ABHD6 antagonists

Abstract

The present invention provides a pharmaceutical agent which contains, as an active ingredient, a compound having ABHD6 inhibitory activity in the prevention and / or treatment of ABHD6-related diseases. A compound represented by general formula (I) or a pharmaceutically acceptable salt thereof (in the formula, all symbols represent the same meaning as the symbols described in the description. ) The compound has ABHD6 inhibitory activity, and thus is useful as a pharmaceutical ingredient having a potent ABHD6 inhibitory activity in the prevention and / or treatment of diseases associated with ABHD6. # imgabs0 #

Description

Technical Field

[0001] The present invention relates to compounds having ABHD6 inhibitory activity or pharmaceutically acceptable salts thereof, and drugs containing them as active ingredients. Specifically, the present invention relates to general formula (I):

[0002] [Chemical formula 1]

[0003]

[0004] (In the formula, all symbols have the same meanings as below.) or a pharmaceutically acceptable salt thereof (hereinafter referred to as the compound of the present invention), and a pharmaceutical composition comprising them as an active ingredient. Background Art

[0005] ABHD6 (alpha / beta-Hydrolase domain containing 6) is known as a serine hydrolase and is one of the metabolic enzymes of 2-arachidonoylglycerol (2-AG), which is an endogenous cannabinoid. 2-AG functions as an important lipid precursor of the eicosanoid signal transduction pathway and also functions as an endogenous signal transduction lipid for the activation of cannabinoid receptors 1 and 2 (CB1 and CB2, respectively). Therefore, ABHD6 and 2-AG are known to be involved in the regulation of various physiological processes including pain, neurotransmission, inflammation, insulin secretion, brown adipogenesis, food intake, autoimmune disorders, neurological diseases, and metabolic diseases (Non-patent Document 1).

[0006] In addition, it is known that inhibition of ABHD6 significantly reduces neuroinflammation and exerts neuroprotection in animal models of traumatic brain injury and multiple sclerosis. It is believed that inhibition of ABHD6 does not cause central side effects based on Cannabinoids and is useful for the prevention and / or treatment of various inflammatory and neurological diseases (Non-Patent Document 2).

[0007] On the other hand, Patent Document 1 describes that a compound represented by the following general formula (A) is a compound having mA ChR receptor antagonistic activity.

[0008] General formula (A):

[0009] [Chemical formula 2]

[0010]

[0011] (wherein, ring A Arepresents a 5-6 membered heteroaryl ring having 1 to 3 heteroatoms selected from N, O and S,

[0012] Q A Indicates NR aA or O,

[0013] mA means 0, 1 or 2,

[0014] R 1A is selected from heteroaryl, aryl, heterocyclyl, cycloalkyl, halogen, -OR bA 、-NR cA R dA and NHCOR eA ,

[0015] nA represents 1 or 2,

[0016] R 2A Selected from hydrogen, C1-4 alkyl, halogen and -OR fA ,

[0017] R 3A is selected from hydrogen and C1-4 alkyl,

[0018] R 4A Selected from -(CR gA R hA ) pA -Y A ', hydrogen, C1-8 alkyl and C1-8 alkenyl,

[0019] R 5A is selected from hydrogen, C1-4 alkyl, halogen, C1-4 haloalkyl, C1-4 alkoxy and C1-4 haloalkoxy,

[0020] Y A ' is selected from cycloalkyl, cycloalkenyl, heterocyclyl, aryl and heteroaryl,

[0021] p A It represents an integer from 0 to 4. (Part of the definition of the group is extracted).

[0022] Furthermore, Patent Document 2 describes that a compound represented by the following general formula (B) is a compound having a FAAH inhibitory effect.

[0023] General formula (B):

[0024] [Chemical formula 3]

[0025]

[0026] (Where R 2B represents hydrogen, fluorine, hydroxyl, cyano, trifluoromethyl, C1-6 alkyl, C1-6 alkoxy or NR 8B R9B base,

[0027] m B 、n B , o B and p B are independently numbers from 0 to 3, representing m B +o B and n B +p B Each is a number less than 4,

[0028] A B represents a covalent bond, an oxygen atom, a C1-6 alkylene group or an -O-C1-6 alkylene group (in this case, the terminal represented by the oxygen atom and the group R 1B bonded, the terminal represented by the alkylene group is bonded to the bicyclic carbon),

[0029] R 1B It is unsubstituted or replaced by one or more R 6B and / or R 7B Replaced by R 5B ,

[0030] R 5B represents a group selected from the group consisting of phenyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, naphthyl, quinolyl, isoquinolyl, phthalazinyl, quinazolinyl, quinoxalinyl, cinnolinyl, naphthyridinyl, benzothiazolyl, benzoxazolyl, benzimidazolyl, benzisothiazolyl, benzisoxazolyl, indazolyl and benzotriazolyl,

[0031] R 3B represents a hydrogen atom, a fluorine atom, a C1-6 alkyl group or a trifluoromethyl group,

[0032] R 4B It represents a 5-membered heterocyclic ring selected from the group consisting of furyl, pyrrolyl, thienyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyrazolyl, oxadiazolyl, thiadiazolyl, imidazolyl, triazolyl and tetrazolyl (part of the group definition is extracted).

[0033] Furthermore, Patent Document 3 describes that the compound represented by the following general formula (C) is a compound having a Ca channel inhibitory effect.

[0034] General formula (C):

[0035] [Chemical formula 4]

[0036]

[0037] Where, L 1C Indicates C(O), S(O)2, SO2N(R 4C ), C(O)O or -(CRaC R bC ) mC ,

[0038] R 1C Alkyl, G 1C 、-CH(G 1C )2, -(CR aC R bC ) mC -G 1C 、-(CR aC R bC ) mC -CH(G 1C )2, -(CR eC R fC ) nC -N(R 5C )2, -(CR eC R fC ) nC -N(R 5C )-C(O)O(alkyl), -(CR eC R fC ) nC -N(R 5C )-C(O)(alkyl) or -(CR eC R fC ) nC -N(R 5C )-SO2R 6C .

[0039] or L 1C ~R 1C Become one, hydrogen, alkyl, hydroxyalkyl, G 1C or -CH(G 1C )2,

[0040] L 2C For-(CR cC R dC ) pC -、C(O)、C(O)N(R 4C )、S(O)2、SO2N(R 5C ) or C(O)O,

[0041] R 2C Alkyl, G 2C ,-C(R cC )(G 2C )(G 3C ),-(CR cC R dC ) pC -G 2C 、-(CR cC R dC )pC -CH(G 2C )(G 3C ),-(CR gC R hC ) qC -N(R 5C )-C(O)O(alkyl), -(CR gC R hC ) qC -N(R 5C )-C(O)OG 2C 、-(CR gC R hC ) qC -N(R 5C )-C(O)(alkyl), -(CR gC R hC ) qC -N(R 5C )-SO2R 6C 、-(CR gC R hC ) qC -N(R 4C )(R 5C ),-(CR gC R hC ) qC -N(R 5C )-C(O)N(R 5C )-(alkyl) or -(CR gC R hC ) qC -N(R 5C )-C(O)N(R 5C )-G 2C ;

[0042] or L 2C ~R 2C Become one, alkyl, G 2C or -C(R cC )(G 2C )(G 3C ),

[0043] G 1C , G 2C and G 3C are independently aryl, cycloalkyl, cycloalkenyl, heteroaryl or heterocycle; 1C , G 2C and G 3C Each independently is unsubstituted or substituted with 1, 2, 3, 4 or 5 substituents; G 1C Other than quinoline, quinazolinedione or pyridopyrimidinedione;

[0044] R3C represents hydrogen, alkyl, haloalkyl, cycloalkyl or cycloalkylalkyl (part of the definition of the group is extracted).

[0045] However, in the prior art documents, there is no disclosure or suggestion that the compounds of the present invention have ABHD6 inhibitory activity.

[0046] Prior art literature

[0047] Patent Literature

[0048] Patent Document 1: International Publication No. 2019 / 089676 Pamphlet

[0049] Patent Document 2: International Publication No. 2010 / 130944 Pamphlet

[0050] Patent Document 3: International Publication No. 2010 / 062927 Pamphlet

[0051] Non-patent literature

[0052] Non-patent literature 1: European Journal of Medicinal Chemistry 198 (2020) 112353

[0053] Non-patent literature 2: Journal of Neuroinflammation (2018) 15:9 Summary of the invention

[0054] Technical problem to be solved by the invention

[0055] The technical problem of the present invention is to provide compounds having inhibitory activity against ABHD6.

[0056] Solutions to technical problems

[0057] The present inventors have conducted intensive studies to solve the above-mentioned technical problems and have found that the compound represented by the general formula (I) described below has a strong inhibitory activity against ABHD6.

[0058] That is, the present invention provides the following embodiments in one aspect:

[0059] A compound represented by the following general formula (I) or a pharmaceutically acceptable salt thereof,

[0060] General formula (I):

[0061] [Chemical formula 5]

[0062]

[0063] In the formula,

[0064] R 1 represents a halogen atom,

[0065] R 2 represents (1) a halogen atom, (2) a C1-6 alkyl group, (3) a C2-6 alkenyl group, (4) a C2-6 alkynyl group, (5) a C1-6 alkoxy group, (6) a C1-6 haloalkyl group, (7) a C2-6 haloalkenyl group, (8) a C2-6 haloalkynyl group or (9) a C1-6 haloalkoxy group,

[0066] 1 to 2 carbon atoms in the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxy, C1-6 haloalkyl, C2-6 haloalkenyl, C2-6 haloalkynyl, C1-6 haloalkoxy are optionally substituted by nitrogen atoms or optionally oxidized sulfur atoms,

[0067] When m is 2, multiple R 2 Can be the same or different.

[0068] Two R's 2 When it represents a C1-6 alkyl group, a C2-6 alkenyl group, a C2-6 alkynyl group, a C1-6 alkoxy group, a C1-6 haloalkyl group, a C2-6 haloalkenyl group, a C2-6 haloalkynyl group or a C1-6 haloalkoxy group, it may optionally form a 5-6 membered cyclic group together with the carbon atom to which it is bonded,

[0069] R 3 represents (1) a halogen atom, (2) a C1-6 alkyl group, (3) a C2-6 alkenyl group, (4) a C2-6 alkynyl group, (5) a C1-6 alkoxy group, (6) a C1-6 haloalkyl group, (7) a C2-6 haloalkenyl group, (8) a C2-6 haloalkynyl group, (9) a C1-6 haloalkoxy group or (10) a hydroxyl group,

[0070] When n is 2 or more, multiple R 3 Can be the same or different.

[0071] Two R on the same carbon atom 3 When it represents a C1-6 alkyl group, it may optionally form a C3-6 cycloalkyl group together with the carbon atom to which it is bonded,

[0072] Ring1 represents a 3-15 membered cyclic group,

[0073] R 4represents (1) a halogen atom, (2) a C1-6 alkyl group, (3) a C2-6 alkenyl group, (4) a C2-6 alkynyl group, (5) a C1-6 alkoxy group, (6) a C1-6 haloalkyl group, (7) a C2-6 haloalkenyl group, (8) a C2-6 haloalkynyl group, (9) a C1-6 haloalkoxy group, (10) a C1-6 alkylthio group, (11) a C1-6 alkylsulfinyl group, (12) a C1-6 alkylsulfonyl group, (13) a C2-6 acyl group, (14) a 3- to 6-membered cyclic group, (15) -L R4 -(3-6 membered cyclic group), (16) hydroxyl, (17) nitro, (18) cyano, (19) oxo, (20) -NR 401 R 402 、(21)-COOR 403 、(22)-CONR 404 R 405 or (23)-SO2NR 406 R 407 , 1 to 2 carbon atoms in the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxy, C1-6 haloalkyl, C2-6 haloalkenyl, C2-6 haloalkynyl, C1-6 haloalkoxy, C1-6 alkylthio, C1-6 alkylsulfinyl, C1-6 alkylsulfonyl or C2-6 acyl are optionally substituted by oxygen atoms or optionally oxidized sulfur atoms,

[0074] When p is 2 or more, multiple R 4 Can be the same or different.

[0075] R 4 The groups in (2) to (15) are optionally substituted with 1 to 9 R 408 ,

[0076] R 408 represents (1) a halogen atom, (2) a C1-4 alkyl group, (3) a C1-4 alkoxy group, (4) a C2-6 acyl group, (5) a C3-6 cycloalkyl group, (6) a hydroxyl group, or (7) -NR 409 R 410 ,

[0077] R 408 When replacing two or more, multiple R 408 Can be the same or different.

[0078] L R4 represents (1) -O-, (2) -(C1-4 alkylene)-, (3) -O-(C1-4 alkylene)-, (4) -(C1-4 alkylene)-O-, (5) -NR 411 -, (6)-S-, (7)-SO- or (8)-SO2-,

[0079] R 401 , R 402 , R 403 , R 404 , R 405 , R 406 , R 407 , R 409 , R 410 or R 411 are each independently a hydrogen atom, (2) a C1-6 alkyl group, (3) a C2-6 acyl group, or (4) a C1-6 alkylsulfonyl group,

[0080] m represents an integer from 0 to 2,

[0081] n represents an integer from 0 to 5,

[0082] p represents an integer of 0-5.

[0083] [2] A pharmaceutical composition comprising the compound described in [1] or a pharmaceutically acceptable salt thereof as an active ingredient, and further comprising a pharmaceutically acceptable carrier.

[0084] [3] The pharmaceutical composition according to [2], which is an ABHD6 inhibitor, etc.

[0085] Effects of the Invention

[0086] The compound of the present invention has an inhibitory activity against ABHD6, has a low excretion ratio based on P-glycoprotein, and is excellent in central transferability, and therefore can be used as an active ingredient of a preventive and / or therapeutic agent for diseases associated with ABHD6. DETAILED DESCRIPTION

[0087] Hereinafter, the present invention is described in detail.

[0088] In the present specification, examples of the halogen atom include fluorine, chlorine, bromine, and iodine atoms.

[0089] In the present specification, examples of the C1-4 alkyl group include a methyl group, an ethyl group, a propyl group, a butyl group, and isomers thereof.

[0090] In the present specification, examples of the C1-6 alkyl group include a methyl group, an ethyl group, a propyl group, a butyl group, a pentyl group, a hexyl group, and isomers thereof.

[0091] In the present specification, examples of the C2-6 alkenyl group include ethenyl, propenyl, butenyl, butadienyl, pentenyl, pentadienyl, hexenyl, hexadienyl, and isomers thereof.

[0092] In the present specification, examples of the C2-6 alkynyl group include ethynyl, propynyl, butynyl, butadiynyl, pentynyl, pentadiynyl, hexynyl, hexadiynyl, and isomers thereof.

[0093] In the present specification, examples of the C1-4 alkylene group include a methylene group, an ethylene group, a propylene group, a butylene group, and isomers thereof.

[0094] In the present specification, C1-6 haloalkyl refers to, for example, an alkyl group substituted by one or more halogen atoms, and specifically includes: 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 isomers thereof.

[0095] In the present specification, C2-6 haloalkenyl refers to, for example, an alkenyl group substituted by 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.

[0096] In the present specification, C2-6 haloalkynyl refers to, for example, an alkynyl group substituted by 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.

[0097] In the present specification, examples of the C1-4 alkoxy group include a methoxy group, an ethoxy group, a propoxy group, a butoxy group, and isomers thereof.

[0098] In the present specification, examples of the C1-6 alkoxy group include a methoxy group, an ethoxy group, a propoxy group, a butoxy group, a pentyloxy group, a hexyloxy group, and isomers thereof.

[0099] In the present specification, C1-6 haloalkoxy refers to, for example, an alkoxy group substituted by 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 isomers thereof.

[0100] In the present specification, examples of the C1-6 alkylthio group include a methylthio group, an ethylthio group, a propylthio group, a butylthio group, a pentylthio group, a hexylthio group, and isomers thereof.

[0101] In the present specification, examples of the C1-6 alkylsulfinyl group include a methylsulfinyl group, an ethylsulfinyl group, a propylsulfinyl group, a butylsulfinyl group, a pentylsulfinyl group, a hexylsulfinyl group, and isomers thereof.

[0102] In the present specification, examples of the C1-6 alkylsulfonyl group include a methylsulfonyl group, an ethylsulfonyl group, a propylsulfonyl group, a butylsulfonyl group, a pentylsulfonyl group, a hexylsulfonyl group, and isomers thereof.

[0103] In the present specification, examples of the C3-6 cycloalkyl group include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0104] In the present specification, examples of the C2-6 acyl group include acetyl, propionyl, butyryl, valeryl, hexanoyl, and isomers thereof.

[0105] In the present specification, a 3- to 6-membered cyclic group refers to a C3-6 carbocyclic ring and a 3- to 6-membered heterocyclic ring.

[0106] In the present specification, examples of the C3-6 carbon ring include cyclopropane, cyclobutane, cyclopentane, cyclohexane, cyclobutene, cyclopentene, cyclohexene, cyclobutadiene, cyclopentadiene, cyclohexadiene, and a benzene ring.

[0107] In the present specification, examples of the 3- to 6-membered heterocyclic ring include aziridine, azetidine, oxirane, oxetane, thiirane, thietane, pyrrole, imidazole, triazole, tetrazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, furan, pyran, thiophene, thiopyran, oxazole, isoxazole, thiazole, isothiazole, furazan, oxadiazole, oxazine, oxadiazine, thiadiazole, thiazine, thiadiazine, pyrroline, tetrahydropyrrole, imidazoline, imidazolidine, triazoline, triazolidine, tetrazoline, tetrazolidine, pyrazoline, pyrazolidine, dihydropyridine, tetrahydropyridine, piperidine, dihydropyrazine, tetrahydropyrazine, piperazine, dihydropyrimidine, tetrahydropyrimidine, perhydropyrimidine, dihydropyridazine, tetrahydropyridazine, perhydropyridazine oxazine, dihydrofuran, tetrahydrofuran, dihydropyran, tetrahydropyran, dihydrothiophene, tetrahydrothiophene, dihydrothiopyran, tetrahydrothiopyran, dihydrooxazole, tetrahydrooxazole (oxazolidine), dihydroisoxazole, tetrahydroisoxazole (isoxazolidine), dihydrothiazole, tetrahydrothiazole (thiazolidine), dihydroisothiazole, tetrahydroisothiazole (isothiazolidine), dihydrofuran, tetrahydrofuran, dihydrooxadiazole, tetrahydrooxadiazole (oxadiazolidine), dihydrooxazine, tetrahydrooxazine, dihydrooxadiazine, tetrahydrooxadiazine, dihydrothiadiazole, tetrahydrothiadiazole (thiadiazolidine), dihydrothiazine, tetrahydrothiazine, dihydrothiadiazine, tetrahydrothiadiazine, morpholine, thiomorpholine, thioxane, dioxolane, dioxane, dithiolane and dithiane ring.

[0108] In the present specification, a 3- to 10-membered cyclic group refers to a C3-10 carbocyclic ring and a 3- to 10-membered heterocyclic ring.

[0109] In the present specification, examples of C3-10 carbon rings include cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, cyclooctane, cyclononane, cyclodecane, cyclobutene, cyclopentene, cyclohexene, cycloheptene, cyclooctene, cyclononene, cyclodecene, cyclobutadiene, cyclopentadiene, cyclohexadiene, cycloheptadiene, cyclooctadiene, benzene, pentalene, perhydropentalene, azulene, perhydroazulene, indene, perhydroindene, indane, naphthalene, dihydronaphthalene, tetralin, perhydronaphthalene, bicyclo[1.1.1]pentane, bicyclo[2.1.1]hexane, bicyclo[2.1.1]hexene, bicyclo[2.2.1]heptane, bicyclo[2.2.1]heptene, bicyclo[3.1.1]heptane, bicyclo[3.1.1]heptene, bicyclo[2.2.2]octane, bicyclo[2.2.2]octene, bicyclo[3.2.1]octane and bicyclo[3.2.1]octene ring, etc.

[0110] In the present specification, examples of the 3- to 10-membered heterocyclic ring include the above-mentioned 3- to 6-membered heterocyclic rings, as well as azepines, diazepines, oxepins, thiazones, oxazepines, oxadiazepines, thiazepines, thiadiazepines, indole, isoindole, indolizine, benzofuran, isobenzofuran, benzothiophene, isobenzothiophene, dithiaphthalene, indazole, quinoline, isoquinoline, quinolizine, purine, phthalazine, pteridine, naphthyridine, quinoxaline, quinazoline, cinnoline, benzoxazole, benzothiazole, benzimidazole, azole, chromene, benzofurazan, benzothiadiazole, benzotriazole, dihydroazepine, tetrahydroazepine, perhydroazepine, dihydrodiazepine, tetrahydrodiazepine, perhydrodiazepine, dihydrooxepin, tetrahydrooxepin, perhydrooxepin, dihydrothiazepine, tetrahydrothiazepine, perhydrothiazepine, dihydrooxyazepine, tetrahydrooxyazepine, perhydrooxyazepine, dihydrooxydiazepine, tetrahydrooxydiazepine, perhydrooxydiazepine, dihydrothiazepine, tetrahydrothiazepine, perhydrothiazepine indole, dihydrothiodiazepine, tetrahydrothiodiazepine, perhydrothiodiazepine, indoline, isoindoline, dihydrobenzofuran, perhydrobenzofuran, dihydroisobenzofuran, perhydroisobenzofuran, dihydrobenzothiophene, perhydrobenzothiophene, dihydroisobenzothiophene, perhydroisobenzothiophene, dihydroindazole, perhydroindazole, dihydroquinoline, tetrahydroquinoline, perhydroquinoline, dihydroisoquinoline, tetrahydroisoquinoline, perhydroisoquinoline, dihydrophthalazine, tetrahydrophthalazine, perhydrophthalazine, dihydronaphthyridine, tetrahydro naphthyridine, perhydronaphthyridine, dihydroquinoxaline, tetrahydroquinoxaline, perhydroquinoxaline, dihydroquinazoline, tetrahydroquinazoline, perhydroquinazoline, dihydrocinnoline, tetrahydrocinnoline, perhydrocinnoline, benzothioxane, dihydrobenzoxazine, dihydrobenzothiazine, pyrazinomorpholine, dihydrobenzoxazole, perhydrobenzoxazole, dihydrobenzothiazole, perhydrobenzothiazole, dihydrobenzimidazole, perhydrobenzimidazole, dioxaindane, benzodioxane ane), chroman, benzodithiolane, benzodithiolane, azaspiro[4.4]nonane, oxaspiro[4.4]nonane, dioxaspiro[4.4]nonane, azaspiro[4.5]decane, thiospiro[4.5]decane, dithiospiro[4.5]decane, dioxaspiro[4.5]decane, oxaspiro[4.5]decane, azabicyclo[3.2.1]octane, oxabicyclo[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, thieno[3,2-c]pyran, thieno[3,2-c]pyran, tetrahydrothieno[2,3-c]pyridine, pyrazolo[5,1-b][1,3]thiazole, 1,3-benzothiazole, thieno[3,2-b]furan, dihydro[1,3]thiazolo[4,5-c]pyridine, dihydrothieno[2,3-c]pyridine and tetrahydrothieno[2,3-d]oxepin ring, etc. .

