Abhd6 antagonists

Abstract

Provided is a medicament that contains, as an active ingredient, a compound having ABHD6 inhibitory activity, in the prevention and / or treatment of a disease associated with ABHD6. A compound represented by General Formula (I-A) (in the formula, all symbols represent the same meanings as those described in the specification), or a pharmaceutically acceptable salt thereof, has ABHD6 inhibitory activity, and is therefore useful as a medicament ingredient having potent ABHD6 inhibitory activity in the prevention and / or treatment of a disease associated with ABHD6.

Description

Technical Field

[0001] This invention relates to compounds having ABHD6 inhibitory activity, or pharmaceutically permissible salts thereof, and medicaments comprising them as active ingredients. Specifically, this invention relates to general formula (IA):

[0002] [Chemical Formula 1]

[0003]

[0004] (In the formula, all symbols have the same meaning as described below) compounds, or pharmaceutically permissible salts thereof (hereinafter referred to as compounds of the present invention), and pharmaceutical compositions containing them as active ingredients, etc. Background Technology

[0005] ABHD6 (alpha / beta-Hydrolase domain containing 6) is known as a serine hydrolase and is one of the metabolic enzymes of 2-arachidoglycerol (2-AG) of endogenous cannabinoids. 2-AG functions as an important lipid precursor in the eicosanoic acid-like signaling pathway and also as an endogenous signaling lipid for the activation of cannabinoid receptors 1 and 2 (CB1 and CB2, respectively). Therefore, ABHD6 and 2-AG are known to participate in the regulation of various physiological processes, including pain, neural transduction, inflammation, insulin secretion, brown adipogenesis, food intake, autoimmune disorders, neurological diseases, and metabolic diseases (Non-Patent Literature 1).

[0006] Furthermore, it is known that inhibition of ABHD6 significantly reduces neuroinflammation and exerts neuroprotective effects 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 Literature 2).

[0007] On the other hand, Patent Document 1 describes that the 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] (where A is a ring) AThis indicates 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 represents 0, 1, or 2.

[0014] R 1A Selected from heteroaryl, aryl, heterocyclic, 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 Selected from hydrogen and C1-4 alkyl groups,

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

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

[0020] Y A Selected from cycloalkyl, cycloalkenyl, heterocyclic, aryl, and heteroaryl groups.

[0021] p A Represents integers from 0 to 4 (excerpt from a part of the group definition).

[0022] Furthermore, the compound represented by the following general formula (B) described in Patent Document 2 is a compound with FAAH inhibitory activity.

[0023] General formula (B):

[0024] [Chemical Formula 3]

[0025]

[0026] (where R is in the formula) 2B Indicates 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 A number that is independent of each other and is between 0 and 3, representing m. B +o B and n B +p B Each of the numbers is 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 terminator represented by the oxygen atom is adjacent to the R group). 1B Bonding (termined by the alkylene group bonded to a bicyclic carbon atom),

[0029] R 1B Indicates that it has not been replaced or has been replaced by one or more R's. 6B and / or R 7B Replacement R 5B ,

[0030] R 5B The group is selected from phenyl, pyridinyl, pyridinyl, pyrazinyl, triazinyl, naphthyl, quinolinyl, isoquinolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, cinnolinyl, naphthinyl, benzothiazolyl, benzoxazolyl, benzimidazolyl, benzisothiazolyl, benzisothiazolyl, indazole, and benzotriazolyl.

[0031] R 3B Indicates hydrogen, fluorine atom, C1-6 alkyl, or trifluoromethyl.

[0032] R 4B This indicates a 5-membered heterocycle selected from furanyl, pyrroleyl, thienyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyrazolyl, oxadiazolyl, thiadiazolyl, imidazoleyl, triazolyl, and tetrazolyl (a portion of the group definition is excerpted).

[0033] Furthermore, the compound represented by the following general formula (C) described in Patent Document 3 is a compound that has Ca channel inhibitory effects.

[0034] General formula (C):

[0035] [Chemical Formula 4]

[0036]

[0037] In the formula, L 1C Represents C(O), S(O)2, SO2N(R) 4 ), C(O)O or -(CR)aC 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 To become one, consisting of hydrogen, alkyl, hydroxyalkyl, G 1C or -CH(G 1C )2,

[0040] L 2C -(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 To become one, for alkyl, G 2C or -C(R) cC (G) 2C (G) 3C ),

[0043] G 1C G 2C and G 3C Each can be independently aryl, cycloalkyl, cycloalkenyl, heteroaryl, or heterocyclic;

[0044] G 1C G 2C and G 3C They are independently unsubstituted or substituted by 1, 2, 3, 4 or 5 substituents;

[0045] G 1COther than quinoline, quinazolinidone, or pyridopyrimidinedione;

[0046] R 3C Indicates hydrogen, alkyl, haloalkyl, cycloalkyl, or cycloalkylalkyl (excerpt from the group definition).

[0047] However, in the prior art literature, there is no disclosure or implication regarding the ABHD6 inhibitory activity of the compounds of the present invention.

[0048] Existing technical documents

[0049] Patent documents

[0050] Patent Document 1: International Publication No. 2019 / 089676

[0051] Patent Document 2: International Publication No. 2010 / 130944

[0052] Patent Document 3: International Publication No. 2010 / 062927

[0053] Non-patent literature

[0054] Non-patent literature 1: European Journal of Medicinal Chemistry 198(2020)112353

[0055] Non-patent literature 2: Journal of Neuroinflammation (2018) 15:9 Summary of the Invention

[0056] The technical problem that the invention aims to solve

[0057] The technical problem of the present invention is to provide a compound that has inhibitory activity against ABHD6.

[0058] means of solving technical problems

[0059] In order to solve the aforementioned technical problem, the inventors conducted in-depth research and found that the compound represented by the general formula (IA) described below has strong inhibitory activity against ABHD6.

[0060] That is, the present invention provides in one manner:

[0061] [1] A compound represented by the following general formula (IA), or a pharmaceutically permissible salt thereof,

[0062] General formula (IA):

[0063] [Chemical Formula 5]

[0064]

[0065] In the formula, X 1 X 2 Represent (1)CH and (2)CR independently, respectively. X 、or (3)N, where X 1 and X 2 At least one of them represents N.

[0066] R 1 Represents halogen atoms,

[0067] R X This indicates (1) a halogen atom, (2) a C1-6 alkyl group, (3) a C2-6 alkenyl group, (4) a C2-6 alkynyl group, (5) a C1-6 alkoxy group, (6) a C1-6 haloalkyl group, (7) a C2-6 haloalkenyl group, (8) a C2-6 haloalkynyl group, (9) a C1-6 haloalkoxy group, or (10) a cyano group.

[0068] R 2 This indicates (1) a halogen atom, (2) a C1-6 alkyl group, (3) a C2-6 alkenyl group, (4) a C2-6 alkynyl group, (5) a C1-6 alkoxy group, (6) a C1-6 haloalkyl group, (7) a C2-6 haloalkenyl group, (8) a C2-6 haloalkynyl group, (9) a C1-6 haloalkoxy group, or (10) a cyano group.

[0069] When m is 2 or more, multiple R 2 They can be the same or different.

[0070] R 3 This represents (1) a hydrogen atom, (2) a C1-6 alkyl group, (3) a C1-6 haloalkyl group, (4) a 3-10 membered cyclic group, (5) -(C1-6 alkylene)-(3-10 membered cyclic group), and (6) -(C1-6 haloalkylene)-(3-10 membered cyclic group), wherein 1 to 2 carbon atoms in the C1-6 alkyl group, C1-6 haloalkyl group, C1-6 alkylene group, and C1-6 haloalkylene group are optionally replaced by oxygen atoms or optionally oxidized sulfur atoms.

[0071] R 3 The 3-10 membered cyclic groups are optionally substituted with 1 to 5 R groups. 301 ,

[0072] R 301 Represents: (1) halogen atom, (2) C1-4 alkyl, (3) C1-4 alkoxy, (4) C1-4 haloalkyl, (5) C1-4 haloalkoxy, (6) COOR 302 (7) CONR 303 R 304(8) C3-6 cycloalkyl, (9) hydroxyl, (10) nitro, (11) cyano, (12) -NR 305 R 306 (13)-SR 307 (14)-SOR 308 (15)-SO2R 309 、or (16) oxo group,

[0073] R 301 When replacing more than two, multiple R 301 They can be the same or different.

[0074] R 302 R 303 R 304 R 305 R 306 R 307 R 308 、or R 309 Each can be independently represented as (1) a hydrogen atom or (2) a C1-4 alkyl group.

[0075] R 2 R represents 2 In (2) to (9), R 3 When representing C1-6 alkyl groups, it can be combined with R 2 and R 3 The bonded atoms together form a 5-6 membered cyclic group.

[0076] R 4 This indicates (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.

[0077] When n is 2 or more, multiple R 4 They can be the same or different.

[0078] Two Rs on the same carbon atom 4 When representing C1-6 alkyl groups, they can form C3-6 cycloalkyl groups together with the bonded carbon atoms.

[0079] ring1 represents a 3-15 membered cyclic group.

[0080] R 5-AThis indicates (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 alkylthioyl group, (7) a C1-6 alkylsulfinyl group, (8) a C1-6 alkylsulfonyl group, (9) a C2-6 acyl group, (10) a 3-6 membered cyclic group, and (11) -L R5 -(3-6 membered cyclic groups), (12) hydroxyl group, (13) nitro group, (14) cyano group, (15) oxo group, (16) -NR group 501 R 502 (17)-COOR 503 (18)-CONR 504 R 505 、or (19)-SO2NR 506 R 507 One or two carbon atoms in the C1-6 alkyl, C2-6 alkenyl, C2-6 alkoxy, C1-6 alkylthio, C1-6 alkylsulfinyl, C1-6 alkylsulfonyl, and C2-6 acyl groups may optionally be replaced by an oxygen atom or an oxidized sulfur atom.

[0081] When p is 2 or higher, multiple R 5-A They can be the same or different.

[0082] R 5-A The groups (2) to (11) in the middle can be optionally substituted to have 1 to 9 R groups. 508 ,

[0083] R 508 This indicates (1) a halogen atom, (2) a C1-4 alkyl group, (3) a C1-4 alkoxy group, (4) a C2-6 acyl group, (5) a C3-6 cycloalkyl group, (6) a hydroxyl group, or (7) -NR. 509 R 510 ,

[0084] R 508 When replacing more than two, multiple R 508 They can be the same or different.

[0085] L R5 The terms (1)-O-, (2)-(C1-4 alkylene)-, (3)-O-(C1-4 alkylene)-, (4)-(C1-4 alkylene)-O-, and (5)-NR are represented. 511 -、(6)-SO 0-2 -,

[0086] R 501 R 502 R 503 R 504 R 505 R 506R 507 R 509 R 510 or R 511 Each of the following can be independently represented as (1) a hydrogen atom, (2) a C1-6 alkyl group, (3) a C2-6 acyl group, or (4) a C1-6 alkylsulfonyl group.

[0087] m represents an integer from 0 to 2.

[0088] n represents an integer from 0 to 5.

[0089] p represents an integer from 0 to 5.

[0090] [2] A compound represented by the following general formula (I), or a pharmaceutically permissible salt thereof,

[0091] General formula (I):

[0092] [Chemical Formula 6]

[0093]

[0094] In the formula, R 5 This indicates (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 alkylthioyl group, (7) a C1-6 alkylsulfinyl group, (8) a C1-6 alkylsulfonyl group, (9) a C2-6 acyl group, (10) a 3-6 membered cyclic group, and (11) -L R5 -(3-6 membered cyclic groups), (12) hydroxyl group, (13) nitro group, (14) cyano group, (15) oxo group, (16) -NR group 501 R 502 (17)-COOR 503 (18)-CONR 504 R 505 、or (19)-SO2NR 506 R 507 ,

[0095] When p is 2 or higher, multiple R 5 They can be the same or different.

[0096] R 5 The groups (2) to (11) in the middle can be optionally substituted to have 1 to 9 R groups. 508 ,

[0097] The other symbols are the same as those described in [1].

[0098] [3] A pharmaceutical composition comprising the compound described in [1] or [2], or a pharmaceutically permissible salt thereof, as an active ingredient, and comprising a pharmaceutically permissible carrier.

[0099] [4] The pharmaceutical composition according to [3] is an ABHD6 inhibitor.

[0100] Invention Effects

[0101] The compounds of this invention have inhibitory activity against ABHD6, and therefore can be used as effective ingredients in the prevention and / or treatment of ABHD6-related diseases. Detailed Implementation

[0102] The present invention will now be described in detail.

[0103] In this specification, examples of halogen atoms include fluorine, chlorine, bromine, and iodine atoms.

[0104] In this specification, C1-4 alkyl groups include methyl, ethyl, propyl, butyl, and their isomers.

[0105] In this specification, C1-6 alkyl groups include: methyl, ethyl, propyl, butyl, pentyl, hexyl, and their isomers.

[0106] In this specification, examples of C2-6 alkenyl groups include: vinyl, propenyl, butenyl, butadienyl, pentenyl, pentadienyl, hexenyl, hexadienyl, and their isomers.

[0107] In this specification, examples of C2-6 ynyl groups include: ethynyl, propynyl, butynyl, butyrynyl, pentynyl, pentynyl, hexynyl, hexynyl, and their isomers.

[0108] In this specification, C1-4 alkylene compounds include: methylene, ethylene, propylene, butylene, and their isomers.

[0109] In this specification, C1-6 alkylene compounds include: methylene, ethylene, propylene, butylene, pentylene, hexylene, and their isomers.

[0110] In this specification, C1-4 haloalkyl means, for example, an alkyl group substituted with one or more halogen atoms, specifically including: fluoromethyl, chloromethyl, bromomethyl, iodomethyl, difluoromethyl, trifluoromethyl, 1-fluoroethyl, 2-fluoroethyl, 2-chloroethyl, pentafluoroethyl, 1-fluoropropyl, 2-chloropropyl, 3-fluoropropyl, 3-chloropropyl, 4,4,4-trifluorobutyl, 4-bromobutyl, and their isomers.

[0111] In this specification, C1-6 haloalkyl means, for example, an alkyl group substituted with one or more halogen atoms, specifically including: fluoromethyl, chloromethyl, bromomethyl, iodomethyl, difluoromethyl, trifluoromethyl, 1-fluoroethyl, 2-fluoroethyl, 2-chloroethyl, pentafluoroethyl, 1-fluoropropyl, 2-chloropropyl, 3-fluoropropyl, 3-chloropropyl, 4,4,4-trifluorobutyl, 4-bromobutyl, 5,5,5-trifluoropentyl, 6,6,6-trifluorohexyl, and their isomers.

[0112] In this specification, C1-6 haloalkylene refers to, for example, an alkylene substituted with one or more halogen atoms, specifically including: fluoromethylene, chloromethylene, bromomethylene, iodomethylene, difluoromethylene, 1-fluoroethylene, 2-fluoroethylene, 2-chloroethylene, pentafluoroethylene, 1-fluoropropylene, 2-chloropropylene, 3-fluoropropylene, 3-chloropropylene, 4-bromobutylene, 5-fluoropentylene, 6-fluorohexylene, and their isomers.

[0113] In this specification, C2-6 haloalkenyl refers to an alkenyl group, for example, that is substituted with one or more halogen atoms, specifically including: 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 their isomers.

[0114] In this specification, C2-6 haloethynyl refers to an alkynyl group substituted with one or more halogen atoms, specifically including: 2-fluoroethynyl, 2-chloroethynyl, 3-fluoropropynyl, 3-chloropropynyl, 4-bromobutynyl, 5,5,5-trifluoropentynyl, 6,6,6-trifluorohexynyl, and their isomers.

[0115] In this specification, examples of C1-4 alkoxy groups include: methoxy, ethoxy, propoxy, butoxy, and their isomers.

[0116] In this specification, examples of C1-6 alkoxy groups include: methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, and their isomers.

[0117] In this specification, C1-4 haloalkoxy refers to an alkoxy group substituted with one or more halogen atoms, specifically including: fluoromethoxy, chloromethoxy, bromomethoxy, iodomethoxy, difluoromethoxy, trifluoromethoxy, 1-fluoroethoxy, 2-fluoroethoxy, 2-chloroethoxy, pentafluoroethoxy, 1-fluoropropoxy, 2-chloropropoxy, 3-fluoropropoxy, 3-chloropropoxy, 4,4,4-trifluorobutoxy, 4-bromobutoxy, and their isomers.

[0118] In this specification, C1-6 haloalkoxy refers to an alkoxy group substituted with one or more halogen atoms, specifically including: fluoromethoxy, chloromethoxy, bromomethoxy, iodomethoxy, difluoromethoxy, trifluoromethoxy, 1-fluoroethoxy, 2-fluoroethoxy, 2-chloroethoxy, pentafluoroethoxy, 1-fluoropropoxy, 2-chloropropoxy, 3-fluoropropoxy, 3-chloropropoxy, 4,4,4-trifluorobutoxy, 4-bromobutoxy, 5,5,5-trifluoropentoxy, 6,6,6-trifluorohexyloxy, and their isomers.

[0119] In this specification, examples of C1-6 alkylthio groups include: methylthio, ethylthio, propylthio, butylthio, pentylthio, hexylthio, and their isomers.

[0120] In this specification, C1-6 alkyl sulfinyl groups include: methyl sulfinyl, ethyl sulfinyl, propyl sulfinyl, butyl sulfinyl, pentyl sulfinyl, hexyl sulfinyl, and their isomers.

[0121] In this specification, C1-6 alkylsulfonyl groups include: methylsulfonyl, ethylsulfonyl, propylsulfonyl, butylsulfonyl, pentylsulfonyl, hexylsulfonyl, and their isomers.

[0122] In this specification, examples of C3-6 cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0123] In this specification, examples of C2-6 acyl groups include acetyl, propionyl, butyryl, valeryl, hexanoyl, and their isomers.

[0124] In this specification, 3-6 membered cyclic groups refer to C3-6 carbon rings and 3-6 membered heterocycles.

[0125] In this specification, examples of C3-6 carbon rings include cyclopropane, cyclobutane, cyclopentane, cyclohexane, cyclobutene, cyclopentene, cyclohexene, cyclobutadiene, cyclopentadiene, cyclohexadiene, and benzene rings.

[0126] In this specification, examples of 3-6 membered heterocycles include: aziridine, aziridine butane, ethylene oxide, oxacyclobutane, thiohexacyclopropane, thiohexacyclobutane, pyrrole, imidazole, triazole, tetraazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, furan, pyran, thiophene, thiaran, oxazole, isoxazole, thiazole, isothiazole, furazine, oxadiazole, oxazine, oxadiazine, thiazine, thiazine, thiazine, pyrroleline, tetrahydropyrrole, imidazoline, imidazoline, triazoline, triazoline, tetraazoline, tetraazoline, pyrazolidine, dihydropyridine, tetrahydropyridine, piperidine, dihydropyrazine, tetrahydropyrazine, piperazine, dihydropyrimidine, tetrahydropyrimidine, perhydropyrimidine, dihydropyridazine, tetrahydropyridazine, perhydropyridazine Azides, dihydrofuran, tetrahydrofuran, dihydropyran, tetrahydropyran, dihydrothiophene, tetrahydrothiophene, dihydrothiophene, tetrahydrothiophene, dihydrothiophene, dihydrooxazole, tetrahydrooxazole (oxazolidine), dihydroisoxazole, tetrahydroisoxazole (isoxazolidine), dihydrothiazole, tetrahydrothiazole (thiazolidin), dihydroisothiazole, tetrahydroisothiazole (isothizolidin), dihydrofurazan, tetrahydrofurazan, dihydrooxadiazole, tetrahydrooxadiazole (oxadiazolidine), dihydrooxazine, tetrahydrooxazine, dihydrooxadiazine, tetrahydrooxadiazine, dihydrothiadiazole, tetrahydrothiadiazole (thiadizolidin), dihydrothiazine, tetrahydrothiazine, dihydrothiadiazine, tetrahydrothiadiazine, morpholine, thiomorpholine, thiazolidinane, dioxane, dithiopentane, dioxane, dithiopentane ring, and dithiazolidinane ring.

[0127] In this specification, 5-6 membered cyclic groups represent C5-6 carbon rings and 5-6 membered heterocycles.

[0128] In this specification, examples of C5-6 carbon rings include cyclopentane, cyclohexane, cyclopentene, cyclohexene, cyclopentadiene, cyclohexadiene, and benzene rings.

[0129] In this specification, examples of 5-6 membered heterocycles include: pyrrole, imidazole, triazole, tetraazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, furan, pyran, thiophene, thiaran, oxazole, isoxazole, thiazole, isothiazole, furazine, oxadiazole, oxazine, oxadiazine, thiazine, thiazine, thiazine, pyrroleline, tetrahydropyrrole, imidazoline, imidazoline, triazoline, triazoline, tetraazoline, tetraazoline, pyrazolidine, dihydropyridine, tetrahydropyridine, piperidine, dihydropyrazine, tetrahydropyrazine, piperazine, dihydropyrimidine, tetrahydropyrimidine, perhydropyrimidine, dihydropyridazine, tetrahydropyridazine, perhydropyridazine, dihydrofuran, tetrahydrofuran, dihydropyran. Tetrahydropyran, dihydrothiophene, tetrahydrothiophene, dihydrothiophene, tetrahydrothiophene, dihydrooxazole, tetrahydrooxazole (oxazolidine), dihydroisoxazole, tetrahydroisoxazole (isoxazolidine), dihydrothiazole, tetrahydrothiazole (thiazolidinidine), dihydroisothiazole, tetrahydroisothiazole (isothizolidinidine), dihydrofurazan, tetrahydrofurazan, dihydrooxadiazole, tetrahydrooxadiazole (oxadiazolidine), dihydrooxazine, tetrahydrooxazine, dihydrooxadiazine, tetrahydrooxadiazine, dihydrothiazolidinidine, tetrahydrothiazolidinidine, dihydrothiazolidinidine, tetrahydrothiazolidinidine, tetrahydrothiazolidinidine, tetrahydrothiazolidinidine, morpholine, thiomorpholine, thiazolidinidine, dioxane, dioxane, dithiopentane, and dithiazolidinidine ring.

[0130] In this specification, 3-10 membered cyclic groups represent C3-10 carbon rings and 3-10 membered heterocycles.

[0131] In this 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, pentanene, perhydropenttanene, azulene, perhydroazine, indene, perhydroindene, indene, naphthalene, dihydronaphthalene. Tetrahydronaphthalene, perhydronaphthalene, bicyclo[1.1.1]pentane, bicyclo[2.1.1]hexane, bicyclo[2.1.1]hexene, bicyclo[2.2.1]heptane, bicyclo[2.2.1]heptene, bicyclo[3.1.1]heptane, bicyclo[3.1.1]heptene, bicyclo[2.2.2]octane, bicyclo[2.2.2]octene, bicyclo[3.2.1]octane and bicyclo[3.2.1]octenyl ring, etc.

[0132] In this specification, examples of 3-10 membered heterocycles include: the aforementioned 3-6 membered heterocycles, as well as azirothalonids, diazirothalonids, oxazirothalonids, thiorothalonids, oxazirothalonids, oxazirothalonids, thiorothalonids, thiodazarothalonids, indole, isoindole, indene, benzofuran, isobenzofuran, benzothiophene, isobenzothiophene, dithionine, indazole, quinoline, isoquinoline, quinazine, purine, phthalazine, pteridine, naphthidine, quinoxaline, quinazoline, cyclophosphine, benzoxazole, benzothiazole, benzimidazole, chromene, benzofuran, benzothiadiazole, benzotriazole, dihydroazirothalonids, tetrahydroazirothalonids, perhydroazirothalonids, dihydrodiazarothalonids, tetrahydrodiazarothalonids, perhydrodiazarothalonids, dihydroxyazirothalonids, tetrahydroxyazirothalonids. All-hydrooxo-zazolide, dihydrosulfo-zazolide, tetrahydrosulfo-zazolide, all-hydrosulfo-zazolide, dihydrooxo-nitro-zazolide, tetrahydrooxo-nitro-zazolide, all-hydrooxo-nitro-zazolide, dihydrooxo-dinitro-zazolide, tetrahydrooxo-dinitro-zazolide, all-hydrooxo-dinitro-zazolide, dihydrosulfo-nitro-zazolide, all-hydrosulfo-nitro-zazolide, dihydrosulfo-dinitro-zazolide, tetrahydrosulfo-dinitro-zazolide, all-hydrosulfo-dinitro-zazolide, indoline, isoindoline, dihydrobenzofuran, all-hydrobenzofuran, dihydroisobenzofuran, all-hydroisobenzofuran, dihydrobenzothiophene, all-hydrobenzothiophene, dihydroisobenzothiophene, all-hydroisobenzothiophene, dihydroindazole, all-hydroindazole, dihydroquinoline, tetrahydroquinoline, all-hydroquinoline, dihydroisoquinoline, tetrahydroisoquinoline, all-hydroisoquinoline, dihydrophthalazine, tetra Hydrophthalazine, perhydrophthalazine, dihydronaphthidine, tetrahydronaphthidine, perhydronaphthidine, dihydroquinoxaline, tetrahydroquinoxaline, perhydroquinoxaline, dihydroquinazoline, tetrahydroquinazoline, perhydroquinazoline, dihydrozoline, tetrahydrozoline, perhydrozoline, benzothiazoline, dihydrobenzoxazine, dihydrobenzothiazine, pyrazinofomorpholine, dihydrobenzoxazole, perhydrobenzoxazole, dihydrobenzothiazole, perhydrobenzothiazole, dihydrobenzimidazole, perhydrobenzimidazole, dioxotropine, benzodioxane, benzodioxane, benzodithiopentane, benzodithiazane, azaspiro[4.4]nonane, oxazaspiro[4.4]nonane, dioxazaspiro[4.4]nonane, azaspiro[4.5]decane, thiospiro[4.5]decane, dithiospiro[4.5]decane 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]thiran, tetrahydrothieno[3,2-b]pyridine, tetrahydrothieno[3,2-c]pyridine and thieno[3,2-c]pyridine ring, etc.

[0133] In this specification, 3-15 membered cyclic groups represent C3-15 carbon rings and 3-15 membered heterocycles.

[0134] In this specification, examples of C3-15 carbon rings include the aforementioned C3-10 carbon rings, as well as heptadecene, biphenylene, as-benzodiindene, s-benzodiindene, acenaphthene, acenaphthene, fluorene, fen, phenanthrene, and anthracene rings.

[0135] In this specification, examples of 3-15 membered heterocycles include: the aforementioned 3-10 membered heterocycles, and benzo[a]oxadiazepine, benzo[a]thiodiazepine, benzo[a]oxadiazepine, benzo[a]thiodiazepine, benzo[a]diazepine, dihydrobenzo[a]diazepine, tetrahydrobenzo[a]diazepine, benzo[a]oxadiazepine, tetrahydrobenzo[a]oxadiazepine, benzo[a]thiodiazepine, benzo[a]diazepine, dihydrobenzo[a]diazepine, tetrahydrobenzo[a]oxadiazepine, benzo[a]thiodiazepine, benzo[a]diazepine, dihydrobenzo[a]diazepine. Tetrahydrobenzozazepine, primidium, β-carbline, dihydrocarbazole, tetrahydrocarbazole, dihydrodibenzofuran, dihydrodibenzothiophene, tetrahydrodibenzofuran, tetrahydrodibenzothiophene, carbazole, dibenzofuran, dibenzothiophene, phenothiazine, phenothiazine, phenothiazine, thiazoline, phenanthrone, dihydroacridine, tetrahydroacridine, acridine, phenanthridine, and dihydropyrrolo[1,2-b]thieno[2,3-d]pyrazole ring, etc.

[0136] In this specification, "one or two carbon atoms may be optionally replaced by an oxygen atom or an oxidized sulfur atom" means that one or two carbon atoms (-CH2-) located at possible positions in the structure of the substituent may be optionally replaced by an oxygen atom (-O-) or an oxidized sulfur atom (-S-, -SO-, or -SO2-). Specifically, when it is a C1-6 alkyl group, examples include: CH3-O-CH2-yl, CH3-CH2-O-CH2-yl, CH3-O-CH2-CH2-yl, CH3-O-CH2-CH2-yl, and CH3-CH2-O-CH2-CH2-yl.

[0137] In this invention, as X 1 X 2 N is preferred.

[0138] In this invention, as R 1 Preferably, it contains chlorine or bromine atoms.

[0139] In this invention, as R 2 Preferably, it is a halogen atom, a C1-6 alkyl group, a C1-6 alkoxy group, a C1-6 haloalkyl group, or a cyano group, and more preferably a chlorine atom, a methoxy group, a trifluoromethyl group, or a cyano group.

[0140] In this invention, as R X Preferably, it is a halogen atom, a C1-6 alkyl group, a C1-6 alkoxy group, a C1-6 haloalkyl group, or a cyano group, and more preferably a chlorine atom, a methoxy group, a trifluoromethyl group, or a cyano group.

[0141] In this invention, as R 3 Preferably, it is a hydrogen atom, a C1-6 alkyl group, a C1-6 haloalkyl group, a 3-10 membered cyclic group, or a -CH2- (3-10 membered cyclic group), more preferably a hydrogen atom, a C1-6 alkyl group, a C1-6 haloalkyl group, a cyclopropyl group, a -CH2-benzene group, a -CH2-pyridine group, or a -CH2-imidazo[2,1-b]thiazole group.

[0142] In this invention, as R 4 Preferably, it is a halogen atom or a C1-6 alkyl group, more preferably a fluorine atom or a methyl group.

[0143] In this invention, ring 1 is preferably a 3-10 membered cyclic group or a compound represented by chemical formula 7 below.

