatoid arthritis, neuropathic pain, post-herpetic 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, and pain associated with dental pulpitis.

[0086] Neurological diseases include, for example, tremor, dyskinesia, dystonia, spasticity, compulsive and obsessive behavior, depression, psychiatric 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 chorea, Alzheimer's disease, sleep disorders, and the like.

[0087] Examples of inflammatory diseases include arthritis, rheumatoid arthritis, osteoarthritis, spondylitis, gout, vasculitis, Crohn's disease, and irritable bowel syndrome.

[0088] Examples of autoimmune diseases include psoriasis, amyotrophic lateral sclerosis (ALS), multiple sclerosis, Sjogren's syndrome, systemic lupus erythematosus, and AIDS.

[0089] Examples of metabolic diseases include obesity, metabolic syndrome, dyslipidemia, diabetes, and fatty liver.

[0090] 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, duodenal Cancer, hepatocellular carcinoma, bile duct cancer, gallbladder cancer, pancreatic cancer, renal cell cancer, renal pelvis and ureter cancer, bladder cancer, penile cancer, testicular cancer, uterine cancer, vaginal cancer, vulvar cancer, skin cancer (e.g., malignant melanoma), malignant bone tumor, soft tissue sarcoma, chondrosarcoma, leukemia (e.g., acute myeloid leukemia, acute lymphocytic leukemia, chronic myeloid leukemia, chronic lymphocytic leukemia), myelodysplastic syndrome, brain tumor, or multiple myeloma.

[0091] As used herein, the prevention and / or treatment of malignant tumors includes, for example, treatments performed to (a) reduce cancer cell proliferation, (b) reduce symptoms caused by cancer and improve the quality of life of cancer patients, (c) reduce the dose of other anticancer drugs or adjuvant cancer treatment drugs already administered, (d) suppress cancer progression, (e) suppress cancer recurrence, and / or (f) extend the survival time of cancer patients. Furthermore, "suppressing cancer progression" means delaying cancer progression, stabilizing cancer-related symptoms, and reversing the progression of symptoms. "Suppressing recurrence" means prophylactically preventing cancer recurrence in patients whose cancer lesions have completely or substantially disappeared or been removed by cancer treatment or surgical resection.

[0092] To use the disclosed compounds for the prevention and / or treatment of the above-mentioned diseases, the active ingredient is typically formulated with a pharmaceutically acceptable carrier, such as various additives or solvents, and then administered systemically or locally, orally or parenterally. Here, a pharmaceutically acceptable carrier refers to a substance other than the active ingredient that is generally used in pharmaceutical formulations. A pharmaceutically acceptable carrier is preferably one that exhibits no pharmacological activity at the dosage of the formulation, is harmless, and does not interfere with the therapeutic effect of the active ingredient. Pharmaceutically acceptable carriers can also be used for purposes such as enhancing the usefulness of the active ingredient and formulation, facilitating formulation, stabilizing quality, or improving usability. Specifically, substances such as those described in "Dictionary of Pharmaceutical Additives," published by Yakuji Nipposha in 2000 (edited by the Japan Pharmaceutical Additives Association) can be appropriately selected depending on the purpose.

[0093] The disclosed compounds are administered to a mammal (preferably a human, more preferably a human patient) in a pharmaceutically effective amount.

[0094] The dosage of the disclosed compound will inevitably vary depending on age, body weight, symptoms, desired therapeutic effect, route of administration, duration of treatment, etc. Generally, it is administered orally in the range of 0.1 ng to 1000 mg per patient per dose, or parenterally in the range of 0.01 ng to 100 mg per patient per dose, or by continuous intravenous administration.

[0095] Of course, as mentioned above, the dosage varies depending on various conditions, so in some cases a smaller dosage than the above may be sufficient, and in other cases a dosage exceeding the range may be necessary.

[0096] Examples of dosage forms used for administration include oral preparations (e.g., tablets, capsules, granules, powders, oral liquids, syrups, oral jellies, etc.), oral preparations (e.g., oral tablets, oral sprays, oral semisolids, mouthwashes, etc.), injectable preparations (e.g., injectable preparations, etc.), dialysis preparations (e.g., dialysis preparations, etc.), inhalation preparations (e.g., inhalants, etc.), ophthalmic preparations (e.g., eye drops, eye ointments, etc.), otic preparations (e.g., ear drops, etc.), nasal preparations (e.g., nasal drops, etc.), rectal preparations (e.g., suppositories, rectal semisolids, enteral injections, etc.), vaginal preparations (e.g., vaginal tablets, vaginal suppositories, etc.), and dermatological preparations (e.g., solid preparations for external application, liquid preparations for external application, sprays, ointments, creams, gels, patches, etc.).

[0097] [Oral administration formulation] Oral formulations include, for example, tablets, capsules, granules, powders, oral liquids, syrups, and oral jellies. Oral formulations include rapidly disintegrating formulations, in which the release of the active ingredient from the formulation is not specifically controlled, and modified-release formulations, such as enteric-coated formulations and sustained-release formulations, in which the release is specifically controlled by a specific formulation design and manufacturing method. Enteric-coated formulations are designed to release the active ingredient primarily in the small intestine rather than in the stomach, for purposes such as preventing the active ingredient from being decomposed in the stomach or reducing the irritating effect of the active ingredient on the stomach. These formulations are typically prepared by coating with an acid-insoluble enteric base. Sustained-release formulations are formulations in which the release rate, release time, and release site of the active ingredient are controlled for purposes such as reducing the frequency of administration or reducing side effects. These formulations are typically prepared by using an appropriate sustained-release agent. Among preparations for oral administration, capsules, granules, tablets, etc. may be coated with an appropriate coating agent such as a sugar, sugar alcohol, or polymer compound for the purpose of facilitating administration or preventing decomposition of the active ingredient.

[0098] (1) Tablets Tablets are solid preparations having a certain shape that are administered orally, and include those generally called tablets, such as plain tablets, film-coated tablets, sugar-coated tablets, multi-layer tablets, and dry-coated tablets, as well as oral rapidly disintegrating tablets, chewable tablets, effervescent tablets, dispersible tablets, and dissolving tablets. When plain tablets are manufactured, the following method (a), (b), or (c) is usually used: (a) Add excipients, binders, disintegrants, and other additives to the active ingredient and mix until homogeneous, then granulate using water or a solution containing a binder in an appropriate manner, add lubricants, mix, and compress; (b) The active ingredient is mixed with additives such as excipients, binders, disintegrants, etc. to form a homogeneous mixture, which is then directly compressed and molded, or the active ingredient and lubricants are added to granules prepared in advance with additives, mixed together to form a homogeneous mixture, and then compressed and molded; (c) The active ingredient is mixed with additives such as excipients and binders to make it homogeneous, and the mixture is moistened with a solvent and poured into a mold to form the mixture, after which it is dried in an appropriate manner; are used. Film-coated tablets can usually be produced by coating a plain tablet with a thin coating of an appropriate coating agent such as a polymer compound. Sugar-coated tablets can usually be produced by coating a plain tablet with a coating agent containing sugars or sugar alcohols. Multilayer tablets can be produced by stacking powder particles of different compositions in layers using an appropriate method and compressing them. Dry-coated tablets can be produced by coating an inner core tablet with an outer layer of different composition. Tablets can also be made into enteric-coated or sustained-release tablets using known appropriate methods. Orally rapidly disintegrating tablets, chewable tablets, effervescent tablets, dispersible tablets, and dissolving tablets are tablets that have unique functions imparted to them by appropriate selection of excipients, and can be produced in accordance with the above-mentioned tablet production methods. Furthermore, an intraorally rapidly disintegrating tablet is a tablet that can be taken by quickly dissolving or disintegrating in the mouth; a chewable tablet is a tablet that is taken by chewing; an effervescent tablet is a tablet that dissolves or disperses while rapidly effervescent in water; a dispersible tablet is a tablet that is taken by dispersing in water; and a dissolving tablet is a tablet that is taken by dissolving in water. Effervescent tablets can be produced by using appropriate acidic substances, carbonates, bicarbonates, etc. as additives.

[0099] (2) Capsules Capsules are preparations filled into capsules or encapsulated with a capsule base, and include hard capsules, soft capsules, etc. Hard capsules can be produced by blending the active ingredient with additives such as excipients to form a homogeneous mixture, or by forming it into granules or molded products using an appropriate method, and then filling the mixture directly into a capsule or by lightly molding it. Soft capsules can be produced by encapsulating the active ingredient with additives and molding it into a specific shape using an appropriate capsule base such as gelatin whose plasticity has been increased by adding glycerin, D-sorbitol, etc. Capsules can also be made into enteric-coated capsules or sustained-release capsules using appropriate known techniques, and coloring agents, preservatives, etc. can also be added to the capsule base.

[0100] (3) Granules Granules are preparations that have been granulated into granules, and include not only those generally called granules but also effervescent granules. When manufacturing granules, the following methods (a), (b), or (c) are usually used: (a) The powdered active ingredient is mixed with an excipient, binder, disintegrant, or other additive to form a homogeneous mixture, and then granulated by a suitable method; (b) Add excipients and other additives to the pre-granulated active ingredient and mix until homogeneous; (c) Add excipients and other additives to the active ingredient that has been prepared in advance into granules, mix them, and form them into granules by an appropriate method; Granules can be coated as needed, and can also be made into enteric coated granules or sustained-release granules using known appropriate methods. Effervescent granules can be produced by using appropriate acidic substances, carbonates, bicarbonates, etc. as additives. Effervescent granules refer to granules that dissolve or disperse in water while rapidly effervescent. Granules can also be made into fine granules by adjusting the particle size.

[0101] (4) Powder Powders are powdered preparations, and can usually be produced by adding excipients or other additives to the active ingredient, mixing them together, and making them homogeneous.

[0102] (5) Oral liquid Oral liquids are liquid or fluid, viscous gel-like preparations, and include not only those commonly referred to as oral liquids but also elixirs, suspensions, emulsions, lemonades, etc. Oral liquids are typically prepared by adding additives and purified water to the active ingredient, mixing to form a homogeneous solution, or emulsifying or suspending the mixture, and then filtering as necessary. Elixirs are clear, liquid oral liquids containing sweet and aromatic ethanol, typically prepared by dissolving a solid active ingredient or its extract in ethanol, purified water, flavoring agents, and sucrose, other sugars, or sweeteners, and then filtering or otherwise preparing a clear liquid. Suspensions are oral liquids in which the active ingredient is finely and homogeneously suspended, typically prepared by adding suspending agents or other additives and purified water or oil to the solid active ingredient, suspending the mixture in an appropriate manner, and homogenizing the entire mixture. An emulsion is an oral liquid preparation in which the active ingredient is finely and homogeneously emulsified, and can usually be produced by adding an emulsifier and purified water to the liquid active ingredient, emulsifying it in an appropriate manner, and making the whole homogeneous. Meanwhile, a lemonade is a clear, liquid oral preparation with a sweet and sour taste.

[0103] (6) Syrup Syrups are viscous liquid or solid preparations containing sugars or sweeteners, including syrup preparations. Syrups are typically prepared by adding an active ingredient to a solution of sucrose, other sugars, or sweeteners, or to a simple syrup, dissolving, mixing, suspending, or emulsifying the mixture, boiling the mixture as needed, and then filtering it while hot. Syrup preparations are granular or powder preparations that become syrups upon addition of water, and are sometimes referred to as dry syrups. Syrup preparations typically use sugars or sweeteners as additives and can be prepared in accordance with the manufacturing methods for the granules or powders described above.

[0104] (7) Oral jelly Oral jellies are non-flowable, molded gel-like preparations, and can usually be produced by mixing the active ingredient with additives and a polymer gel base, gelling it using an appropriate method, and molding it into a specific shape.

[0105] [Injectable preparation] (1) Injectable Injections are solutions, suspensions, emulsions, or solid sterile preparations that are administered subcutaneously, intramuscularly, or directly into body tissues or organs such as blood vessels, and are dissolved or suspended just before use. In addition to what is generally called an injection, these include freeze-dried injections, powder injections, pre-filled syringes, cartridges, infusions, implanted injections, and sustained-release injections. When manufacturing injections, the following method (a) or (b) is usually used: (a) The active ingredient, either as is or with the addition of additives, is dissolved, suspended, or emulsified in water for injection, other aqueous solvents, or non-aqueous solvents to form a homogeneous solution, which is then filled into a container for injection, sealed, and sterilized; (b) The active ingredient, either as it is or with the addition of additives, is dissolved, suspended, or emulsified in water for injection, other aqueous solvents, or non-aqueous solvents to form a homogeneous solution, which is then filtered aseptically, or the homogeneous solution is prepared aseptically and filled into a container for injection and sealed; Freeze-dried injectables are typically prepared by dissolving the active ingredient directly or with additives such as excipients in water for injection, sterile filtering, and filling into an injectable container followed by freeze-drying, or by freeze-drying in a dedicated container and then filling directly into a container. Powdered injectables are typically prepared by sterile filtering, followed by crystallization of the powder, or by adding sterilized additives to the powder, and then filling into an injectable container. Prefilled syringes are typically prepared by filling the syringe with the active ingredient directly or a solution, suspension, or emulsion prepared using the active ingredient and additives. Cartridges are injectables that are inserted into dedicated syringes and used with a drug solution. Cartridges filled with drug solutions are typically prepared by filling the cartridge with the active ingredient directly or a solution, suspension, or emulsion prepared using the active ingredient and additives. Infusion solutions are injectables typically 100 mL or more that are administered intravenously. An implantable injection refers to a solid or gel-like injection that is administered subcutaneously, intramuscularly, etc. using an implantation device or by surgery, with the aim of releasing the active ingredient over a long period of time. An implantable injection can usually be produced by using a biodegradable polymer compound and forming it into pellets, microspheres, or a gel. A sustained-release injection refers to an injection that is administered intramuscularly, etc., with the aim of releasing the active ingredient over a long period of time, and can usually be produced by dissolving or suspending the active ingredient in vegetable oil, etc., or by forming it into a suspension of microspheres using a biodegradable polymer compound.

[0106] The compounds of the present disclosure are 1) complementing and / or enhancing the prophylactic and / or therapeutic effects of the compound; 2) improving the kinetics and absorption of the compound, reducing the dosage, and / or 3) Reducing the side effects of the compound For this purpose, it may be administered in combination with other drugs as a concomitant drug.

[0107] A combination of a compound of the present disclosure and another drug may be administered in the form of a combined preparation in which both components are combined in a single preparation, or in the form of separate preparations. Administration in these separate preparations includes simultaneous administration and administration at different times. Furthermore, administration at different times may involve administering the compound of the present disclosure first and the other drug later, or administering the other drug first and the compound of the present disclosure later. The respective administration methods may be the same or different.

[0108] There are no particular limitations on the diseases for which the above-mentioned combination drug can exert a preventive and / or therapeutic effect, as long as the preventive and / or therapeutic effect of the compound of the present disclosure can be complemented and / or enhanced.

