TW202416956A - Pharmaceutical composition containing ABHD6 antagonist containing a compound that has ABHD6 inhibitory activity - Google Patents

Abstract

The present invention provides a pharmaceutical composition which contains a compound that has ABHD6 (alpha/beta-Hydrolase domain containing 6) inhibitory activity for prevention and/or treatment of a disease associated with ABHD6. A compound represented by a general formula (I-A) or a pharmaceutically acceptable salt thereof has ABHD6 inhibitory activity. Therefore, the pharmaceutical composition contains the compound represented by the general formula (I-A) or the pharmaceutically acceptable salt thereof can be used for prevention and/or treatment of a disease associated with ABHD6. (In the formula, all symbols represent the same meaning as the symbols described in the specification).

Description

Pharmaceutical composition containing ABHD6 antagonist

The present invention relates to a pharmaceutical composition containing a compound having ABHD6 inhibitory activity or a pharmaceutically acceptable salt thereof. Specifically, the present invention relates to a pharmaceutical composition containing a compound represented by general formula (IA) or a pharmaceutically acceptable salt thereof (hereinafter referred to as the compound of the present invention): [Chemical 1] (In the formula, all symbols have the same meanings as below).

ABHD6 (alpha/beta-Hydrolase domain containing 6) is a serine hydrolase and one of the metabolites of the endogenous cannabinoid 2-arachidonoylglycerol (2-AG). 2-AG functions as an important lipid precursor in the eicosanoid signaling pathway and also functions as an endogenous signaling lipid for activating 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, neurotransmission, inflammation, insulin secretion, fat browning, feeding, autoimmune diseases, neurological diseases, and metabolic diseases (non-patent document 1).

In addition, it is known that by inhibiting ABHD6, neuroinflammation is significantly reduced and neuroprotective effects are exerted in animal models of traumatic brain injury and multiple sclerosis. It is believed that inhibition of ABHD6 can be used to prevent and/or treat various inflammatory and neurological diseases without causing central side effects mediated by the cannabinoid system (Non-patent Document 2).

On the other hand, Patent Document 1 states that the compound represented by the following general formula (A) is a compound having mAChR (Muscarinic Acetylcholine Receptor) receptor antagonist activity. General formula (A) is as follows: [Chemical 1] (wherein, Ring ^AA represents a 5-6 membered heteroaromatic ring having 1 to 3 heteroatoms selected from N, O and S, ^QA represents ^NRaA or O, mA represents 0, 1 or 2, ^R1A is selected from heteroaryl, aryl, heterocyclic, cycloalkyl, halogen, ^-ORbA , ^-NRcARdA and ^NHCOReA , nA represents 1 or 2, ^R2A is selected from hydrogen, ^C1-4 alkyl, halogen and ^-ORfA , ^R3A is selected from hydrogen and C1-4 alkyl, ^R4A is selected from -( ^CRgARhA ) _pA - ^{YA '} , hydrogen, C1-8 alkyl and C1-8 alkenyl, R ^5A is selected from hydrogen, C1-4 alkyl, halogen, C1-4 halogenalkyl, C1-4 alkoxy and C1-4 halogenalkoxy, Y ^A' is selected from cycloalkyl, cycloalkenyl, heterocyclo, aryl and heteroaryl, p ^A represents an integer from 0 to 4 (part of the definition of radical is extracted)).

In addition, Patent Document 2 states that the compound represented by the following general formula (B) is a compound having FAAH (Fatty Acid Amide Hydrolase) inhibitory activity. General formula (B) is as follows: [Chemical 1] (wherein, R ^2B represents hydrogen, fluorine, hydroxyl, cyano, trifluoromethyl, C1-6 alkyl, C1-6 alkoxy or NR ^{8BR 9B} , ^mB , ^nB , ^oB and ^pB represent numbers independently from each other ranging from 0 to 3, and ^mB + ^oB and ^nB + ^pB are each 4 or less, A ^B represents a covalent bond, an oxygen atom, a C1-6 alkylene group or -O-C1-6 alkylene group (in this case, the terminal represented by the oxygen atom is bonded to the group R ^1B , and the terminal represented by the alkylene group is bonded to the carbon of the bicyclic ring), R ^1B represents R ^5B which is unsubstituted or substituted by one or more R ^6B and/or R ^7B , R ^R5B represents a group selected from phenyl, pyridyl, pyrimidinyl, pyrimidinyl, triimidinyl, naphthyl, quinolyl, isoquinolyl, quinazolinyl, quinolinyl, oxazolinyl, oxazolinyl, benzothiazolyl, benzoxazolyl, benzimidazolyl, benzoisothiazolyl, benzoisoxazolyl, indazolyl and benzotriazolyl, ^R3B represents a hydrogen atom, a fluorine atom, a C1-6 alkyl group or a trifluoromethyl group, R ^4B represents a 5-membered heterocyclic ring selected from furanyl, pyrrolyl, thienyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyrazolyl, oxadiazolyl, thiadiazolyl, imidazolyl, triazolyl and tetrazolyl (part of the definition of the radical is extracted)).

In addition, Patent Document 3 states that the compound represented by the following general formula (C) is a compound having a calcium ion channel inhibitory effect. General formula (C) is as follows: [Chemical 1] (wherein, ^L1C is C(O), S(O) ₂ , _SO2N ( ^R4 ), C(O)O or -( ^CRaCRbC ) _mC- , ^R1C is alkyl, ^G1C , -CH( ^G1C ) ₂ , -( ^CRaCRbC ) _mC ^{- G1C} , -( ^{CRaCRbC )} _mC -CH( ^G1C ) ₂ ^, -( ^CReCRfC ) _nC - ^{N(R5C)2, -(CReCRfC)nC-N(R5C )} _-C ^{( O} ₎ ^O (alkyl), -( ^CReCRfC ) ^nC - _N ( ^R5C )-C(O)(alkyl) or -( ^CReCRfC ) _nC ^{-N(R5C)-SO2R6C , or} _L1C ^- R ^1C as a whole represents hydrogen, alkyl, hydroxyalkyl, ^G1C or -CH( ^G1C ) ₂ ; ^L2C is -( ^CRcCRdC ) _pC- , C(O), C(O)N( ^R4C ), S(O) ₂ , _SO2N ( ^R5C ) or C(O)O, ^R2C is alkyl, ^G2C , -C( ^RcC )( ^G2C )( ^G3C ), -( ^CRcCRdC ) _pC ^{-G2C ,} -( ^CRcCRdC ) _pC - ^CH ( ^G2C )( ^G3C ), -( ^CRgCRhC ) ^qC - _N ( ^R5C ) _{-C(O)O(alkyl), -(CRgCRhC)qC} ^{-N(R5C ) -C (} O) ^OG2C , -( ^CRgC R ^hC ) _qC -N(R ^5C )-C(O)(alkyl), -(CR ^{gCR hC} ) _qC -N(R ^5C )-SO ₂ R ^6C , -(CR ^{gCR hC} ) _qC -N(R ^4C )(R ^5C ), -(CR ^{gCR hC} ) _qC -N(R ^5C )-C(O)N(R ^5C )-(alkyl), or -(CR ^{gCR hC} ) _qC -N(R ^5C )-C(O)N(R ^5C )-G ^2C , or L ^2C -R ^2C as a whole represents alkyl, G ^2C or -C(R ^cC )(G ^2C )(G ^3C ); G ^1C , G ^2C and G ^G1C , ^G2C and ^G3C are each independently unsubstituted or substituted with 1, 2, ³ , 4 or 5 substituents, ^G1C does not include quinoline, quinazolinedione or pyridopyrimidinedione; ^R3C represents hydrogen, alkyl, haloalkyl, cycloalkyl or cycloalkylalkyl (part of the definition of radical is extracted)).

However, none of the prior art documents describes or suggests that the compounds of the present invention have ABHD6 inhibitory activity. [Prior art document] [Patent document]

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

[Non-patent document 1] European Journal of Medicinal Chemistry, Vol. 198, Article No. 112353, 2020 (European Journal of Medicinal Chemistry 198 (2020) 112353) [Non-patent document 2] Journal of Neuroinflammation, Vol. 15, Article No. 9, 2018 (Journal of Neuroinflammation (2018) 15:9)

[The problem the invention is trying to solve]

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

To solve the above problem, the inventors of the present invention have conducted intensive research and found that pharmaceutical compositions containing compounds represented by the following general formula (IA) have strong inhibitory activity against ABHD6. That is, the present invention provides the following embodiments in one form: [1] A pharmaceutical composition containing the following compound or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, wherein the compound is represented by the general formula (IA): [Chemical 1] (wherein, ^X1 and ^X2 independently represent (1) CH, (2) ^CRX , or (3) N, wherein at least one of ^X1 and ^X2 represents N, ^R1 represents a halogen atom, ^RX represents (1) a halogen atom, (2) a C1-6 alkyl group, (3) a C2-6 alkenyl group, (4) a C2-6 alkynyl group, (5) a C1-6 alkoxy group, (6) a C1-6 halogenalkyl group, (7) a C2-6 halogenalkenyl group, (8) a C2-6 halogenalkynyl group, (9) a C1-6 halogenalkoxy group, or (10) a cyano group, R ^R2 represents (1) a halogen atom, (2) a C1-6 alkyl group, (3) a C2-6 alkenyl group, (4) a C2-6 alkynyl group, (5) a C1-6 alkoxy group, (6) a C1-6 halogen alkyl group, (7) a C2-6 halogen alkenyl group, (8) a C2-6 halogen alkynyl group, (9) a C1-6 halogen alkoxy group, or (10) a cyano group. When m is 2 or more, a plurality of ^R2s may be the same or different. ^{R 3} represents (1) a hydrogen atom, (2) a C1-6 alkyl group, (3) a C1-6 halogen alkyl group, (4) a 3-10 membered cyclic group, (5) -(C1-6 alkylene)-(3-10 membered cyclic group), (6) -(C1-6 halogen alkylene)-(3-10 membered cyclic group), 1 to 2 carbon atoms in the C1-6 alkyl group, C1-6 halogen alkyl group, C1-6 alkylene group and C1-6 halogen alkylene group may be substituted by an oxygen atom or an oxidizable sulfur atom, the 3-10 membered cyclic group in R ³ may be substituted by 1 to 5 R ³⁰¹ , R ³⁰¹ represents (1) a halogen atom, (2) a C1-4 alkyl group, (3) a C1-4 alkoxy group, (4) a C1-4 halogen alkyl group, (5) a C1-4 halogen alkoxy group, (6) COOR ³⁰² , (7) CONR ³⁰³ R ³⁰⁴ , (8) C3-6 cycloalkyl, (9) hydroxyl, (10) nitro, (11) cyano, (12) -NR ³⁰⁵ R ³⁰⁶ , (13) -SR ³⁰⁷ , (14) -SOR ³⁰⁸ , (15) -SO ₂ R ³⁰⁹ , or (16) oxo, when substituted by two or more R ³⁰¹ , the plurality of R ^{301 s} 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, and R ² represents ( ² ) to (9), R When R ³ represents a C1-6 alkyl group, R ² and R ³ may form a 5-6 membered cyclic group together with the atom to which they are bonded. R ⁴ represents (1) a halogen atom, (2) a C1-6 alkyl group, (3) a C2-6 alkenyl group, (4) a C2-6 alkynyl group, (5) a C1-6 alkoxy group, (6) a C1-6 halogen alkyl group, (7) a C2-6 halogen alkenyl group, (8) a C2-6 halogen alkynyl group, or (9) a C1-6 halogen alkoxy group. When n is 2 or more, a plurality of R ⁴ may be the same or different. When two R ⁴ on the same carbon atom represent a C1-6 alkyl group, they may form a C3-6 cycloalkyl group together with the carbon atom to which they are bonded. ring1 represents a 3-15 membered cyclic group. R ^5-A represents (1) a halogen atom, (2) a C1-6 alkyl group, (3) a C2-6 alkenyl group, (4) a C2-6 alkynyl group, (5) a C1-6 alkoxy group, (6) a C1-6 alkylthio group, (7) a C1-6 alkylsulfinyl group, (8) a C1-6 alkylsulfonyl group, (9) a C2-6 acyl group, (10) a 3-6 membered cyclic group, (11) ^-LR5- (3-6 membered cyclic group), (12) a hydroxy group, (13) a nitro group, (14) a cyano group, (15) a ^oxo group ^, (16) ^{-NR501R502 ,} (17) ^{-COOR503 ,} (18) ^-CONR504R505 , or (19) _{-SO2NR506R507} , 1 to 2 carbon atoms in the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxy, C1-6 alkylthio, C1-6 alkylsulfinyl, C1-6 alkylsulfonyl, or C2-6 acyl group may be substituted with an oxygen atom or an oxidizable sulfur atom. When p is 2 or more, the plurality of R ^5-A may be the same or different. The groups (2) to (11) in R ^5-A may be substituted with 1 to 9 R ^508. R ⁵⁰⁸ represents (1) a halogen atom, (2) a C1-4 alkyl, (3) a C1-4 alkoxy, (4) a C2-6 acyl group, (5) a C3-6 cycloalkyl group, (6) a hydroxyl group, or (7) -NR ⁵⁰⁹ R ^510. When substituted with 2 or more R ⁵⁰⁸ , the plurality of R ^{R 508} may be the same or different, L ^R5 represents (1) -O-, (2) -(C1-4 alkylene)-, (3) -O-(C1-4 alkylene)-, (4) -(C1-4 alkylene)-O-, (5) -NR ⁵¹¹ -, or (6) -SO _0-2 -, 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 C1-6 alkyl group, (3) a C2-6 acyl group, or (4) a C1-6 alkylsulfonyl ^group , m represents an integer from 0 to 2, n represents an integer from 0 to 5, and p represents an integer from 0 to 5). [2] A pharmaceutical composition comprising the following compound or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, wherein the compound is represented by the general formula (I): (wherein, R ⁵ represents (1) a halogen atom, (2) a C1-6 alkyl group, (3) a C2-6 alkenyl group, (4) a C2-6 alkynyl group, (5) a C1-6 alkoxy group, (6) a C1-6 alkylthio group, (7) a C1-6 alkylsulfinyl group, (8) a C1-6 alkylsulfonyl group, (9) a C2-6 acyl group, (10) a 3-6 membered cyclic group, (11) ^-LR5- (3-6 membered cyclic group), (12) a hydroxyl group, (13) a nitro group, (14) a cyano group, (15) a oxo group, (16) -NR ⁵⁰¹ R ⁵⁰² , (17) -COOR ⁵⁰³ , (18) -CONR ⁵⁰⁴ R ⁵⁰⁵ , or (19) -SO ₂ NR ⁵⁰⁶ R ⁵⁰⁷ , When p is 2 or more, the plurality of R ⁵ may be the same or different, the groups (2) to (11) in R ⁵ may be substituted by 1 to 9 R ⁵⁰⁸ , and the other symbols have the same meanings as those described in [1] above). [3] The pharmaceutical composition described in [1] or [2] above is an ABHD6 inhibitor. [Effects of the Invention]

The compounds of the present invention have inhibitory activity against ABHD6, and thus the pharmaceutical composition containing the compounds of the present invention can be used as a preventive and/or therapeutic agent for ABHD6-related diseases.

The present invention is described in detail below. In this specification, halogen atoms include fluorine, chlorine, bromine, and iodine atoms.

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

In the present specification, examples of the C2-6 alkenyl group include ethenyl, propenyl, butenyl, butadienyl, pentenyl, pentadienyl, hexenyl, hexadienyl and isomers thereof.

In the present specification, examples of the C2-6 alkynyl group include ethynyl, propynyl, butynyl, butadiynyl, pentynyl, pentadiynyl, hexynyl, hexadiynyl, and isomers thereof.

In this specification, C1-4 alkylene groups include: methylene, ethylene, propylene, butylene and their isomers. In this specification, C1-6 alkylene groups include: methylene, ethylene, propylene, butylene, pentylene, hexylene and their isomers.

In this specification, the so-called C1-4 halogen alkyl refers to, for example, an alkyl group substituted with one or more halogen atoms, specifically, fluoromethyl, chloromethyl, bromomethyl, iodomethyl, difluoromethyl, trifluoromethyl, 1-fluoroethyl, 2-fluoroethyl, 2-chloroethyl, pentafluoroethyl, 1-fluoropropyl, 2-chloropropyl, 3-fluoropropyl, 3-chloropropyl, 4,4,4-trifluorobutyl, 4-bromobutyl and their isomers, etc. In this specification, the so-called C1-6 halogen alkyl group refers to, for example, an alkyl group substituted with one or more halogen atoms, specifically, fluoromethyl, chloromethyl, bromomethyl, iodomethyl, difluoromethyl, trifluoromethyl, 1-fluoroethyl, 2-fluoroethyl, 2-chloroethyl, pentafluoroethyl, 1-fluoropropyl, 2-chloropropyl, 3-fluoropropyl, 3-chloropropyl, 4,4,4-trifluorobutyl, 4-bromobutyl, 5,5,5-trifluoropentyl, 6,6,6-trifluorohexyl and their isomers, etc.

In the present specification, the C1-6 halogenated alkylene group refers to, for example, an alkylene group substituted with one or more halogen atoms, and specifically includes: fluoromethylene, chloromethylene, bromomethylene, iodomethylene, difluoromethylene, 1-fluoroethyl, 2-fluoroethyl, 2-chloroethyl, pentafluoroethyl, 1-fluoropropyl, 2-chloropropyl, 3-fluoropropyl, 3-chloropropyl, 4-bromobutyl, 5-fluoropentyl, 6-fluorohexyl, and isomers thereof.

In the present specification, the C2-6 haloalkenyl group refers to, for example, an alkenyl group substituted with one or more halogen atoms, and specifically includes: 1-fluorovinyl, 2-fluorovinyl, 2-chlorovinyl, 1-fluoropropenyl, 2-chloropropenyl, 3-fluoropropenyl, 3-chloropropenyl, 4-bromobutenyl, 5,5,5-trifluoropentenyl, 6,6,6-trifluorohexenyl and isomers thereof.

In the present specification, the C2-6 halogen alkynyl group refers to, for example, an alkynyl group substituted with one or more halogen atoms, and specifically includes: 2-fluoroethynyl, 2-chloroethynyl, 3-fluoropropynyl, 3-chloropropynyl, 4-bromobutynyl, 5,5,5-trifluoropentynyl, 6,6,6-trifluorohexynyl, and isomers thereof.

In this specification, C1-4 alkoxy groups include methoxy, ethoxy, propoxy, butoxy, and isomers thereof. In this specification, C1-6 alkoxy groups include methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, and isomers thereof.

In this specification, the so-called C1-4 halogen alkoxy group refers to, for example, an alkoxy group substituted with one or more halogen atoms, and specifically, the following can be listed: fluoromethoxy, chloromethoxy, bromomethoxy, iodomethoxy, difluoromethoxy, trifluoromethoxy, 1-fluoroethoxy, 2-fluoroethoxy, 2-chloroethoxy, pentafluoroethoxy, 1-fluoropropoxy, 2-chloropropoxy, 3-fluoropropoxy, 3-chloropropoxy, 4,4,4-trifluorobutoxy, 4-bromobutoxy and isomers thereof. In this specification, the C1-6 halogen alkoxy group refers to, for example, an alkoxy group substituted with one or more halogen atoms, and specifically includes: fluoromethoxy, chloromethoxy, bromomethoxy, iodomethoxy, difluoromethoxy, trifluoromethoxy, 1-fluoroethoxy, 2-fluoroethoxy, 2-chloroethoxy, pentafluoroethoxy, 1-fluoropropoxy, 2-chloropropoxy, 3-fluoropropoxy, 3-chloropropoxy, 4,4,4-trifluorobutoxy, 4-bromobutoxy, 5,5,5-trifluoropentyloxy, 6,6,6-trifluorohexyloxy and their isomers.

In the present specification, examples of the C1-6 alkylthio group include methylthio, ethylthio, propylthio, butylthio, pentylthio, hexylthio and isomers thereof.

In the present specification, examples of the C1-6 alkylsulfinyl group include methylsulfinyl, ethylsulfinyl, propylsulfinyl, butylsulfinyl, pentylsulfinyl, hexylsulfinyl and isomers thereof.

In the present specification, examples of the C1-6 alkylsulfonyl group include methylsulfonyl, ethylsulfonyl, propylsulfonyl, butylsulfonyl, pentylsulfonyl, hexylsulfonyl and isomers thereof.

In the present specification, examples of the C3-6 cycloalkyl group include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

In the present specification, examples of the C2-6 acyl group include acetyl, propionyl, butyryl, pentyl, hexyl and isomers thereof.

In this specification, the 3-6 membered cyclic group refers to a C3-6 carbon ring and a 3-6 membered heterocyclic ring. In this specification, examples of C3-6 carbon rings include: cyclopropane, cyclobutane, cyclopentane, cyclohexane, cyclobutene, cyclopentene, cyclohexene, cyclobutadiene, cyclopentadiene, cyclohexadiene, and benzene ring. In the present specification, examples of the 3-6 membered heterocyclic ring include aziridine, azetidine, oxirane, cyclohexane, cyclothiopropane, cyclothiopropane, pyrrole, imidazole, triazole, tetrazole, pyrazole, pyridine, pyrrol, pyridine, pyrrolidone, pyrimidine, pyrimidine, furan, pyran, thiophene, thiopyran, oxadiazole, isooxazole, thiazole, isothiazole, furoxane, oxadiazole, isooxazole, dihydropyridine, tetrahydropyridine, piperidine, dihydropyridine, tetrahydropyridine, piperidine, dihydropyridine, tetrahydropyridine, piperidine, dihydropyridine, tetrahydropyridine, perhydropyridine, dihydropyrimidine, tetrahydropyrimidine, perhydropyrimidine, dihydrothiazolidine, tetrahydrothiazolidine, perhydrothiazolidine, dihydrofuran, dihydrofuran, dihydrofuran, dihydrofuran, dihydrofuran, dihydrofuran, dihydrofuran, dihydrofuran, dihydrofuran, dihydrofuran, dihydrofuran, dihydrofuran , tetrahydrofuran, dihydropyran, tetrahydropyran, dihydrothiophene, tetrahydrothiophene, dihydrothiopyran, tetrahydrothiopyran, dihydrooxazole, tetrahydrooxazole (oxazolidine), dihydroisooxazole, tetrahydroisooxazole (isooxazolidine), dihydrothiazole, tetrahydrothiazole (thiazolidine), dihydroisothiazole, tetrahydroisothiazole (isothiazolidine), dihydrofuran, tetrahydrofuran, dihydrooxazole oxadiazole, tetrahydrooxadiazole (oxadiazolidine), dihydrothiazolidine, tetrahydrothiazolidine, dihydrothiadiazole, tetrahydrothiadiazole, dihydrothiazolidine, tetrahydrothiazolidine, dihydrothiadiazole, tetrahydrothiadiazole, morpholine, thiomorpholine, oxythiophene, dioxacyclopentane, dioxane, dithiacyclopentane, and dithiane ring, etc.

In this specification, the 5-6 membered cyclic group refers to a C5-6 carbon ring and a 5-6 membered heterocyclic ring. In this specification, examples of the C5-6 carbon ring include: cyclopentane, cyclohexane, cyclopentene, cyclohexene, cyclopentadiene, cyclohexadiene, and benzene ring. In the present specification, examples of the 5- to 6-membered heterocyclic ring include pyrrole, imidazole, triazole, tetrazole, pyrazole, pyridine, pyrrolidine, pyrimidine, pyrimidine, furan, pyran, thiophene, thiopyran, oxadiazole, isooxadiazole, thiazole, isothiazole, furoxane, oxadiazole, oxadiazole, oxadiazole, thiazolidine, thiazolidine, pyrroline, pyrrolidine, imidazoline, imidazodine, triazoline, triazolidine, tetrazoline, tetrazoline, pyrazoline, pyrazolidine, dihydropyridine, tetrahydropyridine, piperidine, dihydropyridine, tetrahydropyridine, piperidine, dihydropyrimidine, tetrahydropyrimidine, perhydropyrimidine, dihydropyrimidine, tetrahydropyrimidine, perhydropyrimidine, dihydrofuran, tetrahydrofuran, dihydropyran, tetrahydropyran , dihydrothiophene, tetrahydrothiophene, dihydrothiopyran, tetrahydrothiopyran, dihydrooxazole, tetrahydrooxazole (oxazolidine), dihydroisooxazole, tetrahydroisooxazole (isooxazolidine), dihydrothiazole, tetrahydrothiazole (thiazolidine), dihydroisothiazole, tetrahydroisothiazole (isothiazolidine), dihydrofuroxane, tetrahydrofuroxane, dihydrooxadiazole, tetrahydrodioxadiazole azole (thiazoline), dihydrothiazolidine, tetrahydrothiazolidine, dihydrothiadiazole, tetrahydrothiadiazole, dihydrothiazolidine, tetrahydrothiazolidine, dihydrothiadiazole, tetrahydrothiadiazole, morpholine, thiomorpholine, oxythiophene, dioxacyclopentane, dioxane, dithiacyclopentane, and dithiane ring, etc.