[0144] [Chemical Formula 7]

[0145]

[0146] (In the formula, * indicates the bonding position with the carbonyl group), more preferably, a ring structure in the group shown in Chemical Formula 8 below,

[0147] [Chemical Formula 8]

[0148]

[0149] (In the formula, * indicates the bonding position with the carbonyl group, and the hydrogen atom represented by NH is optionally bonded to R.) 5-A or R 5 (replacement), more preferably the ring structure in the group shown in chemical formula 9 below,

[0150] [Chemical Formula 9]

[0151]

[0152] (In the formula, * indicates the bonding position with the carbonyl group, and the hydrogen atom represented by NH is optionally bonded to R.) 5-A or R 5 replace).

[0153] In this invention, as R 5 Preferably, it contains halogen atoms, C1-6 alkyl groups, C1-6 alkoxy groups, C1-6 haloalkyl groups, C1-6 haloalkoxy groups, 3-6 membered cyclic groups, oxo groups, or -NR groups. 501 R 502 or -COOR 503More preferably, it is a C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, C1-6 haloalkoxy, cyclopropyl, furan ring, N-methylpyrazole ring, oxo group, dimethylamino or -COOCH3, and even more preferably a C1-6 alkyl, C1-6 haloalkyl, C1-6 haloalkoxy or cyclopropyl.

[0154] In this invention, as R 5-A Preferably, it contains halogen atoms, C1-6 alkyl groups, C1-6 alkoxy groups, C1-6 haloalkyl groups, C1-6 haloalkoxy groups, 3-6 membered cyclic groups, oxo groups, or -NR groups. 501 R 502 or -COOR 503 More preferably, it is a C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, C1-6 haloalkoxy, cyclopropyl, furan ring, N-methylpyrazole ring, oxo group, dimethylamino or -COOCH3, and even more preferably a C1-6 alkyl, C1-6 haloalkyl, C1-6 haloalkoxy or cyclopropyl.

[0155] In this invention, m is preferably 0 or 1.

[0156] In this invention, n is preferably 0, 1 or 2.

[0157] In this invention, p is preferably 0, 1 or 2.

[0158] In this invention, compounds represented by general formula (IA) or general formula (I) are preferably those represented by the following general formula (I-1).

[0159] General formula (I-1):

[0160] [Chemical Formula 10]

[0161]

[0162] (where R is in the formula) 3-a It represents (1) hydrogen atom, (2) C1-6 alkyl, (3) C1-6 haloalkyl, (4) cyclopropyl, or (5) -CH2-Q.

[0163] Q represents (1) benzene, (2) pyridine, or (3) imidazo[2,1-b]thiazole.

[0164] ring1-a represents a ring structure selected from the following ring structures.

[0165] [Chemical Formula 11]

[0166]

[0167] (In the formula, * indicates the bonding position with the carbonyl group, and the hydrogen atom represented by NH is optionally bonded to R.) 5-a replace),

[0168] R 5-a The symbols represent (1) C1-6 alkyl, (2) C1-6 alkoxy, (3) C1-6 haloalkyl, (4) C1-6 haloalkoxy, (5) cyclopropyl, (6) furan ring, (7) N-methylpyrazole ring, (8) oxo, (9) dimethylamino, or (10) -COOCH3, and other symbols represent the same meaning as the symbols above.

[0169] In this invention, the compound represented by general formula (IA) is preferably X. 1 X 2 R 1 R 2 R 3 R 4 R 5-A The optimal combination of ring1, n, m and p is defined by each.

[0170] In this invention, the compound represented by general formula (I) is preferably X. 1 X 2 R 1 R 2 R 3 R 4 R 5 The optimal combination of ring1, n, m and p is defined by each.

[0171] In this invention, as other forms of compounds represented by general formula (IA) or general formula (I), the most preferred are the example compounds described in the examples described later, or pharmaceutically permissible salts thereof.

[0172] In this invention, unless otherwise specified, all isomers are included. For example, alkyl, alkoxy, and alkylene groups contain both straight-chain and branched groups. Furthermore, isomers of double bonds, rings, and fused rings (E, Z, cis, trans isomers), isomers containing asymmetric carbons (R, S, α, β, enantiomers, diastereomers), optically active isomers with optical rotation (D, L, d, l isomers), polar isomers based on chromatographic separation (highly polar isomers, lowly polar isomers), equilibrium compounds, rotational isomers, mixtures of them in any proportion, and racemic mixtures are all included in this invention. In addition, isomers resulting from tautomerism are also included in this invention.

[0173] In this specification, compounds whose names are written as "rel-" indicate that the stereoconfiguration of multiple asymmetric centers is a relative configuration.

[0174] In this invention, unless otherwise specified, the symbols are as will be understood by those skilled in the art.

[0175] [Chemical Formula 12]

[0176]

[0177] This indicates a connection with the opposite side of the paper (i.e., the α-configuration).

[0178] [Chemical Formula 13]

[0179]

[0180] This indicates engagement with the near-front side of the paper (i.e., the β-configuration).

[0181] [Chemical Formula 14]

[0182]

[0183] Represents any mixture of α-configuration and β-configuration.

[0184] [Salt]

[0185] The compound represented by formula (IA) is converted into a salt by known methods.

[0186] Salt is pharmaceutically permissible.

[0187] The salt is preferably a water-soluble salt.

[0188] Examples of pharmaceutically permissible salts include, for example, acid addition salts, alkali metal salts, alkaline earth metal salts, ammonium salts, or amine salts.

[0189] Examples of acid addition salts include inorganic acid salts such as hydrochloride, hydrobromide, hydroiodide, sulfate, phosphate, and nitrate, or organic acid salts such as acetate, lactate, tartrate, benzoate, citrate, methanesulfonate, ethanesulfonate, trifluoroacetate, benzenesulfonate, toluenesulfonate, hydroxyethanesulfonate, glucuronide, or gluconate.

[0190] Examples of alkali metal salts include, for example, potassium salts and sodium salts.

[0191] Examples of alkaline earth metal salts include, for example, calcium and magnesium salts.

[0192] Examples of ammonium salts include, for instance, tetramethylammonium salt.

[0193] Examples of amine salts include, for example, triethylamine salt, methylamine salt, dimethylamine salt, cyclopentylamine salt, benzylamine salt, phenethylamine salt, piperidine salt, monoethanolamine salt, diethanolamine salt, tris(hydroxymethyl)aminomethane salt, lysine salt, arginine salt, and N-methyl-D-glucosamine salt.

[0194] Furthermore, the compounds of the present invention can be converted into N-oxides by any method. N-oxides refer to compounds obtained by oxidizing the nitrogen atom of the compound represented by general formula (IA).

[0195] Compounds represented by general formula (IA) and their pharmaceutically permissible salts may exist in a form that is not solvated or in a form that is solvated with pharmaceutically permissible solvents such as water and ethanol. Hydrates are preferred as solvates. Compounds represented by general formula (IA) and their pharmaceutically permissible salts can be converted into solvates.

[0196] Compounds represented by general formula (IA) can form cocrystallizations with suitable cocrystallization forming agents. Preferably, cocrystallizations are pharmaceutically permissible cocrystallizations formed with pharmaceutically permissible cocrystallization forming agents. Cocrystallization is typically defined as crystallization formed by two or more different molecules through intermolecular interactions different from ionic bonds. Furthermore, cocrystallizations can be complexes of neutral molecules and salts. Cocrystallizations can be prepared by known methods, for example, by melt crystallization, recrystallization from a solvent, or physical pulverization along with the components. Suitable cocrystallization forming agents include those described in WO2006 / 007448.

[0197] In this invention, the description of the compounds of this invention includes all compounds of formula (IA), pharmaceutically permissible salts thereof, their N-oxide bodies, their solvates (e.g., hydrates), or cocrystallizations thereof, or pharmaceutically permissible salts of compounds of formula (IA), their solvates (e.g., hydrates), or cocrystallizations thereof.

[0198] [Prodrug]

[0199] A prodrug of a compound represented by general formula (IA) is a compound that is converted into a compound represented by general formula (IA) through a reaction with enzymes, gastric acid, etc. in living organisms. Examples of prodrugs of compounds represented by general formula (IA) include compounds obtained by acylation, alkylation, or phosphorylation of the amino group (e.g., compounds obtained by eicosanoylation, alanylation, pentylaminocarbonylation, (5-methyl-2-oxo-1,3-dioxacyclopenten-4-yl)methoxycarbonylation, tetrahydrofuranylation, pyrrolidine methylation, neopentyloxymethylation, acetoxymethylation, tert-butylation, etc.); and compounds obtained by acylation, alkylation, phosphorylation, or borateation of the hydroxyl group (e.g., compounds obtained by acylation, alkylation, phosphorylation, or borateation of the amino group). Compounds obtained by acetylation, palmitoylation, propionylation, neopentanoylation, succinylation, fumarylation, alanineylation, or dimethylaminomethyl carbonylation of the hydroxyl group of the compound (e.g., compounds obtained by ethylation, phenylation, carboxylmethylation, dimethylaminomethylation, neopentanoyloxymethylation, 1-{(ethoxycarbonyl)oxy}ethylation, phthalate esterification, (5-methyl-2-oxo-1,3-dioxacyclopenten-4-yl)methylation, 1-{[(cyclohexyloxy)carbonyl]oxy}ethylation, or methylamidation of the carboxyl group of the compound represented by general formula (IA). These compounds can be manufactured by known methods. Furthermore, the prodrug of the compound represented by general formula (IA) can be either a hydrate or a nonhydrate. Furthermore, as recorded in Volume 7, "Molecular Design," of the 1990 issue of "Pharmaceutical Development" published by Hirokawa Shoten, pages 163-198, the prodrug of the compound represented by general formula (IA) can be a compound that is converted into the compound represented by general formula (IA) under physiological conditions.

[0200] Furthermore, the atoms constituting the compound represented by the general formula (IA) can be represented by their isotopes (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 (e.g., I) etc., are replaced.

[0201] [Method for manufacturing the compound of the present invention]

[0202] The compounds of this invention can be manufactured by known methods, for example, by appropriate modifications and combinations of the methods described below, methods referred to therein, methods described in Comprehensive Organic Transformations: A Guide to Functional Group Preparations, 3rd Edition (Richard C. Larock, John Wiley & Sons Inc., 2018), or methods shown in the examples. Salts can be used as starting materials. The order of the reactions can be appropriately varied depending on the introduced protecting group and reaction conditions.

[0203] Furthermore, for compounds having amino, carboxyl, or hydroxyl groups, compounds protected by a protecting group common to these groups, such as that described in TW Greene, Protective Groups in Organic Synthesis, Wiley, New York, 5th Edition, 2014, can be prepared by a known deprotection reaction following an appropriate reaction step.

[0204] Examples of carboxyl protecting groups include: methyl, ethyl, tert-butyl, trichloroethyl, benzyl (Bn), benzoylmethyl, p-methoxybenzyl, triphenylmethyl, 2-chlorotriphenylmethyl, etc.

[0205] Examples of protecting groups for amino or tetrazolium groups include: benzyloxycarbonyl, tert-butoxycarbonyl, allyloxycarbonyl (Alloc), 1-methyl-1-(4-biphenyl)ethoxycarbonyl (Bpoc), trifluoroacetyl, 9-fluorenmethoxycarbonyl, benzyl (Bn), p-methoxybenzyl, benzyloxymethyl (BOM), 2-(trimethylsilyl)ethoxymethyl (SEM), etc.

[0206] Protecting groups for hydroxyl or isohydroxamic acids include, for example: methyl, triphenylmethyl, methoxymethyl (MOM), 1-ethoxyethyl (EE), methoxyethoxymethyl (MEM), 2-tetrahydropyran (THP), trimethylsilyl (TMS), triethylsilyl (TES), tert-butyldimethylsilyl (TBDMS), tert-butyldiphenylsilyl (TBDPS), acetyl (Ac), neopentanoyl, benzoyl, benzyl (Bn), p-methoxybenzyl, allyloxycarbonyl (Alloc), 2,2,2-trichloroethoxycarbonyl (Troc), etc.

[0207] Deprotection reactions are well-known and can be carried out using the following methods. For example,

[0208] (1) Utilizing the deprotection reaction of alkaline hydrolysis,

[0209] (2) Deprotection reaction under acidic conditions

[0210] (3) Utilizing the deprotection reaction of hydrogenolysis,

[0211] (4) Deprotection reaction of silanes

[0212] (5) Using metal deprotection reactions,

[0213] (6) Deprotection reactions using metal complexes, etc.

[0214] These methods will be explained in detail below.

[0215] These methods will be explained in detail.

[0216] (1) Deprotection reaction by alkaline hydrolysis, for example in an organic solvent (e.g., methanol, tetrahydrofuran (hereinafter referred to as THF), dioxane, etc.), using alkali metal hydroxides (e.g., sodium hydroxide, potassium hydroxide, lithium hydroxide, etc.), alkaline earth metal hydroxides (e.g., barium hydroxide, calcium hydroxide, etc.) or carbonates (e.g., sodium carbonate, potassium carbonate, etc.) or aqueous solutions thereof or mixtures thereof, at 0 to 40°C.

[0217] (2) Deprotection reaction under acidic conditions, for example in organic solvents (e.g., dichloromethane, chloroform, dioxane, ethyl acetate, methanol, isopropanol, THF, anisole, etc.), in organic acids (e.g., acetic acid, trifluoroacetic acid, methanesulfonic acid, p-toluenesulfonic acid, etc.) or inorganic acids (e.g., hydrochloric acid, sulfuric acid, etc.) or mixtures thereof (e.g., hydrogen bromide / acetic acid, etc.), in the presence or absence of 2,2,2-trifluoroethanol, at 0–100 °C.

[0218] (3) Deprotection reaction by hydrogenolysis, for example, in a solvent (e.g., ethers (e.g., THF, dioxane, dimethoxyethane, diethyl ether, etc.), alcohols (e.g., methanol, ethanol, etc.), benzenes (e.g., benzene, toluene, etc.), ketones (e.g., acetone, methyl ethyl ketone, etc.), nitriles (e.g., acetonitrile, etc.), amides (e.g., N,N-dimethylformamide (hereinafter referred to as DMF), etc.), water, ethyl acetate, acetic acid, or a mixture of two or more of these solvents), in the presence of a catalyst (e.g., palladium-carbon, palladium black, palladium-carbon hydroxide, platinum oxide, Raney nickel, etc.), under a hydrogen atmosphere at atmospheric or pressurized pressure or in the presence of ammonium formate, at 0–200°C.

[0219] (4) Deprotection reaction of silyl groups, for example, in an organic solvent miscible with water (e.g., THF, acetonitrile, etc.), using tetrabutylammonium fluoride, at 0–40 °C. Alternatively, 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 -10–100 °C.

[0220] (5) Use metal deprotection reaction, for example in an acidic solvent (e.g., acetic acid, buffer solution of pH 4.2 to 7.2 or a mixture of solutions thereof and organic solvents such as THF), in the presence of powdered zinc, and if necessary, while applying ultrasound at 0 to 40°C.

[0221] (6) Deprotection reaction using metal complexes, for example, in organic solvents (e.g., dichloromethane, DMF, THF, ethyl acetate, acetonitrile, dioxane, ethanol, etc.), water, or mixtures thereof, in the presence of capturing reagents (e.g., hydrogenated tributyltin, triethylsilane, dimethyl ketone, morpholine, diethylamine, tetrahydropyrrole, etc.), organic acids (e.g., acetic acid, formic acid, 2-ethylhexanoic acid, etc.) and / or organic acid salts (e.g., sodium 2-ethylhexanoate, potassium 2-ethylhexanoate, etc.), with or without phosphine reagents (e.g., triphenylphosphine, etc.), using metal complexes (e.g., tetratetraphenylphosphine palladium(0), bis(triphenylphosphine)palladium(II) dichloride, palladium(II) acetate, tri(triphenylphosphine)rhodium(I) chloride, etc.), at 0–40 °C.

[0222] The compound represented by general formula (IA) can be produced by reaction process formula 1.

[0223] [Chemical Formula 15]

[0224]

[0225] (In reaction step formula 1, PG represents the protecting group of amino group, Y represents the halogen atom, Z represents the halogen atom, and other symbols have the same meaning as above.)

[0226] In reaction step 1, reaction 1-1 is a halogen substitution reaction or a cross-coupling reaction. Halogen substitution reactions are well known, for example, by reacting the halogen in an organic solvent (DMF, dimethyl sulfoxide, chloroform, dichloromethane, diethyl ether, THF, methyl tert-butyl ether, etc.) in the presence of a base (sodium ethoxide, sodium hydroxide, potassium hydroxide, triethylamine, diisopropylethylamine, sodium carbonate, sodium bicarbonate, potassium carbonate, cesium carbonate, tripotassium phosphate, cesium fluoride, barium hydroxide, tetrabutylammonium fluoride, etc.) or an aqueous solution thereof or a mixture thereof, at 0–200°C.

[0227] Cross-coupling reactions are well known, for example, in organic solvents (benzene, toluene, DMF, dioxane, THF, methanol, acetonitrile, dimethoxyethane, acetone, etc.), in bases (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 aqueous solutions thereof, or mixtures thereof, and catalysts (tetra(triphenylphosphine)palladium (Pd(PPh3)). 4) The reaction is carried out in the presence of bis(triphenylphosphine)palladium dichloride (PdCl2(PPh3)2), palladium acetate (Pd(OAc)2), palladium black, 1,1'-bis(diphenylphosphine-ferrocene)dichloropalladium (PdCl2(dppf)2), diallyl palladium dichloride (PdCl2(allyl)2), phenylbis(triphenylphosphine)palladium iodide (PhPdI(PPh3)2), etc., at room temperature to 120°C.

[0228] In reaction step formula 1, reactions 1-2 are N-alkylation reactions. N-alkylation reactions are well known and can be carried out, for example, by reacting them in an organic solvent (DMF, dimethyl sulfoxide, chloroform, dichloromethane, diethyl ether, THF, methyl tert-butyl ether, etc.) in the presence of alkali metal hydroxides (sodium hydroxide, potassium hydroxide, lithium hydroxide, etc.), alkaline earth metal hydroxides (barium hydroxide, calcium hydroxide, etc.), or carbonates (sodium carbonate, potassium carbonate, etc.) or their aqueous solutions or mixtures thereof at 0–100°C.

[0229] In reaction process formula 1, reactions 1-3 are deprotection reactions, which can be carried out by the same method as described above.

[0230] In reaction step 1, reactions 1-4 are amidation reactions. Amidation reactions are well-known, and examples include: (1) methods using acyl halides, (2) methods using mixed acid anhydrides, and (3) methods using condensing agents. These methods will be described in detail below:

[0231] (1) The method using acyl halides is carried out for example as follows: A carboxylic acid is reacted with an acyl halide agent (oxalyl chloride, thionyl chloride, etc.) in an organic solvent (chloroform, dichloromethane, diethyl ether, THF, etc.) or in the absence of a solvent at a temperature of -20°C to reflux. The resulting acyl halide is then reacted with an amine in the presence of a base (pyridine, triethylamine, dimethylaniline, dimethylaminopyridine, diisopropylethylamine, etc.) at a temperature of 0–40°C in an organic solvent (chloroform, dichloromethane, diethyl ether, THF, etc.). Alternatively, the reaction can be carried out by reacting the obtained acyl halide with an amine in an organic solvent (dioxane, THF, etc.) using an aqueous alkaline solution (sodium bicarbonate solution or sodium hydroxide solution, etc.) at a temperature of 0–40°C.

[0232] (2) The method of using mixed acid anhydrides is as follows: the carboxylic acid is reacted with an acyl halide (neopentyl 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 0-40°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 0-40°C.

[0233] (3) The method using condensing agents is as follows: The carboxylic acid and 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-propanephosphonic acid cyclic anhydride). Anhydride (PPA, etc.), O-(7-azabenzotriazole-1-yl)-N,N,N',N'-tetramethylurea hexafluorophosphate (HATU), reacted in the presence or absence of 1-hydroxybenzotriazole (HOBt) at 0–40 °C.

[0234] These reactions (1), (2) and (3) are preferably carried out under an inert gas atmosphere (argon, nitrogen, etc.) and anhydrous conditions.

[0235] The compound shown in general formula 1a can be produced by reaction process formula 2.

[0236] [Chemical Formula 16]

[0237] Reaction process formula 2

[0238]

[0239] (In reaction process formula 2, all symbols have the same meaning as above.)

[0240] In reaction process formula 2, reaction 2-1 is a cyclization reaction, for example, carried out 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.

[0241] In reaction step 2, reaction 2-2 is a carbonyl reduction reaction, 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.

[0242] In reaction step 2, reaction 2-3 is a toluenesulfonation reaction, which can be carried out by reacting p-toluenesulfonyl chloride in an organic solvent (e.g., dichloromethane, diethyl ether, THF, acetonitrile, benzene, toluene) in the presence of a base (e.g., pyridine, triethylamine, dimethylaniline, dimethylaminopyridine, diisopropylethylamine, etc.) at a temperature of 0-100°C.

[0243] In reaction step formula 2, reactions 2-4 are azide reactions, which can be carried out, for example, by reacting sodium azide in an organic solvent (DMF, dimethyl sulfoxide, chloroform, dichloromethane, diethyl ether, THF, methyl tert-butyl ether, etc.) at a temperature of 0-100°C.

[0244] In reaction step 2, reactions 2-5 are reduction reactions of the azide group, which are carried out in organic solvents (such as THF, dioxane, dimethoxyethane, diethyl ether, methanol, ethanol, benzene, toluene, acetone, methyl ethyl ketone, acetonitrile, DMF, ethyl acetate, acetic acid, or a mixture of two or more of them), in the presence of hydrogenation catalysts (palladium-carbon, palladium black, palladium, palladium hydroxide, platinum dioxide, platinum-carbon, nickel, Raney nickel, ruthenium chloride, etc.), in the presence or absence of acids (hydrochloric acid, sulfuric acid, hypochlorous acid, boric acid, tetrafluoroboric acid, acetic acid, p-toluenesulfonic acid, oxalic acid, trifluoroacetic acid, formic acid, etc.), under atmospheric pressure or a pressurized hydrogen atmosphere, at 0-200°C.

[0245] In each reaction described herein, the compounds used as starting materials, represented by general formulas 1b, 1d, 1g, 2a, and 2b, are known or can be readily prepared by combining known methods, such as those described in Comprehensive Organic Transformations: A Guide to Functional Group Preparations, 3rd Edition (Richard C. Larock, John Wiley & Sons Inc, 2018), or by partially modifying known methods.

[0246] In the compounds of the present invention, optically active compounds can be manufactured by using optically active starting materials or reagents, or by optically resolving racemic intermediates and then converting them into the compounds of the present invention, or by optically resolving racemic compounds of the present invention.

[0247] Optical separation is well known. For example, methods include forming other optically active compounds and salt complexes, purifying the target compound after recrystallization, or directly separating it using chiral columns.

[0248] In the reactions described in this specification, the reactions involving heating can be carried out using water baths, oil baths, sand baths, or microwaves known to those skilled in the art.

[0249] In the reactions described in this specification, solid-phase supported reagents (e.g., polystyrene, polyacrylamide, polypropylene, polyethylene glycol, etc.) may be suitably used.

[0250] In each reaction described in this specification, the reaction products can be purified by conventional purification methods, such as distillation under normal or reduced pressure, high-performance liquid chromatography using silica gel or magnesium silicate, thin-layer chromatography, ion exchange resins, resin removal or column chromatography, washing, recrystallization, etc. Purification can be carried out in individual reactions or after several reactions have concluded.

[0251] [toxicity]

[0252] Because the compounds of this invention have low toxicity, they can be safely used as pharmaceuticals.

[0253] [Applications in pharmaceuticals]

[0254] The compounds of the present invention have inhibitory activity against ABHD6, and are therefore useful as preventive and / or therapeutic agents for ABHD6-related diseases, such as pain, neurological diseases, inflammatory diseases, autoimmune diseases, metabolic diseases, malignant tumors, etc.

[0255] 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, postherpetic neuralgia, pain associated with diabetic neuropathy, fibromyalgia, pain associated with pancreatitis, pain associated with interstitial cystitis and cystitis syndrome, pain associated with endometritis, pain associated with irritable bowel syndrome, migraine, and pain associated with pulpitis.

[0256] As neurological disorders, examples include: tremors, movement disorders, dystonia, spasms, compulsive and obsessive behaviors, depression, anxiety disorders (such as 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, etc.

[0257] Examples of inflammatory diseases include: arthritis, rheumatoid arthritis, osteoarthritis, spondylitis, gout, vasculitis, Crohn's disease, and irritable bowel syndrome.

[0258] Examples of autoimmune diseases include: psoriasis, amyotrophic lateral sclerosis (ALS), multiple sclerosis, Sjögren's syndrome, systemic lupus erythematosus, and AIDS.

[0259] Examples of metabolic diseases include obesity, metabolic syndrome, dyslipidemia, diabetes, and fatty liver.

[0260] 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 neuroma, 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, etc.), malignant bone tumors, soft sarcomas, chondrosarcomas, leukemia (e.g., acute myeloid leukemia, acute lymphoblastic leukemia, chronic myeloid leukemia, chronic lymphoblastic leukemia, etc.), myelodysplastic syndrome, brain tumors, or multiple myeloma, etc.

[0261] In this specification, prevention and / or treatment of malignant tumors include, for example, (a) reducing the proliferation of cancer cells, (b) reducing symptoms arising from cancer, improving the quality of life of cancer patients, (c) reducing the dosage of other anticancer agents or adjuvant cancer treatments already administered, (d) inhibiting cancer progression, (e) inhibiting cancer recurrence, and / or (f) treatment to prolong the survival of cancer patients. Furthermore, "inhibiting cancer progression" means delaying cancer progression, stabilizing cancer-related symptoms, and regressing the progression of symptoms. "Inhibiting recurrence" means prophylactically inhibiting cancer recurrence in patients whose cancerous lesions have been completely or substantially eliminated or removed through cancer treatment or surgical resection.

[0262] To use the compounds of the present invention for the prevention and / or treatment of the aforementioned diseases, the active ingredient is typically formulated together with pharmaceutically permissible carriers such as various additives or solvents, and administered systemically or locally in an oral or non-oral form. Here, a pharmaceutically permissible carrier refers to a substance other than the active ingredient used in the formulation of general pharmaceuticals. Preferably, a pharmaceutically permissible carrier is one that does not exhibit pharmacological effects in the dosage form, is harmless, and does not inhibit the therapeutic effect of the active ingredient. Furthermore, pharmaceutically permissible carriers can be used for purposes such as improving the usefulness of the active ingredient and the formulation, facilitating formulation, stabilizing quality, or improving usability. Specifically, substances described in publications such as the "Encyclopedia of Pharmaceutical Additives" (edited by the Japan Pharmaceutical Additives Association), published by Pharmacy Daily in 2000, can be selected according to appropriate purposes.

[0263] The compounds of the present invention are administered to mammals (preferably humans, more preferably human patients) in pharmaceutically effective amounts.

[0264] The dosage of the compounds of this invention depends on age, weight, symptoms, desired therapeutic effect, route of administration, duration of treatment, etc., and therefore will inevitably vary. Typically, each patient is administered orally in the range of 0.1 ng to 1000 mg once, or non-orally in the range of 0.01 ng to 100 mg once, or continuously intravenously.

[0265] Of course, as mentioned above, the dosage can vary depending on various conditions, so there are cases where a smaller amount than the dosage is sufficient, and cases where an amount exceeding the range is necessary.

[0266] Examples of dosage forms used for drug administration include: oral preparations (e.g., tablets, capsules, granules, powders, oral liquids, syrups, oral jelly, etc.), oral preparations (e.g., oral tablets, oral sprays, oral semi-solid preparations, lozenges, etc.), injectable preparations (e.g., injections, etc.), dialysis preparations (e.g., dialysis solutions, etc.), inhalation preparations (e.g., inhalers, etc.), ophthalmic preparations (e.g., eye drops, ointments, etc.), otological preparations (e.g., ear drops, etc.), nasal preparations (e.g., nasal drops, etc.), rectal preparations (e.g., suppositories, rectal semi-solid preparations, intestinal injections, etc.), vaginal preparations (e.g., vaginal tablets, vaginal suppositories, etc.), and skin preparations (e.g., topical solid preparations, topical liquids, sprays, ointments, creams, gels, patches, etc.).

[0267] [Oral medication]

[0268] Oral medications include, for example, tablets, capsules, granules, powders, oral liquids, syrups, and oral jellies. Furthermore, oral medications include: rapidly disintegrating formulations where the release of the active ingredient is not specifically regulated, and release-regulating formulations, such as enteric-coated formulations and sustained-release formulations, where the release is regulated according to the intended purpose through inherent formulation design and manufacturing methods. Enteric-coated formulations are designed to prevent the active ingredient from decomposing in the stomach or to reduce the irritation of the stomach by the active ingredient, so that the active ingredient is released primarily in the small intestine rather than in the stomach. They are typically manufactured by using an acid-insoluble enteric-coating base with an additional coating. Sustained-release formulations are formulated to reduce the frequency of administration or to reduce side effects by regulating the release rate, release time, and release site of the active ingredient. They are typically manufactured by using appropriate sustained-release agents. In the case of oral medications, such as capsules, granules, and tablets, appropriate coating agents such as sugars, sugar alcohols, or polymers may be used as coatings to make the medication easier to take or to prevent the decomposition of the active ingredient.