[0109] Other drugs for complementing and / or enhancing the preventive and / or therapeutic effects on pain of the compounds of the present disclosure include, for example, acetaminophen, nonsteroidal anti-inflammatory drugs, opioid drugs, antidepressants, antiepileptic drugs, N-methyl-D-aspartate antagonists, muscle relaxants, antiarrhythmic drugs, steroid drugs, and bisphosphonate drugs. Examples of nonsteroidal anti-inflammatory drugs include sazapirin, sodium salicylate, aspirin, aspirin preparations such as aspirin-dialuminate combinations, diflunisal, indomethacin, suprofen, ufenamate, dimethylisopropylazulene, bufexamac, felbinac, diclofenac, tolmetin sodium, clinoryl, fenbufen, napumetone, proglumetacin, indomethacin farnesyl, acemetacin, proglumetacin maleate, amfenac sodium, mofezolac, etodolac, ibuprofen, ibuprofen piconol, naproxen, flurbiprofen, flurbiprofen axetil, ketoprofen, and fenoprofen calcium. Examples of such antipyrine cold medicines include acetaminophen, tiaprofen, oxaprozin, pranoprofen, loxoprofen sodium, aluminoprofen, zaltoprofen, mefenamic acid, aluminum mefenamate, tolfenamic acid, floctafenine, ketophenylbutazone, oxyphenbutazone, piroxicam, tenoxicam, ampiroxicam, Napagern ointment, epirizole, tiaramide hydrochloride, tinoridine hydrochloride, emorfazone, sulpyrine, Migrenin, Salidon, Sedes G, Amipiro-N, Sorbon, pyrazinone cold medicines, acetaminophen, phenacetin, dimethotiazine mesylate, meloxicam, celecoxib, rofecoxib, valdecoxib, simetride combination drugs, and non-pyrine cold medicines. Opioid drugs include, for example, codeine, fentanyl, hydromorphone, levorphanol, meperidine, methadone, morphine, oxycodone, oxymorphone, propoxyphene, and tramadol. Examples of antidepressants include tricyclic antidepressants (e.g., amitriptyline hydrochloride, imipramine hydrochloride, clomipramine hydrochloride, dosulepin 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 noradrenaline 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.). Examples of antiepileptic drugs include phenobarbital, pridomine, phenytoin, ethosuximide, zonisamide, nitrazepam, clonazepam, carbamazepine, sodium valproate, acetazolamide, and sulthiame. Examples of N-methyl-D-aspartate antagonists include ketamine hydrochloride, amantadine hydrochloride, memantine hydrochloride, dextromethorphan, methadone, etc. Examples of muscle relaxants include succinylcholine, succinylcholine, succinylcholine, vecuronium bromide, vancronium bromide, and dantrolene sodium. Antiarrhythmic drugs include, for example, procainamide, disopyramide, cibenzoline, pirmenol, lidocaine, mexiletine, aprindine, pilsicainide, flecainide, propafenone, propranolol, atenolol, bisoprolol, amiodarone, sotalol, verapamil, diltiazem, and bepridil. Examples of steroid drugs include topical medications such as clobetasol propionate, diflorasone acetate, fluocinonide, mometasone furoate, betamethasone dipropionate, betamethasone butyrate propionate, betamethasone valerate, difluprednate, budesonide, diflucortolone valerate, amcinonide, halcinonide, dexamethasone, dexamethasone propionate, dexamethasone valerate, and dexamethasone acetate. These include flumethasone, hydrocortisone acetate, hydrocortisone butyrate, hydrocortisone butyrate propionate, deprodone propionate, prednisolone valerate acetate, fluocinolone acetonide, beclomethasone propionate, triamcinolone acetonide, flumethasone pivalate, alclometasone propionate, clobetasone butyrate, prednisolone, pecclomethasone propionate, and fludroxycortide. Oral or injectable medications include cortisone acetate, hydrocortisone, hydrocortisone sodium phosphate, hydrocortisone sodium succinate, fludrocortisone acetate, prednisolone, prednisolone acetate, prednisolone sodium succinate, prednisolone butylacetate, prednisolone sodium phosphate, halopredone acetate, methylprednisolone, methylprednisolone acetate, methylprednisolone sodium succinate, triamcinolone, triamcinolone acetate, triamcinolone acetonide, dexamethasone, dexamethasone acetate, dexamethasone sodium phosphate, dexamethasone palmitate, paramethasone acetate, and betamethasone. Inhaled medications include beclomethasone propionate, fluticasone propionate, budesonide, flunisolide, triamcinolone, ST-126P, ciclesonide, dexamethasone paromythionate, mometasone furoate, prasterone sulfonate, deflazacort, methylprednisolone suleptanate, and methylprednisolone sodium succinate. Bisphosphonate drugs include, for example, etidronate, vamidronate, alendronate, risedronate, zoledronate, and minodronate. Any two or more of the other drugs may be administered in combination.

[0110] Furthermore, other drugs that complement and / or enhance the preventive and / or therapeutic effects of the compounds of the present disclosure include not only those that have been discovered so far but also those that will be discovered in the future, based on the mechanisms described above.

[0111] Unless otherwise defined, all technical and scientific terms and abbreviations used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.

[0112] Furthermore, the contents of all patent and non-patent literature or references explicitly cited in this specification may be incorporated herein by reference in their entirety.

[0113] In one aspect, the present disclosure provides the following embodiments. [1] General formula (IA): [ka] (In the formula, X 1 , X 2 are independently (1) CH, (2) CR X , or (3) represents N, where X 1 and X 2 At least one of represents N, R 1 represents a halogen atom, R X represents (1) a halogen atom, (2) a C alkyl group, (3) a C alkenyl group, (4) a C alkynyl group, (5) a C alkoxy group, (6) a C haloalkyl group, (7) a C haloalkenyl group, (8) a C haloalkynyl group, (9) a C haloalkoxy group, or (10) a cyano group; R 2represents (1) a halogen atom, (2) a C alkyl group, (3) a C alkenyl group, (4) a C alkynyl group, (5) a C alkoxy group, (6) a C haloalkyl group, (7) a C haloalkenyl group, (8) a C haloalkynyl group, (9) a C haloalkoxy group, or (10) a cyano group; When m is 2 or more, multiple R 2 may be the same or different, R 3 represents (1) a hydrogen atom, (2) a C1-6 alkyl group, (3) a C1-6 haloalkyl group, (4) a 3- to 10-membered cyclic group, (5) -(C1-6 alkylene)-(3- to 10-membered cyclic group), (6) -(C1-6 haloalkylene)-(3- to 10-membered cyclic group), in which 1 to 2 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 optionally oxidized sulfur atom, R 3 The 3-10 membered cyclic group in 301 may be substituted with R 301 is (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, or (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) an oxo group; R 301 When there are two or more substitutions, multiple R 301 may be the same or different, R 302 , R 303 , R 304 , R 305 , R 306 , R 307, R 308 , or R 309 each independently represents (1) a hydrogen atom or (2) a C1-4 alkyl group; R 2 R 2 Represents (2) to (9) in the 3 represents a C1-6 alkyl group, R 2 and R 3 may form a 5- or 6-membered cyclic group together with the atom to which it is attached, R 4 represents (1) a halogen atom, (2) a C alkyl group, (3) a C alkenyl group, (4) a C alkynyl group, (5) a C alkoxy group, (6) a C haloalkyl group, (7) a C haloalkenyl group, (8) a C haloalkynyl group, or (9) a C haloalkoxy group; When n is 2 or more, multiple R 4 may be the same or different, Two R's on the same carbon atom 4 represents a C alkyl group, it may be taken together with the carbon atom to which it is attached to form a C cycloalkyl group; ring1 represents a 3- to 15-membered cyclic group; R 5-A is (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 alkylthio group, (7) a C1-6 alkylsulfinyl group, (8) a C1-6 alkylsulfonyl group, (9) a C2-6 acyl group, (10) a 3- to 6-membered cyclic group, (11) -L R5 -(3- to 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 507wherein 1 to 2 carbon atoms in 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 or C2-6 acyl group may be replaced by an oxygen atom or an optionally oxidized sulfur atom, When p is 2 or more, multiple R 5-A may be the same or different, R 5-A Among these, groups (2) to (11) are each a group having 1 to 9 R 508 may be substituted with R 508 (1) Halogen atoms 、 (2) a C1-4 alkyl group, (3) a C1-4 alkoxy group, (4) a C2-6 acyl group, (5) a C3-6 cycloalkyl group, (6) a hydroxyl group, or (7) -NR 509 R 510 represents R 508 When there are two or more substitutions, multiple R 508 may be the same or different, L R5 are (1) -O-, (2) -(C1-4 alkylene)-, (3) -O-(C1-4 alkylene)-, (4) -(C1-4 alkylene)-O-, and (5) -NR 511 -, (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 independently represents (1) a hydrogen atom, (2) a C alkyl group, (3) a C acyl group, or (4) a C alkylsulfonyl group; m represents an integer of 0 to 2; n represents an integer of 0 to 5, and p represents an integer of 0 to 5.) or a pharmaceutically acceptable salt thereof. [2] General formula (I): [ka] (In the formula, X 1 , X 2 are independently (1) CH, (2) CR X , or (3) represents N, where X 1 and X 2 At least one of represents N, R 1 represents a halogen atom, R X represents (1) a halogen atom, (2) a C alkyl group, (3) a C alkenyl group, (4) a C alkynyl group, (5) a C alkoxy group, (6) a C haloalkyl group, (7) a C haloalkenyl group, (8) a C haloalkynyl group, (9) a C haloalkoxy group, or (10) a cyano group; R 2 represents (1) a halogen atom, (2) a C alkyl group, (3) a C alkenyl group, (4) a C alkynyl group, (5) a C alkoxy group, (6) a C haloalkyl group, (7) a C haloalkenyl group, (8) a C haloalkynyl group, (9) a C haloalkoxy group, or (10) a cyano group; When m is 2 or more, multiple R 2 may be the same or different, R 3 represents (1) a hydrogen atom, (2) a C1-6 alkyl group, (3) a C1-6 haloalkyl group, (4) a 3- to 10-membered cyclic group, (5) -(C1-6 alkylene)-(3- to 10-membered cyclic group), (6) -(C1-6 haloalkylene)-(3- to 10-membered cyclic group), in which 1 to 2 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 optionally oxidized sulfur atom, R 3 The 3-10 membered cyclic group in 301 may be substituted with R 301is (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, or (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) an oxo group; R 301 When there are two or more substitutions, multiple R 301 may be the same or different, R 302 , R 303 , R 304 , R 305 , R 306 , R 307 , R 308 , or R 309 each independently represents (1) a hydrogen atom or (2) a C1-4 alkyl group; R 2 R 2 Represents (2) to (9) in the 3 represents a C1-6 alkyl group, R 2 and R 3 may form a 5- or 6-membered cyclic group together with the atom to which it is attached, R 4 represents (1) a halogen atom, (2) a C alkyl group, (3) a C alkenyl group, (4) a C alkynyl group, (5) a C alkoxy group, (6) a C haloalkyl group, (7) a C haloalkenyl group, (8) a C haloalkynyl group, or (9) a C haloalkoxy group; When n is 2 or more, multiple R 4 may be the same or different, Two R's on the same carbon atom 4represents a C alkyl group, it may be taken together with the carbon atom to which it is attached to form a C cycloalkyl group; ring1 represents a 3- to 15-membered cyclic group; R 5 is (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 alkylthio group, (7) a C1-6 alkylsulfinyl group, (8) a C1-6 alkylsulfonyl group, (9) a C2-6 acyl group, (10) a 3- to 6-membered cyclic group, (11) -L R5 -(3- to 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 represents When p is 2 or more, multiple R 5 may be the same or different, R 5 Among these, groups (2) to (11) are each a group having 1 to 9 R 508 may be substituted with R 508 (1) Halogen atoms 、 (2) a C1-4 alkyl group, (3) a C1-4 alkoxy group, (4) a C2-6 acyl group, (5) a C3-6 cycloalkyl group, (6) a hydroxyl group, or (7) -NR 509 R 510 represents R 508 When there are two or more substitutions, multiple R 508 may be the same or different, L R5 are (1) -O-, (2) -(C1-4 alkylene)-, (3) -O-(C1-4 alkylene)-, (4) -(C1-4 alkylene)-O-, and (5) -NR 511 -, (6)-SO 0-2 -, represents R 501 , R 502 , R503 , R 504 , R 505 , R 506 , R 507 , R 509 , R 510 , or R 511 each independently represents (1) a hydrogen atom, (2) a C alkyl group, (3) a C acyl group, or (4) a C alkylsulfonyl group; m represents an integer of 0 to 2; n represents an integer of 0 to 5, and p represents an integer of 0 to 5.) or a pharmaceutically acceptable salt thereof. [3] ring 1 is a 3- to 10-membered cyclic group or [ka] (wherein the * symbol represents the bonding position to the carbonyl group), or a pharmaceutically acceptable salt thereof. [4] ring 1 is the following ring structure: [ka] (In the formula, the * symbol indicates the bond position with the carbonyl group, and the hydrogen atom represented by NH is R 5-A The compound according to [1] or [3] above, or a pharmaceutically acceptable salt thereof, wherein the ring structure is selected from the group consisting of: [5] ring 1 is the following ring structure: [ka] (In the formula, the * symbol indicates the bond position with the carbonyl group, and the hydrogen atom represented by NH is R 5 The compound according to [2] or [3] above, or a pharmaceutically acceptable salt thereof, wherein the ring structure is selected from the group consisting of: [6] ring 1 is the following ring structure: [ka] (In the formula, the * symbol indicates the bond position with the carbonyl group, and the hydrogen atom represented by NH is R 5-A or R 5 The compound according to any one of the above [1] to [5], or a pharmaceutically acceptable salt thereof, wherein the ring structure is selected from the group consisting of: [7] R 5-A or R 5 is (1) a halogen atom, (2) a C1-6 alkyl group, (3) a C1-6 alkoxy group, (4) a C1-6 haloalkyl group, (5) a C1-6 haloalkoxy group, (6) a 3- to 6-membered cyclic group, (7) an oxo group, or (8) -NR 501 R 502 , or (9)-COOR 503 The compound according to any one of [1] to [6] above, or a pharmaceutically acceptable salt thereof. [8] R 5-A or R 5 is (1) a C alkyl group, (2) a C alkoxy group, (3) a C haloalkyl group, (4) a C 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, or a pharmaceutically acceptable salt thereof. [9] R 3 is (1) a hydrogen atom, (2) a C alkyl group, (3) a C haloalkyl group, (4) a 3- to 10-membered cyclic group, or (5) —CH—(3- to 10-membered cyclic group), or a pharmaceutically acceptable salt thereof.

[10] R 3 is (1) a hydrogen atom, (2) a C alkyl group, (3) a C haloalkyl group, (4) a cyclopropyl group, or (5) -CH-Q; The compound according to any one of the above [1] to [9], wherein Q is (1) benzene, (2) pyridine, or (3) imidazo[2,1-b]thiazole, or a pharmaceutically acceptable salt thereof.

[11] X 1 , X 2are all N, or a pharmaceutically acceptable salt thereof.

[12] The compound represented by general formula (IA) or general formula (I) is a compound represented by general formula (I-1): [ka] (In the formula, R 3-a represents (1) a hydrogen atom, (2) a C alkyl group, (3) a C haloalkyl group, (4) a cyclopropyl group, or (5) -CH-Q; ring1-a is the following ring structure: [ka] (In the formula, the * symbol indicates the bond position with the carbonyl group, and the hydrogen atom represented by NH is R 5-a and R 5-a 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; The other symbols have the same meanings as those in the symbols in the above [1], [2] or

[10] .) The compound according to any one of the above [1] to

[11] , or a pharmaceutically acceptable salt thereof.

[13] ring 1-a is the following ring structure; [ka] (In the formula, the * symbol indicates the bond position with the carbonyl group, and the hydrogen atom represented by NH is R 5ーa The compound according to

[12] above, or a pharmaceutically acceptable salt thereof, wherein the ring structure is selected from the group consisting of:

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

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

[16] A pharmaceutical composition comprising the compound according to any one of [1] to

[15] above, or a pharmaceutically acceptable salt thereof, as an active ingredient, and further comprising a pharmaceutically acceptable carrier.

[17] The pharmaceutical composition according to

[16] above, which is an ABHD6 inhibitor.

[18] The pharmaceutical composition according to

[16] or

[17] , which is an agent for treating and / or preventing a disease associated with ABHD6.

[19] The pharmaceutical composition according to

[18] , wherein the ABHD6-related disease is pain, a neurological disease, an inflammatory disease, an autoimmune disease, a metabolic disease, or a malignant tumor.