In this specification, the so-called 3-10 membered cyclic group refers to a C3-10 carbon ring and a 3-10 membered heterocyclic ring. In the present specification, examples of the C3-10 carbon ring include cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, cyclooctane, cyclononane, cyclodecane, cyclobutene, cyclopentene, cyclohexene, cycloheptene, cyclooctene, cyclononene, cyclodecene, cyclobutadiene, cyclopentadiene, cyclohexadiene, cycloheptadiene, cyclooctadiene, benzene, pentacyclopentadiene, perhydropentacyclopentadiene, azulene, perhydroazulene, indene, perhydroindene, 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]octenyl ring, etc. In the present specification, examples of the 3-10 membered heterocyclic ring include the above-mentioned 3-6 membered heterocyclic rings, and azapine, diazepine, thiazole, thiazepine, thiazepine, thiazepine, thiadiazepine, indole, isoindole, indolium, benzofuran, isobenzofuran, benzothiophene, isobenzothiophene, dithianaphthene, indazole, quinoline, isoquinoline, quinoline, thiophene, purine, thiophene, pteridine, thiophene, quinazoline, quinazoline, benzophenone, benzothiazole, benzimidazole, oxadiene, benzofuroxane, benzothiadiazole, benzotriazole, dihydrogen pyridine, tetrahydrogen pyridine, perhydrogen pyridine, dihydrodiazine, tetrahydrodiazine, perhydrodiazine, dihydroheptazone, tetrahydroheptazone, perhydroheptazone, dihydrothiophene Indole, tetrahydrothiophene, perhydrothiophene, dihydrobenzofuran, tetrahydrobenzofuran, perhydrobenzofuran, dihydrodiazopyran, tetrahydrodiazopyran, perhydrodiazopyran, dihydrothiazepine, tetrahydrothiazepine, perhydrothiazepine, dihydrothiadiazepine, tetrahydrothiazepine, perhydrothiazepine, dihydrothiadiazepine, tetrahydrothiadiazepine, perhydrothiadiazepine, indoline, isoindoline, dihydrobenzofuran, perhydrobenzofuran furan, dihydroisobenzofuran, perhydroisobenzofuran, dihydrobenzothiophene, perhydrobenzothiophene, dihydroisobenzothiophene, perhydroisobenzothiophene, dihydroindazole, perhydroindazole, dihydroquinoline, tetrahydroquinoline, perhydroquinoline, dihydroisoquinoline, tetrahydroisoquinoline, perhydroisoquinoline, dihydroquinoline, tetrahydroquinoline, perhydroquinoline, tetrahydroquinoline, perhydroquinoline, dihydroxanthine, tetrahydroxanthine, perhydroxanthine, dihydroxanthine, tetrahydroxanthine pyridine, perhydroquinoline, dihydroquinoline, tetrahydroquinoline, perhydroquinoline, dihydroquinazoline, tetrahydroquinazoline, perhydroquinazoline, dihydroquinoline, tetrahydroquinazoline, perhydroquinazoline, benzothiophene, dihydrobenzothiol, dihydrobenzothiol, pyridine, dihydrobenzoxazole, perhydrobenzoxazole, dihydrobenzothiazole, perhydrobenzothiazole, di ... Hydrobenzimidazole, perhydrobenzimidazole, dioxindane, benzodioxane, benzodithiocyclopentane, benzodithiane, azaspiro[4.4]nonane, oxaspiro[4.4]nonane, dioxaspiro[4.4]nonane, azaspiro[4.5]decane, thiaspiro[4.5]decane, dithiaspiro[4.5]decane, dioxaspiro[4.5]decane [4.5]decane, oxyheterospiro[4.5]decane, azabicyclo[3.2.1]octane, oxyheterobicyclo[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 ring, etc.

In the present specification, the 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, and α, biphenyl, α-indene, s-indene, vinylnaphthalene, ethanenaphthalene, fluorene, phenanthrene, phenanthrene, and anthracene. In the present specification, examples of the 3-15 membered heterocyclic ring include the above-mentioned 3-10 membered heterocyclic ring, and benzodiazepine, benzothiadiazepine, benzoazepine, benzothiazepine, benzodiazepine, dihydrobenzodiazepine, tetrahydrobenzodiazepine, benzodioxaheptane, dihydrobenzoazepine, tetrahydrobenzoazepine, benzoheptan, benzothiazole, benzazepine, dihydrobenzazepine, tetrahydrobenzazepine, beta-carboline, dihydrocarbazole, tetrahydrocarbazole, dihydrodibenzofuran, dihydrodibenzothiophene, tetrahydrodibenzofuran, tetrahydrodibenzothiophene, carbazole, dibenzofuran, dibenzothiophene, phenath ... , dihydroacridine, tetrahydroacridine, acridine, phenanthidine, and dihydropyrrolo[1,2-b]thieno[2,3-d]pyrazole ring, etc.

In the present specification, the term "1 to 2 carbon atoms may be substituted by an oxygen atom or an oxidizable sulfur atom" means that 1 or 2 carbon atoms ( _-CH2- ) located at possible positions in the structure in the substituent may be substituted by an oxygen atom (-O-) or an oxidizable sulfur atom (-S-, -SO-, or _-SO2- ). Specifically, in the case of a C1-6 alkyl group, for example, the group may include: _CH3 -O- _CH2 -group, _CH3 - _CH2 -O- _CH2 -group, CH3-O-CH2-CH2-group, _CH3 -O- _CH2 - _{CH2 -} group, CH3- _O - _CH2 - _CH2 -group, and _CH3 - _CH2 -O- _CH2 - _CH2 -group.

In the present invention, N is preferably used as X ¹ and X ² .

In the present invention, R ¹ is preferably a chlorine atom or a bromine atom.

In the present invention, R ² is preferably a halogen atom, a C1-6 alkyl group, a C1-6 alkoxy group, a C1-6 halogenalkyl group, or a cyano group, and more preferably a chlorine atom, a methoxy group, a trifluoromethyl group, or a cyano group.

In the present invention, ^RX is preferably a halogen atom, a C1-6 alkyl group, a C1-6 alkoxy group, a C1-6 halogenalkyl group, or a cyano group, and more preferably a chlorine atom, a methoxy group, a trifluoromethyl group, or a cyano group.

In the present invention, R ³ is preferably a hydrogen atom, a C1-6 alkyl group, a C1-6 halogen group, a 3-10 membered cyclic group, or -CH ₂ -(3-10 membered cyclic group), and more preferably a hydrogen atom, a C1-6 alkyl group, a C1-6 halogen group, a cyclopropyl group, -CH ₂ -benzene, -CH ₂ -pyridine, or -CH ₂ -imidazo[2,1-b]thiazole.

In the present invention, R ⁴ is preferably a halogen atom or a C1-6 alkyl group, more preferably a fluorine atom or a methyl group.

In the present invention, ring1 is preferably a 3-10 membered cyclic group, or [Chemical 1] (wherein the asterisk (*) indicates the bonding position to the carbonyl group), preferably selected from [Chemical 1] (wherein the asterisk (*) indicates the bonding position with the carbonyl group, and the hydrogen atom represented by NH may be substituted by R ^5-A or R ⁵ ) is preferably selected from the group consisting of [Chemical 1] (wherein the asterisk (*) indicates the bonding position to the carbonyl group, and the hydrogen atom represented by NH may be substituted by R ^5-A or R ⁵ ) is a ring structure in the group formed. In the present invention, R ⁵ is preferably a halogen atom, a C1-6 alkyl group, a C1-6 alkoxy group, a C1-6 halogenalkyl group, a C1-6 halogenalkoxy group, a 3-6 membered cyclic group, a oxo group, -NR ⁵⁰¹ R ⁵⁰² , or -COOR ⁵⁰³ , more preferably a C1-6 alkyl group, a C1-6 alkoxy group, a C1-6 halogenalkyl group, a C1-6 halogenalkoxy group, a cyclopropyl group, a furan ring, an N-methylpyrazole ring, a oxo group, a dimethylamino group, or -COOCH ₃ , further preferably a C1-6 alkyl group, a C1-6 halogenalkyl group, a C1-6 halogenalkoxy group, or a cyclopropyl group.

In the present invention, R ^5-A is preferably a halogen atom, a C1-6 alkyl group, a C1-6 alkoxy group, a C1-6 halogenalkyl group, a C1-6 halogenalkoxy group, a 3-6 membered cyclic group, a oxo group, -NR ⁵⁰¹ R ⁵⁰² , or -COOR ⁵⁰³ , more preferably a C1-6 alkyl group, a C1-6 alkoxy group, a C1-6 halogenalkyl group, a C1-6 halogenalkoxy group, a cyclopropyl group, a furan ring, an N-methylpyrazole ring, a oxo group, a dimethylamino group, or -COOCH ₃ , further preferably a C1-6 alkyl group, a C1-6 halogenalkyl group, a C1-6 halogenalkoxy group, or a cyclopropyl group.

In the present invention, m is preferably 0 or 1.

In the present invention, n is preferably 0, 1 or 2.

In the present invention, p is preferably 0, 1 or 2.

In the present invention, the compound represented by the general formula (IA) or the general formula (I) is preferably a compound represented by the general formula (I-1): (wherein, R ^3-a represents (1) a hydrogen atom, (2) a C1-6 alkyl group, (3) a C1-6 halogen alkyl group, (4) a cyclopropyl group, or (5) -CH ₂ -Q, Q represents (1) benzene, (2) pyridine, or (3) imidazo[2,1-b]thiazole, ring1-a represents a ring structure selected from the following: [Chemical 1] (wherein the asterisk (*) indicates the bonding position to the carbonyl group, the hydrogen atom represented by NH may be substituted by R ^5-a ), R ^5-a represents (1) C1-6 alkyl, (2) C1-6 alkoxy, (3) C1-6 halogenalkyl, (4) C1-6 halogenalkoxy, (5) cyclopropyl, (6) furan ring, (7) N-methylpyrazole ring, (8) oxo group, (9) dimethylamino group, or (10) -COOCH ₃ , and other symbols have the same meanings as the above symbols).

In the present invention, the compound represented by the general formula (IA) is preferably a combination of the preferred definitions of ^X1 , ^X2 , ^R1 , ^R2 , ^R3 , ^R4 , R5 ^-A , ring1, n, m and p.

In the present invention, the compound represented by the general formula (I) is preferably a combination of the preferred definitions of ^X1 , ^X2 , ^R1 , ^R2 , ^R3 , ^R4 , ^R5 , ring1, n, m and p.

In the present invention, the compound represented by the general formula (I-A) or the general formula (I) in another form is preferably an example compound described in the examples described below or a pharmaceutically acceptable salt thereof.

In the present invention, unless otherwise specified, all isomers are included. For example, alkyl, alkoxy and alkylene groups include straight chain and branched chain. Furthermore, isomers in double bonds, rings, condensed rings (E/Z isomers, cis/trans isomers), isomers caused by the presence of asymmetric carbons (R/S isomers, α/β isomers, mirror image/non-mirror image isomers), optically active forms with optical activity (D/L/d/l isomers), polar isomers (high polarity/low polarity isomers) obtained by chromatography separation, balanced compounds, rotational isomers, mixtures of any ratio of these, and racemic mixtures are all included in the present invention. Furthermore, the present invention also includes all tautomeric isomers.

In this specification, compounds with "rel-" in their names indicate that the stereo configurations of multiple asymmetric centers are relative configurations.

In the present invention, unless otherwise specified, the following symbols are used in accordance with the common understanding of the industry: Indicates that the bond is on the opposite side of the paper (i.e., α-configuration), [Chemistry 1] Indicates that the bond is on the front side of the paper (i.e., β-configuration), [Chemistry 1] It represents any mixture of α-configuration and β-configuration.

[Salt] The compound represented by the general formula (I-A) is converted into a salt by a known method. The salt is a pharmaceutically acceptable salt. The salt is preferably a water-soluble salt.

As pharmaceutically acceptable salts, for example, acid addition salts, alkaline metal salts, alkaline earth metal salts, ammonium salts, or amine salts can be listed. As acid addition salts, for example, inorganic acid salts such as hydrochloric acid salts, hydrobromic acid salts, hydroiodic acid salts, sulfates, phosphates, and nitrates can be listed; or organic acid salts such as acetates, lactates, tartarates, benzoates, citrates, methanesulfonates, ethanesulfonates, trifluoroacetates, benzenesulfonates, toluenesulfonates, hydroxyethanesulfonates, glucuronic acid salts, or gluconates can be listed. Examples of alkali metal salts include potassium salts and sodium salts. Examples of alkali earth metal salts include 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-glucosamine salts.

Furthermore, the compounds of the present invention can be converted into N-oxides by any method. The so-called N-oxide refers to a compound represented by the general formula (I-A) in which the nitrogen atom is oxidized.

The compound represented by the general formula (I-A) and its pharmaceutically acceptable salt may exist in a non-solventized form or in a solventized form with a pharmaceutically acceptable solvent such as water or ethanol. As a solvent complex, a hydrate is preferred. The compound represented by the general formula (I-A) and its pharmaceutically acceptable salt may be converted into a solvent complex.

The compound represented by the general formula (I-A) can form a co-crystal with a suitable co-crystal former. As a co-crystal, it is preferably a pharmaceutically acceptable co-crystal former formed with a pharmaceutically acceptable co-crystal former. Co-crystals are typically defined as crystals formed by two or more different molecules through intermolecular interactions other than ionic bonds. In addition, co-crystals can also be complexes of neutral molecules and salts. Co-crystals can be prepared by known methods, such as by melt crystallization, by recrystallization from a solvent, or by physically pulverizing the components together. Suitable co-crystal formers include those described in WO2006/007448.

In the present invention, the description of the compound of the present invention includes the compound represented by the general formula (I-A), its pharmaceutically acceptable salt, its N-oxide, its solvate (such as hydrate), or its co-crystal, or the N-oxide of a pharmaceutically acceptable salt of the compound represented by the general formula (I-A), its solvate (such as hydrate), or its co-crystal.

[Prodrug] The so-called prodrug of the compound represented by the general formula (I-A) refers to a compound that is converted into the compound represented by the general formula (I-A) through a reaction mediated by enzymes or gastric acid in the body. As prodrugs of the compound represented by the general formula (I-A), for example, when the compound represented by the general formula (I-A) contains an amino group, examples include compounds in which the amino group is acylated, alkylated, or phosphorylated (for example, compounds in which the amino group of the compound represented by the general formula (I-A) is eicosanoylated, propylaminoacylated, pentylaminocarbonylated, (5-methyl-2-oxo-1,3-dioxol-4-yl)methoxycarbonylated, tetrahydrofuranylated, pyrrolidinylmethylated, tivaloyloxymethylated, acetyloxymethylated, or tert-butylated, etc.); when the compound represented by the general formula (I-A) contains a hydroxyl group, examples include compounds in which the hydroxyl group is acylated, alkylated, phosphorylated, or borated (for example, compounds in which the amino group of the compound represented by the general formula (I-A) is eicosanoylated, propylaminoacylated, pentylaminocarbonylated, (5-methyl-2-oxo-1,3-dioxol-4-yl)methoxycarbonylated, tetrahydrofuranylated, pyrrolidinylmethylated, tivaloyloxymethylated, acetyloxymethylated, or tert-butylated, etc. The compounds represented by the general formula (I-A) include compounds obtained by acetylation, palmitylation, propionylation, tivaloylation, succinylation, trans-butylene diacylation, propylamine acylation, dimethylaminomethyl carbonylation, etc. of the hydroxyl group of the compound represented by the general formula (I-A); when the compound represented by the general formula (I-A) contains a carboxyl group, the compounds may be exemplified as compounds obtained by esterification or acylation of the carboxyl group (e.g., compounds represented by the general formula (I-A) The carboxyl group of the compound is ethylated, phenylated, carboxylated, dimethylated, methylated, methylated, methylated, methylated, methylated, etc. The compounds can be prepared by methods known per se. The prodrug of the compound represented by general formula (I-A) may be a hydrate or a non-hydrate. Furthermore, the prodrug of the compound represented by the general formula (I-A) may also be a compound that is converted into the compound represented by the general formula (I-A) under physiological conditions as described in the 1990 edition of Guangchuan Bookstore's "Development of Pharmaceuticals", Vol. 7, "Molecular Design", pp. 163-198.

Furthermore, each atom constituting the compound represented by the general formula (IA) may be substituted by its isotope (e.g., 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.).

[Production method of the compound of the present invention] The compound of the present invention can be produced by adopting a known method, such as the method disclosed below, the method based on the method, 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 method shown in the examples, etc., with appropriate modification and combination. Salts can also be used as starting materials. The order of each reaction can be appropriately changed and adjusted according to the introduced protecting group or reaction conditions.

In addition, regarding compounds containing an amino group, a carboxyl group or a hydroxyl group, the compounds can be prepared by using a compound protected as necessary with a protecting group commonly used for these groups (e.g., protecting groups 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.

Examples of the protecting group for the carboxyl group include methyl, ethyl, t-butyl, trichloroethyl, benzyl (Bn), benzylmethyl, p-methoxybenzyl, trityl, and 2-chlorotrityl.

Examples of the protecting group for an amino group or a tetrazolyl group include benzyloxycarbonyl, tert-butoxycarbonyl, allyloxycarbonyl (Alloc), 1-methyl-1-(4-biphenylyl)ethoxycarbonyl (Bpoc), trifluoroacetyl, 9-fluorenylmethoxycarbonyl, benzyl (Bn), p-methoxybenzyl, benzyloxymethyl (BOM), and 2-(trimethylsilyl)ethoxymethyl (SEM).

Examples of the protecting group for a hydroxyl group or a hydroxyoxime 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), tri-pentyl, benzoyl, benzyl (Bn), p-methoxybenzyl, allyloxycarbonyl (Alloc), and 2,2,2-trichloroethoxycarbonyl (Troc).

The deprotection reaction can be carried out by the following known methods. For example, the following methods can be listed: (1) deprotection reaction by alkaline hydrolysis, (2) deprotection reaction under acidic conditions, (3) deprotection reaction by hydrogenation, (4) deprotection reaction of silane, (5) deprotection reaction using metal, (6) deprotection reaction using metal complex, etc. The specific description of the methods is as follows: (1) The deprotection reaction by alkali hydrolysis is carried out in an organic solvent (e.g. methanol, tetrahydrofuran (hereinafter referred to as THF), dioxane, etc.) using alkali metal hydroxides (e.g. sodium hydroxide, potassium hydroxide, lithium hydroxide, etc.), alkali earth metal hydroxides (e.g. barium hydroxide, calcium hydroxide, etc.), or carbonates (e.g. sodium carbonate, potassium carbonate, etc.) or their aqueous solutions, or mixtures thereof, at 0 to 40°C. (2) Deprotection reaction under acidic conditions, for example, in an organic solvent (e.g., dichloromethane, chloroform, dioxane, ethyl acetate, methanol, isopropanol, THF, anisole, etc.), in an organic acid (e.g., acetic acid, trifluoroacetic acid, methanesulfonic acid, p-toluenesulfonic acid, etc.), or an inorganic acid (e.g., hydrochloric acid, sulfuric acid, etc.), or a mixture thereof (e.g., hydrobromic acid/acetic acid, etc.), in the presence or absence of 2,2,2-trifluoroethanol, at 0-100°C. (3) The deprotection reaction by hydrogenation is carried out 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.), nitrile (e.g., acetonitrile, etc.), amides (e.g., N,N-dimethylformamide (hereinafter referred to as DMF)), water, ethyl acetate, acetic acid, or a mixed solvent of two or more thereof), in the presence of a catalyst (e.g., palladium-carbon, palladium black, palladium hydroxide-carbon, platinum oxide, Raeder nickel, etc.), in a hydrogen atmosphere under normal pressure or pressure, or in the presence of ammonium formate, at 0 to 200°C. (4) The deprotection reaction of silyl groups is carried out, for example, in an organic solvent that can be mixed with water (such as THF, acetonitrile, etc.) using tetrabutylammonium fluoride at 0 to 40°C. Alternatively, it is carried out, for example, in an organic acid (such as acetic acid, trifluoroacetic acid, methanesulfonic acid, p-toluenesulfonic acid, etc.), or an inorganic acid (such as hydrochloric acid, sulfuric acid, etc.), or a mixture thereof (such as hydrobromic acid/acetic acid, etc.) at -10 to 100°C. (5) The deprotection reaction using metals is carried out, for example, in an acidic solvent (such as acetic acid, a buffer solution of pH 4.2 to 7.2, or a mixture of such solutions and an organic solvent such as THF) in the presence of zinc powder, while applying ultrasound as needed at 0 to 40°C. (6) Deprotection reaction using metal complexes, for example, in an organic solvent (e.g., dichloromethane, DMF, THF, ethyl acetate, acetonitrile, dioxane, ethanol, etc.), water, or a mixed solvent thereof, in the presence of a capture agent (e.g., tributyltin hydroxide, triethylsilane, damone, 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., tetrakis(triphenylphosphine)palladium(0), dichlorobis(triphenylphosphine)palladium(II), palladium(II), tris(triphenylphosphine)rhodium(I) chloride, etc.), at 0-40°C.

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

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

The cross-coupling reaction is well known. For example, it is carried out by reacting a base (sodium ethoxide, sodium hydroxide, potassium hydroxide, triethylamine, sodium carbonate, sodium bicarbonate, potassium carbonate, cesium carbonate, potassium carbonate, tripotassium phosphate, cesium fluoride, barium hydroxide, tetrabutylammonium fluoride, etc.) or its aqueous solution or a mixture thereof, and a catalyst (tetrakis(triphenylphosphine)palladium (Pd(PPh ₃ ) ₄ ), bis(triphenylphosphine)palladium dichloride (PdCl ₂ (PPh ₃ ) ₂ ), palladium acetate (Pd(OAc) ₂ ), palladium black, 1,1'-bis(diphenylphosphinoferrocene)palladium dichloride (PdCl ₂ (dppf) ₂ ), diallylpalladium dichloride (PdCl ₂ (allyl) ₂ ), phenylbis(triphenylphosphine)palladium iodide (PhPdI(PPh ₃ ) ₂ ), etc.), and the reaction is carried out at room temperature to 120°C.

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

Reaction 1-3 in Reaction Scheme 1 is a deprotection reaction, which can be carried out by the same method as described above.

Reaction 1-4 in reaction step formula 1 is an acylation reaction. The acylation reaction is well known, and examples thereof include: (1) a method using an acyl halide; (2) a method using a mixed acid anhydride; (3) a method using a condensation agent; etc. The specific description of these methods is as follows: (1) The method using acyl halide can be carried out by, for example, reacting a carboxylic acid with an acyl halogenating agent (oxalyl chloride, sulfinyl chloride, etc.) in an organic solvent (chloroform, dichloromethane, diethyl ether, THF, etc.) or in the absence of a solvent at -20°C to reflux temperature, and reacting the obtained acyl 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 reaction can be carried out by reacting the obtained acyl halide with an amine in an organic solvent (dioxane, THF, etc.) using an alkaline aqueous solution (sodium bicarbonate solution or sodium hydroxide solution, etc.) at 0 to 40°C. (2) The method using mixed acid anhydrides can be carried out by, for example, reacting carboxylic acid with acyl halide (tivalyl chloride, toluenesulfonyl chloride, methanesulfonyl chloride, etc.) or acid derivatives (ethyl chloroformate, isobutyl chloroformate, etc.) in an organic solvent (chloroform, dichloromethane, diethyl ether, THF, etc.) or in the absence of a solvent in the presence of a base (pyridine, triethylamine, dimethylaniline, dimethylaminopyridine, diisopropylethylamine, etc.) at 0 to 40°C, and reacting the obtained mixed acid anhydride with amine in an organic solvent (chloroform, dichloromethane, diethyl ether, THF, etc.) at 0 to 40°C. (3) Methods using a condensing agent: For example, a carboxylic acid and an amine may be reacted in an organic solvent (chloroform, dichloromethane, DMF, diethyl ether, THF, etc.) or in the absence of a solvent, in the presence or absence of a base (pyridine, triethylamine, dimethylaniline, dimethylaminopyridine, etc.), using 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-propanephosphonic acid cyclic anhydride) anhydride, PPA, etc.), O-(7-azabenzotriazole-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU), in the presence or absence of 1-hydroxybenzotriazole (HOBt) at 0-40°C. The reactions (1), (2) and (3) are preferably carried out in an inert gas (argon, nitrogen, etc.) atmosphere and under anhydrous conditions.

The compound represented by general formula 1a can be prepared according to reaction step 2. [Chemistry 1] (In reaction step 2, all symbols have the same meanings as above)

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

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

Reaction 2-3 in reaction formula 2 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.

Reaction 2-4 in reaction formula 2 is an aziridation reaction, which can be carried out, for example, by reacting sodium aziridation in an organic solvent (DMF, dimethyl sulfoxide, chloroform, dichloromethane, diethyl ether, THF, methyl tert-butyl ether, etc.) at a temperature of 0 to 100°C.

Reaction 2-5 in reaction formula 2 is a reduction reaction of an azido 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 mixed solvent of two or more thereof), in the presence of a hydrogenation catalyst (palladium-carbon, palladium black, palladium, palladium hydroxide, platinum dioxide, platinum-carbon, nickel, Raney nickel, ruthenium chloride, etc.), in the presence or absence of an acid (hydrochloric acid, sulfuric acid, hypochlorous acid, boric acid, tetrafluoroboric acid, acetic acid, p-toluenesulfonic acid, oxalic acid, trifluoroacetic acid, formic acid, etc.), at normal pressure or in a hydrogen atmosphere under pressure, at 0 to 200°C.

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

The optically active compounds in the compounds of the present invention can be produced by using optically active starting materials or reagents, or by optically resolving the racemic intermediates and then introducing them into the compounds of the present invention, or by optically resolving the racemic compounds of the present invention. The optical resolution is well known, and examples thereof include: forming salts, complexes, etc. with other optically active compounds, isolating the target compound after recrystallization, or directly using chiral columns, etc. for separation.

In each reaction in this specification, the reaction accompanied by heating can be carried out in a water bath, oil bath, sand bath or microwave as known to those skilled in the art.

In each reaction in this specification, a solid phase supporting reagent supported on a high molecular polymer (such as polystyrene, polyacrylamide, polypropylene, polyethylene glycol, etc.) can be used appropriately.