[0111] In the present specification, a 3- to 15-membered cyclic group refers to a C3-15 carbocyclic ring and a 3- to 15-membered heterocyclic ring.

[0112] In the present specification, examples of the C3-15 carbon ring include the above-mentioned C3-10 carbon ring, as well as heptacene, biphenylene, as-indacene, s-indacene, acenaphthylene, acenaphthene, fluorene, phenanthrene, phenanthrene, and anthracene ring.

[0113] In the present specification, examples of the 3- to 15-membered heterocycle include the above-mentioned 3- to 10-membered heterocycles, as well as benzoxadiazepine, benzothiadiazepine, benzoxazepine, benzothiazepine, benzodiazepine, dihydrobenzodiazepine, tetrahydrobenzodiazepine, benzodioxepane, dihydrobenzoxazepine, tetrahydrobenzoxazepine, benzooxepin, benzothiazepine, benzoazepine, dihydrobenzozepine, Tetrahydrobenzazepine, primary idine, β-carboline, dihydrocarbazole, tetrahydrocarbazole, dihydrodibenzofuran, dihydrodibenzothiophene, tetrahydrodibenzofuran, tetrahydrodibenzothiophene, carbazole, dibenzofuran, dibenzothiophene, phenothiazine, phenoxazine, phenoxathiol, thianthrene, phenazine, phenanthroline, xanthene, dihydroacridine, tetrahydroacridine, acridine, phenanthridine, and dihydropyrrolo[1,2-b]thieno[2,3-d]pyrazole ring, etc.

[0114] In the present specification, a 5-6 membered cyclic group refers to a C5-6 carbocyclic ring and a 5-6 membered heterocyclic ring.

[0115] In the present specification, examples of the C5-6 carbon ring include cyclopentane, cyclohexane, cyclopentene, cyclohexene, cyclopentadiene, cyclohexadiene, and a benzene ring.

[0116] In the present specification, examples of the 5- to 6-membered heterocyclic ring include pyrrole, imidazole, triazole, tetrazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, furan, pyran, thiophene, thiopyran, oxazole, isoxazole, thiazole, isothiazole, furazan, oxadiazole, oxazine, oxadiazine, thiazine, thiadiazine, pyrroline, tetrahydropyrrole, imidazoline, imidazolidine, triazoline, triazolidine, tetrazoline, tetrazolidine, pyrazoline, pyrazolidine, dihydropyridine, tetrahydropyridine, piperidine, dihydropyrazine, tetrahydropyrazine, piperazine, dihydropyrimidine, tetrahydropyrimidine, perhydropyrimidine, dihydropyridazine, tetrahydropyridazine, perhydropyridazine, dihydrofuran, tetrahydrofuran, dihydropyran, Tetrahydropyran, dihydrothiophene, tetrahydrothiophene, dihydrothiopyran, tetrahydrothiopyran, dihydrooxazole, tetrahydrooxazole (oxazolidine), dihydroisoxazole, tetrahydroisoxazole (isoxazolidine), dihydrothiazole, tetrahydrothiazole (thiazolidine), dihydroisothiazole, tetrahydroisothiazole (isothiazolidine), dihydrofurazan, tetrahydrofurazan, dihydrooxadiazole, tetrahydrooxadiazole (oxadiazolidine), dihydrooxazine, tetrahydrooxazine, dihydrooxadiazine, tetrahydrooxadiazine, dihydrothiadiazole, tetrahydrothiadiazole (thiadiazolidine), dihydrothiazine, tetrahydrothiazine, dihydrothiadiazine, tetrahydrothiadiazine, morpholine, thiomorpholine, thioxane, dioxolane, dioxane, dithiolane and dithiane ring.

[0117] In the present specification, "1 to 2 carbon atoms are optionally substituted by an oxygen atom or an optionally oxidized sulfur atom" means that 1 or 2 carbon atoms (-CH2-) located at possible positions in the structure of the substituent are optionally substituted by an oxygen atom (-O-) or an optionally oxidized sulfur atom (-S-, -SO-, or -SO2-). Specifically, in the case of a C1-6 alkyl group, examples 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.

[0118] In the present specification, "1 to 2 carbon atoms are optionally substituted by a nitrogen atom or an optionally oxidized sulfur atom" means that 1 or 2 carbon atoms (-CH2-) located at possible positions in the structure of the substituent are optionally substituted by a nitrogen atom (-NH- or -N=) or an optionally oxidized sulfur atom (-S-, -SO-, or -SO2-). Specifically, in the case of a C1-6 alkyl group, examples thereof include: CH3-NH-CH2- group, CH3-CH2-NH-CH2- group, CH3-NH-CH2-CH2- group, CH3-NH-CH2-CH2- group, CH3-NH-CH2-CH2- group and CH3-CH2-NH-CH2-CH2- group.

[0119] In this manual, “two R 2When it represents a C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxy, C1-6 haloalkyl, C2-6 haloalkenyl, C2-6 haloalkynyl or C1-6 haloalkoxy, it may form a 5-6 membered cyclic group together with the carbon atom to which it is bonded. The partial structure of the following general formula (I)

[0120] [Chemical formula 6]

[0121]

[0122] (In the formula, all symbols have the same meanings as above.) 2 represents (1) a halogen atom, (2) a C1-6 alkyl group, (3) a C2-6 alkenyl group, (4) a C2-6 alkynyl group, (5) a C1-6 alkoxy group, (6) a C1-6 haloalkyl group, (7) a C2-6 haloalkenyl group, (8) a C2-6 haloalkynyl group or (9) a C1-6 haloalkoxy group, and when 1 to 2 carbon atoms in the C1-6 alkyl group, C2-6 alkenyl group, C2-6 alkynyl group, C1-6 alkoxy group, C1-6 haloalkyl group, C2-6 haloalkenyl group, C2-6 haloalkynyl group or C1-6 haloalkoxy group are optionally substituted with a nitrogen atom or an optionally oxidized sulfur atom, the two R 2 Together with the carbon atom to which it is bonded, it forms a 5- to 6-membered cyclic group, thereby forming, for example, the following formula

[0123] [Chemical formula 7]

[0124]

[0125] Such a 9-membered cyclic group or a 10-membered cyclic group.

[0126] In the present invention, R 3 Any hydrogen atom in the hexahydrocyclopenta[c]pyrrole may be substituted.

[0127] In the present invention, as R 1 , preferably a chlorine atom or a bromine atom.

[0128] In the present invention, as R 2 , preferably C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, or C1-6 haloalkoxy, more preferably methoxy or trifluoromethyl.

[0129] In the present invention, as R 3 , preferably a halogen atom, a C1-6 alkyl group, a C1-6 alkoxy group or a hydroxy group, more preferably a fluorine atom or a methyl group.

[0130] In the present invention, ring 1 is preferably a 3-10-membered cyclic group, and more preferably a ring structure in the group represented by the following chemical formula 8:

[0131] [Chemical formula 8]

[0132]

[0133] In the formula, the * mark indicates the bonding position to the carbonyl group, and the hydrogen atom represented by NH is optionally replaced by R 4 More preferably, it is a ring structure in the group shown in the following chemical formula 9,

[0134] [Chemical formula 9]

[0135]

[0136] In the formula, the * mark indicates the bonding position to the carbonyl group, and the hydrogen atom represented by NH is optionally replaced by R 4 replace.

[0137] In the present invention, as R 4 , preferably a halogen atom, a C1-6 alkyl group, a C1-6 alkoxy group, a C1-6 haloalkyl group, a C1-6 haloalkoxy group, a 3-6 membered cyclic group, -COOR 403 Or cyano, more preferably a fluorine atom, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, C1-6 haloalkoxy, cyclopropyl, a benzene ring, a pyridine ring, -COOCH3, -COOtBu or cyano, further preferably methyl, difluoromethyl, 2-fluoroethoxy or cyclopropyl.

[0138] In the present invention, m is preferably 0 or 1.

[0139] In the present invention, n is preferably 0, 1 or 2.

[0140] In the present invention, p is preferably 0, 1 or 2.

[0141] In the present invention, the compound represented by the general formula (I) is preferably a compound represented by the following general formula (I-1):

[0142] General formula (I-1):

[0143] [Chemical formula 10]

[0144]

[0145] In the formula, R 2-1 represents (1) C1-6 alkyl, (2) C1-6 alkoxy, (3) C1-6 haloalkyl or (4) C1-6 haloalkoxy,

[0146] R 4-1represents (1) a halogen atom, (2) a C1-6 alkyl group, (3) a C1-6 alkoxy group, (4) a C1-6 haloalkyl group, (5) a C1-6 haloalkoxy group, (6) a cyclopropyl group, (7) a benzene ring, (8) a pyridine ring, (9) -COOCH3, (10) -COOtBu or (11) a cyano group,

[0147] ring1-1 represents a ring structure selected from the following ring structures,

[0148] [Chemical formula 11]

[0149]

[0150] In the formula, the * mark indicates the bonding position to the carbonyl group, and the hydrogen atom represented by NH is optionally replaced by R 4-1 replace,

[0151] Other symbols have the same meanings as those described above.

[0152] In the present invention, the compound represented by the general formula (I) is preferably the R 1 , R 2 , R 3 , R 4 , ring1, n, m and p are each preferably defined in combination.

[0153] In the present invention, as another embodiment of the compound represented by the general formula (I), the most preferred are the example compounds described in the examples described below or pharmaceutically acceptable salts thereof.

[0154] In the present invention, unless otherwise specified, all isomers are included. For example, alkyl, alkoxy and alkylene etc. contain straight-chain groups and branched groups. In addition, double bonds, rings, condensed ring isomers (E, Z, cis, trans isomers), isomers (R, S, α, β, enantiomers, diastereomers) formed by the presence of asymmetric carbons, etc., optically active bodies (D, L, d, l bodies) with optical activity, polar bodies (high polar body, low polar body) based on chromatographic separation, balanced compounds, rotational isomers, mixtures of any proportion thereof, racemic mixtures are also all included in the present invention. In addition, isomers caused by tautomerism are also all included in the present invention.

[0155] In the present invention, unless otherwise specified, the symbols are as clearly understood by those skilled in the art.

[0156] [Chemical formula 12]

[0157]

[0158] indicates binding to the opposite side of the paper (i.e., α-configuration),

[0159] [Chemical formula 13]

[0160]

[0161] Indicates binding to the front side of the paper (i.e., β-configuration),

[0162] [Chemical formula 14]

[0163]

[0164] It represents any mixture of α-configuration and β-configuration.

[0165] [Salt]

[0166] The compound represented by the formula (I) is converted into a salt by a known method.

[0167] Salts are pharmaceutically acceptable salts.

[0168] The salt is preferably a water-soluble salt.

[0169] Examples of the pharmaceutically acceptable salt include acid addition salts, alkali metal salts, alkaline earth metal salts, ammonium salts, and amine salts.

[0170] Examples of the acid addition salt include inorganic acid salts such as hydrochlorides, hydrobromides, hydroiodides, sulfates, phosphates and nitrates, and organic acid salts such as acetates, lactates, tartrates, benzoates, citrates, methanesulfonates, ethanesulfonates, trifluoroacetates, benzenesulfonates, toluenesulfonates, isethionates, glucuronates and gluconates.

[0171] Examples of the alkali metal salt include potassium salt and sodium salt.

[0172] Examples of the alkaline earth metal salt include calcium salt and magnesium salt.

[0173] Examples of the ammonium salt include tetramethylammonium salt and the like.

[0174] Examples of the amine salt include triethylamine salts, methylamine salts, dimethylamine salts, cyclopentylamine salts, benzylamine salts, phenethylamine salts, piperidine salts, monoethanolamine salts, diethanolamine salts, tris(hydroxymethyl)aminomethane salts, lysine salts, arginine salts, and N-methyl-D-glucamine salts.

[0175] Furthermore, the compound of the present invention can be converted into an N-oxide by any method. An N-oxide is a compound obtained by oxidizing the nitrogen atom of the compound represented by the general formula (I).

[0176] The compound represented by the general formula (I) and its pharmaceutically acceptable salt may exist in a non-solvated form or in a solvated form with a pharmaceutically acceptable solvent such as water or ethanol. As a solvate, a hydrate is preferred. The compound represented by the general formula (I) and its pharmaceutically acceptable salt may be converted into a solvate.

[0177] The compound represented by the general formula (I) can form cocrystals with appropriate cocrystal formers. As cocrystals, preferably pharmaceutically acceptable cocrystals formed with pharmaceutically acceptable cocrystal formers. Cocrystals are typically defined as crystals formed by intermolecular interactions different from ionic bonds between two or more different molecules. In addition, cocrystals can be complexes of neutral molecules and salts. Cocrystals can be prepared by known methods, for example, by melt crystallization, recrystallization from a solvent, or physical pulverization with the components. As for appropriate cocrystal formers, cocrystal formers described in WO2006 / 007448 are included.

[0178] In the present invention, the description of the compounds of the present invention all include the compounds represented by general formula (I), their pharmaceutically acceptable salts, N-oxides, solvates (such as hydrates), or co-crystals thereof, or N-oxides of pharmaceutically acceptable salts of the compounds represented by general formula (I), their solvates (such as hydrates), or co-crystals thereof.

[0179] [Prodrug]

[0180] The prodrug of the compound represented by the general formula (I) refers to a compound that is converted into the compound represented by the general formula (I) by a reaction with an enzyme, gastric acid, etc. in the living body. As the prodrug of the compound represented by the general formula (I), for example, if the compound represented by the general formula (I) has an amino group, examples include: compounds obtained by acylation, alkylation, or phosphorylation of the amino group (for example, compounds obtained by eicosanoylation, alanylation, pentylaminocarbonylation, (5-methyl-2-oxo-1,3-dioxol-4-yl)methoxycarbonylation, tetrahydrofuranylation, pyrrolidinomethylation, pivaloyloxymethylation, acetoxymethylation, or tert-butylation of the amino group of the compound represented by the general formula (I); if the compound represented by the general formula (I) has a hydroxyl group, examples include: compounds obtained by acylation, alkylation, phosphorylation, or borylation of the hydroxyl group (for example, compounds represented by the general formula (I) The hydroxyl group of the compound is acetylated, palmitoylated, propionylated, pivaloylated, succinylated, fumarylated, alanylated, dimethylaminomethyl carbonylated, etc.); if the compound represented by the general formula (I) has a carboxyl group, it can be cited as: the carboxyl group is esterified, amidated and obtained compounds (for example, the carboxyl group of the compound represented by the general formula (I) is ethyl esterified, phenyl esterified, carboxymethyl esterified, dimethylaminomethyl esterified, pivaloyloxymethyl esterified, 1-{(ethoxycarbonyl)oxy}ethyl esterified, phthalic acid esterified, (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl esterified, 1-{[(cyclohexyloxy)carbonyl]oxy}ethyl esterified, methyl amidated and obtained compounds, etc.). These compounds themselves can be manufactured by known methods. In addition, the prodrug of the compound represented by the general formula (I) may be any one of a hydrate, a solvate and a non-hydrate. Furthermore, as described in "Drug Development" published by Hirokawa Bookstore in 1990, Vol. 7, "Molecular Design", pp. 163-198, the prodrug of the compound represented by general formula (I) may be a compound that is converted into the compound represented by general formula (I) under physiological conditions.

[0181] In addition, each atom constituting the compound represented by the general formula (I) 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.) etc.

[0182] In one embodiment, the compound represented by general formula (I) is a compound, a salt thereof, or a solvate thereof in which one or more atoms are radioactive isotopes of the atom. The radioactive isotope is selected from 15 O. 13 N. 11 C and 18 F, etc., are not particularly limited. The radioactive isotope is preferably 11 C or 18 F. The radioisotope is more preferably 18 F.

[0183] The C1-6 haloalkoxy group bonded to ring 1 is preferably a group containing a radioactive isotope. The 2-fluoroethoxy group is more preferably a group containing a radioactive isotope.

[0184] The compound represented by the general formula (I) containing a radioactive isotope is preferably [ 18 F]-[(3aS,4R,6aR)-4-[(6-bromo-3-pyridazinyl)oxy]hexahydrocyclopenta[c]pyrrol-2(1H)-yl][5-(2-fluoroethoxy)-2-thienyl]methanone.

[0185] [Method for producing the compound of the present invention]

[0186] The compounds of the present invention can be manufactured by known methods, for example, the methods shown below, the methods with reference to them, the methods described in Comprehensive Organic Transformations: A Guide to Functional Group Preparations, 3rd Edition (Richard C. Larock, John Wiley & Sons Inc, 2018) or the methods shown in the embodiments are appropriately improved and combined to manufacture. Salt can be used as the starting material. The order of carrying out each reaction can be appropriately changed according to the imported protecting group and reaction conditions.

[0187] In addition, for compounds having an amino group, a carboxyl group or a hydroxyl group, as required, compounds protected with a protecting group commonly used for these groups, such as a protecting group described in TW Greene, Protective Groups in Organic Synthesis, Wiley, New York, 5th Edition, 2014, can be produced by performing a known deprotection reaction after an appropriate reaction step.

[0188] Examples of the protective group for the carboxyl group include a methyl group, an ethyl group, a tert-butyl group, a trichloroethyl group, a benzyl group (Bn), a phenacyl group, a p-methoxybenzyl group, a trityl group, and a 2-chlorotrityl group.

[0189] Examples of the protecting group for an amino group or a tetrazolyl group include a benzyloxycarbonyl group, a tert-butyloxycarbonyl group, an allyloxycarbonyl group (Alloc), a 1-methyl-1-(4-biphenylyl)ethoxycarbonyl group (Bpoc), a trifluoroacetyl group, a 9-fluorenylmethoxycarbonyl group, a benzyl (Bn) group, a p-methoxybenzyl group, a benzyloxymethyl group (BOM), and a 2-(trimethylsilyl)ethoxymethyl group (SEM).

[0190] Examples of the protecting group for a hydroxyl group or a hydroxamic acid include a methyl group, a trityl group, a methoxymethyl group (MOM), a 1-ethoxyethyl group (EE), a methoxyethoxymethyl group (MEM), a 2-tetrahydropyranyl group (THP), a trimethylsilyl group (TMS), a triethylsilyl group (TES), a tert-butyldimethylsilyl group (TBDMS), a tert-butyldiphenylsilyl group (TBDPS), an acetyl group (Ac), a pivaloyl group, a benzoyl group, a benzyl group (Bn), a p-methoxybenzyl group, an allyloxycarbonyl group (Alloc), and a 2,2,2-trichloroethoxycarbonyl group (Troc).

[0191] Deprotection reactions are well known and can be carried out by the following methods. For example,

[0192] (1) Deprotection reaction using alkaline hydrolysis,

[0193] (2) Deprotection reaction under acidic conditions,

[0194] (3) Deprotection reaction using hydrogenolysis,

[0195] (4) Deprotection reaction of silyl group,

[0196] (5) Deprotection reaction using metals,

[0197] (6) Deprotection reaction using a metal complex, etc.

[0198] These methods are described in detail below.

[0199] (1) Deprotection reaction by alkaline hydrolysis, for example, in an organic solvent (e.g., methanol, tetrahydrofuran (hereinafter referred to as THF), dioxane, etc.), using an alkali metal hydroxide (e.g., sodium hydroxide, potassium hydroxide, lithium hydroxide, etc.), an alkaline earth metal hydroxide (e.g., barium hydroxide, calcium hydroxide, etc.) or a carbonate (e.g., sodium carbonate, potassium carbonate, etc.) or an aqueous solution thereof or a mixture thereof at 0 to 40°C.

[0200] (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., hydrogen bromide / acetic acid, etc.), in the presence or absence of 2,2,2-trifluoroethanol, at 0 to 100°C.

[0201] (3) Deprotection reaction by hydrogenolysis, for example, in a solvent (for example, ethers (for example, THF, dioxane, dimethoxyethane, diethyl ether, etc.), alcohols (for example, methanol, ethanol, etc.), benzenes (for example, benzene, toluene, etc.), ketones (for example, acetone, methyl ethyl ketone, etc.), nitriles (for example, acetonitrile, etc.), amides (for example, 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 (for example, palladium-carbon, palladium black, palladium hydroxide-carbon, platinum oxide, Raney nickel, etc.), under normal pressure or under pressurized hydrogen atmosphere or in the presence of ammonium formate, at 0 to 200°C.

[0202] (4) The deprotection reaction of the silyl group is carried out, for example, in an organic solvent miscible with water (e.g., THF, acetonitrile, etc.) using tetrabutylammonium fluoride at 0 to 40°C. Alternatively, it can be carried out, for example, 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., hydrogen bromide / acetic acid, etc.) at -10 to 100°C.

[0203] (5) A deprotection reaction using a metal can be carried out, for example, in an acidic solvent (e.g., acetic acid, a buffer solution at pH 4.2 to 7.2, or a mixture of a solution thereof and an organic solvent such as THF) in the presence of powdered zinc, while applying ultrasound if necessary, at 0 to 40°C.