[0269] (1) Tablets

[0270] Tablets are solid dosage forms with a specific shape that are administered orally. Besides uncoated tablets, film-coated tablets, sugar-coated tablets, multilayer tablets, and tablets with a core, which are generally referred to as tablets, they also include intraorally disintegrating tablets, chewable tablets, effervescent tablets, dispersible tablets, and dissolving tablets. In manufacturing uncoated tablets, the following methods (a), (b), or (c) are typically used:

[0271] (a) Add excipients, binders, disintegrants and other additives to the active ingredient and mix until homogeneous. Use a solution containing water or binder to make it into granules by an appropriate method, then add lubricant and the like and mix, and compress and shape.

[0272] (b) Adding excipients, binders, disintegrants and other additives to the active ingredient and mixing until homogeneous, and then directly compressing it; or adding the active ingredient and lubricant to the granules prepared with additives in advance and mixing until homogeneous, and then compressing it.

[0273] (c) The kneaded mixture, in which excipients, binders and other additives are added to the active ingredient and mixed until homogeneous and wetted with solvent, is poured into a mold with a specific mold for shaping and then dried by an appropriate method.

[0274] Film-coated tablets are typically manufactured by attaching a thin coating to a plain tablet using a suitable coating agent such as a polymer compound. Sugar-coated tablets are typically manufactured by attaching a coating to a plain tablet using a coating agent containing sugars or sugar alcohols. Multilayer tablets are manufactured by using appropriate methods to laminate powders of different compositions in layers and compress them. Cored tablets are manufactured by coating a core tablet with an outer layer of different compositions. Furthermore, tablets can be formulated into enteric-coated or sustained-release tablets using known and appropriate methods. Intraorally disintegrating tablets, chewable tablets, effervescent tablets, dispersible tablets, and dissolving tablets are tablets that impart unique functions to the tablet through the appropriate selection of additives, and can be manufactured with reference to the methods described for manufacturing tablets. It should be noted that intraorally disintegrating tablets are tablets that dissolve or disintegrate rapidly in the mouth for oral administration; chewable tablets are tablets that are chewed; effervescent tablets are tablets that rapidly effervesce and dissolve or disperse in water; dispersible tablets are tablets that are dispersed in water for oral administration; and dissolving tablets are tablets that are dissolved in water for oral administration. Foam sheets can be manufactured by using appropriate acidic substances, carbonates, bicarbonates, etc. as additives.

[0275] (2) Capsules

[0276] Capsules are preparations filled into capsules or encapsulated with a capsule base, including hard capsules and soft capsules. Hard capsules can be manufactured by adding excipients and other additives to the active ingredient and mixing until homogeneous, or by forming granules or pre-formed materials using appropriate methods, and then filling them into capsules or slightly shaping them before filling. Soft capsules can be manufactured by adding additives to the active ingredient, and then encapsulating it in a specific shape using a suitable capsule base such as gelatin containing glycerol, D-sorbitol, etc., to improve plasticity. Capsules can be formulated into enteric-coated capsules or sustained-release capsules using known and appropriate methods, and colorants or preservatives can be added to the capsule base.

[0277] (3) Granules

[0278] Granules are preparations granulated into granule form. Besides preparations generally referred to as granules, this also includes foaming granules, etc. In manufacturing granules, methods (a), (b), or (c) below are typically used:

[0279] (a) Add excipients, binders, disintegrants or other additives to the powdered active ingredient and mix until homogeneous, then granulate it by appropriate method;

[0280] (b) Add excipients and other additives to the pre-granulated active ingredient and mix until homogeneous;

[0281] (c) Add excipients and other additives to the pre-granulated active ingredient and mix them, and then granulate them using an appropriate method.

[0282] Regarding granules, an additive coating can be added as needed. Furthermore, enteric-coated or sustained-release granules can be formulated using well-known and appropriate methods. Foaming granules can be manufactured by using suitable acidic substances, carbonates, bicarbonates, etc., as additives. It should be noted that foaming granules refer to granules that rapidly foam, dissolve, or disperse in water. Granules can be formulated into fine granules by adjusting the particle size.

[0283] (4) Powder

[0284] Powders are powdered preparations that are typically manufactured by adding excipients or other additives to the active ingredient and mixing them until homogeneous.

[0285] (5) Oral liquid

[0286] Oral liquids are liquid or free-flowing viscous gel-like preparations. Besides those commonly referred to as oral liquids, they also include elixirs, suspensions, emulsions, and lemonades. Oral liquids are typically manufactured by adding additives and purified water to the active ingredient, dissolving, emulsifying, or suspending it until homogeneous, and then filtering as needed. Elisms are clear, liquid oral liquids containing ethanol that have a sweet and aromatic taste. They are typically manufactured by adding ethanol, purified water, flavoring agents, and sugar, other sugars, or sweeteners to a solid active ingredient or its extract, dissolving it, and then filtering or using other methods to create a clear liquid. Suspensions are oral liquids in which the active ingredient is suspended in a finely homogeneous form. They are typically manufactured by adding suspending agents or other additives and purified water or oil to a solid active ingredient, suspending it using appropriate methods to achieve overall homogeneity. Emulsions are oral liquid preparations in which the active ingredients are emulsified in a fine, homogeneous form. Typically, this is achieved by adding emulsifiers and purified water to the liquid active ingredients and then emulsifying them using appropriate methods to achieve overall homogeneity. It should be noted that lemonade refers to a clear, liquid oral liquid preparation with a sweet and sour taste.

[0287] (6) Syrup

[0288] Syrups are viscous liquid or solid preparations containing sugars or sweeteners, including syrup formulations. Syrups are typically manufactured by adding the active ingredient to a solution or simple syrup of white sugar, other sugars, or sweeteners, and then dissolving, mixing, suspending, or emulsifying it. If necessary, the mixture can be boiled and then hot-filtered. Syrup formulations refer to granular or powdered preparations that become syrups upon the addition of water; these are also called dry syrups. Syrup formulations typically use sugars or sweeteners as additives and can be manufactured using the same methods as granular or powder formulations.

[0289] (7) Oral jelly-like preparation

[0290] Oral jelly-like preparations are gel-like formulations that do not flow. They are typically manufactured by adding additives and high molecular weight gelling agents to the active ingredients, mixing them, and then gelling them using appropriate methods to shape them into a specific form.

[0291] [Injectable formulation]

[0292] (1) Injectable

[0293] Injectable preparations are sterile, solid formulations that are solutions, suspensions, or emulsions, or dissolved or suspended before use, for direct administration to tissues or organs within the body, such as subcutaneous, intramuscular, or vascular sites. Besides preparations generally referred to as injectables, they also include lyophilized injectables, powdered injectables, pre-filled syringes, cartridges, infusions, implantable injections, and continuous injections. In the manufacture of injectable preparations, the following methods (a) or (b) are typically used:

[0294] (a) The active ingredient is dissolved directly or after the additive is added to the active ingredient in water for injection, other aqueous solvents or non-aqueous solvents, etc., and suspended or emulsified until homogeneous, and then filled into a container for injection, sealed and sterilized.

[0295] (b) The active ingredient is dissolved directly or after the additive is added to the active ingredient in water for injection, other aqueous solvents or non-aqueous solvents, etc., suspended or emulsified to homogenize, then sterilely filtered or prepared to homogenize under sterile conditions, and then filled into a container for injection and sealed.

[0296] Lyophilized injections are typically manufactured by: dissolving the active ingredient directly, or dissolving the active ingredient and additives such as excipients, in water for injection, sterilizing and filtering, then filling the solution into an injection container for lyophilization, or lyophilizing in a dedicated container and then filling it directly into the container. Powder injections are typically manufactured by: filling an injection container with a powder obtained through crystallization after sterile filtration, or by adding sterilized additives to the powder. Pre-filled syringes are typically manufactured by: filling a syringe with the active ingredient directly, or by preparing a solution, suspension, or emulsion using the active ingredient and additives. Cartridge-filled injections refer to injections that are administered by loading a cartridge containing a drug solution into a dedicated syringe. Cartridge-filled injections are typically manufactured by: filling a cartridge with the active ingredient directly, or by preparing a solution, suspension, or emulsion using the active ingredient and additives. Infusion solutions are injectable preparations administered intravenously, typically in doses of 100 mL or more. Implantable injections are solid or gel-like injections intended for long-term release of the active ingredient, administered via subcutaneous or intramuscular implantation or surgical placement. Implantable injections are usually manufactured by using biodegradable polymers, formulated into particles, microbeads, or gels. Continuous-release injections are injections intended for long-term release of the active ingredient, suitable for intramuscular or other applications. They are typically manufactured by dissolving or suspending the active ingredient in plant oils or by creating suspensions containing microbeads containing biodegradable polymers.

[0297] The compounds of the present invention can be combined with other pharmaceutical agents for the following purposes 1) to 3) and administered as a combination agent.

[0298] 1) To complement and / or enhance the preventive and / or therapeutic effects of the compound;

[0299] 2) Improved dynamic absorption of the compound, reduced dosage; and / or

[0300] 3) Reduction of the side effects of this compound.

[0301] The combination of the compound of the present invention and other pharmaceutical agents can be administered as a complex formulation containing two components in a single formulation, or as separate formulations. If administered in separate formulations, this includes simultaneous administration and administration with a time difference. Furthermore, regarding administration with a time difference, the compound of the present invention can be administered first, followed by the other pharmaceutical agent, or vice versa. The administration methods can be the same or different.

[0302] There are no particular limitations on the diseases for which the combined use of the agent exerts preventive and / or therapeutic effects, as long as the preventive and / or therapeutic effects of the compounds of the present invention are supplemented and / or enhanced in the disease.

[0303] Other agents that can supplement and / or enhance the preventive and / or therapeutic effects of the compounds of the present invention on pain include, for example, acetaminophen, nonsteroidal anti-inflammatory drugs, opioids, antidepressants, antiepileptics, N-methyl-D-aspartate antagonists, muscle relaxants, antiarrhythmic drugs, steroids, and bisphosphonates.

[0304] Examples of nonsteroidal anti-inflammatory drugs (NSAIDs) include: disalicylate, sodium salicylate, aspirin, and aspirin-diatomate combinations; difluorophenylsalicylic acid, indomethacin, sulprofen, urfenadine, and dimethylsalicylate. Isopropylazulene, Butylphenylacetic acid, Biphenylacetic acid, Diclofenac, Tometidine sodium, Sulindac, Fenbufen, Nabumetone, Promethene, Indomethacin, Farnesyl ester, Acemexin, Promethene maleate, Amantadine sodium, Mofazol, Etodoxuric acid, Ibuprofen, Pico ibuprofen, Naproxen, Flurbiprofen, Flurbiprofen ester, Ketoprofen, Fenolofen calcium, Thiaprofen acid, Oxaprazin, Pramipexole, Loxoprofen sodium, Aminprofen, Zaltopibuprofen, Paracetamol, Paracetamol aluminum, Tofenamic acid, Fulofen, Ketophenylbutazone, Hydroxyphenylbutazone, Pyloxicam, Tenoxicam, Ampicillin, Napageln ointment, Epilazole, Tiaramide hydrochloride, Tenoridone hydrochloride, Emofazine, Sulpirimine, Migraine, Sanlitong tablets, Sedes G, Aminopropion-N, Solbon, pyrine-based cold medicines, acetaminophen, phenacetin, dimethicone mesylate, meloxicam, celecoxib, rofecoxib, vardicoxib, simvastatin combination drugs, and nonpyrine-based cold medicines, etc.

[0305] Examples of opioids include: codeine, fentanyl, hydromorphone, levonorgestrel, meperidine, methadone, morphine, oxycodone, hydroxymorphone, propoxyphene, and tramadol.

[0306] Examples of antidepressants include: tricyclic antidepressants (such as amitriptyline hydrochloride, mimipramine hydrochloride, clomipramine hydrochloride, duthiramine hydrochloride, nortriptyline hydrochloride, lofepramine hydrochloride, trimipramine maleate, amoxapine, etc.), tetracyclic antidepressants (such as maprotiline hydrochloride, mianserin hydrochloride, septoprine maleate, etc.), monoamine oxidase (MAO) inhibitors (savzine hydrochloride), serotonin and norepinephrine reuptake inhibitors (SNRIs) (such as mirtazapine hydrochloride, venlafaxine hydrochloride, etc.), selective serotonin reuptake inhibitors (SSRIs) (such as fluvoxamine maleate, paroxetine hydrochloride, fluoxetine hydrochloride, and citalopram hydrochloride, etc.), and serotonin reuptake inhibitors (such as trazodone hydrochloride, etc.).

[0307] Examples of antiepileptic drugs include: phenobarbital, prednisone, phenytoin, ethosuximide, zonisamide, nitrazepam, clonazepam, carbamazepine, sodium valproate, acetazolamide, and sutoazin.

[0308] Examples of N-methyl-D-aspartic acid antagonists include ketamine hydrochloride, amantadine hydrochloride, memantine hydrochloride, dextromethorphan, methadone, etc.

[0309] Examples of muscle relaxants include succinylcholine, vecuronium bromide, pancuronium bromide, and dantrolene sodium.

[0310] Examples of antiarrhythmic drugs include: procainamide, disopyramide, ciprozoline, pirfenoxanol, lidocaine, mexiletine, apralindine, piscicarboxyli, flecainide, propafenone, propranolol, atenolol, bisoprolol, amiodarone, sotalol, verapamil, diltiazem, and benprodil.

[0311] Examples of steroidal drugs, for instance, as topical medications, include: clobetasol propionate, difluralasone diacetate, fluocinolone acetonide, mometasone furoate, betamethasone dipropionate, betamethasone butyrate propionate, betamethasone valerate, difluprednisolone, budesonide, diflucorone valerate, ancinonide, halcinonide, dexamethasone, dexamethasone propionate, dexamethasone valerate, dexamethasone acetate, hydrocortisone acetate, hydrocortisone butyrate, hydrocortisone butyrate propionate, diprednisolone propionate, prednisolone acetate valerate, flurfluronone acetate, beclomethasone dipropionate, triamcinolone acetate, flumethasone neovalerate, aclomethasone dipropionate, clobetasol butyrate, prednisolone, beclomethasone propionate, and fludrosperidone, etc.

[0312] Examples of oral or injectable medications include: cortisone acetate, hydrocortisone, hydrocortisone sodium phosphate, hydrocortisone sodium succinate, fludrocortisone acetate, prednisolone, prednisolone acetate, prednisolone sodium succinate, prednisolone butyrate, prednisolone sodium phosphate, prednisolone haloacetate, methylprednisolone, methylprednisolone acetate, methylprednisolone sodium succinate, triamcinolone, triamcinolone acetate, triamcinolone acetonide, dexamethasone, dexamethasone acetate, dexamethasone sodium phosphate, dexamethasone palmitate, peramisone acetate, and betamethasone, etc.

[0313] Examples of inhaled medications include: beclomethasone dipropionate, fluticasone propionate, budesonide, flunisolone, triamcinolone, ST-126P, cicsolone, dexamethasone palmitate, mometasone furoate, prastorone sulfonate, difcosine, methylprednisolone sulfonylurea, and sodium methylprednisolone succinate.

[0314] Examples of bisphosphonate drugs include etidronate, pamidronate, alendronate, risedronate, zoledronic acid, and minodronate.

[0315] Other medications can be administered in combination of any two or more.

[0316] Furthermore, any other agents that supplement and / or enhance the preventive and / or therapeutic effects of the compounds of the present invention, provided they are based on the described mechanism, include not only those agents currently discovered but also those agents that will be discovered in the future.

[0317] Unless otherwise defined, all technical and scientific terms and abbreviations used in this specification shall have the same meaning as commonly understood by those skilled in the art to which this invention pertains.

[0318] Furthermore, all patent and non-patent documents or references expressly cited in this specification are incorporated herein by reference.

[0319] The present invention provides, in one aspect, the following embodiments.

[0320] [1] The compound represented by the following general formula (IA), or a pharmaceutically permissible salt thereof,

[0321] General formula (IA):

[0322] [Chemical Formula 17]

[0323]

[0324] In the formula, X 1 X 2 Represent (1)CH and (2)CR independently, respectively. X 、or (3)N, where X 1 and X 2 At least one of them represents N.

[0325] R 1 Represents halogen atoms,

[0326] R X This indicates (1) a halogen atom, (2) a C1-6 alkyl group, (3) a C2-6 alkenyl group, (4) a C2-6 alkynyl group, (5) a C1-6 alkoxy group, (6) a C1-6 haloalkyl group, (7) a C2-6 haloalkenyl group, (8) a C2-6 haloalkynyl group, (9) a C1-6 haloalkoxy group, or (10) a cyano group.

[0327] R 2 This indicates (1) a halogen atom, (2) a C1-6 alkyl group, (3) a C2-6 alkenyl group, (4) a C2-6 alkynyl group, (5) a C1-6 alkoxy group, (6) a C1-6 haloalkyl group, (7) a C2-6 haloalkenyl group, (8) a C2-6 haloalkynyl group, (9) a C1-6 haloalkoxy group, or (10) a cyano group.

[0328] When m is 2 or more, multiple R 2 They can be the same or different.

[0329] R 3This represents (1) a hydrogen atom, (2) a C1-6 alkyl group, (3) a C1-6 haloalkyl group, (4) a 3-10 membered cyclic group, (5) -(C1-6 alkylene)-(3-10 membered cyclic group), and (6) -(C1-6 haloalkylene)-(3-10 membered cyclic group), wherein 1 to 2 carbon atoms in the C1-6 alkyl group, C1-6 haloalkyl group, C1-6 alkylene group, and C1-6 haloalkylene group are optionally replaced by oxygen atoms or optionally oxidized sulfur atoms.

[0330] R 3 The 3-10 membered cyclic groups are optionally substituted with 1 to 5 R groups. 301 ,

[0331] R 301 Represents: (1) halogen atom, (2) C1-4 alkyl, (3) C1-4 alkoxy, (4) C1-4 haloalkyl, (5) C1-4 haloalkoxy, (6) COOR 302 (7) CONR 303 R 304 (8) C3-6 cycloalkyl, (9) hydroxyl, (10) nitro, (11) cyano, (12) -NR 305 R 306 (13)-SR 307 (14)-SOR 308 (15)-SO2R 309 、or (16) oxo group,

[0332] R 301 When replacing more than two, multiple R 301 They can be the same or different.

[0333] R 302 R 303 R 304 R 305 R 306 R 307 R 308 、or R 309 Each can be independently represented as (1) a hydrogen atom or (2) a C1-4 alkyl group.

[0334] R 2 R represents 2 In (2) to (9), R 3 When representing C1-6 alkyl groups, it can be combined with R 2 and R 3 The bonded atoms together form a 5-6 membered cyclic group.

[0335] R 4This indicates (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.

[0336] When n is 2 or more, multiple R 4 They can be the same or different.

[0337] Two Rs on the same carbon atom 4 When representing C1-6 alkyl groups, they can form C3-6 cycloalkyl groups together with the bonded carbon atoms.

[0338] ring1 represents a 3-15 membered cyclic group.

[0339] R 5-A This indicates (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 alkylthioyl group, (7) a C1-6 alkylsulfinyl group, (8) a C1-6 alkylsulfonyl group, (9) a C2-6 acyl group, (10) a 3-6 membered cyclic group, and (11) -L R5 -(3-6 membered cyclic groups), (12) hydroxyl group, (13) nitro group, (14) cyano group, (15) oxo group, (16) -NR group 501 R 502 (17)-COOR 503 (18)-CONR 504 R 505 、or (19)-SO2NR 506 R 507 One or two carbon atoms in the C1-6 alkyl, C2-6 alkenyl, C2-6 alkoxy, C1-6 alkylthio, C1-6 alkylsulfinyl, C1-6 alkylsulfonyl, and C2-6 acyl groups may optionally be replaced by an oxygen atom or an oxidized sulfur atom.

[0340] When p is 2 or higher, multiple R 5-A They can be the same or different.

[0341] R 5-A The groups (2) to (11) in the middle can be optionally substituted to have 1 to 9 R groups. 508 ,

[0342] R 508 This indicates (1) a halogen atom, (2) a C1-4 alkyl group, (3) a C1-4 alkoxy group, (4) a C2-6 acyl group, (5) a C3-6 cycloalkyl group, (6) a hydroxyl group, or (7) -NR. 509 R 510 ,

[0343] R 508 When replacing more than two, multiple R 508 They can be the same or different.

[0344] L R5 The terms (1)-O-, (2)-(C1-4 alkylene)-, (3)-O-(C1-4 alkylene)-, (4)-(C1-4 alkylene)-O-, and (5)-NR are represented. 511 -、(6)-SO 0-2 -,

[0345] R 501 R 502 R 503 R 504 R 505 R 506 R 507 R 509 R 510 or R 511 Each of the following can be independently represented as (1) a hydrogen atom, (2) a C1-6 alkyl group, (3) a C2-6 acyl group, or (4) a C1-6 alkylsulfonyl group.

[0346] m represents an integer from 0 to 2.

[0347] n represents an integer from 0 to 5.

[0348] p represents an integer from 0 to 5.

[0349] [2] The compounds represented by the following general formula (I), or their pharmaceutically permissible salts,

[0350] General formula (I):

[0351] [Chemical Formula 18]

[0352]

[0353] In the formula, X 1 X 2 Represent (1)CH and (2)CR independently, respectively. X 、or (3)N, where X 1 and X 2 At least one of them represents N.

[0354] R 1 Represents halogen atoms,

[0355] R XThis indicates (1) a halogen atom, (2) a C1-6 alkyl group, (3) a C2-6 alkenyl group, (4) a C2-6 alkynyl group, (5) a C1-6 alkoxy group, (6) a C1-6 haloalkyl group, (7) a C2-6 haloalkenyl group, (8) a C2-6 haloalkynyl group, (9) a C1-6 haloalkoxy group, or (10) a cyano group.

[0356] R 2 This indicates (1) a halogen atom, (2) a C1-6 alkyl group, (3) a C2-6 alkenyl group, (4) a C2-6 alkynyl group, (5) a C1-6 alkoxy group, (6) a C1-6 haloalkyl group, (7) a C2-6 haloalkenyl group, (8) a C2-6 haloalkynyl group, (9) a C1-6 haloalkoxy group, or (10) a cyano group.

[0357] When m is 2 or more, multiple R 2 They can be the same or different.

[0358] R 3 This represents (1) a hydrogen atom, (2) a C1-6 alkyl group, (3) a C1-6 haloalkyl group, (4) a 3-10 membered cyclic group, (5) -(C1-6 alkylene)-(3-10 membered cyclic group), and (6) -(C1-6 haloalkylene)-(3-10 membered cyclic group), wherein 1 to 2 carbon atoms in the C1-6 alkyl group, C1-6 haloalkyl group, C1-6 alkylene group, and C1-6 haloalkylene group are optionally replaced by oxygen atoms or optionally oxidized sulfur atoms.

[0359] R 3 The 3-10 membered cyclic groups are optionally substituted with 1 to 5 R groups. 301 ,

[0360] R 301 Represents: (1) halogen atom, (2) C1-4 alkyl, (3) C1-4 alkoxy, (4) C1-4 haloalkyl, (5) C1-4 haloalkoxy, (6) COOR 302 (7) CONR 303 R 304 (8) C3-6 cycloalkyl, (9) hydroxyl, (10) nitro, (11) cyano, (12) -NR 305 R 306 (13)-SR 307 (14)-SOR 308 (15)-SO2R 309 、or (16) oxo group,

[0361] R 301 When replacing more than two, multiple R 301 They can be the same or different.

[0362] R302 R 303 R 304 R 305 R 306 R 307 R 308 、or R 309 Each can be independently represented as (1) a hydrogen atom or (2) a C1-4 alkyl group.

[0363] R 2 R represents 2 In (2) to (9), R 3 When representing C1-6 alkyl groups, it can be combined with R 2 and R 3 The bonded atoms together form a 5-6 membered cyclic group.

[0364] R 4 This indicates (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.

[0365] When n is 2 or more, multiple R 4 They can be the same or different.

[0366] Two Rs on the same carbon atom 4 When representing C1-6 alkyl groups, they can form C3-6 cycloalkyl groups together with the bonded carbon atoms.

[0367] ring1 represents a 3-15 membered cyclic group.

[0368] R 5 This indicates (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 alkylthioyl group, (7) a C1-6 alkylsulfinyl group, (8) a C1-6 alkylsulfonyl group, (9) a C2-6 acyl group, (10) a 3-6 membered cyclic group, and (11) -L R5 -(3-6 membered cyclic groups), (12) hydroxyl group, (13) nitro group, (14) cyano group, (15) oxo group, (16) -NR group 501 R 502 (17)-COOR 503 (18)-CONR 504 R 505 、or (19)-SO2NR 506 R 507 ,

[0369] When p is 2 or higher, multiple R5 They can be the same or different.

[0370] R 5 The groups (2) to (11) in the middle can be optionally substituted to have 1 to 9 R groups. 508 ,

[0371] R 508 This indicates (1) a halogen atom, (2) a C1-4 alkyl group, (3) a C1-4 alkoxy group, (4) a C2-6 acyl group, (5) a C3-6 cycloalkyl group, (6) a hydroxyl group, or (7) -NR. 509 R 510 ,

[0372] When R 508 When replacing more than two, multiple R 508 They can be the same or different.

[0373] L R5 The terms (1)-O-, (2)-(C1-4 alkylene)-, (3)-O-(C1-4 alkylene)-, (4)-(C1-4 alkylene)-O-, and (5)-NR are represented. 511 -、(6)-SO 0-2 -,

[0374] R 501 R 502 R 503 R 504 R 505 R 506 R 507 R 509 R 510 or R 511 Each of the following can be independently represented: (1) a hydrogen atom, (2) a C1-6 alkyl group, (3) a C2-6 acyl group, or (4) a C1-6 alkylsulfonyl group.

[0375] m represents an integer from 0 to 2.

[0376] n represents an integer from 0 to 5.

[0377] p represents an integer from 0 to 5.

[0378] [3] According to the compound described in [1] or [2], or a pharmaceutically permissible salt thereof, wherein,

[0379] ring1 is a 3-10 membered cyclic group or a group represented by the following chemical formula 19.

[0380] [Chemical Formula 19]

[0381]

[0382] In the formula, * indicates the bonding position with the carbonyl group.

[0383] [4] According to the compound described in [1] or [3], or a pharmaceutically permissible salt thereof, wherein,

[0384] ring1 is a ring structure selected from the following ring structures.

[0385] [Chemical Formula 20]

[0386]

[0387] In the formula, * indicates the bonding position with the carbonyl group, and the hydrogen atom represented by NH is optionally bonded to R. 5-A replace.

[0388] [5] According to the compound described in [2] or [3], or a pharmaceutically permissible salt thereof, wherein,

[0389] ring1 is a ring structure selected from the following ring structures.

[0390] [Chemical Formula 21]

[0391]

[0392] In the formula, * indicates the bonding position with the carbonyl group, and the hydrogen atom represented by NH is optionally bonded to R. 5 replace.

[0393] [6] The compound according to any one of [1] to [5], or a pharmaceutically permissible salt thereof, wherein ring1 is a ring structure selected from the following ring structures.

[0394] [Chemical Formula 22]

[0395]

[0396] In the formula, * indicates the bonding position with the carbonyl group, and the hydrogen atom represented by NH is optionally bonded to R. 5-A or R 5 replace.

[0397] [7] The compound according to any one of [1] to [6], or a pharmaceutically permissible salt thereof, wherein,

[0398] R 5-A or R 5 This indicates (1) a halogen atom, (2) a C1-6 alkyl group, (3) a C1-6 alkoxy group, (4) a C1-6 haloalkyl group, (5) a C1-6 haloalkoxy group, (6) a 3- to 6-membered cyclic group, (7) an oxo group, and (8) -NR. 501 R 502 Or (9)-COOR 503.

[0399] [8] The compound according to any one of [1] to [7], or a pharmaceutically permissible salt thereof, wherein,

[0400] R 5-A or R 5 It represents (1) C1-6 alkyl, (2) C1-6 alkoxy, (3) C1-6 haloalkyl, (4) C1-6 haloalkoxy, (5) cyclopropyl, (6) furan ring, (7) N-methylpyrazole ring, (8) oxo group, (9) dimethylamino or (10) -COOCH3.

[0401] [9] The compound according to any one of [1] to [8], or a pharmaceutically permissible salt thereof, wherein,

[0402] R 3 It represents (1) hydrogen atom, (2) C1-6 alkyl, (3) C1-6 haloalkyl, (4) 3-10 membered cyclic group, or (5) -CH2- (3- to 10 membered cyclic group).

[0403]

[10] The compound according to any one of [1] to [9], or a pharmaceutically permissible salt thereof, wherein,

[0404] R 3 It represents (1) hydrogen atom, (2) C1-6 alkyl, (3) C1-6 haloalkyl, (4) cyclopropyl or (5) -CH2-Q,

[0405] Q represents (1) benzene, (2) pyridine, or (3) imidazo[2,1-b]thiazole.

[0406]

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

[10] , or a pharmaceutically permissible salt thereof, wherein,

[0407] X 1 X 2 All are N.

[0408]

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

[11] , or a pharmaceutically permissible salt thereof, wherein,

[0409] Compounds represented by general formula (IA) or general formula (I) are represented by the following general formula (I-1).

[0410] [Chemical Formula 23]

[0411]

[0412] In the formula, R 3-aIt represents (1) hydrogen atom, (2) C1-6 alkyl, (3) C1-6 haloalkyl, (4) cyclopropyl, or (5) -CH2-Q.

[0413] ring1-a represents a ring structure selected from the following ring structures.

[0414] [Chemical Formula 24]

[0415]

[0416] In the formula, * indicates the bonding position with the carbonyl group, and the hydrogen atom represented by NH is optionally bonded to R. 5-a replace,

[0417] R 5-a This indicates (1) C1-6 alkyl, (2) C1-6 alkoxy, (3) C1-6 haloalkyl, (4) C1-6 haloalkoxy, (5) cyclopropyl, (6) furan ring, (7) N-methylpyrazole ring, (8) oxo group, (9) dimethylamino, or (10) -COOCH3.