In each reaction in this specification, the reaction product can be purified by conventional purification means, such as distillation under normal pressure or reduced pressure, high performance liquid chromatography using silica gel or magnesium silicate, thin layer chromatography, ion exchange resin, resin removal or column chromatography or washing, recrystallization, etc. Purification can be performed for each reaction one by one, or after several reactions are completed.

[Toxicity] The compound of the present invention has low toxicity, and therefore, the pharmaceutical composition containing the compound of the present invention can be used safely.

[Pharmaceutical composition] The compound of the present invention has inhibitory activity against ABHD6. Therefore, the pharmaceutical composition containing the compound of the present invention can be used as a preventive and/or therapeutic agent for ABHD6-related diseases such as pain, neurological diseases, inflammatory diseases, autoimmune diseases, metabolic diseases, malignant tumors, etc.

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, fracture pain, pain associated with rheumatoid arthritis, neurological pain, post-herpetic pain, pain associated with diabetic neuropathy, fibromyalgia, pain associated with pancreatitis, pain associated with interstitial cystitis and bladder pain syndrome, pain associated with endometrial disease, pain associated with irritable bowel syndrome, migraine, and pain associated with pulpitis.

Examples of neurological diseases include: tremor, dyskinesia, dystonia, contracture, compulsive and obsessive behaviors, depression, mental illness including anxiety (e.g. panic disorder, acute stress reaction, post-traumatic stress disorder, obsessive-compulsive disorder, space phobia, social anxiety disorder), affective disorders, epilepsy, traumatic brain injury, spinal cord injury, multiple sclerosis, encephalomyelitis, Parkinson's disease, Huntington's chorea, Alzheimer's disease, sleep disorders, etc.

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

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

Examples of metabolic diseases include obesity, metabolic syndrome, lipid abnormalities, diabetes, and fatty liver.

Examples of malignant tumors include breast cancer, ovarian cancer, colorectal cancer (e.g., colon cancer, etc.), lung cancer (e.g., non-small cell lung cancer, etc.), 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, vestibular schwannoma, etc.). schwannoma), lymphoma (e.g. B-cell lymphoma, T-cell lymphoma), uveal malignant melanoma, thymoma, mesothelioma, esophageal cancer, gastric cancer, duodenal cancer, hepatocellular carcinoma, bile duct cancer, gallbladder cancer, pancreatic cancer, renal cell cancer, renal pelvis and urethra 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, etc.

In this specification, the prevention and/or treatment of malignant tumors includes treatments based on the following purposes, such as (a) to reduce the proliferation of cancer cells; (b) to reduce the symptoms caused by cancer and to improve the quality of life of cancer patients; (c) to reduce the dose of other anticancer agents or cancer treatment adjuvants that have been administered; (d) to inhibit cancer development; (e) for cancer recurrence; and/or (f) to prolong the survival of cancer patients. In addition, the so-called "inhibiting cancer development" means delaying the progression of cancer, stabilizing cancer-related symptoms, and delaying the progression of symptoms. The so-called "inhibiting recurrence" means preventively inhibiting the recurrence of cancer in patients whose cancer lesions have been completely or substantially eliminated or removed through treatment or surgical resection.

The pharmaceutical composition containing the compound of the present invention usually contains a pharmaceutically acceptable carrier. When the pharmaceutical composition containing the compound of the present invention is used for the purpose of preventing and/or treating the above-mentioned diseases, the compound of the present invention as an active ingredient is usually formulated together with various additives or solvents and pharmaceutically acceptable carriers, and then administered systemically or locally in an oral or parenteral form. Here, the so-called pharmaceutically acceptable carrier refers to a substance other than the active ingredient that can be generally used in the preparation of a pharmaceutical product. The pharmaceutically acceptable carrier is preferably one that does not cause pharmacological effects, is harmless, and does not affect the therapeutic effect of the active ingredient in the amount administered in the preparation. In addition, pharmaceutically acceptable carriers may be used for the purpose of improving the usefulness of active ingredients and preparations, facilitating preparation, achieving quality stabilization, or optimizing usability. Specifically, depending on the purpose, substances listed in the 2000 edition of the Yakuji Nichijyousha "Dictionary of Pharmaceutical Additives" (compiled by the Japan Pharmaceutical Additives Association) may be appropriately selected.

The pharmaceutical composition containing the compound of the present invention can be a pharmaceutical composition for administration to a subject (preferably a mammal, more preferably a human, and even more preferably a human patient) in a pharmaceutically effective amount of the compound of the present invention.

The dosage of the compound of the present invention depends on age, weight, symptoms, desired therapeutic effect, route of administration, duration of treatment, etc., and therefore will inevitably vary. Generally speaking, the dosage is orally administered within the range of 0.1 ng to 1000 mg per patient per time, or parenterally administered within the range of 0.01 ng to 100 mg per patient per time, or continuously administered intravenously.

Of course, as described above, the dosage of the compound of the present invention varies depending on various conditions, and there are cases where a smaller dosage than the above dosage is sufficient, or where the required dosage exceeds the above range.

The pharmaceutical composition containing the compound of the present invention can be prepared in various dosage forms. Examples of the dosage forms include: oral preparations (e.g., tablets, capsules, granules, powders, oral liquids, syrups, oral jelly, etc.), oral preparations (e.g., oral tablets, oral sprays, oral semisolids, gargles, etc.), injection preparations (e.g., injections, etc.), dialysis preparations (e.g., dialysis preparations, etc.), inhalation preparations, and oral preparations. Preparations for use in the treatment of diseases such as cataracts (e.g., inhalants, etc.), ophthalmic preparations (e.g., eye drops, eye ointments, etc.), otologic preparations (e.g., ear drops, etc.), nasal preparations (e.g., nasal drops, etc.), rectal preparations (e.g., suppositories, rectal semisolids, enema, etc.), vaginal preparations (e.g., vaginal tablets, vaginal suppositories, etc.), and dermal preparations (e.g., external solid preparations, external liquids, sprays, ointments, creams, gels, patches, etc.).

[Oral preparations] Oral preparations include, for example, tablets, capsules, granules, powders, oral liquids, syrups, oral jelly, etc. In addition, oral preparations include fast-disintegrating preparations in which the release of the active ingredient from the preparation is not specially adjusted, and release-regulated preparations such as enteric preparations or sustained-release preparations in which the release is adjusted according to the purpose by inherent preparation design and production methods. Enteric preparations are designed to prevent the active ingredients from being decomposed in the stomach or to reduce the irritation of the active ingredients to the stomach. They are mainly released in the small intestine and are usually manufactured by using an acid-insoluble enteric base to form a film. Sustained-release preparations are preparations that adjust the release rate, release time, and release site of the active ingredients from the preparation in order to reduce the number of doses or reduce side effects. They are usually manufactured by using appropriate sustained-release agents. For capsules, granules, tablets, etc. in oral preparations, in order to facilitate administration or prevent the decomposition of active ingredients, appropriate film coating agents such as sugars, sugar alcohols, and high molecular compounds can also be used to form the coating.

(1) Tablets Tablets are solid preparations of a certain shape that are administered orally, including plain tablets, film-coated tablets, sugar-coated tablets, multi-layer tablets, core tablets, etc., as well as rapidly disintegrating tablets, chewable tablets, foaming tablets, dispersible tablets, and dissolving tablets. When making plain tablets, the following methods (a), (b) or (c) are usually used: (a) Adding excipients, binders, disintegrants and other additives to the active ingredients, mixing them into a homogeneous mixture, using water or a solution containing a binder, making granules by an appropriate method, adding lubricants and the like, mixing, and compressing to form; (b) Adding excipients, binders, disintegrants and other additives to the active ingredients and mixing them into a homogeneous mixture, and then directly compressing to form, or adding active ingredients and lubricants to granules previously made with additives, mixing them into a homogeneous mixture, and then compressing to form; (c) Adding additives such as excipients and binders to the active ingredients, mixing them into a homogeneous mixture and wetting them with a solvent to form a kneaded product, which is then poured into a certain mold for molding and then dried by an appropriate method. Film-coated tablets can usually be manufactured by using a suitable film-coating agent such as a polymer compound to form a thin film on a plain tablet. Sugar-coated tablets can usually be manufactured by using a film-coating agent containing sugars or sugar alcohols to form a film on a plain tablet. Multi-layer tablets can be manufactured by stacking powders and particles of different compositions in layers by an appropriate method and compressing them into shape. Core tablets can be manufactured by coating an inner core tablet with an outer layer of a different composition from the inner core tablet. Tablets can also be made into enteric tablets or sustained-release tablets by known appropriate methods. Orally rapidly disintegrating tablets, chewable tablets, foaming tablets, dispersible tablets and dissolving tablets are tablets that are endowed with unique functions by selecting appropriate additives, and can be manufactured according to the manufacturing methods of the above-mentioned tablets. Furthermore, the so-called orally rapidly disintegrating tablets refer to tablets that can be quickly dissolved or disintegrated in the mouth; the so-called chewable tablets refer to tablets that are chewed and taken; the so-called foaming tablets refer to tablets that dissolve or disperse while rapidly foaming in water; the so-called dispersible tablets refer to tablets that are dispersed in water and taken; the so-called dissolving tablets refer to tablets that are dissolved in water and taken. Effervescent tablets can be manufactured by using appropriate acidic substances, carbonates, bicarbonates, etc. in additives.

(2) Capsules Capsules are preparations that are filled into capsules or formed by coating with a capsule base, including hard capsules, soft capsules, etc. Hard capsules can be made by adding additives such as excipients to the active ingredients and mixing them into a homogeneous mixture, or by making them into granules or shapes using an appropriate method, and then filling them into capsules after direct or slight shaping. Soft capsules can be made by using an appropriate capsule base such as gelatin to which glycerin, D-sorbitol, etc. are added to enhance plasticity, coating the active ingredients with additives, and then forming them into a certain shape. Capsules can also be made into enteric-soluble capsules or sustained-release capsules by known appropriate methods. In addition, colorants or preservatives can be added to the capsule base.

(3) Granules Granules are preparations that are granulated into granules, including those generally called granules and foamable granules. When making granules, the following methods (a), (b) or (c) are usually adopted: (a) Adding excipients, binders, disintegrants or other additives to the powdered active ingredient, mixing them into a homogeneous mixture, and then making them into granules by an appropriate method; (b) Adding excipients and other additives to the active ingredient that has been pre-granulated into granules, and mixing them into a homogeneous mixture; (c) Adding excipients and other additives to the active ingredient that has been pre-granulated into granules, mixing them, and making them into granules by an appropriate method. If necessary, the granules can be coated with a coating, and can also be made into enteric soluble granules or sustained-release granules by known appropriate methods. Foaming granules can be made by using appropriate acidic substances, carbonates, bicarbonates, etc. in additives. Furthermore, the so-called foaming granules refer to granules that dissolve or disperse in water while rapidly foaming. Granules can also be made into fine granules by adjusting the size of the particles.

(4) Powders Powders are powdered preparations that are usually made by adding excipients or other additives to the active ingredients and mixing them into a homogeneous mixture.

(5) Oral liquids Oral liquids are liquid preparations or viscous gel preparations with fluidity, including those generally referred to as oral liquids, as well as elixirs, suspensions, emulsions, lemonades, etc. Oral liquids are usually produced by adding purified water and additives to the active ingredients, mixing them to dissolve, emulsify or suspend them homogeneously, and filtering them as needed. The so-called elixir refers to a clear liquid oral liquid containing ethanol with a sweet taste and aroma. It is usually produced by adding ethanol, purified water, flavoring agents, and white sugar, other sugars, or sweeteners to the solid active ingredients or their extracts to dissolve them, and then filtering or other methods to make a clear liquid. The so-called suspension refers to an oral liquid in which the active ingredient is finely and uniformly suspended. It can usually be made by adding a suspending agent or other additives and purified water or oil to the solid active ingredient, suspending it by an appropriate method, and making the whole into a homogeneous state. The so-called emulsion refers to an oral liquid in which the active ingredient is finely and uniformly emulsified. It can usually be made by adding an emulsifier and purified water to the liquid active ingredient, emulsifying it by an appropriate method, and making the whole into a homogeneous state. In addition, the so-called lemonade refers to a clear liquid oral liquid with sweet and sour taste.

(6) Syrups Syrups are viscous liquid or solid preparations containing sugars or sweeteners, including syrup preparations. Syrups are usually made by adding active ingredients to a solution of white sugar, other sugars, or sweeteners, or a monosaccharide syrup, dissolving, mixing, suspending or emulsifying the mixture, and then boiling the mixture as needed and hot filtering it. The so-called syrup preparation refers to a granular or powdered preparation that is made into a syrup by adding water, and is sometimes also called dry syrup. Syrup preparations are usually made using sugars or sweeteners as additives according to the manufacturing methods of the above-mentioned granules or powders.

(7) Oral jelly Oral jelly is a non-flowable, shaped gel preparation. It is usually produced by adding a mixed additive and a polymer gel base to the active ingredient, gelling it using an appropriate method and shaping it into a certain shape.

[Injectable preparations] (1) Injectables Injectables are solutions, suspensions or emulsions that are directly administered into tissues or organs in the body, such as the subcutaneous, intramuscular or blood vessels, or solid sterile preparations that are dissolved or suspended for use. They include those generally known as injectables, as well as freeze-dried injectables, powdered injectables, prefilled injectables, syringe-filled injectables (cartridges), infusions, implantable injectables, and continuous injectables. When manufacturing injections, the following methods (a) or (b) are usually used: (a) The active ingredient is directly dissolved, suspended or emulsified in water for injection, other aqueous solvents or non-aqueous solvents to form a homogeneous state, or the active ingredient is added with additives, and then filled into a container for injection, sealed and sterilized; (b) The active ingredient is directly dissolved, suspended or emulsified in water for injection, other aqueous solvents or non-aqueous solvents to form a homogeneous state, or the active ingredient is aseptically filtered, or aseptically prepared and homogenized, and then filled into a container for injection and sealed. Freeze-dried injections are usually produced by freeze-drying the active ingredient directly, or dissolving the active ingredient and additives such as excipients in water for injection, aseptically filtering, filling in a container for injection and then freeze-drying, or freeze-drying in a special container and then filling in a direct container. Powder injections are usually produced by filling a container for injection with a powder obtained by crystallization after aseptic filtration or adding a sterilized additive to the powder. Pre-filled injections are usually produced by directly using the active ingredient, or using the active ingredient and additives to prepare a solution, suspension or emulsion and then filling it in a syringe. The so-called syringe-filled injection refers to an injection that is used by installing a syringe filled with liquid medicine in a special syringe. The syringe filled with liquid medicine can usually be manufactured by directly using the active ingredient, or by using the active ingredient and additives to prepare a solution, suspension or emulsion and then filling it into the syringe. The so-called infusion refers to an injection of usually more than 100 mL that is administered intravenously. The so-called implantable injection refers to a solid or gel-like drug that is suitable for injection subcutaneously, intramuscularly, etc. using an implantable device or by surgery in order to release the active ingredient for a long time. Implantable injections can usually be manufactured by using biodegradable polymer compounds to form particles, microspheres (microspheres) or gels. The so-called sustained-release injection refers to an injection that is applied intramuscularly, etc., in order to release the active ingredient for a long time. It can usually be manufactured by dissolving or suspending the active ingredient in vegetable oil, etc., or making a suspension of microspheres using biodegradable polymer compounds.

The pharmaceutical composition containing the compound of the present invention may also be a pharmaceutical composition (or adjuvant) administered in combination with other drugs, thereby 1) assisting and/or enhancing the preventive and/or therapeutic effects of the compound of the present invention; 2) improving the pharmacokinetics and absorption of the compound of the present invention, reducing the dosage; and/or 3) reducing the side effects of the compound of the present invention.

As the above-mentioned pharmaceutical composition (or agent), it can be administered in the form of a compound in which two components are prepared in one preparation, or it can be administered separately in the form of separate preparations. In the case of separate administration of separate preparations, it includes simultaneous administration and administration with a time difference. In addition, when administering with a time difference, the compound of the present invention can be administered first and then other drugs, or other drugs can be administered first and then the compound of the present invention. The respective administration methods can be the same or different.

The diseases for which the pharmaceutical composition (or adjuvant) exerts preventive and/or therapeutic effects are not particularly limited, and the above-mentioned adjuvant may assist and/or enhance the preventive and/or therapeutic effects of the compound of the present invention.

Other drugs used to assist and/or enhance the preventive and/or therapeutic effects of the compounds of the present invention on pain include, for example: acetaminophen, nonsteroidal anti-inflammatory drugs, opioids, antidepressants, antiepileptic drugs, N-methyl-D-aspartate antagonists, muscle relaxants, antiarrhythmic drugs, steroids, and bisphosphonates, etc. Examples of nonsteroidal anti-inflammatory drugs include: salicylic acid, sodium salicylate, aspirin, aspirin preparations such as aspirin-dialuminate combination, diflunisal, indomethacin, suprofen, ulfenamic acid, dimethylisopropylazulene, bufenac, felbinac, diclofenac, tolmetin sodium, sulindac, phentermine, nabumetone, proglumetacin, indomethacin farnesate, acemetacin, proglumetacin citric acid, amfenac sodium, mofetil, etofenadine, ibuprofen, ibuprofen pyridoxine, Methyl ester, naproxen, flurbiprofen, flurbiprofen axetil, ketoprofen, fenoprofen calcium, thiaprofen, oxaprozin, pranoprofen, loxoprofen sodium, alminoprofen, zatoprofen, mefenamic acid, mefenamic acid aluminum, tolfenamic acid, flofenine, ketobutazone, oxybutazone, piroxicam, tenoxicam, ampiroxicam, Napageln ointment, epiriazole, thiamide hydrochloride, tenolidine hydrochloride, emfazone, serbilin, migrenin, salidomide, Sedes G, Amipylo-N, Sorbon, pyrine cold medicine, acetaminophen, phenacetin, dimethylphenidate mesylate, meloxicam, celecoxib, rofecoxib, valdecoxib, simetride combination, and pyrine cold medicine, etc. As opium-like drugs, for example, codeine, fentanyl, hydromorphone, levomotor, meperidine, methadone, morphine, oxycodone, oxymorphone, propoxyphene, and tramadol, etc. Examples of antidepressants include tricyclic antidepressants (e.g., amitriptyline hydrochloride, imipramine hydrochloride, clomipramine hydrochloride, dosiopin hydrochloride, nortriptyline hydrochloride, lofepramine hydrochloride, trimipramine citric acid, amoxapine, etc.), tetracyclic antidepressants (e.g., maprotiline hydrochloride, mianserin hydrochloride, setiptiline citric acid, etc.), monoamine oxidase (MAO) inhibitors (safrazine hydrochloride, hydrochloride), serotonin and norepinephrine reuptake inhibitors (SNRI) (e.g., milnacipran hydrochloride, venlafaxine hydrochloride, etc.), selective serotonin reuptake inhibitors (SSRI) (e.g., fluvoxamine citric acid, paroxetine hydrochloride, fluoxetine hydrochloride, citalopram hydrochloride, etc.), and serotonin reuptake inhibitors (e.g., trazodone hydrochloride, etc.). Anti-epileptic drugs include, for example, phenobarbital, puridomin, phenytoin, ethosuximide, zonisamide, nitrazepam, clonazepam, carbazapine, sodium valproate, acetazolamide, and sulthiamide. Examples of N-methyl-D-aspartate antagonists include ketamine hydrochloride, adamantamine hydrochloride, methaquinone hydrochloride, dextromethorphan, and methadone. Examples of muscle relaxants include succinylcholine, suxamethonium, vecuronium bromide, pancuronium bromide, and dantrolene sodium. As antiarrhythmic drugs, for example, procainamide, disopyramide, cibenzoline, pirmenol, lidocaine, mexiletine, apridin, pilsicainide, flecainide, propafenone, propranolol, atenolol, bisoprolol, amiodarone, sotalol, verapamil, diltiazem, and bepridil, etc. As steroid drugs, for example, as topical drugs, mometasone furoate, betamethasone dipropionate, betamethasone dipropionate, betamethasone valerate, difluprednate, budesonide, diflumethasone valerate, amcinonide, clobetasol propionate, dexamethasone, propionic acid Dexamethasone, dexamethasone valerate, dexamethasone acetate, hydrocortisone acetate, hydrocortisone butyrate, hydrocortisone butyrate propionate, depoxetine propionate, prednisolone valerate acetate, fluocinolone, beclomethasone dipropionate, triamcinolone acetonide, flumethasone pivalate, alclomethasone dipropionate, clobetasone butyrate, prednisolone, beclomethasone dipropionate, and fluanolone solnide, etc. As oral or injectable drugs, the following can be listed: cortisone acetate, hydrocortisone, hydrocortisone sodium phosphate, hydrocortisone sodium succinate, fluhydrocortisone acetate, prednisolone, prednisolone acetate, prednisolone sodium succinate, butyl prednisolone acetate, prednisolone sodium phosphate, halogen prednisolone acetate, methyl prednisolone, methyl prednisolone acetate, methyl prednisolone sodium succinate, triamcinolone, triamcinolone acetate, triamcinolone acetonide, dexamethasone, dexamethasone acetate, dexamethasone sodium phosphate, dexamethasone palmitate, paramethasone acetate, and betamethasone, etc. As inhaled drugs, for example, beclomethasone dipropionate, fluticasone propionate, budesonide, flunisolide, triamcinolone, ST-126P, ciclesonide, dexamethasone palmitate, mometasone furoate, prasterone sulfonate, deflazacort, methylprednisolone sulfonate heptazone, and methylprednisolone sodium succinate, etc. As bisphosphonates, for example, etidronate, pamidronate, alendronate, risedronate, zoledronic acid, and minodronic acid, etc. Any two or more other drugs may be administered in combination.

Furthermore, other drugs used to assist and/or enhance the preventive and/or therapeutic effects of the compounds of the present invention include not only those currently discovered based on the above-mentioned mechanism, but also those discovered in the future.

Unless otherwise explained, all technical/scientific terms and abbreviations used in this specification have the same meaning as generally understood by those skilled in the art to which the present invention belongs.

In addition, the contents of all patent documents, non-patent documents or reference documents explicitly cited in this specification may be cited as part of this specification.