[0204] (6) Deprotection reaction using a metal complex, 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 reagent (e.g., tributyltin hydride, triethylsilane, dimedone, morpholine, diethylamine, tetrahydropyrrole, etc.), an organic acid (e.g., acetic acid, formic acid, 2-ethylhexanoic acid, etc.) and / or an organic acid salt (e.g., sodium 2-ethylhexanoate, potassium 2-ethylhexanoate, etc.), in the presence or absence of a phosphine reagent (e.g., triphenylphosphine, etc.), using a metal complex (e.g., tetrakistriphenylphosphine palladium (0), dichlorobis(triphenylphosphine)palladium (II), palladium (II) acetate, tris(triphenylphosphine)rhodium (I) chloride, etc.), at 0 to 40°C.

[0205] The compound represented by the general formula (I) can be produced by the reaction process of formula 1.

[0206] [Chemical formula 15]

[0207] Reaction process formula 1

[0208]

[0209] (In reaction process formula 1, PG represents a protective group of an amino group, Y represents a halogen atom, and other symbols have the same meanings as above.)

[0210] In the reaction process formula 1, reaction 1-1 is a halogen substitution reaction or a cross-coupling reaction. Halogen substitution reactions are well known, for example, by reacting them at 0 to 200° C. 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 its aqueous solution or a mixture thereof.

[0211] Cross-coupling reactions are well known. For example, in an organic solvent (benzene, toluene, DMF, dioxane, THF, methanol, acetonitrile, dimethoxyethane, acetone, etc.), in the presence of a base (sodium ethoxide, sodium hydroxide, potassium hydroxide, triethylamine, sodium carbonate, sodium bicarbonate, potassium carbonate, cesium carbonate, thallium carbonate, tripotassium phosphate, cesium fluoride, barium hydroxide, tetrabutylammonium fluoride, etc.) or an aqueous solution thereof, or a mixture thereof and a catalyst (tetrakis(triphenylphosphine)palladium (Pd(PPh3) 4), dichlorobis(triphenylphosphine)palladium (PdCl2(PPh3)2), palladium acetate (Pd(OAc)2), palladium black, dichloro1,1'-bis(diphenylphosphinopheneylferrocene)palladium (PdCl2(dppf)2), diallylpalladium dichloride (PdCl2(allyl)2), phenylbis(triphenylphosphine)palladium iodide (PhPdI(PPh3)2), etc.), and the reaction is carried out at room temperature to 120°C.

[0212] In the reaction process formula 1, reaction 1-2 is a deprotection reaction, which can be carried out by the same method as described above.

[0213] In the reaction process formula 1, reaction 1-3 is an amidation reaction. Amidation reactions are well known, and examples thereof include:

[0214] (1) Method using acyl halide,

[0215] (2) Method using mixed acid anhydride,

[0216] (3) Methods using a condensing agent, etc.

[0217] These methods are described in detail below.

[0218] (1) The method using an acid halide is carried out, for example, by reacting a carboxylic acid with an acid halogenating agent (such as oxalyl chloride and thionyl chloride) in an organic solvent (such as chloroform, dichloromethane, diethyl ether and THF) or without a solvent at a temperature between -20°C and reflux, and reacting the obtained acid halide in the presence of a base (such as pyridine, triethylamine, dimethylaniline, dimethylaminopyridine and diisopropylethylamine) in an amine and an organic solvent (such as chloroform, dichloromethane, diethyl ether and THF) at a temperature of 0 to 40°C. Alternatively, the method can be carried out by reacting the obtained acid halide with an amine in an organic solvent (such as dioxane and THF) using an alkaline aqueous solution (such as sodium bicarbonate solution or sodium hydroxide solution) at a temperature of 0 to 40°C.

[0219] (2) The method using a mixed acid anhydride is carried out, for example, as follows: a carboxylic acid is reacted with an acid halide (pivaloyl chloride, toluenesulfonyl chloride, methanesulfonyl chloride, etc.) or an acid derivative (ethyl chloroformate, isobutyl chloroformate, etc.) in an organic solvent (chloroform, dichloromethane, diethyl ether, THF, etc.) or in the absence of a solvent at 0 to 40°C in the presence of a base (pyridine, triethylamine, dimethylaniline, dimethylaminopyridine, diisopropylethylamine, etc.), and the resulting mixed acid anhydride is reacted with an amine in an organic solvent (chloroform, dichloromethane, diethyl ether, THF, etc.) at 0 to 40°C.

[0220] (3) The method using a condensing agent is carried out, for example, as follows: a carboxylic acid and an amine are 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-propylphosphonic acid cyclic anhydride (1-propanephosphonic acid cyclic anhydride, PPA, etc.), O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU), in the presence or absence of 1-hydroxybenzotriazole (HOBt), at 0 to 40°C.

[0221] The reactions (1), (2) and (3) are preferably carried out in an inert gas (argon, nitrogen, etc.) atmosphere under anhydrous conditions.

[0222] The compound represented by the general formula 1a can be prepared by the reaction process formula 2.

[0223] [Chemical formula 16]

[0224] Reaction process formula 2

[0225]

[0226] (In reaction process formula 2, all symbols have the same meanings as above)

[0227] In reaction process formula 2, reaction 2-1 is a cyclization reaction, which is carried out, for example, in an organic solvent (DMF, dimethyl sulfoxide, chloroform, dichloromethane, diethyl ether, THF, methyl tert-butyl ether, etc.) in the presence of an acid (trifluoroacetic acid, etc.) at a temperature of 0 to 100°C.

[0228] In reaction process formula 2, reaction 2-2 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.

[0229] In the compound represented by general formula (I), the fluorine atom is 18 The compound F can be prepared by reacting a precursor having a leaving group with [ 18 F] and is produced by reaction with potassium fluoride, etc.

[0230] In each reaction in this specification, the compounds represented by general formula 1b, general formula 1e, general formula 2a and general formula 2b, respectively, used as starting materials are well-known, or can be easily manufactured by combining known methods, such as the method described in Comprehensive Organic Transformations: A Guide to Functional Group Preparations, 3rd Edition (Richard C. Larock, John Wiley & Sons Inc, 2018), or a method in which a known method is partially modified.

[0231] Among the compounds of the present invention, optically active compounds can be produced by using optically active starting materials or reagents, or by optically resolving racemic production intermediates and converting them into the compounds of the present invention, or by optically resolving racemic compounds of the present invention.

[0232] This optical resolution is well known, and examples thereof include a method of forming a salt or complex with other optically active compounds, followed by recrystallization and then purifying the target compound, or directly separating using a chiral column or the like.

[0233] In each reaction in the present specification, the reaction to be heated can be carried out by using a water bath, an oil bath, a sand bath or a microwave known to those skilled in the art.

[0234] In each reaction in the present specification, a solid phase supported reagent supported on a high molecular polymer (for example, polystyrene, polyacrylamide, polypropylene, polyethylene glycol, etc.) can be used as appropriate.

[0235] In each reaction in this specification, the reaction product can be purified by common purification means, for example, distillation under normal pressure or reduced pressure, high performance liquid chromatography using silica gel or magnesium silicate, thin layer chromatography, ion exchange resin, scavenger resin or column chromatography, washing, recrystallization, etc. Purification can be carried out in each reaction or after several reactions are completed.

[0236] [toxicity]

[0237] Since the compound of the present invention has low toxicity, it can be safely used as a medicine.

[0238] [Application in medicine]

[0239] The compound of the present invention has an inhibitory activity against ABHD6 and is therefore useful as a preventive and / or therapeutic agent for diseases associated with ABHD6, such as pain, neurological diseases, inflammatory diseases, autoimmune diseases, metabolic diseases, malignant tumors, and the like.

[0240] 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, neuropathic pain, post-herpetic pain, pain associated with diabetic neuropathy, fibromyalgia, pain associated with pancreatitis, pain associated with interstitial cystitis and painful bladder syndrome, pain associated with endometriosis, pain associated with irritable bowel syndrome, migraine, and pain associated with pulpitis.

[0241] Examples of neurological diseases include tremors, movement disorders, dystonia, cramps, compulsive and obsessive behaviors, depression, mental disorders including anxiety disorders (e.g., panic disorder, acute stress reaction, post-traumatic stress disorder, obsessive-compulsive disorder, agoraphobia, social phobia), mood disorders, epilepsy, traumatic brain injury, spinal cord injury, multiple sclerosis, encephalomyelitis, Parkinson's disease, Huntington's disease, Alzheimer's disease, sleep disorders, and the like.

[0242] Examples of inflammatory diseases include arthritis, rheumatoid arthritis, osteoarthritis, spondylitis, gout, vasculitis, Crohn's disease, and irritable bowel syndrome.

[0243] Examples of the autoimmune disease include psoriasis, amyotrophic lateral sclerosis (ALS), multiple sclerosis, Sjögren's syndrome, systemic lupus erythematosus, and AIDS.

[0244] Examples of metabolic diseases include obesity, metabolic syndrome, dyslipidemia, diabetes, and fatty liver.

[0245] Examples of malignant tumors include breast cancer, ovarian cancer, colorectal cancer (e.g., colon cancer), lung cancer (e.g., non-small cell lung cancer), prostate cancer, head and neck cancer (e.g., oral squamous cell carcinoma, head and neck squamous cell carcinoma, pharyngeal cancer, laryngeal cancer, tongue cancer, thyroid cancer, acoustic neurothecatheter tumor, etc.), lymphoma (e.g., B-cell lymphoma, T-cell lymphoma, etc.), uveal malignant melanoma, thymoma, mesothelioma, esophageal cancer, gastric cancer, duodenal cancer, hepatocellular carcinoma, bile duct cancer, gallbladder cancer, pancreatic cancer, renal cell carcinoma, renal pelvis and ureter cancer, bladder cancer, penile cancer, testicular cancer, uterine cancer, vaginal cancer, vulvar cancer, skin cancer (e.g., malignant melanoma), malignant bone tumor, soft part sarcoma, chondrosarcoma, leukemia (e.g., acute myeloid leukemia, acute lymphocytic leukemia, chronic myeloid leukemia, chronic lymphocytic leukemia, etc.), myelodysplastic syndrome, brain tumor, multiple myeloma, etc.

[0246] In this specification, the prevention and / or treatment of malignant tumors include, for example: (a) to reduce the proliferation of cancer cells, (b) to reduce symptoms caused by cancer, to improve the quality of life of cancer patients, (c) to reduce the dosage of other anticancer agents or cancer treatment adjuvants that have been administered, (d) to inhibit the progression of cancer, (e) to inhibit the recurrence of cancer, and / or (f) to prolong the survival of cancer patients. In addition, "inhibiting the progression of cancer" refers to delaying the progression of cancer, stabilizing symptoms related to cancer, and retarding the progression of symptoms. "Inhibiting recurrence" refers to preventively inhibiting the recurrence of cancer in patients whose cancer lesions have been completely or substantially eliminated or removed by cancer treatment or cancer surgery.

[0247] To use the compounds of the present invention for the purpose of preventing and / or treating the disease, usually, the substance as the active ingredient is formulated together with pharmaceutically acceptable carriers such as various additives or solvents, and is administered to the whole body or locally in an oral or parenteral form. Here, a pharmaceutically acceptable carrier refers to a substance other than the active ingredient used in the preparation of a general drug. A pharmaceutically acceptable carrier is preferably a carrier that does not show a pharmacological effect, is harmless, and does not inhibit the therapeutic effect of the active ingredient in the dosage of its preparation. In addition, a pharmaceutically acceptable carrier can be used for the purpose of improving the usefulness of the active ingredient and the preparation, facilitating preparation, stabilizing the quality, or improving usability. Specifically, a substance recorded in the 2000 edition of the Pharmaceutical Additives Dictionary (edited by the Japanese Pharmaceutical Additives Association) of the Yakuji Daily can be selected according to an appropriate purpose.

[0248] The compounds of the present invention are administered to mammals (preferably humans, more preferably human patients) in a pharmaceutically effective amount.

[0249] The dosage of the compound of the present invention depends on age, body weight, symptoms, desired therapeutic effect, route of administration, duration of treatment, etc., and therefore inevitably varies. Usually, each patient is orally administered in a range of 0.1 ng to 1000 mg at a time, or each patient is parenterally administered in a range of 0.01 ng to 100 mg at a time, or continuously administered intravenously.

[0250] Of course, as described above, the dosage varies depending on various conditions, so there are cases where a smaller dosage than the above dosage is sufficient, and there are also cases where a dosage exceeding the range is necessary.

[0251] Examples of dosage forms used for administration include oral preparations (e.g., tablets, capsules, granules, powders, oral liquids, syrups, oral gels, etc.), oral preparations (e.g., oral tablets, oral sprays, oral semisolid preparations, mouthwashes, etc.), injectable preparations (e.g., injectables, etc.), dialysis preparations (e.g., dialysis preparations, etc.), inhalation preparations (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 semisolid preparations, enemas, etc.), vaginal preparations (e.g., vaginal tablets, vaginal suppositories, etc.), and skin preparations (e.g., external solid preparations, external liquids, sprays, ointments, pastes, gels, patches, etc.).

[0252] [Oral preparations]

[0253] Preparations for oral administration include, for example, tablets, capsules, granules, powders, oral liquids, syrups, oral gels, and the like. In addition, preparations for oral administration include: rapidly disintegrating preparations in which the release of the active ingredient from the preparation is not particularly adjusted, and release-regulated preparations such as enteric preparations and sustained-release preparations in which the release is adjusted according to the purpose by inherent preparation design and manufacturing methods. Enteric preparations refer to preparations designed so that the active ingredient is not released in the stomach but mainly released in the small intestine for the purpose of preventing the active ingredient from decomposing in the stomach or reducing the irritation of the active ingredient to the stomach. Usually, they can be manufactured by adding a coating using an acid-insoluble enteric base. Sustained-release preparations refer to preparations in which the release rate, release time, and release site of the active ingredient from the preparation are adjusted for the purpose of reducing the number of administrations or reducing side effects. Usually, they can be manufactured by using an appropriate sustained-release agent. Orally administered preparations such as capsules, granules, tablets, etc. may be coated with an appropriate coating agent such as sugars, sugar alcohols, or polymer compounds for the purpose of facilitating administration or preventing decomposition of the active ingredient.

[0254] (1) Tablets

[0255] Tablets are solid preparations with a certain shape for oral administration. In addition to tablets generally referred to as tablets such as plain tablets, film-coated tablets, sugar-coated tablets, multilayer tablets, and core tablets, they also include rapidly disintegrating tablets in the mouth, chewable tablets, foaming tablets, dispersible tablets, and dissolving tablets. When making plain tablets, the following methods (a), (b), or (c) are usually used:

[0256] (a) Adding additives such as excipients, binders, disintegrants, etc. to the active ingredient and mixing until homogeneous, using a solution containing water or a binder, granulating it by an appropriate method, adding a lubricant, etc., mixing, and compression molding;

[0257] (b) adding additives such as excipients, binders, disintegrants, etc. to the active ingredient and mixing until homogeneous, and then directly compressing the mixture; or adding the active ingredient and lubricants to granules prepared with additives in advance and mixing until homogeneous, and then compressing the mixture;

[0258] (c) Adding additives such as excipients and binders to the active ingredient, mixing until homogeneous, and moistening the kneaded product with a solvent, pouring it into a specific mold for molding, and then drying it by an appropriate method.

[0259] Film-coated tablets can usually be manufactured by adding a thin coating to a plain tablet using an appropriate coating agent such as a polymer compound. Sugar-coated tablets can usually be manufactured by adding a coating to a plain tablet using a coating agent containing sugars or sugar alcohols. Multilayer tablets can be manufactured by using an appropriate method to stack powders and granules of different compositions in layers and compress them. Core tablets can be manufactured by coating a core tablet with an outer layer of different compositions. In addition, tablets can be made into enteric-coated tablets or sustained-release tablets using a known appropriate technique. Orally rapidly disintegrating tablets, chewable tablets, foaming tablets, dispersible tablets, and dissolving tablets are tablets that give unique functions to the tablets by appropriately selecting additives, and can be manufactured with reference to the manufacturing techniques of the tablets. It should be noted that an orally rapidly disintegrating tablet refers to a tablet that can be taken by rapidly dissolving or disintegrating in the mouth; a chewable tablet refers to a tablet that is taken by chewing; a foaming tablet refers to a tablet that rapidly foams and dissolves or disperses in water; a dispersible tablet refers to a tablet that is dispersed in water and taken; and a dissolving tablet refers to a tablet that is dissolved in water and taken. The foamed sheet can be produced by using an appropriate acidic substance, carbonate, bicarbonate, or the like as an additive.

[0260] (2) Capsules

[0261] Capsules are preparations filled into capsules or coated with capsule bases, including hard capsules, soft capsules, etc. Hard capsules can be manufactured in the following manner: additives such as excipients are added to active ingredients and mixed to homogeneity or made into granules or formed objects in an appropriate manner, and then filled into capsules or slightly formed and filled again. Soft capsules can be manufactured in the following manner: additives are added to active ingredients, and then appropriate capsule bases such as gelatin with glycerol, D-sorbitol, etc. added and plasticity is improved, and coated and formed with a certain shape. Capsules can be made into enteric capsules or sustained-release capsules by known appropriate techniques, and colorants or preservatives, etc. can also be added to capsule bases.

[0262] (3) Granules

[0263] Granules are granulated preparations, and include foamable granules, in addition to preparations generally referred to as granules. When making granules, the following methods (a), (b), or (c) are usually used:

[0264] (a) adding excipients, binders, disintegrants or other additives to the powdered active ingredient and mixing until homogeneous, and then granulating by an appropriate method;

[0265] (b) adding additives such as excipients to the active ingredient that has been granulated in advance and mixing until homogeneous;

[0266] (c) Additives such as excipients are added to the active ingredient that has been granulated in advance, mixed, and granulated by an appropriate method.

[0267] Granules can be coated as needed, and can be made into enteric granules or sustained-release granules using known appropriate methods. Foaming granules can be made by using appropriate acidic substances, carbonates, bicarbonates, etc. as additives. It should be noted that foaming granules refer to granules that rapidly foam and dissolve or disperse in water. Granules can be made into fine granules by adjusting the size of the particles.

[0268] (4) Powder

[0269] Powders are powdered preparations, which are generally produced by adding excipients or other additives to active ingredients and mixing until homogeneous.

[0270] (5) Oral liquid

[0271] Oral liquid preparations are liquid or fluid viscous gel preparations. In addition to preparations generally referred to as oral liquid preparations, they also include elixirs, suspensions, emulsions, lemonades, etc. Oral liquid preparations can usually be made by adding additives and purified water to the active ingredients, mixing, dissolving or emulsifying or suspending to homogeneity, and filtering as needed. Elixirs refer to clear liquid oral liquid preparations containing ethanol that are sweet and fragrant. Usually, they can be made by adding ethanol, purified water, flavoring agents and white sugar, other sugars or sweeteners to solid active ingredients or their extracts and dissolving them, and then filtering or other methods to make a clear liquid. Suspension preparations refer to oral liquid preparations in which the active ingredients are suspended in a fine and homogeneous form. Usually, they can be made by adding suspending agents or other additives and purified water or oil to solid active ingredients, suspending them by appropriate methods, and making the whole homogeneous. An emulsion is an oral liquid in which the active ingredient is emulsified in a fine and homogeneous form, and can generally be prepared by adding an emulsifier and purified water to the liquid active ingredient, emulsifying it by an appropriate method, and making the whole homogeneous. It should be noted that lemonade is a clear liquid oral liquid with sweet and sour taste.

[0272] (6) Syrup

[0273] Syrups are liquid or solid preparations containing sugars or sweeteners and having viscosity, including syrup preparations. Syrups can usually be made by adding active ingredients to a solution or monosyrup of white sugar, other sugars or sweeteners and dissolving, mixing, suspending or emulsifying, boiling the mixture as needed, and hot filtering. Syrup preparations refer to granular or powdered preparations that become syrups after adding water, also known as dry syrups. Syrup preparations usually use sugars or sweeteners as additives and can be made according to the manufacturing techniques of the granules or powders.

[0274] (7) Oral gel

[0275] Oral gel preparations are gel-like preparations that are not fluid and are generally produced by adding additives and a polymer gel base to an active ingredient, mixing the mixture, gelling the mixture by an appropriate method, and molding the mixture into a predetermined shape.

[0276] [Injection preparations]

[0277] (1) Injection

[0278] Injections are sterile preparations that are administered directly to tissues and organs in the body, such as the subcutaneous, intramuscular or blood vessels, and are solutions, suspensions or emulsions, or solid preparations that are dissolved or suspended before use. In addition to preparations generally referred to as injections, they also include freeze-dried injections, powder injections, filled syringes, cartridges, infusions, implantable injections, and continuous injections. When manufacturing injections, the following (a) or (b) methods are usually used:

[0279] (a) dissolving the active ingredient directly or after adding additives to the active ingredient in water for injection, other aqueous solvents or non-aqueous solvents, suspending or emulsifying until homogeneous, filling into a container for injection, sealing and sterilizing;

[0280] (b) The active ingredient is dissolved directly or after adding additives to the active ingredient in water for injection, other aqueous solvents or non-aqueous solvents, etc., suspended or emulsified to homogeneity, and then aseptically filtered or prepared under aseptic conditions to homogeneity, and then filled into a container for injection and sealed.

[0281] Freeze-dried injections can usually be manufactured in the following ways: directly dissolving the active ingredient or the active ingredient and additives such as excipients into water for injection, sterile filtering, filling it into a container for injection and then freeze-drying it or freeze-drying it in a special container and then directly filling it into the container. Powder injections can usually be manufactured in the following ways: filling the powder obtained by crystallization after sterile filtration, or adding sterilized additives to the powder into a container for injection. Filled syringes can usually be manufactured in the following ways: directly filling the active ingredient or filling it into a syringe after preparing a solution, suspension or emulsion using the active ingredient and additives. Cartridges refer to injections that are filled with a cartridge filled with a liquid medicine and are loaded into a special syringe for use. Cartridges filled with liquid medicine can usually be manufactured in the following ways: directly filling the active ingredient or filling it into a cartridge after preparing a solution, suspension or emulsion using the active ingredient and additives. Infusion refers to an injection that is administered intravenously, usually in a volume of more than 100 mL. Implantable injections refer to solid or gel-like injections that are used for the purpose of long-term release of active ingredients, using an instrument for implantation subcutaneously, intramuscularly, etc., or by surgery. Implantable injections can usually be manufactured by using a macromolecular compound that is degradable in the body and making it into particles, microbeads or gels. Sustained injections refer to injections that are suitable for intramuscular use, etc., for the purpose of long-term release of active ingredients. Usually, they can be manufactured by dissolving or suspending the active ingredients in vegetable oils, etc., or by making a suspension of microbeads using a macromolecular compound that is degradable in the body.