[0418] Other symbols have the same meaning as those described in [1], [2] or

[10] .

[0419]

[13] According to the compound described in

[12] , or a pharmaceutically permissible salt thereof, wherein,

[0420] ring1-a is a ring structure selected from the following ring structures.

[0421] [Chemical Formula 25]

[0422]

[0423] In the formula, * indicates the bonding position with the carbonyl group, and the hydrogen atom represented by NH is optionally bonded to R. 5-a replace.

[0424]

[14] According to the compound described in [1] or [2], or a pharmaceutically permissible salt thereof, wherein,

[0425] The compounds represented by general formula (IA) or general formula (I) are selected from the following compounds:

[0426] (1){(3aS,4R,6aR)-4-[(6-chloro-3-pyridazinyl)amino]hexahydrocyclopentano[c]pyrrolo-2(1H)-yl}[5-(difluoromethyl)-2-thienyl]methyl ketone,

[0427] (2){(3aS,4R,6aR)-4-[(6-chloro-3-pyridazinyl)amino]hexahydrocyclopentano[c]pyrrolo-2(1H)-yl}(5-methyl-2-thienyl)methyl ketone,

[0428] (3)[(3aS,4R,6aR)-4-[(6-chloro-3-pyridazinyl)amino]hexahydrocyclopentano[c]pyrrolo-2(1H)-yl](6,7-dihydro-4H-thieno[3,2-c]pyran-2-yl)methyl ketone,

[0429] (4) [(3aS,4R,6aR)-4-[(6-bromo-3-pyridazinyl)amino]hexahydrocyclopentano[c]pyrrolo-2(1H)-yl](5-methyl-2-thienyl)methyl ketone,

[0430] (5) [(3aS,4R,6aR)-4-[(6-bromo-3-pyridazinyl)amino]hexahydrocyclopentano[c]pyrrolo-2(1H)-yl](6,7-dihydro-4H-thieno[3,2-c]pyran-2-yl) methyl ketone,

[0431] (6)[(3aS,4R,6aR)-4-[(6-bromo-3-pyridazinyl)amino]hexahydrocyclopentano[c]pyrrolo-2(1H)-yl](2-methyl-2H-thieno[3,2-c]pyrazol-5-yl) methyl ketone,

[0432] (7) [(3aS,4R,6aR)-4-[benzyl(6-bromo-3-pyridazinyl)amino]hexahydrocyclopentano[c]pyrrolo-2(1H)-yl](5-methyl-2-thienyl)methyl ketone,

[0433] (8) rel-6-chloro-3-({(3aS,4R,6aR)-2-[(5-methyl-2-thienyl)carbonyl]octahydrocyclopenta[c]pyrrolo-4-yl}amino)-4-pyridazine carboxynitrile,

[0434] (9) {(3aR,4R,6aS)-4-[(6-chloro-3-pyridazinyl)amino]-3a-fluorohexahydrocyclopentano[c]pyrrolo-2(1H)-yl}(6,7-dihydro-4H-thieno[3,2-c]pyran-2-yl) ketone, and

[0435] (10)[(3aR,6R,6aS)-6-[(6-bromo-3-pyridazinyl)amino]-4,4-difluorohexahydrocyclopentano[c]pyrrolo-2(1H)-yl](6,7-dihydro-4H-thieno[3,2-c]pyran-2-yl) methyl ketone.

[0436]

[15] According to the compound described in [1] or [2], or a pharmaceutically permissible salt thereof, wherein,

[0437] The compounds represented by general formula (IA) or general formula (I) are selected from the following compounds:

[0438] (1) [(3aS,4R,6aR)-4-[(6-bromo-3-pyridazinyl)(methyl)amino]hexahydrocyclopentano[c]pyrrolo-2(1H)-yl](5-methyl-2-thienyl)methyl ketone,

[0439] (2) [(3aS,4R,6aR)-4-[(6-bromo-3-pyridazinyl)(methyl)amino]hexahydrocyclopentano[c]pyrrolo-2(1H)-yl]{5-[2-(2-fluoroethoxy)ethyl]-2-thienyl}methyl ketone,

[0440] (3)[(3aS,4R,6aR)-4-[(6-bromo-3-pyridazinyl)(methyl)amino]hexahydrocyclopentano[c]pyrrolo-2(1H)-yl][5-(2-fluoroethoxy)-2-thienyl}methyl ketone, and

[0441] (4) [(3aS,4R,6aR)-4-{(6-bromo-3-pyridazinyl)[2-(2-fluoroethoxy)ethyl]amino}hexahydrocyclopenta[c]pyrrole-2(1H)-yl](5-methyl-2-thienyl)methyl ketone.

[0442]

[16] A pharmaceutical composition comprising, as an active ingredient, any one of the compounds described in any one of [1] to

[15] or a pharmaceutically permissible salt thereof, and further comprising a pharmaceutically permissible carrier.

[0443]

[17] The pharmaceutical composition according to

[16] is an ABHD6 inhibitor.

[0444]

[18] The pharmaceutical composition according to

[16] or

[17] is a therapeutic and / or preventive agent for diseases associated with ABHD6.

[0445]

[19] According to the pharmaceutical composition described in

[18] , wherein,

[0446] Diseases associated with ABHD6 include pain, neurological disorders, inflammatory diseases, autoimmune diseases, metabolic diseases, or malignant tumors.

[0447]

[20] According to the pharmaceutical composition described in

[18] or

[19] , wherein,

[0448] The diseases associated with ABHD6 include pain, such as pain associated with osteoarthritis, cancer pain, chemotherapy pain, chronic low back pain, low back pain associated with osteoporosis, fracture pain, pain associated with rheumatoid arthritis, neuropathic pain, postherpetic neuralgia, pain associated with diabetic neuropathy, fibromyalgia, pain associated with pancreatitis, pain associated with interstitial cystitis and cystic dysplasia syndrome, pain associated with endometritis, pain associated with irritable bowel syndrome, migraine, or pain associated with pulpitis.

[0449]

[21] The pharmaceutical composition according to any one of

[16] to

[20] is administered in combination with at least one of the following ingredients:

[0450] Acetaminophen, nonsteroidal anti-inflammatory drugs, opioids, antidepressants, antiepileptics, N-methyl-D-aspartate antagonists, muscle relaxants, antiarrhythmic drugs, steroids, and bisphosphonates.

[0451]

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

[0452] The compound or a pharmaceutically permissible salt thereof as described in any one of [1] to

[15] .

[0453]

[23] A method for the prevention and / or treatment of ABHD6-related diseases, wherein,

[0454] The compound described in any one of [1] to

[15] , or a pharmaceutically permissible salt thereof, or the pharmaceutical composition described in

[16] or

[17] , shall be administered to a patient who requires prevention and / or treatment of ABHD6-related disease.

[0455]

[24] The compound or a pharmaceutically permissible salt thereof according to any one of [1] to

[15] is used for the prevention and / or treatment of diseases associated with ABHD6.

[0456]

[25] Use of any one of the compounds described in any one of [1] to

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

[0457] [Synthesis Example]

[0458] The solvent in parentheses in the chromatographic separation and TLC sections indicates the dissolution or development solvent used, and the proportion indicates the volume ratio.

[0459] The solvent in parentheses shown in the NMR section indicates the solvent used in the measurement.

[0460] The compound names used in this specification are generally named using the ACD / Name (registered trademark) program according to IUPAC rules, or using Chemdraw Ultra (version 12.0, manufactured by Cambridge Soft) or according to IUPAC nomenclature.

[0461] LC-MS / ELSD was performed under the following TFA or formic acid conditions.

[0462] TFA conditions;

[0463] Column: YMC Triart C 18 (Particle size: 1.9×10) -6 m; Column length: 30×2.0mm (ID); Flow rate: 1.0mL / min; Column temperature: 30℃; Mobile phase (A): 0.1% trifluoroacetic acid aqueous solution; Mobile phase (B): 0.1% trifluoroacetic acid-acetonitrile solution; Gradient (record 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; Detector: UV (PDA), ELSD, MS.

[0464] Formic acid conditions;

[0465] Column: YMC Triart C 18 (Particle size: 1.9×10) -6 m; Column length: 30×2.0mm (ID); Flow rate: 1.0mL / min; Column temperature: 30℃; Mobile phase (A): 0.1% formic acid aqueous solution; Mobile phase (B): 0.1% formic acid-acetonitrile solution; Gradient (record 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; Detector: UV (PDA), ELSD, MS.

[0466] Unless otherwise stated, HPLC retention times refer to the retention times under the conditions described in the LC-MS / ELSD. The description in parentheses for HPLC retention times indicates the determination conditions.

[0467] Reference Example 1: 2-Benzylhexahydrocyclopentano[c]pyrrole-4(1H)-one

[0468] A solution of N-benzyl-N-(methoxymethyl)-N-trimethylsilylmethylamine (CAS No.: 93102-05-7, 50 g) in dichloromethane (600 mL) was mixed with 2-cyclopentenone (CAS No.: 930-30-3, 17 g) and trifluoroacetic acid (CAS No.: 76-05-1, 240 mg), and stirred at room temperature for 16 hours. Triethylamine (430 mg) was then added to the reaction mixture, and the mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the title compound (30 g).

[0469] HPLC retention time (minutes): 0.65 (TFA);

[0470] MS(ESI,Pos.): 226(M+H) + .

[0471] Reference Example 2: (R)-N-((3aS,6aR,E)-2-benzylhexahydrocyclopentano[c]pyrrole-4(1H)-xylidene)-2-methylpropane-2-sulfinamide

[0472] Titanium ethoxide (IV) (CAS No.: 3037-36-3, 46.6 g) and (R)-(+)-2-methyl-2-propanesulfinamide (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 mixture was slowly injected into a saturated aqueous solution of sodium bicarbonate and dichloromethane and filtered. The solution was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound (12.4 g).

[0473] HPLC retention time (minutes): 0.80 (TFA);

[0474] MS(ESI,Pos.): 319(M+H) + .

[0475] Reference Example 3: (3aS,6aR)-2-benzylhexahydrocyclopentano[c]pyrrole-4(1H)-one

[0476] 2N hydrochloric acid (60 mL) was added to a THF (60 mL) solution of the compound (20 g) prepared in Reference Example 2, and the mixture was 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 resulting title compound was used in subsequent reactions without purification.

[0477] Reference Example 4: (3aS,6aR)-4-oxohexahydrocyclopentano[c]pyrrole-2(1H)-carboxylic acid 2-methyl-2-propyl ester

[0478] Di-tert-butyl dicarbonate (CAS No.: 24424-99-5, 9.4 g) and 20% palladium hydroxide (CAS No.: 12135-22-7, 700 mg) were added to a THF (60 mL) solution of the compound prepared in Reference Example 3, and the mixture was stirred at room temperature for 15 hours under a hydrogen atmosphere. The reaction solution was filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound (7.0 g).

[0479] 1 H-NMR (CD3OD): δ3.66-3.53, 3.14, 3.06-2.98, 2.76-2.71, 2.39-2.35, 2.21-2.12, 1.87 1.45.

[0480] Reference Example 5: (3aS,4S,6aR)-4-hydroxyhexahydrocyclopentano[c]pyrrole-2(1H)-carboxylic acid 2-methyl-2-propyl ester

[0481] In a 200 mL THF solution of the compound (7.3 g) prepared in Reference Example 4, a 1 M lithium trisec-butylborohydride THF solution (CAS No.: 38721-52-7, 49 mL) was added at -78 °C, and the mixture was stirred at -78 °C for 1 hour. A 35% aqueous hydrogen peroxide solution was slowly added to the reaction mixture at 0 °C until no foaming occurred, 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 residue was purified by silica gel column chromatography to give the title compound (6.5 g).

[0482] 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.

[0483] Reference Example 6: (3aS,4S,6aR)-4-{[(4-methylphenyl)sulfonyl]oxy}hexahydrocyclopentano[c]pyrrole-2(1H)-carboxylic acid 2-methyl-2-propyl ester

[0484] In a 100 mL solution of dichloromethane containing 6.5 g of the compound prepared in Reference Example 5, 12 mL of triethylamine, 8.2 g of p-toluenesulfonyl chloride (CAS No.: 98-59-9), and 820 mg of trimethylamine hydrochloride were added, and the mixture was stirred at room temperature for 6 hours. A saturated aqueous solution of sodium bicarbonate was added to the reaction mixture, and the mixture was extracted with dichloromethane. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound (9.3 g).

[0485] HPLC retention time (minutes): 1.2 (TFA);

[0486] MS(ESI,Pos.): 382(M+H) + .

[0487] Reference Example 7: (3aS,4R,6aR)-4-azidohexahydrocyclopentano[c]pyrrole-2(1H)-carboxylic acid 2-methyl-2-propyl ester

[0488] Sodium azide (CAS No.: 26628-22-8, 3.2 g) was added to a 72 mL solution of dimethyl sulfoxide containing the compound (9.3 g) prepared in Reference Example 6, and the mixture was stirred at 60 °C for 6 hours. Water was added to the reaction mixture, and the solution was extracted with dichloromethane. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. This unpurified organic layer was used in subsequent reactions.

[0489] Reference Example 8: (3aS,4R,6aR)-4-aminohexahydrocyclopentano[c]pyrrole-2(1H)-carboxylic acid 2-methyl-2-propyl ester

[0490] 20% palladium hydroxide (930 mg) was added to an ethanol (240 mL) solution of the compound (6.5 g) prepared in Reference Example 7, and the mixture was stirred at room temperature for 15 hours under a hydrogen atmosphere. The reaction solution was filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound (4.5 g).

[0491] HPLC retention time (minutes): 0.77 (TFA);

[0492] MS(ESI,Pos.): 227(M+H) + .

[0493] Reference Example 9: (3aS,4R,6aR)-4-[(6-chloro-3-pyridazinyl)amino]hexahydrocyclopentano[c]pyrrole-2(1H)-carboxylic acid 2-methyl-2-propyl ester

[0494] In a 25 mL solution of N,N-dimethylacetamide (hereinafter referred to as DMA) containing 1.5 g of the compound prepared in Reference Example 8, 6.9 mL of N,N-diisopropylethylamine (hereinafter referred to as DIPEA) and 3,6-dichloropyridazine (CAS No.: 141-30-0, 1.5 g) were added, and the mixture was stirred at 160 °C for 1 hour. Water was added to the reaction mixture, and 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 residue was purified by silica gel column chromatography to give the title compound (1.5 g).

[0495] HPLC retention time (minutes): 0.89 (formic acid);

[0496] MS(ESI,Pos.): 339(M+H) + .

[0497] Reference Example 10: (3aS,4R,6aR)-N-(6-chloro-3-pyridazinyl)octahydrocyclopentano[c]pyrrole-4-amine dihydrochloride

[0498] 4N hydrochloric acid (1,4-dioxane solution, 12 mL) was added to the compound (1.2 g) prepared in Reference Example 9, and the mixture was stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure to obtain the title compound (1.0 g).

[0499] HPLC retention time (minutes): 0.59 (formic acid);

[0500] MS(ESI,Pos.): 239(M+H) + .

[0501] Reference Example 10-1: racemic mixture of rel-(3aS,4R,6aR)-N-(6-chloro-3-pyridazinyl)octahydrocyclopentano[c]pyrrole-4-amine dihydrochloride

[0502] Using the compound prepared in Reference Example 1 instead of the compound prepared in Reference Example 3, the same operations as in Reference Example 4 → Reference Example 5 → Reference Example 6 → Reference Example 7 → Reference Example 8 → Reference Example 9 → Reference Example 10 were performed to obtain the title compound.

[0503] Example 1: {(3aS,4R,6aR)-4-[(6-chloro-3-pyridazinyl)amino]hexahydrocyclopenta[c]pyrrolo-2(1H)-yl}[5-(difluoromethyl)-2-thienyl]methyl ketone

[0504] [Chemical Formula 26]

[0505]

[0506] In a DMA (0.5 mL) solution of the compound (30 mg) prepared in Reference Example 10, DIPEA (0.083 mL), 5-(difluoromethyl)thiophene-2-carboxylic acid (CAS No.: 189330-23-2, 19 mg), and O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethylurea hexafluorophosphate (hereinafter referred to as HATU) (CAS No.: 148893-10-1, 38 mg) were added, and the mixture was stirred at room temperature for 3 hours. Water was added to the reaction 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 residue was purified by silica gel column chromatography to give the title compound (32 mg).

[0507] HPLC retention time (minutes): 0.88 (TFA);

[0508] MS(ESI,Pos.): 399(M+H) + ;

[0509] 1 H-NMR (CDCl3): δ7.43,7.18,6.83,6.63,4.78-4.52,4.12,3.88,3.67,3.49,2.99-2.80,2.79-2.61,2.36,2.13,1.69-1.57.

[0510] Examples 1-1 to 1-6

[0511] The title compound was obtained by replacing 5-(difluoromethyl)thiophene-2-carboxylic acid with the corresponding carboxylic acid compound, replacing the compound prepared in Reference Example 10-1 with the compound prepared in Reference Example 10, and performing the same operation as in Example 1.

[0512] Example 1-1: Racemic mixture of rel-1,3-benzothiazol-2-yl{(3aS,4R,6aR)-4-[(6-chloro-3-pyridazinyl)amino]hexahydrocyclopenta[c]pyrrole-2(1H)-yl} methyl ketone

[0513] [Chemical Formula 27]

[0514]

[0515] HPLC retention time (minutes): 1.10 (formic acid);

[0516] MS (ESI, Pos.): 400 (M+H) + ;

[0517] 1H-NMR (DMSO-d6): δ8.23-8.14,7.64-7.55,7.42-7.30,6.92,4.44-4.27,4.14-4.07,4.24-4.03,3.93-3.81 ,3.78-3.66,3.55-3.47,3.35-3.24,3.23-3.05,3.00-2.70,2.61-2.54,2.26-2.16,2.13-1.97,1.66-1.49.

[0518] Examples 1-2: {(3aS,4R,6aR)-4-[(6-chloro-3-pyridazinyl)amino]hexahydrocyclopenta[c]pyrrolo-2(1H)-yl}(5-methyl-2-thienyl)methyl ketone

[0519] [Chemical Formula 28]

[0520]

[0521] HPLC retention time (minutes): 0.85 (TFA);

[0522] MS(ESI,Pos.): 363(M+H) + ;

[0523] 1 H-NMR (CDCl3): δ7.35-7.28,7.16,6.76-6.71,6.65,4.96,4.14-3.96,3.96- 3.86,3.82,3.65,2.88,2.79-2.62,2.50,2.41-2.27,2.18-2.04,1.72-1.54.

[0524] Examples 1-3: [(3aS,4R,6aR)-4-[(6-chloro-3-pyridazinyl)amino]hexahydrocyclopentano[c]pyrrolo-2(1H)-yl](thienano[3,2-c]pyridin-2-yl)methyl ketone

[0525] [Chemical Formula 29]

[0526]

[0527] HPLC retention time (minutes): 0.74 (formic acid);

[0528] MS (ESI, Pos.): 400 (M+H) + ;

[0529] 1H-NMR(DMSO-d6): δ9.46-9.25,8.63-8.43,8.40-8.30,8.29-8.14,7.43-7.30,6.97-6.83,4.20-4. 00,3.99-3.65,3.15-3.04,3.04-2.79,2.77-2.57,2.27-2.15,2.14-1.98,1.70-1.58,1.58-1.48.

[0530] Examples 1-4: [(3aS,4R,6aR)-4-[(6-chloro-3-pyridazinyl)amino]hexahydrocyclopentano[c]pyrrolo-2(1H)-yl](6,7-dihydro-4H-thieno[3,2-c]pyran-2-yl) methyl ketone

[0531] [Chemical Formula 30]

[0532]

[0533] HPLC retention time (minutes): 0.83 (TFA);

[0534] MS (ESI, Pos.): 405 (M+H) + ;

[0535] 1 H-NMR (CDCl3): δ7.22-7.13,6.66,5.04,4.76-4.65,4.12,3.98,3.86,3.64,2.89,2.70,2.39-2.28,2.17-2.07,1.69-1.55.

[0536] Examples 1-5: [(3aS,4R,6aR)-4-[(6-chloro-3-pyridazinyl)amino]hexahydrocyclopentano[c]pyrrolo-2(1H)-yl][4-(2-furanyl)phenyl]methyl ketone

[0537] [Chemical Formula 31]

[0538]

[0539] HPLC retention time (minutes): 1.00 (formic acid);

[0540] MS(ESI,Pos.): 409(M+H) + ;

[0541] 1H-NMR(DMSO-d6): δ8.14-8.07,8.07-7.93,7.73-7.47,7.43-7.22,6.98-6.88,6.88-6.78,4.11-3.99 ,3.99-3.88,3.76-3.65,3.10,2.86-2.70,2.21-2.09,2.09-1.98,1.98-1.84,1.65-1.43,1.43-1.29.

[0542] Examples 1-6: 1-Benzofuran-2-yl[(3aS,4R,6aR)-4-[(6-chloro-3-pyridazinyl)amino]hexahydrocyclopenta[c]pyrrole-2(1H)-yl] methyl ketone

[0543] [Chemical Formula 32]

[0544]

[0545] HPLC retention time (minutes): 1.00 (formic acid);

[0546] MS(ESI,Pos.): 383(M+H) + ;

[0547] 1 H-NMR (DMSO-d6): δ7.79-7.74,7.71-7.65,7.57-7.49,7.49-7.43,7.41-7.32,7.31-7.25,6.96-6.84,4.14-4. 01,3.83-3.72,3.34-3.25,2.97-2.76,2.73-2.66,2.64-2.53,2.25-2.15,2.10-1.98,1.65-1.57,1.56-1.46.

[0548] Reference Example 11: (3aS,4R,6aR)-4-[(6-bromo-3-pyridazinyl)amino]hexahydrocyclopentano[c]pyrrole-2(1H)-carboxylic acid 2-methyl-2-propyl ester

[0549] In a DMA (25 mL) solution of the compound (4.0 g) prepared in Reference Example 8, DIPEA (18 mL) and 3,6-dibromopyridazine (CAS No.: 17973-86-3, 6.3 g) were added, and the mixture was stirred at 160 °C for 15 hours. Water was added to the reaction mixture, and the solution was extracted with dichloromethane. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound (4.0 g).

[0550] HPLC retention time (minutes): 0.91 (formic acid);

[0551] MS(ESI,Pos.): 383(M+H) + .

[0552] Reference Example 12: (3aS,4R,6aR)-N-(6-bromo-3-pyridazinyl)octahydrocyclopentano[c]pyrrole-4-amine dihydrochloride

[0553] 4N hydrochloric acid (1,4-dioxane solution, 12 mL) was added to the compound (4.0 g) prepared in Reference Example 11, and the mixture was stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure to give the title compound (3.7 g).

[0554] HPLC retention time (minutes): 0.59 (formic acid);

[0555] MS(ESI,Pos.): 283(M+H) + .

[0556] Reference Example 12-1: Racemic mixture of rel-(3aS,4R,6aR)-N-(6-bromo-3-pyridazinyl)octahydrocyclopentano[c]pyrrole-4-amine dihydrochloride

[0557] Using the compound prepared in Reference Example 1 instead of the compound prepared in Reference Example 3, the same operations as in Reference Example 4 → Reference Example 5 → Reference Example 6 → Reference Example 7 → Reference Example 8 → Reference Example 11 → Reference Example 12 were performed to obtain the title compound.

[0558] Example 2: [(3aS,4R,6aR)-4-[(6-bromo-3-pyridazinyl)amino]hexahydrocyclopentano[c]pyrrolo-2(1H)-yl](5-methyl-2-thienyl)methyl ketone

[0559] [Chemical Formula 33]

[0560]

[0561] In a DMA (20 mL) solution of the compound (3.0 g) prepared in Reference Example 12, DIPEA (2.9 mL), 5-methyl-2-thiophenic acid (CAS No.: 1918-79-2, 6.6 g), and HATU (3.8 g) were added, and the mixture was stirred at room temperature for 3 hours. Water was added to the reaction 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 residue was purified by silica gel column chromatography to give the title compound (1.8 g).

[0562] HPLC retention time (minutes): 0.87 (TFA);

[0563] MS(ESI,Pos.): 407(M+H) + ;

[0564] 1 H-NMR (CDCl3): δ7.33-7.27,6.75-6.72,6.54,5.00,4.15-3.99,3.98-3.78,3.66,2.88,2.68,2.50,2.39-2.29,2.14-2.03,1.68-1.59.

[0565] Examples 2-1 to 2-14

[0566] The same procedure as in Example 2 was performed using the corresponding carboxylic acid compound instead of 5-methyl-2-thiophenic acid to obtain the title compound.

[0567] Example 2-1: [(3aS,4R,6aR)-4-[(6-bromo-3-pyridazinyl)amino]hexahydrocyclopentano[c]pyrrolo-2(1H)-yl](6,7-dihydro-4H-thieno[3,2-c]pyran-2-yl) methyl ketone

[0568] [Chemical Formula 34]

[0569]

[0570] HPLC retention time (minutes): 0.93 (TFA);

[0571] MS(ESI,Pos.): 451(M+H) + ;

[0572] 1 H-NMR (CDCl3): δ7.32-7.27,7.17,6.54,4.77-4.63,4.10,4.04-3.93,3.87,3.65,2.89,2.69,2.40-2.29,2.17-2.07,1.68-1.57.

[0573] Example 2-2: [(3aS,4R,6aR)-4-[(6-bromo-3-pyridazinyl)amino]hexahydrocyclopentano[c]pyrrolo-2(1H)-yl][5-(difluoromethyl)-2-thienyl]methyl ketone

[0574] [Chemical Formula 35]

[0575]

[0576] HPLC retention time (minutes): 1.00 (formic acid);

[0577] MS(ESI,Pos.): 443(M+H) + ;

[0578] 1 H-NMR(DMSO-d6): δ7.63-7.56,7.50-7.47,7.46-7.43,7.34-7.27,7.32,6.86-6.73,4.11 -3.87,3.87-3.70,3.71-3.54,2.96-2.72,2.71-2.56,2.23-2.11,2.09-1.95,1.59,1.51.

[0579] Examples 2-3: [(3aS,4R,6aR)-4-[(6-bromo-3-pyridazinyl)amino]hexahydrocyclopentano[c]pyrrolo-2(1H)-yl](5-methyl-1,3-thiazolyl)methyl ketone

[0580] [Chemical Formula 36]

[0581]

[0582] HPLC retention time (minutes): 0.96 (formic acid);

[0583] MS (ESI, Pos.): 408 (M+H) + ;

[0584] 1 H-NMR(DMSO-d6): δ7.77-7.68,7.50-7.41,7.41-7.28,6.87-6.77,4.29-3.93,3. 84-3.62,3.18-3.04,2.97-2.60,2.24-2.11,2.11-1.95,1.66-1.54,1.54-1.43.

[0585] Examples 2-4: [(3aS,4R,6aR)-4-[(6-bromo-3-pyridazinyl)amino]hexahydrocyclopentano[c]pyrrolo-2(1H)-yl](thienano[3,2-c]pyridin-2-yl)methyl ketone

[0586] [Chemical Formula 37]

[0587]

[0588] HPLC retention time (minutes): 0.75 (formic acid);

[0589] MS(ESI,Pos.): 444(M+H) + ;

[0590] 1 H-NMR (DMSO-d6): δ9.42-9.26,8.60,8.44-8.31,8.31-8.17,7.52-7.42,7.42-7.31,6. 88-6.74,4.17-4.00,3.89-3.67,3.14-3.06,2.87,2.28-2.14,2.13-1.97,1.70-1.45.

[0591] Examples 2-5: [(3aS,4R,6aR)-4-[(6-bromo-3-pyridazinyl)amino]hexahydrocyclopentano[c]pyrrolo-2(1H)-yl](6,7-dihydro-4H-pyrano[3,4-d][1,3]thiazolyl-2-yl)methyl ketone

[0592] [Chemical Formula 38]

[0593]

[0594] HPLC retention time (minutes): 0.84 (TFA);

[0595] MS(ESI,Pos.): 452(M+H) + ;

[0596] 1 H-NMR (CDCl3): δ7.31-7.27,6.54,4.85-4.78,4.73,4.34-4.27,4.21,4.15-3.97,3.9 5-3.84,3.78,3.65,2.97,2.90-2.71,2.69-2.59,2.39-2.28,2.18-2.01,1.69-1.61.

[0597] Examples 2-6: [(3aS,4R,6aR)-4-[(6-bromo-3-pyridazinyl)amino]hexahydrocyclopentano[c]pyrrolo-2(1H)-yl][2-(dimethylamino)-1,3-thiazolyl-5-yl]methyl ketone

[0598] [Chemical Formula 39]

[0599]

[0600] HPLC retention time (minutes): 0.74 (TFA);

[0601] MS(ESI,Pos.): 438(M+H) + ;

[0602] 1H-NMR (CDCl3): δ7.57,7.26,6.55,4.92,4.15-4.02,3.98-3.89,3.87,3.78,3.61,3.15,2.89,2.69,2.39-2.29,2.17-2.07,1.62-1.55.

[0603] Examples 2-7: [(3aS,4R,6aR)-4-[(6-bromo-3-pyridazinyl)amino]hexahydrocyclopentano[c]pyrrolo-2(1H)-yl](5,5-dioxide-6,7-dihydro-4H-thienano[3,2-c]thiaran-2-yl) methyl ketone

[0604] [Chemical Formula 40]

[0605]

[0606] HPLC retention time (minutes): 0.88 (formic acid);

[0607] MS(ESI,Pos.): 497(M+H) + ;

[0608] 1 H-NMR(DMSO-d6): δ7.46,7.33,6.82,4.39,4.11-3.99,3.97-3.83,3.81-3. 65,3.18-3.05,2.99-2.72,2.70-2.58,2.24-2.09,2.09-1.96,1.58,1.49.