The present invention provides the following embodiments in one form. [1] A pharmaceutical composition comprising the following compound or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, wherein the compound is represented by the general formula (IA): (wherein, ^X1 and ^X2 independently represent (1) CH, (2) ^CRX , or (3) N, wherein at least one of ^X1 and ^X2 represents N, ^R1 represents a halogen atom, ^RX represents (1) a halogen atom, (2) a C1-6 alkyl group, (3) a C2-6 alkenyl group, (4) a C2-6 alkynyl group, (5) a C1-6 alkoxy group, (6) a C1-6 halogenalkyl group, (7) a C2-6 halogenalkenyl group, (8) a C2-6 halogenalkynyl group, (9) a C1-6 halogenalkoxy group, or (10) a cyano group, R ^R2 represents (1) a halogen atom, (2) a C1-6 alkyl group, (3) a C2-6 alkenyl group, (4) a C2-6 alkynyl group, (5) a C1-6 alkoxy group, (6) a C1-6 halogen alkyl group, (7) a C2-6 halogen alkenyl group, (8) a C2-6 halogen alkynyl group, (9) a C1-6 halogen alkoxy group, or (10) a cyano group. When m is 2 or more, a plurality of ^R2s may be the same or different. ^{R 3} represents (1) a hydrogen atom, (2) a C1-6 alkyl group, (3) a C1-6 halogen alkyl group, (4) a 3-10 membered cyclic group, (5) -(C1-6 alkylene)-(3-10 membered cyclic group), (6) -(C1-6 halogen alkylene)-(3-10 membered cyclic group), 1 to 2 carbon atoms in the C1-6 alkyl group, C1-6 halogen alkyl group, C1-6 alkylene group and C1-6 halogen alkylene group may be substituted by an oxygen atom or an oxidizable sulfur atom, the 3-10 membered cyclic group in R ³ may be substituted by 1 to 5 R ³⁰¹ , R ³⁰¹ represents (1) a halogen atom, (2) a C1-4 alkyl group, (3) a C1-4 alkoxy group, (4) a C1-4 halogen alkyl group, (5) a C1-4 halogen alkoxy group, (6) COOR ³⁰² , (7) CONR ³⁰³ R ³⁰⁴ , (8) C3-6 cycloalkyl, (9) hydroxyl, (10) nitro, (11) cyano, (12) -NR ³⁰⁵ R ³⁰⁶ , (13) -SR ³⁰⁷ , (14) -SOR ³⁰⁸ , (15) -SO ₂ R ³⁰⁹ , or (16) oxo, when substituted by two or more R ³⁰¹ , the plurality of R ^{301 s} 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, and R ² represents ( ² ) to (9), R When R ³ represents a C1-6 alkyl group, R ² and R ³ may form a 5-6 membered cyclic group together with the atom to which they are bonded. R ⁴ represents (1) a halogen atom, (2) a C1-6 alkyl group, (3) a C2-6 alkenyl group, (4) a C2-6 alkynyl group, (5) a C1-6 alkoxy group, (6) a C1-6 halogen alkyl group, (7) a C2-6 halogen alkenyl group, (8) a C2-6 halogen alkynyl group, or (9) a C1-6 halogen alkoxy group. When n is 2 or more, a plurality of R ⁴ may be the same or different. When two R ⁴ on the same carbon atom represent a C1-6 alkyl group, they may form a C3-6 cycloalkyl group together with the carbon atom to which they are bonded. ring1 represents a 3-15 membered cyclic group. R ^5-A represents (1) a halogen atom, (2) a C1-6 alkyl group, (3) a C2-6 alkenyl group, (4) a C2-6 alkynyl group, (5) a C1-6 alkoxy group, (6) a C1-6 alkylthio group, (7) a C1-6 alkylsulfinyl group, (8) a C1-6 alkylsulfonyl group, (9) a C2-6 acyl group, (10) a 3-6 membered cyclic group, (11) ^-LR5- (3-6 membered cyclic group), (12) a hydroxy group, (13) a nitro group, (14) a cyano group, (15) a ^oxo group ^, (16) ^{-NR501R502 ,} (17) ^{-COOR503 ,} (18) ^-CONR504R505 , or (19) _{-SO2NR506R507} , 1 to 2 carbon atoms in the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxy, C1-6 alkylthio, C1-6 alkylsulfinyl, C1-6 alkylsulfonyl, or C2-6 acyl group may be substituted with an oxygen atom or an oxidizable sulfur atom. When p is 2 or more, the plurality of R ^5-A may be the same or different. The groups (2) to (11) in R ^5-A may be substituted with 1 to 9 R ^508. R ⁵⁰⁸ represents (1) a halogen atom, (2) a C1-4 alkyl, (3) a C1-4 alkoxy, (4) a C2-6 acyl group, (5) a C3-6 cycloalkyl group, (6) a hydroxyl group, or (7) -NR ⁵⁰⁹ R ^510. When substituted with 2 or more R ⁵⁰⁸ , the plurality of R ^{R 508} may be the same or different, L ^R5 represents (1) -O-, (2) -(C1-4 alkylene)-, (3) -O-(C1-4 alkylene)-, (4) -(C1-4 alkylene)-O-, (5) -NR ⁵¹¹ -, or (6) -SO _0-2 -, 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 C1-6 alkyl group, (3) a C2-6 acyl group, or (4) a C1-6 alkylsulfonyl ^group , m represents an integer from 0 to 2, n represents an integer from 0 to 5, and p represents an integer from 0 to 5). [2] A pharmaceutical composition comprising the following compound or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, wherein the compound is represented by the general formula (I): (wherein, ^X1 and ^X2 independently represent (1) CH, (2) ^CRX , or (3) N, wherein at least one of ^X1 and ^X2 represents N, ^R1 represents a halogen atom, ^RX represents (1) a halogen atom, (2) a C1-6 alkyl group, (3) a C2-6 alkenyl group, (4) a C2-6 alkynyl group, (5) a C1-6 alkoxy group, (6) a C1-6 halogenalkyl group, (7) a C2-6 halogenalkenyl group, (8) a C2-6 halogenalkynyl group, (9) a C1-6 halogenalkoxy group, or (10) a cyano group, R ^R2 represents (1) a halogen atom, (2) a C1-6 alkyl group, (3) a C2-6 alkenyl group, (4) a C2-6 alkynyl group, (5) a C1-6 alkoxy group, (6) a C1-6 halogen alkyl group, (7) a C2-6 halogen alkenyl group, (8) a C2-6 halogen alkynyl group, (9) a C1-6 halogen alkoxy group, or (10) a cyano group. When m is 2 or more, a plurality of ^R2s may be the same or different. ^{R 3} represents (1) a hydrogen atom, (2) a C1-6 alkyl group, (3) a C1-6 halogen alkyl group, (4) a 3-10 membered cyclic group, (5) -(C1-6 alkylene)-(3-10 membered cyclic group), (6) -(C1-6 halogen alkylene)-(3-10 membered cyclic group), 1 to 2 carbon atoms in the C1-6 alkyl group, C1-6 halogen alkyl group, C1-6 alkylene group and C1-6 halogen alkylene group may be substituted by an oxygen atom or an oxidizable sulfur atom, the 3-10 membered cyclic group in R ³ may be substituted by 1 to 5 R ³⁰¹ , R ³⁰¹ represents (1) a halogen atom, (2) a C1-4 alkyl group, (3) a C1-4 alkoxy group, (4) a C1-4 halogen alkyl group, (5) a C1-4 halogen alkoxy group, (6) COOR ³⁰² , (7) CONR ³⁰³ R ³⁰⁴ , (8) C3-6 cycloalkyl, (9) hydroxyl, (10) nitro, (11) cyano, (12) -NR ³⁰⁵ R ³⁰⁶ , (13) -SR ³⁰⁷ , (14) -SOR ³⁰⁸ , (15) -SO ₂ R ³⁰⁹ , or (16) oxo, when substituted by two or more R ³⁰¹ , the plurality of R ^{301 s} 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, and R ² represents ( ² ) to (9), R When R ³ represents a C1-6 alkyl group, R ² and R ³ may form a 5-6 membered cyclic group together with the atom to which they are bonded. R ⁴ represents (1) a halogen atom, (2) a C1-6 alkyl group, (3) a C2-6 alkenyl group, (4) a C2-6 alkynyl group, (5) a C1-6 alkoxy group, (6) a C1-6 halogen alkyl group, (7) a C2-6 halogen alkenyl group, (8) a C2-6 halogen alkynyl group, or (9) a C1-6 halogen alkoxy group. When n is 2 or more, a plurality of R ⁴ may be the same or different. When two R ⁴ on the same carbon atom represent a C1-6 alkyl group, they may form a C3-6 cycloalkyl group together with the carbon atom to which they are bonded. ring1 represents a 3-15 membered cyclic group. R ⁵ represents (1) a halogen atom, (2) a C1-6 alkyl group, (3) a C2-6 alkenyl group, (4) a C2-6 alkynyl group, (5) a C1-6 alkoxy group, (6) a C1-6 alkylthio group, (7) a C1-6 alkylsulfinyl group, (8) a C1-6 alkylsulfonyl group, (9) a C2-6 acyl group, (10) a 3-6 membered cyclic group, (11) ^-LR5- (3-6 membered cyclic group), (12) a hydroxyl group, (13) a nitro group, ( ¹⁴ ) a cyano group, (15) a ^oxo group ^, (16) ^-NR501R502 , (17) ^-COOR503 , (18) ^-CONR504R505 , or (19) _{-SO2NR506R507} , and when p is 2 or more, ^a plurality of R R ⁵⁰¹ , R 502 , R 503 , R 504 , R ⁵⁰⁵ , R ⁵⁰⁶ , R 507 , R ⁵⁰⁸ , R 509 , R 510 , R 511 , R 512 , R 513 , R 514 , R ⁵¹⁵ , R ⁵¹⁶ , R 517 , R 518 , R ⁵¹⁹ , R 520 , R 521 , R ⁵²² , R 523 , R 524 , R 525 , R 526 , ^R 527 , R ⁵²⁸ , R ₅₂₉ , R ⁵³⁰ , R ⁵³¹ , R ⁵³² R ⁵⁰⁴ , R ⁵⁰⁵ , R ⁵⁰⁶ , R ⁵⁰⁷ , R ^{509 , R 510 or} R ⁵¹¹ each independently represents (1) a hydrogen atom, (2) a C1-6 alkyl group, (3) a C2-6 acyl group, or (4) a C1-6 alkylsulfonyl group, m represents an integer from 0 to 2, n represents an integer from 0 to 5, and p represents an integer from 0 to 5). [3] The pharmaceutical composition according to [1] or [2] above, wherein ring1 is a 3-10 membered cyclic group, or [1] (wherein the asterisk (*) indicates the bonding position to the carbonyl group) [4] The pharmaceutical composition as described in [1] or [3] above, wherein ring1 is selected from the following ring structures: [Chemical 1] (wherein the asterisk (*) indicates the bonding position to the carbonyl group, and the hydrogen atom represented by NH may be substituted by R ^5-A ) [5] The pharmaceutical composition as described in [2] or [3] above, wherein ring1 is a ring structure selected from the following ring structures: [Chemical 1] (wherein the asterisk (*) indicates the bonding position with the carbonyl group, and the hydrogen atom represented by NH may be substituted by R ⁵ ). [6] A pharmaceutical composition as described in any one of [1] to [5] above, wherein ring 1 is a ring structure selected from the following: [Chemical 1] (wherein the asterisk (*) indicates the bonding position to the carbonyl group, and the hydrogen atom represented by NH may be substituted by R ^5-A or R ⁵ ). [7] The pharmaceutical composition as described in any one of [1] to [6] above, wherein 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 halogenalkyl group, (5) a C1-6 halogenalkoxy group, (6) a 3-6 membered cyclic group, (7) a pendoxy group, (8) -NR ⁵⁰¹ R ⁵⁰² , or (9) -COOR ⁵⁰³ . [8] The pharmaceutical composition as described in any one of [1] to [7] above, wherein R ^5-A or R ⁵ is (1) a C1-6 alkyl group, (2) a C1-6 alkoxy group, (3) a C1-6 halogen alkyl group, (4) a C1-6 halogen alkoxy group, (5) a cyclopropyl group, (6) a furan ring, (7) an N-methylpyrazole ring, (8) a oxo group, (9) a dimethylamino group, or (10) -COOCH ₃ . [9] The pharmaceutical composition as described in any one of [1] to [8] above, wherein R ³ is (1) a hydrogen atom, (2) a C1-6 alkyl group, (3) a C1-6 halogen alkyl group, (4) a 3-10 membered cyclic group, or (5) -CH ₂ -(3-10 membered cyclic group). [10] The pharmaceutical composition as described in any one of [1] to [9] above, wherein R ³ is (1) a hydrogen atom, (2) a C1-6 alkyl group, (3) a C1-6 halogen alkyl group, (4) a cyclopropyl group, or (5) -CH ₂ -Q, and Q is (1) benzene, (2) pyridine, or (3) imidazo[2,1-b]thiazole. [11] The pharmaceutical composition as described in any one of [1] to [10] above, wherein X ¹ and X ² are both N. [12] The pharmaceutical composition as described in any one of [1] to [11] above, wherein the compound represented by the general formula (IA) or the general formula (I) or a pharmaceutically acceptable salt thereof is a compound represented by the general formula (I-1) or a pharmaceutically acceptable salt thereof: [Chemical 1] (wherein, R ^3-a represents (1) a hydrogen atom, (2) a C1-6 alkyl group, (3) a C1-6 halogen alkyl group, (4) a cyclopropyl group, or (5) -CH ₂ -Q, and ring1-a represents a ring structure selected from the following: [Chemical 1] (wherein the asterisk (*) indicates the bonding position with the carbonyl group, the hydrogen atom represented by NH may be substituted by R ^5-a ), R ^5-a represents (1) C1-6 alkyl, (2) C1-6 alkoxy, (3) C1-6 halogenalkyl, (4) C1-6 halogenalkoxy, (5) cyclopropyl, (6) furan ring, (7) N-methylpyrazole ring, (8) pendoxy, (9) dimethylamino, or (10) -COOCH ₃ , and the other symbols have the same meanings as those described in [1], [2] or [10] above). [13] The pharmaceutical composition described in [12] above, wherein ring1-a is a ring structure selected from the following ring structures: [Chemical 1] (wherein the asterisk (*) indicates the bonding position to the carbonyl group, and the hydrogen atom represented by NH may be substituted by R ^5-a ) is a ring structure in the group formed. [14] The pharmaceutical composition according to [1] or [2], wherein the compound represented by the general formula (IA) or the general formula (I) or a pharmaceutically acceptable salt thereof is selected from the group consisting of the following compounds or pharmaceutically acceptable salts thereof: (1) {(3aS,4R,6aR)-4-[(6-chloro-3-pyrimidine-1-yl)amino]hexahydrocyclopenta[c]pyrrol-2(1H)-yl}[5-(difluoromethyl)-2-thienyl]methanone, (2) {(3aS,4R,6aR)-4-[(6-chloro-3-pyrimidine-1-yl)amino]hexahydrocyclopenta[c]pyrrol-2(1H)-yl}(5-methyl-2-thienyl)methanone, (3) [(3aS,4R,6aR)-4-[(6-chloro-3-pyridinyl)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-pyridinyl)amino]hexahydrocyclopenta[c]pyrrol-2(1H)-yl](5-methyl-2-thienyl)methanone, (5) [(3aS,4R,6aR)-4-[(6-bromo-3-pyrrolyl)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-pyrrolyl)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-pyrrolidinyl)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-pyrrolidinonecarbonitrile, (9) {(3aR,4R,6aS)-4-[(6-chloro-3-pyrrolyl)amino]-3a-fluorohexahydrocyclopenta[c]pyrrol-2(1H)-yl}(6,7-dihydro-4H-thieno[3,2-c]pyran-2-yl)methanone, and (10) [(3aR,6R,6aS)-6-[(6-bromo-3-pyrrolyl)amino]-4,4-difluorohexahydrocyclopenta[c]pyrrol-2(1H)-yl](6,7-dihydro-4H-thieno[3,2-c]pyran-2-yl)methanone. [15] The pharmaceutical composition according to [1] or [2], wherein the compound represented by the general formula (IA) or the general formula (I) or a pharmaceutically acceptable salt thereof is selected from the group consisting of the following compounds or pharmaceutically acceptable salts thereof: (1) [(3aS,4R,6aR)-4-[(6-bromo-3-pyridinyl)(methyl)amino]hexahydrocyclopenta[c]pyrrol-2(1H)-yl](5-methyl-2-thienyl)methanone, (2) [(3aS,4R,6aR)-4-[(6-bromo-3-pyridinyl)(methyl)amino]hexahydrocyclopenta[c]pyrrol-2(1H)-yl]{5-[2-(2-fluoroethoxy)ethyl]-2-thienyl}methanone, (3) [(3aS,4R,6aR)-4-[(6-bromo-3-pyridinyl)(methyl)amino]hexahydrocyclopenta[c]pyrrol-2(1H)-yl][5-(2-fluoroethoxy)-2-thienyl]methanone, and (4) [(3aS,4R,6aR)-4-{(6-bromo-3-pyridinyl)[2-(2-fluoroethoxy)ethyl]amino}hexahydrocyclopenta[c]pyrrol-2(1H)-yl](5-methyl-2-thienyl)methanone. [16] The pharmaceutical composition as described in any one of [1] to [15] above, which is an ABHD6 inhibitor. [17] The pharmaceutical composition as described in any one of [1] to [16] above, which is a therapeutic and/or preventive agent for ABHD6-related diseases. [18] The pharmaceutical composition as described in [17] above, wherein the ABHD6-related disease is pain, neurological disease, inflammatory disease, autoimmune disease, metabolic disease or malignant tumor. [19] The pharmaceutical composition as described in [17] or [18] above, wherein the ABHD6-related disease is pain, and the pain includes 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, neurological 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 endometrial disease, pain associated with irritable bowel syndrome, migraine, or pain associated with pulpitis. [20] The pharmaceutical composition as described in [17] or [18] above, wherein the ABHD6-related disease is a neurological disease, and the neurological disease includes tremor, dyskinesia, dystonia, contracture, compulsive and obsessive behavior, depression, anxiety, panic disorder, acute stress response, post-traumatic stress disorder, obsessive-compulsive disorder, space phobia, social anxiety disorder, affective disorder, epilepsy, traumatic brain injury, spinal cord injury, multiple sclerosis, encephalomyelitis, Parkinson's disease, Henlein's chorea, Alzheimer's disease, and sleep disorder. [21] A pharmaceutical composition as described in any one of [16] to [20] above, characterized in that it is administered in combination with at least one selected from the group consisting of acetaminophen, nonsteroidal anti-inflammatory drugs, opioids, antidepressants, antiepileptics, N-methyl-D-aspartate antagonists, muscle relaxants, antiarrhythmic drugs, steroids and bisphosphonates. [22] A therapeutic and/or preventive agent for ABHD6-related diseases, comprising a compound as described in any one of [1] to [15] above or a pharmaceutically acceptable salt thereof. [23] A method for preventing and/or treating an ABHD6-related disease, characterized in that a pharmaceutical composition containing a compound as described in any one of [1] to [15] or a pharmaceutically acceptable salt thereof is administered to a patient who needs to be treated for the prevention and/or treatment of an ABHD6-related disease. [24] A pharmaceutical composition containing a compound as described in any one of [1] to [15] or a pharmaceutically acceptable salt thereof, for use in preventing and/or treating an ABHD6-related disease. [25] Use of a compound as described in any one of [1] to [15] or a pharmaceutically acceptable salt thereof, for the manufacture of an agent for preventing and/or treating an ABHD6-related disease.

[Synthesis Example] The solvents in brackets in the fractions separated by chromatography and TLC indicate the elution solvent or development solvent used, and the ratio indicates the volume ratio.

The solvents in parentheses in the NMR section indicate the solvents used in the measurement.

The compound names used in this specification are generally named according to the IUPAC rules using the computer program ACD/Name (registered trademark) or Chemdraw Ultra (version 12.0, manufactured by Cambridge Soft), or according to the IUPAC nomenclature.

LC-MS/ELSD was performed under the following TFA conditions or formic acid conditions. TFA conditions: Column: YMC Triart C ₁₈ (particle size: 1.9×10 ^-6 m; column length: 30×2.0 mm ID); flow rate: 1.0 mL/min; column temperature: 30°C; mobile phase (A): 0.1% trifluoroacetic acid in water; mobile phase (B): 0.1% trifluoroacetic acid-acetonitrile solution; gradient (recording the ratio of mobile phase (A): mobile phase (B)): [0 min] 95:5, [0.1 min] 95:5, [1.2 min] 5:95, [1.6 min] 5:95; detectors: UV (PDA), ELSD, MS. Formic acid conditions: Column: YMC Triart C ₁₈ (particle size: 1.9×10 ^-6 m; column length: 30×2.0 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 (recording the ratio of mobile phase (A): mobile phase (B)): [0 min] 95:5, [0.1 min] 95:5, [1.2 min] 5:95, [1.6 min] 5:95; detectors: UV (PDA), ELSD, MS.

Unless otherwise specified, HPLC (High Performance Liquid Chromatography) retention times refer to the retention times under the conditions described in the above LC-MS/ELSD. The data in parentheses that appear in the HPLC retention time part indicate the measurement conditions.

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

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

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

Reference Example 4 : (3aS,6aR)-4- oxohexahydrocyclopenta [c] pyrrole -2(1H) -carboxylic acid (2- methyl -2- propyl ) ester To a THF (60 mL) solution of the compound prepared in Reference Example 3, di-tert-butyl dicarbonate (CAS No.: 24424-99-5, 9.4 g) and 20% potassium hydroxide (CAS No.: 12135-22-7, 700 mg) were added and stirred at room temperature in a hydrogen atmosphere for 15 hours. The reaction solution was filtered and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain the title compound (7.0 g). ¹ H-NMR (CD ₃ OD) : δ 3.66-3.53, 3.14, 3.06-2.98, 2.76-2.71, 2.39-2.35, 2.21-2.12, 1.87 1.45.

Reference Example 5 : (3aS,4S,6aR)-4- Hydroxyhexahydrocyclopenta [c] pyrrole -2(1H)-carboxylic acid (2- methyl -2- propyl ) ester A 1M THF solution of lithium tri-sec-butylborohydride (CAS No.: 38721-52-7, 49 mL) was added to a solution of the compound (7.3 g) prepared in Reference Example 4 in THF (200 mL) at -78°C, and stirred at -78°C for 1 hour. A 35% aqueous hydrogen peroxide solution was slowly added to the reaction solution at 0°C until bubbling stopped, and extraction was performed with dichloromethane. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain the title compound (6.5 g). ¹ H-NMR (CDCl ₃ ): δ 4.30-4.25, 3.63-3.50, 3.38-3.30, 3.17-3.15, 2.67, 1.90-1.73, 1.73-1.54, 1.47.

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

Reference Example 7 : (3aS,4R,6aR)-4- azidohexahydrocyclopenta [c] pyrrole -2(1H) -carboxylic acid (2- methyl -2- propyl ) ester To a solution of the compound (9.3 g) prepared in Reference Example 6 in dimethyl sulfoxide (72 mL) was added sodium azide (CAS No.: 26628-22-8, 3.2 g), and stirred at 60°C for 6 hours. Water was added to the reaction solution, and extraction was performed 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.

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

Reference Example 9 : (3aS,4R, 6aR )-4-[(6- chloro -3- pyrrolidinyl ) amino ] hexahydrocyclopenta [ c] pyrrole -2(1H)-carboxylic acid (2- methyl -2- propyl ) ester To a solution of the compound prepared in Reference Example 8 (1.5 g) in N,N-dimethylacetamide (hereinafter referred to as DMA) (25 mL) were added N,N-diisopropylethylamine (hereinafter referred to as DIPEA) (6.9 mL) and 3,6-dichloropyrrolidinyl (CAS No.: 141-30-0, 1.5 g), and the mixture was stirred at 160°C for 1 hour. Water was added to the reaction solution, and extraction was performed with dichloromethane. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the title compound (1.5 g). HPLC retention time (min): 0.89 (formic acid); MS (ESI, Pos.): 339 (M+H) ⁺ .

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

Reference Example 10-1 : rel-(3aS,4R,6aR)-N-(6- chloro -3- pyridine ) octahydrocyclopenta [ c] pyrrole -4- amine dihydrochloride racemic mixture Using the compound produced in Reference Example 1 instead of the compound produced in Reference Example 3, the same operation as Reference Example 4 → Reference Example 5 → Reference Example 6 → Reference Example 7 → Reference Example 8 → Reference Example 9 → Reference Example 10 was carried out to obtain the title compound.

Example 1 : {(3aS,4R,6aR)-4-[(6- chloro-3-thiophene ) amino ] hexahydrocyclopenta [ c ] pyrrol - 2 (1H)-yl } [5-( difluoromethyl )-2 -thienyl ] methanone [Chemical 1] To a solution of the compound prepared in Reference Example 10 (30 mg) in DMA (0.5 mL) were added DIPEA (0.083 mL), 5-(difluoromethyl)thiophene-2-carboxylic acid (CAS No.: 189330-23-2, 19 mg) and O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (hereinafter referred to as HATU) (CAS No.: 148893-10-1, 38 mg), and the mixture was stirred at room temperature for 3 hours. Water was added to the reaction solution, and extraction was performed with dichloromethane. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the title compound (32 mg). HPLC retention time (min): 0.88 (TFA); MS (ESI, Pos.): 399 (M + H) ⁺ ; ¹ H-NMR (CDCl ₃ ): δ 7.43, 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.

In Examples 1-1 to 1-6 , the title compound was obtained by using the corresponding carboxylic acid compound instead of 5-(difluoromethyl)thiophene-2-carboxylic acid, using the compound prepared in Reference Example 10, or using the compound prepared in Reference Example 10-1 instead of the compound prepared in Reference Example 10.

Example 1-1 : rel-1,3- benzothiazol -2- yl {(3aS,4R,6aR)-4-[(6- chloro - 3 - pyridinyl ) amino ] hexahydrocyclopenta [c] pyrrole -2(1H) -yl } methanone racemic mixture [Chemical 1] HPLC retention time (min): 1.10 (formic acid); MS (ESI, Pos.): 400 (M＋H) ^＋ ; ¹ H-NMR (DMSO-d ₆ ): δ 8.23-8.14, 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.

Example 1-2 : {(3aS,4R,6aR)-4-[(6- chloro - 3- thiophene ) amino ] hexahydrocyclopenta [ c] pyrrol -2(1H)-yl } (5- methyl -2- thienyl ) methanone [Chemical 1] HPLC retention time (min): 0.85 (TFA); MS (ESI, Pos.): 363 (M + H) ⁺ ; ¹ H-NMR (CDCl ₃ ): δ 7.35-7.28, 7.16, 6.76-6.71, 6.65, 4.96, 4.14-3.96, 3.96-3.86, 3.82, 3.65, 2.88, 2.79-2.62, 2.50, 2.41-2.27, 2.18-2.04, 1.72-1.54.

Example 1-3 : [(3aS,4R,6aR)-4-[(6- chloro - 3 - pyridinyl ) amino ] hexahydrocyclopenta [c] pyrrol -2(1H)-yl ] ( thieno [3,2-c] pyridin -2- yl ) methanone [Chemical 1] HPLC retention time (min): 0.74 (formic acid); MS (ESI, Pos.): 400 (M＋H) ^＋ ; ¹ H-NMR (DMSO-d ₆ ): δ 9.46-9.25, 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.

Example 1-4 : [(3aS,4R,6aR)-4-[(6- chloro-3-pyrrolyl ) amino ] hexahydrocyclopenta [ c ] pyrrol - 2 (1H) -yl ](6,7- dihydro -4H- thieno [3,2-c] pyran -2- yl ) methanone [Chemical 1] HPLC retention time (min): 0.83 (TFA); MS (ESI, Pos.): 405 (M + H) ⁺ ; ¹ H-NMR (CDCl ₃ ): δ 7.22-7.13, 6.66, 5.04, 4.76-4.65, 4.12, 3.98, 3.86, 3.64, 2.89, 2.70, 2.39-2.28, 2.17-2.07, 1.69-1.55.

Example 1-5 : [(3aS,4R,6aR)-4-[(6- chloro - 3- pyridinyl ) amino ] hexahydrocyclopenta [ c] pyrrol -2(1H) -yl ][4-(2- furanyl ) phenyl ] methanone [Chemical 1] HPLC retention time (min): 1.00 (formic acid); MS (ESI, Pos.): 409 (M + H) ⁺ ; ¹ H-NMR (DMSO-d ₆ ): δ 8.14-8.07, 8.07-7.93, 7.73-7.47, 7.43-7.22, 6.98-6.88, 6.88-6.78, 4.11-3.99, 3.99-3.88, 3.76-3.65, 3.10, 2.86-2.70, 2.21-2.09, 2.09-1.98, 1.98-1.84, 1.65-1.43, 1.43-1.29.