[20] The pharmaceutical composition according to

[18] or

[19] , 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, post-herpetic 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 dental pulpitis.

[21] The pharmaceutical composition according to any one of

[16] to

[20] above, which 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, steroid drugs, and bisphosphonate drugs.

[22] A therapeutic and / or preventive agent for a disease associated with ABHD6, comprising the compound according to any one of [1] to

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

[23] A method for preventing and / or treating an ABHD6-associated disease, comprising administering a compound according to any one of [1] to

[15] above, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to

[16] or

[17] above, to a patient in need of such prevention and / or treatment.

[24] The compound according to any one of [1] to

[15] above, or a pharmaceutically acceptable salt thereof, for use in the prevention and / or treatment of an ABHD6-associated disease.

[25] Use of the compound according to any one of [1] to

[15] above, or a pharmaceutically acceptable salt thereof, for the manufacture of an agent for the prophylaxis and / or treatment of a disease associated with ABHD6.

[0114] [Synthesis Example] The solvents in parentheses shown in the chromatographic separations and TLCs indicate the eluting or developing solvents used, and the ratios are by volume.

[0115] The solvent in parentheses shown in the NMR section indicates the solvent used in the measurement.

[0116] The compound names used in this specification were created using ACD / Name (registered trademark), a computer program that generally creates names according to IUPAC rules, or Chemdraw Ultra (version 12.0, Cambridge Soft), or were created according to IUPAC nomenclature.

[0117] 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) is listed): [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 in water; mobile phase (B): 0.1% formic acid-acetonitrile solution; gradient (ratio of mobile phase (A):mobile phase (B) is listed): [0 min] 95:5; [0.1 min] 95:5; [1.2 min] 5:95; [1.6 min] 5:95; detector: UV (PDA), ELSD, MS.

[0118] Unless otherwise specified, the HPLC retention time indicates the retention time under the conditions described above for LC-MS / ELSD. The description in parentheses next to the HPLC retention time indicates the measurement conditions.

[0119] Reference Example 1: 2-benzylhexahydrocyclopenta[c]pyrrol-4(1H)-one 2-Cyclopentenone (CAS No.: 930-30-3, 17 g) and trifluoroacetic acid (CAS No.: 76-05-1, 240 mg) were added to a dichloromethane solution (600 mL) of N-benzyl-N-(methoxymethyl)-N-trimethylsilylmethylamine (CAS No.: 93102-05-7, 50 g), 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 give the title compound (30 g). HPLC retention time (min): 0.65 (TFA); MS(ESI, Pos.):226(M+H) + .

[0120] Reference Example 2: (R)—N-((3aS,6aR,E)-2-benzylhexahydrocyclopenta[c]pyrrol-4(1H)-ylidene)-2-methylpropane-2-sulfinamide Titanium(IV) ethoxide (CAS number: 3037-36-3, 46.6 g) and (R)-(+)-2-methyl-2-propanesulfinamide (CAS number: 196929-78-9, 11.8 g) were added to a solution of the compound (20 g) prepared in Reference Example 1 in THF (300 mL), and the mixture was stirred at 60°C for 15 hours. The reaction mixture was slowly poured into saturated aqueous sodium bicarbonate and dichloromethane, and filtered. The mixture was washed with saturated brine, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to give the title compound (12.4 g). HPLC retention time (min): 0.80 (TFA); MS(ESI, Pos.):319(M+H) + .

[0121] Reference Example 3: (3aS,6aR)-2-benzylhexahydrocyclopenta[c]pyrrol-4(1H)-one To a solution of the compound (20 g) prepared in Reference Example 2 in THF (60 mL) was added 2N hydrochloric acid (60 mL) 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 then concentrated under reduced pressure. The resulting title compound was used in the next reaction without further purification.

[0122] Reference Example 4: 2-Methyl-2-propanyl (3aS,6aR)-4-oxohexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate To a solution of the compound prepared in Reference Example 3 in THF (60 mL), di-tert-butyl dicarbonate (CAS number: 24424-99-5, 9.4 g) and 20% palladium hydroxide (CAS number: 12135-22-7, 700 mg) were 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 give 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.

[0123] Reference Example 5: 2-Methyl-2-propanyl (3aS,4S,6aR)-4-hydroxyhexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate To a solution of the compound (7.3 g) prepared in Reference Example 4 in THF (200 mL) was added 1 M lithium tri-sec-butylborohydride THF solution (CAS number: 38721-52-7, 49 mL) at -78°C, and the mixture was stirred at -78°C for 1 hour. A 35% aqueous solution of hydrogen peroxide was slowly added to the reaction solution at 0°C until bubbling ceased, followed by extraction 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 give 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.

[0124] 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) produced in Reference Example 5 in dichloromethane (100 mL), triethylamine (12 mL), p-toluenesulfonyl chloride (CAS number: 98-59-9, 8.2 g), and trimethylamine hydrochloride (CAS number: 75-50-3, 820 mg) were added and stirred at room temperature for 6 hours. A saturated aqueous solution of sodium bicarbonate was added to the reaction solution, and the mixture was extracted with dichloromethane. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to give the title compound (9.3 g). HPLC retention time (min): 1.2 (TFA); MS(ESI, Pos.):382(M+H) + .

[0125] Reference Example 7: 2-Methyl-2-propanyl (3aS,4R,6aR)-4-azidohexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate Sodium azide (CAS number: 26628-22-8, 3.2 g) was added to a solution of the compound (9.3 g) produced in Reference Example 6 in dimethyl sulfoxide (72 mL), and the mixture was stirred at 60°C for 6 hours. Water was added to the reaction solution, and the mixture was 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.

[0126] 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) was added 20% palladium hydroxide (930 mg), 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 give the title compound (4.5 g). HPLC retention time (min): 0.77 (TFA); MS(ESI, Pos.):227(M+H) + .

[0127] 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 prepared in Reference Example 8 (1.5 g) in N,N-dimethylacetamide (hereinafter, DMA) (25 mL), N,N-diisopropylethylamine (hereinafter, DIPEA) (6.9 mL) and 3,6-dichloropyridazine (CAS number: 141-30-0, 1.5 g) were added and stirred at 160°C for 1 hour. Water was added to the reaction solution, and the mixture was extracted with dichloromethane. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to give the title compound (1.5 g). HPLC retention time (min): 0.89 (formic acid); MS(ESI, Pos.):339(M+H) + .

[0128] Reference Example 10: (3aS,4R,6aR)-N-(6-chloro-3-pyridazinyl)octahydrocyclopenta[c]pyrrol-4-amine dihydrochloride To the compound (1.2 g) prepared in Reference Example 9, 4N hydrochloric acid (1,4-dioxane solution, 12 mL) was added and stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure to give the title compound (1.0 g). HPLC retention time (min): 0.59 (formic acid); MS(ESI, Pos.):239(M+H) + .

[0129] Reference Example 10-1: rel-(3aS,4R,6aR)-N-(6-chloro-3-pyridazinyl)octahydrocyclopenta[c]pyrrol-4-amine dihydrochloride racemic mixture The title compound was obtained by performing the same operations as in Reference Example 4 → Reference Example 5 → Reference Example 6 → Reference Example 7 → Reference Example 8 → Reference Example 9 → Reference Example 10 using the compound prepared in Reference Example 1 instead of the compound prepared in Reference Example 3.

[0130] Example 1: {(3aS,4R,6aR)-4-[(6-chloro-3-pyridazinyl)amino]hexahydrocyclopenta[c]pyrrol-2(1H)-yl}[5-(difluoromethyl)-2-thienyl]methanone [ka] To a solution of the compound prepared in Reference Example 10 (30 mg) in DMA (0.5 mL), DIPEA (0.083 mL), 5-(difluoromethyl)thiophene-2-carboxylic acid (CAS number: 189330-23-2, 19 mg), and O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (hereinafter referred to as HATU) (CAS number: 148893-10-1, 38 mg) were added and stirred at room temperature for 3 hours. Water was added to the reaction solution, and the mixture was extracted with dichloromethane. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to give 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.

[0131] Examples 1-1 to 1-6 The same procedure as in Example 1 was carried out using the corresponding carboxylic acid compound instead of 5-(difluoromethyl)thiophene-2-carboxylic acid, and 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, to obtain the title compound.

[0132] Example 1-1: rel-1,3-Benzothiazol-2-yl{(3aS,4R,6aR)-4-[(6-chloro-3-pyridazinyl)amino]hexahydrocyclopenta[c]pyrrol-2(1H)-yl}methanone Racemic mixture [ka] HPLC retention time (min): 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.

[0133] Example 1-2: {(3aS,4R,6aR)-4-[(6-chloro-3-pyridazinyl)amino]hexahydrocyclopenta[c]pyrrol-2(1H)-yl}(5-methyl-2-thienyl)methanone

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[0134] Example 1-3: [(3aS,4R,6aR)-4-[(6-chloro-3-pyridazinyl)amino]hexahydrocyclopenta[c]pyrrol-2(1H)-yl](thieno[3,2-c]pyridin-2-yl)methanone

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[0135] Example 1-4: [(3aS,4R,6aR)-4-[(6-chloro-3-pyridazinyl)amino]hexahydrocyclopenta[c]pyrrol-2(1H)-yl](6,7-dihydro-4H-thieno[3,2-c]pyran-2-yl)methanone

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[0136] Example 1-5: [(3aS,4R,6aR)-4-[(6-chloro-3-pyridazinyl)amino]hexahydrocyclopenta[c]pyrrol-2(1H)-yl][4-(2-furyl)phenyl]methanone

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[0137] Examples 1-6: 1-Benzofuran-2-yl[(3aS,4R,6aR)-4-[(6-chloro-3-pyridazinyl)amino]hexahydrocyclopenta[c]pyrrol-2(1H)-yl]methanone

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[0138] Reference Example 11: 2-Methyl-2-propanyl (3aS,4R,6aR)-4-[(6-bromo-3-pyridazinyl)amino]hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate To a solution of the compound (4.0 g) produced in Reference Example 8 in DMA (25 mL) were added DIPEA (18 mL) and 3,6-dibromopyridazine (CAS number: 17973-86-3, 6.3 g), and the mixture was stirred at 160°C for 15 hours. Water was added to the reaction mixture, and the mixture was extracted with dichloromethane. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to give the title compound (4.0 g). HPLC retention time (min): 0.91 (formic acid); MS(ESI, Pos.):383(M+H) + .

[0139] Reference Example 12: (3aS,4R,6aR)-N-(6-bromo-3-pyridazinyl)octahydrocyclopenta[c]pyrrol-4-amine dihydrochloride To the compound (4.0 g) prepared in Reference Example 11, 4N hydrochloric acid (1,4-dioxane solution, 12 mL) was added, and the mixture was stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure to give the title compound (3.7 g). HPLC retention time (min): 0.59 (formic acid); MS(ESI, Pos.):283(M+H) + .

[0140] Reference Example 12-1: rel-(3aS,4R,6aR)-N-(6-bromo-3-pyridazinyl)octahydrocyclopenta[c]pyrrol-4-amine dihydrochloride racemic mixture The title compound was obtained by performing the same operations as in Reference Example 4 → Reference Example 5 → Reference Example 6 → Reference Example 7 → Reference Example 8 → Reference Example 11 → Reference Example 12, using the compound prepared in Reference Example 1 instead of the compound prepared in Reference Example 3.

[0141] Example 2: [(3aS,4R,6aR)-4-[(6-bromo-3-pyridazinyl)amino]hexahydrocyclopenta[c]pyrrol-2(1H)-yl](5-methyl-2-thienyl)methanone [ka] To a solution of the compound (3.0 g) prepared in Reference Example 12 in DMA (20 mL) were added DIPEA (2.9 mL), 5-methyl-2-thiophenecarboxylic acid (CAS number: 1918-79-2, 6.6 g), and HATU (3.8 g), and the mixture was stirred at room temperature for 3 hours. Water was added to the reaction mixture, and the mixture was extracted with dichloromethane. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to give the title compound (1.8 g). 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.

[0142] Examples 2-1 to 2-14 The same procedure as in Example 2 was carried out except that the corresponding carboxylic acid compound was used in place of 5-methyl-2-thiophenecarboxylic acid to give the title compound.

[0143] Example 2-1: [(3aS,4R,6aR)-4-[(6-bromo-3-pyridazinyl)amino]hexahydrocyclopenta[c]pyrrol-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.

[0144] Example 2-2: [(3aS,4R,6aR)-4-[(6-bromo-3-pyridazinyl)amino]hexahydrocyclopenta[c]pyrrol-2(1H)-yl][5-(difluoromethyl)-2-thienyl]methanone

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[0145] Example 2-3: [(3aS,4R,6aR)-4-[(6-bromo-3-pyridazinyl)amino]hexahydrocyclopenta[c]pyrrol-2(1H)-yl](5-methyl-1,3-thiazol-2-yl)methanone

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[0146] Example 2-4: [(3aS,4R,6aR)-4-[(6-bromo-3-pyridazinyl)amino]hexahydrocyclopenta[c]pyrrol-2(1H)-yl](thieno[3,2-c]pyridin-2-yl)methanone

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[0147] Example 2-5: [(3aS,4R,6aR)-4-[(6-bromo-3-pyridazinyl)amino]hexahydrocyclopenta[c]pyrrol-2(1H)-yl](6,7-dihydro-4H-pyrano[3,4-d][1,3]thiazol-2-yl)methanone

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[0148] Example 2-6: [(3aS,4R,6aR)-4-[(6-bromo-3-pyridazinyl)amino]hexahydrocyclopenta[c]pyrrol-2(1H)-yl][2-(dimethylamino)-1,3-thiazol-5-yl]methanone

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[0149] Example 2-7: [(3aS,4R,6aR)-4-[(6-bromo-3-pyridazinyl)amino]hexahydrocyclopenta[c]pyrrol-2(1H)-yl](5,5-dioxido-6,7-dihydro-4H-thieno[3,2-c]thiopyran-2-yl)methanone

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[0150] Example 2-8: [(3aS,4R,6aR)-4-[(6-bromo-3-pyridazinyl)amino]hexahydrocyclopenta[c]pyrrol-2(1H)-yl](6,7-dihydro-4H-thieno[3,2-c]thiopyran-2-yl)methanone

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[0151] Example 2-9: [(3aS,4R,6aR)-4-[(6-bromo-3-pyridazinyl)amino]hexahydrocyclopenta[c]pyrrol-2(1H)-yl](1-methyl-1H-thieno[2,3-c]pyrazol-5-yl)methanone

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[0152] Example 2-10: [(3aS,4R,6aR)-4-[(6-bromo-3-pyridazinyl)amino]hexahydrocyclopenta[c]pyrrol-2(1H)-yl][2-(dimethylamino)thieno[2,3-d][1,3]thiazol-5-yl]methanone

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[0153] Example 2-11: [(3aS,4R,6aR)-4-[(6-bromo-3-pyridazinyl)amino]hexahydrocyclopenta[c]pyrrol-2(1H)-yl](3-methyl-3H-thieno[2,3-d][1,2,3]triazol-5-yl)methanone

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[0154] Example 2-12: [(3aS,4R,6aR)-4-[(6-bromo-3-pyridazinyl)amino]hexahydrocyclopenta[c]pyrrol-2(1H)-yl](5-methoxy-2-furyl)methanone

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[0155] Example 2-13: [(3aS,4R,6aR)-4-[(6-bromo-3-pyridazinyl)amino]hexahydrocyclopenta[c]pyrrol-2(1H)-yl](1,3-dimethyl-1H-thieno[2,3-c]pyrazol-5-yl)methanone

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[0156] Example 2-14: Bicyclo[2.2.2]oct-2-yl[(3aS,4R,6aR)-4-[(6-bromo-3-pyridazinyl)amino]hexahydrocyclopenta[c]pyrrol-2(1H)-yl]methanone

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[0157] 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 number: 38239-32-6, 120 mg) in 1,2-dimethoxyethane (3 mL), DIPEA (0.083 mL), tripotassium phosphate (CAS number: 7778-53-2, 1730 mg), (E)-ethyl 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)acrylate (CAS number: 1009307-13-4, 300 mg), and bis(triphenylphosphine)palladium(II) chloride (CAS number: 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, which was then 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 give the title compound (97 mg). HPLC retention time (min): 1.20 (formic acid); MS(ESI, Pos.):286(M+H) + .