[0282] The compound of the present invention can be combined with other drugs for the following purposes 1) to 3) and administered as a combination agent.

[0283] 1) Supplementing and / or enhancing the preventive and / or therapeutic effects of the compound;

[0284] 2) Improved dynamics and absorption of the compound, and reduced dosage; and / or

[0285] 3) Reduction of the side effects of the compound.

[0286] The combination of the compound of the present invention and other agents can be administered in the form of a compounding agent with two components in a single preparation, or in the form of administration with respective preparations. If the respective preparations are administered, simultaneous administration and administration with a time difference are included. In addition, with respect to administration with a time difference, the compound of the present invention can be administered first, and then other agents can be administered, or other agents can be administered first, and then the compound of the present invention can be administered. Each administration method can be the same or different.

[0287] The disease for which the combination agent exerts a preventive and / or therapeutic effect is not particularly limited, as long as the preventive and / or therapeutic effect of the compound of the present invention is supplemented and / or enhanced in the disease.

[0288] Examples of other drugs used to supplement and / or enhance the preventive and / or therapeutic effects of the compounds of the present invention on pain include acetaminophen, nonsteroidal anti-inflammatory drugs, opioids, antidepressants, antiepileptics, N-methyl-D-aspartate antagonists, muscle relaxants, antiarrhythmic drugs, steroids, and bisphosphonates.

[0289] Examples of the nonsteroidal anti-inflammatory drugs include: aspirin preparations such as disalicylate, sodium salicylate, aspirin, and aspirin and dialuminate combination; diflunisal, indomethacin, suprofen, uffenamate, dimethyl isopropylazulene, bufenac, felbinac, diclofenac, tolmetin sodium, sulindac, fenbufen, nabumetone, proglumetasin, indomethacin farnesate, acemetacin, proglumetasin maleate, amfenac sodium, mofezoic acid, etodolac, ibuprofen, picoprofen, naproxen, flurbiprofen, flurbiprofen axetil, ketoprofen, fenoprofen calcium, tiaprofenic acid, oxaprozin, pranoprofen, loxoprofen sodium, amin Profen, zaltoprofen, profenofen, profenofen aluminum, tolfenamic acid, flofenin, ketobutazone, hydroxyphenylbutazone, piroxicam, tenoxicam, ampiroxicam, Napageln ointment, epiriazole, thiamide hydrochloride, tenoridine hydrochloride, emofazone, sulbinin, pyrine cold medicines, phenacetin, dimethoate mesylate, meloxicam, celecoxib, rofecoxib, valdecoxib, simetret compound and non-pyrine cold medicines, etc.

[0290] Examples of the opioid include codeine, fentanyl, hydromorphone, levorphanol, pethidine, methadone, morphine, oxycodone, oxymorphone, propoxyphene, and tramadol.

[0291] Examples of the antidepressant include tricyclic antidepressants (e.g., amitriptyline hydrochloride, imipramine hydrochloride, clomipramine hydrochloride, dosulpin hydrochloride, nortriptyline hydrochloride, lofepramine hydrochloride, trimipramine maleate, amoxapine, etc.), tetracyclic antidepressants (e.g., maprotiline hydrochloride, mianserin hydrochloride, setiptiline maleate, etc.), monoamine oxidase (MAO) inhibitors (safrazine hydrochloride), serotonin and norepinephrine reuptake inhibitors (SNRI) (e.g., milnacipran hydrochloride, venlafaxine hydrochloride, etc.), selective serotonin reuptake inhibitors (SSRI) (e.g., fluvoxamine maleate, paroxetine hydrochloride, fluoxetine hydrochloride, citalopram hydrochloride, etc.), and serotonin reuptake inhibitors (e.g., trazodone hydrochloride, etc.).

[0292] Examples of the antiepileptic drug include phenobarbital, primidone, phenytoin, ethosuximide, zonisamide, nitrazepam, clonazepam, carbamazepine, sodium valproate, acetazolamide, and sulthiazine.

[0293] Examples of the N-methyl-D-aspartate antagonist include ketamine hydrochloride, amantadine hydrochloride, memantine hydrochloride, dextromethorphan, and methadone.

[0294] Examples of the muscle relaxant include succinylcholine, succinylcholine, vecuronium bromide, pancuronium bromide, and dantrolene sodium.

[0295] Examples of the antiarrhythmic drug include procainamide, disopyramide, cibenzoline, pirmenol, lidocaine, mexiletine, aprindine, pilsicainide, flecainide, propafenone, propranolol, atenolol, bisoprolol, amiodarone, sotalol, verapamil, diltiazem, and bepridil.

[0296] Steroidal drugs include external medicines, internal medicines, injections, and inhaled medicines. For example, external medicines include clobetasol propionate, diflorasone diacetate, fluocinolone acetate, mometasone furoate, betamethasone dipropionate, betamethasone propionate butyrate, betamethasone valerate, difluprednate, budesonide, diflucortolone valerate, amcinonide, halcinonide, dexamethasone, dexamethasone propionate, dexamethasone valerate, dexamethasone acetate, hydrocortisone acetate, hydrocortisone butyrate, hydrocortisone butyrate propionate, deproton propionate, prednisolone acetate valerate, fluvalonide acetate, beclomethasone dipropionate, triamcinolone acetate, flumethasone pivalate, alclomethasone dipropionate, clobetasone butyrate, prednisolone, beclomethasone propionate, and flurandrenolide.

[0297] Examples of the oral or injectable medicine include cortisone acetate, hydrocortisone, hydrocortisone sodium phosphate, hydrocortisone sodium succinate, fludrocortisone acetate, prednisolone, prednisolone acetate, prednisolone sodium succinate, prednisolone butyrate, prednisolone sodium phosphate, halopednisolone acetate, methylprednisolone, methylprednisolone acetate, methylprednisolone sodium succinate, triamcinolone, triamcinolone acetate, triamcinolone acetonide, dexamethasone, dexamethasone acetate, dexamethasone sodium phosphate, dexamethasone palmitate, paramethasone acetate, and betamethasone.

[0298] Examples of the inhalation drug include beclomethasone dipropionate, fluticasone propionate, budesonide, flunisolide, triamcinolone acetonide, ST-126P, ciclesonide, dexamethasone palmitate, mometasone furoate, prasterone sulfonate, deflazacort, methylprednisolone sulfonate, and methylprednisolone sodium succinate.

[0299] Examples of the bisphosphonate drug include etidronate, pamidronate, alendronate, risedronate, zoledronate, and minodronic acid.

[0300] Other drugs may be administered in combination of any two or more.

[0301] Furthermore, other drugs that complement and / or enhance the preventive and / or therapeutic effects of the compounds of the present invention include not only currently discovered drugs but also drugs to be discovered in the future, as long as they are based on the aforementioned mechanism.

[0302] Unless otherwise defined, all technical, scientific terms and abbreviations used in this specification have the same meaning as commonly understood by those skilled in the art to which the present invention belongs.

[0303] Furthermore, the contents of all patent documents, non-patent documents, or reference documents explicitly cited in this specification are all incorporated herein by reference as part of this specification.

[0304] The present invention provides the following embodiments in one form.

[0305] [1] A compound represented by the following general formula (I) or a pharmaceutically acceptable salt thereof,

[0306] General formula (I):

[0307] [Chemical formula 17]

[0308]

[0309] In the formula,

[0310] R 1 represents a halogen atom,

[0311] R 2 represents (1) a halogen atom, (2) a C1-6 alkyl group, (3) a C2-6 alkenyl group, (4) a C2-6 alkynyl group, (5) a C1-6 alkoxy group, (6) a C1-6 haloalkyl group, (7) a C2-6 haloalkenyl group, (8) a C2-6 haloalkynyl group or (9) a C1-6 haloalkoxy group,

[0312] 1 to 2 carbon atoms in the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxy, C1-6 haloalkyl, C2-6 haloalkenyl, C2-6 haloalkynyl or C1-6 haloalkoxy are optionally substituted by nitrogen atoms or optionally oxidized sulfur atoms,

[0313] When m is 2, multiple R 2 Can be the same or different.

[0314] Two R's 2 When it represents a C1-6 alkyl group, a C2-6 alkenyl group, a C2-6 alkynyl group, a C1-6 alkoxy group, a C1-6 haloalkyl group, a C2-6 haloalkenyl group, a C2-6 haloalkynyl group or a C1-6 haloalkoxy group, it may optionally form a 5-6 membered cyclic group together with the carbon atom to which it is bonded,

[0315] R 3represents (1) a halogen atom, (2) a C1-6 alkyl group, (3) a C2-6 alkenyl group, (4) a C2-6 alkynyl group, (5) a C1-6 alkoxy group, (6) a C1-6 haloalkyl group, (7) a C2-6 haloalkenyl group, (8) a C2-6 haloalkynyl group, (9) a C1-6 haloalkoxy group or (10) a hydroxyl group,

[0316] When n is 2 or more, multiple R 3 Can be the same or different.

[0317] Two R on the same carbon atom 3 When it represents a C1-6 alkyl group, it may optionally form a C3-6 cycloalkyl group together with the carbon atom to which it is bonded,

[0318] Ring1 represents a 3-15 membered cyclic group,

[0319] 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 haloalkyl group, (7) a C2-6 haloalkenyl group, (8) a C2-6 haloalkynyl group, (9) a C1-6 haloalkoxy group, (10) a C1-6 alkylthio group, (11) a C1-6 alkylsulfinyl group, (12) a C1-6 alkylsulfonyl group, (13) a C2-6 acyl group, (14) a 3- to 6-membered cyclic group, (15) -L R4 -(3-6 membered cyclic group), (16) hydroxyl, (17) nitro, (18) cyano, (19) oxo, (20) -NR 401 R 402 、(21)-COOR 403 、(22)-CONR 404 R 405 or (23)-SO2NR 406 R 407 , 1 to 2 carbon atoms in the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxy, C1-6 haloalkyl, C2-6 haloalkenyl, C2-6 haloalkynyl, C1-6 haloalkoxy, C1-6 alkylthio, C1-6 alkylsulfinyl, C1-6 alkylsulfonyl or C2-6 acyl are optionally substituted by oxygen atoms or optionally oxidized sulfur atoms,

[0320] When p is 2 or more, multiple R 4 Can be the same or different.

[0321] R 4 The groups in (2) to (15) are optionally substituted with 1 to 9 R 408 ,

[0322] R408 represents (1) a halogen atom, (2) a C1-4 alkyl group, (3) a C1-4 alkoxy group, (4) a C2-6 acyl group, (5) a C3-6 cycloalkyl group, (6) a hydroxyl group, or (7) -NR 409 R 410 ,

[0323] R 408 When replacing two or more, multiple R 408 Can be the same or different.

[0324] L R4 represents (1) -O-, (2) -(C1-4 alkylene)-, (3) -O-(C1-4 alkylene)-, (4) -(C1-4 alkylene)-O-, (5) -NR 411 -, (6)-S-, (7)-SO- or (8)-SO2-,

[0325] R 401 , R 402 , R 403 , R 404 , R 405 , R 406 , R 407 , R 409 , R 410 or R 411 are each independently a hydrogen atom, (2) a C1-6 alkyl group, (3) a C2-6 acyl group, or (4) a C1-6 alkylsulfonyl group,

[0326] m represents an integer from 0 to 2,

[0327] n represents an integer from 0 to 5,

[0328] p represents an integer of 0-5.

[0329] [2] The compound according to [1] or a pharmaceutically acceptable salt thereof, wherein:

[0330] Ring 1 is a 3-10 membered cyclic group.

[0331] [3] The compound according to [1] or [2] or a pharmaceutically acceptable salt thereof, wherein:

[0332] ring1 is a ring structure selected from the following ring structures,

[0333] [Chemical formula 18]

[0334]

[0335] In the formula, the * mark indicates the bonding position to the carbonyl group, and the hydrogen atom represented by NH is optionally replaced by R 4 replace.

[0336] [4] The compound or pharmaceutically acceptable salt thereof according to any one of [1] to [3], wherein

[0337] R 4 is (1) a halogen atom, (2) a C1-6 alkyl group, (3) a C1-6 alkoxy group, (4) a C1-6 haloalkyl group, (5) a C1-6 haloalkoxy group, (6) a cyclopropyl group, (7) a benzene ring, (8) a pyridine ring, (9) -COOCH3, (10) -COOtBu or (11) a cyano group.

[0338] [5] The compound or pharmaceutically acceptable salt thereof according to any one of [1] to [4], wherein

[0339] R 2 is (1) C1-6 alkyl, (2) C1-6 alkoxy, (3) C1-6 haloalkyl or (4) C1-6 haloalkoxy.

[0340] [6] The compound or pharmaceutically acceptable salt thereof according to any one of [1] to [5], wherein

[0341] The compound represented by general formula (I) is represented by general formula (I-1),

[0342] [Chemical formula 19]

[0343]

[0344] In the formula, R 2-1 represents (1) C1-6 alkyl, (2) C1-6 alkoxy, (3) C1-6 haloalkyl or (4) C1-6 haloalkoxy,

[0345] R 4-1 represents (1) a halogen atom, (2) a C1-6 alkyl group, (3) a C1-6 alkoxy group, (4) a C1-6 haloalkyl group, (5) a C1-6 haloalkoxy group, (6) a cyclopropyl group, (7) a benzene ring, (8) a pyridine ring, (9) -COOCH3, (10) -COOtBu or (11) a cyano group,

[0346] ring1-1 represents a ring structure selected from the following ring structures,

[0347] [Chemical formula 20]

[0348]

[0349] In the formula, the * mark indicates the bonding position to the carbonyl group, and the hydrogen atom represented by NH is optionally replaced by R 4-1 replace,

[0350] Other symbols have the same meanings as those in claim 1.

[0351] [7] The compound according to [1] or [2] or a pharmaceutically acceptable salt thereof, wherein:

[0352] The compound represented by general formula (I) is selected from the following compounds:

[0353] (1) [(3aS,4R,6aR)-4-[(6-bromo-3-pyridazinyl)oxy]hexahydrocyclopenta[c]pyrrol-2(1H)-yl](6,7-dihydro-4H-thieno[3,2-c]pyran-2-yl)methanone,

[0354] (2) [(3aS,4R,6aR)-4-[(6-bromo-3-pyridazinyl)oxy]hexahydrocyclopenta[c]pyrrol-2(1H)-yl](5-methyl-2-thienyl)methanone,

[0355] (3) [(3aS,4R,6aR)-4-[(6-bromo-3-pyridazinyl)oxy]hexahydrocyclopenta[c]pyrrol-2(1H)-yl](2-methyl-2H-thieno[3,2-c]pyrazol-5-yl)methanone,

[0356] (4) [(3aS,4R,6aR)-4-[(6-bromo-3-pyridazinyl)oxy]hexahydrocyclopenta[c]pyrrol-2(1H)-yl](6-methylpyrazolo[5,1-b][1,3]thiazol-2-yl)methanone,

[0357] (5) [(3aS,4R,6aR)-4-[(6-bromo-3-pyridazinyl)oxy]hexahydrocyclopenta[c]pyrrol-2(1H)-yl](2-cyclopropyl-2H-thieno[3,2-c]pyrazol-5-yl)methanone,

[0358] (6) [(3aS,4R,6aR)-4-[(6-bromo-3-pyridazinyl)oxy]hexahydrocyclopenta[c]pyrrol-2(1H)-yl][2-(difluoromethyl)-2H-thieno[3,2-c]pyrazol-5-yl]methanone,

[0359] (7) [(3aS,4R,6aR)-4-[(6-bromo-3-pyridazinyl)oxy]hexahydrocyclopenta[c]pyrrol-2(1H)-yl](6-fluoro-1,3-benzothiazol-2-yl)methanone,

[0360] (8) [(3aS, 4R, 6aR)-4-[(6-bromo-3-pyridazinyl)oxy]hexahydrocyclopenta[c]pyrrol-2(1H)-yl][5-(difluoromethyl)-2-thienyl]methanone,

[0361] (9) [(3aS,4R,6aR)-4-[(6-bromo-3-pyridazinyl)oxy]hexahydrocyclopenta[c]pyrrol-2(1H)-yl](thieno[3,2-c]pyridin-2-yl)methanone,

[0362] (10) [(3aS,4R,6aR)-4-[(6-bromo-3-pyridazinyl)oxy]hexahydrocyclopenta[c]pyrrol-2(1H)-yl](thieno[3,2-b]furan-5-yl)methanone,

[0363] (11) [(3aS,4R,6aR)-4-[(6-bromo-3-pyridazinyl)oxy]hexahydrocyclopenta[c]pyrrol-2(1H)-yl](1-methyl-1H-thieno[2,3-c]pyrazol-5-yl)methanone,

[0364] (12) 5-{[(3aS,4R,6aR)-4-[(6-bromo-3-pyridazinyl)oxy]hexahydrocyclopenta[c]pyrrol-2(1H)-yl]carbonyl}-2-methyl-3-thiophenecarbonitrile,

[0365] (13) 2-[(3aS,4R,6aR)-4-[(6-bromo-3-pyridazinyl)oxy]hexahydrocyclopenta[c]pyrrol-2(1H)-yl]carbonyl}-6,7-dihydro[1,3]thiazolo[4,5-c]pyridine-5(4H)-carboxylic acid 2-methyl-2-propyl ester,

[0366] (14) methyl 2-[(3aS,4R,6aR)-4-[(6-bromo-3-pyridazinyl)oxy]hexahydrocyclopenta[c]pyrrol-2(1H)-yl]carbonyl}-6,7-dihydrothieno[3,2-c]pyridine-5(4H)-carboxylate,

[0367] (15) [(3aS,4R,6aR)-4-[(6-bromo-3-pyridazinyl)oxy]hexahydrocyclopenta[c]pyrrol-2(1H)-yl](2-phenyl-2H-thieno[3,2-c]pyrazol-5-yl)methanone,

[0368] (16) [(3aS,4R,6aR)-4-[(6-bromo-3-pyridazinyl)oxy]hexahydrocyclopenta[c]pyrrol-2(1H)-yl][2-(3-pyridyl)-2H-thieno[3,2-c]pyrazol-5-yl]methanone,

[0369] (17) [(3aS,4R,6aR)-4-[(6-bromo-3-pyridazinyl)oxy]hexahydrocyclopenta[c]pyrrol-2(1H)-yl](4,5-dimethyl-1,3-thiazol-2-yl)methanone,

[0370] (18) methyl 2-[(3aS,4R,6aR)-4-[(6-bromo-3-pyridazinyl)oxy]hexahydrocyclopenta[c]pyrrol-2(1H)-yl]carbonyl}-4,7-dihydrothieno[2,3-c]pyridine-6(5H)-carboxylate,

[0371] (19) [(3aS,4R,6aR)-4-[(6-bromo-3-pyridazinyl)oxy]hexahydrocyclopenta[c]pyrrol-2(1H)-yl](4,5,7,8-tetrahydrothieno[2,3-d]oxepin-2-yl)methanone,

[0372] (20) [(3aS, 4R, 6aR)-4-[(6-bromo-3-pyridazinyl)oxy]hexahydrocyclopenta[c]pyrrol-2(1H)-yl][5-(2-fluoroethoxy)-2-thienyl]methanone,

[0373] (21) [(3aS, 4R, 6aR)-4-[(6-bromo-3-pyridazinyl)oxy]hexahydrocyclopenta[c]pyrrol-2(1H)-yl](4-fluoro-5-methyl-2-thienyl)methanone,

[0374] (22) [(3aS,4R,6aR)-4-[(6-chloro-3-pyridazinyl)oxy]hexahydrocyclopenta[c]pyrrol-2(1H)-yl](6,7-dihydro-4H-thieno[3,2-c]pyran-2-yl)methanone,

[0375] (23) [(3aS,4R,6aR)-4-{[6-chloro-4-(trifluoromethyl)-3-pyridazinyl]oxy}hexahydrocyclopenta[c]pyrrol-2(1H)-yl](6,7-dihydro-4H-thieno[3,2-c]pyran-2-yl)methanone,

[0376] (24) {4-[(5-chloropyrido[2,3-d]pyridazin-8-yl)oxy]hexahydrocyclopenta[c]pyrrol-2(1H)-yl}(6,7-dihydro-4H-thieno[3,2-c]pyran-2-yl)methanone,

[0377] (25) {4-[(4-chlorothieno[2,3-d]pyridazin-7-yl)oxy]hexahydrocyclopenta[c]pyrrol-2(1H)-yl}(6,7-dihydro-4H-thieno[3,2-c]pyran-2-yl)methanone,

[0378] (26) [(3aS,4R,6aR)-4-[(6-chloro-5-methoxy-3-pyridazinyl)oxy]hexahydrocyclopenta[c]pyrrol-2(1H)-yl](6,7-dihydro-4H-thieno[3,2-c]pyran-2-yl)methanone,

[0379] (27) [(3aS,4R,6aR)-4-[(6-chloro-4-methoxy-3-pyridazinyl)oxy]hexahydrocyclopenta[c]pyrrol-2(1H)-yl](6,7-dihydro-4H-thieno[3,2-c]pyran-2-yl)methanone,

[0380] (28) [(3aS,4R,6aR)-4-[(6-chloro-3-pyridazinyl)oxy]hexahydrocyclopenta[c]pyrrol-2(1H)-yl](2-methyl-2H-thieno[3,2-c]pyrazol-5-yl)methanone,

[0381] (29) [(3aS,4S,6aR)-4-[(6-bromo-3-pyridazinyl)oxy]tetrahydro-1H-spiro[cyclopenta[c]pyrrol-5,1'-cyclopropane]-2(3H)-yl](6,7-dihydro-4H-thieno[3,2-c]pyran-2-yl)methanone,

[0382] (30) [(3aS,4R,6aR)-4-[(6-bromo-3-pyridazinyl)oxy]-3a-methylhexahydrocyclopenta[c]pyrrol-2(1H)-yl](6,7-dihydro-4H-thieno[3,2-c]pyran-2-yl)methanone,

[0383] (31) [(3aS,4S,6aR)-4-[(6-bromo-3-pyridazinyl)oxy]-5,5-dimethylhexahydrocyclopenta[c]pyrrol-2(1H)-yl](6,7-dihydro-4H-thieno[3,2-c]pyran-2-yl)methanone,

[0384] (32) [(3aR,4R,6aS)-4-[(6-bromo-3-pyridazinyl)oxy]-3a-hydroxyhexahydrocyclopenta[c]pyrrol-2(1H)-yl](6,7-dihydro-4H-thieno[3,2-c]pyran-2-yl)methanone,

[0385] (33) [(3aR,4R,6aS)-4-[(6-bromo-3-pyridazinyl)oxy]-3a-methoxyhexahydrocyclopenta[c]pyrrol-2(1H)-yl](6,7-dihydro-4H-thieno[3,2-c]pyran-2-yl)methanone, and

[0386] (34) [(3aS,4S,5S,6aR)-4-[(6-Bromo-3-pyridazinyl)oxy]-5-fluorohexahydrocyclopenta[c]pyrrol-2(1H)-yl](6,7-dihydro-4H-thieno[3,2-c]pyran-2-yl)methanone.