Example 1-6 : 1- Benzofuran -2- yl [(3aS,4R,6aR)-4-[(6- chloro - 3- pyridinyl ) amino ] hexahydrocyclopenta [ c] pyrrole -2(1H)-yl ] methanone [ Chemical 1] HPLC retention time (min): 1.00 (formic acid); MS (ESI, Pos.): 383 (M + H) ⁺ ; ¹ H-NMR (DMSO-d ₆ ): δ 7.79-7.74, 7.71-7.65, 7.57-7.49, 7.49-7.43, 7.41-7.32, 7.31-7.25, 6.96-6.84, 4.14-4.01, 3.83-3.72, 3.34-3.25, 2.97-2.76, 2.73-2.66, 2.64-2.53, 2.25-2.15, 2.10-1.98, 1.65-1.57, 1.56-1.46.

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

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

Reference Example 12-1 : rel-(3aS,4R,6aR)-N-(6- bromo -3- pyridine ) octahydrocyclopenta [ c] pyrrole -4- amine dihydrochloride racemic mixture Using the compound produced in Reference Example 1 instead of the compound produced in Reference Example 3, the same operation as Reference Example 4 → Reference Example 5 → Reference Example 6 → Reference Example 7 → Reference Example 8 → Reference Example 11 → Reference Example 12 was carried out to obtain the title compound.

Example 2 : [(3aS, 4R, 6aR)-4-[(6- bromo-3-thiophene ) amino ] hexahydrocyclopenta [ c ] pyrrol - 2 (1H)-yl ] (5- methyl -2- thienyl ) methanone [Chemical 1] To a solution of the compound prepared in Reference Example 12 (3.0 g) in DMA (20 mL) were added DIPEA (2.9 mL), 5-methyl-2-thiophenecarboxylic acid (CAS No.: 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 solution, and extraction was performed with dichloromethane. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain the title compound (1.8 g). HPLC retention time (min): 0.87 (TFA); MS (ESI, Pos.): 407 (M＋H) ^＋ ; ¹ H-NMR (CDCl ₃ ): δ 7.33-7.27, 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.

In Examples 2-1 to 2-14 , corresponding carboxylic acid compounds were used instead of 5-methyl-2-thiophenecarboxylic acid, and the same procedures as in Example 2 were performed to obtain the title compound.

Example 2-1 : [(3aS,4R,6aR)-4-[(6- bromo -3- thiazol -1- yl ) amino ] hexahydrocyclopenta [c] pyrrol -2(1H) -yl ](6,7- dihydro -4H- thieno [3,2-c] pyran -2- yl ) methanone [Chemical 1] HPLC retention time (min): 0.93 (TFA); MS (ESI, Pos.): 451 (M + H) ⁺ ; ¹ H-NMR (CDCl ₃ ): δ 7.32-7.27, 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.

Example 2-2 : [(3aS, 4R, 6aR)-4-[(6- bromo -3- thiazol- 1 -yl ) amino ] hexahydrocyclopenta [c] pyrrol -2(1H) -yl ][5-( difluoromethyl )-2 -thienyl ] methanone [Chemical 1] HPLC retention time (min): 1.00 (formic acid); MS (ESI, Pos.): 443 (M + H) ⁺ ; ¹ H-NMR (DMSO-d ₆ ): δ 7.63-7.56, 7.50-7.47, 7.46-7.43, 7.34-7.27, 7.32, 6.86-6.73, 4.11-3.87, 3.87-3.70, 3.71-3.54, 2.96-2.72, 2.71-2.56, 2.23-2.11, 2.09-1.95, 1.59, 1.51.

Example 2-3 : [(3aS,4R,6aR)-4-[(6- bromo -3 - thiazol- 2- yl ) amino ] hexahydrocyclopenta [c] pyrrol -2(1H) -yl ](5- methyl -1,3- thiazol -2- yl ) methanone [Chemical 1] HPLC retention time (min): 0.96 (formic acid); MS (ESI, Pos.): 408 (M＋H) ^＋ ; ¹ H-NMR (DMSO-d ₆ ): δ 7.77-7.68, 7.50-7.41, 7.41-7.28, 6.87-6.77, 4.29-3.93, 3.84-3.62, 3.18-3.04, 2.97-2.60, 2.24-2.11, 2.11-1.95, 1.66-1.54, 1.54-1.43.

Example 2-4 : [(3aS,4R,6aR)-4-[(6- bromo - 3 - pyridinyl ) amino ] hexahydrocyclopenta [c] pyrrol -2(1H)-yl ] ( thieno [3,2-c] pyridin -2- yl ) methanone [Chemical 1] HPLC retention time (min): 0.75 (formic acid); MS (ESI, Pos.): 444 (M＋H) ^＋ ; ¹ H-NMR (DMSO-d ₆ ): δ 9.42-9.26, 8.60, 8.44-8.31, 8.31-8.17, 7.52-7.42, 7.42-7.31, 6.88-6.74, 4.17-4.00, 3.89-3.67, 3.14-3.06, 2.87, 2.28-2.14, 2.13-1.97, 1.70-1.45.

Example 2-5 : [(3aS,4R,6aR)-4-[(6- bromo -3- thiazol -1- yl ) amino ] hexahydrocyclopenta [c] pyrrol -2(1H) -yl ](6,7- dihydro -4H- pyrano [3,4-d][1,3] thiazol -2- yl ) methanone [Chemical 1] HPLC retention time (min): 0.84 (TFA); MS (ESI, Pos.): 452 (M + H) ⁺ ; ¹ H-NMR (CDCl ₃ ): δ 7.31-7.27, 6.54, 4.85-4.78, 4.73, 4.34-4.27, 4.21, 4.15-3.97, 3.95-3.84, 3.78, 3.65, 2.97, 2.90-2.71, 2.69-2.59, 2.39-2.28, 2.18-2.01, 1.69-1.61.

Example 2-6 : [(3aS,4R,6aR)-4-[(6- bromo -3 -thiazol- 1 -yl ) amino ] hexahydrocyclopenta [c] pyrrol -2(1H) -yl ][2-( dimethylamino )-1,3- thiazol -5- yl ] methanone [Chemical 1] HPLC retention time (min): 0.74 (TFA); MS (ESI, Pos.): 438 (M + H) ⁺ ; ¹ H-NMR (CDCl ₃ ): δ 7.57, 7.26, 6.55, 4.92, 4.15-4.02, 3.98-3.89, 3.87, 3.78, 3.61, 3.15, 2.89, 2.69, 2.39-2.29, 2.17-2.07, 1.62-1.55.

Example 2-7 : [(3aS,4R,6aR)-4-[(6- bromo-3-pyridinyl ) amino ] hexahydrocyclopenta [ c ] pyrrol - 2 (1H) -yl ](5,5- dihydro -6,7- dihydro -4H- thieno [3,2-c] thiopyran -2- yl ) methanone [Chemical 1] HPLC retention time (min): 0.88 (formic acid); MS (ESI, Pos.): 497 (M + H) ⁺ ; ¹ H-NMR (DMSO-d ₆ ): δ 7.46, 7.33, 6.82, 4.39, 4.11-3.99, 3.97-3.83, 3.81-3.65, 3.18-3.05, 2.99-2.72, 2.70-2.58, 2.24-2.09, 2.09-1.96, 1.58, 1.49.

Example 2-8 : [(3aS,4R,6aR)-4-[(6- bromo-3-pyridinyl ) amino ] hexahydrocyclopenta [ c ] pyrrol - 2 (1H) -yl ](6,7- dihydro -4H- thieno [3,2-c] thiopyran -2- yl ) methanone [Chemical 1] HPLC retention time (min): 1.00 (formic acid); MS (ESI, Pos.): 465 (M + H) ⁺ ; ¹ H-NMR (DMSO-d ₆ ): δ 7.46, 7.41-7.31, 6.86-6.77, 4.11-4.02, 4.02-3.86, 3.71, 3.69-3.58, 3.46, 3.15-3.05, 3.04-2.96, 2.94-2.88, 2.88-2.71, 2.25-2.12, 2.10-1.94, 1.68-1.54, 1.54-1.39.

Example 2-9 : [(3aS,4R,6aR)-4-[(6- bromo - 3- pyrrolyl ) amino ] hexahydrocyclopenta [ c] pyrrol -2(1H) -yl ](1- methyl -1H- thieno [2,3-c] pyrazol -5- yl ) methanone [Chemical 1] HPLC retention time (min): 0.90 (formic acid); MS (ESI, Pos.): 447 (M＋H) ^＋ ; ¹ H-NMR (DMSO-d ₆ ): δ 7.85, 7.69-7.57, 7.52-7.43, 7.43-7.28, 6.89-6.70, 4.12-4.00, 3.96, 3.92-3.67, 3.15-3.05, 2.96-2.75, 2.75-2.57, 2.26-2.11, 2.09-1.94, 1.66-1.55, 1.55-1.44.

Example 2-10 : [(3aS,4R,6aR)-4-[(6- bromo -3- thiazol- 1 -yl ) amino ] hexahydrocyclopenta [c] pyrrol -2(1H) -yl ][2-( dimethylamino ) thieno [2,3-d][1,3] thiazol -5- yl ] methanone [Chemical 1] HPLC retention time (min): 0.88 (TFA); MS (ESI, Pos.): 493 (M + H) ⁺ ; ¹ H-NMR (DMSO-d ₆ ): δ 7.79, 7.44, 7.25, 6.79, 4.16-3.94, 3.86, 3.74, 3.56, 3.44-3.36, 3.31-3.23, 3.13, 2.87, 2.61, 2.19, 2.07-1.98, 1.63-1.47.

Example 2-11 : [(3aS,4R,6aR)-4-[(6- bromo-3-pyridinyl ) amino ] hexahydrocyclopenta [ c ] pyrrol - 2 (1H) -yl ](3- methyl -3H- thieno [2,3-d][1,2,3] triazol -5- yl ) methanone [Chemical 1] HPLC retention time (min): 0.87 (formic acid); MS (ESI, Pos.): 448 (M＋H) ^＋ ; ¹ H-NMR (DMSO-d ₆ ): δ 7.91, 7.46, 7.44-7.36, 6.84, 4.24, 4.14-3.98, 3.95-3.61, 3.00-2.79, 2.77-2.59, 2.27-2.16, 2.11-1.98, 1.65-1.57, 1.57-1.50.

Example 2-12 : [(3aS, 4R, 6aR)-4-[(6- bromo - 3- pyridinyl ) amino ] hexahydrocyclopenta [ c] pyrrol -2(1H) -yl ](5- methoxy -2- furanyl ) methanone [Chemical 1] HPLC retention time (min): 0.80 (TFA); MS (ESI, Pos.): 407 (M + H) ⁺ ; ¹ H-NMR (CDCl ₃ ): δ 7.31-7.27, 7.05, 6.54, 5.31, 4.81-4.66, 4.12, 3.92, 3.94-3.77, 3.76-3.58, 2.95-2.76, 2.72-2.52, 2.34, 2.05, 1.66-1.56.

Example 2-13 : [(3aS,4R,6aR)-4-[(6- bromo - 3- pyrrolyl ) amino ] hexahydrocyclopenta [ c] pyrrol -2(1H) -yl ](1,3 -dimethyl -1H- thieno [2,3-c] pyrazol -5- yl ) methanone [Chemical 1] HPLC retention time (min): 0.93 (formic acid); MS (ESI, Pos.): 461 (M + H) ⁺ ; ¹ H-NMR (DMSO-d ₆ ): δ 7.62, 7.51-7.44, 7.45-7.36, 6.88-6.79, 4.13-4.04, 3.85, 4.01-3.66, 3.36-3.24, 2.95-2.80, 2.71-2.58, 2.37, 2.26-2.15, 2.11-2.00, 1.64-1.57, 1.56-1.48.

Example 2-14 : Bicyclo [2.2.2] oct -2- yl [(3aS,4R,6aR)-4-[(6- bromo - 3 - pyridinyl ) amino ] hexahydrocyclopenta [c] pyrrol -2(1H)-yl ] methanone [ Chemical 1] HPLC retention time (min): 1.10 (formic acid); MS (ESI, Pos.): 419 (M＋H) ^＋ ; ¹ H-NMR (DMSO-d ₆ ): δ 7.51-7.39, 7.38-7.25, 6.85-6.74, 4.07-3.85, 3.73-3.51, 3.29-3.16, 2.87-2.59, 2.18-1.82, 1.72-1.14.

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

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

Reference Example 15 : 5 -oxo -4,5,6,7- tetrahydrothieno [3,2-b] pyridine -2- carboxylic acid methyl ester To a solution of the compound (20 mg) prepared in Reference Example 14 in methanol (1 mL) was added p-toluenesulfonic acid monohydrate (CAS No.: 6192-52-5, 1.5 mg), and the mixture was stirred at 60°C for 15 hours. Saturated sodium bicarbonate was added to the reaction solution, and extraction was performed with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain the title compound (5 mg). HPLC retention time (min): 0.81 (formic acid); MS (ESI, Pos.): 212 (M+H) ⁺ .

Reference Example 16 : 4- methyl -5- oxo -4,5,6,7 -tetrahydrothieno [3,2-b] pyridine -2- carboxylic acid methyl ester To a solution of the compound (5 mg) prepared in Reference Example 15 in DMF (0.25 mL) were added sodium hydroxide (CAS No.: 7646-69-7, 2.9 mg) and iodomethane (CAS No.: 74-88-4, 22 mg), and the mixture was stirred at room temperature for 3 hours. 2N hydrochloric acid was added to the reaction solution, and extraction was performed with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain the title compound (7 mg). HPLC retention time (min): 0.88 (formic acid); MS (ESI, Pos.): 225 (M + H) ⁺ .

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 a 2N aqueous sodium hydroxide solution (0.5 mL), and the mixture was stirred at 60°C for 1 hour. 1N hydrochloric acid was added to the reaction solution, and the precipitate was separated by filtration to obtain the title compound (5.0 mg).

Reference Example 18 : DMF (0.70 mL) was added to a solution of 5- chloro -3,4- dihydro -2H- pyran -6- carboxaldehyde 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 No.: 23462-75-1, 900 mg) was added to the mixture, and the mixture was stirred at room temperature for 2 hours. A saturated aqueous sodium bicarbonate solution was added to the reaction mixture, and extraction was performed using dichloromethane. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain the title compound, which was used in the next reaction without purification.

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

Reference Example 20 : 6,7- dihydro -5H- thieno [3,2-b] pyran -2- carboxylic acid methyl ester To a methanol (10 mL) solution of the compound prepared in Reference Example 19, add 28% sodium methoxide (CAS No.: 124-41-4, 0.85 mL) and stir at 70°C for 1 hour. The reaction solution was concentrated under reduced pressure, 2N hydrochloric acid was added, and extraction was performed with dichloromethane. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain the title compound (220 mg).

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 a 2N aqueous sodium hydroxide solution (0.5 mL), and the mixture was stirred at 60°C for 1 hour. 1N hydrochloric acid was added to the reaction solution, and extraction was performed with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the title compound, which 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-d ₆ ): δ 7.55-7.43, 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.

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

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

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

Reference Example 25 : 4,4- Dimethyl -6,7- dihydrothieno [3,2-c] pyran -2- carboxylic acid To a solution of the compound (284 mg) prepared in Reference Example 24 in THF (10 mL) was added a 1.6 M hexane solution of n-butyl lithium (CAS No.: 109-72-8, 1.2 mL) at -78°C, and stirred at -78°C for 2 hours. Thereafter, dry ice (1 g) was added to the reaction solution, and stirred at room temperature for 2 hours. Water and a 1N aqueous sodium hydroxide solution were added to the reaction solution, and the aqueous layer was washed with methyl tert-butyl ether. A 1N aqueous hydrochloric acid solution was added to the aqueous layer to adjust the pH of the aqueous layer to 1, and then extraction was performed with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain the title compound (306 mg). HPLC retention time (min): 0.89 (TFA); MS (ESI, Pos.): 213 (M+H) ⁺ .

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 No.: 1253281-38-7, 873 mg) in THF (17.5 mL) was added n-amyl nitrite (CAS No.: 463-04-7, 0.97 mL) and stirred at 60°C for 15 hours. Water was added to the reaction solution and extraction was performed with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain the title compound (568 mg). TLC: Rf 0.28 (ethyl acetate:n-hexane=1:2).

Reference Example 27 : 7- methylene -4H- pyrano [3,4-d] thiazole To a solution of methyltriphenylphosphonium bromide (CAS No.: 1779-49-3, 253 mg) in THF (1.5 mL) was added 1.3N lithium bis(trimethylsilyl)amide in THF (CAS No.: 4039-32-1, 0.55 mL) at 0°C, and stirred at 0°C for 1 hour. Then, the compound prepared in Reference Example 26 (100 mg) was added, and stirred at 0°C for 40 minutes. Saturated aqueous ammonium chloride solution was added to the reaction solution, and the aqueous layer was extracted with dichloromethane. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain the title compound (90 mg). TLC: Rf 0.5 (ethyl acetate:n-hexane=1:2).

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

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

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

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

Reference Example 32 : 5-( Difluoromethoxy )-2- thiophenecarboxylic acid To a solution of the compound (31 mg) prepared in Reference Example 31 in THF (0.2 mL), methanol (0.1 mL) and 1N aqueous lithium hydroxide solution (CAS No.: 1310-65-2, 0.2 mL) were added and stirred at room temperature for 16 hours. 1N aqueous hydrochloric acid solution was added to the reaction solution to adjust the pH of the aqueous layer to 1, and then extraction was performed with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the title compound (21 mg). HPLC retention time (min): 0.91 (TFA); MS (ESI, Pos.): 195 (M+H) ⁺ .

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

Reference Example 34 : 3-(3- Hydroxy -1- propyn -1- yl )-1H -thieno [3,2-c] pyrazole -5- carboxylic acid methyl ester To a solution of the compound (40 mg) prepared in Reference Example 33 in THF (1 mL) were added propargyl alcohol (CAS No.: 107-19-7, 11 mg), copper (I) iodide (CAS No.: 7681-65-4, 2.5 mg), tetrakis(triphenylphosphine)palladium (0) (CAS No.: 14221-01-3, 15 mg) and triethylamine (0.09 mL), and the mixture was stirred at 60°C for 1 hour. Water was added to the reaction solution, and extraction was performed with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the title compound (23 mg). HPLC retention time (min): 0.84 (formic acid); MS (ESI, Pos.): 237 (M+H) ⁺ .

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

Reference Example 36 : 7,8- dihydro -6H- pyrrolo [1,2-b] thieno [2,3-d] pyrazole -2- carboxylic acid methyl ester To a solution of the compound prepared in Reference Example 35 (18 mg) in toluene (0.5 mL) was added cyanomethylenetributylphosphane (CAS No.: 157141-27-0, 27 mg), and the mixture was stirred at 60°C for 1 hour. Purification was performed by silica gel column chromatography to obtain the title compound (10 mg). ¹ H-NMR (CDCl ₃ ): δ 7.85, 4.38, 3.83, 3.10, 2.73.

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 a 2N aqueous sodium hydroxide solution (0.5 mL), and the mixture was stirred at 60°C for 1 hour. 1N hydrochloric acid was added to the reaction solution, and extraction was performed with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the title compound, which was used in the next reaction without purification.

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

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 a 2N aqueous sodium hydroxide solution (0.5 mL), and the mixture was stirred at 60°C for 1 hour. 1N hydrochloric acid was added to the reaction solution, and extraction was performed with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the title compound, which was used in the next reaction without purification.

Reference Example 40 : 2,3- Dimethyl -2H- thieno [2,3-c] pyrazole -5- carboxylic acid methyl ester To a solution of 3-methyl-1H-thieno[2,3-c]pyrazole-5-carboxylic acid methyl ester (CAS No.: 873072-42-5, 20 mg) in DMF (1.0 mL) were added sodium hydroxide (2.9 mg) and iodomethane (22 mg), and the mixture was stirred at room temperature for 3 hours. 2N hydrochloric acid was added to the reaction solution, and extraction was performed with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain the title compound (10 mg). ¹ H-NMR (CDCl ₃ ): δ 7.69, 3.95, 3.89, 2.52.

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 a 2N aqueous sodium hydroxide solution (0.5 mL), and the mixture was stirred at 60°C for 1 hour. 1N hydrochloric acid was added to the reaction solution, and extraction was performed with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the title compound, which was used in the next reaction without purification.

Reference Example 42 : 2- Methyl -2H- thieno [3,2-c] pyrazole -5- carboxylic acid methyl ester To a solution of 1H-thieno[3,2-c]pyrazole-5-carboxylic acid methyl ester (2.0 g) in THF (40 mL) were added cesium carbonate (7.2 g) and iodomethane (1.6 g), and the mixture was stirred at room temperature for 3 hours. 2N hydrochloric acid was added to the reaction solution, and extraction was performed with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain the title compound (1.05 g). ¹ H-NMR (CDCl ₃ ) : δ 7.70, 7.66, 4.06, 3.93.

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 a 2N aqueous sodium hydroxide solution (0.5 mL), and the mixture was stirred at 60°C for 1 hour. 1N hydrochloric acid was added to the reaction solution, and extraction was performed with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the title compound, which was used in the next reaction without purification.

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

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

Reference Example 46 : 2-( Difluoromethyl )-2H- thieno [3,2-c] pyrazole -5- carboxylic acid methyl ester To a solution of 1H-thieno[3,2-c]pyrazole-5-carboxylic acid methyl ester (500 mg) in DMF (10 mL) were added sodium difluorochloroacetate (CAS No.: 1895-39-2, 2100 mg) and potassium carbonate (1900 mg), and the mixture was stirred at 100°C for 20 hours. Water was added to the reaction solution, and extraction was performed with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain the title compound (85 mg).

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 a 2N aqueous sodium hydroxide solution (0.5 mL), and the mixture was stirred at 60°C for 1 hour. 1N hydrochloric acid was added to the reaction solution, and extraction was performed with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the title compound, which was used in the next reaction without purification.

Reference Example 48 : (1) 2-(2,2,2- trifluoroethyl )-2H- thieno [3,2-c] pyrazole -5- carboxylic acid methyl ester, and (2) 1-(2,2,2- trifluoroethyl )-2H- thieno [3,2-c] pyrazole -5- carboxylic acid methyl ester. To a solution of 1H-thieno[3,2-c]pyrazole-5-carboxylic acid methyl ester (200 mg) in DMF (5 mL), cesium carbonate (720 mg) and 2,2,2-trifluoroethyl trifluoromethanesulfonate (CAS No.: 6226-25-1, 510 mg) were added and stirred at room temperature for 15 hours. Water was added to the reaction solution and extraction was performed with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain 61 mg of the title compound (1) and 71 mg of the title compound (2). (1) TLC: Rf 0.31 (ethyl acetate: n-hexane = 1:3); (2) TLC: Rf 0.34 (ethyl acetate: n-hexane = 1:3).

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 a 2N aqueous sodium hydroxide solution (0.5 mL), and the mixture was stirred at 60°C for 1 hour. 1N hydrochloric acid was added to the reaction solution, and extraction was performed with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the title compound, which was used in the next reaction without purification.

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 a 2N aqueous sodium hydroxide solution (0.5 mL), and the mixture was stirred at 60°C for 1 hour. 1N hydrochloric acid was added to the reaction solution, and extraction was performed with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the title compound, which was used in the next reaction without purification.

Reference Example 51 : 2,3- Dimethyl -2H- thieno [3,2-c] pyrazole -5- carboxylic acid Using 3-methyl-1H-thieno[3,2-c]pyrazole-5-carboxylic acid methyl ester (CAS No.: 1379258-29-3) instead of 3-methyl-1H-thieno[2,3-c]pyrazole-5-carboxylic acid methyl ester, the same procedures as Reference Example 40 → Reference Example 41 were performed to obtain the title compound.

Example 3 : 2-{[(3aS,4R,6aR)-4-[(6- bromo - 3- pyridinyl ) amino ] hexahydrocyclopenta [ c] pyrrol -2(1H)-yl ] carbonyl } -4- methyl -6,7- dihydrothieno [3,2-b] pyridin -5(4H)-one [ Chemical 1] 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) were added DIPEA (0.016 mL) and HATU (10 mg), and the mixture was stirred at room temperature for 3 hours. Water was added to the reaction solution, and extraction was performed with dichloromethane. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain the title compound (4.7 mg). HPLC retention time (min): 0.89 (formic acid); MS (ESI, Pos.): 476 (M + H) ⁺ ; ¹ H-NMR (DMSO-d ₆ ): δ 7.44, 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.

In Examples 3-1 to 3-14, 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 was used instead of the compound prepared in Reference Example 17, and the compound prepared in Reference Example 12 was used, or the compound prepared in Reference Example 10 was used instead of the compound prepared in Reference Example 12, and the same operation as in Example 3 was performed to obtain the title compound.

Example 3-1 : [(3aS,4R,6aR)-4-[(6- bromo-3-pyrrolyl ) amino ] hexahydrocyclopenta [ c ] pyrrol - 2 (1H) -yl ](6,7- dihydro -5H- thieno [3,2-b] pyran -2- yl ) methanone [Chemical 1] HPLC retention time (min): 0.74 (formic acid); MS (ESI, Pos.): 400 (M＋H) ^＋ ; ¹ H-NMR (DMSO-d ₆ ): δ 9.46-9.25, 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.

Example 3-2 : 2-{[(3aS,4R,6aR)-4-[(6- bromo-3-pyrrolyl ) amino ] hexahydrocyclopenta [ c ] pyrrol - 2 (1H)-yl ] carbonyl } -6,7- dihydrothieno [3,2-c] pyridine -5(4H)-carboxylic acid methyl ester [Chemical 1] HPLC retention time (min): 0.97 (formic acid); MS (ESI, Pos.): 506 (M＋H) ^＋ ; ¹ H-NMR (DMSO-d ₆ ): δ 7.49-7.44, 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.