[0158] Reference Example 14: Methyl 4-amino-5-(3-ethoxy-3-oxopropyl)-2-thiophenecarboxylate To a solution of the compound (50 mg) prepared in Reference Example 13 in methanol (2 mL) was added 20% palladium hydroxide (100 mg) 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 give the title compound (30 mg). HPLC retention time (min): 0.80 (formic acid); MS(ESI, Pos.):258(M+H) + .

[0159] Reference Example 15: Methyl 5-oxo-4,5,6,7-tetrahydrothieno[3,2-b]pyridine-2-carboxylate p-Toluenesulfonic acid monohydrate (CAS number: 6192-52-5, 1.5 mg) was added to a solution of the compound (20 mg) produced in Reference Example 14 in methanol (1 mL), and the mixture was stirred at 60°C for 15 hours. Saturated aqueous sodium bicarbonate was added to the reaction solution, 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 residue was purified by silica gel column chromatography to give the title compound (5 mg). HPLC retention time (min): 0.81 (formic acid); MS(ESI, Pos.):212(M+H) + .

[0160] Reference Example 16: Methyl 4-methyl-5-oxo-4,5,6,7-tetrahydrothieno[3,2-b]pyridine-2-carboxylate To a solution of the compound (5 mg) prepared in Reference Example 15 in DMF (0.25 mL) were added sodium hydride (CAS number: 7646-69-7, 2.9 mg) and iodomethane (CAS number: 74-88-4, 22 mg), and the mixture was stirred at room temperature for 3 hours. 2N 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 residue was purified by silica gel column chromatography to give the title compound (7 mg). HPLC retention time (min): 0.88 (formic acid); MS (ESI, Pos.): 225 (M+H) + .

[0161] Reference Example 17: 4-methyl-5-oxo-4,5,6,7-tetrahydrothieno[3,2-b]pyridine-2-carboxylic acid To a solution of the compound (7 mg) prepared in Reference Example 16 in methanol (1 mL) was added 2N aqueous sodium hydroxide solution (0.5 mL), and the mixture was stirred for 1 hour at 60° C. 1N hydrochloric acid was added to the reaction solution, and the precipitate was collected by filtration to obtain the title compound (5.0 mg).

[0162] Reference Example 18: 5-chloro-3,4-dihydro-2H-pyran-6-carbaldehyde DMF (0.70 mL) was added to a solution of phosphoryl chloride (CAS number: 10025-87-3, 1400 mg) in dichloromethane (5 mL) 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. A saturated aqueous solution of sodium bicarbonate was added to the reaction mixture, 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 title compound was used in the next reaction without purification.

[0163] Reference Example 19: Methyl [(6-formyl-3,4-dihydro-2H-pyran-5-yl)thio]acetate To a dichloroethane (20 mL) solution of the compound prepared in Reference Example 18, triethylamine (2.5 mL) and methyl thioglycolate (CAS number: 2365-48-2, 1100 mg) were added, and the mixture was stirred for 15 hours at 70° C. The reaction solution was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography to give the title compound (300 mg).

[0164] Reference Example 20: Methyl 6,7-dihydro-5H-thieno[3,2-b]pyran-2-carboxylate To a solution of the compound prepared in Reference Example 19 in methanol (10 mL) was added 28% sodium methoxide (CAS number: 124-41-4, 0.85 mL), and the mixture was stirred at 70°C for 1 hour. The reaction mixture was concentrated under reduced pressure, and 2N hydrochloric acid was added, followed by extraction with dichloromethane. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to give the title compound (220 mg).

[0165] Reference Example 21: 6,7-Dihydro-5H-thieno[3,2-b]pyran-2-carboxylic acid To a solution of the compound (20 mg) prepared in Reference Example 20 in methanol (1 mL) was added 2N aqueous sodium hydroxide solution (0.5 mL), and the mixture was stirred for 1 hour at 60° C. 1N hydrochloric acid was added to the reaction mixture, which was then 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 (min): 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.

[0166] 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 number: 221316-61-6, 50 mg) in dichloromethane (1 mL), triethylamine (0.11 mL) and methyl chloroformate (CAS number: 79-22-1, 72 mg) were added at 0°C and stirred at room temperature for 15 hours. 2N hydrochloric acid was added to the reaction mixture, which was then 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 further purification.

[0167] Reference Example 23: 5-(Methoxycarbonyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxylic acid To a solution of the compound (20 mg) prepared in Reference Example 22 in methanol (1 mL) was added 2N aqueous sodium hydroxide solution (0.5 mL), and the mixture was stirred for 1 hour at 50° C. 1N hydrochloric acid was added to the reaction solution, and 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.

[0168] Reference Example 24: 4,4-dimethyl-6,7-dihydrothieno[3,2-c]pyran To a solution of 2-(2-thienyl)ethanol (CAS number: 160774-13-8, 400 mg) in toluene (4 mL), 2,2-dimethoxypropane (CAS number: 77-76-9, 0.38 mL) and iron(III) trifluoromethanesulfonate (CAS number: 63295-48-7, 15.7 mg) were added and stirred at 70°C for 17 hours. Triethylamine (0.22 mL) was added to the reaction mixture, which was then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to give 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) + .

[0169] Reference Example 25: 4,4-dimethyl-6,7-dihydrothieno[3,2-c]pyran-2-carboxylic acid To a solution of the compound prepared in Reference Example 24 (284 mg) in THF (10 mL) was added 1.6 M n-butyllithium solution in hexane (CAS number: 109-72-8, 1.2 mL) at -78°C, and the mixture was stirred at -78°C for 2 hours. Dry ice (1 g) was then added to the reaction mixture, and the mixture was stirred at room temperature for 2 hours. Water and 1N aqueous sodium hydroxide solution were added to the reaction mixture, and the aqueous layer was washed with methyl tert-butyl ether. 1N aqueous hydrochloric acid was added to the aqueous layer to adjust the pH of the aqueous layer to 1, and the mixture was then extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the title compound (306 mg). HPLC retention time (min): 0.89 (TFA); MS(ESI, Pos.):213(M+H) + .

[0170] Reference Example 26: 4H-pyrano[3,4-d]thiazol-7-one To a solution of 2-amino-4H-pyrano[3,4-d]thiazol-7-one (CAS number: 1253281-38-7, 873 mg) in THF (17.5 mL) was added n-pentyl nitrite (CAS number: 463-04-7, 0.97 mL) and the mixture was stirred at 60°C for 15 hours. Water 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 residue was purified by silica gel column chromatography to give the title compound (568 mg). TLC: Rf 0.28 (ethyl acetate:n-hexane=1:2).

[0171] Reference Example 27: 7-Methylene-4H-pyrano[3,4-d]thiazole To a solution of methyltriphenylphosphonium bromide (CAS number: 1779-49-3, 253 mg) in THF (1.5 mL) was added 1.3 N lithium bis(trimethylsilyl)amide THF solution (CAS number: 4039-32-1, 0.55 mL) at 0°C, and the mixture was stirred at 0°C for 1 hour. Then, the compound prepared in Reference Example 26 (100 mg) was added, and the mixture was stirred at 0°C for 40 minutes. A saturated aqueous ammonium chloride 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 then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to give the title compound (90 mg). TLC: Rf 0.5 (ethyl acetate:n-hexane=1:2).

[0172] Reference Example 28: 7-Methyl-6,7-dihydro-4H-pyrano[3,4-d][1,3]thiazole To a solution of the compound prepared in Reference Example 27 in methanol (1.8 mL), 20% palladium hydroxide (10 mg) was added and the mixture was 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 give the title compound (40 mg).

[0173] 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) was added 1.6 M n-butyllithium hexane solution (0.16 mL) at -78°C, and the mixture was stirred at -78°C for 1 hour. Dry ice (300 mg) was then added to the reaction mixture, and the mixture was stirred at room temperature for 1 hour. Water and 1N aqueous sodium hydroxide solution were added to the reaction mixture, and the aqueous layer was washed with methyl tert-butyl ether. 1N aqueous hydrochloric acid was added to the aqueous layer to adjust the pH of the aqueous layer to 1, and the aqueous layer was then extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the title compound (20 mg). HPLC retention time (min): 0.76 (TFA); MS (ESI, Pos.): 200 (M+H) + .

[0174] Reference Example 30: Methyl 5-hydroxy-2-thiophenecarboxylate To a solution of thiophene-2-carboxylic acid methyl ester-5-boronic acid (CAS number: 876189-21-8, 120 mg) in polyethylene glycol 200 (CAS number: 25322-68-3, 0.64 mL) was added 30% aqueous hydrogen peroxide solution (CAS number: 7722-84-1, 0.11 mL) and stirred at room temperature for 2 hours. Water was added to the reaction solution, and the mixture was 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 give the title compound (23 mg). HPLC retention time (min): 0.84 (TFA); MS (ESI, Pos.): 171 (M+Na) + .

[0175] Reference Example 31: Methyl 5-(difluoromethoxy)-2-thiophenecarboxylate To a solution of the compound prepared in Reference Example 30 (23 mg) in DMF (0.2 mL) were added chlorodifluoroacetic acid (CAS number: 76-04-0, 0.027 mL) and cesium carbonate (CAS number: 534-17-8, 142 mg), and the mixture was stirred at 100°C for 10 minutes. Water 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 residue was purified by silica gel column chromatography to give the title compound (31 mg). HPLC retention time (min): 1.06 (TFA); MS(ESI, Pos.):209(M+H) + .

[0176] Reference Example 32: 5-(Difluoromethoxy)-2-thiophenecarboxylic acid Methanol (0.1 mL) and 1N aqueous lithium hydroxide solution (CAS number: 1310-65-2, 0.2 mL) were added to a solution of the compound (31 mg) prepared in Reference Example 31 in THF (0.2 mL), and the mixture was stirred at room temperature for 16 hours. 1N aqueous hydrochloric acid was added to the reaction mixture to adjust the pH of the aqueous layer to 1, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure to give the title compound (21 mg). HPLC retention time (min): 0.91 (TFA); MS(ESI, Pos.):195(M+H) + .

[0177] Reference Example 33: Methyl 3-iodo-1H-thieno[3,2-c]pyrazole-5-carboxylate Potassium hydroxide (CAS number: 1310-58-3, 140 mg) and iodine (CAS number: 7553-56-2, 570 mg) were added to a solution of methyl 1H-thieno[3,2-c]pyrazole-5-carboxylate (CAS number: 1246552-43-1, 185 mg) in DMF (2 mL), and the mixture was stirred at 0°C for 1 hour. To the reaction mixture, 2N hydrochloric acid and saturated aqueous sodium thiosulfate were 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 give the title compound (180 mg).

[0178] Reference Example 34: Methyl 3-(3-hydroxy-1-propyn-1-yl)-1H-thieno[3,2-c]pyrazole-5-carboxylate To a solution of the compound prepared in Reference Example 33 (40 mg) in THF (1 mL), propargyl alcohol (CAS number: 107-19-7, 11 mg), copper(I) iodide (CAS number: 7681-65-4, 2.5 mg), tetrakis(triphenylphosphine)palladium(0) (CAS number: 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 solution, 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 residue was purified by silica gel column chromatography to give the title compound (23 mg). HPLC retention time (min): 0.84 (formic acid); MS(ESI, Pos.):237(M+H) + .

[0179] Reference Example 35: Methyl 3-(3-hydroxypropyl)-1H-thieno[3,2-c]pyrazole-5-carboxylate To a solution of the compound (23 mg) prepared in Reference Example 34 in methanol (1 mL) was added 20% palladium hydroxide (25 mg), and the mixture was stirred at room temperature under a hydrogen atmosphere for 6 hours. The reaction mixture was filtered and concentrated under reduced pressure, and the resulting title compound was used in the next reaction without purification.

[0180] 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 (18 mg) prepared in Reference Example 35 in toluene (0.5 mL) was added cyanomethylenetributylphosphorane (CAS number: 157141-27-0, 27 mg), and the mixture was stirred at 60° C. for 1 hour. The mixture was purified by silica gel column chromatography to obtain the title compound (10 mg). 1 H-NMR (CDCl3): δ7.85, 4.38, 3.83, 3.10, 2.73.

[0181] Reference Example 37: 7,8-Dihydro-6H-pyrrolo[1,2-b]thieno[2,3-d]pyrazole-2-carboxylic acid To a solution of the compound (20 mg) prepared in Reference Example 36 in methanol (1 mL) was added 2N aqueous sodium hydroxide solution (0.5 mL), and the mixture was stirred for 1 hour at 60° C. 1N hydrochloric acid was added to the reaction mixture, which was then 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.

[0182] Reference Example 38: Methyl 5-methyl-4-(1-methyl-1H-pyrazol-4-yl)-2-thiophenecarboxylate To a solution of methyl 4-bromo-5-methylthiophene-2-carboxylate (CAS number: 237385-15-8, 30 mg) in toluene (0.75 mL), water (0.37 mL), 1-methyl-1H-pyrazole-4-boronic acid (CAS number: 847818-55-7, 48 mg), cesium carbonate (124 mg), and tetrakis(triphenylphosphine)palladium(0) (15 mg) were added and 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 give the title compound (10 mg). HPLC retention time (min): 1.00 (formic acid); MS(ESI, Pos.):237(M+H) + .

[0183] Reference Example 39: 5-methyl-4-(1-methyl-1H-pyrazol-4-yl)-2-thiophenecarboxylic acid To a solution of the compound (20 mg) prepared in Reference Example 38 in methanol (1 mL) was added 2N aqueous sodium hydroxide solution (0.5 mL), and the mixture was stirred for 1 hour at 60° C. 1N hydrochloric acid was added to the reaction mixture, which was then extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The title compound obtained was used in the next reaction without purification.

[0184] 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 stirred at room temperature for 3 hours. 2N 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 residue was purified by silica gel column chromatography to give the title compound (10 mg). 1 H-NMR (CDCl3): δ7.69, 3.95, 3.89, 2.52.

[0185] Reference Example 41: 2,3-dimethyl-2H-thieno[2,3-c]pyrazole-5-carboxylic acid To a solution of the compound (20 mg) prepared in Reference Example 40 in methanol (1 mL) was added 2N aqueous sodium hydroxide solution (0.5 mL), and the mixture was stirred for 1 hour at 60° C. 1N hydrochloric acid was added to the reaction mixture, which was then extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The title compound obtained was used in the next reaction without purification.

[0186] Reference Example 42: Methyl 2-methyl-2H-thieno[3,2-c]pyrazole-5-carboxylate Cesium carbonate (7.2 g) and iodomethane (1.6 g) were added to a solution of methyl 1H-thieno[3,2-c]pyrazole-5-carboxylate (2.0 g) in THF (40 mL) and the mixture was stirred at room temperature for 3 hours. 2N 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 residue was purified by silica gel column chromatography to give the title compound (1.05 g). 1 H-NMR (CDCl3): δ7.70, 7.66, 4.06, 3.93.

[0187] Reference Example 43: 2-methyl-2H-thieno[3,2-c]pyrazole-5-carboxylic acid To a solution of the compound (20 mg) prepared in Reference Example 42 in methanol (1 mL) was added 2N aqueous sodium hydroxide solution (0.5 mL), and the mixture was stirred for 1 hour at 60° C. 1N hydrochloric acid was added to the reaction mixture, which was then 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.