[0609] Examples 2-8: [(3aS,4R,6aR)-4-[(6-bromo-3-pyridazinyl)amino]hexahydrocyclopentano[c]pyrrolo-2(1H)-yl](6,7-dihydro-4H-thieno[3,2-c]thiaran-2-yl) methyl ketone

[0610] [Chemical Formula 41]

[0611]

[0612] HPLC retention time (minutes): 1.00 (formic acid);

[0613] MS (ESI, Pos.): 465 (M+H) + ;

[0614] 1H-NMR(DMSO-d6): δ7.46,7.41-7.31,6.86-6.77,4.11-4.02,4.02-3.86,3.71,3.69-3.58,3.46 ,3.15-3.05,3.04-2.96,2.94-2.88,2.88-2.71,2.25-2.12,2.10-1.94,1.68-1.54,1.54-1.39.

[0615] Examples 2-9: [(3aS,4R,6aR)-4-[(6-bromo-3-pyridazinyl)amino]hexahydrocyclopentano[c]pyrrolo-2(1H)-yl](1-methyl-1H-thieno[2,3-c]pyrazol-5-yl) methyl ketone

[0616] [Chemical Formula 42]

[0617]

[0618] HPLC retention time (minutes): 0.90 (formic acid);

[0619] MS(ESI,Pos.): 447(M+H) + ;

[0620] 1 H-NMR(DMSO-d6): δ7.85,7.69-7.57,7.52-7.43,7.43-7.28,6.89-6.70,4.12-4.00,3.96,3. 92-3.67,3.15-3.05,2.96-2.75,2.75-2.57,2.26-2.11,2.09-1.94,1.66-1.55,1.55-1.44.

[0621] Examples 2-10: [(3aS,4R,6aR)-4-[(6-bromo-3-pyridazinyl)amino]hexahydrocyclopentano[c]pyrrolo-2(1H)-yl][2-(dimethylamino)thieno[2,3-d][1,3]thiazolyl-5-yl] methyl ketone

[0622] [Chemical Formula 43]

[0623]

[0624] HPLC retention time (minutes): 0.88 (TFA);

[0625] MS (ESI, Pos.): 493 (M+H) + ;

[0626] 1H-NMR (DMSO-d6): δ7.79,7.44,7.25,6.79,4.16-3.94,3.86,3.74,3.56,3.44-3.36,3.31-3.23,3.13,2.87,2.61,2.19,2.07-1.98,1.63-1.47.

[0627] Example 2-11: [(3aS,4R,6aR)-4-[(6-bromo-3-pyridazinyl)amino]hexahydrocyclopentano[c]pyrrolo-2(1H)-yl](3-methyl-3H-thieno[2,3-d][1,2,3]triazol-5-yl) methyl ketone

[0628] [Chemical Formula 44]

[0629]

[0630] HPLC retention time (minutes): 0.87 (formic acid);

[0631] MS(ESI,Pos.): 448(M+H) + ;

[0632] 1 H-NMR(DMSO-d6): δ7.91,7.46,7.44-7.36,6.84,4.24,4.14-3.98,3.95-3. 61,3.00-2.79,2.77-2.59,2.27-2.16,2.11-1.98,1.65-1.57,1.57-1.50.

[0633] Examples 2-12: [(3aS,4R,6aR)-4-[(6-bromo-3-pyridazinyl)amino]hexahydrocyclopentano[c]pyrrolo-2(1H)-yl](5-methoxy-2-furanyl)methyl ketone

[0634] [Chemical Formula 45]

[0635]

[0636] HPLC retention time (minutes): 0.80 (TFA);

[0637] MS(ESI,Pos.): 407(M+H) + ;

[0638] 1H-NMR (CDCl3): δ7.31-7.27,7.05,6.54,5.31,4.81-4.66,4.12,3.92,3.94-3.77,3.76-3.58,2.95-2.76,2.72-2.52,2.34,2.05,1.66-1.56.

[0639] Examples 2-13: [(3aS,4R,6aR)-4-[(6-bromo-3-pyridazinyl)amino]hexahydrocyclopentano[c]pyrrolo-2(1H)-yl](1,3-dimethyl-1H-thieno[2,3-c]pyrazol-5-yl) methyl ketone

[0640] [Chemical Formula 46]

[0641]

[0642] HPLC retention time (minutes): 0.93 (formic acid);

[0643] MS(ESI,Pos.): 461(M+H) + ;

[0644] 1 H-NMR(DMSO-d6): δ7.62,7.51-7.44,7.45-7.36,6.88-6.79,4.13-4.04,3.85,4.01-3.66 ,3.36-3.24,2.95-2.80,2.71-2.58,2.37,2.26-2.15,2.11-2.00,1.64-1.57,1.56-1.48.

[0645] Examples 2-14: Bicyclo[2.2.2]oct-2-yl[(3aS,4R,6aR)-4-[(6-bromo-3-pyridazinyl)amino]hexahydrocyclopenta[c]pyrrole-2(1H)-yl] methyl ketone

[0646] [Chemical Formula 47]

[0647]

[0648] HPLC retention time (minutes): 1.10 (formic acid);

[0649] MS(ESI,Pos.): 419(M+H) + ;

[0650] 1H-NMR (DMSO-d6): δ7.51-7.39,7.38-7.25,6.85-6.74,4.07-3.85,3.73-3.51,3.29-3.16,2.87-2.59,2.18-1.82,1.72-1.14.

[0651] Reference Example 13: 5-[(1E)-3-ethoxy-3-oxo-1-propen-1-yl]-4-nitro-2-thiophene carboxylic acid methyl ester

[0652] In a 1,2-dimethoxyethane (3 mL) solution of methyl 5-bromo-4-nitrothiophene-2-carboxylic acid (CAS No.: 38239-32-6, 120 mg), DIPEA (0.083 mL), tripotassium phosphate (CAS No.: 7778-53-2, 1730 mg), (E)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)acrylate (CAS No.: 1009307-13-4, 300 mg), and bis(triphenylphosphine)palladium(II) chloride (CAS No.: 13965-03-2, 63 mg) were added, and the mixture was stirred at 55 °C for 3 hours. Water was added to the reaction 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 residue was purified by silica gel column chromatography to give the title compound (97 mg).

[0653] HPLC retention time (minutes): 1.20 (formic acid);

[0654] MS(ESI,Pos.): 286(M+H) + .

[0655] Reference Example 14: Methyl 4-amino-5-(3-ethoxy-3-oxopropyl)-2-thiophenecarboxylate

[0656] 20% palladium hydroxide (100 mg) was added to a methanol (2 mL) solution of the compound (50 mg) prepared in Reference Example 13, and the mixture was stirred at room temperature for 1 hour under a hydrogen atmosphere. The reaction solution was filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound (30 mg).

[0657] HPLC retention time (minutes): 0.80 (formic acid);

[0658] MS(ESI,Pos.): 258(M+H) + .

[0659] Reference Example 15: Methyl 5-oxo-4,5,6,7-tetrahydrothieno[3,2-b]pyridine-2-carboxylate

[0660] In a methanol (1 mL) solution of the compound (20 mg) prepared in Reference Example 14, p-toluenesulfonic acid monohydrate (CAS No.: 6192-52-5, 1.5 mg) was added, and the mixture was stirred at 60 °C for 15 hours. A saturated aqueous solution of sodium bicarbonate was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound (5 mg).

[0661] HPLC retention time (minutes): 0.81 (formic acid);

[0662] MS(ESI,Pos.): 212(M+H) + .

[0663] Reference Example 16: Methyl 4-methyl-5-oxo-4,5,6,7-tetrahydrothieno[3,2-b]pyridine-2-carboxylic acid ester

[0664] Sodium hydride (CAS No.: 7646-69-7, 2.9 mg) and methyl iodide (CAS No.: 74-88-4, 22 mg) were added to a DMF (0.25 mL) solution of the compound (5 mg) prepared in Reference Example 15, and the mixture was stirred at room temperature for 3 hours. 2N hydrochloric acid was added to the reaction mixture, and extraction was performed with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound (7 mg).

[0665] HPLC retention time (minutes): 0.88 (formic acid);

[0666] MS(ESI,Pos.): 225(M+H) + .

[0667] Reference Example 17: 4-Methyl-5-oxo-4,5,6,7-tetrahydrothieno[3,2-b]pyridine-2-carboxylic acid

[0668] A 2N aqueous solution of sodium hydroxide (0.5 mL) was added to a methanol (1 mL) solution of the compound (7 mg) prepared in Reference Example 16, and the mixture was stirred at 60 °C for 1 hour. 1N hydrochloric acid was added to the reaction mixture, and the precipitate was filtered off to give the title compound (5.0 mg).

[0669] Reference Example 18: 5-Chloro-3,4-dihydro-2H-pyran-6-carbaldehyde

[0670] DMF (0.70 mL) was added to a 5 mL solution of phosphoryl chloride (CAS No.: 10025-87-3, 1400 mg) in dichloromethane at 0 °C, and the mixture was stirred at 0 °C for 1 hour. Dihydro-2H-pyran-3(4H)-one (CAS No.: 23462-75-1, 900 mg) was added to the mixture, and the mixture was stirred at room temperature for 2 hours. A saturated aqueous solution of sodium bicarbonate was added to the reaction mixture, and the mixture was extracted with dichloromethane. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting title compound was used in subsequent reactions without purification.

[0671] Reference Example 19: Methyl [(6-formyl-3,4-dihydro-2H-pyran-5-yl)thio]acetate

[0672] In a 20 mL solution of the compound prepared in Reference Example 18, triethylamine (2.5 mL) and methyl mercaptoacetate (CAS No.: 2365-48-2, 1100 mg) were added, and the mixture was stirred at 70 °C for 15 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to obtain the title compound (300 mg).

[0673] Reference Example 20: Methyl 6,7-dihydro-5H-thieno[3,2-b]pyran-2-carboxylic acid

[0674] 28% sodium methoxide (CAS No.: 124-41-4, 0.85 mL) was added to a methanol (10 mL) solution of the compound prepared in Reference Example 19, and the mixture was stirred at 70 °C for 1 hour. The reaction solution was concentrated under reduced pressure, and 2N hydrochloric acid was added, followed by extraction with dichloromethane. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound (220 mg).

[0675] Reference Example 21: 6,7-dihydro-5H-thieno[3,2-b]pyran-2-carboxylic acid

[0676] A 2N sodium hydroxide aqueous solution (0.5 mL) was added to a methanol (1 mL) solution of the compound (20 mg) prepared in Reference Example 20, and the mixture was stirred at 60 °C for 1 hour. 1N hydrochloric acid was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting title compound was used in subsequent reactions without purification.

[0677] HPLC retention time (minutes): 1.00 (formic acid);

[0678] MS(ESI,Pos.): 449(M+H) + ;

[0679] 1 H-NMR(DMSO-d6): δ7.55-7.43,7.10,6.89-6.60,4.67-4.62,4.17-4.07,4.05-3.87,3.73,3.67 ,3.42-3.40,3.37-3.33,3.30,3.22-3.04,2.79-2.70,2.58-2.53,2.17,2.09-1.85,1.71-1.37.

[0680] Reference Example 22: 6,7-Dihydrothiopheno[3,2-c]pyridine-2,5(4H)-dicarboxylic acid dimethyl ester

[0681] In a 1 mL solution of methyl 4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxylic acid (CAS No.: 221316-61-6, 50 mg) in dichloromethane, 0.11 mL of triethylamine and methyl chloroformate (CAS No.: 79-22-1, 72 mg) were added at 0 °C, and the mixture was stirred at room temperature for 15 hours. 2N hydrochloric acid was added to the reaction mixture, and the mixture was extracted with dichloromethane. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting title compound was used in subsequent reactions without purification.

[0682] Reference Example 23: 5-(methoxycarbonyl)-4,5,6,7-tetrahydrothiopheno[3,2-c]pyridine-2-carboxylic acid

[0683] A 2N sodium hydroxide aqueous solution (0.5 mL) was added to a methanol (1 mL) solution of the compound (20 mg) prepared in Reference Example 22, and the mixture was stirred at 50 °C for 1 hour. 1N hydrochloric acid was added to the reaction mixture, the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting title compound was used in subsequent reactions without purification.

[0684] Reference Example 24: 4,4-Dimethyl-6,7-dihydrothiopheno[3,2-c]pyran

[0685] 2,2-Dimethoxypropane (CAS No.: 77-76-9, 0.38 mL) and ferric trifluoromethanesulfonate (CAS No.: 63295-48-7, 15.7 mg) were added to a 4 mL solution of 2-(2-thienyl)ethanol (CAS No.: 160774-13-8, 400 mg) in toluene, and the mixture was stirred at 70 °C for 17 hours. Triethylamine (0.22 mL) was added to the reaction mixture, and the mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the title compound (284 mg).

[0686] TLC: Rf 0.50 (ethyl acetate: n-hexane = 1:9);

[0687] HPLC retention time (minutes): 1.07 (TFA);

[0688] MS (ESI, Pos.): 169 (M+H) + .

[0689] Reference Example 25: 4,4-Dimethyl-6,7-dihydrothieno[3,2-c]pyran-2-carboxylic acid

[0690] In a THF (10 mL) solution of the compound (284 mg) prepared in Reference Example 24, 1.6 M n-butyllithium solution and hexane solution (CAS No.: 109-72-8, 1.2 mL) were added at -78 °C, and the mixture was stirred at -78 °C for 2 hours. Then, dry ice (1 g) was added to the reaction mixture, and the mixture was stirred at room temperature for 2 hours. Water and a 1 N aqueous sodium hydroxide solution were added to the reaction mixture, and the aqueous layer was washed with methyl tert-butyl ether. A 1 N aqueous hydrochloric acid solution was added to the aqueous layer to adjust the pH to 1, and the layer was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the title compound (306 mg).

[0691] HPLC retention time (minutes): 0.89 (TFA);

[0692] MS(ESI,Pos.): 213(M+H) + .

[0693] Reference Example 26: 4H-pyrano[3,4-d]thiazolyl-7-one

[0694] A solution of 2-amino-4H-pyrano[3,4-d]thiazolyl-7-one (CAS No.: 1253281-38-7, 873 mg) in THF (17.5 mL) was mixed with 0.97 mL of n-amyl nitrite (CAS No.: 463-04-7), and stirred at 60 °C for 15 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound (568 mg).

[0695] TLC: Rf 0.28 (ethyl acetate: n-hexane = 1:2).

[0696] Reference Example 27: 7-Methylene-4H-pyrano[3,4-d]thiazole

[0697] A 1.3N lithium bis(trimethylsilyl)amide THF solution (CAS No.: 4039-32-1, 0.55 mL) was added to a 1.5 mL THF solution of methyltriphenylphosphonium bromide (CAS No.: 1779-49-3, 253 mg) at 0 °C, and the mixture was stirred at 0 °C for 1 hour. Then, the compound prepared in Reference Example 26 (100 mg) was added, and the mixture was stirred at 0 °C for 40 minutes. A saturated aqueous solution of ammonium chloride was added to the reaction mixture, and the aqueous layer was extracted with dichloromethane. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound (90 mg).

[0698] TLC: Rf 0.5 (ethyl acetate: n-hexane = 1:2).

[0699] Reference Example 28: 7-Methyl-6,7-dihydro-4H-pyrano[3,4-d][1,3]thiazole

[0700] 20% palladium hydroxide (10 mg) was added to a methanol (1.8 mL) solution of the compound prepared in Reference Example 27, and the mixture was stirred at room temperature for 7 hours under a hydrogen atmosphere. The reaction solution was filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound (40 mg).

[0701] Reference Example 29: 7-Methyl-6,7-dihydro-4H-pyrano[3,4-d][1,3]thiazole-2-carboxylic acid

[0702] In a 2 mL THF solution of the compound (40 mg) prepared in Reference Example 28, 0.16 mL of 1.6 M n-butyllithium hexane solution was added at -78 °C, and the mixture was stirred at -78 °C for 1 hour. Then, 300 mg of dry ice was added to the reaction mixture, and the mixture was stirred at room temperature for 1 hour. Water and a 1 N aqueous sodium hydroxide solution were added to the reaction mixture, and the aqueous layer was washed with methyl tert-butyl ether. A 1 N aqueous hydrochloric acid solution was added to the aqueous layer to adjust the pH to 1, and the layer was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the title compound (20 mg).

[0703] HPLC retention time (minutes): 0.76 (TFA);

[0704] MS(ESI,Pos.): 200(M+H) + .

[0705] Reference Example 30: Methyl 5-hydroxy-2-thiophenecarboxylate

[0706] A solution of thiophene-2-carboxylic acid methyl ester-5-boronic acid (CAS No.: 876189-21-8, 120 mg) in polyethylene glycol 200 (CAS No.: 25322-68-3, 0.64 mL) was added to a 30% aqueous hydrogen peroxide solution (CAS No.: 7722-84-1, 0.11 mL), and the mixture was stirred at room temperature for 2 hours. Water was added to the reaction mixture, and the mixture was extracted with methyl tert-butyl ether. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound (23 mg).

[0707] HPLC retention time (minutes): 0.84 (TFA);

[0708] MS (ESI, Pos.): 171 (M+Na) + .

[0709] Reference Example 31: Methyl 5-(difluoromethoxy)-2-thiophenecarboxylate

[0710] In a DMF (0.2 mL) solution of the compound (23 mg) prepared in Reference Example 30, dichlorofluoroacetic acid (CAS No.: 76-04-0, 0.027 mL) and cesium carbonate (CAS No.: 534-17-8, 142 mg) were added, and the mixture was stirred at 100 °C for 10 minutes. Water was added to the reaction 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 residue was purified by silica gel column chromatography to give the title compound (31 mg).

[0711] HPLC retention time (minutes): 1.06 (TFA);

[0712] MS(ESI,Pos.): 209(M+H) + .

[0713] Reference Example 32: 5-(difluoromethoxy)-2-thiophenic acid

[0714] Methanol (0.1 mL) and 1N lithium hydroxide aqueous solution (CAS No.: 1310-65-2, 0.2 mL) were added to a THF (0.2 mL) solution of the compound (31 mg) prepared in Reference Example 31, and the mixture was stirred at room temperature for 16 hours. 1N hydrochloric acid aqueous solution was added to the reaction mixture to adjust the pH of the aqueous layer to 1, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the title compound (21 mg).

[0715] HPLC retention time (minutes): 0.91 (TFA);

[0716] MS (ESI, Pos.): 195 (M+H) + .

[0717] Reference Example 33: Methyl 3-iodo-1H-thieno[3,2-c]pyrazole-5-carboxylic acid

[0718] Potassium hydroxide (CAS No.: 1310-58-3, 140 mg) and iodine (CAS No.: 7553-56-2, 570 mg) were added to a 2 mL solution of methyl 1H-thieno[3,2-c]pyrazole-5-carboxylate (CAS No.: 1246552-43-1, 185 mg) in DMF, and the mixture was stirred at 0 °C for 1 hour. 2N hydrochloric acid was added to the reaction mixture, followed by a saturated aqueous solution of sodium thiosulfate, 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 residue was washed with hexane and ethyl acetate to give the title compound (180 mg).

[0719] Reference Example 34: Methyl 3-(3-hydroxy-1-propyn-1-yl)-1H-thieno[3,2-c]pyrazole-5-carboxylic acid

[0720] In a 1 mL THF solution of the compound (40 mg) prepared in Reference Example 33, propargyl alcohol (CAS No.: 107-19-7, 11 mg), copper iodide (I) (CAS No.: 7681-65-4, 2.5 mg), tetrakis(triphenylphosphine)palladium (0) (CAS No.: 14221-01-3, 15 mg), and triethylamine (0.09 mL) were added, and the mixture was stirred at 60 °C for 1 hour. Water was added to the reaction 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 residue was purified by silica gel column chromatography to give the title compound (23 mg).

[0721] HPLC retention time (minutes): 0.84 (formic acid);

[0722] MS(ESI,Pos.): 237(M+H) + .

[0723] Reference Example 35: Methyl 3-(3-hydroxypropyl)-1H-thieno[3,2-c]pyrazole-5-carboxylic acid

[0724] 20% palladium hydroxide (25 mg) was added to a methanol (1 mL) solution of the compound (23 mg) prepared in Reference Example 34, and the mixture was stirred at room temperature for 6 hours under a hydrogen atmosphere. The reaction solution was filtered, concentrated under reduced pressure, and the resulting title compound was used in subsequent reactions without purification.

[0725] Reference Example 36: methyl 7,8-dihydro-6H-pyrrolo[1,2-b]thieno[2,3-d]pyrazole-2-carboxylate

[0726] A solution of the compound (18 mg) prepared in Reference Example 35 in toluene (0.5 mL) was mixed with cyanomethylenetributylphosphine (CAS No.: 157141-27-0, 27 mg), and stirred at 60 °C for 1 hour. The title compound (10 mg) was obtained by purification by silica gel column chromatography.

[0727] 1 H-NMR (CDCl3): δ7.85, 4.38, 3.83, 3.10, 2.73.

[0728] Reference Example 37: 7,8-dihydro-6H-pyrrolo[1,2-b]thieno[2,3-d]pyrazole-2-carboxylic acid

[0729] A 2N sodium hydroxide aqueous solution (0.5 mL) was added to a methanol (1 mL) solution of the compound (20 mg) prepared in Reference Example 36, and the mixture was stirred at 60 °C for 1 hour. 1N hydrochloric acid was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting title compound was used in subsequent reactions without purification.

[0730] Reference Example 38: Methyl 5-methyl-4-(1-methyl-1H-pyrazole-4-yl)-2-thiophenecarboxylate

[0731] A solution of methyl 4-bromo-5-methylthiophene-2-carboxylic acid (CAS No.: 237385-15-8, 30 mg) in toluene (0.75 mL) was mixed with water (0.37 mL), 1-methyl-1H-pyrazole-4-boronic acid (CAS No.: 847818-55-7, 48 mg), cesium carbonate (124 mg), and tetrakis(triphenylphosphine)palladium (0) (15 mg). The mixture was stirred at 80 °C for 13 hours. The reaction mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound (10 mg).

[0732] HPLC retention time (minutes): 1.00 (formic acid);

[0733] MS(ESI,Pos.): 237(M+H) + .

[0734] Reference Example 39: 5-Methyl-4-(1-Methyl-1H-pyrazole-4-yl)-2-thiophenic acid

[0735] A 2N sodium hydroxide aqueous solution (0.5 mL) was added to a methanol (1 mL) solution of the compound (20 mg) prepared in Reference Example 38, and the mixture was stirred at 60 °C for 1 hour. 1N hydrochloric acid was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting title compound was used in subsequent reactions without purification.

[0736] Reference Example 40: Methyl 2,3-dimethyl-2H-thieno[2,3-c]pyrazole-5-carboxylic acid

[0737] Sodium hydride (2.9 mg) and methyl iodo[2,3-c]pyrazole-5-carboxylic acid methyl ester (CAS No.: 873072-42-5, 20 mg) were added to a DMF (1.0 mL) solution, and the mixture was stirred at room temperature for 3 hours. 2N hydrochloric acid was added to the reaction solution, and the organic layer was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the title compound (10 mg).

[0738] 1 H-NMR (CDCl3): δ7.69, 3.95, 3.89, 2.52.

[0739] Reference Example 41: 2,3-Dimethyl-2H-thieno[2,3-c]pyrazole-5-carboxylic acid

[0740] A 2N sodium hydroxide aqueous solution (0.5 mL) was added to a methanol (1 mL) solution of the compound (20 mg) prepared in Reference Example 40, and the mixture was stirred at 60 °C for 1 hour. 1N hydrochloric acid was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting title compound was used in subsequent reactions without purification.

[0741] Reference Example 42: methyl 2-methyl-2H-thieno[3,2-c]pyrazole-5-carboxylic acid methyl ester

[0742] Cesium carbonate (7.2 g) and methyl iodomethane (1.6 g) were added to a THF (40 mL) solution of methyl 1H-thieno[3,2-c]pyrazole-5-carboxylic acid ester (2.0 g), and the mixture was stirred at room temperature for 3 hours. 2N hydrochloric acid was added to the reaction solution, and the organic layer was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound (1.05 g).

[0743] 1H-NMR (CDCl3): δ7.70, 7.66, 4.06, 3.93.

[0744] Reference Example 43: 2-Methyl-2H-thieno[3,2-c]pyrazole-5-carboxylic acid

[0745] A 2N sodium hydroxide aqueous solution (0.5 mL) was added to a methanol (1 mL) solution of the compound (20 mg) prepared in Reference Example 42, and the mixture was stirred at 60 °C for 1 hour. 1N hydrochloric acid was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting title compound was used in subsequent reactions without purification.

[0746] Reference Example 44: methyl 2-cyclopropyl-2H-thieno[3,2-c]pyrazole-5-carboxylate

[0747] A solution of methyl 1H-thieno[3,2-c]pyrazole-5-carboxylate (1.0 g) in dichloroethane (20 mL) was mixed with cyclopropylboronic acid (CAS No. 873072-42-5, 940 mg), sodium carbonate (CAS No. 497-19-8, 1200 mg), copper(II) acetate (CAS No. 142-71-2, 1.1 g), and 1,10-phenanthroline (CAS No. 66-71-7, 1.1 g), and stirred at 70 °C for 15 hours. 1 N hydrochloric acid was added to the reaction mixture, and the organic layer was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound (200 mg).

[0748] HPLC retention time (minutes): 1.00 (formic acid);

[0749] MS(ESI,Pos.): 223(M+H) + .

[0750] Reference Example 45: 2-Cyclopropyl-2H-thieno[3,2-c]pyrazole-5-carboxylic acid

[0751] A 2N sodium hydroxide aqueous solution (0.5 mL) was added to a methanol (1 mL) solution of the compound (20 mg) prepared in Reference Example 44, and the mixture was stirred at 60 °C for 1 hour. 1N hydrochloric acid was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting title compound was used in subsequent reactions without purification.

[0752] Reference Example 46: Methyl 2-(difluoromethyl)-2H-thieno[3,2-c]pyrazole-5-carboxylic acid

[0753] Sodium dichlorofluoroacetate (CAS No.: 1895-39-2, 2100 mg) and potassium carbonate (1900 mg) were added to a DMF (10 mL) solution of methyl 1H-thieno[3,2-c]pyrazole-5-carboxylate (500 mg) and 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 residue was purified by silica gel column chromatography to give the title compound (85 mg).

[0754] Reference Example 47: 2-(difluoromethyl)-2H-thieno[3,2-c]pyrazole-5-carboxylic acid

[0755] A 2N sodium hydroxide aqueous solution (0.5 mL) was added to a methanol (1 mL) solution of the compound (20 mg) prepared in Reference Example 46, and the mixture was stirred at 60 °C for 1 hour. 1N hydrochloric acid was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting title compound was used in subsequent reactions without purification.

[0756] Reference Example 48: (1) methyl 2-(2,2,2-trifluoroethyl)-2H-thieno[3,2-c]pyrazole-5-carboxylate and (2) methyl 1-(2,2,2-trifluoroethyl)-2H-thieno[3,2-c]pyrazole-5-carboxylate

[0757] Cesium carbonate (720 mg) and 2,2,2-trifluoroethyl trifluoromethanesulfonate (CAS No.: 6226-25-1, 510 mg) were added to a DMF (5 mL) solution of methyl 1H-thieno[3,2-c]pyrazole-5-carboxylate (200 mg) and stirred at room temperature for 15 hours. Water was added to the reaction solution and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain (1) 61 mg and (2) 71 mg of the title compound, respectively.

[0758] (1) TLC: Rf 0.31 (ethyl acetate: n-hexane = 1:3);

[0759] (2) TLC: Rf 0.34 (ethyl acetate: n-hexane = 1:3).

[0760] Reference Example 49: 2-(2,2,2-trifluoroethyl)-2H-thieno[3,2-c]pyrazole-5-carboxylic acid

[0761] A 2N aqueous solution of sodium hydroxide (0.5 mL) was added to a methanol (1 mL) solution of the compound (60 mg) prepared in Reference Example 48(1), and the mixture was stirred at 60 °C for 1 hour. 1N hydrochloric acid was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting title compound was used in subsequent reactions without purification.

[0762] Reference Example 50: 1-(2,2,2-trifluoroethyl)-1H-thieno[3,2-c]pyrazole-5-carboxylic acid

[0763] A 2N sodium hydroxide aqueous solution (0.5 mL) was added to a methanol (1 mL) solution of the compound (60 mg) prepared in Reference Example 48(2), 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 resulting title compound was used in subsequent reactions without purification.

[0764] Reference Example 51: 2,3-Dimethyl-2H-thieno[3,2-c]pyrazole-5-carboxylic acid

[0765] The title compound was obtained by replacing methyl 3-methyl-1H-thieno[3,2-c]pyrazole-5-carboxylate (CAS No.: 1379258-29-3) with methyl 3-methyl-1H-thieno[2,3-c]pyrazole-5-carboxylate and performing the same operation as in Reference Examples 40 to 41.

[0766] Example 3: 2-{[(3aS,4R,6aR)-4-[(6-bromo-3-pyridazinyl)amino]hexahydrocyclopentano[c]pyrrolo-2(1H)-yl]carbonyl}-4-methyl-6,7-dihydrothiopheno[3,2-b]pyridin-5(4H)-one

[0767] [Chemical Formula 48]

[0768]

[0769] DIPEA (0.016 mL) and HATU (10 mg) were added to a DMA (0.25 mL) solution of the compound (5 mg) prepared in Reference Example 12 and the compound (9.2 mg) prepared in Reference Example 17, and the mixture was stirred at room temperature for 3 hours. Water was added to the reaction mixture, and the mixture was extracted with dichloromethane. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound (4.7 mg).