Example 3-3 : [(3aS,4R,6aR)-4-[(6- chloro - 3 - thiazolidine ) amino ] hexahydrocyclopenta [c] pyrrol -2(1H) -yl ](4,4 -dimethyl -6,7- dihydro -4H- thieno [3,2-c] pyran -2- yl ) methanone [Chemical 1] HPLC retention time (min): 0.88 (TFA); MS (ESI, Pos.): 435 (M + H) ⁺ ; ¹ H-NMR (CDCl ₃ ): δ 7.23, 7.18, 6.63, 4.70, 4.11, 3.98, 3.95-3.83, 3.66, 3.49, 2.89, 2.83, 2.69, 2.40-2.30, 2.17-2.08, 1.68-1.58, 1.48.

Example 3-4 : [(3aS,4R,6aR)-4-[(6- chloro - 3- pyridinyl ) amino ] hexahydrocyclopenta [ c] pyrrol -2(1H) -yl ](7- methyl -6,7- dihydro -4H- pyrano [3,4-d][1,3] thiazol -2- yl ) methanone [Chemical 1] HPLC retention time (min): 0.88 (TFA); MS (ESI, Pos.): 420 (M + H) ⁺ ; ¹ H-NMR (CDCl ₃ ): δ 7.18, 6.63, 4.85-4.66, 4.25-4.17, 4.15-4.02, 3.85, 3.55-3.46, 3.22, 3.03-2.55, 2.35, 2.13, 1.68-1.57, 1.29.

Example 3-5 : [(3aS,4R,6aR)-4-[(6- chloro -3- thiazol -1 -yl ) amino ] hexahydrocyclopenta [c] pyrrol -2(1H) -yl ][5-( difluoromethoxy )-2 -thienyl ] methanone [Chemical 1] HPLC retention time (min): 0.91 (TFA); MS (ESI, Pos.): 415 (M+H) ⁺ ; ¹ H-NMR (CDCl ₃ ): δ 7.32-7.28, 7.26-7.16, 6.67-6.61, 6.64, 4.69, 4.16-4.06, 4.02, 3.87, 3.66, 3.66, 2.88, 2.70, 2.41-2.31, 2.18-2.08, 1.69-1.58.

Example 3-6 : [(3aS,4R,6aR)-4-[(6- bromo - 3- pyrrolyl ) amino ] hexahydrocyclopenta [ c] pyrrol -2(1H) -yl ](7,8- dihydro -6H- pyrrolo [1,2-b] thieno [2,3-d] pyrazol -2- yl ) methanone [Chemical 1] HPLC retention time (min): 0.92 (formic acid); MS (ESI, Pos.): 473 (M + H) ⁺ ; ¹ H-NMR (DMSO-d ₆ ): δ 7.63, 7.50-7.42, 7.41-7.28, 6.88-6.76, 4.32-4.21, 4.10-3.95, 3.91-3.61, 3.07-2.96, 2.96-2.77, 2.68-2.58, 2.24-2.14, 2.10-1.92, 1.69-1.55, 1.55-1.46.

Example 3-7 : [(3aS, 4R, 6aR)-4-[(6- bromo - 3- pyridine ) amino ] hexahydrocyclopenta [ c] pyrrol -2(1H) -yl ][5- methyl -4-(1- methyl -1H- pyrazol -4- yl )-2- thienyl ] methanone [Chemical 1] HPLC retention time (min): 0.88 (formic acid); MS (ESI, Pos.): 487 (M + H) ⁺ ; ¹ H-NMR (DMSO-d ₆ ): δ 8.05-7.98, 7.78-7.70, 7.59, 7.49-7.42, 7.42-7.32, 6.87-6.76, 4.09-4.00, 3.88, 3.34-3.18, 2.94-2.75, 2.72-2.57, 2.48, 2.26-2.14, 2.09-1.95, 1.64-1.55, 1.55-1.46.

Example 3-8 : [(3aS,4R,6aR)-4-[(6- bromo - 3- pyrrolyl ) amino ] hexahydrocyclopenta [ c] pyrrol -2(1H) -yl ](2,3 -dimethyl -2H- thieno [2,3-c] pyrazol -5- yl ) methanone [Chemical 1] HPLC retention time (min): 0.83 (TFA); MS (ESI, Pos.): 461 (M + H) ⁺ ; ¹ H-NMR (CDCl ₃ ): δ 7.33-7.27, 7.26, 6.55, 4.80, 4.15-4.06, 4.02-3.93, 3.91, 3.69, 2.88, 2.70, 2.55-2.47, 2.39-2.24, 2.18-2.02, 1.69-1.61.

Example 3-9 : [(3aS,4R,6aR)-4-[(6- bromo -3- thiazol -1 -yl ) amino ] hexahydrocyclopenta [c] pyrrol -2(1H) -yl ](2- methyl -2H- thieno [3,2-c] pyrazol -5- yl ) methanone [Chemical 1] HPLC retention time (min): 0.87 (TFA); MS (ESI, Pos.): 447 (M + H) ⁺ ; ¹ H-NMR (CDCl ₃ ): δ 7.57, 7.43, 7.33-7.27, 6.54, 4.83, 4.17-4.10, 4.10-4.02, 3.94, 3.91-3.80, 3.69, 2.92, 2.71, 2.40-2.30, 2.18-2.04, 1.70-1.61.

Example 3-10 : [(3aS,4R,6aR)-4-[(6- bromo - 3- pyrrolyl ) amino ] hexahydrocyclopenta [ c] pyrrol -2(1H) -yl ](2- cyclopropyl -2H- thieno [3,2-c] pyrazol -5- yl ) methanone [Chemical 1] HPLC retention time (min): 0.86 (TFA); MS (ESI, Pos.): 473 (M + H) ⁺ ; ¹ H-NMR (CDCl ₃ ): δ 7.67, 7.40, 7.34-7.27, 6.55, 4.92, 4.15-3.95, 3.93, 3.90-3.78, 3.68, 2.90, 2.70, 2.39-2.28, 2.18-2.03, 1.71-1.65, 1.30-1.09.

Example 3-11 : [(3aS,4R,6aR)-4-[(6- bromo - 3- pyrrolyl ) amino ] hexahydrocyclopenta [ c] pyrrol -2(1H) -yl ][2-( difluoromethyl )-2H- thieno [3,2-c] pyrazol -5- yl ] methanone [Chemical 1] HPLC retention time (min): 0.90 (TFA); MS (ESI, Pos.): 483 (M + H) ⁺ ; ¹ H-NMR (CDCl ₃ ): δ 8.02, 7.48, 7.42, 7.35-7.27, 7.18, 6.71-6.49, 4.14-3.98, 3.89, 3.69, 3.05-2.83, 2.74, 2.40-2.31, 2.15, 2.05, 1.68.

Example 3-12 : [(3aS,4R,6aR)-4-[(6- bromo - 3- pyrrolyl ) amino ] hexahydrocyclopenta [ c] pyrrol -2(1H) -yl ][1-(2,2,2- trifluoroethyl )-1H- thieno [3,2-c] pyrazol -5- yl ] methanone [Chemical 1] HPLC retention time (min): 1.00 (formic acid); MS (ESI, Pos.): 515 (M＋H) ^＋ ; ¹ H-NMR (DMSO-d ₆ ): δ 7.97, 7.89-7.81, 7.52-7.43, 7.43-7.33, 6.90-6.72, 5.48-5.31, 4.19-4.05, 4.04-3.92, 3.92-3.71, 3.01-2.63, 2.27-2.15, 2.12-2.00, 1.66-1.57, 1.57-1.47.

Example 3-13 : [(3aS,4R,6aR)-4-[(6- bromo - 3- pyrrolyl ) amino ] hexahydrocyclopenta [ c] pyrrol -2(1H) -yl ][2-(2,2,2- trifluoroethyl )-2H- thieno [3,2-c] pyrazol -5- yl ] methanone [Chemical 1] HPLC retention time (min): 0.90 (TFA); MS (ESI, Pos.): 515 (M + H) ⁺ ; ¹ H-NMR (CDCl ₃ ): δ 7.71, 7.42, 7.26, 6.55, 4.90, 4.16-3.97, 3.94, 3.86, 3.68, 2.92, 2.72, 2.40-2.30, 2.15-2.07, 1.71-1.55.

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

Reference Example 52 : 1-(5-((3aS,4R,6aR)-4-((6- bromothiophene -3- yl ) amino ) octahydrocyclopenta [ c] pyrrole -2- carbonyl ) thiophen -2- yl ) ethane -1- one To a solution of the compound prepared in Reference Example 12 (10 mg) 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 solution, and extraction was performed with dichloromethane. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain the title compound (15 mg).

Example 4 : [(3aS, 4R, 6aR)-4-[(6- bromo - 3- thiazolidine ) amino ] hexahydrocyclopenta [ c] pyrrol -2(1H)-yl ] [5-(2- hydroxy -2- propyl )-2 -thienyl ] methanone [Chemical 1] To a solution of the compound prepared in Reference Example 52 (5 mg) 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 solution, and extraction was performed with dichloromethane. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain the title compound (1.3 mg). HPLC retention time (min): 0.89 (formic acid); MS (ESI, Pos.): 451 (M+H) ⁺ .

Example 5 : [(3aS, 4R, 6aR)-4-[(6- iodo-3-thiophene ) amino ] hexahydrocyclopenta [ c ] pyrrol - 2 (1H)-yl ] (5- methyl -2- thienyl ) methanone [Chemical 1] To a solution of the compound prepared in Example 2 (10 mg) in 1,4-dioxane (0.1 mL) were added 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), and the mixture was stirred at 110°C for 18 hours. Aqueous ammonia solution was added to the reaction solution, and extraction was performed with dichloromethane. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain the title compound (7.6 mg). HPLC retention time (min): 0.88 (TFA); MS (ESI, Pos.): 455 (M + H) ⁺ .

Example 6 : rel-{(3aS,4R,6aR)-4-[(6- bromo - 3- thiophene ) ( methyl ) amino ] hexahydrocyclopenta [c] pyrrol -2(1H)-yl } (5- methyl -2 -thienyl ) methanone racemic mixture [Chemical 1] The compound prepared in Reference Example 12-1 was used instead of the compound prepared in Reference Example 12, and the same operation as in Example 2 → Reference Example 16 was performed to obtain the title compound. HPLC retention time (min): 1.10 (formic acid); MS (ESI, Pos.): 421 (M+H) ⁺ ; ¹ H-NMR (DMSO-d ₆ ): δ 7.55, 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.

In Examples 6-1 to 6-9 , methyl iodide or a corresponding halogen compound is used instead of methyl iodide, 5-methyl-2-thiophenecarboxylic acid or a corresponding carboxylic acid is used instead of 5-methyl-2-thiophenecarboxylic acid, the compound prepared in Reference Example 12 or the compound prepared in Reference Example 10-1 or the compound prepared in Reference Example 12-1 is used instead of Reference Example 12, and the same operation as in Example 2 → Reference Example 16 is performed to obtain the title compound.

Example 6-1 : rel-{(3aS,4R,6aR)-4-[(6- bromo-3-thiophene ) ( butyl ) amino ] hexahydrocyclopenta [ c ] pyrrol - 2(1H)-yl } (5- methyl -2- thienyl ) methanone racemic mixture [Chemical 1] HPLC retention time (min): 1.30 (formic acid); MS (ESI, Pos.): 463 (M + H) ⁺ ; ¹ H-NMR (DMSO-d ₆ ): δ 7.51, 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.

Example 6-2 : [(3aS, 4R, 6aR)-4-[ benzyl(6-bromo-3-thienyl ) amino ] hexahydrocyclopenta [ c ] pyrrol - 2 ( 1H )-yl ] (5- methyl -2- thienyl ) methanone [Chemical 1] HPLC retention time (min): 1.20 (TFA); MS (ESI, Pos.): 497 (M + H) ⁺ ; ¹ H-NMR (CDCl ₃ ): δ 7.36-7.27, 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.

Example 6-3 : [(3aS,4R,6aR)-4-[(6- bromo-3-pyrrolyl ) ( methyl ) amino ] hexahydrocyclopenta [ c ] pyrrol - 2(1H)-yl ] (6,7- dihydro -4H- thieno [3,2-c] pyran -2- yl ) methanone [Chemical 1] HPLC retention time (min): 1.00 (formic acid); MS (ESI, Pos.): 463 (M + H) ⁺ ; ¹ H-NMR (DMSO-d ₆ ): δ 7.61-7.49, 7.32, 7.21-7.06, 4.95-4.81, 4.59, 3.87, 3.82-3.56, 3.37-3.29, 3.14-3.03, 2.92, 2.09-1.93, 1.84-1.71, 1.57-1.45.

Example 6-4 : rel-{(3aS,4R,6aR)-4-[(6- chloro - 3 - thiophene )(3- methoxypropyl ) amino ] hexahydrocyclopenta [c] pyrrol -2(1H)-yl } [5-( difluoromethyl )-2- thienyl ] methanone racemic mixture [Chemical 1] HPLC retention time (min): 1.10 (formic acid); MS (ESI, Pos.): 471 (M＋H) ^＋ ; ¹ H-NMR (DMSO-d ₆ ): δ 7.68-7.54, 7.52-7.42, 7.43-7.21, 7.25-7.15, 4.71-4.59, 4.04-3.84, 3.64, 3.44-3.41, 3.31, 3.26, 3.24-3.15, 3.01-2.71, 2.07-1.91, 1.85-1.68, 1.58-1.44.

Example 6-5 : rel-{(3aS,4R,6aR)-4-[(6- chloro -3- thiazol - 6- yl )( imidazo [2,1-b][1,3] thiazol -6 -ylmethyl ) amino ] hexahydrocyclopenta [c] pyrrol -2(1H)-yl } [5-( difluoromethyl )-2- thienyl ] methanone racemic mixture [Chemical 1] HPLC retention time (min): 0.98 (formic acid); MS (ESI, Pos.): 535 (M＋H) ^＋ ; ¹ H-NMR (DMSO-d ₆ ): δ 7.88-7.75, 7.71-7.53, 7.53-7.17, 5.03-4.78, 4.65, 4.03-3.59, 3.15-3.05, 2.97-2.74, 2.14-1.97, 1.96-1.79, 1.58-1.43.

Example 6-6 : rel-{(3aS,4R,6aR)-4-[(6- chloro-3-thiophene ) ( 4 - pyridylmethyl ) amino ] hexahydrocyclopenta [ c] pyrrol -2(1H)-yl } [5-( difluoromethyl )-2- thienyl ] methanone racemic mixture [Chemical 1] HPLC retention time (min): 0.88 (formic acid); MS (ESI, Pos.): 490 (M + H) ⁺ ; ¹ H-NMR (DMSO-d ₆ ): δ 8.61, 7.59, 7.53, 7.50-7.40, 7.24, 7.43-7.21, 4.93-4.83, 4.80, 3.95, 3.87, 3.66, 3.23-3.08, 3.00, 2.88, 2.78, 2.67, 2.55, 2.10, 1.99, 1.77-1.63, 1.62-1.45, 1.32-1.22, 1.18.

Example 6-7 : rel-2-{[(6- chloro -3- thiophene ) ( (3aS,4R,6aR)-2-{[5-( difluoromethyl )-2- thienyl ] carbonyl } octahydrocyclopenta [c] pyrrol -4- yl ) amino ] methyl } benzonitrile racemic mixture [Chemical 1] HPLC retention time (min): 1.20 (formic acid); MS (ESI, Pos.): 514 (M + H) ⁺ ; ¹ H-NMR (DMSO-d ₆ ): δ 7.91-7.84, 7.62, 7.56-7.51, 7.50-7.40, 7.43-7.22, 7.27-7.19, 4.95-4.85, 4.87-4.76, 4.02-3.87, 3.71, 3.42, 3.32-3.24, 3.14-3.05, 2.96-2.67, 2.16-2.07, 2.06-1.94, 1.57-1.38.

Example 6-8 : [(3aS,4R,6aR)-4-[(6- bromo - 3 - thiophene )(3- fluoropropyl ) amino ] hexahydrocyclopenta [c] pyrrol -2(1H) -yl ](5- methyl -2- thienyl ) methanone [Chemical 1] HPLC retention time (min): 1.10 (TFA); MS (ESI, Pos.): 467 (M + H) ⁺ ; ¹ H-NMR (CDCl ₃ ): δ 7.32-7.28, 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.

Example 6-9 : [(3aS, 4R, 6aR)-4-[(6- bromo - 3- thiophene ) ( methyl ) amino ] hexahydrocyclopenta [c] pyrrol -2(1H)-yl ] (5- methyl -2- thienyl ) methanone [Chemical 1] HPLC retention time (min): 0.93 (TFA); MS (ESI, Pos.): 421 (M + H) ⁺ ; ¹ H-NMR (CDCl ₃ ): δ 7.32-7.23, 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.

Reference Example 53 : rel-(3aS,6aR) -hexahydrocyclopenta [c] pyrrole -4(1H)-one hydrochloride racemic mixture Using the compound prepared in Reference Example 1 instead of the compound prepared in Reference Example 3, the same operation as Reference Example 4 → Reference Example 10 was carried out to obtain the title compound.

Reference Example 53-1 : (3aS, 6aR) -Hexahydrocyclopenta [c] pyrrole -4(1H)-one hydrochloride Using the compound prepared in Reference Example 3 instead of the compound prepared in Reference Example 9, the same operation as in Reference Example 10 was carried out to obtain the title compound.

Reference Example 54 : Racemic mixture of rel-(3aS,6aR)-2-(5- methylthiophene -2- carbonyl ) hexahydrocyclopenta [c] pyrrole -4(1H)-one. To a solution of the compound prepared in Reference Example 53 (5.0 g) 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 solution, and extraction was performed with dichloromethane. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain the title compound (7.0 g). HPLC retention time (min): 0.88 (formic acid); MS (ESI, Pos.): 250 (M + H) ⁺ .

Reference Example 54-1 : (3aS, 6aR)-2-(5- methylthiophene -2- carbonyl ) hexahydrocyclopenta [c] pyrrole -4(1H)-one Using the compound produced in Reference Example 53-1 instead of the compound produced in Reference Example 53, the same operation as in Reference Example 54 was performed to obtain the title compound.

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

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

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

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

Example 8 : rel-[(3aS,4R,6aR)-4-(3- chloro -5,6- dihydro -7H- pyrrolo [2,3-c] pyrrol - 7 - yl ) hexahydrocyclopenta [c] pyrrol -2(1H)-yl ] (5 - methyl -2 -thienyl ) methanone racemic mixture [Chemical 1] To a solution of the compound prepared in Reference Example 57 (10 mg) in THF (1 mL) were added 60% sodium hydroxide (3 mg) and 3-chloro-6,7-dihydro-5H-pyrrolo[2,3-c]tetramethyleneimine (CAS No.: 2089649-63-6, 7.7 mg), and the mixture was stirred at 50° C. for 20 hours. Water was added to the reaction solution, and the mixture was purified by reverse phase column chromatography to obtain the title compound (1.3 mg). HPLC retention time (min): 0.90 (formic acid); MS (ESI, Pos.): 389 (M + H) ⁺ ; ¹ H-NMR (DMSO-d ₆ ): δ 7.45-7.38, 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.

In Examples 8-1 to 8-4, the corresponding amine compounds were used instead of 3-chloro-6,7-dihydro-5H-pyrrolo[2,3-c]pyridinium, and the same operation as in Example 8 was performed to obtain the title compound.

Example 8-1 : rel-[(3aS,4R,6aR)-4-(3- chloro -7H- pyrrolo [2,3-c] pyrrolo [ 7 - yl ) hexahydrocyclopenta [c] pyrrol -2(1H)-yl ] (5- methyl -2 -thienyl ) methanone racemic mixture [Chemical 1] HPLC retention time (min): 1.10 (TFA); MS (ESI, Pos.): 387 (M + H) ⁺ ; ¹ H-NMR (CDCl ₃ ): δ 7.69, 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.

Example 8-2 : rel-{(3aS,4R,6aR)-4-[(6- chloro -4- methoxy -3 -thiazol -1 -yl ) amino ] hexahydrocyclopenta [c] pyrrol -2(1H)-yl } (5- methyl -2- thienyl ) methanone racemic mixture [Chemical 1] HPLC retention time (min): 0.89 (TFA); MS (ESI, Pos.): 393 (M + H) ⁺ ; ¹ H-NMR (CDCl ₃ ): δ 7.35-7.28, 6.76-6.70, 6.56, 4.88, 4.34-4.26, 4.15-4.02, 3.94-3.73, 3.73-3.60, 2.85, 2.74, 2.50, 2.46-2.29, 2.17-1.99, 1.70-1.60.

Example 8-3 : rel-((3aS,4R,6aR)-4-((6- chloropyridin -3 -yl ) amino ) hexahydrocyclopenta [c] pyrrole -2(1H)-yl ) (5- methylthiophene -2- yl ) methanone racemic mixture [Chemical 1] HPLC retention time (min): 1.10 (formic acid); MS (ESI, Pos.): 362 (M + H) ⁺ .

Example 8-4 : rel-((3aS,4R,6aR)-4-((4,6- dichloropyridin -3- yl ) amino ) hexahydrocyclopenta [c] pyrrole -2(1H) -yl )(5- methylthiophene -2- yl ) methanone racemic mixture [Chemical 1] HPLC retention time (min): 1.20 (formic acid); MS (ESI, Pos.): 396 (M + H) ⁺ .

Reference Example 58 : rel-(3aS,4R,6aR)-4-((6- chloro -4- cyanotathimide - 3- yl ) amino ) hexahydrocyclopenta [c] pyrrole -2(1H) -carboxylic acid tert-butyl ester racemic mixture : using the compound produced in Reference Example 1 instead of the compound produced in Reference Example 3, using 3,6-dichlorootathimide-4-carbonitrile (CAS No.: 35857-93-3, 45 mg) instead of 3,6-dichlorootathimide, and carrying out the same operation as Reference Example 4 → Reference Example 5 → Reference Example 6 → Reference Example 7 → Reference Example 8 → Reference Example 9, thereby obtaining the title compound.

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

Example 9 : rel-6- chloro -3-({(3aS,4R,6aR)-2-[(5- methyl -2- thienyl ) carbonyl ] octahydrocyclopenta [c] pyrrol -4- yl } amino )-4 - thiazolidinecarbonitrile racemic mixture [Chemical 1] The compound prepared in Reference Example 59 was used instead of the compound prepared in Reference Example 12, and the same operation as in Example 2 was performed to obtain the title compound. HPLC retention time (min): 1.10 (TFA); MS (ESI, Pos.): 388 (M+H) ⁺ ; ¹ H-NMR (CDCl ₃ ): δ 7.42, 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.

In Example 9-1, the title compound was obtained by using the corresponding halogen compound instead of 3,6-dichlorothiophene, and the corresponding carboxylic acid instead of 5-(difluoromethyl)thiophene-2-carboxylic acid, and performing the same operation as Reference Example 9 → Reference Example 10 → Example 1.

Example 9-1 : [(3aS,4R,6aR)-4-{[6- chloro -4-( trifluoromethyl )-3 - pyranyl ] amino } hexahydrocyclopenta [ c] pyrrol -2(1H) -yl ](6,7- dihydro -4H- thieno [3,2-c] pyran -2- yl ) methanone [Chemical 1] HPLC retention time (min): 1.10 (formic acid); MS (ESI, Pos.): 473 (M + H) ⁺ ; ¹ H-NMR (DMSO-d ₆ ): δ 7.94-7.83, 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.

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- propyl ) 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) were added triethylamine (2.4 mL) and tert-butyldimethylsilyl trifluoromethanesulfonate (CAS No.: 69739-34-0, 2.0 mL) and stirred at 40°C for 2 hours. A saturated sodium bicarbonate aqueous solution was added to the reaction solution and extracted with dichloromethane. The organic layer was washed with saturated saline, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain 1.9 g of the title compound (1) and 1.0 g of the title compound (2), respectively.

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 prepared in Reference Example 60(1) (1.9 g) in acetonitrile (38 mL) was added 1-chloromethyl-4-fluoro-1,4-diazobicyclo[2.2.2]octane bis(tetrafluoroborate) (CAS No.: 140681-55-6, 2.2 g), and the mixture was stirred at room temperature for 20 minutes. The reaction solution was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography to obtain the title compound (540 mg). HPLC retention time (min): 0.95 (TFA); MS (ESI, Pos.): 268 (M + H) ⁺ .

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 To a solution of the compound (1.9 g) prepared in Reference Example 61 in methanol (19 mL) and THF (19 mL) was added sodium borohydride (CAS No.: 16940-66-2, 405 mg) at 0°C and stirred at 0°C for 1 hour. Water was added to the reaction solution and extraction was performed with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain the title compound (872 mg). HPLC retention time (min): 0.88 (TFA); MS (ESI, Pos.): 270 (M + H) ⁺ .

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

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 To a solution of the compound (1.4 g) prepared in Reference Example 63 in dimethyl sulfoxide (13 mL) was added sodium azide (560 mg), and the mixture was stirred at 100°C for 90 hours. Water was added to the reaction solution, and extraction was performed with dichloromethane. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the title compound, which was used in the next reaction without purification. HPLC retention time (min): 1.08 (TFA); MS (ESI, Pos.): 295 (M + H) ⁺ .

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% potassium hydroxide (1.8 g), and the mixture was stirred at room temperature in a hydrogen atmosphere for 15 hours. The reaction solution was filtered and concentrated under reduced pressure to obtain the title compound, which was used in the next reaction without purification. HPLC retention time (min): 0.72 (TFA); MS (ESI, Pos.): 269 (M+H) ⁺ .