[0188] 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 number: 873072-42-5, 940 mg), sodium carbonate (CAS number: 497-19-8, 1200 mg), copper(II) acetate (CAS number: 142-71-2, 1.1 g), and 1,10-phenanthroline (CAS number: 66-71-7, 1.1 g) were added and stirred at 70°C for 15 hours. 1N hydrochloric acid was added to the reaction solution, 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 give the title compound (200 mg). HPLC retention time (min): 1.00 (formic acid); MS(ESI, Pos.):223(M+H) + .

[0189] Reference Example 45: 2-Cyclopropyl-2H-thieno[3,2-c]pyrazole-5-carboxylic acid To a solution of the compound prepared in Reference Example 44 (20 mg) in methanol (1 mL) was added 2N aqueous sodium hydroxide solution (0.5 mL), and the mixture was stirred for 1 hour at 60° C. 1N hydrochloric acid was added to the reaction mixture, which was then extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The title compound obtained was used in the next reaction without purification.

[0190] 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 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 residue was purified by silica gel column chromatography to give the title compound (85 mg).

[0191] Reference Example 47: 2-(Difluoromethyl)-2H-thieno[3,2-c]pyrazole-5-carboxylic acid To a solution of the compound (20 mg) prepared in Reference Example 46 in methanol (1 mL) was added 2N aqueous sodium hydroxide solution (0.5 mL), and the mixture was stirred for 1 hour at 60° C. 1N hydrochloric acid was added to the reaction mixture, which was then extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The title compound obtained was used in the next reaction without purification.

[0192] 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 Cesium carbonate (720 mg) and 2,2,2-trifluoroethyl trifluoromethanesulfonate (CAS number: 6226-25-1, 510 mg) were added to a solution of methyl 1H-thieno[3,2-c]pyrazole-5-carboxylate (200 mg) in DMF (5 mL) and stirred at room temperature for 15 hours. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to give the title compounds (1) 61 mg and (2) 71 mg, respectively. (1) TLC: Rf 0.31 (ethyl acetate: n-hexane = 1:3); (2) TLC: Rf 0.34 (ethyl acetate:n-hexane=1:3).

[0193] Reference Example 49: 2-(2,2,2-trifluoroethyl)-2H-thieno[3,2-c]pyrazole-5-carboxylic acid To a solution of the compound (60 mg) prepared in Reference Example 48(1) in methanol (1 mL) was added 2N aqueous sodium hydroxide solution (0.5 mL), and the mixture was stirred for 1 hour at 60° C. 1N hydrochloric acid was added to the reaction mixture, which was then extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The title compound obtained was used in the next reaction without purification.

[0194] Reference Example 50: 1-(2,2,2-trifluoroethyl)-1H-thieno[3,2-c]pyrazole-5-carboxylic acid To a solution of the compound (60 mg) prepared in Reference Example 48(2) in methanol (1 mL) was added 2N aqueous sodium hydroxide solution (0.5 mL), and the mixture was stirred for 1 hour at 60° C. 1N hydrochloric acid was added to the reaction mixture, which was then extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The title compound obtained was used in the next reaction without purification.

[0195] Reference Example 51: 2,3-dimethyl-2H-thieno[3,2-c]pyrazole-5-carboxylic acid The same procedure as in Reference Example 40 → Reference Example 41 was carried out 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 to obtain the title compound.

[0196] Example 3: 2-{[(3aS,4R,6aR)-4-[(6-bromo-3-pyridazinyl)amino]hexahydrocyclopenta[c]pyrrol-2(1H)-yl]carbonyl}-4-methyl-6,7-dihydrothieno[3,2-b]pyridin-5(4H)-one [ka] To a solution of the compound prepared in Reference Example 12 (5 mg) and the compound prepared in Reference Example 17 (9.2 mg) in DMA (0.25 mL), DIPEA (0.016 mL) and HATU (10 mg) were added and stirred at room temperature for 3 hours. Water was added to the reaction solution, and the mixture was extracted with dichloromethane. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to give the title compound (4.7 mg). HPLC retention time (min): 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.

[0197] Examples 3-1 to 3-14 The same operation as in Example 3 was carried out 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 the compound prepared in Reference Example 10 instead of the compound prepared in Reference Example 12 or the compound prepared in Reference Example 12, to obtain the title compound.

[0198] Example 3-1: [(3aS,4R,6aR)-4-[(6-bromo-3-pyridazinyl)amino]hexahydrocyclopenta[c]pyrrol-2(1H)-yl](6,7-dihydro-5H-thieno[3,2-b]pyran-2-yl)methanone [ka] HPLC retention time (min): 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.

[0199] Example 3-2: Methyl 2-{[(3aS,4R,6aR)-4-[(6-bromo-3-pyridazinyl)amino]hexahydrocyclopenta[c]pyrrol-2(1H)-yl]carbonyl}-6,7-dihydrothieno[3,2-c]pyridine-5(4H)-carboxylate [ka] HPLC retention time (min): 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.

[0200] Example 3-3: [(3aS,4R,6aR)-4-[(6-chloro-3-pyridazinyl)amino]hexahydrocyclopenta[c]pyrrol-2(1H)-yl](4,4-dimethyl-6,7-dihydro-4H-thieno[3,2-c]pyran-2-yl)methanone

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[0201] Example 3-4: [(3aS,4R,6aR)-4-[(6-chloro-3-pyridazinyl)amino]hexahydrocyclopenta[c]pyrrol-2(1H)-yl](7-methyl-6,7-dihydro-4H-pyrano[3,4-d][1,3]thiazol-2-yl)methanone

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[0202] Example 3-5: [(3aS,4R,6aR)-4-[(6-chloro-3-pyridazinyl)amino]hexahydrocyclopenta[c]pyrrol-2(1H)-yl][5-(difluoromethoxy)-2-thienyl]methanone

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[0203] Example 3-6: [(3aS,4R,6aR)-4-[(6-bromo-3-pyridazinyl)amino]hexahydrocyclopenta[c]pyrrol-2(1H)-yl](7,8-dihydro-6H-pyrrolo[1,2-b]thieno[2,3-d]pyrazol-2-yl)methanone

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[0204] Example 3-7: [(3aS,4R,6aR)-4-[(6-bromo-3-pyridazinyl)amino]hexahydrocyclopenta[c]pyrrol-2(1H)-yl][5-methyl-4-(1-methyl-1H-pyrazol-4-yl)-2-thienyl]methanone

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[0205] Example 3-8: [(3aS,4R,6aR)-4-[(6-bromo-3-pyridazinyl)amino]hexahydrocyclopenta[c]pyrrol-2(1H)-yl](2,3-dimethyl-2H-thieno[2,3-c]pyrazol-5-yl)methanone

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[0206] Example 3-9: [(3aS,4R,6aR)-4-[(6-bromo-3-pyridazinyl)amino]hexahydrocyclopenta[c]pyrrol-2(1H)-yl](2-methyl-2H-thieno[3,2-c]pyrazol-5-yl)methanone

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[0207] Example 3-10: [(3aS,4R,6aR)-4-[(6-bromo-3-pyridazinyl)amino]hexahydrocyclopenta[c]pyrrol-2(1H)-yl](2-cyclopropyl-2H-thieno[3,2-c]pyrazol-5-yl)methanone

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[0208] Example 3-11: [(3aS,4R,6aR)-4-[(6-bromo-3-pyridazinyl)amino]hexahydrocyclopenta[c]pyrrol-2(1H)-yl][2-(difluoromethyl)-2H-thieno[3,2-c]pyrazol-5-yl]methanone

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[0209] Example 3-12: [(3aS,4R,6aR)-4-[(6-bromo-3-pyridazinyl)amino]hexahydrocyclopenta[c]pyrrol-2(1H)-yl][1-(2,2,2-trifluoroethyl)-1H-thieno[3,2-c]pyrazol-5-yl]methanone

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[0210] Example 3-13: [(3aS,4R,6aR)-4-[(6-bromo-3-pyridazinyl)amino]hexahydrocyclopenta[c]pyrrol-2(1H)-yl][2-(2,2,2-trifluoroethyl)-2H-thieno[3,2-c]pyrazol-5-yl]methanone

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[0211] Example 3-14: [(3aS,4R,6aR)-4-[(6-bromo-3-pyridazinyl)amino]hexahydrocyclopenta[c]pyrrol-2(1H)-yl](2,3-dimethyl-2H-thieno[3,2-c]pyrazol-5-yl)methanone [ka] HPLC retention time (min): 0.91 (formic acid); MS(ESI, Pos.):461(M+H) + .

[0212] Reference Example 52: 1-(5-((3aS,4R,6aR)-4-((6-bromopyridazin-3-yl)amino)octahydrocyclopenta[c]pyrrole-2-carbonyl)thiophen-2-yl)ethan-1-one To a solution of the compound (10 mg) prepared in Reference Example 12 in DMA (0.25 mL) were added 5-acetylthiophene-2-carboxylic acid (CAS: 4066-41-5, 6.0 mg), DIPEA (0.030 mL), and HATU (20 mg), and the mixture was stirred at room temperature for 3 hours. Water was added to the reaction mixture, and the mixture was extracted with dichloromethane. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to give the title compound (15 mg).

[0213] Example 4: [(3aS,4R,6aR)-4-[(6-bromo-3-pyridazinyl)amino]hexahydrocyclopenta[c]pyrrol-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) was added 3 M methylmagnesium bromide (CAS: 75-16-1, 0.03 mL) and the mixture was stirred at room temperature for 3 hours. Water was added to the reaction mixture, and the mixture was extracted with dichloromethane. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to give the title compound (1.3 mg). HPLC retention time (min): 0.89 (formic acid); MS(ESI, Pos.):451(M+H) + .

[0214] Example 5: [(3aS,4R,6aR)-4-[(6-iodo-3-pyridazinyl)amino]hexahydrocyclopenta[c]pyrrol-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 the mixture was extracted with dichloromethane. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to give the title compound (7.6 mg). HPLC retention time (min): 0.88 (TFA); MS(ESI, Pos.):455(M+H) + .

[0215] Example 6: rel-{(3aS,4R,6aR)-4-[(6-bromo-3-pyridazinyl)(methyl)amino]hexahydrocyclopenta[c]pyrrol-2(1H)-yl}(5-methyl-2-thienyl)methanone Racemic Mixture [ka] The title compound was obtained by carrying out the same procedures as in Example 2→Reference Example 16, except that the compound prepared in Reference Example 12-1 was used instead of the compound prepared in Reference Example 12. HPLC retention time (min): 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.

[0216] Examples 6-1 to 6-9 The same operations as in Example 2 → Reference Example 16 were carried out using iodomethane or a corresponding halogen compound instead of iodomethane, a corresponding carboxylic acid instead of 5-methyl-2-thiophenecarboxylic acid or 5-methyl-2-thiophenecarboxylic acid, and a compound prepared in Reference Example 10-1 or a compound prepared in Reference Example 12-1 instead of a compound prepared in Reference Example 12, to obtain the title compound.

[0217] Example 6-1: rel-{(3aS,4R,6aR)-4-[(6-bromo-3-pyridazinyl)(butyl)amino]hexahydrocyclopenta[c]pyrrol-2(1H)-yl}(5-methyl-2-thienyl)methanone Racemic mixture [ka] HPLC retention time (min): 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.

[0218] Example 6-2: [(3aS,4R,6aR)-4-[benzyl(6-bromo-3-pyridazinyl)amino]hexahydrocyclopenta[c]pyrrol-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.

[0219] Example 6-3: [(3aS,4R,6aR)-4-[(6-bromo-3-pyridazinyl)(methyl)amino]hexahydrocyclopenta[c]pyrrol-2(1H)-yl](6,7-dihydro-4H-thieno[3,2-c]pyran-2-yl)methanone

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[0220] Example 6-4: rel-{(3aS,4R,6aR)-4-[(6-chloro-3-pyridazinyl)(3-methoxypropyl)amino]hexahydrocyclopenta[c]pyrrol-2(1H)-yl}[5-(difluoromethyl)-2-thienyl]methanone Racemic mixture

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[0221] Example 6-5: rel-{(3aS,4R,6aR)-4-[(6-chloro-3-pyridazinyl)(imidazo[2,1-b][1,3]thiazol-6-ylmethyl)amino]hexahydrocyclopenta[c]pyrrol-2(1H)-yl}[5-(difluoromethyl)-2-thienyl]methanone Racemic mixture

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[0222] Example 6-6: rel-{(3aS,4R,6aR)-4-[(6-chloro-3-pyridazinyl)(4-pyridinylmethyl)amino]hexahydrocyclopenta[c]pyrrol-2(1H)-yl}[5-(difluoromethyl)-2-thienyl]methanone Racemic mixture

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[0223] Examples 6-7: rel-2-{[(6-chloro-3-pyridazinyl)((3aS,4R,6aR)-2-{[5-(difluoromethyl)-2-thienyl]carbonyl}octahydrocyclopenta[c]pyrrol-4-yl)amino]methyl}benzonitrile Racemic mixture

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[0224] Examples 6-8: [(3aS,4R,6aR)-4-[(6-bromo-3-pyridazinyl)(3-fluoropropyl)amino]hexahydrocyclopenta[c]pyrrol-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.

[0225] Example 6-9: [(3aS,4R,6aR)-4-[(6-bromo-3-pyridazinyl)(methyl)amino]hexahydrocyclopenta[c]pyrrol-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.

[0226] Reference Example 53: rel-(3aS,6aR)-hexahydrocyclopenta[c]pyrrol-4(1H)-one hydrochloride racemic mixture The title compound was obtained by carrying out the same procedures as in Reference Example 4→Reference Example 10, using the compound prepared in Reference Example 1 instead of the compound prepared in Reference Example 3.

[0227] Reference Example 53-1: (3aS,6aR)-hexahydrocyclopenta[c]pyrrol-4(1H)-one hydrochloride The title compound was obtained by the same procedure as in Reference Example 10, except that the compound prepared in Reference Example 3 was used instead of the compound prepared in Reference Example 9.

[0228] Reference Example 54: rel-(3aS,6aR)-2-(5-methylthiophene-2-carbonyl)hexahydrocyclopenta[c]pyrrol-4(1H)-one racemic mixture To a solution of the compound (5.0 g) prepared in Reference Example 53 and 5-methyl-2-thiophenecarboxylic acid (6.6 g) in DMA (100 mL), DIPEA (22 mL) and HATU (17.6 g) were added and stirred at room temperature for 3 hours. 2N hydrochloric acid was added to the reaction mixture, and the mixture was extracted with dichloromethane. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to give the title compound (7.0 g). HPLC retention time (min): 0.88 (formic acid); MS (ESI, Pos.): 250 (M+H) + .

[0229] Reference Example 54-1: (3aS,6aR)-2-(5-methylthiophene-2-carbonyl)hexahydrocyclopenta[c]pyrrol-4(1H)-one The title compound was obtained by the same procedure as in Reference Example 54, except that the compound prepared in Reference Example 53-1 was used instead of the compound prepared in Reference Example 53.

[0230] Reference Example 55: (rel-(3aS,4R,6aR)-4-(cyclopropylamino)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)(5-methylthiophen-2-yl)methanone Racemic mixture To a solution of the compound prepared in Reference Example 54 (300 mg) in dichloromethane (10 mL), cyclopropylamine (CAS: 765-30-0, 0.25 mL) and acetic acid (0.34 mL) were added and 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 solution, and the mixture was extracted with dichloromethane. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to give the title compound (22 mg). HPLC retention time (min): 0.78 (formic acid); MS(ESI, Pos.):291(M+H) + .

[0231] Example 7: rel-{(3aS,4R,6aR)-4-[(6-bromo-3-pyridazinyl)(cyclopropyl)amino]hexahydrocyclopenta[c]pyrrol-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. The reaction solution was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography to give the title compound (1.0 mg). HPLC retention time (min): 1.20 (formic acid); MS(ESI, Pos.):447(M+H) + .