[0770] HPLC retention time (minutes): 0.89 (formic acid);

[0771] MS(ESI,Pos.): 476(M+H) + ;

[0772] 1 H-NMR (DMSO-d6): δ7.44,7.38,7.28,6.80,4.10-3.96,3.24,3.18-3.03,3.01-2.87,2.85,2.71-2.57,2.25-2.10,2.10-1.96,1.62-1.45.

[0773] Examples 3-1 to 3-14

[0774] The compound prepared in Reference Example 21, Reference Example 23, Reference Example 25, Reference Example 29, Reference Example 32, Reference Example 37, Reference Example 39, Reference Example 41, Reference Example 43, Reference Example 45, Reference Example 47, Reference Example 49, Reference Example 50 or Reference Example 51 was used instead of the compound prepared in Reference Example 17. The compound prepared in Reference Example 12 or the compound prepared in Reference Example 10 was used instead of the compound prepared in Reference Example 12. The same operation as in Example 3 was performed to obtain the title compound.

[0775] Example 3-1: [(3aS,4R,6aR)-4-[(6-bromo-3-pyridazinyl)amino]hexahydrocyclopentano[c]pyrrolo-2(1H)-yl](6,7-dihydro-5H-thieno[3,2-b]pyran-2-yl) methyl ketone

[0776] [Chemical Formula 49]

[0777]

[0778] HPLC retention time (minutes): 0.74 (formic acid);

[0779] MS (ESI, Pos.): 400 (M+H) + ;

[0780] 1 H-NMR(DMSO-d6): δ9.46-9.25,8.63-8.43,8.40-8.30,8.29-8.14,7.43-7.30,6.97-6.83,4.20-4. 00,3.99-3.65,3.15-3.04,3.04-2.79,2.77-2.57,2.27-2.15,2.14-1.98,1.70-1.58,1.58-1.48.

[0781] Example 3-2: 2-{[(3aS,4R,6aR)-4-[(6-bromo-3-pyridazinyl)amino]hexahydrocyclopentano[c]pyrrolo-2(1H)-yl]carbonyl}-6,7-dihydrothiopheno[3,2-c]pyridine-5(4H)-carboxylic acid methyl ester

[0782] [Chemical Formula 50]

[0783]

[0784] HPLC retention time (minutes): 0.97 (formic acid);

[0785] MS(ESI,Pos.): 506(M+H) + ;

[0786] 1 H-NMR(DMSO-d6): δ7.49-7.44,7.44-7.31,6.86-6.78,4.57-4.41,4.07-4.00,3.67 ,3.64,3.20-3.05,2.81,2.71-2.45,2.27-2.12,2.09-1.95,1.64-1.54,1.54-1.42.

[0787] Example 3-3: [(3aS,4R,6aR)-4-[(6-chloro-3-pyridazinyl)amino]hexahydrocyclopentano[c]pyrrolo-2(1H)-yl](4,4-dimethyl-6,7-dihydro-4H-thieno[3,2-c]pyran-2-yl) methyl ketone

[0788] [Chemical Formula 51]

[0789]

[0790] HPLC retention time (minutes): 0.88 (TFA);

[0791] MS (ESI, Pos.): 435 (M+H) + ;

[0792] 1 H-NMR (CDCl3): δ7.23,7.18,6.63,4.70,4.11,3.98,3.95-3.83,3.66,3.49,2.89,2.83,2.69,2.40-2.30,2.17-2.08,1.68-1.58,1.48.

[0793] Examples 3-4: [(3aS,4R,6aR)-4-[(6-chloro-3-pyridazinyl)amino]hexahydrocyclopentano[c]pyrrolo-2(1H)-yl](7-methyl-6,7-dihydro-4H-pyrano[3,4-d][1,3]thiazolyl-2-yl) methyl ketone

[0794] [Chemical Formula 52]

[0795]

[0796] HPLC retention time (minutes): 0.88 (TFA);

[0797] MS(ESI,Pos.): 420(M+H) + ;

[0798] 1 H-NMR (CDCl3): δ7.18,6.63,4.85-4.66,4.25-4.17,4.15-4.02,3.85,3.55-3.46,3.22,3.03-2.55,2.35,2.13,1.68-1.57,1.29.

[0799] Examples 3-5: [(3aS,4R,6aR)-4-[(6-chloro-3-pyridazinyl)amino]hexahydrocyclopenta[c]pyrrolo-2(1H)-yl][5-(difluoromethoxy)-2-thienyl]methyl ketone

[0800] [Chemical Formula 53]

[0801]

[0802] HPLC retention time (minutes): 0.91 (TFA);

[0803] MS(ESI,Pos.): 415(M+H) + ;

[0804] 1 H-NMR (CDCl3): δ7.32-7.28,7.26-7.16,6.67-6.61,6.64,4.69,4.16-4.0 6,4.02,3.87,3.66,3.66,2.88,2.70,2.41-2.31,2.18-2.08,1.69-1.58.

[0805] Examples 3-6: [(3aS,4R,6aR)-4-[(6-bromo-3-pyridazinyl)amino]hexahydrocyclopentano[c]pyrrolo-2(1H)-yl](7,8-dihydro-6H-pyrrolo[1,2-b]thieno[2,3-d]pyrazol-2-yl) methyl ketone

[0806] [Chemical Formula 54]

[0807]

[0808] HPLC retention time (minutes): 0.92 (formic acid);

[0809] MS(ESI,Pos.): 473(M+H) + ;

[0810] 1 H-NMR(DMSO-d6): δ7.63,7.50-7.42,7.41-7.28,6.88-6.76,4.32-4.21,4.10-3.95,3.91 -3.61,3.07-2.96,2.96-2.77,2.68-2.58,2.24-2.14,2.10-1.92,1.69-1.55,1.55-1.46.

[0811] Examples 3-7: [(3aS,4R,6aR)-4-[(6-bromo-3-pyridazinyl)amino]hexahydrocyclopentano[c]pyrrolo-2(1H)-yl][5-methyl-4-(1-methyl-1H-pyrazol-4-yl)-2-thienyl] methyl ketone

[0812] [Chemical Formula 55]

[0813]

[0814] HPLC retention time (minutes): 0.88 (formic acid);

[0815] MS(ESI,Pos.): 487(M+H) + ;

[0816] 1 H-NMR(DMSO-d6): δ8.05-7.98,7.78-7.70,7.59,7.49-7.42,7.42-7.32,6.87-6.76,4.09-4.00 ,3.88,3.34-3.18,2.94-2.75,2.72-2.57,2.48,2.26-2.14,2.09-1.95,1.64-1.55,1.55-1.46.

[0817] Examples 3-8: [(3aS,4R,6aR)-4-[(6-bromo-3-pyridazinyl)amino]hexahydrocyclopentano[c]pyrrolo-2(1H)-yl](2,3-dimethyl-2H-thieno[2,3-c]pyrazol-5-yl) methyl ketone

[0818] [Chemical Formula 56]

[0819]

[0820] HPLC retention time (minutes): 0.83 (TFA);

[0821] MS(ESI,Pos.): 461(M+H) + ;

[0822] 1 H-NMR (CDCl3): δ7.33-7.27,7.26,6.55,4.80,4.15-4.06,4.02-3.93,3.91,3.69,2.88,2.70,2.55-2.47,2.39-2.24,2.18-2.02,1.69-1.61.

[0823] Examples 3-9: [(3aS,4R,6aR)-4-[(6-bromo-3-pyridazinyl)amino]hexahydrocyclopentano[c]pyrrolo-2(1H)-yl](2-methyl-2H-thieno[3,2-c]pyrazol-5-yl) methyl ketone

[0824] [Chemical Formula 57]

[0825]

[0826] HPLC retention time (minutes): 0.87 (TFA);

[0827] MS(ESI,Pos.): 447(M+H) + ;

[0828] 1 H-NMR(CDCl3): δ7.57,7.43,7.33-7.27,6.54,4.83,4.17-4.10,4.10-4.0 2,3.94,3.91-3.80,3.69,2.92,2.71,2.40-2.30,2.18-2.04,1.70-1.61.

[0829] Examples 3-10: [(3aS,4R,6aR)-4-[(6-bromo-3-pyridazinyl)amino]hexahydrocyclopentano[c]pyrrolo-2(1H)-yl](2-cyclopropyl-2H-thieno[3,2-c]pyrazol-5-yl) methyl ketone

[0830] [Chemical Formula 58]

[0831]

[0832] HPLC retention time (minutes): 0.86 (TFA);

[0833] MS(ESI,Pos.): 473(M+H) + ;

[0834] 1 H-NMR (CDCl3): δ7.67,7.40,7.34-7.27,6.55,4.92,4.15-3.95,3.93,3.9 0-3.78,3.68,2.90,2.70,2.39-2.28,2.18-2.03,1.71-1.65,1.30-1.09.

[0835] Example 3-11: [(3aS,4R,6aR)-4-[(6-bromo-3-pyridazinyl)amino]hexahydrocyclopentano[c]pyrrolo-2(1H)-yl][2-(difluoromethyl)-2H-thieno[3,2-c]pyrazol-5-yl] methyl ketone

[0836] [Chemical Formula 59]

[0837]

[0838] HPLC retention time (minutes): 0.90 (TFA);

[0839] MS(ESI,Pos.): 483(M+H) + ;

[0840] 1 H-NMR (CDCl3): δ8.02,7.48,7.42,7.35-7.27,7.18,6.71-6.49,4.14-3.98,3.89,3.69,3.05-2.83,2.74,2.40-2.31,2.15,2.05,1.68.

[0841] Examples 3-12: [(3aS,4R,6aR)-4-[(6-bromo-3-pyridazinyl)amino]hexahydrocyclopentano[c]pyrrolo-2(1H)-yl][1-(2,2,2-trifluoroethyl)-1H-thieno[3,2-c]pyrazol-5-yl] methyl ketone

[0842] [Chemical Formula 60]

[0843]

[0844] HPLC retention time (minutes): 1.00 (formic acid);

[0845] MS(ESI,Pos.): 515(M+H) + ;

[0846] 1 H-NMR(DMSO-d6): δ7.97,7.89-7.81,7.52-7.43,7.43-7.33,6.90-6.72,5.48-5.31,4.19 -4.05,4.04-3.92,3.92-3.71,3.01-2.63,2.27-2.15,2.12-2.00,1.66-1.57,1.57-1.47.

[0847] Examples 3-13: [(3aS,4R,6aR)-4-[(6-bromo-3-pyridazinyl)amino]hexahydrocyclopentano[c]pyrrolo-2(1H)-yl][2-(2,2,2-trifluoroethyl)-2H-thieno[3,2-c]pyrazol-5-yl] methyl ketone

[0848] [Chemical Formula 61]

[0849]

[0850] HPLC retention time (minutes): 0.90 (TFA);

[0851] MS(ESI,Pos.): 515(M+H) + ;

[0852] 1 H-NMR (CDCl3): δ7.71,7.42,7.26,6.55,4.90,4.16-3.97,3.94,3.86,3.68,2.92,2.72,2.40-2.30,2.15-2.07,1.71-1.55.

[0853] Examples 3-14: [(3aS,4R,6aR)-4-[(6-bromo-3-pyridazinyl)amino]hexahydrocyclopentano[c]pyrrolo-2(1H)-yl](2,3-dimethyl-2H-thieno[3,2-c]pyrazol-5-yl) methyl ketone

[0854] [Chemical Formula 62]

[0855]

[0856] HPLC retention time (minutes): 0.91 (formic acid);

[0857] MS(ESI,Pos.): 461(M+H) + .

[0858] Reference Example 52: 1-(5-((3aS,4R,6aR)-4-((6-bromopyridazine-3-yl)amino)octahydrocyclopentano[c]pyrrole-2-carbonyl)thiophene-2-yl)ethane-1-one

[0859] In a DMA (0.25 mL) solution of the compound (10 mg) prepared in Reference Example 12, 5-acetylthiophene-2-carboxylic acid (CAS: 4066-41-5, 6.0 mg), DIPEA (0.030 mL), and HATU (20 mg) were added, and the mixture was stirred at room temperature for 3 hours. Water was added to the reaction 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 residue was purified by silica gel column chromatography to give the title compound (15 mg).

[0860] Example 4: [(3aS,4R,6aR)-4-[(6-bromo-3-pyridazinyl)amino]hexahydrocyclopentano[c]pyrrole-2(1H)-yl][5-(2-hydroxy-2-propyl)-2-thienyl]methyl ketone

[0861] [Chemical Formula 63]

[0862]

[0863] 3M methylmagnesium bromide (CAS: 75-16-1, 0.03 mL) was added to a THF (0.3 mL) solution of the compound (5 mg) prepared in Reference Example 52, and the mixture was stirred at room temperature for 3 hours. Water was added to the reaction mixture, and the solution was extracted with dichloromethane. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound (1.3 mg).

[0864] HPLC retention time (minutes): 0.89 (formic acid);

[0865] MS(ESI,Pos.): 451(M+H) + .

[0866] Example 5: [(3aS,4R,6aR)-4-[(6-iodo-3-pyridazinyl)amino]hexahydrocyclopenta[c]pyrrolo-2(1H)-yl](5-methyl-2-thienyl)methyl ketone

[0867] [Chemical Formula 64]

[0868]

[0869] In a 1,4-dioxane (0.1 mL) solution of the compound (10 mg) prepared in Example 2, copper iodide (I) (3.0 mg), sodium iodide (CAS: 7681-82-5, 7.4 mg), and N,N'-dimethylethylenediamine (CAS: 110-70-3, 2.8 mg) were added, and the mixture was stirred at 110 °C for 18 hours. Ammonia solution was added to the reaction mixture, and the solution was extracted with dichloromethane. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound (7.6 mg).

[0870] HPLC retention time (minutes): 0.88 (TFA);

[0871] MS(ESI,Pos.): 455(M+H) + .

[0872] Example 6: Racemic mixture of rel-{(3aS,4R,6aR)-4-[(6-bromo-3-pyridazinyl)(methyl)amino]hexahydrocyclopenta[c]pyrrolo-2(1H)-yl}(5-methyl-2-thienyl)methyl ketone

[0873] [Chemical Formula 65]

[0874]

[0875] The compound prepared in Reference Example 12-1 was used instead of the compound prepared in Reference Example 12, and the same operation as in Examples 2 to 16 was performed to obtain the title compound.

[0876] HPLC retention time (minutes): 1.10 (formic acid);

[0877] MS(ESI,Pos.): 421(M+H) + ;

[0878] 1 H-NMR (DMSO-d6): δ7.55,7.38,7.19-7.10,6.83,4.86,3.62,3.27,3.22-3.05,2.93,2.81,2.49-2.43,2.06-1.96,1.90-1.75,1.58-1.45.

[0879] Examples 6-1 to 6-9

[0880] The title compound was obtained by using iodomethane or a corresponding halogen compound instead of iodomethane, using 5-methyl-2-thiophenic acid or a corresponding carboxylic acid instead of 5-methyl-2-thiophenic acid, using the compound prepared in Reference Example 12 or the compound prepared in Reference Example 10-1 or the compound prepared in Reference Example 12-1 instead of the compound prepared in Reference Example 12, and performing the same operations as in Examples 2 to 16.

[0881] Example 6-1: rel-{(3aS,4R,6aR)-4-[(6-bromo-3-pyridazinyl)(butyl)amino]hexahydrocyclopenta[c]pyrrolo-2(1H)-yl}(5-methyl-2-thienyl)methyl ketone racemic mixture

[0882] [Chemical Formula 66]

[0883]

[0884] HPLC retention time (minutes): 1.30 (formic acid);

[0885] MS(ESI,Pos.): 463(M+H) + ;

[0886] 1 H-NMR(DMSO-d6): δ7.51,7.38,7.12-7.05,6.83,4.66-4.58,3.62,3.47,3.45-3.43,3.35 -3.25,3.22-3.05,2.84,2.45,2.06-1.91,1.83-1.75,1.54-1.40,1.38-1.23,1.18,0.92.

[0887] Example 6-2: [(3aS,4R,6aR)-4-[benzyl(6-bromo-3-pyridazinyl)amino]hexahydrocyclopentano[c]pyrrole-2(1H)-yl](5-methyl-2-thienyl)methyl ketone

[0888] [Chemical Formula 67]

[0889]

[0890] HPLC retention time (minutes): 1.20 (TFA);

[0891] MS(ESI,Pos.): 497(M+H) + ;

[0892] 1H-NMR (CDCl3): δ7.36-7.27,7.21-7.16,6.73,6.48,5.09,4.60,3.92-3.73,3.62,2.82,2.50,2.29-2.21,2.14-2.03,1.89,1.62-1.56.

[0893] Example 6-3: [(3aS,4R,6aR)-4-[(6-bromo-3-pyridazinyl)(methyl)amino]hexahydrocyclopentano[c]pyrrolo-2(1H)-yl](6,7-dihydro-4H-thieno[3,2-c]pyran-2-yl) methyl ketone

[0894] [Chemical Formula 68]

[0895]

[0896] HPLC retention time (minutes): 1.00 (formic acid);

[0897] MS(ESI,Pos.): 463(M+H) + ;

[0898] 1 H-NMR (DMSO-d6): δ7.61-7.49,7.32,7.21-7.06,4.95-4.81,4.59,3.87,3. 82-3.56,3.37-3.29,3.14-3.03,2.92,2.09-1.93,1.84-1.71,1.57-1.45.

[0899] Example 6-4: rel-{(3aS,4R,6aR)-4-[(6-chloro-3-pyridazinyl)(3-methoxypropyl)amino]hexahydrocyclopenta[c]pyrrolo-2(1H)-yl}[5-(difluoromethyl)-2-thienyl]methyl ketone racemic mixture

[0900] [Chemical Formula 69]

[0901]

[0902] HPLC retention time (minutes): 1.10 (formic acid);

[0903] MS(ESI,Pos.): 471(M+H) + ;

[0904] 1H-NMR(DMSO-d6): δ7.68-7.54,7.52-7.42,7.43-7.21,7.25-7.15,4.71-4.59,4.04-3.84 ,3.64,3.44-3.41,3.31,3.26,3.24-3.15,3.01-2.71,2.07-1.91,1.85-1.68,1.58-1.44.

[0905] Examples 6-5: rel-{(3aS,4R,6aR)-4-[(6-chloro-3-pyridazinyl)(imidazo[2,1-b][1,3]thiazo-6-ylmethyl)amino]hexahydrocyclopenta[c]pyrrolo-2(1H)-yl}[5-(difluoromethyl)-2-thienyl]methyl ketone racemic mixture

[0906] [Chemical Formula 70]

[0907]

[0908] HPLC retention time (minutes): 0.98 (formic acid);

[0909] MS(ESI,Pos.): 535(M+H) + ;

[0910] 1 H-NMR (DMSO-d6): δ7.88-7.75,7.71-7.53,7.53-7.17,5.03-4.78,4.65,4.03-3.59,3.15-3.05,2.97-2.74,2.14-1.97,1.96-1.79,1.58-1.43.

[0911] Examples 6-6: rel-{(3aS,4R,6aR)-4-[(6-chloro-3-pyridazinyl)(4-pyridylmethyl)amino]hexahydrocyclopenta[c]pyrrolo-2(1H)-yl}[5-(difluoromethyl)-2-thienyl]methyl ketone racemic mixture

[0912] [Chemical Formula 71]

[0913]

[0914] HPLC retention time (minutes): 0.88 (formic acid);

[0915] MS (ESI, Pos.): 490 (M+H) + ;

[0916] 1H-NMR (DMSO-d6): δ8.61,7.59,7.53,7.50-7.40,7.24,7.43-7.21,4.93-4.83,4.80,3.95,3.87,3. 66,3.23-3.08,3.00,2.88,2.78,2.67,2.55,2.10,1.99,1.77-1.63,1.62-1.45,1.32-1.22,1.18.

[0917] Examples 6-7: rel-2-{[(6-chloro-3-pyridazinyl)((3aS,4R,6aR)-2-{[5-(difluoromethyl)-2-thienyl]carbonyl}octahydrocyclopentano[c]pyrrolo-4-yl)amino]methyl}benzonitrile racemic mixture

[0918] [Chemical Formula 72]

[0919]

[0920] HPLC retention time (minutes): 1.20 (formic acid);

[0921] MS(ESI,Pos.): 514(M+H) + ;

[0922] 1 H-NMR (DMSO-d6): δ7.91-7.84,7.62,7.56-7.51,7.50-7.40,7.43-7.22,7.27-7.19,4.95-4.85,4.87 -4.76,4.02-3.87,3.71,3.42,3.32-3.24,3.14-3.05,2.96-2.67,2.16-2.07,2.06-1.94,1.57-1.38.

[0923] Examples 6-8: [(3aS,4R,6aR)-4-[(6-bromo-3-pyridazinyl)(3-fluoropropyl)amino]hexahydrocyclopenta[c]pyrrolo-2(1H)-yl](5-methyl-2-thienyl)methyl ketone

[0924] [Chemical Formula 73]

[0925]

[0926] HPLC retention time (minutes): 1.10 (TFA);

[0927] MS(ESI,Pos.): 467(M+H) + ;

[0928] 1H-NMR (CDCl3): δ7.32-7.28,6.79-6.72,4.60,4.48,3.82,3.71-3.52,2.91,2.51,2.20-2.02,1.98,1.66-1.58,1.50,1.33-1.19,0.82.

[0929] Examples 6-9: [(3aS,4R,6aR)-4-[(6-bromo-3-pyridazinyl)(methyl)amino]hexahydrocyclopenta[c]pyrrolo-2(1H)-yl](5-methyl-2-thienyl)methyl ketone

[0930] [Chemical Formula 74]

[0931]

[0932] HPLC retention time (minutes): 0.93 (TFA);

[0933] MS(ESI,Pos.): 421(M+H) + ;

[0934] 1 H-NMR (CDCl3): δ7.32-7.23,6.78-6.65,4.92-4.75,4.01-3.85,3.85-3.77,3.64,2.98,2.92-2.77,2.50,2.17-2.05,1.91-1.79,1.61-1.52.

[0935] Reference Example 53: Racemic mixture of rel-(3aS,6aR)-hexahydrocyclopentano[c]pyrrole-4(1H)-one hydrochloride

[0936] Using the compound prepared in Reference Example 1 instead of the compound prepared in Reference Example 3, the same operations as in Reference Examples 4 to 10 were performed to obtain the title compound.

[0937] Reference Example 53-1: (3aS,6aR)-hexahydrocyclopentano[c]pyrrole-4(1H)-keto hydrochloride

[0938] The title compound was obtained by replacing the compound prepared in Reference Example 9 with the compound prepared in Reference Example 3 and performing the same operation as in Reference Example 10.

[0939] Reference Example 54: racemic mixture of rel-(3aS,6aR)-2-(5-methylthiophene-2-carbonyl)hexahydrocyclopentano[c]pyrrole-4(1H)-one

[0940] In a DMA (100 mL) solution of the compound (5.0 g) prepared in Reference Example 53 and 5-methyl-2-thiophenic acid (6.6 g), DIPEA (22 mL) and HATU (17.6 g) were added, and the mixture was stirred at room temperature for 3 hours. 2N hydrochloric acid was added to the reaction mixture, and 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 residue was purified by silica gel column chromatography to give the title compound (7.0 g).

[0941] HPLC retention time (minutes): 0.88 (formic acid);

[0942] MS (ESI, Pos.): 250 (M+H) + .

[0943] Reference Example 54-1: (3aS,6aR)-2-(5-methylthiophene-2-carbonyl)hexahydrocyclopentano[c]pyrrole-4(1H)-one

[0944] The title compound was obtained by replacing the compound prepared in Reference Example 53 with the compound prepared in Reference Example 53-1 and performing the same operation as in Reference Example 54.

[0945] Reference Example 55: (rel-(3aS,4R,6aR)-4-(cyclopropylamino)hexahydrocyclopentano[c]pyrrole-2(1H)-yl)(5-methylthiophen-2-yl)methyl ketone racemic mixture

[0946] Cyclopropylamine (CAS: 765-30-0, 0.25 mL) and acetic acid (0.34 mL) were added to a 10 mL solution of the compound (300 mg) prepared in Reference Example 54 in dichloromethane, and the mixture was stirred at room temperature for 10 minutes. Sodium triacetoxyborohydride (CAS: 56553-60-7, 760 mg) was added, and the mixture was stirred at 40 °C for 3 hours. 2N sodium hydroxide was added to the reaction mixture, and 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 residue was purified by silica gel column chromatography to give the title compound (22 mg).

[0947] HPLC retention time (minutes): 0.78 (formic acid);

[0948] MS(ESI,Pos.): 291(M+H) + .

[0949] Example 7: Racemic mixture of rel-{(3aS,4R,6aR)-4-[(6-bromo-3-pyridazinyl)(cyclopropyl)amino]hexahydrocyclopenta[c]pyrrolo-2(1H)-yl}(5-methyl-2-thienyl)methyl ketone

[0950] [Chemical Formula 75]

[0951]

[0952] In a solution of the compound (20 mg) prepared in Reference Example 55 in tert-amyl alcohol (CAS: 75-85-4, 0.3 mL), 3-bromo-6-fluoropyridazine (CAS: 1353854-35-9, 39 mg) and DIPEA (0.083 mL) were added, and the mixture was stirred at 180 °C for 1 hour in a sealed tube. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound (1.0 mg).

[0953] HPLC retention time (minutes): 1.20 (formic acid);

[0954] MS(ESI,Pos.): 447(M+H) + .

[0955] Reference Example 56: (rel-(3aS,4S,6aR)-4-hydroxyhexahydrocyclopentano[c]pyrrole-2(1H)-yl)(5-methylthiophen-2-yl)methyl ketone racemic mixture

[0956] In a THF (42 mL) solution of the compound (1.4 g) prepared in Reference Example 54, 8.5 mL of 1 M trisec-butylborohydride THF solution was added at -78 °C, and the mixture was stirred at -78 °C for 1 hour. A 35% aqueous hydrogen peroxide solution was slowly added to the reaction mixture at 0 °C until no foaming occurred, followed by extraction with dichloromethane. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound (600 mg).

[0957] HPLC retention time (minutes): 0.86 (TFA);

[0958] MS(ESI,Pos.): 252(M+H) + .

[0959] Reference Example 57: Racemic mixture of rel-(3aS,4S,6aR)-2-(5-methylthiophene-2-carbonyl)octahydrocyclopentano[c]pyrrole-4-yl-4-methylbenzenesulfonate

[0960] In a solution of the compound (3.6 g) prepared in Reference Example 56 in dichloromethane (70 mL), triethylamine (4 mL), p-toluenesulfonyl chloride (4.1 g), and trimethylamine hydrochloride (280 mg) were added, and the mixture was stirred at room temperature for hours. A saturated aqueous solution of sodium bicarbonate was added to the reaction mixture, and the mixture was extracted with dichloromethane. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound (3.6 g).

[0961] HPLC retention time (minutes): 1.16 (TFA);

[0962] MS(ESI,Pos.): 406(M+H) + .

[0963] Example 8: Racemic mixture of rel-[(3aS,4R,6aR)-4-(3-chloro-5,6-dihydro-7H-pyrrolo[2,3-c]pyrrolo-7-yl)hexahydrocyclopenta[c]pyrrolo-2(1H)-yl](5-methyl-2-thienyl)methyl ketone

[0964] [Chemical Formula 76]

[0965]

[0966] In a 1 mL THF solution of the compound (10 mg) prepared in Reference Example 57, 3 mg of 60% sodium hydride and 7.7 mg of 3-chloro-6,7-dihydro-5H-pyrrolo[2,3-c]pyridazine (CAS No.: 2089649-63-6) were added, and the mixture was stirred at 50 °C for 20 hours. Water was then added to the reaction solution, and the mixture was purified by reversed-phase column chromatography to obtain the title compound (1.3 mg).

[0967] HPLC retention time (minutes): 0.90 (formic acid);

[0968] MS(ESI,Pos.): 389(M+H) + ;

[0969] 1 H-NMR(DMSO-d6): δ7.45-7.38,7.21-7.17,6.88-6.80,4.33-4.23,3.67-3.59,3.54-3. 44,3.08-2.99,2.92-2.77,2.29-2.14,2.08-1.94,1.94-1.76,1.68-1.54,1.57-1.42.

[0970] Examples 8-1 to 8-4

[0971] The same procedure as in Example 8 was performed using the corresponding amine compound instead of 3-chloro-6,7-dihydro-5H-pyrrolo[2,3-c]pyridazine to obtain the title compound.

[0972] Example 8-1: Racemic mixture of rel-[(3aS,4R,6aR)-4-(3-chloro-7H-pyrrolo[2,3-c]pyridazin-7-yl)hexahydrocyclopenta[c]pyrrolo-2(1H)-yl](5-methyl-2-thienyl)methyl ketone

[0973] [Chemical Formula 77]

[0974]

[0975] HPLC retention time (minutes): 1.10 (TFA);

[0976] MS(ESI,Pos.): 387(M+H) + ;

[0977] 1 H-NMR (CDCl3): δ7.69,7.55,7.33,6.74,6.46,5.14-4.96,4.01-3.86,3.73,3.35-3.25,3.13,2.62,2.51,2.48-2.29,1.80-1.65.