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

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

Example 11 : [(3aR,4R,6aS)-4-[(6- bromo-3-pyranyl ) amino ] -3a - fluorohexahydrocyclopenta [ c ] pyrrol -2(1H) -yl ](6,7- dihydro -4H- thieno [3,2-c] pyran -2- yl ) methanone [Chemical 1] 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) were added DIPEA (0.02 mL) and HATU (31 mg), and the mixture was stirred at room temperature for 3 hours. 2N hydrochloric acid was added to the reaction solution, and extraction was performed with dichloromethane. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain the title compound (22 mg). HPLC retention time (min): 0.89 (TFA); MS (ESI, Pos.): 467 (M + H) ⁺ ; ¹ H-NMR (CDCl ₃ ): δ 7.29, 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.

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

Example 11-1 : [(3aR,4R,6aS)-4-[(6- bromo - 3- pyrrolyl ) amino ] -3a- fluorohexahydrocyclopenta [c] pyrrol -2(1H) -yl ](2- cyclopropyl -2H- thieno [3,2-c] pyrazol -5- yl ) methanone [Chemical 1] HPLC retention time (min): 0.91 (TFA); MS (ESI, Pos.): 491 (M＋H) ^＋ ; ¹ H-NMR (DMSO-d ₆ ): δ 8.17, 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.

Example 11-2 : [(3aR, 4R, 6aS)-4-[(6- bromo -3- thiazol -1 -yl ) amino ]-3a- fluorohexahydrocyclopenta [c] pyrrol -2(1H) -yl ][5-( fluoromethyl )-2 -thienyl ] methanone [Chemical 1] HPLC retention time (min): 0.92 (TFA); MS (ESI, Pos.): 443 (M + H) ⁺ ; ¹ H-NMR (CDCl ₃ ): δ 7.40, 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.

Example 11-3 : [(3aR, 4R, 6aS)-4-[(6- bromo -3- thiazol -1 -yl ) amino ]-3a- fluorohexahydrocyclopenta [c] pyrrol -2(1H) -yl ][5-(2- fluoroethyl )-2 -thienyl ] methanone [Chemical 1] HPLC retention time (min): 0.94 (TFA); MS (ESI, Pos.): 457 (M + H) ⁺ ; ¹ H-NMR (CDCl ₃ ): δ 7.36-7.27, 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.

Example 12 : {(3aR,4R,6aS)-4-[(6- chloro -3- thiazol -1 -yl ) amino ]-3a -fluorohexahydrocyclopenta [c] pyrrol -2(1H) -yl }(6,7- dihydro -4H- thieno [3,2-c] pyran -2- yl ) methanone [Chemical 1] Using 3,6-dichloroindole instead of 3-bromo-6-fluoroindole and the corresponding carboxylic acid instead of 6,7-dihydro-4H-thieno[3,2-c]pyran-2-carboxylic acid, the same procedures as in Example 10 → Reference Example 66 → Example 11 were carried out to obtain the title compound. HPLC retention time (min): 0.89 (TFA); MS (ESI, Pos.): 423 (M + H) ⁺ ; ¹ H-NMR (CDCl ₃ ): δ 7.22-7.15, 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.

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 prepared in Reference Example 60(2) (1.3 g) in acetonitrile (25 mL) was added 1-chloromethyl-4-fluoro-1,4-diazobicyclo[2.2.2]octane bis(tetrafluoroborate) (1.5 g), and the mixture was stirred at room temperature for 3 hours. The reaction solution was concentrated under reduced pressure, water was added to the obtained residue, and extraction was performed with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the title compound (633 mg). HPLC retention time (min): 0.81 (TFA); MS (ESI, Pos.): 304 (M+H) ⁺ .

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 To a solution of the compound (500 mg) prepared in Reference Example 67 in methanol (10 mL) was added sodium borohydride (106 mg) at 0°C and stirred at 0°C for 1 hour. Water was added to the reaction solution and extraction was performed with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain the title compound (200 mg).

Reference Example 69 : 4- Methylbenzenesulfonic acid [(3aS,4R,5R,6aR)-5- fluoro -2-(5- methylthiophene -2- carbonyl )-3,3a,4,5,6,6a -hexahydro -1H- cyclopenta [c] pyrrol -4- yl ] ester 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 extraction was performed with dichloromethane. After concentration, the obtained residue was purified by silica gel column chromatography to obtain the title compound (190 mg). HPLC retention time (min): 1.13 (TFA); MS (ESI, Pos.): 424 (M + H) ⁺ .

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

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) was added 20% potassium hydroxide (50 mg), and the mixture was stirred at room temperature in a hydrogen atmosphere for 2 hours. The reaction solution was filtered and concentrated under reduced pressure to obtain the title compound, which was used in the next reaction without purification. HPLC retention time (min): 0.75 (TFA); MS (ESI, Pos.): 269 (M+H) ⁺ .

Example 13 : [(3aS,4S,5R,6aR)-4-[(6- bromothiophene - 3- yl ) amino ]-5- fluoro -3,3a,4,5,6,6a -hexahydro -1H- cyclopenta [c] pyrrol -2- yl ]-(5- methyl -2- thienyl ) methanone [Chemical 1] To a solution of the compound prepared in Reference Example 71 (50 mg) in 2-methyl-2-butanol (0.23 mL) were added DIPEA (0.19 mL) and 3-bromo-6-fluorotitanium (132 mg), and the mixture was stirred at 160° C. for 1 hour. The reaction mixture was purified by reverse phase column chromatography to obtain the title compound (8.9 mg). HPLC retention time (min): 0.94 (TFA); MS (ESI, Pos.): 426 (M + H) ⁺ ; ¹ H-NMR (CDCl ₃ ): δ 7.32, 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.

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

Reference Example 73 : [(3aS,6aR)-6-{[ dimethyl (2- methyl -2- propyl ) silanyl ] 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) were added triethylamine (2.8 mL) and tert-butyldimethylsilyl trifluoromethanesulfonate (2.3 mL) at 0°C, and the mixture was stirred at 50°C for 22 hours. A saturated aqueous sodium bicarbonate solution was added to the reaction solution, and extraction was performed with dichloromethane. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain the title compound, which was used in the next reaction without purification.

Reference Example 74 : (3aS,5R,6aR)-2-(6,7- dihydro -4H- thieno [3,2-c] pyran -2- ylcarbonyl )-5- methylhexahydrocyclopenta [c] pyrrole -4(1H)-one To a DMF (10 mL) solution of the compound prepared in Reference Example 73, iodomethane (9.5 g) and 1M tetra(N-butyl)ammonium fluoride (CAS No.: 429-41-4, 0.74 mL, THF solution) were added and stirred at room temperature for 3 hours. The reaction solution was concentrated under reduced pressure, water was added to the obtained residue, and extraction was performed with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain the title compound (100 mg).

Example 14 : [(3aS,4R,5R,6aR)-4-[(6- bromo - 3- pyranyl ) amino ] -5- methylhexahydrocyclopenta [c] pyrrol -2(1H) -yl ](6,7- dihydro -4H- thieno [3,2-c] pyran -2- yl ) methanone [Chemical 1] The compound prepared in Reference Example 74 was used instead of the compound prepared in Reference Example 61, and the same operation as Reference Example 62 → Reference Example 63 → Reference Example 64 → Reference Example 65 → Example 10 was performed to obtain the title compound. HPLC retention time (min): 0.86 (TFA); MS (ESI, Pos.): 463 (M + H) ⁺ ; ¹ H-NMR (CDCl ₃ ): δ 7.33-7.28, 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.

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

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

Reference Example 77 : [(3aS,4S,6aR)-4- azidospiro [1,3,3a,4,6,6a- hexahydrocyclopenta [c] pyrrole -5,1'- cyclopropane ]-2- yl ]-(6,7- dihydro -4H- thieno [3,2-c] pyran -2- yl ) methanone To a solution of the compound prepared in Reference Example 76 (95 mg) in THF (0.2 mL) were added triphenylphosphine (CAS No.: 603-35-0, 102 mg), 2.2 M diethyl azodicarboxylate solution (CAS No.: 1972-28-7, 0.18 mL) and diphenyl azidophosphate (CAS No.: 26386-88-9, 82 mg), and the mixture was stirred at room temperature for 30 minutes. The reaction solution 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) ⁺ .

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

Example 15 : [(3aS,4S,6aR)-4-[(6- bromothiophene - 3- yl ) amino ] spiro [1,3,3a,4,6,6a- hexahydrocyclopenta [c] pyrrole -5,1' -cyclopropane ]-2- yl ]-(6,7- dihydro -4H- thieno [3,2-c] pyran -2- yl ) methanone [Chemical 1] To a solution of the compound prepared in Reference Example 78 (17 mg) in 2-methyl-2-butanol (0.5 mL) were added DIPEA (0.92 mL) and 3-bromo-6-fluorotitanium (18.9 mg), and the mixture was stirred at 180° C. for 4 hours. Water was added to the reaction solution, and extraction was performed with dichloromethane. The organic layer was purified by silica gel column chromatography to obtain the title compound (13 mg). HPLC retention time (min): 0.97 (TFA); MS (ESI, Pos.): 477 (M + H) ⁺ ; ¹ H-NMR (CD ₃ OD): δ 7.37, 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.

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

Reference Example 80 : rel-[(3aS,4R,6aR)-2- benzyl -6,6- difluorooctahydrocyclopenta [c] pyrrol -4- yl ] carbamic acid (2- methyl -2- propyl ) ester racemic mixture To a solution of the compound (300 mg) prepared in Reference Example 79 in dichloromethane (5 mL) was added bis(2-methoxyethyl)aminosulfur trifluoride (CAS No.: 202289-38-1, 1.2 g) at 0°C and stirred at room temperature for 15 hours. Saturated aqueous sodium bicarbonate solution was added to the reaction solution and extracted with dichloromethane. The mixture was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the title compound (120 mg). HPLC retention time (min): 0.91 (TFA); MS (ESI, Pos.): 353 (M + H) ⁺ .

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

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

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 prepared in Reference Example 82 (100 mg), 4N hydrochloric acid (1,4-dioxane solution, 3 mL) was added and stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure to obtain the title compound (80 mg).

Example 16 : [(3aR,6R,6aS)-6-[(6- bromo -3- thiazol -1 -yl ) amino ]-4,4 -difluorohexahydrocyclopenta [c] pyrrol -2(1H) -yl ](6,7 -dihydro -4H- thieno [3,2-c] pyran -2- yl ) methanone [Chemical 1] To a solution of the compound prepared in Reference Example 83 (80 mg) in DMA (1 mL) were added DIPEA (0.24 mL) and 3,6-dibromopyralidinium (120 mg), and the mixture was stirred at 160°C for 1 hour. Water was added to the reaction solution, and extraction was performed with dichloromethane. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography, and then two non-mirror isomers were separated by supercritical fluid chromatography (CHIRALPAK IC, CO ₂ : methanol = 70:30) to obtain a less polar isomer (19 mg). HPLC retention time (min): 1.00 (TFA); MS (ESI, Pos.): 485 (M + H) ⁺ ; ¹ H-NMR (DMSO-d ₆ ): δ 7.54-7.45, 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.

Reference Example 84 : 2 - Bromo -5-[2-(2- fluoroethoxy ) ethyl ] thiophene To a solution of 2-(5-bromothiophen-2-yl)ethane-1-ol (CAS No.: 57070-78-7, 653 mg) in dimethylacetamide (15 mL), 1-iodo-2-fluoroethane (CAS No.: 762-51-6, 1.52 mL) and sodium hydroxide (757 mg) were added and stirred at room temperature for 17 hours. Thereafter, the mixture was stirred at 60°C for 24 hours. Water was added to the reaction solution, and extraction was performed using 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 obtained residue was purified by silica gel column chromatography to obtain the title compound (396 mg). HPLC retention time (min): 0.828 (TFA); ¹ H-NMR (CDCl ₃ ): δ 6.86, 6.61, 4.66-4.61, 4.54-4.49, 3.77-3.66, 3.04.

Reference Example 85 : 5-[2-(2- fluoroethoxy ) ethyl ]-2- thiophenecarboxylic acid To a solution of the compound (396 mg) prepared in Reference Example 84 in THF (1 mL) were added water (0.135 mL) and trans-bis[2-(di-O-methylphenylphosphino)benzyl]dipalladium(II) diacetate (CAS No.: 172418-32-5, 141 mg), DBU (0.673 mL), tri-tert-butylphosphonium tetrafluoroborate (CAS No.: 131274-22-1, 43 mg) and molybdenum hexacarbonyl (CAS No.: 13939-06-5, 595 mg). The reaction solution was heated at 120° C. for 1 hour. A 1M aqueous hydrochloric acid solution and ethyl acetate were added to the reaction solution, and the mixture was filtered. The organic layer was washed with water, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the title compound (190 mg). ¹ H-NMR (CDCl ₃ ): δ 7.72, 6.91, 4.72-4.61, 4.55-4.49, 3.84-3.68, 3.15, 2.50.

Reference Example 86 : [(3aS,4R,6aR)-4-[(6- bromo - 3- pyridinyl ) 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) were added DIPEA (0.024 mL) and (1H-benzotriazol-1-yl-oxy)tripyrrolidinophosphonium hexafluorophosphate (hereinafter referred to as PyBOP, 22 mg, CAS No.: 128625-52-5), and the mixture was stirred at room temperature for 1 hour. Water was added to the reaction solution, and extraction was performed with dichloromethane. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the title compound (5.0 mg). HPLC retention time (min): 0.88 (TFA); MS (ESI, Pos.): 483 (M+H) ⁺ .

Example 17 : [(3aS,4R,6aR)-4-[(6- bromo -3 - thiazol -1- yl )( methyl ) 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 86 (5.0 mg) in DMF (1.0 mL) was added sodium hydride (4.1 mg). 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 solution, and extraction was performed with dichloromethane. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain the title compound (3.9 mg). HPLC retention time (min): 0.95 (TFA); MS (ESI, Pos.): 497 (M + H) ⁺ ; ¹ H-NMR (CDCl ₃ ): δ 7.34-7.27, 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.

Reference Example 87 : To a solution of 5-(2- fluoroethoxy )-2 -thiophenecarboxylic acid in DMA (15 mL) of 2-fluoroethanol (CAS No.: 371-62-0, 1578 mg) was added sodium hydroxide (1313 mg) at room temperature, and then 5-fluorothiophene-2-carboxylic acid (CAS No.: 4377-58-6, 600 mg) was added. The reaction solution was stirred at 100°C for 2 days. Water was added to the reaction solution, and extraction was performed using 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 obtained residue was dissolved in methanol (4 mL), trimethylsilyldiazomethane (CAS No.: 18107-18-1, 1 mL) was added, and the mixture was stirred at room temperature for 1 hour. The reaction solution was purified by silica gel column chromatography to obtain a methyl ester compound (60 mg). The obtained methyl ester compound (60 mg) was dissolved in methanol (4 mL), and a 2M aqueous sodium hydroxide solution (1.5 mL) was added. The reaction solution was stirred at 50°C for 18 hours. 1M hydrochloric acid was added to the reaction solution, and extraction was performed with ethyl acetate. The organic layer was washed with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the title compound (57 mg). HPLC retention time (min): 0.83 (TFA); MS (ESI, Pos.): 191 (M + H) ⁺ ; ¹ H-NMR (CDCl ₃ ): δ 7.53, 6.28, 4.84-4.79, 4.72-4.67, 4.38-4.27.

Reference Example 88 : [(3aS,4R,6aR)-4-[(6- bromo - 3- pyridine ) 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 solution, and extraction was performed with dichloromethane. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the title compound (7.0 mg). HPLC retention time (min): 0.89 (TFA); MS (ESI, Pos.): 455 (M+H) ⁺ .

Example 18 : [(3aS,4R,6aR)-4-[(6- bromo -3 - thiazol -1 -yl )( methyl ) amino ] hexahydrocyclopenta [c] pyrrol -2(1H)-yl ] [5-(2- fluoroethoxy )-2- thienyl ] methanone To a solution of the compound prepared in Reference Example 88 (7.0 mg) in DMF (1.0 mL) was added sodium hydride (6.1 mg), and the mixture was stirred at room temperature for 15 minutes. Thereafter, iodomethane (0.005 mL) was added, and the mixture was stirred at room temperature for 1 hour. Water was added to the reaction solution, and extraction was performed with dichloromethane. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain the title compound (3.9 mg). HPLC retention time (min): 0.95 (TFA); MS (ESI, Pos.): 469 (M + H) ⁺ ; ¹ H-NMR (CDCl ₃ ): δ 7.28, 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.

Reference Example 89 : 2-{2-[(6- bromo -3- pyridinyl ) {(3aS,4R,6aR)-2-[(5- methyl - 2- thienyl ) carbonyl ] octahydrocyclopenta [c] pyrrol -4 - yl } amino ] ethoxy } ethyl 4- methylbenzenesulfonate To a solution of the compound (300 mg) prepared in Example 2 in DMF (7.4 mL) was added sodium hydroxide (88 mg), and the mixture was stirred at room temperature for 30 minutes. Subsequently, diethylene glycol ditoluenesulfonate (CAS No.: 7460-82-4, 305 mg) was added, and the mixture was stirred at room temperature for 4 hours. Aqueous sodium bicarbonate solution was added to the reaction solution, and extraction was performed with dichloromethane. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the title compound (100 mg). HPLC retention time (min): 1.18 (TFA); MS (ESI, Pos.): 649 (M + H) ⁺ .

Example 19 : [(3aS,4R,6aR)-4-{(6- bromo -3- thiazol -1 - yl )[2-(2- fluoroethoxy ) ethyl ] amino } hexahydrocyclopenta [c] pyrrol -2(1H) -yl ](5- methyl -2- thienyl ) methanone Potassium fluoride (27 mg) and 4,7,13,16,21,24-hexaoxa-1,10-diazobicyclo[8.8.8]hexacosane (CAS No.: 23978-09-8, 174 mg) were added to a solution of the compound prepared in Reference Example 89 (100 mg) in acetonitrile (1.5 mL), and the mixture was stirred at 80° C. for 40 minutes. The reaction solution was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography to obtain the title compound (41.6 mg). HPLC retention time (min): 1.05 (TFA); MS (ESI, Pos.): 497 (M + H) ⁺ ; ¹ H-NMR (CDCl ₃ ): δ 7.37-7.30, 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.

Pharmacological Experiment Example 1 : Evaluation of ABHD6 Enzyme Inhibitory Activity In an assay buffer containing 50 mM Tris-HCl (pH 7.4), 100 mM NaCl, and 0.05% BSA, 1-Arachidonoyl Glycerol (Cayman) as a substrate was prepared at a final concentration of 10 μmol/L, and compounds were added at 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 final concentration of DMSO was 0.3%). In addition, the group to which DMSO was added at a final concentration of 0.3% was designated as the group without compound addition. Recombinant human ABHD6 (33-337) prepared in the same assay buffer was added to the mixed solution of the substrate and the compound at a final concentration of 300 μg/mL to induce the enzyme reaction. Recombinant human ABHD6 (33-337) was expressed in Escherichia coli and purified using Glutathione-Sepharose 4B resin and then concentrated. The enzyme reaction was carried out at room temperature using a 384-well polypropylene microplate, and the wells without enzyme addition were set as the blank control group. One hour after the start of the enzyme reaction, arachidonic acid-d8 (Cayman) as an internal standard and methanol containing 1% formic acid were added to stop the enzyme reaction. After the top of the enzyme reaction plate was sealed with aluminum, the plate was centrifuged at 560 g for 5 minutes at room temperature, and then the RapidFire (registered trademark)-Mass Spectrometry system was used to quantify arachidonic acid as the enzyme reaction product and arachidonic acid- _d8 as the internal standard substance. The ratio of each quantitative value was taken, and the average value of the blank control group (Blank group) was set as 100% inhibition, and the average value of the compound non-added group was set as 0% inhibition. The inhibition rate of arachidonic acid production at each compound concentration was calculated to obtain the _IC50 value. According to the above pharmacological experiments, it can be seen that the compounds of the present invention have strong ABHD6 inhibitory activity. For example, the _IC50 values of several compounds of the present invention are shown in the following Table 1. [Table 1] Example No. IC ₅₀ (μM) Example No. IC ₅₀ (μM) 1 0.001 3-10 0.001 1-2 0.001 5 0.001 1-4 0.001 6 0.002 2 <0.001 6-2 0.001 2-1 0.001 8-1 0.001 2-6 0.002 9 0.002 2-14 0.002 10 <0.001 3 0.005 12 0.001 3-6 0.002 15 0.001 3-9 0.001 16 0.001

Pharmacological Experiment Example 2 : Binding affinity measurement for human ABHD6 HEK293 cells forced to express NanoLuc-human ABHD6 fusion protein were used to allow fluorescent probe molecules to compete with the test compound, and the bioluminescence resonance energy transfer (hereinafter referred to as BRET) caused by the proximity of the probe molecule and NanoLuc-human ABHD6 fusion protein was used as an indicator to measure the binding affinity of the test compound for human ABHD6. <Compound treatment> The test compound and the compound described in Example 2 as a control substance were dissolved in dimethyl sulfoxide (DMSO) to prepare a 10 mmol/L solution. When used, the prepared 10 mmol/L solution was thawed and serially diluted with DMSO for experimental use. ＜Cell Culture＞ HEK293 cells expressing NanoLuc-human ABHD6 fusion protein were cultured in 9.8 vol% non-dialyzed FBS (containing 0.5 vol% genomycin and 1% penicillin-streptomycin) in the presence of 5% CO ₂ at 37°C. Subculture was performed as follows. The culture medium was removed and washed once with phosphate-buffered saline without Ca ^{2 +} and Mg ^{2 +} . An appropriate amount of trypsin-EDTA was added and cultured at room temperature. After detaching the cells, a 10-fold volume of culture medium was added to the trypsin-EDTA (0.05%) to stop the enzyme reaction. Recover the cells into a centrifuge tube, centrifuge at 120 g for 3 minutes at room temperature, and remove the supernatant. Suspend the cells in an appropriate amount of culture medium and inoculate them into a culture flask. Prepare HEK293 cells expressing NanoLuc-human ABHD6 fusion protein and store them frozen in CELLBANKER2 at 5.0×10 ⁶ cells/mL/vial for experimental use. Also, prepare HBSS(+) containing 20 mmol/L HEPES (pH 7.3) and 0.1% BSA for use as assay buffer. Thaw the cells and suspend them in assay buffer at 2×10 ⁵ cells/mL. The cell suspension (25 μL) was added to a 384-well assay plate pre-added with the test compound to initiate the reaction. After standing for 30 minutes at 37°C in the presence of 5% CO ₂ , the fluorescent probe molecule (10 mmol/L DMSO solution) was diluted with assay buffer to a final concentration of 100 nmol/L, and then 15 μL was added to each well of the assay plate. After incubation at 37°C for 30 minutes in the presence of 5% CO ₂ , Nano-Glo (registered trademark) Vivazine (trademark) substrate (PROMEGA) was diluted with analytical buffer according to the method described in the attached operating instructions and added to the analytical plate at 10 μL per well. After incubation at room temperature for 1 hour, luminescence and luminescence intensity were measured using GloMax (registered trademark) Discover system. The ratio of the luminescence intensity passing through a 450 nm bandpass filter to the fluorescence intensity passing through a 600 nm longpass filter was used as the measured value of each sample. The measured value of the group containing the control substance at a final concentration of 30 μmol/L was set as 100% inhibition, and the measured value of the group without compound addition was set as 0% inhibition. The IC ₅₀ value of the test compound was calculated from the measured values at each test compound concentration. In the above cell evaluation system, it was confirmed that the compounds of the present invention have a strong ABHD6 binding activity. For example, the IC ₅₀ values of several compounds of the present invention are shown in the following Table 2. [Table 2] Example No. IC ₅₀ (μM) Example No. IC ₅₀ (μM) 1 0.011 3-10 0.002 1-2 0.005 5 0.003 1-4 0.002 6 0.005 2 0.001 6-2 0.001 2-1 0.003 8-1 0.005 2-6 0.025 9 0.008 2-14 0.016 10 0.002 3 0.062 12 0.001 3-6 0.006 15 0.001 3-9 0.005 16 0.004