[0387] [8] A pharmaceutical composition comprising the compound described in any one of [1] to [7] or a pharmaceutically acceptable salt thereof as an active ingredient,

[0388] The pharmaceutical composition further contains a pharmaceutically acceptable carrier.

[0389] [9] The pharmaceutical composition according to [8], which is an ABHD6 inhibitor.

[0390]

[10] The pharmaceutical composition according to [8] or [9], which is a therapeutic and / or preventive agent for diseases associated with ABHD6.

[0391]

[11] The pharmaceutical composition according to

[10] , wherein

[0392] Diseases associated with ABHD6 are pain, neurological diseases, inflammatory diseases, autoimmune diseases, metabolic diseases or malignant tumors.

[0393]

[12] The pharmaceutical composition according to

[10] or

[11] , wherein

[0394] The disease associated with ABHD6 is pain, and the pain is pain associated with osteoarthritis, cancer pain, pain associated with chemotherapy, chronic low back pain, low back pain associated with osteoporosis, fracture pain, pain associated with rheumatoid arthritis, neuropathic pain, post-herpetic pain, pain associated with diabetic neuropathy, fibromyalgia, pain associated with pancreatitis, pain associated with interstitial cystitis / painful bladder syndrome, pain associated with endometriosis, pain associated with irritable bowel syndrome, migraine, or pain associated with pulpitis.

[0395]

[13] The pharmaceutical composition according to

[10] or

[11] , wherein

[0396] The disease associated with ABHD6 is a neurological disease, and the neurological disease is tremor, movement disorder, dystonia, spasticity, obsessive and compulsive behavior, depression, anxiety disorder, panic disorder, acute stress reaction, post-traumatic stress disorder, obsessive-compulsive disorder, agoraphobia, social phobia, mood disorder, epilepsy, traumatic brain injury, spinal cord injury, multiple sclerosis, encephalomyelitis, Parkinson's disease, Huntington's disease, Alzheimer's disease or sleep disorder.

[0397]

[14] The pharmaceutical composition according to any one of [8] to

[13] , which is administered in combination with at least one selected from the following ingredients:

[0398] Acetaminophen, nonsteroidal anti-inflammatory drugs, opioids, antidepressants, antiepileptics, N-methyl-D-aspartate antagonists, muscle relaxants, antiarrhythmics, steroids, and bisphosphonates.

[0399]

[15] A therapeutic and / or preventive agent for a disease associated with ABHD6, comprising:

[0400] The compound described in any one of [1] to [7] above, or a pharmaceutically acceptable salt thereof.

[0401]

[16] A method for preventing and / or treating a disease associated with ABHD6, comprising administering the compound described in any one of [1] to [7] or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition described in [8] or [9] to a patient in need of prevention and / or treatment of a disease associated with ABHD6.

[0402]

[17] The compound according to any one of [1] to [7] or a pharmaceutically acceptable salt thereof, for use in preventing and / or treating a disease associated with ABHD6.

[0403]

[18] A use of the compound or a pharmaceutically acceptable salt thereof according to any one of [1] to [7] for manufacturing a preventive and / or therapeutic agent for a disease associated with ABHD6.

[0404] [Synthesis Example]

[0405] The solvents in parentheses shown at the separation point based on chromatography and TLC point indicate the elution solvent or developing solvent used, and the ratio indicates the volume ratio.

[0406] The solvent in parentheses shown in NMR indicates the solvent used in the measurement.

[0407] The compound names used in this specification are generally named using ACD / Name (registered trademark), a program for naming in accordance with IUPAC rules, or using Chemdraw Ultra (version 12.0, manufactured by Cambridge Soft) or in accordance with IUPAC nomenclature.

[0408] LC-MS / ELSD was performed under the following trifluoroacetic acid (hereinafter, TFA) conditions or formic acid conditions.

[0409] TFA conditions;

[0410] Column: YMC Triart C 18 (Particle size: 1.9×10 -6m; 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), ELS D, MS.

[0411] Formic acid conditions;

[0412] 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.

[0413] Unless otherwise specified, the HPLC retention time indicates the retention time under the conditions specified in the LC-MS / ELSD. The information in parentheses at the HPLC retention time indicates the measurement conditions.

[0414] Reference Example 1: 2-Benzylhexahydrocyclopenta[c]pyrrol-4(1H)-one

[0415] 2-Cyclopentenone (CAS No.: 930-30-3, 17 g) and trifluoroacetic acid (CAS No.: 76-05-1, 240 mg) were added to a dichloromethane solution (600 mL) of N-benzyl-N-(methoxymethyl)-N-trimethylsilylmethylamine (CAS No.: 93102-05-7, 50 g), and stirred at room temperature for 16 hours. Triethylamine (430 mg) was added to the reaction solution, and it was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain the title compound (30 g).

[0416] HPLC retention time (min): 0.65 (TFA);

[0417] MS (ESI, Pos.): 226 (M+H) + .

[0418] Reference Example 2: (R)-N-((3aS,6aR,E)-2-Benzylhexahydrocyclopenta[c]pyrrole-4(1H)-ylidene)-2-methylpropane Alkane-2-sulfenamide

[0419] 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) were added to a THF (300 mL) solution of the compound (20 g) prepared in Reference Example 1, and the mixture was stirred at 60° C. for 15 hours. The reaction solution was slowly injected into a saturated aqueous sodium bicarbonate solution and dichloromethane and filtered. The filtrate 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 (12.4 g).

[0420] HPLC retention time (min): 0.80 (TFA);

[0421] MS (ESI, Pos.): 319 (M+H) + .

[0422] Reference Example 3: (3aS, 6aR)-2-Benzylhexahydrocyclopenta[c]pyrrol-4(1H)-one

[0423] 2N hydrochloric acid (60 mL) was added to a THF (60 mL) solution of the compound (20 g) prepared in Reference Example 2, and stirred at room temperature for 1 hour. The reaction solution was neutralized with 2N sodium hydroxide and extracted with dichloromethane. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained title compound was used for the next reaction without purification.

[0424] Reference Example 4: (3aS, 6aR)-4-oxohexahydrocyclopenta[c]pyrrole-2(1H)-carboxylic acid 2-methyl-2-propyl ester

[0425] Di-tert-butyl dicarbonate (CAS No.: 24424-99-5, 9.4 g) and 20% palladium hydroxide (CAS No.: 12135-22-7, 700 mg) were added to a THF (60 mL) solution of the compound prepared in Reference Example 3, and stirred at room temperature for 15 hours under a hydrogen atmosphere. 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).

[0426] 1 H-NMR (CD3OD): δ3.66-3.53, 3.14, 3.06-2.98, 2.76-2.71, 2.39-2.35, 2.21-2.12, 1.871.45.

[0427] Reference Example 5: (3aS, 4S, 6aR)-4-Hydroxyhexahydrocyclopenta[c]pyrrole-2(1H)-carboxylic acid 2-methyl-2-propyl ester

[0428] To a solution of the compound (7.3 g) prepared in Reference Example 4 in THF (200 mL), 1 M lithium tri-sec-butylborohydride THF solution (CAS No.: 38721-52-7, 49 mL) was added 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 no bubbling occurred, and 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 (6.5 g).

[0429] 1 H-NMR (CDCl3): δ4.30-4.25, 3.63-3.50, 3.38-3.30, 3.17-3.15, 2.67, 1.90-1.73, 1.73-1.54, 1.47.

[0430] Reference Example 6: (3aS, 4R, 6aR)-4-(Formyloxy)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylic acid 2-methyl- 2-Propyl Ester

[0431] Triphenylphosphine (4.50 g) and formic acid (1.29 mL) were added to a solution of the compound (2.6 g) prepared in Reference Example 5 in THF (26 mL). The reaction solution was cooled to 0°C, and diethyl azodicarboxylate (2.2 M toluene solution, 7.8 mL) was added dropwise, and stirred at room temperature for 5 hours. After the reaction solution was concentrated, the precipitate was filtered out, and the filtrate was concentrated. The residue was purified by silica gel column chromatography to obtain the title compound (2.69 g).

[0432] TLC: Rf = 0.59 (hexane: ethyl acetate = 1:1);

[0433] 1 H-NMR (CDCl3): δ8.03-8.00,5.07,3.65-3.46,3.29-3.13,2.82,2.72-2.63,2.14-2.00,1.84-1.73,1.61,1.45.

[0434] Reference Example 7: (3aS, 4R, 6aR)-4-Hydroxyhexahydrocyclopenta[c]pyrrole-2(1H)-carboxylic acid 2-methyl-2-propyl ester

[0435] Potassium carbonate (4.30 g) was added to a methanol (27 mL) solution of the compound (2650 mg) prepared in Reference Example 6 and stirred at room temperature for 3 hours. After the reaction solution was concentrated, water was added and extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained title compound was used for the next reaction without purification.

[0436] Reference Example 8: (3aS, 4R, 6aR)-4-[(6-bromo-3-pyridazinyl)oxy]hexahydrocyclopenta[c]pyrrole-2(1H)- 2-Methyl-2-propyl carboxylate

[0437] To a solution of N,N-dimethylacetamide (hereinafter, DMA) (25 mL) of the compound prepared in Reference Example 7 was added sodium hydride (60% by weight, 955 mg) at 0°C and stirred for 30 minutes. 3,6-dibromopyridazine (CAS No.: 17973-86-3, 4.94 g) was added to the reaction solution and stirred at room temperature for 2 hours. Water 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. The obtained residue was purified by silica gel column chromatography to obtain the title compound (2.8 g).

[0438] HPLC retention time (min): 1.186 (TFA);

[0439] MS (ESI, Pos.): 384 (M+H) + .

[0440] Reference Example 9: (3aS, 4R, 6aR)-4-[(6-bromo-3-pyridazinyl)oxy]octahydrocyclopenta[c]pyrrole

[0441] Trifluoroacetic acid (4.1 mL) was added to a solution of the compound (2.56 g) prepared in Reference Example 8 in dichloromethane (10 mL), and the mixture was stirred at room temperature for 18 hours. After the reaction solution was concentrated, methanol (30 mL) and AMBERLYST A26HYDROXIDE FORM (trade name, CAS number: 39339-85-0, 23 g) were added, and the mixture was stirred at room temperature for 15 minutes. After the reaction solution was filtered, the filtrate was concentrated to obtain the title compound (1.83 g).

[0442] HPLC retention time (min): 0.718 (TFA);

[0443] MS (ESI, Pos.): 284 (M+H) + ;

[0444] 1 H-NMR (CDCl3): δ7.46, 6.81, 5.32-5.28, 3.21, 3.08, 2.79-2.65, 2.56, 2.09-1.98, 1.97-1.84, 1.55-1.43.

[0445] Reference Example 10: 2-Methyl-2H-thieno[3,2-c]pyrazole-5-carboxylic acid methyl ester

[0446] Cesium carbonate (7.2 g) and iodomethane (1.6 g) were added to a THF (40 mL) solution of 1H-thieno[3,2-c]pyrazole-5-carboxylic acid methyl ester (CAS No.: 1246552-43-1, 2.0 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).

[0447] 1 H-NMR (CDCl3): δ7.70, 7.66, 4.06, 3.93.

[0448] Reference Example 11: 2-Methyl-2H-thieno[3,2-c]pyrazole-5-carboxylic acid

[0449] A 2N aqueous sodium hydroxide solution (0.5 mL) was added to a methanol (1 mL) solution of the compound (20 mg) prepared in Reference Example 10, and the mixture was stirred at 60°C for 1 hour. 1N hydrochloric acid was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was used in the next reaction without purification.

[0450] Reference Example 12: 2-Cyclopropyl-2H-thieno[3,2-c]pyrazole-5-carboxylic acid methyl ester

[0451] 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 obtained residue was purified by silica gel column chromatography to obtain the title compound (200 mg).

[0452] HPLC retention time (min): 1.00 (formic acid);

[0453] MS (ESI, Pos.): 223 (M+H) + .

[0454] Reference Example 13: 2-Cyclopropyl-2H-thieno[3,2-c]pyrazole-5-carboxylic acid

[0455] A 2N aqueous sodium hydroxide solution (0.5 mL) was added to a methanol (1 mL) solution of the compound (20 mg) prepared in Reference Example 12, and the mixture was stirred at 60 ° C for 1 hour. 1N hydrochloric acid 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 used for the next reaction without purification.

[0456] Reference Example 14: 2-(Difluoromethyl)-2H-thieno[3,2-c]pyrazole-5-carboxylic acid methyl ester

[0457] Sodium chlorodifluoroacetate (CAS No.: 1895-39-2, 2100 mg) and potassium carbonate (1900 mg) were added to a solution of 1H-thieno[3,2-c]pyrazole-5-carboxylic acid methyl ester (500 mg) in DMF (10 mL), and the mixture was stirred at 100°C for 20 hours. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain the title compound (85 mg).

[0458] Reference Example 15: 2-(Difluoromethyl)-2H-thieno[3,2-c]pyrazole-5-carboxylic acid

[0459] A 2N aqueous sodium hydroxide solution (0.5 mL) was added to a methanol (1 mL) solution of the compound (20 mg) prepared in Reference Example 14, and the mixture was stirred at 60 ° C for 1 hour. 1N hydrochloric acid 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 used for the next reaction without purification.

[0460] Reference Example 16: 4-Cyano-5-methyl-2-thiophenecarboxylic acid methyl ester

[0461] To a DMF (1 mL) solution of methyl 4-bromo-5-methyl-2-thiophenecarboxylate (CAS No.: 237385-15-8, 160 mg) was added copper cyanide (CAS No.: 544-92-3, 304 mg), and stirred at 140°C for 6 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 (53 mg).

[0462] TLC: Rf 0.31 (ethyl acetate:n-hexane=9:1).

[0463] Reference Example 17: 4-Cyano-5-methyl-2-thiophenecarboxylic acid

[0464] A 2N aqueous sodium hydroxide solution (0.1 mL) was added to a solution of methanol (0.4 mL) and THF (0.2 mL) of the compound (20 mg) prepared in Reference Example 16, and the mixture was stirred at room temperature for 2 hours. 2N 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. The obtained title compound was used for the next reaction without purification.

[0465] HPLC retention time (min): 0.95 (TFA).

[0466] Reference Example 18: 2-phenyl-2H-thieno[3,2-c]pyrazole-5-carboxylic acid methyl ester

[0467] Phenylboronic acid (CAS No.: 98-80-6, 200 mg), copper (II) acetate (110 mg) and pyridine (0.44 mL) were added to a DMF solution (2 mL) of 1H-thieno[3,2-c]pyrazole-5-carboxylic acid methyl ester (CAS No.: 1246552-43-1), and the mixture was stirred at room temperature for 15 hours. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain the title compound (55 mg).

[0468] TLC: Rf 0.35 (ethyl acetate:n-hexane=9:1).

[0469] Reference Example 19: 2-Phenyl-2H-thieno[3,2-c]pyrazole-5-carboxylic acid

[0470] The title compound was obtained by performing the same reaction as in Reference Example 11, using the compound prepared in Reference Example 18 instead of the compound prepared in Reference Example 10.

[0471] HPLC retention time (min): 1.00 (TFA);

[0472] MS (ESI, Pos.): 245 (M+H) + .

[0473] Reference Example 20: 2-(3-pyridyl)-2H-thieno[3,2-c]pyrazole-5-carboxylic acid methyl ester

[0474] 3-iodopyridine (CAS No.: 1120-90-7, 112 mg), copper (I) iodide (CAS No.: 7681-65-4, 20 mg), N,N'-dimethylethylenediamine (CAS No.: 110-70-3, 0.02 mL) and cesium carbonate (304 mg) were added to a DMF solution (2 mL) of 1H-thieno[3,2-c]pyrazole-5-carboxylic acid methyl ester and stirred at room temperature for 15 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 (10 mg).

[0475] TLC: Rf 0.35 (ethyl acetate:n-hexane=2:3).

[0476] Reference Example 21: 2-(3-pyridyl)-2H-thieno[3,2-c]pyrazole-5-carboxylic acid

[0477] The title compound was obtained by performing the same reaction as in Reference Example 11, using the compound prepared in Reference Example 20 instead of the compound prepared in Reference Example 10.

[0478] HPLC retention time (min): 0.74 (TFA);

[0479] MS (ESI, Pos.): 246 (M+H) + .

[0480] Reference Example 22: Dimethyl 4,7-dihydrothieno[2,3-c]pyridine-2,6(5H)-dicarboxylate

[0481] Methyl chloroformate (7.0 μL), triethylamine (7.0 μL) and N,N-dimethylaminopyridine (0.60 mg) were added to a dichloromethane solution (0.50 mL) of 4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxylic acid methyl ester hydrochloride (CAS No.: 1956377-82-4, 11.5 mg) and stirred at room temperature for 16 hours. 1N hydrochloric acid 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 title compound was used in the next reaction without purification.

[0482] HPLC retention time (min): 1.00 (TFA);

[0483] MS (ESI, Pos.): 256 (M+H) + .

[0484] Reference Example 23: 6-(Methoxycarbonyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxylic acid

[0485] 2N sodium hydroxide aqueous solution (0.2mL) was added to a mixed solution of THF (0.6mL) and methanol (0.2mL) of the compound manufactured in Reference Example 22, and stirred at 60°C for 1 hour. 1N hydrochloric acid 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 title compound was used for the next reaction without purification.

[0486] Reference Example 24: 5-(2-Fluoroethoxy)-2-thiophenecarboxylic acid

[0487] To a solution of 2-fluoroethanol (CAS No.: 371-62-0, 1.58 g) in DMA (15 mL) was added sodium hydride (60% by weight, 1.30 g) and 5-fluoro-2-thiophenecarboxylic acid (600 mg) at room temperature. The reaction solution was stirred at 100 ° C for 18 hours. Hydrochloric acid was added to the reaction solution and extracted with ethyl acetate / hexane solution. The organic phase was washed with water, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained title compound was used for the next reaction without purification.

[0488] Example 1: [(3aS, 4R, 6aR)-4-[(6-bromo-3-pyridazinyl)oxy]hexahydrocyclopenta[c]pyrrole-2(1H)- [6,7-dihydro-4H-thieno[3,2-c]pyran-2-yl]methanone

[0489] [Chemical formula 21]

[0490]

[0491] N,N-diisopropylethylamine (hereinafter, DIPEA) (2.0 mL) and HATU (1500 mg) were added to a solution of the compound prepared in Reference Example 9 (1100 mg) and 6,7-dihydro-4H-thieno[3,2-c]pyran-2-carboxylic acid (CAS: 933747-41-2, 820 mg) in DMA (17 mL), and stirred at room temperature for 3 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. The obtained residue was purified by silica gel column chromatography to obtain the title compound (1350 mg).

[0492] HPLC retention time (min): 1.06 (TFA);

[0493] MS (ESI, Pos.): 450 (M+H) + ;

[0494] 1H-NMR (CDCl3): δ7.49,7.15,6.83,5.39,4.71,4.08,3.88-4.04,3.80,3.64,2.87-2.97,2.11-2.33,1.93-2.04,1.59-1.69,1.19-1.32.

[0495] Examples 1-1 to 1-20

[0496] The title compound was obtained by carrying out the same operation as in Example 1 using the corresponding carboxylic acid compound instead of 6,7-dihydro-4H-thieno[3,2-c]pyran-2-carboxylic acid.

[0497] Example 1-1: [(3aS, 4R, 6aR)-4-[(6-bromo-3-pyridazinyl)oxy]hexahydrocyclopenta[c]pyrrole-2-yl] (1H)-methyl](5-methyl-2-thienyl)methanone

[0498] [Chemical formula 22]

[0499]

[0500] HPLC retention time (min): 1.10 (TFA);

[0501] MS (ESI, Pos.): 408 (M+H) + ;

[0502] 1 H-NMR(DMSO-d6): δ7.88,7.41,7.23,7.86,5.32,4.12-3.47,2.94-2.80,2.47,2.17,2.04,1.86,1.55.

[0503] Example 1-2: [(3aS, 4R, 6aR)-4-[(6-bromo-3-pyridazinyl)oxy]hexahydrocyclopenta[c]pyrrole-2-yl] (1H)-[2-methyl-2H-thieno[3,2-c]pyrazol-5-yl]methanone

[0504] [Chemical formula 23]

[0505]

[0506] HPLC retention time (min): 1.00 (TFA);

[0507] MS (ESI, Pos.): 448 (M+H) + ;

[0508] 1 H-NMR(CDCl3): δ7.57,7.52-7.42,6.83,5.41,4.12,3.95,3.83,3.68,3.49,2.95,2.36-2.27,2.22-2.12,2.01-1.93,1.69-1.59,1.52-1.38.