[0978] Example 8-2: rel-{(3aS,4R,6aR)-4-[(6-chloro-4-methoxy-3-pyridazinyl)amino]hexahydrocyclopenta[c]pyrrolo-2(1H)-yl}(5-methyl-2-thienyl)methyl ketone racemic mixture

[0979] [Chemical Formula 78]

[0980]

[0981] HPLC retention time (minutes): 0.89 (TFA);

[0982] MS(ESI,Pos.): 393(M+H) + ;

[0983] 1 H-NMR(CDCl3): δ7.35-7.28,6.76-6.70,6.56,4.88,4.34-4.26,4.15-4.02, 3.94-3.73,3.73-3.60,2.85,2.74,2.50,2.46-2.29,2.17-1.99,1.70-1.60.

[0984] Example 8-3: Racemic mixture of rel-((3aS,4R,6aR)-4-((6-chloropyridin-3-yl)amino)hexahydrocyclopentano[c]pyrrole-2(1H)-yl)(5-methylthiophen-2-yl)methyl ketone

[0985] [Chemical Formula 79]

[0986]

[0987] HPLC retention time (minutes): 1.10 (formic acid);

[0988] MS(ESI,Pos.): 362(M+H) + .

[0989] Example 8-4: racemic mixture of rel-((3aS,4R,6aR)-4-((4,6-dichloropyridin-3-yl)amino)hexahydrocyclopentano[c]pyrrole-2(1H)-yl)(5-methylthiophen-2-yl)methyl ketone

[0990] [Chemical Formula 80]

[0991]

[0992] HPLC retention time (minutes): 1.20 (formic acid);

[0993] MS(ESI,Pos.): 396(M+H) + .

[0994] Reference Example 58: Racemic mixture of rel-(3aS,4R,6aR)-4-((6-chloro-4-cyanopyridazin-3-yl)amino)hexahydrocyclopentano[c]pyrrole-2(1H)-carboxylic acid tert-butyl ester

[0995] The compound prepared in Reference Example 1 was used instead of the compound prepared in Reference Example 3, and 3,6-dichloropyridazine-4-carboxynitrile (CAS No.: 35857-93-3, 45 mg) was used instead of 3,6-dichloropyridazine. The same operation as in Reference Example 4 → Reference Example 5 → Reference Example 6 → Reference Example 7 → Reference Example 8 → Reference Example 9 was performed to obtain the title compound.

[0996] Reference Example 59: racemic mixture of rel-6-chloro-3-(((3aS,4R,6aR)-octahydrocyclopentano[c]pyrrolo-4-yl)amino)pyridazine-4-carboxylonitrile

[0997] 4N hydrochloric acid (1,4-dioxane solution, 3 mL) was added to the compound (100 mg) prepared in Reference Example 58, and the mixture was stirred at room temperature for 1 hour. The title compound (5 mg) was obtained by concentrating the reaction solution under reduced pressure.

[0998] Example 9: Racemic mixture of rel-6-chloro-3-({(3aS,4R,6aR)-2-[(5-methyl-2-thienyl)carbonyl]octahydrocyclopentano[c]pyrrolo-4-yl}amino)-4-pyridazine carboxynitrile

[0999] [Chemical Formula 81]

[1000]

[1001] The title compound was obtained by replacing the compound prepared in Reference Example 12 with the compound prepared in Reference Example 59 and performing the same operation as in Example 2.

[1002] HPLC retention time (minutes): 1.10 (TFA);

[1003] MS(ESI,Pos.): 388(M+H) + ;

[1004] 1 H-NMR (CDCl3): δ7.42,7.37-7.27,6.75,5.11,4.47-4.39,4.05,3.99-3.82,3.68,2.91,2.74,2.53-2.50,2.50-2.42,2.21-1.98,1.78-1.54.

[1005] Example 9-1

[1006] The title compound was obtained by replacing 3,6-dichloropyridazine with the corresponding halogen compound and 5-(difluoromethyl)thiophene-2-carboxylic acid with the corresponding carboxylic acid, and performing the same operations as in Reference Example 9 → Reference Example 10 → Example 1.

[1007] Example 9-1: [(3aS,4R,6aR)-4-{[6-chloro-4-(trifluoromethyl)-3-pyridazinyl]amino}hexahydrocyclopentano[c]pyrrolo-2(1H)-yl](6,7-dihydro-4H-thieno[3,2-c]pyran-2-yl) methyl ketone

[1008] [Chemical Formula 82]

[1009]

[1010] HPLC retention time (minutes): 1.10 (formic acid);

[1011] MS(ESI,Pos.): 473(M+H) + ;

[1012] 1H-NMR (DMSO-d6): δ7.94-7.83,7.37-7.24,6.85-6.70,4.60,4.48-4.37,3.88,3. 82-3.63,2.84-2.78,2.97-2.67,2.29-2.12,2.10-1.98,1.83-1.70,1.58-1.43.

[1013] Reference Example 60: (1) [(R)-4-[tert-butyl(dimethyl)silyl]oxy-3,5,6,6a-tetrahydro-1H-cyclopentano[c]pyrrolo-2-yl]-(5-methyl-2-thienyl) ketone, and

[1014] (2)[(3aR,6aS)-6-{[dimethyl(2-methyl-2-propionyl)silyl]oxy}-3,3a,4,6a-tetrahydrocyclopentano[c]pyrrolo-2(1H)-yl](5-methyl-2-thienyl)methyl ketone

[1015] In a dichloromethane (86 mL) solution of the compound (4.3 g) prepared in Reference Example 54-1, triethylamine (2.4 mL) and tert-butyldimethylsilyltrifluoromethanesulfonic acid (CAS No.: 69739-34-0, 2.0 mL) were added, and the mixture was stirred at 40 °C for 2 hours. A saturated aqueous solution of sodium bicarbonate was added to the reaction mixture, and the mixture was extracted with dichloromethane. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give the title compounds (1) (1.9 g) and (2) (1.0 g), respectively.

[1016] Reference Example 61: (3aR,6aS)-3a-fluoro-2-(5-methylthiophene-2-carbonyl)-3,5,6,6a-tetrahydro-1H-cyclopentano[c]pyrrole-4-one

[1017] In a 38 mL solution of acetonitrile containing 1.9 g of the compound prepared in Reference Example 60(1), 1-chloromethyl-4-fluoro-1,4-diazobicyclo[2.2.2]octanebis(tetrafluoroborate) (CAS No.: 140681-55-6, 2.2 g) was added and the mixture was stirred at room temperature for 20 minutes. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound (540 mg).

[1018] HPLC retention time (minutes): 0.95 (TFA);

[1019] MS(ESI,Pos.): 268(M+H) + .

[1020] Reference Example 62: [(3aR,4S,6aS)-3a-fluoro-4-hydroxy-1,3,4,5,6,6a-hexahydrocyclopentano[c]pyrrole-2-yl]-(5-methyl-2-thienyl)methyl ketone

[1021] Sodium borohydride (CAS No.: 16940-66-2, 405 mg) was added to a methanol (19 mL) and THF (19 mL) solution of the compound (1.9 g) prepared in Reference Example 61 at 0 °C, and the mixture was stirred at 0 °C for 1 hour. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound (872 mg).

[1022] HPLC retention time (minutes): 0.88 (TFA);

[1023] MS(ESI,Pos.): 270(M+H) + .

[1024] Reference Example 63: [(3aR,4R,6aS)-3a-fluoro-2-(5-methylthiophene-2-carbonyl)-1,3,4,5,6,6a-hexahydro-1H-cyclopentano[c]pyrrole-4-yl]4-methylbenzenesulfonate

[1025] In a solution of the compound (872 mg) prepared in Reference Example 62, in 13 mL of dichloromethane, triethylamine (1.4 mL), p-toluenesulfonyl chloride (1.2 g), and trimethylamine hydrochloride (154 mg) were added, and the mixture was stirred at room temperature for 23 hours. Water was added to the reaction mixture, and 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 residue was purified by silica gel column chromatography to give the title compound (1.0 g).

[1026] HPLC retention time (minutes): 1.16 (TFA);

[1027] MS(ESI,Pos.): 424(M+H) + .

[1028] Reference Example 64: [(3aR,4R,6aS)-4-azido-3a-fluoro-1,3,4,5,6,6a-hexahydrocyclopentano[c]pyrrole-2-yl]-(5-methyl-2-thienyl)methyl ketone

[1029] Sodium azide (560 mg) was added to a 13 mL solution of dimethyl sulfoxide containing 1.4 g of the compound prepared in Reference Example 63, and the mixture was stirred at 100 °C for 90 hours. Water was added to the reaction mixture, and the mixture was extracted with dichloromethane. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting title compound was used in subsequent reactions without purification.

[1030] HPLC retention time (minutes): 1.08 (TFA);

[1031] MS(ESI,Pos.): 295(M+H) + .

[1032] Reference Example 65: [(3aR,4R,6aS)-4-amino-3a-fluoro-1,3,4,5,6,6a-hexahydrocyclopentano[c]pyrrole-2-yl]-(5-methyl-2-thienyl)methyl ketone

[1033] 20% palladium hydroxide (1.8 g) was added to an ethanol (18 mL) solution of the compound (892 mg) prepared in Reference Example 64, and the mixture was stirred at room temperature for 15 hours under a hydrogen atmosphere. The reaction solution was filtered and concentrated under reduced pressure, and the resulting title compound was used in subsequent reactions without purification.

[1034] HPLC retention time (minutes): 0.72 (TFA);

[1035] MS(ESI,Pos.): 269(M+H) + .

[1036] Example 10: [(3aR,4R,6aS)-4-[(6-bromopyridazin-3-yl)amino]-3a-fluoro-1,3,4,5,6,6a-hexahydrocyclopentano[c]pyrrole-2-yl]-(5-methyl-2-thienyl)methyl ketone

[1037] [Chemical Formula 83]

[1038]

[1039] In a solution of the compound (470 mg) prepared in Reference Example 65 in 9.4 mL of 2-methyl-2-butanol, DIPEA (0.91 mL) and 3-bromo-6-fluoropyridazine (619 mg) were added, and the mixture was stirred at 180 °C for 3 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound (141 mg).

[1040] HPLC retention time (minutes): 1.00 (TFA);

[1041] MS(ESI,Pos.): 427(M+H) + .

[1042] Reference Example 66: (3aR,4R,6aS)-N-(6-bromo-3-pyridazinyl)-3a-fluorooctahydrocyclopentano[c]pyrrole-4-amine

[1043] In a 2 mL THF solution of 40 mg of the compound prepared in Example 10, 1 mL of methanol and 1 mL of 5N sodium hydroxide aqueous solution were added, and the mixture was stirred at 50 °C for 16 hours. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting title compound was used in subsequent reactions without purification.

[1044] Example 11: [(3aR,4R,6aS)-4-[(6-bromo-3-pyridazinyl)amino]-3a-fluorohexahydrocyclopentano[c]pyrrolo-2(1H)-yl](6,7-dihydro-4H-thieno[3,2-c]pyran-2-yl) methyl ketone

[1045] [Chemical Formula 84]

[1046]

[1047] The compound prepared in Reference Example 66 was reacted with a solution of 6,7-dihydro-4H-thieno[3,2-c]pyran-2-carboxylic acid (14 mg) in DMA (0.22 mL), and DIPEA (0.02 mL) and HATU (31 mg) were added. The mixture was stirred at room temperature for 3 hours. 2N hydrochloric acid was added to the reaction mixture, and the mixture was extracted with dichloromethane. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound (22 mg).

[1048] HPLC retention time (minutes): 0.89 (TFA);

[1049] MS(ESI,Pos.): 467(M+H) + ;

[1050] 1H-NMR (CDCl3): δ7.29,7.24-7.16,6.59,4.78,4.75-4.67,4.56,4.28,4.22-4.0 8,4.01-3.89,3.61,2.89,2.51-2.40,2.26-2.17,1.86-1.75,1.60,1.52-1.34.

[1051] Examples 11-1 to 11-3

[1052] The same procedure as in Example 11 was performed using the corresponding carboxylic acid compound instead of 6,7-dihydro-4H-thiopheno[3,2-c]pyran-2-carboxylic acid to obtain the title compound.

[1053] Example 11-1: [(3aR,4R,6aS)-4-[(6-bromo-3-pyridazinyl)amino]-3a-fluorohexahydrocyclopentano[c]pyrrolo-2(1H)-yl](2-cyclopropyl-2H-thieno[3,2-c]pyrazol-5-yl) methyl ketone

[1054] [Chemical Formula 85]

[1055]

[1056] HPLC retention time (minutes): 0.91 (TFA);

[1057] MS(ESI,Pos.): 491(M+H) + ;

[1058] 1 H-NMR(DMSO-d6): δ8.17,7.64,7.47,7.30,6.92,4.55-4.41,4.00,2.89,2.73-2.68 ,2.56-2.53,2.29-2.16,2.14-2.01,1.87-1.72,1.47-1.35,1.28-1.12,1.12-1.01.

[1059] Example 11-2: [(3aR,4R,6aS)-4-[(6-bromo-3-pyridazinyl)amino]-3a-fluorohexahydrocyclopentano[c]pyrrole-2(1H)-yl][5-(fluoromethyl)-2-thienyl] methyl ketone

[1060] [Chemical Formula 86]

[1061]

[1062] HPLC retention time (minutes): 0.92 (TFA);

[1063] MS(ESI,Pos.): 443(M+H) + ;

[1064] 1 H-NMR (CDCl3): δ7.40,7.31,7.28,7.10,6.60,5.54,5.42,4.84-4.74,4.62-4.48,4.27-4.1 3,4.01-3.93,3.87,3.61,3.49,3.00-2.83,2.50,2.19,2.28-2.14,1.61-1.58,1.53-1.36.

[1065] Examples 11-3: [(3aR,4R,6aS)-4-[(6-bromo-3-pyridazinyl)amino]-3a-fluorohexahydrocyclopentano[c]pyrrole-2(1H)-yl][5-(2-fluoroethyl)-2-thienyl] methyl ketone

[1066] [Chemical Formula 87]

[1067]

[1068] HPLC retention time (minutes): 0.94 (TFA);

[1069] MS(ESI,Pos.): 457(M+H) + ;

[1070] 1 H-NMR (CDCl3): δ7.36-7.27,6.87,6.59,4.71,4.59,4.19,4.01,3.63,3.49,3.2 8-3.17,2.98-2.79,2.57-2.41,2.28-2.14,1.87-1.73,1.61-1.57,1.53-1.45.

[1071] Example 12: {(3aR,4R,6aS)-4-[(6-chloro-3-pyridazinyl)amino]-3a-fluorohexahydrocyclopentano[c]pyrrole-2(1H)-yl}(6,7-dihydro-4H-thieno[3,2-c]pyran-2-yl) methyl ketone

[1072] [Chemical Formula 88]

[1073]

[1074] The title compound was obtained by replacing 3-bromo-6-fluoropyridazine with 3,6-dichloropyridazine and 6,7-dihydro-4H-thieno[3,2-c]pyran-2-carboxylic acid with the corresponding carboxylic acid, and by performing the same procedures as in Example 10 → Reference Example 66 → Example 11.

[1075] HPLC retention time (minutes): 0.89 (TFA);

[1076] MS(ESI,Pos.): 423(M+H) + ;

[1077] 1 H-NMR (CDCl3): δ7.22-7.15,6.70,4.85,4.71,4.66-4.47,4.27,4.19-4.0 9,4.03-3.90,3.61,2.96-2.82,2.45,2.27-2.15,1.88-1.66,1.58-1.37.

[1078] Reference Example 67: (3aS,5R,6aR)-5-fluoro-2-(5-methylthiophene-2-carbonyl)-1,3,3a,5,6,6a-hexahydrocyclopentano[c]pyrrole-4-one

[1079] In a 25 mL solution of acetonitrile (1.3 g) of the compound prepared in Reference Example 60(2), 1-chloromethyl-4-fluoro-1,4-diazobicyclo[2.2.2]octanebis(tetrafluoroborate) (1.5 g) was added, and the mixture was stirred at room temperature for 3 hours. The reaction solution was concentrated under reduced pressure, and water was added to the residue, which was then extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound (633 mg).

[1080] HPLC retention time (minutes): 0.81 (TFA);

[1081] MS(ESI,Pos.): 304(M+H) + .

[1082] Reference Example 68: [(3aS,4R,5R,6aR)-5-fluoro-4-hydroxy-3,3a,4,5,6,6a-hexahydro-1H-cyclopentano[c]pyrrole-2-yl]-(5-methyl-2-thienyl)methyl ketone

[1083] Sodium borohydride (106 mg) was added to a methanol (10 mL) solution of the compound (500 mg) prepared in Reference Example 67 at 0 °C, and the mixture was stirred at 0 °C for 1 hour. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound (200 mg).

[1084] Reference Example 69: [(3aS,4R,5R,6aR)-5-fluoro-2-(5-methylthiophene-2-carbonyl)-3,3a,4,5,6,6a-hexahydro-1H-cyclopentano[c]pyrrole-4-yl]4-methylbenzenesulfonate

[1085] In a 1.2 mL solution of the compound (120 mg) prepared in Reference Example 68, DIPEA (0.23 mL), p-toluenesulfonyl chloride (127 mg), and trimethylamine hydrochloride (21 mg) were added, and the mixture was stirred at room temperature for 24 hours. Water was added to the reaction mixture, and the solution was extracted with dichloromethane. After concentration, the residue was purified by silica gel column chromatography to give the title compound (190 mg).

[1086] HPLC retention time (minutes): 1.13 (TFA);

[1087] MS(ESI,Pos.): 424(M+H) + .

[1088] Reference Example 70: [(3aS,4S,5R,6aR)-4-azido-5-fluorohexahydrocyclopentano[c]pyrrole-2(1H)-yl](5-methyl-2-thienyl)methyl ketone

[1089] Sodium azide (145 mg) was added to a solution of the compound (190 mg) prepared in Reference Example 69 in dimethyl sulfoxide (0.8 mL), and the mixture was stirred at 100 °C for 17 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting title compound was used in subsequent reactions without purification.

[1090] HPLC retention time (minutes): 1.05 (TFA);

[1091] MS(ESI,Pos.): 295(M+H) + .

[1092] Reference Example 71: [(3aS,4S,5R,6aR)-4-amino-5-fluoro-3,3a,4,5,6,6a-hexahydro-1H-cyclopentano[c]pyrrole-2-yl]-(5-methyl-2-thienyl)methyl ketone

[1093] 20% palladium hydroxide (50 mg) was added to an ethanol (2 mL) solution of the compound prepared in Reference Example 70, and the mixture was stirred at room temperature for 2 hours under a hydrogen atmosphere. The reaction solution was filtered and concentrated under reduced pressure, and the resulting title compound was used in subsequent reactions without purification.

[1094] HPLC retention time (minutes): 0.75 (TFA);

[1095] MS(ESI,Pos.): 269(M+H) + .

[1096] Example 13: [(3aS,4S,5R,6aR)-4-[(6-bromopyridazin-3-yl)amino]-5-fluoro-3,3a,4,5,6,6a-hexahydro-1H-cyclopentano[c]pyrrole-2-yl]-(5-methyl-2-thienyl)methyl ketone

[1097] [Chemical Formula 89]

[1098]

[1099] In a solution of the compound (50 mg) prepared in Reference Example 71 in 0.23 mL of 2-methyl-2-butanol, DIPEA (0.19 mL) and 3-bromo-6-fluoropyridazine (132 mg) were added, and the mixture was stirred at 160 °C for 1 hour. The reaction solution was purified by reversed-phase column chromatography to obtain the title compound (8.9 mg).

[1100] HPLC retention time (minutes): 0.94 (TFA);

[1101] MS(ESI,Pos.): 426(M+H) + ;

[1102] 1 H-NMR (CDCl3): δ7.32,7.28-7.26,6.73,6.62,5.42-5.10,4.89,4.51-4.38,4.13-3.88,3.63,3.09-2.99,2.82-2.75,2.50,1.95-1.77.

[1103] Reference Example 72: (3aS,6aR)-2-(6,7-dihydro-4H-thieno[3,2-c]pyran-2-ylcarbonyl)hexahydrocyclopenta[c]pyrrole-4(1H)-one

[1104] In a DMA (230 mL) solution of the compound (2.8 g) prepared in Reference Example 53-1, 4.6 g of 6,7-dihydro-4H-thieno[3,2-c]pyran-2-carboxylic acid, 13 mL of DIPEA, and 9.5 g of HATU were added, and the mixture was stirred at room temperature for 3 hours. Water was added to the reaction solution, and the mixture was extracted with dichloromethane. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound (4.1 g).

[1105] Reference Example 73: [(3aS,6aR)-6-{[dimethyl(2-methyl-2-propionyl)silyl]oxy}-3,3a,4,6a-tetrahydrocyclopentano[c]pyrrole-2(1H)-yl](6,7-dihydro-4H-thieno[3,2-c]pyran-2-yl) methyl ketone

[1106] Triethylamine (2.8 mL) and tert-butyldimethylsilyl trifluoromethanesulfonate (2.3 mL) were added to a dichloromethane (40 mL) solution of the compound (2.0 g) prepared in Reference Example 72 at 0 °C, and the mixture was stirred at 50 °C for 22 hours. A saturated aqueous solution of sodium bicarbonate was added to the reaction mixture, and the mixture was extracted with dichloromethane. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting title compound was used in subsequent reactions without purification.

[1107] Reference Example 74: (3aS,5R,6aR)-2-(6,7-dihydro-4H-thieno[3,2-c]pyran-2-ylcarbonyl)-5-methylhexahydrocyclopenta[c]pyrrole-4(1H)-one

[1108] In a 10 mL DMF solution of the compound prepared in Reference Example 73, 9.5 g of iodomethane, 0.74 mL of 1 M tetra-N-butylammonium fluoride (CAS No.: 429-41-4), and THF solution were added, and the mixture was stirred at room temperature for 3 hours. The reaction solution was concentrated under reduced pressure, and water was added to the residue, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound (100 mg).

[1109] Example 14: [(3aS,4R,5R,6aR)-4-[(6-bromo-3-pyridazinyl)amino]-5-methylhexahydrocyclopentano[c]pyrrolo-2(1H)-yl](6,7-dihydro-4H-thieno[3,2-c]pyran-2-yl) methyl ketone

[1110] [Chemical Formula 90]

[1111]

[1112] Using the compound prepared in Reference Example 74 instead of the compound prepared in Reference Example 61, the same operations as in Reference Example 62 → Reference Example 63 → Reference Example 64 → Reference Example 65 → Example 10 were performed to obtain the title compound.

[1113] HPLC retention time (minutes): 0.86 (TFA);

[1114] MS(ESI,Pos.): 463(M+H) + ;

[1115] 1 H-NMR (CDCl3): δ7.33-7.28,7.13,6.65-6.58,5.21,4.70,4.04-3.83,3.66,2.93-2.85,2.76,2.55,1.88-1.69,0.95.

[1116] Reference Example 75: (3aS,6aR)-2-(6,7-dihydro-4H-thieno[3,2-c]pyran-2-carbonyl)spiro[3,3a,6,6a-tetrahydro-1H-cyclopentano[c]pyrrole-5,1'-cyclopropane]-4-one

[1117] In a 7.5 mL solution of dimethyl sulfoxide (DMSO) containing 300 mg of the compound prepared in Reference Example 72, 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, and the mixture was stirred at room temperature for 1 hour. Water and a 1 N hydrochloric acid aqueous solution were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound (100 mg).

[1118] HPLC retention time (minutes): 0.90 (TFA);

[1119] MS(ESI,Pos.): 318(M+H) + .

[1120] Reference Example 76: [(3aS,4R,6aR)-4-hydroxyspiro[1,3,3a,4,6,6a-hexahydrocyclopentano[c]pyrrole-5,1'-cyclopropane]-2-yl]-(6,7-dihydro-4H-thieno[3,2-c]pyran-2-yl) methyl ketone

[1121] Sodium borohydride (25 mg) was added to a methanol (2.8 mL) solution of the compound (138 mg) prepared in Reference Example 75 at 0 °C, and the mixture was stirred at 0 °C for 30 minutes. Water was added to the reaction mixture, and the solution was extracted with dichloromethane. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound (95 mg).

[1122] HPLC retention time (minutes): 0.91 (TFA);

[1123] MS(ESI,Pos.): 320(M+H) + .

[1124] Reference Example 77: [(3aS,4S,6aR)-4-azidospiro[1,3,3a,4,6,6a-hexahydrocyclopentano[c]pyrrole-5,1'-cyclopropane]-2-yl]-(6,7-dihydro-4H-thieno[3,2-c]pyran-2-yl) methyl ketone

[1125] Triphenylphosphine (CAS No.: 603-35-0, 102 mg), 2.2 M diethyl azodicarboxylate solution (CAS No.: 1972-28-7, 0.18 mL), and diphenylphosphine azide (CAS No.: 26386-88-9, 82 mg) were added to a THF (0.2 mL) solution of the compound (95 mg) prepared in Reference Example 76, and the mixture was stirred at room temperature for 30 minutes. The reaction solution was purified by silica gel column chromatography to give the title compound (43 mg).

[1126] HPLC retention time (minutes): 1.08 (TFA);

[1127] MS (ESI, Pos.): 345 (M+H) + .

[1128] Reference Example 78: [(3aS,4S,6aR)-4-aminospiro[1,3,3a,4,6,6a-hexahydrocyclopentano[c]pyrrole-5,1'-cyclopropane]-2-yl]-(6,7-dihydro-4H-thieno[3,2-c]pyran-2-yl) methyl ketone

[1129] 20% palladium hydroxide (20 mg) was added to a methanol (1 mL) solution of the compound (43 mg) prepared in Reference Example 77, and the mixture was stirred at room temperature for 30 minutes under a hydrogen atmosphere. The reaction solution was filtered, concentrated under reduced pressure, and purified by silica gel column chromatography to obtain the title compound (20 mg).

[1130] HPLC retention time (minutes): 0.73 (TFA);

[1131] MS(ESI,Pos.): 319(M+H) + .

[1132] Example 15: [(3aS,4S,6aR)-4-[(6-bromopyridazin-3-yl)amino]spiro[1,3,3a,4,6,6a-hexahydrocyclopentano[c]pyrrole-5,1'-cyclopropane]-2-yl]-(6,7-dihydro-4H-thieno[3,2-c]pyran-2-yl) methyl ketone

[1133] [Chemical Formula 91]

[1134]

[1135] DIPEA (0.92 mL) and 3-bromo-6-fluoropyridazine (18.9 mg) were added to a 0.5 mL solution of the compound (17 mg) prepared in Reference Example 78 in 2-methyl-2-butanol, and the mixture was stirred at 180 °C for 4 hours. Water was added to the reaction mixture, and the mixture was extracted with dichloromethane. The organic layer was purified by silica gel column chromatography to give the title compound (13 mg).

[1136] HPLC retention time (minutes): 0.97 (TFA);

[1137] MS(ESI,Pos.): 477(M+H) + ;

[1138] 1 H-NMR(CD3OD): δ7.37,7.34-7.18,6.84,4.68,4.12-3.91,3.80,2.97,2.9 3-2.81,2.36,2.07-1.95,1.50,1.41-1.17,0.74-0.65,0.60,0.53-0.35.

[1139] Reference Example 79: Racemic mixture of rel-[(3aS,4R,6aR)-2-benzyl-6-oxooctahydrocyclopentano[c]pyrrole-4-yl]carbamate 2-methyl-2-propyl ester

[1140] In a 20 mL solution of N-benzyl-N-(methoxymethyl)-N-trimethylsilylmethylamine (3.6 g) in dichloromethane, tert-butyl N-(4-oxocyclopent-2-en-1-yl)carbamate (CAS No.: 657396-97-9, 17 g) and trifluoroacetic acid (58 mg) were added, and the mixture was stirred at room temperature for 16 hours. Triethylamine (430 mg) was then added to the reaction mixture, and the mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the title compound (300 mg).

[1141] HPLC retention time (minutes): 0.86 (TFA);

[1142] MS(ESI,Pos.): 331(M+H) + .

[1143] Reference Example 80: Racemic mixture of rel-[(3aS,4R,6aR)-2-benzyl-6,6-difluorooctahedrocyclopenta[c]pyrrole-4-yl]carbamate 2-methyl-2-propyl ester

[1144] In a 5 mL solution of dichloromethane containing 300 mg of the compound prepared in Reference Example 79, 1.2 g of bis(2-methoxyethyl)aminosulfur trifluoride (CAS No.: 202289-38-1) was added at 0 °C, and the mixture was stirred at room temperature for 15 hours. A saturated aqueous solution of sodium bicarbonate was added to the reaction mixture, and the mixture was extracted with dichloromethane. The solution was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound (120 mg).

[1145] HPLC retention time (minutes): 0.91 (TFA);

[1146] MS(ESI,Pos.): 353(M+H) + .

[1147] Reference Example 81: Racemic mixture of rel-[(3aS,4R,6aR)-6,6-difluorooctahedrocyclopenta[c]pyrrolo-4-yl]carbamate 2-methyl-2-propyl ester

[1148] 20% palladium hydroxide (120 mg) was added to an ethanol (10 mL) solution of the compound (120 mg) prepared in Reference Example 80, and the mixture was stirred at room temperature for 2 hours under a hydrogen atmosphere. The reaction solution was filtered and concentrated under reduced pressure. The resulting residue was used in subsequent reactions without purification.

[1149] Reference Example 82: racemic mixture of rel-[(3aS,4R,6aR)-2-(6,7-dihydro-4H-thieno[3,2-c]pyran-2-ylcarbonyl)-6,6-difluorooctahedrocyclopenta[c]pyrrole-4-yl]carbamate 2-methyl-2-propyl ester

[1150] In a DMA (3 mL) solution of the compound prepared in Reference Example 81, 112 mg of 6,7-dihydro-4H-thieno[3,2-c]pyran-2-carboxylic acid, 0.26 mL of DIPEA, and 210 mg of HATU were added, and the mixture was stirred at room temperature for 3 hours. Water was added to the reaction solution, and the mixture was extracted with dichloromethane. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound (100 mg).