[0232] Reference Example 56: (rel-(3aS,4S,6aR)-4-hydroxyhexahydrocyclopenta[c]pyrrol-2(1H)-yl)(5-methylthiophen-2-yl)methanone Racemic mixture To a solution of the compound (1.4 g) prepared in Reference Example 54 in THF (42 mL) was added 1 M lithium tri-sec-butylborohydride THF solution (8.5 mL) at -78°C, and the mixture was stirred at -78°C for 1 hour. A 35% aqueous solution of hydrogen peroxide was slowly added to the reaction mixture at 0°C until bubbling ceased, followed by extraction 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 yield the title compound (600 mg). HPLC retention time (min): 0.86 (TFA); MS(ESI, Pos.):252(M+H) + .

[0233] Reference Example 57: rel-(3aS,4S,6aR)-2-(5-methylthiophene-2-carbonyl)octahydrocyclopenta[c]pyrrol-4-yl 4-methylbenzenesulfonate racemic mixture To a solution of the compound (3.6 g) prepared in Reference Example 56 in dichloromethane (70 mL) were added triethylamine (4 mL), p-toluenesulfonyl chloride (4.1 g) and trimethylamine hydrochloride (280 mg), and the mixture was heated at room temperature. Stir with The mixture was stirred. A saturated aqueous solution of sodium bicarbonate was added to the reaction mixture, and the mixture was extracted with dichloromethane. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to give the title compound (3.6 g). HPLC retention time (min): 1.16 (TFA); MS(ESI, Pos.):406(M+H) + .

[0234] Example 8: rel-[(3aS,4R,6aR)-4-(3-chloro-5,6-dihydro-7H-pyrrolo[2,3-c]pyridazin-7-yl)hexahydrocyclopenta[c]pyrrol-2(1H)-yl](5-methyl-2-thienyl)methanone Racemic Mixture [ka] To a solution of the compound (10 mg) produced 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, followed by stirring for 20 hours at 50° C. Water was added to the reaction mixture, which was then purified by reverse phase column chromatography to give the title compound (1.3 mg). HPLC retention time (min): 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.

[0235] Examples 8-1 to 8-4 The title compound was obtained by the same procedure as in Example 8, except that the corresponding amine compound was used instead of 3-chloro-6,7-dihydro-5H-pyrrolo[2,3-c]pyridazine.

[0236] Example 8-1: rel-[(3aS,4R,6aR)-4-(3-chloro-7H-pyrrolo[2,3-c]pyridazin-7-yl)hexahydrocyclopenta[c]pyrrol-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.

[0237] Example 8-2: rel-{(3aS,4R,6aR)-4-[(6-chloro-4-methoxy-3-pyridazinyl)amino]hexahydrocyclopenta[c]pyrrol-2(1H)-yl}(5-methyl-2-thienyl)methanone Racemic mixture

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[0238] Example 8-3: rel-((3aS,4R,6aR)-4-((6-chloropyridin-3-yl)amino)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)(5-methylthiophen-2-yl)methanone Racemic mixture

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[0239] Example 8-4: rel-((3aS,4R,6aR)-4-((4,6-dichloropyridin-3-yl)amino)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)(5-methylthiophen-2-yl)methanone Racemic mixture

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[0240] Reference Example 58: rel-tert-butyl (3aS,4R,6aR)-4-((6-chloro-4-cyanopyridazin-3-yl)amino)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate racemic mixture The title compound was obtained by performing the same operations as in Reference Example 4 → Reference Example 5 → Reference Example 6 → Reference Example 7 → Reference Example 8 → Reference Example 9, using the compound prepared in Reference Example 1 instead of the compound prepared in Reference Example 3, and using 3,6-dichloropyridazine-4-carbonitrile (CAS number: 35857-93-3, 45 mg) instead of 3,6-dichloropyridazine.

[0241] Reference Example 59: rel-6-chloro-3-(((3aS,4R,6aR)-octahydrocyclopenta[c]pyrrol-4-yl)amino)pyridazine-4-carbonitrile Racemic mixture To the compound (100 mg) prepared in Reference Example 58, 4N hydrochloric acid (1,4-dioxane solution, 3 mL) was added, followed by stirring at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure to give the title compound (5 mg).

[0242] Example 9: rel-6-chloro-3-({(3aS,4R,6aR)-2-[(5-methyl-2-thienyl)carbonyl]octahydrocyclopenta[c]pyrrol-4-yl}amino)-4-pyridazinecarbonitrile Racemic Mixture [ka] The same procedure as in Example 2 was carried out except that the compound prepared in Reference Example 59 was used instead of the compound prepared in Reference Example 12 to obtain the title compound. 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.

[0243] Example 9-1 The same operations as in Reference Example 9 → Reference Example 10 → Example 1 were carried out using the corresponding halogen compound instead of 3,6-dichloropyridazine and the corresponding carboxylic acid instead of 5-(difluoromethyl)thiophene-2-carboxylic acid to obtain the title compound.

[0244] Example 9-1: [(3aS,4R,6aR)-4-{[6-chloro-4-(trifluoromethyl)-3-pyridazinyl]amino}hexahydrocyclopenta[c]pyrrol-2(1H)-yl](6,7-dihydro-4H-thieno[3,2-c]pyran-2-yl)methanone [ka] HPLC retention time (min): 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.

[0245] Reference Example 60: (1) [(R)-4-[tert-butyl(dimethyl)silyl]oxy-3,5,6,6a-tetrahydro-1H-cyclopenta[c]pyrrol-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]pyrrol-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 trifluoromethanesulfonate (CAS number: 69739-34-0, 2.0 mL) were added, and the mixture was stirred at 40°C for 2 hours. A saturated aqueous solution of sodium bicarbonate was added to the reaction mixture, and the mixture was extracted with dichloromethane. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to give the title compounds (1) (1.9 g) and (2) (1.0 g), respectively.

[0246] Reference Example 61: (3aR,6aS)-3a-fluoro-2-(5-methylthiophene-2-carbonyl)-3,5,6,6a-tetrahydro-1H-cyclopenta[c]pyrrol-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 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 give the title compound (540 mg). HPLC retention time (min): 0.95 (TFA); MS(ESI, Pos.):268(M+H) + .

[0247] Reference Example 62: [(3aR,4S,6aS)-3a-fluoro-4-hydroxy-1,3,4,5,6,6a-hexahydrocyclopenta[c]pyrrol-2-yl]-(5-methyl-2-thienyl)methanone Sodium borohydride (CAS number: 16940-66-2, 405 mg) was added to a solution of the compound (1.9 g) produced in Reference Example 61 in methanol (19 mL) and THF (19 mL) at 0°C, and the mixture was stirred at 0°C for 1 hour. Water 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 residue was purified by silica gel column chromatography to give the title compound (872 mg). HPLC retention time (min): 0.88 (TFA); MS(ESI, Pos.):270(M+H) + .

[0248] Reference Example 63: [(3aR,4R,6aS)-3a-fluoro-2-(5-methylthiophene-2-carbonyl)-1,3,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrol-4-yl] 4-methylbenzenesulfonate To a solution of the compound prepared in Reference Example 62 (872 mg) in dichloromethane (13 mL), triethylamine (1.4 mL), p-toluenesulfonyl chloride (1.2 g), and trimethylamine hydrochloride (154 mg) were added and stirred at room temperature for 23 hours. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to give the title compound (1.0 g). HPLC retention time (min): 1.16 (TFA); MS(ESI, Pos.):424(M+H) + .

[0249] Reference Example 64: [(3aR,4R,6aS)-4-Azido-3a-fluoro-1,3,4,5,6,6a-hexahydrocyclopenta[c]pyrrol-2-yl]-(5-methyl-2-thienyl)methanone Sodium azide (560 mg) was added to a solution of the compound (1.4 g) prepared in Reference Example 63 in dimethyl sulfoxide (13 mL), and the mixture was stirred at 100° C. for 90 hours. Water was added to the reaction mixture, and the mixture was extracted with dichloromethane. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The title compound obtained was used in the next reaction without purification. HPLC retention time (min): 1.08 (TFA); MS(ESI, Pos.):295(M+H) + .

[0250] Reference Example 65: [(3aR,4R,6aS)-4-amino-3a-fluoro-1,3,4,5,6,6a-hexahydrocyclopenta[c]pyrrol-2-yl]-(5-methyl-2-thienyl)methanone To a solution of the compound (892 mg) prepared in Reference Example 64 in ethanol (18 mL) was added 20% palladium hydroxide (1.8 g), and the mixture was stirred under a hydrogen atmosphere at room temperature for 15 hours. The reaction mixture was filtered and 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) + .

[0251] Example 10: [(3aR,4R,6aS)-4-[(6-bromopyridazin-3-yl)amino]-3a-fluoro-1,3,4,5,6,6a-hexahydrocyclopenta[c]pyrrol-2-yl]-(5-methyl-2-thienyl)methanone [ka] To a solution of the compound prepared in Reference Example 65 (470 mg) 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 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 residue was purified by silica gel column chromatography to give the title compound (141 mg). HPLC retention time (min): 1.00 (TFA); MS(ESI, Pos.):427(M+H) + .

[0252] Reference Example 66: (3aR,4R,6aS)-N-(6-bromo-3-pyridazinyl)-3a-fluorooctahydrocyclopenta[c]pyrrol-4-amine Methanol (1 mL) and 5N aqueous sodium hydroxide solution (1 mL) were added to a solution of the compound prepared in Example 10 (40 mg) in THF (2 mL), and the mixture was stirred at 50°C for 16 hours. Water 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.

[0253] Example 11: [(3aR,4R,6aS)-4-[(6-bromo-3-pyridazinyl)amino]-3a-fluorohexahydrocyclopenta[c]pyrrol-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 stirred at room temperature for 3 hours. 2N hydrochloric acid was added to the reaction mixture, and the mixture was extracted with dichloromethane. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to give 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.

[0254] Examples 11-1 to 11-3 The same procedure as in Example 11 was carried out using the corresponding carboxylic acid compound instead of 6,7-dihydro-4H-thieno[3,2-c]pyran-2-carboxylic acid to give the title compound.

[0255] Example 11-1: [(3aR,4R,6aS)-4-[(6-bromo-3-pyridazinyl)amino]-3a-fluorohexahydrocyclopenta[c]pyrrol-2(1H)-yl](2-cyclopropyl-2H-thieno[3,2-c]pyrazol-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.

[0256] Example 11-2: [(3aR,4R,6aS)-4-[(6-bromo-3-pyridazinyl)amino]-3a-fluorohexahydrocyclopenta[c]pyrrol-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.

[0257] Example 11-3: [(3aR,4R,6aS)-4-[(6-bromo-3-pyridazinyl)amino]-3a-fluorohexahydrocyclopenta[c]pyrrol-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.

[0258] Example 12: {(3aR,4R,6aS)-4-[(6-chloro-3-pyridazinyl)amino]-3a-fluorohexahydrocyclopenta[c]pyrrol-2(1H)-yl}(6,7-dihydro-4H-thieno[3,2-c]pyran-2-yl)methanone [ka] The same operations as in Example 10 → Reference Example 66 → Example 11 were carried out 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 to obtain the title compound. 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.

[0259] Reference Example 67: (3aS,5R,6aR)-5-fluoro-2-(5-methylthiophene-2-carbonyl)-1,3,3a,5,6,6a-hexahydrocyclopenta[c]pyrrol-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 stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure, and water was added to the resulting residue, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to give the title compound (633 mg). HPLC retention time (min): 0.81 (TFA); MS(ESI, Pos.):304(M+H) + .

[0260] Reference Example 68: [(3aS,4R,5R,6aR)-5-fluoro-4-hydroxy-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrol-2-yl]-(5-methyl-2-thienyl)methanone Sodium borohydride (106 mg) was added to a solution of the compound prepared in Reference Example 67 (500 mg) in methanol (10 mL) at 0°C, and the mixture was stirred at 0°C for 1 hour. Water 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 residue was purified by silica gel column chromatography to give the title compound (200 mg).

[0261] Reference Example 69: [(3aS,4R,5R,6aR)-5-fluoro-2-(5-methylthiophene-2-carbonyl)-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrol-4-yl] 4-methylbenzenesulfonate To a solution of the compound prepared in Reference Example 68 (120 mg) in acetonitrile (1.2 mL), DIPEA (0.23 mL), p-toluenesulfonyl chloride (127 mg), and trimethylamine hydrochloride (21 mg) were added and stirred at room temperature for 24 hours. Water was added to the reaction solution, and the mixture was extracted with dichloromethane. After concentration, the resulting residue was purified by silica gel column chromatography to give the title compound (190 mg). HPLC retention time (min): 1.13 (TFA); MS(ESI, Pos.):424(M+H) + .

[0262] Reference Example 70: [(3aS,4S,5R,6aR)-4-Azido-5-fluorohexahydrocyclopenta[c]pyrrol-2(1H)-yl](5-methyl-2-thienyl)methanone Sodium azide (145 mg) was added to a solution of the compound prepared in Reference Example 69 (190 mg) in dimethyl sulfoxide (0.8 mL), and the mixture was stirred at 100° C. for 17 hours. Water 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 (min): 1.05 (TFA); MS(ESI, Pos.):295(M+H) + .

[0263] Reference Example 71: [(3aS,4S,5R,6aR)-4-amino-5-fluoro-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrol-2-yl]-(5-methyl-2-thienyl)methanone To a solution of the compound prepared in Reference Example 70 in ethanol (2 mL), 20% palladium hydroxide (50 mg) was added and the mixture was stirred at room temperature for 2 hours under a hydrogen atmosphere. The reaction mixture was filtered and 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) + .

[0264] Example 13: [(3aS,4S,5R,6aR)-4-[(6-bromopyridazin-3-yl)amino]-5-fluoro-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrol-2-yl]-(5-methyl-2-thienyl)methanone [ka] DIPEA (0.19 mL) and 3-bromo-6-fluoropyridazine (132 mg) were added to a solution of the compound (50 mg) prepared in Reference Example 71 in 2-methyl-2-butanol (0.23 mL), and the mixture was stirred at 160° C. for 1 hour. The reaction solution 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.

[0265] Reference Example 72: (3aS,6aR)-2-(6,7-dihydro-4H-thieno[3,2-c]pyran-2-ylcarbonyl)hexahydrocyclopenta[c]pyrrol-4(1H)-one To a solution of the compound (2.8 g) prepared in Reference Example 53-1 in DMA (230 mL) were added 6,7-dihydro-4H-thieno[3,2-c]pyran-2-carboxylic acid (4.6 g), DIPEA (13 mL), and HATU (9.5 g), followed by stirring at room temperature for 3 hours. Water was added to the reaction mixture, which was then extracted with dichloromethane. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to give the title compound (4.1 g).

[0266] Reference Example 73: [(3aS,6aR)-6-{[dimethyl(2-methyl-2-propanyl)silyl]oxy}-3,3a,4,6a-tetrahydrocyclopenta[c]pyrrol-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. A saturated aqueous solution of sodium bicarbonate was added to the reaction mixture, 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 title compound was used in the next reaction without purification.

[0267] Reference Example 74: (3aS,5R,6aR)-2-(6,7-dihydro-4H-thieno[3,2-c]pyran-2-ylcarbonyl)-5-methylhexahydrocyclopenta[c]pyrrol-4(1H)-one To a DMF (10 mL) solution of the compound prepared in Reference Example 73, iodomethane (9.5 g) and 1 M tetra-N-butylammonium fluoride (CAS number: 429-41-4, 0.74 mL, THF solution) were added and stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure, and water was added to the resulting residue, which was then 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 residue was purified by silica gel column chromatography to give the title compound (100 mg).

[0268] Example 14: [(3aS,4R,5R,6aR)-4-[(6-bromo-3-pyridazinyl)amino]-5-methylhexahydrocyclopenta[c]pyrrol-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 procedures as in Reference Example 62 → Reference Example 63 → Reference Example 64 → Reference Example 65 → Example 10 were carried out 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.