[0509] Example 1-3: [(3aS, 4R, 6aR)-4-[(6-bromo-3-pyridazinyl)oxy]hexahydrocyclopenta[c]pyrrole-2-yl] (1H)-[(6-methylpyrazolo[5,1-b][1,3]thiazol-2-yl)methanone

[0510] [Chemical formula 24]

[0511]

[0512] HPLC retention time (min): 1.04 (TFA);

[0513] MS (ESI, Pos.): 448 (M+H) + ;

[0514] 1 H-NMR(DMSO-d6): δ8.07,7.52-7.47,6.87-6.81,6.15,5.40,4.10,3.92,3.83,3.65,2.97,2.43-2.29,2.27-2.11,2.08-1.92,1.64,1.44.

[0515] Example 1-4: [(3aS, 4R, 6aR)-4-[(6-bromo-3-pyridazinyl)oxy]hexahydrocyclopenta[c]pyrrole-2-yl] (1H)-[2-cyclopropyl-2H-thieno[3,2-c]pyrazol-5-yl]methanone

[0516] [Chemical formula 25]

[0517]

[0518] HPLC retention time (min): 1.07 (TFA);

[0519] MS (ESI, Pos.): 474 (M+H) + ;

[0520] 1 H-NMR(CDCl3): δ7.67,7.49-7.47,7.40,6.84-6.81,5.39,4.17-4.03,4.01-3.90,3.87-3.77, 3.71-3.64,3.02-2.89,2.37-2.24,2.23-2.11,2.02-1.93,1.70-1.58,1.34-1.22,1.17-1.08.

[0521] Example 1-5: [(3aS, 4R, 6aR)-4-[(6-bromo-3-pyridazinyl)oxy]hexahydrocyclopenta[c]pyrrole-2-yl] (1H)-thieno[3,2-c]pyrazol-5-yl]methanone

[0522] [Chemical formula 26]

[0523]

[0524] HPLC retention time (min): 1.08 (TFA);

[0525] MS (ESI, Pos.): 483 (M+H) + ;

[0526] 1 H-NMR(CDCl3): δ8.01,7.49,7.42,7.34,6.83,4.12,3.68,2.95,2.30,2.1 7,2.05,2.04-1.90,1.79-1.60,1.61-1.56,1.50,1.37-1.28,1.34-1.19.

[0527] Example 1-6: [(3aS, 4R, 6aR)-4-[(6-bromo-3-pyridazinyl)oxy]hexahydrocyclopenta[c]pyrrole-2-yl] (1H)-[6-fluoro-1,3-benzothiazol-2-yl]methanone

[0528] [Chemical formula 27]

[0529]

[0530] HPLC retention time (min): 1.25 (TFA);

[0531] MS (ESI, Pos.): 463 (M+H) + ;

[0532] 1 H-NMR(DMSO-d6): δ8.25-8.18,8.12,7.89,7.52-7.48,7.24,5.37,4.54-4.30,4.22 -4.10,4.00-3.82,3.76-3.49,3.08-2.80,2.32-2.25,2.12-2.04,1.88,1.67-1.58.

[0533] Example 1-7: [(3aS, 4R, 6aR)-4-[(6-bromo-3-pyridazinyl)oxy]hexahydrocyclopenta[c]pyrrole-2-yl] (1H)-[5-(difluoromethyl)-2-thienyl]methanone

[0534] [Chemical formula 28]

[0535]

[0536] HPLC retention time (min): 1.12 (TFA);

[0537] MS (ESI, Pos.): 444 (M+H) + ;

[0538] 1 H-NMR(DMSO-d6): δ7.88,7.61,7.50,7.34,7.23,5.33,4.22-3.42,3.06-2.75,2.27,2.05,1.86,1.58.

[0539] Example 1-8: [(3aS, 4R, 6aR)-4-[(6-bromo-3-pyridazinyl)oxy]hexahydrocyclopenta[c]pyrrole-2-yl] (1H)-[(1H)-thieno[3,2-c]pyridin-2-yl)methanone

[0540] [Chemical formula 29]

[0541]

[0542] HPLC retention time (min): 0.82 (TFA);

[0543] MS (ESI, Pos.): 445 (M+H) + ;

[0544] 1 H-NMR (DMSO-d6): δ9.34-9.27,8.56,8.25,8.17,7.89,7.23,5.37,4.27-3.66,3.00,2.55,2.30,2.16-2.03,1.94-1.82,1.62.

[0545] Example 1-9: [(3aS, 4R, 6aR)-4-[(6-bromo-3-pyridazinyl)oxy]hexahydrocyclopenta[c]pyrrole-2-yl] (1H)-[(1H)-thieno[3,2-b]furan-5-yl)methanone

[0546] [Chemical formula 30]

[0547]

[0548] HPLC retention time (min): 1.12 (TFA);

[0549] MS (ESI, Pos.): 434 (M+H) + ;

[0550] 1 H-NMR(DMSO-d6): δ8.03,7.88,7.82,7.23,7.05,5.35,4.11-3.57,3.37-3.34,2.99-2.79,2.55-2.52,2.28,2.06,1.90-1.84,1.59.

[0551] Example 1-10: [(3aS, 4R, 6aR)-4-[(6-bromo-3-pyridazinyl)oxy]hexahydrocyclopenta[c]pyrrole-2-yl] (1H)-thieno[2,3-c]pyrazol-5-yl)methanone

[0552] [Chemical formula 31]

[0553]

[0554] HPLC retention time (min): 1.02 (TFA);

[0555] MS (ESI, Pos.): 448 (M+H) + ;

[0556] 1 H-NMR (DMSO-d6): δ7.90-7.85,7.62,7.23,5.3,3.95,3.69-3.47,3.31-3.28,2.95,2.34-2.23,2.05,1.91-1.82,1.63-1.55.

[0557] Example 1-11: 5-{[(3aS,4R,6aR)-4-[(6-bromo-3-pyridazinyl)oxy]hexahydrocyclopenta[c]pyrrole- 2(1H)-methyl]carbonyl}-2-methyl-3-thiophenecarbonitrile

[0558] [Chemical formula 32]

[0559]

[0560] HPLC retention time (min): 1.10 (TFA);

[0561] MS (ESI, Pos.): 433 (M+H) + ;

[0562] 1 H-NMR(DMSO-d6): δ7.90-7.82,7.22,5.41-5.28,4.12-3.50,3.01-2.73,2.64,2.26,2.05,1.85,1.58.

[0563] Example 1-12: 2-[(3aS,4R,6aR)-4-[(6-bromo-3-pyridazinyl)oxy]hexahydrocyclopenta[c]pyrrole-2-yl]- 2-Methyl-2-propyl (1H)-thiazolo[4,5-c]pyridine-5(4H)-carboxylate

[0564] [Chemical formula 33]

[0565]

[0566] HPLC retention time (min): 1.26 (TFA);

[0567] MS (ESI, Pos.): 550 (M+H) + ;

[0568] 1 H-NMR(DMSO-d6): δ7.88,7.23,5.33,4.57,4.36,4.21-4.15,4.41-4.14,4.00,4.10-3.97,3.88,3.79,3. 93-3.75,3.70-3.66,3.65-3.43,3.00,2.94-2.89,2.89-2.74,2.55,2.24,2.09-2.01,1.86,1.57,1.44.

[0569] Example 1-13: 2-[(3aS,4R,6aR)-4-[(6-bromo-3-pyridazinyl)oxy]hexahydrocyclopenta[c]pyrrole-2-yl]- (1H)-yl]carbonyl}-6,7-dihydrothieno[3,2-c]pyridine-5(4H)-carboxylic acid methyl ester

[0570] [Chemical formula 34]

[0571]

[0572] HPLC retention time (min): 1.079 (TFA);

[0573] MS (ESI, Pos.): 507 (M+H) + ;

[0574] 1 H-NMR (CDCl3): δ7.49,7.19,6.84,5.39,4.55,4.07,3.99-3.84,3.81-3.73,3.64,2.98-2.83,2.34-2.22,2.21-2.10,1.97,1.70-1.62.

[0575] Example 1-14: [(3aS, 4R, 6aR)-4-[(6-bromo-3-pyridazinyl)oxy]hexahydrocyclopenta[c]pyrrole-2-yl] (1H)-[2-phenyl-2H-thieno[3,2-c]pyrazol-5-yl]methanone

[0576] [Chemical formula 35]

[0577]

[0578] HPLC retention time (min): 1.21 (TFA);

[0579] MS (ESI, Pos.): 510 (M+H) + ;

[0580] 1 H-NMR(CDCl3): δ8.11,7.80-7.78,7.54-7.47,7.40-7.35,6.85-6.83,5.41,4.2 5-3.80,3.77-3.65,3.03-2.92,2.40-2.27,2.23-2.14,2.05-1.95,1.73-1.59.

[0581] Example 1-15: [(3aS, 4R, 6aR)-4-[(6-bromo-3-pyridazinyl)oxy]hexahydrocyclopenta[c]pyrrole-2-yl] (1H)-[2-(3-pyridyl)-2H-thieno[3,2-c]pyrazol-5-yl]methanone

[0582] [Chemical formula 36]

[0583]

[0584] HPLC retention time (min): 0.98 (TFA);

[0585] MS (ESI, Pos.): 511 (M+H) + ;

[0586] 1 H-NMR(CDCl3): δ9.10-9.09,8.63-8.62,8.17-8.13,7.53-7.46,6.85-6.83,5.41, 4.26-3.79,3.74-3.64,3.07-2.91,2.38-2.27,2.24-2.13,2.04-1.97,1.74-1.62.

[0587] Example 1-16: [(3aS, 4R, 6aR)-4-[(6-bromo-3-pyridazinyl)oxy]hexahydrocyclopenta[c]pyrrole-2-yl] (1H)-methyl](4,5-dimethyl-1,3-thiazol-2-yl)methanone

[0588] [Chemical formula 37]

[0589]

[0590] HPLC retention time (min): 1.16 (TFA);

[0591] MS (ESI, Pos.): 423 (M+H) + ;

[0592] 1 H-NMR(DMSO-d6): δ7.88,7.23,5.32,4.40-4.14,4.10-3.98,3.91-3.74,3.67 -3.42,3.02-2.89,2.89-2.72,2.39,2.34,2.24,2.09-2.00,1.86,1.63-1.51.

[0593] Example 1-17: 2-[(3aS,4R,6aR)-4-[(6-bromo-3-pyridazinyl)oxy]hexahydrocyclopenta[c]pyrrole-2-yl] (1H)-yl]carbonyl}-4,7-dihydrothieno[2,3-c]pyridine-6(5H)-carboxylic acid methyl ester

[0594] [Chemical formula 38]

[0595]

[0596] HPLC retention time (min): 1.08 (TFA);

[0597] MS (ESI, Pos.): 507 (M+H) + ;

[0598] 1 H-NMR(DMSO-d6): δ7.88,7.64-7.33,7.22,5.33,4.63,4.12-4.06,3.79,3.69-3.61 ,3.51-3.46,3.15-3.04,3.00,2.94-2.74,2.68,2.55,2.26,2.05,1.87,1.63-1.52.

[0599] Example 1-18: [(3aS, 4R, 6aR)-4-[(6-bromo-3-pyridazinyl)oxy]hexahydrocyclopenta[c]pyrrole-2-yl] (1H)-[4,5,7,8-tetrahydrothieno[2,3-d]oxepin-2-yl]methanone

[0600] [Chemical formula 39]

[0601]

[0602] HPLC retention time (min): 1.09 (TFA);

[0603] MS (ESI, Pos.): 464 (M+H) + ;

[0604] 1 H-NMR (CDCl3): δ7.49,7.20,6.84,5.40,4.11,3.93-3.74,3.64,3.04-2.85,2.16,1.96,1.69-1.58.

[0605] Example 1-19: [(3aS, 4R, 6aR)-4-[(6-bromo-3-pyridazinyl)oxy]hexahydrocyclopenta[c]pyrrole-2-yl] (1H)-[5-(2-fluoroethoxy)-2-thienyl]methanone

[0606] [Chemical formula 40]

[0607]

[0608] HPLC retention time (min): 1.086 (TFA);

[0609] MS (ESI, Pos.): 456 (M+H) + ;

[0610] 1 H-NMR(CDCl3): δ7.49,7.21,6.84,6.26,5.42-5.37,4.82-4.79,4.71-4.67,4.37-4.34,4.30- 4.27,4.14-4.04,3.91,3.85-3.74,3.64,2.93,2.35-2.25,2.21-2.11,2.01-1.93,1.68-1.57.

[0611] Example 1-20: [(3aS, 4R, 6aR)-4-[(6-bromo-3-pyridazinyl)oxy]hexahydrocyclopenta[c]pyrrole-2-yl] (1H)-methyl](4-fluoro-5-methyl-2-thienyl)methanone

[0612] [Chemical formula 41]

[0613]

[0614] HPLC retention time (min): 1.168 (TFA);

[0615] MS (ESI, Pos.): 426 (M+H) + ;

[0616] 1 H-NMR(CD3OD): δ7.49,7.15,6.84,5.39,4.08,3.91,3.84-3.72,3.63,2.94,2.37-2.27,2.22-2.11,2.07-1.90,1.72-1.63,1.61-1.51.

[0617] Example 2: [(3aS, 4R, 6aR)-4-[(6-chloro-3-pyridazinyl)oxy]hexahydrocyclopenta[c]pyrrole-2(1H)- [6,7-dihydro-4H-thieno[3,2-c]pyran-2-yl]methanone

[0618] [Chemical formula 42]

[0619]

[0620] The title compound was obtained by carrying out the same procedures as in Reference Example 8 → Reference Example 9 → Example 1 except that 3,6-dichloropyridazine (CAS No.: 141-30-0) was used instead of 3,6-dibromopyridazine.

[0621] HPLC retention time (min): 1.04 (TFA);

[0622] MS (ESI, Pos.): 406 (M+H) + ;

[0623] 1 H-NMR (CDCl3): δ7.37,7.15,6.93,5.41,4.71,4.08,4.04-3.88,3.80,3.64,2.97-2.86,2.34-2.24,2.23-2.11,2.01-1.93,1.68-1.57.

[0624] Examples 2-1 to 2-5

[0625] The title compound was obtained by using the corresponding halogen compound instead of 3,6-dibromopyridazine and carrying out the same procedures as Reference Example 8 → Reference Example 9 → Example 1.

[0626] Example 2-1: [(3aS, 4R, 6aR)-4-{[6-chloro-4-(trifluoromethyl)-3-pyridazinyl]oxy}hexahydrocyclopentane [c]pyrrol-2(1H)-yl](6,7-dihydro-4H-thieno[3,2-c]pyran-2-yl)methanone

[0627] [Chemical formula 43]

[0628]

[0629] HPLC retention time (min): 1.15 (TFA);

[0630] MS (ESI, Pos.): 496 (M+H) + ;

[0631] 1 H-NMR(CDCl3): δ7.63,7.18,5.57,4.71,4.08,4.04-3.91,3.85-3.75,3.69,3.50,3.04-2.79,2.35-2.14,2.10-1.97,1.64.

[0632] Example 2-2: {4-[(5-chloropyrido[2,3-d]pyridazin-8-yl)oxy]hexahydrocyclopenta[c]pyrrole-2 (1H)-methyl}(6,7-dihydro-4H-thieno[3,2-c]pyran-2-yl)methanone

[0633] [Chemical formula 44]

[0634]

[0635] HPLC retention time (min): 0.99 (TFA);

[0636] MS (ESI, Pos.): 457 (M+H) + ;

[0637] 1 H-NMR(DMSO-d6): δ9.34,8.61,8.13,7.35,5.55,4.62,3.89,3.07-2.91,2.86-2.80,2.57-2.52,2.36,2.18-1.98,1.66-1.58.

[0638] Example 2-3: {4-[(4-chlorothieno[2,3-d]pyridazin-7-yl)oxy]hexahydrocyclopenta[c]pyrrole-2 (1H)-methyl}(6,7-dihydro-4H-thieno[3,2-c]pyran-2-yl)methanone

[0639] [Chemical formula 45]

[0640]

[0641] HPLC retention time (min): 1.16 (TFA);

[0642] MS (ESI, Pos.): 462 (M+H) + ;

[0643] 1 H-NMR(DMSO-d6): δ8.35,7.69,7.35,5.52,4.62,3.89,2.96,2.83,2.31,2.12,1.97,1.60.

[0644] Example 2-4: [(3aS,4R,6aR)-4-[(6-chloro-5-methoxy-3-pyridazinyl)oxy]hexahydrocyclopenta[c] [2(1H)-pyrrolyl](6,7-dihydro-4H-thieno[3,2-c]pyran-2-yl)methanone

[0645] [Chemical formula 46]

[0646]

[0647] HPLC retention time (min): 1.05 (TFA);

[0648] MS (ESI, Pos.): 436 (M+H) + ;

[0649] 1 H-NMR(CDCl3): δ7.21,6.35,5.38,4.72,4.17-4.03,4.01-3.91,3.84-3.71,3.66,3.01-2.84,2.28,1.97,1.64.

[0650] Example 2-5: [(3aS,4R,6aR)-4-[(6-chloro-4-methoxy-3-pyridazinyl)oxy]hexahydrocyclopenta[c] [2(1H)-pyrrolyl](6,7-dihydro-4H-thieno[3,2-c]pyran-2-yl)methanone

[0651] [Chemical formula 47]

[0652]

[0653] HPLC retention time (min): 1.00 (TFA);

[0654] MS (ESI, Pos.): 436 (M+H) + ;

[0655] 1 H-NMR (CDCl3): δ7.25-7.18,6.79,5.39,4.72,4.21-4.06,4.01-3.87,3.76-3.62,3.02-2.87,2.28,2.01,1.64.

[0656] Example 3: [(3aS, 4R, 6aR)-4-[(6-chloro-3-pyridazinyl)oxy]hexahydrocyclopenta[c]pyrrole-2(1H)- [2-methyl-2H-thieno[3,2-c]pyrazol-5-yl]methanone

[0657] [Chemical formula 48]

[0658]

[0659] The title compound was obtained by the same procedures as in Reference Example 8 → Reference Example 9 → Example 1, except that 3,6-dichloropyridazine (CAS No.: 141-30-0) was used instead of 3,6-dibromopyridazine and the compound prepared in Reference Example 11 was used instead of 6,7-dihydro-4H-thieno[3,2-c]pyran-2-carboxylic acid.

[0660] HPLC retention time (min): 0.992 (TFA);

[0661] MS (ESI, Pos.): 404 (M+H) + ;

[0662] 1 H-NMR (CDCl3): δ7.57,7.43,7.37,6.92,5.42,4.12,3.95,3.84,3.68,3.49,2.95,2.37-2.26,2.22-2.10,2.02-1.93,1.71-1.59.

[0663] Reference Example 25: (3aS, 6aR)-Hexahydrocyclopenta[c]pyrrole-4(1H)-one hydrochloride

[0664] 4N hydrochloric acid (1,4-dioxane solution, 26 mL) was added to a methanol (26 mL) solution of the compound prepared in Reference Example 4 (5.1 g), and the mixture was stirred at room temperature for 3 hours and then concentrated under reduced pressure. The obtained residue was azeotroped with toluene to obtain the title compound (2.8 g).

[0665] Reference Example 26: (3aS, 6aR)-2-(6,7-dihydro-4H-thieno[3,2-c]pyran-2-ylcarbonyl)hexahydrocyclopentane 4-(1H)-pyrrol-1-one

[0666] 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 to a DMA (230 mL) solution of the compound (2.8 g) prepared in Reference Example 25, and stirred at room temperature for 3 hours. Water 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. The obtained residue was purified by silica gel column chromatography to obtain the title compound (4.1 g).

[0667] Reference Example 27: (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

[0668] 1,8-diazabicyclo[5.4.0]undec-7-ene (CAS No.: 6674-22-2, 0.31 mL) and diphenylvinylsulfonium trifluoromethanesulfonate (CAS No.: 247129-88-0, 410 mg) were added to a solution of the compound (300 mg) prepared in Reference Example 26 and stirred at room temperature for 1 hour. Water and 1N aqueous hydrochloric acid solution were 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 (100 mg).

[0669] HPLC retention time (min): 0.90 (TFA);

[0670] MS (ESI, Pos.): 318 (M+H) + .

[0671] Reference Example 28: [(3aS,4S,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

[0672] Sodium borohydride (25 mg) was added to a methanol (2.8 mL) solution of the compound (138 mg) prepared in Reference Example 27 at 0°C, and the mixture was stirred at 0°C for 30 minutes. Water was added to the reaction solution, and the mixture was extracted with dichloromethane. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain the title compound (15 mg).

[0673] HPLC retention time (min): 0.847 (TFA);

[0674] MS (ESI, Pos.): 320 (M+H) + .

[0675] Example 4: [(3aS,4S,6aR)-4-[(6-bromo-3-pyridazinyl)oxy]tetrahydro-1H-spiro[cyclopenta[c]pyrrolidone] [5,1'-cyclopropane]-2(3H)-yl](6,7-dihydro-4H-thieno[3,2-c]pyran-2-yl)methanone

[0676] [Chemical formula 49]

[0677]

[0678] The title compound was obtained by performing the same reaction as in Reference Example 8 using the compound prepared in Reference Example 28 instead of the compound prepared in Reference Example 7.

[0679] HPLC retention time (min): 1.086 (TFA);

[0680] MS (ESI, Pos.): 497 (M+H) + ;

[0681] 1 H-NMR(CDCl3): δ7.48,7.14,6.87,6.87,5.03-4.78,4.72,4.12,4.03-3.91,3.79,3.0 0,2.90,2.50,2.05,1.53-1.46,1.39,1.33-1.24,0.91-0.84,0.81,0.66,0.63-0.54.

[0682] Reference Example 29: 6a-Methylhexahydrocyclopenta[c]pyrrole-1,6-dione

[0683] Potassium carbonate (0.9 g) and iodomethane (0.27 mL) were added to a solution of hexahydrocyclopenta[c]pyrrole-1,6-dione (CAS No.: 1792179-55-8, 300 mg) in acetonitrile (6 mL), and the mixture was stirred at room temperature 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 (240 mg).