Pharmacological Experiment Example 3 : Evaluation of ABHD6 Selectivity Rat brain membrane fractions were used to allow the fluorescent probe molecule to interact with the test compound. After protein separation by electrophoresis, the fluorescence intensity of ABHD6, MAGL (Monoacylglycerol lipase), and FAAH was used as an indicator to measure the binding affinity of the test compound. <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 adjust the concentration to 50 times higher than the final concentration. <Preparation of Rat Brain Membrane Fractions> The rat was bled under anesthesia and the brain was removed. Add 1 mL of ice-cooled phosphate buffer (PBS, pH 7.5) to every 200 mg of brain weight and homogenize using a homogenizer. Centrifuge 1000 g of the homogenized solution at 4°C for 10 minutes and recover the supernatant. Centrifuge 100,000 g of the supernatant obtained at 4°C for 45 minutes, add ice-cooled PBS to the sediment and resuspend it to prepare the brain fraction. Quantify the protein concentration of the prepared membrane fraction solution and store it in a -80°C freezer before use. <ABPP (Activity-based protein profiling)> Adjust the membrane fraction solution to 3 mg/mL using PBS. 1 μL of DMSO or compound solution was added to 50 μL of 3 mg/mL membrane fraction solution, and the reaction was carried out at 37°C for 30 minutes. Then, 1 μL of a probe molecule with a fluorescent group (ActivX (trade name) TAMRA-FP Serine Hydrolase Probe, final concentration 1 μmol/L, DMSO solution) was added, and the reaction was carried out at room temperature for 30 minutes. The reaction was stopped using 4× SDS-PAGE (sodium dodecyl sulfate-polyacrylamide gel electrophoresis) loading buffer. After heating the sample at 95°C for 5 minutes, protein separation was performed by SDS-PAGE using 10% acrylamide gel. The fluorescence of the gel after SDS-PAGE was visualized by a chemiluminescence imaging system. In each band of ABHD6, MAGL, and FAAH, the fluorescence band intensity of the control group (DMSO treatment group) was set to 0% inhibition, and the IC ₅₀ value of the test compound was calculated from the fluorescence intensity at each test compound concentration. Based on the results, it can be seen that the compound of the present invention has selective inhibitory activity against ABHD6 compared to MAGL and FAAH. Pharmacological Experiment Example 4 : Analgesic effect on sodium monoiodoacetate-induced model rats Sodium monoiodoacetate (hereinafter referred to as MIA) (Sigma-Aldrich Japan) was used to induce model rats to evaluate the analgesic effect of the compound of the present invention. (1) Preparation of MIA-induced rat model The hair around the knee of the right hind limb of the rat was shaved under isoflurane anesthesia, and 25 μL of 120 mg/mL MIA solution was injected into the joint cavity of the right hind limb using a syringe with a 29G injection needle (BD Rhoads, Becton Dickinson, Japan). The normal control group was injected with 25 μL of physiological saline. (2) Groups and grouping The normal control group, the disease control group, the test substance administration group, and the tramadol administration group or the morphine administration group were set up. In addition to the normal control group, the right hind limb load weight ratio of the model rats prepared according to the method of (1) above 13 or 14 days after MIA induction was measured (the measurement method is described below), and the groups were divided in a way that there was no deviation in the right hind limb load weight ratio among the groups. (3) Administration of test substance, tramadol or morphine The compound of the present invention as the test substance was dissolved in a solubilizing medium (Kolliphor:PEG=7:3 solution) to prepare a 0.4 or 8 mg/mL solution. The prepared solution was diluted 4 times with distilled water to prepare a 0.1 or 2 mg/mL solution (final concentration of the solubilizing medium: 25%). Tramadol as a positive control drug was dissolved in saline to prepare a 2 mg/mL solution. Or morphine as a positive control drug was dissolved in saline to prepare a 0.6 mg/mL solution. The test substance was orally administered at 5 mL/kg 5 hours before the start of the assessment, and tramadol and morphine were subcutaneously administered at 5 mL/kg 1 hour before the start of the assessment. (4) Determination of the right hind limb load ratio The load weight of the left and right hind limbs was measured using the Linton Incapacitance Tester (MJS Technology INC., UK). That is, the rat was transferred to a special cage on the Linton Incapacitance Tester, and the posture was corrected so that the left and right hind limbs stood on two pairs of weight measurement sensors respectively. After confirming that the posture of the rat was balanced left and right and front and back, the load weight of the left and right hind limbs was measured for 3 seconds respectively. The load weight measurement was repeated 3 times for each individual. In order to obtain stable measurement values, the rats were placed in a special cage for more than 20 minutes for more than 5 days from the day of MIA induction to 14 days after induction. Furthermore, the rats were allowed to adapt for about 10 minutes before the load weight measurement, and then the load weight was measured. The weights of the left and right hind limbs were measured before grouping 14 days after MIA induction, and 14 days after MIA induction in the normal control group, the diseased control group, the test substance administration group (5 hours after administration), the tramadol administration group (1 hour after administration), and the morphine administration group (1 hour after administration). Based on the average value of the weights of the left and right hind limbs, the weight ratio of the right hind limb in the weights of the two hind limbs was calculated by the following formula 1. Based on the weight ratio of the right hind limb of each group 14 days after MIA induction, the improvement rate of the weight ratio of the right hind limb when the compound of the present invention as the test substance was administered was calculated by the following formula 2, and the analgesic effect of the test substance (compound of the present invention) was evaluated. [Figure 1] Ratio of right hind limb weight bearing B (%) = { _AR /( _AR + _AL ) × 100} _AR : weight bearing of right hind limb (average of 3 measurements of the same individual) _AL : weight bearing of left hind limb (average of 3 measurements of the same individual) [Figure 2] Improvement rate of test substance (%) = {1-( _BT - _BC )/( _BN - _BC )} × _100BC : average value of right hind limb weight bearing ratio of normal control groupBN: average value of right hind limb weight bearing ratio of diseased control _groupBT : average value of _right hind limb weight bearing ratio of test substance-administered group The results show that the compound of the present invention has analgesic effect equivalent to or better than tramadol and morphine, which are commonly used analgesics. Pharmacological Experiment Example 5 : Antidepressant Effect in Rat Forced Swim Test The rat forced swimming test was used to evaluate the antidepressant effect of the compound of the present invention. (1) Groups and Divisions The medium administration group, the test substance administration group, and the imipramine administration group were set up. According to the body weight value on the day of grouping, the rats were randomly divided into 5 groups. (2) Administration of test substance and imipramine The compound of the present invention as the test substance was dissolved in a solubilizing medium (Kolliphor: PEG = 7:3 solution) to prepare a 4 mg/mL solution. The prepared solution was diluted 4 times with distilled water to prepare a 1 mg/mL solution (final concentration of the solubilizing medium: 25%). Furthermore, the 1 mg/mL solution was diluted 10-fold or 100-fold using a 25% solubilizing medium to prepare a 0.1 mg/mL or 0.01 mg/mL solution. As a positive control drug, imipenem was dissolved in physiological saline to prepare a 15 mg/mL solution. The test substance was orally administered at 5 mL/kg 5 hours before the start of the assessment, and imipenem was intraperitoneally administered at 2 mL/kg 0.5 hours before the start of the assessment. (3) Determination of immobility time On the day before the measurement, the rats were placed in a water tank (water depth: 20 cm, water temperature: 24±1℃) and forced to swim for 15 minutes (measurement of acclimatization). 24 hours later, the rats were again placed in a water tank (water depth: 20 cm, water temperature: 24±1℃) and forced to swim for 5 minutes. The immobility time during this period was measured as depressive-like behavior. Use a stopwatch to measure the immobility time, take the measured value to one decimal place, round it up, and record the integer value. According to the results, it can be seen that the compound of the present invention has an antidepressant effect of the same degree as imipramine, which is an antidepressant. Pharmacological Experiment Example 6 : Anti-anxiety effect in the rat social interaction test The rat social interaction test was used to evaluate the anti-anxiety effect of the compound of the present invention. (1) Groups and grouping A medium administration group, a test substance administration group, and a diazepam administration group were set up. According to the body weight value on the day of grouping, the rats were randomly divided into 5 groups. (2) Administration of test substance and diazepam The compound of the present invention as the test substance was dissolved in a solubilizing medium (Kolliphor:PEG=7:3 solution) to prepare a 4 mg/mL solution. The prepared solution was diluted 4-fold with distilled water to prepare a 1 mg/mL solution (final concentration of the solubilizing medium: 25%). Furthermore, the 1 mg/mL solution was diluted 10-fold or 100-fold with 25% solubilizing medium to prepare a 0.1 mg/mL or 0.01 mg/mL solution. As a positive control, diazepam was suspended in a 0.5% methylcellulose solution to prepare a 0.6 mg/mL suspension. The test substance was orally administered at 5 mL/kg 2 hours before the start of the evaluation, and diazepam was orally administered at 5 mL/kg 1 hour before the start of the evaluation. (3) Determination of social interaction time Two hours after administration of the test substance or one hour after administration of the positive control substance, two rats (a pair) with a weight difference of less than 20 g were placed in the field test device and their behavior was recorded for 10 minutes. The time during the 10-minute behavior state that matched the social behavior analysis items shown in Table 3 was measured. When the behavior time was prolonged, it was confirmed that the test substance showed an anti-anxiety effect. [Table 3] Project content Wrestling Wrestling-like behavior Biting Biting behavior Boxing Boxing-like behavior Mounting Climbing behavior Grooming of the partner Grooming behavior Following Tailing behavior Sniffing Sniffing behavior The results show that the compound of the present invention has an antianxiety effect comparable to that of diazepam, an antianxiety agent.

[Preparation Example] Preparation Example The following ingredients are mixed by a conventional method and then tableted to obtain a tablet containing 10 mg of the active ingredient in approximately 10,000 tablets. ・{(3aS,4R,6aR)-4-[(6-chloro-3-pyridinyl)amino]hexahydrocyclopenta[c]pyrrole-2(1H)-yl}[5-(difluoromethyl)-2-thienyl]methanone ……100 g ・Calcium carboxymethylcellulose (disintegrant) ……20 g ・Magnesium stearate (lubricant) ……10 g ・Microcrystalline cellulose ……870 g [Industrial Availability]

The compounds of the present invention have ABHD6 inhibitory activity. Therefore, the pharmaceutical composition containing the compounds of the present invention as an active ingredient can be used as a preventive and/or therapeutic agent for ABHD6-related diseases.

Claims (20)

A pharmaceutical composition comprising the following compound or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, wherein the compound is represented by the general formula (IA): (wherein, ^X1 and ^X2 independently represent (1) CH, (2) ^CRX , or (3) N, wherein at least one of ^X1 and ^X2 represents N, ^R1 represents a halogen atom, ^RX represents (1) a halogen atom, (2) a C1-6 alkyl group, (3) a C2-6 alkenyl group, (4) a C2-6 alkynyl group, (5) a C1-6 alkoxy group, (6) a C1-6 halogenalkyl group, (7) a C2-6 halogenalkenyl group, (8) a C2-6 halogenalkynyl group, (9) a C1-6 halogenalkoxy group, or (10) a cyano group, R ^R2 represents (1) a halogen atom, (2) a C1-6 alkyl group, (3) a C2-6 alkenyl group, (4) a C2-6 alkynyl group, (5) a C1-6 alkoxy group, (6) a C1-6 halogen alkyl group, (7) a C2-6 halogen alkenyl group, (8) a C2-6 halogen alkynyl group, (9) a C1-6 halogen alkoxy group, or (10) a cyano group. When m is 2 or more, a plurality of ^R2s may be the same or different. ^{R 3} represents (1) a hydrogen atom, (2) a C1-6 alkyl group, (3) a C1-6 halogen alkyl group, (4) a 3-10 membered cyclic group, (5) -(C1-6 alkylene)-(3-10 membered cyclic group), (6) -(C1-6 halogen alkylene)-(3-10 membered cyclic group), 1 to 2 carbon atoms in the C1-6 alkyl group, C1-6 halogen alkyl group, C1-6 alkylene group and C1-6 halogen alkylene group may be substituted by an oxygen atom or an oxidizable sulfur atom, the 3-10 membered cyclic group in R ³ may be substituted by 1 to 5 R ³⁰¹ , R ³⁰¹ represents (1) a halogen atom, (2) a C1-4 alkyl group, (3) a C1-4 alkoxy group, (4) a C1-4 halogen alkyl group, (5) a C1-4 halogen alkoxy group, (6) COOR ³⁰² , (7) CONR ³⁰³ R ³⁰⁴ , (8) C3-6 cycloalkyl, (9) hydroxyl, (10) nitro, (11) cyano, (12) -NR ³⁰⁵ R ³⁰⁶ , (13) -SR ³⁰⁷ , (14) -SOR ³⁰⁸ , (15) -SO ₂ R ³⁰⁹ , or (16) oxo, when substituted by two or more R ³⁰¹ , the plurality of R ^{301 s} 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, and R ² represents ( ² ) to (9), R When R ³ represents a C1-6 alkyl group, R ² and R ³ may form a 5-6 membered cyclic group together with the atom to which they are bonded. R ⁴ represents (1) a halogen atom, (2) a C1-6 alkyl group, (3) a C2-6 alkenyl group, (4) a C2-6 alkynyl group, (5) a C1-6 alkoxy group, (6) a C1-6 halogen alkyl group, (7) a C2-6 halogen alkenyl group, (8) a C2-6 halogen alkynyl group, or (9) a C1-6 halogen alkoxy group. When n is 2 or more, a plurality of R ⁴ may be the same or different. When two R ⁴ on the same carbon atom represent a C1-6 alkyl group, they may form a C3-6 cycloalkyl group together with the carbon atom to which they are bonded. ring1 represents a 3-15 membered cyclic group. R ^5-A represents (1) a halogen atom, (2) a C1-6 alkyl group, (3) a C2-6 alkenyl group, (4) a C2-6 alkynyl group, (5) a C1-6 alkoxy group, (6) a C1-6 alkylthio group, (7) a C1-6 alkylsulfinyl group, (8) a C1-6 alkylsulfonyl group, (9) a C2-6 acyl group, (10) a 3-6 membered cyclic group, (11) ^-LR5- (3-6 membered cyclic group), (12) a hydroxyl group, (13) a nitro group, (14) a cyano group, (15) a ^pendoxy group ^, (16) ^{-NR501R502 ,} (17) ^{-COOR503 ,} (18) ^-CONR504R505 , or (19) _{-SO2NR506R507} , 1 to 2 carbon atoms in the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxy, C1-6 alkylthio, C1-6 alkylsulfinyl, C1-6 alkylsulfonyl, or C2-6 acyl group may be substituted with an oxygen atom or an oxidizable sulfur atom. When p is 2 or more, the plurality of R ^5-A may be the same or different. The groups (2) to (11) in R ^5-A may be substituted with 1 to 9 R ^508. R ⁵⁰⁸ represents (1) a halogen atom, (2) a C1-4 alkyl, (3) a C1-4 alkoxy, (4) a C2-6 acyl group, (5) a C3-6 cycloalkyl group, (6) a hydroxyl group, or (7) -NR ⁵⁰⁹ R ^510. When substituted with 2 or more R ⁵⁰⁸ , the plurality of R ^{R 508} may be the same or different, L ^R5 represents (1) -O-, (2) -(C1-4 alkylene)-, (3) -O-(C1-4 alkylene)-, (4) -(C1-4 alkylene)-O-, (5) -NR ⁵¹¹ -, or (6) -SO _0-2 -, 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 C1-6 alkyl group, (3) a C2-6 acyl group, or (4) a C1-6 alkylsulfonyl ^group , m represents an integer from 0 to 2, n represents an integer from 0 to 5, and p represents an integer from 0 to 5). A pharmaceutical composition comprising the following compound or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, wherein the compound is represented by the general formula (I): (wherein, ^X1 and ^X2 independently represent (1) CH, (2) ^CRX , or (3) N, wherein at least one of ^X1 and ^X2 represents N, ^R1 represents a halogen atom, ^RX represents (1) a halogen atom, (2) a C1-6 alkyl group, (3) a C2-6 alkenyl group, (4) a C2-6 alkynyl group, (5) a C1-6 alkoxy group, (6) a C1-6 halogenalkyl group, (7) a C2-6 halogenalkenyl group, (8) a C2-6 halogenalkynyl group, (9) a C1-6 halogenalkoxy group, or (10) a cyano group, R ^R2 represents (1) a halogen atom, (2) a C1-6 alkyl group, (3) a C2-6 alkenyl group, (4) a C2-6 alkynyl group, (5) a C1-6 alkoxy group, (6) a C1-6 halogen alkyl group, (7) a C2-6 halogen alkenyl group, (8) a C2-6 halogen alkynyl group, (9) a C1-6 halogen alkoxy group, or (10) a cyano group. When m is 2 or more, a plurality of ^R2s may be the same or different. ^{R 3} represents (1) a hydrogen atom, (2) a C1-6 alkyl group, (3) a C1-6 halogen alkyl group, (4) a 3-10 membered cyclic group, (5) -(C1-6 alkylene)-(3-10 membered cyclic group), (6) -(C1-6 halogen alkylene)-(3-10 membered cyclic group), 1 to 2 carbon atoms in the C1-6 alkyl group, C1-6 halogen alkyl group, C1-6 alkylene group and C1-6 halogen alkylene group may be substituted by an oxygen atom or an oxidizable sulfur atom, the 3-10 membered cyclic group in R ³ may be substituted by 1 to 5 R ³⁰¹ , R ³⁰¹ represents (1) a halogen atom, (2) a C1-4 alkyl group, (3) a C1-4 alkoxy group, (4) a C1-4 halogen alkyl group, (5) a C1-4 halogen alkoxy group, (6) COOR ³⁰² , (7) CONR ³⁰³ R ³⁰⁴ , (8) C3-6 cycloalkyl, (9) hydroxyl, (10) nitro, (11) cyano, (12) -NR ³⁰⁵ R ³⁰⁶ , (13) -SR ³⁰⁷ , (14) -SOR ³⁰⁸ , (15) -SO ₂ R ³⁰⁹ , or (16) oxo, when substituted by two or more R ³⁰¹ , the plurality of R ^{301 s} 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, and R ² represents ( ² ) to (9), R When R ³ represents a C1-6 alkyl group, R ² and R ³ may form a 5-6 membered cyclic group together with the atom to which they are bonded. R ⁴ represents (1) a halogen atom, (2) a C1-6 alkyl group, (3) a C2-6 alkenyl group, (4) a C2-6 alkynyl group, (5) a C1-6 alkoxy group, (6) a C1-6 halogen alkyl group, (7) a C2-6 halogen alkenyl group, (8) a C2-6 halogen alkynyl group, or (9) a C1-6 halogen alkoxy group. When n is 2 or more, a plurality of R ⁴ may be the same or different. When two R ⁴ on the same carbon atom represent a C1-6 alkyl group, they may form a C3-6 cycloalkyl group together with the carbon atom to which they are bonded. ring1 represents a 3-15 membered cyclic group. R ⁵ represents (1) a halogen atom, (2) a C1-6 alkyl group, (3) a C2-6 alkenyl group, (4) a C2-6 alkynyl group, (5) a C1-6 alkoxy group, (6) a C1-6 alkylthio group, (7) a C1-6 alkylsulfinyl group, (8) a C1-6 alkylsulfonyl group, (9) a C2-6 acyl group, (10) a 3-6 membered cyclic group, (11) ^-LR5- (3-6 membered cyclic group), (12) a hydroxyl group, (13) a nitro group, ( ¹⁴ ) a cyano group, (15) a ^oxo group ^, (16) ^-NR501R502 , (17) ^-COOR503 , (18) ^-CONR504R505 , or (19) _{-SO2NR506R507} , and when p is 2 or more, ^a plurality of R R ⁵⁰¹ , R 502 , R 503 , R 504 , R ⁵⁰⁵ , R ⁵⁰⁶ , R 507 , R ⁵⁰⁸ , R 509 , R 510 , R 511 , R 512 , R 513 , R 514 , R ⁵¹⁵ , R ⁵¹⁶ , R 517 , R 518 , R ⁵¹⁹ , R 520 , R 521 , R ⁵²² , R 523 , R 524 , R 525 , R 526 , ^R 527 , R ⁵²⁸ , R ₅₂₉ , R ⁵³⁰ , R ⁵³¹ , R ⁵³² R ⁵⁰⁴ , R ⁵⁰⁵ , R ⁵⁰⁶ , R ⁵⁰⁷ , R ^{509 , R 510 or} R ⁵¹¹ each independently represents (1) a hydrogen atom, (2) a C1-6 alkyl group, (3) a C2-6 acyl group or (4) a C1-6 alkylsulfonyl group, m represents an integer from 0 to 2, n represents an integer from 0 to 5, and p represents an integer from 0 to 5). The pharmaceutical composition of claim 1, wherein ring1 is selected from the following ring structures: [Chemical 1] (wherein the asterisk (*) indicates the bonding position to the carbonyl group, and the hydrogen atom represented by NH may be replaced by R ^5-A ) is a ring structure in the group formed. The pharmaceutical composition of claim 2, wherein ring1 is selected from the following ring structures: [Chemical 1] (wherein the asterisk (*) indicates the bonding position with the carbonyl group, and the hydrogen atom represented by NH may be replaced by R ⁵ ) is a ring structure in the group formed. The pharmaceutical composition of claim 1 or 3, wherein R ^5-A is (1) C1-6 alkyl, (2) C1-6 alkoxy, (3) C1-6 halogenalkyl, (4) C1-6 halogenalkoxy, (5) cyclopropyl, (6) furan ring, (7) N-methylpyrazole ring, (8) oxo group, (9) dimethylamino group, or (10) -COOCH ₃ . The pharmaceutical composition of claim 2 or 4, wherein R ⁵ is (1) C1-6 alkyl, (2) C1-6 alkoxy, (3) C1-6 halogenalkyl, (4) C1-6 halogenalkoxy, (5) cyclopropyl, (6) furan ring, (7) N-methylpyrazole ring, (8) oxo group, (9) dimethylamino group, or (10) -COOCH ₃ . The pharmaceutical composition of any one of claims 1 to 4, wherein R ³ is (1) a hydrogen atom, (2) a C1-6 alkyl group, (3) a C1-6 halogen alkyl group, (4) a cyclopropyl group, or (5) -CH ₂ -Q, and Q is (1) benzene, (2) pyridine, or (3) imidazo[2,1-b]thiazole. The pharmaceutical composition of any one of claims 1 to 4, wherein X ¹ and X ² are both N. The pharmaceutical composition of any one of claims 1 to 4, wherein the compound represented by the general formula (IA) or the general formula (I) or a pharmaceutically acceptable salt thereof is a compound represented by the general formula (I-1) or a pharmaceutically acceptable salt thereof: [Chemical 1] (wherein, R ^3-a represents (1) a hydrogen atom, (2) a C1-6 alkyl group, (3) a C1-6 halogen alkyl group, (4) a cyclopropyl group, or (5) -CH ₂ -Q, and ring1-a represents a ring structure selected from the following: (wherein the asterisk (*) indicates the bonding position to the carbonyl group, the hydrogen atom represented by NH may be substituted by R ^5-a ), R ^5-a represents (1) C1-6 alkyl, (2) C1-6 alkoxy, (3) C1-6 halogenalkyl, (4) C1-6 halogenalkoxy, (5) cyclopropyl, (6) furan ring, (7) N-methylpyrazole ring, (8) pendoxy, (9) dimethylamino, or (10) -COOCH ₃ , and other symbols have the same meanings as those in claim 1, 2 or 7). The pharmaceutical composition of claim 1 or 2, wherein the compound represented by general formula (I-A) or general formula (I) or a pharmaceutically acceptable salt thereof is selected from the group consisting of the following compounds or pharmaceutically acceptable salts thereof: (1) {(3aS,4R,6aR)-4-[(6-chloro-3-pyridinyl)amino]hexahydrocyclopenta[c]pyrrol-2(1H)-yl}[5-(difluoromethyl)-2-thienyl]methanone, (2) {(3aS,4R,6aR)-4-[(6-chloro-3-pyridinyl)amino]hexahydrocyclopenta[c]pyrrol-2(1H)-yl}(5-methyl-2-thienyl)methanone, (3) [(3aS, 4R, 6aR)-4-[(6-chloro-3-pyrrolidinyl)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-pyrrolidinyl)amino]hexahydrocyclopenta[c]pyrrol-2(1H)-yl](5-methyl-2-thienyl)methanone, (5) [(3aS, 4R, 6aR)-4-[(6-bromo-3-pyridine) 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-pyridine) 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-pyrrolidinyl)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-pyrrolidinylcarbonitrile, (9) {(3aR,4R,6aS)-4-[(6-chloro-3-pyrrolidinyl)amino]-3a-fluorohexahydrocyclopentano[c]pyrrol-2(1H)-yl}(6,7-dihydro-4H-thieno[3,2-c]pyran-2-yl)methanone, and (10) [(3aR,6R,6aS)-6-[(6-bromo-3-pyrrolidinyl)amino]-4,4-difluorohexahydrocyclopentano[c]pyrrol-2(1H)-yl](6,7-dihydro-4H-thieno[3,2-c]pyran-2-yl)methanone. A pharmaceutical composition according to any one of claims 1 to 4, which is an ABHD6 inhibitor. A pharmaceutical composition according to any one of claims 1 to 4, which is a therapeutic and/or preventive agent for ABHD6-related diseases. The pharmaceutical composition of claim 12, wherein the ABHD6-related disease is pain, neurological disease, inflammatory disease, autoimmune disease, metabolic disease or malignant tumor. The pharmaceutical composition of claim 12, wherein the ABHD6-related disease is pain, and the pain includes pain associated with deforming arthritis, cancer pain, pain associated with chemotherapy, chronic low back pain, low back pain associated with osteoporosis, fracture pain, pain associated with rheumatoid arthritis, neurological 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 endometrial disease, pain associated with irritable bowel syndrome, migraine, or pain associated with pulpitis. The pharmaceutical composition of claim 12, wherein the ABHD6-related disease is a neurological disease, and the neurological disease includes tremor, dyskinesia, dystonia, contracture, compulsive and obsessive behavior, depression, anxiety, panic disorder, acute stress response, post-traumatic stress disorder, obsessive-compulsive disorder, space phobia, social anxiety disorder, affective disorder, epilepsy, traumatic brain injury, spinal cord injury, multiple sclerosis, encephalomyelitis, Parkinson's disease, Henton's chorea, Alzheimer's disease, and sleep disorders. The pharmaceutical composition of claim 11 is administered in combination with at least one selected from the group consisting of acetaminophen, nonsteroidal anti-inflammatory drugs, opioids, antidepressants, antiepileptics, N-methyl-D-aspartate antagonists, muscle relaxants, antiarrhythmics, steroids and bisphosphonates. A therapeutic and/or preventive agent for ABHD6-related diseases, comprising the compound of any one of claims 1 to 4 or a pharmaceutically acceptable salt thereof. A method for preventing and/or treating ABHD6-related diseases, characterized in that a pharmaceutical composition containing a compound of any one of claims 1 to 4 or a pharmaceutically acceptable salt thereof is administered to a patient who needs to be prevented and/or treated for ABHD6-related diseases. A pharmaceutical composition containing the compound of any one of claims 1 to 4 or a pharmaceutically acceptable salt thereof, for use in the prevention and/or treatment of ABHD6-related diseases. A use of a compound according to any one of claims 1 to 4 or a pharmaceutically acceptable salt thereof for the manufacture of a preventive and/or therapeutic agent for ABHD6-related diseases.