[0269] 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'-cyclopropan]-4-one To a solution of the compound prepared in Reference Example 72 (300 mg) in dimethyl sulfoxide (7.5 mL), 1,8-diazabicyclo[5.4.0]undec-7-ene (CAS number: 6674-22-2, 0.31 mL) and diphenylvinylsulfonium triflate (CAS number: 247129-88-0, 410 mg) were added and stirred at room temperature for 1 hour. Water and 1N aqueous hydrochloric acid were added to the reaction solution, 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 purified by silica gel column chromatography to give the title compound (100 mg). HPLC retention time (min): 0.90 (TFA); MS(ESI, Pos.):318(M+H) + .

[0270] Reference Example 76: [(3aS,4R,6aR)-4-hydroxyspiro[1,3,3a,4,6,6a-hexahydrocyclopenta[c]pyrrole-5,1'-cyclopropan]-2-yl]-(6,7-dihydro-4H-thieno[3,2-c]pyran-2-yl)methanone Sodium borohydride (25 mg) was added to a solution of the compound prepared in Reference Example 75 (138 mg) in methanol (2.8 mL) at 0°C, and the mixture was stirred at 0°C for 30 minutes. Water was added to the reaction mixture, and the mixture was extracted with dichloromethane. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to give the title compound (95 mg). HPLC retention time (min): 0.91 (TFA); MS(ESI, Pos.):320(M+H) + .

[0271] Reference Example 77: [(3aS,4S,6aR)-4-azidospiro[1,3,3a,4,6,6a-hexahydrocyclopenta[c]pyrrole-5,1'-cyclopropan]-2-yl]-(6,7-dihydro-4H-thieno[3,2-c]pyran-2-yl)methanone To a solution of the compound prepared in Reference Example 76 (95 mg) in THF (0.2 mL), triphenylphosphine (CAS number: 603-35-0, 102 mg), 2.2 M diethyl azodicarboxylate solution (CAS number: 1972-28-7, 0.18 mL), and diphenylphosphoryl azide (CAS number: 26386-88-9, 82 mg) were added and 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) + .

[0272] Reference Example 78: [(3aS,4S,6aR)-4-aminospiro[1,3,3a,4,6,6a-hexahydrocyclopenta[c]pyrrole-5,1'-cyclopropan]-2-yl]-(6,7-dihydro-4H-thieno[3,2-c]pyran-2-yl)methanone To a solution of the compound (43 mg) prepared in Reference Example 77 in methanol (1 mL) was added 20% palladium hydroxide (20 mg), and the mixture was stirred at room temperature under a hydrogen atmosphere for 30 minutes. 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) + .

[0273] Example 15: [(3aS,4S,6aR)-4-[(6-bromopyridazin-3-yl)amino]spiro[1,3,3a,4,6,6a-hexahydrocyclopenta[c]pyrrole-5,1′-cyclopropan]-2-yl]-(6,7-dihydro-4H-thieno[3,2-c]pyran-2-yl)methanone [ka] To a solution of the compound prepared in Reference Example 78 (17 mg) 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 the mixture was extracted with dichloromethane. The organic layer was purified by silica gel column chromatography to give 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.

[0274] Reference Example 79: 2-Methyl-2-propanyl rel-[(3aS,4R,6aR)-2-benzyl-6-oxooctahydrocyclopenta[c]pyrrol-4-yl]carbamate racemic mixture To a solution (20 mL) of N-benzyl-N-(methoxymethyl)-N-trimethylsilylmethylamine (3.6 g) in dichloromethane, tert-butyl N-(4-oxocyclopent-2-en-1-yl)carbamate (CAS number: 657396-97-9, 17 g) and trifluoroacetic acid (58 mg) were added and stirred at room temperature for 16 hours. Triethylamine (430 mg) was added to the reaction mixture, which was then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to give the title compound (300 mg). HPLC retention time (min): 0.86 (TFA); MS(ESI, Pos.):331(M+H) + .

[0275] Reference Example 80: 2-Methyl-2-propanyl rel-[(3aS,4R,6aR)-2-benzyl-6,6-difluorooctahydrocyclopenta[c]pyrrol-4-yl]carbamate racemic mixture To a solution of the compound prepared in Reference Example 79 (300 mg) in dichloromethane (5 mL) was added bis(2-methoxyethyl)aminosulfur trifluoride (CAS number: 202289-38-1, 1.2 g) at 0°C and stirred at room temperature for 15 hours. A saturated aqueous solution of sodium bicarbonate was added to the reaction solution, and the mixture was extracted with dichloromethane. The mixture was washed with saturated brine, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to give the title compound (120 mg). HPLC retention time (min): 0.91 (TFA); MS(ESI, Pos.):353(M+H) + .

[0276] Reference Example 81: 2-Methyl-2-propanyl rel-[(3aS,4R,6aR)-6,6-difluorooctahydrocyclopenta[c]pyrrol-4-yl]carbamate racemic mixture To a solution of the compound prepared in Reference Example 80 (120 mg) in ethanol (10 mL), 20% palladium hydroxide (120 mg) was added and stirred at room temperature under a hydrogen atmosphere for 2 hours. The reaction solution was filtered and concentrated under reduced pressure. The resulting residue was used in the next reaction without purification.

[0277] 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]pyrrol-4-yl]carbamate racemic mixture To a solution of the compound prepared in Reference Example 81 in DMA (3 mL), 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 stirred at room temperature for 3 hours. Water was added to the reaction mixture, and the mixture was extracted with dichloromethane. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to give the title compound (100 mg). HPLC retention time (min): 1.00 (formic acid); MS(ESI, Pos.):429(M+H) + .

[0278] Reference Example 83: rel-[(3aR,6R,6aS)-6-amino-4,4-difluorohexahydrocyclopenta[c]pyrrol-2(1H)-yl](6,7-dihydro-4H-thieno[3,2-c]pyran-2-yl)methanone Racemic mixture To the compound (100 mg) prepared in Reference Example 82, 4N hydrochloric acid (1,4-dioxane solution, 3 mL) was added, followed by stirring at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure to give the title compound (80 mg).

[0279] Example 16: [(3aR,6R,6aS)-6-[(6-bromo-3-pyridazinyl)amino]-4,4-difluorohexahydrocyclopenta[c]pyrrol-2(1H)-yl](6,7-dihydro-4H-thieno[3,2-c]pyran-2-yl)methanone [ka] To a solution of the compound (80 mg) prepared in Reference Example 83 in DMA (1 mL) were added DIPEA (0.24 mL) and 3,6-dibromopyridazine (120 mg), and the mixture was stirred at 160°C for 1 hour. Water was added to the reaction mixture, and the mixture was extracted with dichloromethane. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography, and the two diastereomers were separated using supercritical fluid chromatography (CHIRALPAK IC, CO2:methanol = 70:30) to obtain the less polar form (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.

[0280] Reference Example 84: 2-Bromo-5-[2-(2-fluoroethoxy)ethyl]thiophene To a solution of 2-(5-bromothiophen-2-yl)ethan-1-ol (CAS number: 57070-78-7, 653 mg) in dimethylacetamide (15 mL), 1-iodo-2-fluoroethane (CAS number: 762-51-6, 1.52 mL) and sodium hydride (757 mg) were added and stirred at room temperature for 17 hours. The mixture was then stirred at 60°C for 24 hours. Water was added to the reaction mixture, which was then 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 give 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.

[0281] Reference Example 85: 5-[2-(2-fluoroethoxy)ethyl]-2-thiophenecarboxylic acid To a solution of the compound prepared in Reference Example 84 (396 mg) in THF (1 mL) was added water (0.135 mL), trans-bisacetatobis[2-(di-O-tolylphosphino)benzyl]dipalladium(II) (CAS number: 172418-32-5, 141 mg), DBU (0.673 mL), tri-tert-butylphosphonium tetrafluoroborate (CAS number: 131274-22-1, 43 mg), and molybdenum hexacarbonyl (CAS number: 13939-06-5, 595 mg). The reaction mixture was heated at 120°C for 1 hour. 1M aqueous hydrochloric acid and ethyl acetate were added to the reaction mixture, followed by filtration. 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 yield 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.

[0282] Reference Example 86: [(3aS,4R,6aR)-4-[(6-bromo-3-pyridazinyl)amino]hexahydrocyclopenta[c]pyrrol-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 1H-benzotriazol-1-yloxytripyrrolidinophosphonium hexafluorophosphate (hereinafter referred to as PyBOP, 22 mg, CAS number: 128625-52-5) were added and stirred at room temperature for 1 hour. Water was added to the reaction solution, and the mixture was extracted with dichloromethane. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to give the title compound (5.0 mg). HPLC retention time (min): 0.88 (TFA); MS(ESI, Pos.):483(M+H) + .

[0283] Example 17: [(3aS,4R,6aR)-4-[(6-bromo-3-pyridazinyl)(methyl)amino]hexahydrocyclopenta[c]pyrrol-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 further stirred at room temperature for 1 hour. Water was added to the reaction mixture, which was then 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 give 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.

[0284] Reference Example 87: 5-(2-fluoroethoxy)-2-thiophenecarboxylic acid Sodium hydride (1313 mg) was added to a solution of 2-fluoroethanol (CAS number: 371-62-0, 1578 mg) in DMA (15 mL) at room temperature, followed by the addition of 5-fluorothiophene-2-carboxylic acid (CAS number: 4377-58-6, 600 mg). The reaction mixture was stirred at 100°C for 2 days. Water was added to the reaction mixture, which was then 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 number: 18107-18-1, 1 mL) was added. The mixture was stirred at room temperature for 1 hour. The reaction mixture was purified by silica gel column chromatography to obtain the methyl ester compound (60 mg). The resulting methyl ester compound (60 mg) was dissolved in methanol (4 mL), and then 2 M aqueous sodium hydroxide solution (1.5 mL) was added. The reaction mixture was stirred at 50°C for 18 hours. To the reaction mixture was added 1M hydrochloric acid, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give 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.

[0285] Reference Example 88: [(3aS,4R,6aR)-4-[(6-bromo-3-pyridazinyl)amino]hexahydrocyclopenta[c]pyrrol-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 stirred at room temperature for 1 hour. Water was added to the reaction mixture, and the mixture was extracted with dichloromethane. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to give the title compound (7.0 mg). HPLC retention time (min): 0.89 (TFA); MS(ESI, Pos.):455(M+H) + .

[0286] Example 18: [(3aS,4R,6aR)-4-[(6-bromo-3-pyridazinyl)(methyl)amino]hexahydrocyclopenta[c]pyrrol-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. Iodomethane (0.005 mL) was then added and the mixture was stirred at room temperature for an additional 1 hour. Water was added to the reaction mixture, which was then 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 give 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.

[0287] Reference Example 89: 2-{2-[(6-bromo-3-pyridazinyl){(3aS,4R,6aR)-2-[(5-methyl-2-thienyl)carbonyl]octahydrocyclopenta[c]pyrrol-4-yl}amino]ethoxy}ethyl 4-methylbenzenesulfonate 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. Diethylene glycol ditosylate (CAS number: 7460-82-4, 305 mg) was then added and the mixture was stirred at room temperature for 4 hours. Aqueous sodium bicarbonate solution was added to the reaction mixture, and the mixture was extracted with dichloromethane. The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to give the title compound (100 mg). HPLC retention time (min): 1.18 (TFA); MS(ESI, Pos.):649(M+H) + .

[0288] Example 19: [(3aS,4R,6aR)-4-{(6-bromo-3-pyridazinyl)[2-(2-fluoroethoxy)ethyl]amino}hexahydrocyclopenta[c]pyrrol-2(1H)-yl](5-methyl-2-thienyl)methanone [ka] To a solution of the compound prepared in Reference Example 89 (100 mg) in acetonitrile (1.5 mL), potassium fluoride (27 mg) and 4,7,13,16,21,24-hexaoxa-1,10-diazabicyclo[8.8.8]hexacosane (CAS number: 23978-09-8, 174 mg) were added, followed by stirring for 40 minutes at 80° C. The reaction solution was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography to give 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.

[0289] Pharmacological Experiment Example 1: Evaluation of ABHD6 Enzyme Inhibitory Activity Assay buffer containing 50 mM Tris-HCl (pH 7.4), 100 mM NaCl, and 0.05% BSA was added at a final concentration of 10 μmol / LThe substrate, 1-Arachidonoyl Glycerol (Cayman), was prepared to achieve a final concentration of 0.0003, 0.001, 0.003, 0.01, 0.03, 0.1, 0.3, 1, 3, or 10 μmol / L. The compound was added to a final concentration of 0.3% DMSO. A compound-free control was also prepared by adding DMSO to a final concentration of 0.3%. The enzyme reaction was initiated by adding recombinant human ABHD6 (33-337) prepared in the same assay buffer to a final concentration of 300 μg / mL. The recombinant human ABHD6 (33-337) was GST-tagged and expressed in E. coli, purified on Glutathione-Sepharose 4B resin, and concentrated. The enzyme reaction was carried out at room temperature using a 384-well polypropylene microplate, and wells to which no enzyme was added were used as the blank group. One hour after the start of the enzyme reaction, the enzyme reaction was stopped by adding arachidonic acid-d8 (Cayman) as an internal standard and methanol containing 1% formic acid. The top of the enzyme reaction plate was sealed with aluminum, and the plate was centrifuged at 560 g for 5 minutes at room temperature. The enzyme reaction product, arachidonic acid, and the internal standard, arachidonic acid-d8, were then quantified using a RapidFire (registered trademark) Mass Spectrometry system. The ratio of the respective quantified values ​​was calculated, and the average value of the blank group was set to 100% inhibition, and the average value of the compound-free group was set to 0% inhibition. The arachidonic acid production inhibition rate at each compound concentration was calculated, and the IC 50 The value was calculated. The above pharmacological experiments have revealed that the compounds of the present disclosure have potent ABHD6 inhibitory activity. For example, the IC of some of the compounds of the present disclosure 50 The values ​​are shown in Table 1 below. [Table 1]

[0290] Pharmacological Experiment Example 2: Measurement of binding affinity to human ABHD6 Using HEK293 cells overexpressing NanoLuc-human ABHD6 fusion protein, a fluorescent probe molecule was allowed to react competitively with the test compound, and the binding affinity of the test compound to human ABHD6 was measured using bioluminescence resonance energy transfer (BRET) induced by the proximity of the probe molecule and 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 10 mmol / L solutions. The prepared 10 mmol / L solutions were thawed before use, serially diluted with DMSO, and used in the experiment. <Cell culture> HEK293 cells expressing NanoLuc-human ABHD6 fusion protein were cultured statically at 37°C in 5% CO2 using inactivated (56°C, 30 minutes) 9.8 vol% non-dialyzed FBS (containing 0.5 vol% GENETICIN and 1% penicillin-streptomycin). Subculture was performed as follows. Remove the medium and 2+ and Mg 2+ The cells were washed once with phosphate-buffered saline (PBS) containing no trypsin. An appropriate amount of trypsin-EDTA was added and incubated at room temperature. After detaching the cells, 10 volumes of medium containing 0.05% trypsin-EDTA were added to stop the enzyme reaction. The cells were collected in a centrifuge tube and centrifuged at 120 g for 3 minutes at room temperature, after which the supernatant was removed. The cells were suspended in an appropriate amount of medium and seeded into a culture flask. HEK293 cells expressing NanoLuc-human ABHD6 fusion protein were prepared and cultured at 5.0x10 in CELLBANKER2. 6 The cells were cryopreserved at 2 x 10 cells / mL / vial and used for the experiment. 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 diluted to 2 x 10 cells / mL. 5The cells were suspended in assay buffer to a concentration of 100 cells / mL. The cell suspension (25 μL) was added to a 384-well assay plate containing the test compound. After incubation at 37°C for 30 minutes in the presence of 5% CO2, a fluorophore-containing probe molecule (10 mmol / L in DMSO) was diluted with assay buffer to a final concentration of 100 nmol / L and added in 15 μL aliquots to the assay plate. After incubation at 37°C for 30 minutes in the presence of 5% CO2, Nano-Glo® Vivazine™ substrate (PROMEGA) was diluted with assay buffer according to the manufacturer's protocol and added in 10 μL aliquots to the assay plate. After incubation at room temperature for 1 hour, luminescence and fluorescence intensities were measured using a GloMax® Discover system. The ratio of the luminescence intensity through a 450 nm band-pass filter to the fluorescence intensity through a 600 nm long-pass filter was used as the measured value for each sample. The measured value for the group containing the control substance at a final concentration of 30 μmol / L was set as 100% inhibition, and the measured value for the group without compound was set as 0% inhibition. The IC value of the test compound was calculated from the measured values ​​at each test compound concentration. 50 The value was calculated. In the above cell evaluation system, the compounds of the present disclosure were found to have potent ABHD6 binding activity. For example, the IC 50 The values ​​are shown in Table 2 below. [Table 2]