[0684] 1 H-NMR (Acetonitrile-d3): δ 6.23, 3.66-3.47, 3.23-3.03, 2.95-2.69, 2.43-2.14, 1.94-1.68, 1.37-1.10.

[0685] Reference Example 30: 3a-Methyloctahydrocyclopenta[c]pyrrol-4-ol

[0686] Lithium aluminum hydride (131 mg) was added to a solution of the compound (213 mg) prepared in Reference Example 29 in THF (6.4 mL), and the mixture was stirred at 0°C for 20 minutes. Water, 2N sodium hydroxide, and water were added to the reaction solution in sequence, and the mixture was filtered. The filtrate was concentrated under reduced pressure to obtain the title compound (196 mg).

[0687] 1 H-NMR(DMSO-d6): δ3.68-3.48,3.47-3.37,3.01-2.77,2.74-2.52,2.46-2. 21,2.20-2.06,1.91-1.80,1.78-1.49,1.30-1.17,1.16-0.99,0.95-0.83.

[0688] Reference Example 31: 6,7-dihydro-4H-thieno[3,2-c]pyran-2-yl[(3aS,4R,6aR)-4-hydroxy-3a-methyl [c]pyrrol-2(1H)-yl]methanone

[0689] The title compound was obtained by performing the same reaction as in Reference Example 26, using the compound prepared in Reference Example 30 instead of the compound prepared in Reference Example 25.

[0690] HPLC retention time (min): 0.847 (TFA);

[0691] MS (ESI, Pos.): 308 (M+H) + .

[0692] Example 5: [(3aS, 4R, 6aR)-4-[(6-bromo-3-pyridazinyl)oxy]-3a-methylhexahydrocyclopenta[c]pyrrolidone [2-(1H)-pyran-2-yl](6,7-dihydro-4H-thieno[3,2-c]pyran-2-yl)methanone

[0693] [Chemical formula 50]

[0694]

[0695] A racemic mixture of the title compound was obtained by performing the same reaction as in Reference Example 8 using the compound prepared in Reference Example 31 instead of the compound prepared in Reference Example 7. The obtained racemic mixture was optically resolved by supercritical fluid chromatography (CHIRALPAK ID, CO2:ethanol=55:45) to obtain the title compound.

[0696] HPLC retention time (min): 1.084 (TFA);

[0697] MS (ESI, Pos.): 464 (M+H) + ;

[0698] 1 H-NMR (CDCl3): δ7.52-7.50,7.48,7.31,7.21,7.18,6.87,6.84,5.52,4.71,3.98,3.87-3.36,2.89,2.67-2.33,2.22-2.05,2.00-1.79.

[0699] Reference Example 32: (3aS, 6aR)-5,5-dimethyl-4-oxohexahydrocyclopenta[c]pyrrole-2(1H)-carboxylic acid 2-methyl 2-Propyl ester

[0700] Potassium tert-butoxide (5230 mg) and iodomethane (6615 mg) were added to a solution of the compound (5000 mg) prepared in Reference Example 4 in THF (220 mL) at 0°C and stirred at room temperature for 1 hour. A saturated aqueous sodium bicarbonate solution was added to the reaction solution and extracted with dichloromethane. The organic layer was 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 (3500 mg).

[0701] Reference Example 33: (3aS, 4S, 6aR)-4-Hydroxy-5,5-dimethylhexahydrocyclopenta[c]pyrrole-2(1H)-carboxylic acid 2- Methyl-2-propyl ester

[0702] Sodium borohydride (784 mg) was added to a methanol (70 mL) solution of the compound (3500 mg) prepared in Reference Example 32 at 0°C and stirred at room temperature for 1 hour. A saturated aqueous solution of ammonium chloride was added to the reaction solution and extracted with dichloromethane. After drying the organic layer with anhydrous sodium sulfate, it was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain the title compound (1080 mg).

[0703] Example 6: [(3aS,4S,6aR)-4-[(6-bromo-3-pyridazinyl)oxy]-5,5-dimethylhexahydrocyclopenta[c] [2(1H)-pyrrolyl](6,7-dihydro-4H-thieno[3,2-c]pyran-2-yl)methanone

[0704] [Chemical formula 51]

[0705]

[0706] The title compound was obtained by performing the same reaction as in Reference Example 8 → Reference Example 9 → Example 1, using the compound prepared in Reference Example 33 instead of the compound prepared in Reference Example 7.

[0707] HPLC retention time (min): 1.181 (TFA);

[0708] MS (ESI, Pos.): 477 (M+H) + ;

[0709] 1 H-NMR(DMSO-d6)δ7.88,7.39,7.26,5.08,4.62,3.89,3.72,3.61,3.34-3.29, 3.23,3.00,2.92-2.74,2.55,2.35-2.22,1.86,1.46-1.36,1.09-1.02,1.06.

[0710] Reference Example 34: 6,7-dihydro-4H-thieno[3,2-c]pyran-2-yl(3,3a,4,5-tetrahydrocyclopenta[c]pyran 2-(1H)-pyrrolidine-2-methanone

[0711] The title compound was obtained by conducting the same reaction as in Example 1 using 1H,2H,3H,3aH,4H,5H-cyclopenta[c]pyrrole hydrochloride (CAS No.: 2361634-32-2) instead of the compound prepared in Reference Example 9.

[0712] HPLC retention time (min): 1.036 (TFA);

[0713] MS (ESI, Pos.): 276 (M+H) + .

[0714] Reference Example 35: 6,7-dihydro-4H-thieno[3,2-c]pyran-2-yl (3a,4-dihydroxyhexahydrocyclopenta[c] Pyrrol-2(1H)-yl)methanone

[0715] To a solution of the compound (365 mg) prepared in Reference Example 34 in THF (3.7 mL) was added a 50% aqueous solution of 4-methylmorpholine N-oxide (CAS No.: 7529-22-8, 0.34 mL) and microencapsulated osmium tetroxide (CAS No.: 20816-12-0, 59 mg, containing 17%), and stirred at room temperature for 10 hours. A saturated aqueous sodium bicarbonate solution was added to the reaction solution, and extracted with dichloromethane. After drying the organic layer with anhydrous sodium sulfate, it was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain the title compound (220 mg).

[0716] HPLC retention time (min): 0.748 (TFA);

[0717] MS (ESI, Pos.): 310 (M+H) + .

[0718] Example 7: [(3aR, 4R, 6aS)-4-[(6-bromo-3-pyridazinyl)oxy]-3a-hydroxyhexahydrocyclopenta[c]pyrrolidone [2-(1H)-pyran-2-yl](6,7-dihydro-4H-thieno[3,2-c]pyran-2-yl)methanone

[0719] [Chemical formula 52]

[0720]

[0721] A racemic mixture of the title compound was obtained by performing the same reaction as in Reference Example 8 using the compound prepared in Reference Example 35 instead of the compound prepared in Reference Example 7. The obtained racemic mixture was optically resolved by supercritical fluid chromatography (CHIRALPAK IB, CO2:methanol=80:20) to obtain the title compound.

[0722] HPLC retention time (min): 0.921 (TFA);

[0723] MS (ESI, Pos.): 466 (M+H) + ;

[0724] 1 H-NMR(CDCl3): δ7.57-7.52,7.17,6.96-6.92,5.49-5.44,4.71,4.06-3.8 8,3.82,3.49,2.90,2.83,2.69,2.45-2.35,2.27-2.16,2.09-1.99,1.43.

[0725] Example 8: [(3aR, 4R, 6aS)-4-[(6-bromo-3-pyridazinyl)oxy]-3a-methoxyhexahydrocyclopenta[c] [2(1H)-pyrrolyl](6,7-dihydro-4H-thieno[3,2-c]pyran-2-yl)methanone

[0726] [Chemical formula 53]

[0727]

[0728] To a solution of the compound (20 mg) prepared in Example 7 in THF (0.3 mL) and DMF (0.03 mL) was added iodomethane (0.008 mL) and sodium hydride (60% by weight, 8.6 mg), and the mixture was stirred at room temperature for 3 hours. A saturated aqueous solution of ammonium chloride was added to the reaction solution, and the mixture was extracted with dichloromethane. The organic layer was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain the title compound (19 mg).

[0729] HPLC retention time (min): 1.00 (TFA);

[0730] MS (ESI, Pos.): 480 (M+H) + ;

[0731] 1 H-NMR (CDCl3): δ7.52,7.24-7.17,6.96,5.75,4.71,4.12,3.99,3.80,3.49,3.28,2.90,2.38-2.20,2.06-1.97,1.42,0.82.

[0732] Reference Example 36: (3aS,5S,6aR)-2-(6,7-dihydro-4H-thieno[3,2-c]pyran-2-ylcarbonyl)-5-fluoro Hexahydrocyclopenta[c]pyrrol-4(1H)-one

[0733] 2,6-lutidine (CAS No.: 108-48-5, 1.26 mL) and tert-butyldimethylsilyl trifluoromethanesulfonate (CAS No.: 69739-34-0, 2.0 mL) were added to the dichloromethane (15 mL) solution of the compound (792 mg) prepared in Reference Example 26, and stirred at room temperature for 24 hours. A saturated aqueous sodium bicarbonate solution was added to the reaction solution, and extracted with dichloromethane. After drying the organic layer with anhydrous sodium sulfate, it was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography. 1-Chloromethyl-4-fluoro-1,4-diazabicyclo[2.2.2]octane bis(tetrafluoroborate) (CAS No.: 140681-55-6, 345 mg) was added to the acetonitrile (10 mL) solution of the obtained compound, and stirred at room temperature for 2 hours. A saturated aqueous sodium bicarbonate solution was added to the reaction solution, and extracted with dichloromethane. The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound (33 mg).

[0734] HPLC retention time (min): 0.852 (TFA);

[0735] MS (ESI, Pos.): 310 (M+H) + .

[0736] Example 9: [(3aS,4S,5S,6aR)-4-[(6-bromo-3-pyridazinyl)oxy]-5-fluorohexahydrocyclopenta[c]pyrrolidone [2-(1H)-pyran-2-yl](6,7-dihydro-4H-thieno[3,2-c]pyran-2-yl)methanone

[0737] [Chemical formula 54]

[0738]

[0739] The title compound was obtained by subjecting the compound prepared in Reference Example 36 to the compound prepared in Reference Example 4 in the same manner as in Reference Example 5 → Reference Example 6 → Reference Example 7 → Reference Example 8.

[0740] HPLC retention time (min): 1.00 (TFA);

[0741] MS (ESI, Pos.): 468 (M+H) + ;

[0742] 1H-NMR (CDCl3): δ7.54,7.26,6.89,5.49,5.21,4.72,4.21,4.09,4.00-3.89,3.78,3.00-2.88,2.49-2.32,2.06-1.92,1.30-1.28.

[0743] Pharmacological Experiment Example 1: Evaluation of ABHD6 Enzyme Inhibitory Activity

[0744] In an assay buffer containing 50 mM Tris-HCl (pH 7.4), 100 mM NaCl, and 0.05% BSA, 1-Arachid onoyl Glycerol (Cayman) as a substrate was prepared to a final concentration of 10 μmol / L, and the compound was added to a final concentration of 0.0003, 0.001, 0.003, 0.01, 0.03, 0.1, 0.3, 1, 3, or 10 μmol / L (DMSO was a final concentration of 0.3%). In addition, DMSO was added to a final concentration of 0.3%, and this was used as a group without compound addition. Recombinant human ABHD6 (33-337) prepared in the assay buffer was added to a mixed solution of the substrate and the compound to a final concentration of 300 μg / mL, thereby initiating the enzyme reaction. It should be noted that the recombinant human ABHD6 (33-337) was GST-tagged and expressed in E. coli and purified using Glutathione-Sepharose 4B resin and concentrated. The enzyme reaction was carried out at room temperature using a 384-well polypropylene microplate, and the wells without enzyme addition were used as blank groups.

[0745] One hour after the start of the enzyme reaction, methanol containing arachidonic acid-d8 (Cayman Company) and 1% formic acid as an internal standard substance was added to stop the enzyme reaction. The upper part of the enzyme reaction plate was sealed with aluminum, and after centrifugation at 560g for 5 minutes at room temperature, the arachidonic acid as the enzyme reaction product and the internal standard arachidonic acid-d8 were quantified using the RapidFire (registered trademark)-Mass Spectrometry system. The ratio of each quantitative value was taken, the average value of the blank group was set to 100% inhibition, and the average value of the group without compound addition was set to 0% inhibition. The inhibition rate of arachidonic acid production at each compound concentration was calculated to obtain the IC 50 value.

[0746] The pharmacological experiments show that the compounds of the present invention have strong ABHD6 inhibitory activity. 50 The values ​​are shown in Table 1 below.

[0747] [Table 1]

[0748] Example No. <![CDATA[IC 50 (μM)]]> Example No. <![CDATA[IC 50 (μM)]]> 1 ＜0.001 1-19 ＜0.001 1-1 0.001 2-3 0.001 1-4 ＜0.001 2-5 0.002 1-7 ＜0.001 4 ＜0.001 1-10 ＜0.001 7 0.002 1-13 ＜0.001 9 ＜0.001

[0749] Pharmacological Experiment Example 2: Binding Affinity Determination for Human ABHD6

[0750] HEK293 cells that were forcibly expressed with the NanoLuc-human ABHD6 fusion protein were used to allow the fluorescent probe molecules to compete with the test compounds, thereby measuring the binding affinity of the test compounds for human ABHD6 using the bioluminescence resonance energy transfer (hereinafter abbreviated as BRET) caused by the proximity of the probe molecules and the NanoLuc-human ABHD6 fusion protein as an indicator.

[0751] <Compound Treatment>

[0752] 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. The prepared 10 mmol / L solution was thawed before use, and diluted stepwise with DMSO and used in the experiment.

[0753] <Cell Culture>

[0754] HEK293 cells expressing NanoLuc-human ABHD6 fusion protein were cultured statically in the presence of 5% CO2 at 37°C using inactivated (56°C, 30 minutes) 9.8 vol% non-dialyzed FBS (containing 0.5 vol% GENETICIN and 1% penicillin-streptomycin). Subculture was performed by the following method.

[0755] Remove the medium and replace with Ca-free 2+ and Mg 2+ Wash once with phosphate buffered saline. Add an appropriate amount of trypsin-EDTA, incubate at room temperature, and after detaching the cells, add 10 times the volume of culture medium of trypsin-EDTA (0.05%) to stop the enzyme reaction. Recover 120g of cells in a centrifuge tube, centrifuge at room temperature for 3 minutes, and remove the supernatant. Suspend the cells in an appropriate amount of culture medium and inoculate them in a culture flask.

[0756] After preparing HEK293 cells expressing NanoLuc-human ABHD6 fusion protein, 5.0×10 6 Cells frozen and stored in the form of cells / mL / vial were used for the experiment. In addition, HBSS (+) containing 20 mmol / L HEPES (pH 7.3) and 0.1% BSA was prepared and used as the experimental buffer. The cells were thawed to 2×10 5cells / mL in the test buffer. In a 384-well test plate pre-added with the test compound, the cell suspension (25 μL) was added to start the reaction, and after standing at 37°C for 30 minutes in the presence of 5% CO2, the probe molecule with a fluorescent group (10 mmol / L in DMSO) was diluted with the test buffer to a final concentration of 100 nmol / L, and 15 μL was added to the test plate each time. In addition, after standing at 37°C for 30 minutes in the presence of 5% CO2, Nano-Glo (registered trademark) Vivazine (trademark) substrate (PROMEGA) was diluted with the test buffer according to the method described in the company's manual, and 10 μL was added to the test plate each time. After standing at room temperature for 1 hour, luminescence and fluorescence intensity were measured using GloMax (registered trademark) Discover system. The ratio of the fluorescence intensity after passing through a 450 nm bandpass filter to the fluorescence intensity after passing through a 600 nm longpass filter was set as the measured value for 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 value of the test compound was calculated from the measured values ​​at each test compound concentration. 50 value.

[0757] In the cell evaluation system, it was confirmed that the compounds of the present invention have strong ABHD6 binding activity. 50 The values ​​are shown in Table 2 below.

[0758] [Table 2]

[0759] Example No. <![CDATA[IC 50 (μM)]]> Example No. <![CDATA[IC 50 (μM)]]> 1 0.003 1-19 0.010 1-1 0.011 2-3 0.009 1-4 0.004 2-5 0.009 1-7 0.020 4 0.001 1-10 0.004 7 0.003 1-13 0.005 9 0.002

[0760] Pharmacological Experiment Example 3: Evaluation of ABHD6 Selectivity

[0761] Rat brain membrane fractions were used to allow fluorescent probe molecules to act on test compounds, and after protein separation by electrophoresis, the binding affinity of the test compounds was measured using the fluorescence intensity of ABHD6, MAGL, and FAAH as an index.

[0762] <Compound Treatment>

[0763] 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 diluted stepwise with DMSO to prepare a concentration 50 times higher than the final concentration.

[0764] <Preparation of rat brain membrane fractions>

[0765] After bleeding the rat under anesthesia, the brain was removed. 1 mL of ice-cold phosphate buffer (PBS, pH 7.5) was added for every 200 mg of brain weight and homogenized with a homogenizer. The homogenate solution was centrifuged at 1000 g, 4°C, and 10 minutes, and the supernatant was recovered. The obtained supernatant was centrifuged at 100,000 g at 4°C for 45 minutes, and ice-cold PBS was added to the sediment to resuspend it as a membrane fraction. The protein concentration of the prepared membrane fraction solution was quantified and stored in a -80°C freezer until use.

[0766] <abpp>

[0767] The membrane component solution was prepared into 3 mg / mL with PBS. 1 μL of DMSO or compound solution was added to 50 μL of 3 mg / mL membrane component solution and reacted at 37°C for 30 minutes. Then, 1 μL of probe molecule with fluorescent group (ActivX (trade name) TAMRA-FP Serine Hydrolase Probe, final concentration 1 μmol / L, DMSO solution) was added and reacted at room temperature for 30 minutes. The reaction was stopped by 4× sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) loading buffer. After heating the sample at 95°C for 5 minutes, protein separation was performed by SDS-PAGE using 10% acrylamide gel. The gel after SDS-PAGE was visualized for fluorescence in a chemical imaging system.

[0768] In each band of ABHD6, MAGL, and FAAH, the fluorescence band intensity of the control group (DMSO-treated group) was regarded as 0% inhibition, and the IC value of the test compound was calculated from the fluorescence intensity at each test compound concentration. 50 The results showed that the compound of the present invention has a selective inhibitory activity against ABHD6 relative to MAGL and FAAH.

[0769] Pharmacological Experiment Example 4: Analgesic Effect on Sodium Monoiodoacetate-Induced Model Rats

[0770] The analgesic effect of the compound of the present invention was evaluated using a rat model induced by sodium monoiodoacetate (hereinafter referred to as MIA) (Sigma-Aldrich Japan).

[0771] (1) Preparation of MIA-induced rat model

[0772] The rats were anesthetized with isoflurane and the hair around the knee of the right hind limb was shaved. A syringe with a 29G injection needle (BD LO-DOSE, Becton, Dickinson, Japan) was used to inject 25 μL of 120 mg / mL MIA solution into the right hind limb joint cavity. The normal control group was injected with 25 μL of physiological saline.

[0773] (2) Group composition and grouping

[0774] The experiment was conducted with a normal control group, an onset control group, a test substance administration group, and a tramadol administration group or a morphine administration group. In addition to the normal control group, the right hind limb load weight ratio of the model rats prepared by the method of (1) 13 or 14 days after MIA induction was measured (the measurement method will be described later), and the groups were divided so that the right hind limb load weight ratio did not deviate among the groups.

[0775] (3) Administration of test substance, tramadol or morphine

[0776] 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. Alternatively, 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 evaluation, and tramadol and morphine were subcutaneously administered at 5 mL / kg 1 hour before the evaluation.

[0777] (4) Determination of the right hind limb load ratio

[0778] The load weight of the left and right hind limbs was measured using Linton Incapacitance Tester (MJS Technology INC., UK). That is, the rat was moved to a special cage on the Linton Incapacitance Tester, and the posture was corrected by mounting two pairs of weight measuring sensors on the left and right hind limbs. After confirming that the posture of the rat was not biased in the left and right and front and back, the load weight of the left and right hind limbs was measured for 3 seconds. The measurement of the load weight was repeated 3 times for each individual. In order to obtain a stable measured value, the rat was placed in a special cage for more than 5 days from the day of MIA induction to 14 days after induction, and it was tamed for more than 20 minutes. In addition, it was tamed for about 10 minutes before the load weight was measured, and the load weight was measured. The load weight of the left and right hind limbs was measured before the grouping after MIA induction for 14 days, and in the normal control group, the onset 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) after 14 days. Based on the average value of the load weights of the left and right hind limbs, the load weight ratio of the right hind limb in the load weights of the two hind limbs was calculated by the following mathematical formula 1. Based on the right hind limb load weight ratio of each group 14 days after MIA induction, the improvement rate of the right hind limb load weight ratio when the compound of the present invention as the test substance was administered was calculated by the following mathematical formula 2 to evaluate the analgesic effect of the test substance (compound of the present invention).

[0779] [Mathematical formula 1]

[0780] The right hind limb load ratio B (%) = {A R / (A R +A L )×100}

[0781] A R : Load weight of right hind limb (average value of values ​​measured 3 times for the same individual)

[0782] A L : Load weight of left hind limb (average value of values ​​measured 3 times for the same individual)

[0783] [Mathematical formula 2]

[0784] Improvement rate of the tested substance (%) = {1-(B T -B C ) / (B N -B C )}×100

[0785] B C : Average value of right hind limb load weight ratio in normal control group

[0786] B N : Average value of right hind limb weight ratio in the disease control group

[0787] B T : Average value of right hind limb load weight ratio in the test substance administration group

[0788] The results showed that the analgesic effect of the compound of the present invention is equal to or better than that of tramadol and morphine, which are commonly used analgesics.

[0789] Pharmacological Experiment Example 5: Antidepressant Effect in Rat Forced Swim Test

[0790] The antidepressant effects of the compounds of the present invention can be evaluated using the rat forced swim test.

[0791] (1) Group composition and grouping

[0792] The experiment was conducted with a vehicle-administered group, a test substance-administered group, and an imipramine-administered group, and the subjects were randomly assigned to five groups based on their body weight on the day of grouping.

[0793] (2) Administration of test substance and imipramine

[0794] 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%). In addition, the 1 mg / mL solution was diluted 10 times or 100 times with a 25% solubilizing medium to prepare a 0.1 mg / mL or 0.01 mg / mL solution. As a positive control drug, imipramine 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 evaluation, and imipramine was intraperitoneally administered at 2 mL / kg 0.5 hours before the evaluation.

[0795] (3) Determination of immobility time

[0796] The day before the measurement, the rats were placed in a water tank (water depth: 20 cm, water temperature: 24 ± 1 ° C) and forced to swim for 15 minutes (measurement of acclimatization). 24 hours later, the rats were placed in a water tank (water depth: 20 cm, water temperature: 24 ± 1 ° C) again and forced to swim for 5 minutes, and the immobility time during this period was measured as depressive-like behavior. The immobility time was measured using a stopwatch, and the measured value was recorded as an integer value obtained by rounding off to one decimal place.

[0797] Pharmacological Experiment Example 6: Anxiolytic Effect in the Social Interaction Test in Rats

[0798] The anxiolytic effects of the compounds of the invention can be evaluated using the rat social interaction assay.

[0799] (1) Group composition and grouping

[0800] The experiment was conducted with a vehicle-administered group, a test substance-administered group, and a diazepam-administered group. The subjects were randomly assigned to five groups based on their body weight on the day of grouping.

[0801] (2) Administration of test substance and diazepam

[0802] 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%). In addition, the 1 mg / mL solution was diluted 10 times or 100 times with a 25% solubilizing medium to prepare a 0.1 mg / mL or 0.01 mg / mL solution. As a positive control drug, 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 evaluation, and diazepam was orally administered at 5 mL / kg 1 hour before the evaluation.

[0803] (3) Measurement of social interaction time

[0804] Two hours after the administration of the test substance or one hour after the administration of the positive control substance, two rats (a pair) with a weight difference of less than 20 g were placed in the open field test apparatus and the behavior was video recorded for 10 minutes. Based on the 10-minute behavior, the time that met the social behavior analysis items shown in Table 3 was measured. When these action times were prolonged, it was confirmed that the test substance exhibited an anxiolytic effect.

[0805] [Table 3]

[0806]

[0807] Pharmacological Experiment Example 7: MDR1 substrate screening test

[0808] Human MDR1-expressing MDCK cells were cultured and extracellular transport assays were performed. Transwell 96-well permeable supports (96 well permeable supports) with polycarbonate membranes (pore size 0.4 μm, surface area 0.143 cm 2 ) (manufactured by Life Sciences) to proliferate the cells. The cells were pre-incubated with Hanks balanced salt solution (hereinafter, HBSS) at 37°C for 10 minutes, and then HBSS was added to the top compartment (75μL) or the side bottom compartment (250μL) containing 1 or 10μmol / L of the test substance to start extracellular transport. After 1 hour, each test plate was separated, thereby terminating the test. An aliquot (25μL) from the compartment on the opposite side was mixed with acetonitrile. After centrifugation, the compound concentration in the supernatant was determined by LC / MS / MS using a UFLC system with TripleQUAD (trade name) 5500 and a Unison UK-C18 HT column (3.0μm, 2.0×20mm). The apparent permeability (Papp) of the test compound in the receiving well was measured, and the excretion ratio (ER) relative to the membrane permeability test was calculated using the following mathematical formula 3.

[0809] [Mathematical formula 3]

[0810] ER=Papp,BtoA / Papp,AtoB

[0811] Here, Papp, AtoB and Papp, BtoA represent the apparent permeability in the direction from the apical membrane side to the basement membrane side and from the basement membrane side to the apical membrane side, respectively.

[0812] The results showed that the compound of the present invention has a relatively low excretion via P-glycoprotein and is excellent in central transferability.

[0813] [Preparation Example]

[0814] Preparation Examples

[0815] The following ingredients were mixed by a conventional method and then tableted to obtain about 10,000 tablets containing 10 mg of the active ingredient per tablet.

[0816] ·[(3aS,4R,6aR)-4-[(6-bromo-3-pyridazinyl)oxy]hexahydrocyclopenta[c]pyrrol-2(1H)-yl](6,7-dihydro-4H-thieno[3,2-c]pyran-2-yl)methanone 100g

[0817] ·Carboxymethylcellulose calcium (disintegrant) 20g

[0818] ·Magnesium stearate (lubricant) 10g

[0819] ·Microcrystalline cellulose 870g

[0820] Industrial Applicability

[0821] The compound of the present invention has ABHD6 inhibitory activity, and thus a medicament comprising the compound of the present invention as an active ingredient is useful as a preventive and / or therapeutic agent for diseases associated with ABHD6.< / abpp>

Claims

1. A compound represented by the following general formula (I) or a pharmaceutically acceptable salt thereof, General formula (I): [Chemical formula 1] In the formula, R 1 represents a halogen atom, R 2 represents (1) a halogen atom, (2) a C1-6 alkyl group, (3) a C2-6 alkenyl group, (4) a C2-6 alkynyl group, (5) a C1-6 alkoxy group, (6) a C1-6 haloalkyl group, (7) a C2-6 haloalkenyl group, (8) a C2-6 haloalkynyl group or (9) a C1-6 haloalkoxy group, 1 to 2 carbon atoms in the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxy, C1-6 haloalkyl, C2-6 haloalkenyl, C2-6 haloalkynyl or C1-6 haloalkoxy are optionally substituted by nitrogen atoms or optionally oxidized sulfur atoms, When m is 2, multiple R 2 Can be the same or different. Two R's 2 When it represents a C1-6 alkyl group, a C2-6 alkenyl group, a C2-6 alkynyl group, a C1-6 alkoxy group, a C1-6 haloalkyl group, a C2-6 haloalkenyl group, a C2-6 haloalkynyl group or a C1-6 haloalkoxy group, it may optionally form a 5-6 membered cyclic group together with the carbon atom to which it is bonded, R 3 represents (1) a halogen atom, (2) a C1-6 alkyl group, (3) a C2-6 alkenyl group, (4) a C2-6 alkynyl group, (5) a C1-6 alkoxy group, (6) a C1-6 haloalkyl group, (7) a C2-6 haloalkenyl group, (8) a C2-6 haloalkynyl group, (9) a C1-6 haloalkoxy group or (10) a hydroxyl group, When n is 2 or more, multiple R 3 Can be the same or different. Two R on the same carbon atom 3 When it represents a C1-6 alkyl group, it may optionally form a C3-6 cycloalkyl group together with the carbon atom to which it is bonded, Ring1 represents a 3-15 membered cyclic group, 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 haloalkyl group, (7) a C2-6 haloalkenyl group, (8) a C2-6 haloalkynyl group, (9) a C1-6 haloalkoxy group, (10) a C1-6 alkylthio group, (11) a C1-6 alkylsulfinyl group, (12) a C1-6 alkylsulfonyl group, (13) a C2-6 acyl group, (14) a 3- to 6-membered cyclic group, (15) -L R4 -(3-6 membered cyclic group), (16) hydroxyl, (17) nitro, (18) cyano, (19) oxo, (20) -NR 401 R 402 、(21)-COOR 403 、(22)-CONR 404 R 405 or (23)-SO2NR 406 R 407 , 1 to 2 carbon atoms in the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxy, C1-6 haloalkyl, C2-6 haloalkenyl, C2-6 haloalkynyl, C1-6 haloalkoxy, C1-6 alkylthio, C1-6 alkylsulfinyl, C1-6 alkylsulfonyl or C2-6 acyl are optionally substituted by oxygen atoms or optionally oxidized sulfur atoms, When p is 2 or more, multiple R 4 Can be the same or different. R 4 The groups in (2) to (15) are optionally substituted with 1 to 9 R 408 , R 408 represents (1) a halogen atom, (2) a C1-4 alkyl group, (3) a C1-4 alkoxy group, (4) a C2-6 acyl group, (5) a C3-6 cycloalkyl group, (6) a hydroxyl group, or (7) -NR 409 R 410 , R 408 When replacing two or more, multiple R 408 Can be the same or different. L R4 represents (1) -O-, (2) -(C1-4 alkylene)-, (3) -O-(C1-4 alkylene)-, (4) -(C1-4 alkylene)-O-, (5) -NR 411 -, (6)-S-, (7)-SO- or (8)-SO2-, R 401 , R 402 , R 403 , R 404 , R 405 , R 406 , R 407 , R 409 , R 410 or R 411 are each independently 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, p represents an integer of 0-5.

2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein ring1 is a ring structure selected from the following ring structures, [Chemical formula 2] In the formula, the * mark indicates the bonding position to the carbonyl group, and the hydrogen atom represented by NH is optionally replaced by R 4 replace.

3. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R 4 is (1) a halogen atom, (2) a C1-6 alkyl group, (3) a C1-6 alkoxy group, (4) a C1-6 haloalkyl group, (5) a C1-6 haloalkoxy group, (6) a cyclopropyl group, (7) a benzene ring, (8) a pyridine ring, (9) -COOCH3, (10) -COOtBu or (11) a cyano group.

4. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R 2 is (1) C1-6 alkyl, (2) C1-6 alkoxy, (3) C1-6 haloalkyl or (4) C1-6 haloalkoxy.

5. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein The compound represented by the general formula (I) is represented by the general formula (I-1), [Chemical formula 3] In the formula, R 2-1 represents (1) C1-6 alkyl, (2) C1-6 alkoxy, (3) C1-6 haloalkyl or (4) C1-6 haloalkoxy, R 4-1 represents (1) a halogen atom, (2) a C1-6 alkyl group, (3) a C1-6 alkoxy group, (4) a C1-6 haloalkyl group, (5) a C1-6 haloalkoxy group, (6) a cyclopropyl group, (7) a benzene ring, (8) a pyridine ring, (9) -COOCH3, (10) -COOtBu or (11) a cyano group, ring1-1 represents a ring structure selected from the following ring structures, [Chemical formula 4] In the formula, the * mark indicates the bonding position to the carbonyl group, and the hydrogen atom represented by NH is optionally replaced by R 4-1 replace, Other symbols have the same meanings as those in claim 1.

6. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein The compound represented by general formula (I) is selected from the following compounds: (1) [(3aS,4R,6aR)-4-[(6-bromo-3-pyridazinyl)oxy]hexahydrocyclopenta[c]pyrrol-2(1H)-yl](6,7-dihydro-4H-thieno[3,2-c]pyran-2-yl)methanone, (2) [(3aS,4R,6aR)-4-[(6-bromo-3-pyridazinyl)oxy]hexahydrocyclopenta[c]pyrrol-2(1H)-yl](5-methyl-2-thienyl)methanone, (3) [(3aS,4R,6aR)-4-[(6-bromo-3-pyridazinyl)oxy]hexahydrocyclopenta[c]pyrrol-2(1H)-yl](2-methyl-2H-thieno[3,2-c]pyrazol-5-yl)methanone, (4) [(3aS,4R,6aR)-4-[(6-bromo-3-pyridazinyl)oxy]hexahydrocyclopenta[c]pyrrol-2(1H)-yl](6-methylpyrazolo[5,1-b][1,3]thiazol-2-yl)methanone, (5) [(3aS,4R,6aR)-4-[(6-bromo-3-pyridazinyl)oxy]hexahydrocyclopenta[c]pyrrol-2(1H)-yl](2-cyclopropyl-2H-thieno[3,2-c]pyrazol-5-yl)methanone, (6) [(3aS,4R,6aR)-4-[(6-bromo-3-pyridazinyl)oxy]hexahydrocyclopenta[c]pyrrol-2(1H)-yl][2-(difluoromethyl)-2H-thieno[3,2-c]pyrazol-5-yl]methanone, (7) [(3aS,4R,6aR)-4-[(6-bromo-3-pyridazinyl)oxy]hexahydrocyclopenta[c]pyrrol-2(1H)-yl](6-fluoro-1,3-benzothiazol-2-yl)methanone, (8) [(3aS, 4R, 6aR)-4-[(6-bromo-3-pyridazinyl)oxy]hexahydrocyclopenta[c]pyrrol-2(1H)-yl][5-(difluoromethyl)-2-thienyl]methanone, (9) [(3aS,4R,6aR)-4-[(6-bromo-3-pyridazinyl)oxy]hexahydrocyclopenta[c]pyrrol-2(1H)-yl](thieno[3,2-c]pyridin-2-yl)methanone, (10) [(3aS,4R,6aR)-4-[(6-bromo-3-pyridazinyl)oxy]hexahydrocyclopenta[c]pyrrol-2(1H)-yl](thieno[3,2-b]furan-5-yl)methanone, (11) [(3aS,4R,6aR)-4-[(6-bromo-3-pyridazinyl)oxy]hexahydrocyclopenta[c]pyrrol-2(1H)-yl](1-methyl-1H-thieno[2,3-c]pyrazol-5-yl)methanone, (12) 5-{[(3aS,4R,6aR)-4-[(6-bromo-3-pyridazinyl)oxy]hexahydrocyclopenta[c]pyrrol-2(1H)-yl]carbonyl}-2-methyl-3-thiophenecarbonitrile, (13) 2-[(3aS,4R,6aR)-4-[(6-bromo-3-pyridazinyl)oxy]hexahydrocyclopenta[c]pyrrol-2(1H)-yl]carbonyl}-6,7-dihydro[1,3]thiazolo[4,5-c]pyridine-5(4H)-carboxylic acid 2-methyl-2-propyl ester, (14) methyl 2-[(3aS,4R,6aR)-4-[(6-bromo-3-pyridazinyl)oxy]hexahydrocyclopenta[c]pyrrol-2(1H)-yl]carbonyl}-6,7-dihydrothieno[3,2-c]pyridine-5(4H)-carboxylate, (15) [(3aS,4R,6aR)-4-[(6-bromo-3-pyridazinyl)oxy]hexahydrocyclopenta[c]pyrrol-2(1H)-yl](2-phenyl-2H-thieno[3,2-c]pyrazol-5-yl)methanone, (16) [(3aS,4R,6aR)-4-[(6-bromo-3-pyridazinyl)oxy]hexahydrocyclopenta[c]pyrrol-2(1H)-yl][2-(3-pyridyl)-2H-thieno[3,2-c]pyrazol-5-yl]methanone, (17) [(3aS,4R,6aR)-4-[(6-bromo-3-pyridazinyl)oxy]hexahydrocyclopenta[c]pyrrol-2(1H)-yl](4,5-dimethyl-1,3-thiazol-2-yl)methanone, (18) methyl 2-[(3aS,4R,6aR)-4-[(6-bromo-3-pyridazinyl)oxy]hexahydrocyclopenta[c]pyrrol-2(1H)-yl]carbonyl}-4,7-dihydrothieno[2,3-c]pyridine-6(5H)-carboxylate, (19) [(3aS,4R,6aR)-4-[(6-bromo-3-pyridazinyl)oxy]hexahydrocyclopenta[c]pyrrol-2(1H)-yl](4,5,7,8-tetrahydrothieno[2,3-d]oxepin-2-yl)methanone, (20) [(3aS, 4R, 6aR)-4-[(6-bromo-3-pyridazinyl)oxy]hexahydrocyclopenta[c]pyrrol-2(1H)-yl][5-(2-fluoroethoxy)-2-thienyl]methanone, (21) [(3aS, 4R, 6aR)-4-[(6-bromo-3-pyridazinyl)oxy]hexahydrocyclopenta[c]pyrrol-2(1H)-yl](4-fluoro-5-methyl-2-thienyl)methanone, (22) [(3aS,4R,6aR)-4-[(6-chloro-3-pyridazinyl)oxy]hexahydrocyclopenta[c]pyrrol-2(1H)-yl](6,7-dihydro-4H-thieno[3,2-c]pyran-2-yl)methanone, (23) [(3aS,4R,6aR)-4-{[6-chloro-4-(trifluoromethyl)-3-pyridazinyl]oxy}hexahydrocyclopenta[c]pyrrol-2(1H)-yl](6,7-dihydro-4H-thieno[3,2-c]pyran-2-yl)methanone, (24) {4-[(5-chloropyrido[2,3-d]pyridazin-8-yl)oxy]hexahydrocyclopenta[c]pyrrol-2(1H)-yl}(6,7-dihydro-4H-thieno[3,2-c]pyran-2-yl)methanone, (25) {4-[(4-chlorothieno[2,3-d]pyridazin-7-yl)oxy]hexahydrocyclopenta[c]pyrrol-2(1H)-yl}(6,7-dihydro-4H-thieno[3,2-c]pyran-2-yl)methanone, (26) [(3aS,4R,6aR)-4-[(6-chloro-5-methoxy-3-pyridazinyl)oxy]hexahydrocyclopenta[c]pyrrol-2(1H)-yl](6,7-dihydro-4H-thieno[3,2-c]pyran-2-yl)methanone, (27) [(3aS,4R,6aR)-4-[(6-chloro-4-methoxy-3-pyridazinyl)oxy]hexahydrocyclopenta[c]pyrrol-2(1H)-yl](6,7-dihydro-4H-thieno[3,2-c]pyran-2-yl)methanone, (28) [(3aS,4R,6aR)-4-[(6-chloro-3-pyridazinyl)oxy]hexahydrocyclopenta[c]pyrrol-2(1H)-yl](2-methyl-2H-thieno[3,2-c]pyrazol-5-yl)methanone, (29) [(3aS,4S,6aR)-4-[(6-bromo-3-pyridazinyl)oxy]tetrahydro-1H-spiro[cyclopenta[c]pyrrol-5,1'-cyclopropane]-2(3H)-yl](6,7-dihydro-4H-thieno[3,2-c]pyran-2-yl)methanone, (30) [(3aS,4R,6aR)-4-[(6-bromo-3-pyridazinyl)oxy]-3a-methylhexahydrocyclopenta[c]pyrrol-2(1H)-yl](6,7-dihydro-4H-thieno[3,2-c]pyran-2-yl)methanone, (31) [(3aS,4S,6aR)-4-[(6-bromo-3-pyridazinyl)oxy]-5,5-dimethylhexahydrocyclopenta[c]pyrrol-2(1H)-yl](6,7-dihydro-4H-thieno[3,2-c]pyran-2-yl)methanone, (32) [(3aR,4R,6aS)-4-[(6-bromo-3-pyridazinyl)oxy]-3a-hydroxyhexahydrocyclopenta[c]pyrrol-2(1H)-yl](6,7-dihydro-4H-thieno[3,2-c]pyran-2-yl)methanone, (33) [(3aR,4R,6aS)-4-[(6-bromo-3-pyridazinyl)oxy]-3a-methoxyhexahydrocyclopenta[c]pyrrol-2(1H)-yl](6,7-dihydro-4H-thieno[3,2-c]pyran-2-yl)methanone, and (34) [(3aS,4S,5S,6aR)-4-[(6-Bromo-3-pyridazinyl)oxy]-5-fluorohexahydrocyclopenta[c]pyrrol-2(1H)-yl](6,7-dihydro-4H-thieno[3,2-c]pyran-2-yl)methanone.

7. A pharmaceutical composition comprising the compound according to any one of claims 1 to 6 or a pharmaceutically acceptable salt thereof as an active ingredient, The pharmaceutical composition further contains a pharmaceutically acceptable carrier. The pharmaceutical composition according to claim 7 , which is an ABHD6 inhibitor. 9 . The pharmaceutical composition according to claim 7 , which is a therapeutic and / or preventive agent for a disease associated with ABHD6.

10. The pharmaceutical composition according to claim 9, wherein Diseases associated with ABHD6 are pain, neurological diseases, inflammatory diseases, autoimmune diseases, metabolic diseases or malignant tumors.

11. The pharmaceutical composition according to claim 9, wherein The disease associated with ABHD6 is pain, and the pain is pain associated with osteoarthritis, cancer pain, pain associated with chemotherapy, chronic low back pain, low back pain associated with osteoporosis, fracture pain, pain associated with rheumatoid arthritis, neuropathic pain, post-herpetic pain, pain associated with diabetic neuropathy, fibromyalgia, pain associated with pancreatitis, pain associated with interstitial cystitis / painful bladder syndrome, pain associated with endometriosis, pain associated with irritable bowel syndrome, migraine, or pain associated with pulpitis.

12. The pharmaceutical composition according to claim 9, wherein The disease associated with ABHD6 is a neurological disease, and the neurological disease is tremor, movement disorder, dystonia, spasticity, obsessive and compulsive behavior, depression, anxiety disorder, panic disorder, acute stress reaction, post-traumatic stress disorder, obsessive-compulsive disorder, agoraphobia, social phobia, mood disorder, epilepsy, traumatic brain injury, spinal cord injury, multiple sclerosis, encephalomyelitis, Parkinson's disease, Huntington's disease, Alzheimer's disease or sleep disorder.

13. The pharmaceutical composition according to claim 7, which is administered in combination with at least one selected from the following ingredients: Acetaminophen, nonsteroidal anti-inflammatory drugs, opioids, antidepressants, antiepileptics, N-methyl-D-aspartate antagonists, muscle relaxants, antiarrhythmics, steroids, and bisphosphonates.

14. A therapeutic and / or preventive agent for a disease associated with ABHD6, comprising: A compound according to any one of claims 1 to 6 or a pharmaceutically acceptable salt thereof.

15. A method for preventing and / or treating a disease associated with ABHD6, comprising administering a compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 6, or a pharmaceutical composition to a patient in need of prevention and / or treatment of a disease associated with ABHD6, wherein the pharmaceutical composition contains a compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 6 as an active ingredient and further contains a pharmaceutically acceptable carrier. 16 . The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, for use in preventing and / or treating a disease associated with ABHD6. 17 . Use of the compound according to claim 1 or a pharmaceutically acceptable salt thereof for producing a preventive and / or therapeutic agent for a disease associated with ABHD6.

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