[0291] Pharmacological Experiment Example 3: Evaluation of ABHD6 Selectivity Using rat brain membrane fractions, fluorescent probe molecules and test compounds were reacted with each other, and after separating the proteins by electrophoresis, the binding affinity of the test compounds 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 prepare a concentration 50 times higher than the final concentration. <Preparation of rat brain membrane fraction> After exsanguination under anesthesia, the rats were extracted and their brains were then resuspended in 1 mL of ice-cold phosphate buffered saline per 200 mg of brain weight. saline The mixture was homogenized using a homogenizer. The homogenate was centrifuged at 1000g for 10 minutes at 4°C, and the supernatant was collected. The resulting supernatant was centrifuged at 100,000g for 45 minutes at 4°C, and the pellet was resuspended in ice-cold PBS to prepare the membrane fraction. The protein concentration of the prepared brain membrane fraction solution was quantified, and it was stored in a -80°C freezer until use. <abpp> Brain membrane fraction solutions were prepared at 3 mg / mL in PBS. 1 μL of DMSO or compound solution was added to 50 μL of the 3 mg / mL membrane fraction solution and incubated at 37°C for 30 minutes. Then, 1 μL of a fluorophore-containing probe molecule (ActivX™ TAMRA-FP Serine Hydrolase Probe, final concentration 1 μmol / L, DMSO solution) was added and incubated at room temperature for 30 minutes. The reaction was stopped with 4x sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE) loading buffer. The samples were heated at 95°C for 5 minutes, after which proteins were separated by SDS-PAGE on a 10% acrylamide gel. Fluorescence from the SDS-PAGE gel was visualized using a Chemiluminescence Imaging System. For each band of ABHD6, MAGL, and FAAH, the fluorescence band intensity of the control group (DMSO-treated group) was set as 0% inhibition, and the IC of the test compound was calculated from the fluorescence intensity at each test compound concentration. 50 As a result, it was found that the compounds of the present disclosure have selective inhibitory activity on ABHD6 relative to MAGL and FAAH. Pharmacological Experiment Example 4: Analgesic effect on sodium monoiodoacetate-induced rat model The analgesic effect of the compound of the present disclosure was evaluated using a rat model induced with sodium monoiodoacetate (hereinafter abbreviated as MIA) (Sigma-Aldrich Japan). (1) Creation of MIA-induced rat model Under isoflurane anesthesia, rats were shaved around the right hind knee, and 25 μL of 120 mg / mL MIA solution was administered into the right hind joint cavity using a syringe with a 29G needle (BD Lordose, Becton Dickinson Japan). Normal controls received 25 μL of saline. (2) Group composition and group division The groups were composed of a normal control group, a disease control group, a test substance administration group, and a tramadol or morphine administration group. Model rats prepared by the method in (1) above 13 or 14 days after MIA induction were measured for the right hind paw load weight ratio (measurement method described below), and the rats were divided into groups so that there was no bias in the right hind paw load weight ratio among the groups. (3) Administration of the test substance, tramadol, or morphine The test substance, a compound of the present disclosure, was dissolved in a solubilization medium (corifol:PEG = 7:3 solution) to prepare a 0.4 or 8 mg / mL solution. The prepared solution was diluted 4-fold with distilled water to prepare a 0.1 or 2 mg / mL solution (final concentration of solubilization medium: 25%). The positive control drug, tramadol, was dissolved in physiological saline to prepare a 2 mg / mL solution. Alternatively, the positive control drug, morphine, was dissolved in physiological saline to prepare a 0.6 mg / mL solution. The test substance was orally administered at 5 mL / kg 5 hours before evaluation, and tramadol and morphine were administered subcutaneously at 5 mL / kg 1 hour before evaluation. (4) Measurement of right hindlimb load weight ratio The left and right hind paw load weights were measured using a Linton Incapacitance Tester (MJS Technology Inc., UK). Rats were placed in a dedicated cage on the Linton Incapacitance Tester and positioned so that each hind paw rested on two separate pairs of weight sensors. After confirming that the rat's posture was evenly balanced, the left and right hind paw load weights were measured for 3 seconds. Each rat was measured three times. To obtain consistent measurements, rats were placed in dedicated cages for at least 20 minutes for acclimation for at least 5 days between the day of MIA induction and 14 days after induction. An additional 10 minutes of acclimation was also performed immediately before the load weight measurement. The left and right hind paw load weights were measured 14 days after MIA induction in the normal control group, disease control group, test substance-treated group (5 hours after administration), tramadol-treated group (1 hour after administration), and morphine-treated group (1 hour after administration). Based on the average values ​​of the left and right hind paw load weights, the ratio of the right hind paw load weight to the total load weights of both hind paws was calculated using the following formula 1. Based on the right hind paw load weight ratio for each group 14 days after the induction of MIA, the improvement rate of the right hind paw load weight ratio upon administration of the test substance, a compound of the present disclosure, was calculated using the following formula 2 to evaluate the analgesic effect of the test substance (compound of the present disclosure).

number

number

[0292] [Formulation example] Formulation example The following ingredients are mixed by a conventional method and then compressed into tablets to obtain approximately 10,000 tablets, each containing 10 mg of active ingredient. {(3aS,4R,6aR)-4-[(6-chloro-3-pyridazinyl)amino]hexahydrocyclopenta[c]pyrrol-2(1H)-yl}[5-(difluoromethyl)-2-thienyl]methanone ……100g Carboxymethylcellulose calcium (disintegrant) …… 20g Magnesium stearate (lubricant) …… 10g Microcrystalline cellulose...870g [Industrial Applicability]

[0293] Since the compound of the present disclosure has ABHD6 inhibitory activity, pharmaceuticals containing the compound of the present disclosure as an active ingredient are useful as agents for preventing and / or treating diseases associated with ABHD6.< / abpp>

Claims

1. General formula (IA): 【Chemical 1】 (In the formula, X １ , X ２ are each independently (1) CH, (2) CR Ｘ or (3) represents N, provided that X １ and X ２ at least one of represents N; R １ represents a halogen atom, R Ｘ represents (1) a halogen atom, (2) a C alkyl group, (3) a C alkenyl group, (4) a C alkynyl group, (5) a C alkoxy group, (6) a C haloalkyl group, (7) a C haloalkenyl group, (8) a C haloalkynyl group, (9) a C haloalkoxy group, or (10) a cyano group; R ２ represents (1) a halogen atom, (2) a C alkyl group, (3) a C alkenyl group, (4) a C alkynyl group, (5) a C alkoxy group, (6) a C haloalkyl group, (7) a C haloalkenyl group, (8) a C haloalkynyl group, (9) a C haloalkoxy group, or (10) a cyano group; When m is 2 or more, a plurality of R ２ may be the same or different, R ３ represents (1) a hydrogen atom, (2) a C1-6 alkyl group, (3) a C1-6 haloalkyl group, (4) a 3- to 10-membered cyclic group, (5) a -(C1-6 alkylene)-(3- to 10-membered cyclic group), or (6) a -(C1-6 haloalkylene)-(3- to 10-membered cyclic group), and 1 to 2 carbon atoms in the C1-6 alkyl group, C1-6 haloalkyl group, C1-6 alkylene, and C1-6 haloalkylene are optionally replaced by an oxygen atom or an optionally oxidized sulfur atom, R ３ The 3- to 10-membered cyclic group in ３０１ may be substituted with R ３０１ is (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, or (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 R are substituted, ３０１ may be the same or different, R ３０２ , R ３０３ , R ３０４ , R ３０５ , R ３０６ , R ３０７ , R ３０８ , or R ３０９ each independently represents (1) a hydrogen atom or (2) a C1-4 alkyl group; R ２ is R ２ represents (2) to (9) in R ３ represents a C1-6 alkyl group, R ２ and R ３ may form a 5- or 6-membered cyclic group together with the atom to which it is attached, R ４ represents (1) a halogen atom, (2) a C alkyl group, (3) a C alkenyl group, (4) a C alkynyl group, (5) a C alkoxy group, (6) a C haloalkyl group, (7) a C haloalkenyl group, (8) a C haloalkynyl group, or (9) a C haloalkoxy group; When n is 2 or more, a plurality of R ４ may be the same or different, Two R's present on the same carbon atom ４ represents a C1-6 alkyl group, it may be taken together with the carbon atom to which it is attached to form a C3-6 cycloalkyl group; ring 1 is the following ring structure: 【Chemistry 2】 (wherein the * symbol represents the bonding position to the carbonyl group, and the hydrogen atom represented by NH may be replaced by R 5-A ), R ５－Ａ is (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 alkylthio group, (7) a C1-6 alkylsulfinyl group, (8) a C1-6 alkylsulfonyl group, (9) a C2-6 acyl group, (10) a 3- to 6-membered cyclic group, (11) -L Ｒ５ -(3- to 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 wherein 1 to 2 carbon atoms in 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 or C2-6 acyl group are optionally replaced by oxygen atoms or optionally oxidized sulfur atoms, When p is 2 or more, a plurality of R ５－Ａ may be the same or different, R ５－Ａ Among these, groups (2) to (11) are each a group having 1 to 9 R ５０８ may be substituted with R ５０８ is (1) a halogen atom, (2) a C1-4 alkyl group, (3) a C1-4 alkoxy group, (4) a C2-6 acyl group, (5) a C3-6 cycloalkyl group, (6) a hydroxyl group, or (7) -NR ５０９ R ５１０ represents R ５０８ When two or more R are substituted, ５０８ 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 -, (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 independently represents (1) a hydrogen atom, (2) a C alkyl group, (3) a C acyl group, or (4) a C alkylsulfonyl group; m represents an integer of 0 to 2; n represents an integer of 0 to 5; p represents an integer of 0 to 5; However, excluding [(3aS,4R,6aR)-4-[(6-bromo-3-pyridazinyl)amino]hexahydrocyclopenta[c]pyrrol-2(1H)-yl](5-methyl-2-thienyl)methanone, or a pharmaceutically acceptable salt thereof.

2. General formula (I): 【Chemistry 3】 (In the formula, X １ , X ２ are each independently (1) CH, (2) CR Ｘ or (3) represents N, provided that X １ and X ２ at least one of represents N; R １ represents a halogen atom, R Ｘ represents (1) a halogen atom, (2) a C alkyl group, (3) a C alkenyl group, (4) a C alkynyl group, (5) a C alkoxy group, (6) a C haloalkyl group, (7) a C haloalkenyl group, (8) a C haloalkynyl group, (9) a C haloalkoxy group, or (10) a cyano group; R ２ represents (1) a halogen atom, (2) a C alkyl group, (3) a C alkenyl group, (4) a C alkynyl group, (5) a C alkoxy group, (6) a C haloalkyl group, (7) a C haloalkenyl group, (8) a C haloalkynyl group, (9) a C haloalkoxy group, or (10) a cyano group; When m is 2 or more, a plurality of R ２ may be the same or different, R ３ represents (1) a hydrogen atom, (2) a C1-6 alkyl group, (3) a C1-6 haloalkyl group, (4) a 3- to 10-membered cyclic group, (5) a -(C1-6 alkylene)-(3- to 10-membered cyclic group), or (6) a -(C1-6 haloalkylene)-(3- to 10-membered cyclic group), and 1 to 2 carbon atoms in the C1-6 alkyl group, C1-6 haloalkyl group, C1-6 alkylene, and C1-6 haloalkylene are optionally replaced by an oxygen atom or an optionally oxidized sulfur atom, R ３ The 3- to 10-membered cyclic group in ３０１ may be substituted with R ３０１ is (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, or (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 R are substituted, ３０１ may be the same or different, R ３０２ , R ３０３ , R ３０４ , R ３０５ , R ３０６ , R ３０７ , R ３０８ , or R ３０９ each independently represents (1) a hydrogen atom or (2) a C1-4 alkyl group; R ２ is R ２ represents (2) to (9) in R ３ represents a C1-6 alkyl group, R ２ and R ３ may form a 5- or 6-membered cyclic group together with the atom to which it is attached, R ４ represents (1) a halogen atom, (2) a C alkyl group, (3) a C alkenyl group, (4) a C alkynyl group, (5) a C alkoxy group, (6) a C haloalkyl group, (7) a C haloalkenyl group, (8) a C haloalkynyl group, or (9) a C haloalkoxy group; When n is 2 or more, a plurality of R ４ may be the same or different, Two R's present on the same carbon atom ４ represents a C1-6 alkyl group, it may be taken together with the carbon atom to which it is attached to form a C3-6 cycloalkyl group; ring 1 is the following ring structure: 【Chemistry 4】 (wherein the * symbol represents the bonding position to the carbonyl group, and the hydrogen atom represented by NH may be replaced by R 5 ), R ５ is (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 alkylthio group, (7) a C1-6 alkylsulfinyl group, (8) a C1-6 alkylsulfonyl group, (9) a C2-6 acyl group, (10) a 3- to 6-membered cyclic group, (11) -L Ｒ５ -(3- to 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 represents When p is 2 or more, a plurality of R ５ may be the same or different, R ５ Among these, groups (2) to (11) are each a group having 1 to 9 R ５０８ may be substituted with R ５０８ is (1) a halogen atom, (2) a C1-4 alkyl group, (3) a C1-4 alkoxy group, (4) a C2-6 acyl group, (5) a C3-6 cycloalkyl group, (6) a hydroxyl group, or (7) -NR ５０９ R ５１０ represents R ５０８ When two or more R are substituted, ５０８ 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 -, (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 independently represents (1) a hydrogen atom, (2) a C alkyl group, (3) a C acyl group, or (4) a C alkylsulfonyl group; m represents an integer of 0 to 2; n represents an integer of 0 to 5; p represents an integer of 0 to 5; However, excluding [(3aS,4R,6aR)-4-[(6-bromo-3-pyridazinyl)amino]hexahydrocyclopenta[c]pyrrol-2(1H)-yl](5-methyl-2-thienyl)methanone, or a pharmaceutically acceptable salt thereof.

3. R ５－Ａ is (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) —COOCH ３ 2. The compound of claim 1, wherein:

4. R ５ is (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) —COOCH ３ 3. The compound of claim 2, wherein:

5. R ３ is (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, The compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, wherein Q is (1) benzene, (2) pyridine, or (3) imidazo[2,1-b]thiazole.

6. X １ , X ２ The compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, wherein each of

7. The compound represented by general formula (IA) or general formula (I) is a compound represented by general formula (I-1): 【Chemistry 5】 (In the formula, R ３－ａ is (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 is the following ring structure: 【Chemistry 6】 (In the formula, * indicates the bonding position with the carbonyl group, and the hydrogen atom represented by NH is R ５－ａ and R ５－ａ is (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) -COOCH ３ represents The other symbols have the same meanings as those in claim 1, 2 or 5. The compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof.

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

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