[1151] HPLC retention time (minutes): 1.00 (formic acid);

[1152] MS(ESI,Pos.): 429(M+H) + .

[1153] Reference Example 83: rel-[(3aR,6R,6aS)-6-amino-4,4-difluorohexahydrocyclopentano[c]pyrrole-2(1H)-yl](6,7-dihydro-4H-thieno[3,2-c]pyran-2-yl)methyl ketone racemic mixture

[1154] 4N hydrochloric acid (1,4-dioxane solution, 3 mL) was added to the compound (100 mg) prepared in Reference Example 82, and the mixture was stirred at room temperature for 1 hour. The title compound (80 mg) was obtained by concentrating the reaction solution under reduced pressure.

[1155] Example 16: [(3aR,6R,6aS)-6-[(6-bromo-3-pyridazinyl)amino]-4,4-difluorohexahydrocyclopentano[c]pyrrolo-2(1H)-yl](6,7-dihydro-4H-thieno[3,2-c]pyran-2-yl) methyl ketone

[1156] [Chemical Formula 92]

[1157]

[1158] In a DMA (1 mL) solution of the compound (80 mg) prepared in Reference Example 83, DIPEA (0.24 mL) and 3,6-dibromopyridazine (120 mg) were added, and the mixture was stirred at 160 °C for 1 hour. Water was added to the reaction mixture, and 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 residue was purified by silica gel column chromatography, and the two diastereomers were separated by supercritical fluid chromatography (CHIRALP AK IC, CO2:methanol = 70:30) to give the low-polarity isomer (19 mg).

[1159] HPLC retention time (minutes): 1.00 (TFA);

[1160] MS (ESI, Pos.): 485 (M+H) + ;

[1161] 1 H-NMR (DMSO-d6): δ7.54-7.45,7.36-7.35,7.40-7.32,6.85,4.62,4.23-4. 15,3.88,3.57-3.50,3.38-3.31,3.31-3.16,2.99-2.88,2.83,2.30-2.17.

[1162] Reference Example 84: 2-Bromo-5-[2-(2-fluoroethoxy)ethyl]thiophene

[1163] A solution of 2-(5-bromothiophene-2-yl)ethane-1-ol (CAS No.: 57070-78-7, 653 mg) in dimethylacetamide (15 mL) was mixed with 1-iodo-2-fluoroethane (CAS No.: 762-51-6, 1.52 mL) and sodium hydride (757 mg), and stirred at room temperature for 17 hours. Then, the mixture was stirred at 60 °C for 24 hours. Water was added to the reaction mixture, and the solution was extracted with a mixture of ethyl acetate and n-hexane. The organic layer was washed with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound (396 mg).

[1164] HPLC retention time (minutes): 0.828 (TFA);

[1165] 1 H-NMR (CDCl3): δ6.86, 6.61, 4.66-4.61, 4.54-4.49, 3.77-3.66, 3.04.

[1166] Reference Example 85: 5-[2-(2-fluoroethoxy)ethyl]-2-thiophenic acid

[1167] To a THF (1 mL) solution of the compound (396 mg) prepared in Reference Example 84, water (0.135 mL) and trans-bis(acetyl)bis[2-(di-O-tolylphosphino)benzyl]dipalladium(II) (CAS No.: 172418-32-5, 141 mg), DBU (0.673 mL), tri-tert-butylphosphonium tetrafluoroborate (CAS No.: 131274-22-1, 43 mg), and molybdenum hexacarbonyl (CAS No.: 13939-06-5, 595 mg) were added. The reaction mixture was heated at 120 °C for 1 hour. 1 M hydrochloric acid aqueous solution and ethyl acetate were added to the reaction mixture, and the mixture was filtered. The organic layer was washed with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound (190 mg).

[1168] 1 H-NMR (CDCl3): δ7.72, 6.91, 4.72-4.61, 4.55-4.49, 3.84-3.68, 3.15, 2.50.

[1169] Reference Example 86: [(3aS,4R,6aR)-4-[(6-bromo-3-pyridazinyl)amino]hexahydrocyclopentano[c]pyrrolo-2(1H)-yl]{5-[2-(2-fluoroethoxy)ethyl]-2-thienyl} methyl ketone

[1170] DIPEA (0.024 mL) and 1H-benzotriazol-1-yloxytripyrrolidinephosphonium hexafluorophosphate (hereinafter referred to as PyBOP, 22 mg, CAS No.: 128625-52-5) were added to a DMF (1.0 mL) solution of the compound (10 mg) prepared in Reference Example 12 and the compound (9.2 mg) prepared in Reference Example 85, and the mixture was stirred at room temperature for 1 hour. Water was added to the reaction solution, and the mixture was extracted with dichloromethane. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound (5.0 mg).

[1171] HPLC retention time (minutes): 0.88 (TFA);

[1172] MS(ESI,Pos.): 483(M+H) + .

[1173] Example 17: [(3aS,4R,6aR)-4-[(6-bromo-3-pyridazinyl)(methyl)amino]hexahydrocyclopenta[c]pyrrolo-2(1H)-yl]{5-[2-(2-fluoroethoxy)ethyl]-2-thienyl} methyl ketone

[1174] [Chemical Formula 93]

[1175]

[1176] Sodium hydride (4.1 mg) was added to a DMF (1.0 mL) solution of the compound (5.0 mg) prepared in Reference Example 86. After stirring at room temperature for 15 minutes, iodomethane (0.003 mL) was added, and the mixture was stirred further at room temperature for 1 hour. Water was added to the reaction mixture, and the mixture was extracted with dichloromethane. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound (3.9 mg).

[1177] HPLC retention time (minutes): 0.95 (TFA);

[1178] MS(ESI,Pos.): 497(M+H) + ;

[1179] 1 H-NMR (CDCl3): δ7.34-7.27,6.82,6.70,4.84,4.64-4.61,4.53-4.49,3.91,3.83,3.80-3.63,3.11,2.98,2.92-2.77,2.17-2.08,1.90-1.80.

[1180] Reference Example 87: 5-(2-fluoroethoxy)-2-thiophenic acid

[1181] Sodium hydride (1313 mg) was added to a DMA (15 mL) solution of 2-fluoroethanol (CAS No.: 371-62-0, 1578 mg) at room temperature, followed by the addition of 5-fluorothiophene-2-carboxylic acid (CAS No.: 4377-58-6, 600 mg). The reaction mixture was stirred at 100 °C for 2 days. Water was added to the reaction mixture, and extraction was performed using a mixed solvent of ethyl acetate and n-hexane. The organic layer was washed with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was dissolved in methanol (4 mL), and trimethylsilyldiazomethane (CAS No.: 18107-18-1, 1 mL) was added. The mixture was stirred at room temperature for 1 hour. The reaction mixture was purified by silica gel column chromatography to obtain a methyl ester compound (60 mg). The obtained methyl ester compound (60 mg) was dissolved in methanol (4 mL), and then 2M sodium hydroxide aqueous solution (1.5 mL) was added. The reaction mixture was stirred at 50 °C for 18 hours. 1N hydrochloric acid was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the title compound (57 mg).

[1182] HPLC retention time (minutes): 0.83 (TFA);

[1183] MS(ESI,Pos.): 191(M+H) + ;

[1184] 1 H-NMR (CDCl3): δ7.53, 6.28, 4.84-4.79, 4.72-4.67, 4.38-4.27.

[1185] Reference Example 88: [(3aS,4R,6aR)-4-[(6-bromo-3-pyridazinyl)amino]hexahydrocyclopenta[c]pyrrolo-2(1H)-yl][5-(2-fluoroethoxy)-2-thienyl]methyl ketone

[1186] DIPEA (0.024 mL) and PyBOP (22 mg) were added to a DMF (1.0 mL) solution of the compound (10 mg) prepared in Reference Example 12 and the compound (8.1 mg) prepared in Reference Example 87, and the mixture was stirred at room temperature for 1 hour. Water was added to the reaction mixture, and the mixture was extracted with dichloromethane. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound (7.0 mg).

[1187] HPLC retention time (minutes): 0.89 (TFA);

[1188] MS(ESI,Pos.): 455(M+H) + .

[1189] Example 18: [(3aS,4R,6aR)-4-[(6-bromo-3-pyridazinyl)(methyl)amino]hexahydrocyclopentano[c]pyrrolo-2(1H)-yl][5-(2-fluoroethoxy)-2-thienyl]methyl ketone

[1190] [Chemical Formula 94]

[1191]

[1192] Sodium hydride (6.1 mg) was added to a DMF (1.0 mL) solution of the compound (7.0 mg) prepared in Reference Example 88, and the mixture was stirred at room temperature for 15 minutes. Then, iodomethane (0.005 mL) was added, and the mixture was stirred further at room temperature for 1 hour. Water was added to the reaction mixture, and the mixture was extracted with dichloromethane. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound (3.9 mg).

[1193] HPLC retention time (minutes): 0.95 (TFA);

[1194] MS(ESI,Pos.): 469(M+H) + ;

[1195] 1 H-NMR(CDCl3): δ7.28,7.19,6.71,6.24,4.91-4.78,4.71-4.66,4.37-4.33, 4.30-4.26,3.95-3.78,3.63,2.98,2.92-2.77,2.17-2.09,1.91-1.80,1.60.

[1196] Reference Example 89: 2-{2-[(6-bromo-3-pyridazinyl){(3aS,4R,6aR)-2-[(5-methyl-2-thienyl)carbonyl]octahydrocyclopenta[c]pyrrolo-4-yl}amino]ethoxy}ethyl 4-methylbenzenesulfonate

[1197] Sodium hydride (88 mg) was added to a DMF (7.4 mL) solution of the compound (300 mg) prepared in Example 2, and the mixture was stirred at room temperature for 30 minutes. Then, diethylene glycol dimethyl sulfonate (CAS No.: 7460-82-4, 305 mg) was added, and the mixture was stirred at room temperature for 4 hours. An aqueous solution of sodium bicarbonate was added to the reaction mixture, and the mixture was extracted with dichloromethane. After drying the organic layer with anhydrous sodium sulfate, the mixture was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to give the title compound (100 mg).

[1198] HPLC retention time (minutes): 1.18 (TFA);

[1199] MS(ESI,Pos.): 649(M+H) + .

[1200] Example 19: [(3aS,4R,6aR)-4-{(6-bromo-3-pyridazinyl)[2-(2-fluoroethoxy)ethyl]amino}hexahydrocyclopentano[c]pyrrole-2(1H)-yl](5-methyl-2-thienyl)methyl ketone

[1201] [Chemical Formula 95]

[1202]

[1203] Potassium fluoride (27 mg) and 4,7,13,16,21,24-hexaoxa-1,10-diazabicyclo[8.8.8]hexadecane (CAS No.: 23978-09-8, 174 mg) were added to a 1.5 mL acetonitrile solution of the compound (100 mg) prepared in Reference Example 89, and the mixture was stirred at 80 °C for 40 min. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound (41.6 mg).

[1204] HPLC retention time (minutes): 1.05 (TFA);

[1205] MS(ESI,Pos.): 497(M+H) + ;

[1206] 1 H-NMR (CDCl3): δ7.37-7.30,7.28-7.21,6.85,6.73,4.60-4.53,4.48-4.41,4.3 2-4.23,3.89,3.87-3.79,3.78-3.61,3.04-2.83,2.50,2.20-2.01,1.98-1.87.

[1207] Pharmacological Experiment Example 1: Evaluation of ABHD6 Enzyme Inhibitory Activity

[1208] 1-Arachidonoyl Glycerol (Cayman) was prepared as a substrate in a test buffer containing 50 mM Tris-HCl (pH 7.4), 100 mM NaCl, and 0.05% BSA at a final concentration of 10 μmol / L. The compound was added at final concentrations of 0.0003, 0.001, 0.003, 0.01, 0.03, 0.1, 0.3, 1, 3, or 10 μmol / L (DMSO at a final concentration of 0.3%). Alternatively, DMSO was added at a final concentration of 0.3%, which was considered the unadded group. Recombinant human ABHD6 (33-337) prepared using this test buffer was added to the substrate-compound mixture at a final concentration of 300 μg / mL, thereby initiating the enzyme reaction. It should be noted that the recombinant human ABHD6(33-337) carries a GST tag and is the product expressed in E. coli, purified and concentrated using glutathione-agarose gel 4B resin. Enzymatic reactions were performed in 384-well polypropylene microplates at room temperature, with wells without added enzyme serving as blanks.

[1209] One hour after the start of the enzyme reaction, methanol containing arachidonic acid-d8 (Cayman) and 1% formic acid as internal standards was added to stop the enzyme reaction. The top of the enzyme reaction plate was sealed with aluminum foil, and the plate was centrifuged at 560g at room temperature for 5 minutes. The arachidonic acid (the enzyme product) and the internal standard arachidonic acid-d8 were then quantified using a RapidFire-Mass Spectrometry system. The ratio of their respective quantification values ​​was used, with the average value of the blank group set as 100% inhibition and the average value of the group without added compounds set as 0% inhibition. The inhibition rate of arachidonic acid at each compound concentration was calculated, and the IC50 was determined. 50 value.

[1210] The pharmacological experiments demonstrated that the compounds of this invention possess potent ABHD6 inhibitory activity. For example, the IC50 values ​​of several compounds of this invention were analyzed. 50 The values ​​are shown in Table 1 below.

[1211] [Table 1]

[1212] 1 0.001 3-10 0.001 1-2 0.001 5 0.001 1-4 0.001 6 0.002 2 ＜0.001 6-2 0.001 2-1 0.001 8-1 0.001 2-6 0.002 9 0.002 2-14 0.002 10 ＜0.001 3 0.005 12 0.001 3-6 0.002 15 0.001 3-9 0.001 16 0.001

[1213] Pharmacological Experiment Example 2: Determination of Binding Affinity to Human ABHD6

[1214] HEK293 cells forcibly expressing the NanoLuc-human ABHD6 fusion protein were used to competitively interact with the test compound. The binding affinity of the test compound for human ABHD6 was determined by bioluminescent resonance energy transfer (BRET) induced by the proximity of the probe molecule to the NanoLuc-human ABHD6 fusion protein.

[1215] <Compound Treatment>

[1216] The test compound and the compound described in Example 2 as a control were dissolved in dimethyl sulfoxide (DMSO) to prepare a 10 mmol / L solution. The prepared 10 mmol / L solution was thawed before use and then diluted in stages with DMSO for experimental purposes.

[1217] Cell Culture

[1218] HEK293 cells expressing the NanoLuc-human ABHD6 fusion protein were cultured statically at 37°C in the presence of 5% CO2 using 9.8 vol% non-dialysis-FBS (containing 0.5 vol% GENETICIN and 1% penicillin-streptomycin) that had been passivated (56°C for 30 min). Subculture was performed using the following method.

[1219] Remove the culture medium and use a calcium-free solution. 2+ and Mg 2+ Wash once with phosphate-buffered saline. Add an appropriate amount of trypsin-EDTA and incubate at room temperature. After cell separation, add 10 times the volume of culture medium containing trypsin-EDTA (0.05%) to stop the enzyme reaction. Recover 120g of cells in a centrifuge tube, centrifuge for 3 minutes at room temperature, and remove the supernatant. Resuspend the cells in an appropriate amount of culture medium and seed them into culture flasks.

[1220] After preparing HEK293 cells expressing the NanoLuc-human ABHD6 fusion protein, they were cultured in CELLB ANKER2 at a rate of 5.0 × 10⁻⁶. 6 Cells were cryopreserved at cells / mL / vial for experiments. Additionally, HBSS(+) containing 20 mmol / L HEPES (pH 7.3) and 0.1% BSA was prepared as the assay buffer. Cells were thawed to a density of 2 × 10⁶ cells / mL / vial. 5Cells were suspended in the test buffer at a concentration of cells / mL. In a 384-well plate pre-added with the test compound, 25 μL of cell suspension was added to initiate the reaction. After standing at 37°C for 30 minutes in the presence of 5% CO2, the sample was diluted with test buffer to a final concentration of 100 nmol / L with a fluorescent probe molecule (10 mmol / L in DMSO), and added to the plate in 15 μL increments. Additionally, after standing at 37°C for 30 minutes in the presence of 5% CO2, Nano-Glo (registered trademark) Vivazine (registered trademark) substrate (PROMEGA) was diluted with test buffer according to the company's instructions, and added to the plate in 10 μL increments. After standing at room temperature for 1 hour, luminescence and fluorescence intensity were measured using a GloMax (registered trademark) Discover system. The ratio of the luminescence intensity passing through a 450 nm bandpass filter to the fluorescence intensity passing through a 600 nm longpass filter was used as the measured value 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 added compound was set as 0% inhibition. The IC50 of the test compound was calculated from the measured values ​​at each test compound concentration. 50 value.

[1221] In the cell evaluation system, the compounds of the present invention were confirmed to possess strong ABHD6 binding activity. For example, the IC50 values ​​of several compounds of the present invention were analyzed. 50 The values ​​are shown in Table 2 below.

[1222] [Table 2]

[1223] 1 0.011 3-10 0.002 1-2 0.005 5 0.003 1-4 0.002 6 0.005 2 0.001 6-2 0.001 2-1 0.003 8-1 0.005 2-6 0.025 9 0.008 2-14 0.016 10 0.002 3 0.062 12 0.001 3-6 0.006 15 0.001 3-9 0.005 16 0.004

[1224] Pharmacological Experiment Example 3: Evaluation of the Selectivity of ABHD6

[1225] Using rat meningeal components, fluorescent probe molecules interact with the test compounds. After protein separation by electrophoresis, the binding affinity of the test compounds is determined by the fluorescence intensity of ABHD6, MAGL, and FAAH.

[1226] <Compound Treatment>

[1227] 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 then diluted in stages with DMSO to achieve a final concentration 50 times higher than the original concentration.

[1228] <Preparation of Rat Meningeal Components>

[1229] After bloodletting under anesthesia, the brain of rats was removed. 1 mL of ice-cold phosphate-buffered saline (PBS, pH 7.5) was added for every 200 mg of brain weight, and the mixture was homogenized using a homogenizer. The homogenate solution was centrifuged at 1000 g at 4°C for 10 minutes, and the supernatant was collected. 100,000 g of the obtained supernatant was centrifuged at 4°C for 45 minutes, and ice-cold PBS was added to the sediment to resuspend it, which was then used as the membrane fraction. The protein concentration of the prepared meningeal fraction solution was quantified, and it was stored in a -80°C freezer until use.

[1230] <abpp>

[1231] Meningeal fraction solution was prepared to 3 mg / mL using PBS. 1 μL of DMSO or a compound solution was added to 50 μL of the 3 mg / mL membrane fraction solution, and the mixture was reacted at 37 °C for 30 min. Then, 1 μL of a fluorescent probe molecule (ActivX (trade name) TAMRA-FP Serine Hydrolase Probe, final concentration 1 μmol / L, DMSO solution) was added, and the mixture was reacted at room temperature for 30 min. The reaction was stopped by loading with sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) buffer. After heating the sample at 95 °C for 5 min, proteins were separated by SDS-PAGE using a 10% acrylamide gel. The SDS-PAGE gel was then visualized for fluorescence in a chemical imaging system.

[1232] In each frequency band of ABHD6, MAGL, and FAAH, the fluorescence intensity of the control group (DMSO treatment group) was taken as 0% inhibition, and the IC50 of the test compound was determined from the fluorescence intensity at each test compound concentration. 50 The results show that the compounds of this invention exhibit selective inhibitory activity against ABHD 6, relative to MAGL and FAAH.

[1233] Pharmacological Experiment Example 4: Analgesic effect on sodium monoiodate-induced rat model

[1234] The analgesic effect of the compounds of this invention was evaluated in rats induced by sodium monoiodoacetate (hereinafter referred to as MIA) (Sigma-Aldrich Japan).

[1235] (1) Preparation of MIA-induced rat model

[1236] Under isoflurane anesthesia, the hair around the knee of the right hind limb of rats was shaved, and 25 μL of 120 mg / mL MIA solution was administered intra-articularly into the right hind limb joint cavity using a syringe (BDRoads, BD Corporation, Japan) with a 29G injection needle. The normal control group was administered 25 μL of physiological saline.

[1237] (2) Group composition and grouping

[1238] The study consisted of a normal control group, a disease control group, a test substance administration group, and a tramadol or morphine administration group. Except for the normal control group, the proportion of right hind limb load weight in model rats induced by MIA for 13 or 14 days after preparation by the method described in (1) was measured (the measurement method is described later), and the rats were grouped in a manner in which the proportion of right hind limb load weight was not biased in each group.

[1239] (3) Administration of the test substance, tramadol, or morphine.

[1240] The compound of the present invention, used as the test substance, was dissolved in a soluble medium (Kolliphor:PEG = 7:3 solution) to prepare a 0.4 or 8 mg / mL solution. The prepared solution was diluted 4-fold with distilled water to prepare a 0.1 or 2 mg / mL solution (final concentration of soluble medium: 25%). Tramadol, used as a positive control, was dissolved in physiological saline to prepare a 2 mg / mL solution. Alternatively, morphine, used as a positive control, was dissolved in physiological saline to prepare a 0.6 mg / mL solution. The test substance was administered orally at 5 mL / kg 5 hours before evaluation, and tramadol and morphine were administered subcutaneously at 5 mL / kg 1 hour before evaluation.

[1241] (4) Determination of the proportion of the load on the right hind limb

[1242] The load weight on the left and right hind limbs was measured using the Linton Incapacitance Tester (MJS Technology INC., UK). Specifically, rats were placed in a dedicated cage on the Linton Incapacitance Tester, and their posture was corrected by placing each hind limb on one of two pairs of weight-measuring sensors. After confirming that the rat's posture was correct in both left and right and front and back directions, the load weight on each hind limb was measured for 3 seconds. The load weight measurement was repeated three times for each individual. To obtain stable measurements, rats were placed in the dedicated cage for at least 5 days from the day of MIA induction until 14 days after induction, allowing them to acclimatize for at least 20 minutes. Furthermore, they were acclimatized for approximately 10 minutes before the load weight measurement. The load weight on the left and right hind limbs was measured before grouping 14 days after MIA induction, and again 14 days later in the normal control group, the disease control group, the test substance administration group (5 hours after administration), the tramadol administration group (1 hour after administration), and the morphine administration group (1 hour after administration). Based on the average load weight of the left and right hind limbs, the proportion of the load weight of the right hind limb in the total load weight of the two hind limbs is calculated using the following mathematical formula 1. Based on the proportion of the right hind limb load weight of each group 14 days after MIA induction, the improvement rate of the proportion of the right hind limb load weight when the compound of the present invention, as the test substance, is administered is calculated using the following mathematical formula 2, thereby evaluating the analgesic effect of the test substance (the compound of the present invention).

[1243] [Number 1]

[1244] The percentage of the load on the right hind limb is B (%) = {A R / (A R +A L )×100}

[1245] A R Load weight on the right hind limb (average of three measurements taken from the same individual).

[1246] A L Load weight on the left hind limb (average of three measurements taken from the same individual).

[1247] [Number 2]

[1248] Improvement rate (%) of the test substance = {1-(B T -B C ) / (B N -B C )}×100

[1249] B C The average proportion of the load on the right hind limb in the normal control group

[1250] B N The average proportion of the load on the right hind limb in the disease control group.

[1251] B T The average proportion of the right hind limb load weight in the test substance administration group

[1252] The results show that the analgesic effect of the compound of the present invention is equivalent to or greater than that of tramadol and morphine, which are commonly used as analgesics.

[1253] [Formulation Example]

[1254] Formulation example

[1255] The following ingredients are mixed using conventional methods and then compressed into tablets to obtain approximately 10,000 tablets containing 10 mg of active ingredient per tablet.

[1256] ·{(3aS,4R,6aR)-4-[(6-chloro-3-pyridazinyl)amino]hexahydrocyclopenta[c]pyrrolo-2(1H)-yl}[5-(difluoromethyl)-2-thienyl]methyl ketone…100g

[1257] ·Carboxymethyl cellulose calcium (disintegrant)…20g

[1258] Magnesium stearate (lubricant)……10g

[1259] Microcrystalline cellulose…870g

[1260] Industrial applicability

[1261] The compounds of the present invention have ABHD6 inhibitory activity, and therefore pharmaceuticals containing the compounds of the present invention as active ingredients are useful as preventive and / or therapeutic agents for ABHD6-related diseases.< / abpp>

Claims

1. A compound represented by the following general formula (IA), or a pharmaceutically permissible salt thereof, General formula (IA): [Chemical Formula 1] ， wherein X 1 , X 2 each independently represents N, R 1 represents a halogen atom, R 2 represents (1) a halogen atom, (2) a Ci-6 alkyl group, (5) a Ci-6 alkoxy group, (6) a Ci-6 haloalkyl group, (9) a Ci-6 haloalkoxy group, or (10) a cyano group, When m is 2 or more, multiple R 2 They can be the same or different. R 3 This represents (1) a hydrogen atom, (2) a C1-6 alkyl group, (3) a C1-6 haloalkyl group, (4) a phenyl group, (5) -(C1-6 alkylene)-phenyl group, and (6) -(C1-6 haloalkylene)phenyl group, wherein one or two carbon atoms in the C1-6 alkyl group, C1-6 haloalkyl group, C1-6 alkylene group, and C1-6 haloalkylene group are optionally substituted with oxygen atoms or optional oxidized sulfur atoms. R 3 The phenyl group can be optionally substituted with 1 to 5 R groups. 301 , R 301 Represents: (1) halogen atom, (2) C1-4 alkyl, (3) C1-4 alkoxy, (4) C1-4 haloalkyl, (5) C1-4 haloalkoxy, (6) COOR 302 (7) CONR 303 R 304 (8) C3-6 cycloalkyl, (9) hydroxyl, (10) nitro, (11) cyano, (12) -NR 305 R 306 (13)-SR 307 (14)-SOR 308 (15)-SO2R 309 、or (16) oxo group, R 301 When replacing more than two, multiple R 301 They can be the same or different. R 302 R 303 R 304 R 305 R 306 R 307 R 308 、or R 309 Each can be independently represented as (1) a hydrogen atom or (2) a C1-4 alkyl group. R 2 R represents 2 In (2), (5), (6), (9), R 3 When representing C1-6 alkyl groups, it can be combined with R 2 and R 3 The bonded atoms together form a 5-6 membered cyclic group. R 4 This indicates (1) a halogen atom, (2) a C1-6 alkyl group, (5) a C1-6 alkoxy group, (6) a C1-6 haloalkyl group, or (9) a C1-6 haloalkoxy group. When n is 2 or more, multiple R 4 They can be the same or different. Two Rs on the same carbon atom 4 When representing C1-6 alkyl groups, they can form C3-6 cycloalkyl groups together with the bonded carbon atoms. ring1 is a ring structure selected from the following ring structures. [Chemical Formula 3] ， In the formula, * indicates the bonding position with the carbonyl group, and the hydrogen atom represented by NH is optionally bonded to R. 5-A replace, R 5-A This indicates (1) a halogen atom, (2) a C1-6 alkyl group, (5) a C1-6 alkoxy group, or (10) a cyclopropyl group, wherein one or two carbon atoms in the C1-6 alkyl group or C1-6 alkoxy group are optionally replaced by an oxygen atom or an oxidized sulfur atom. When p is 2 or higher, multiple R 5-A They can be the same or different. R 5-A The groups (2), (5), and (10) can be optionally substituted with 1 to 9 R groups. 508 , R 508 This indicates (1) a halogen atom, (2) a C1-4 alkyl group, (3) a C1-4 alkoxy group, (4) a C2-6 acyl group, (5) a C3-6 cycloalkyl group, (6) a hydroxyl group, or (7) -NR. 509 R 510 , R 508 When replacing more than two, multiple R 508 They can be the same or different. R 509 Or R 510 Each of the following can be independently represented as (1) a hydrogen atom, (2) a C1-6 alkyl group, (3) a C2-6 acyl group, or (4) a C1-6 alkylsulfonyl group. m represents an integer between 0 and 2. n represents an integer from 0 to 5. p represents an integer from 0 to 5.

2. A compound represented by the following general formula (I), or a pharmaceutically permissible salt thereof, General formula (I): [Chemical Formula 2] ， In the formula, X 1 X 2 N can be represented independently. R 1 Represents halogen atoms, R 2 This indicates (1) a halogen atom, (2) a C1-6 alkyl group, (5) a C1-6 alkoxy group, (6) a C1-6 haloalkyl group, (9) a C1-6 haloalkoxy group, or (10) a cyano group. When m is 2 or more, multiple R 2 They can be the same or different. R 3 This represents (1) a hydrogen atom, (2) a C1-6 alkyl group, (3) a C1-6 haloalkyl group, (4) a phenyl group, (5) -(C1-6 alkylene)-phenyl group, and (6) -(C1-6 haloalkylene)-phenyl group, wherein one or two carbon atoms in the C1-6 alkyl group, C1-6 haloalkyl group, C1-6 alkylene group, and C1-6 haloalkylene group are optionally substituted with oxygen atoms or optional oxidized sulfur atoms. R 3 The phenyl group can be optionally substituted with 1 to 5 R groups. 301 , R 301 Represents: (1) halogen atom, (2) C1-4 alkyl, (3) C1-4 alkoxy, (4) C1-4 haloalkyl, (5) C1-4 haloalkoxy, (6) COOR 302 (7) CONR 303 R 304 (8) C3-6 cycloalkyl, (9) hydroxyl, (10) nitro, (11) cyano, (12) -NR 305 R 306 (13)-SR 307 (14)-SOR 308 (15)-SO2R 309 、or (16) oxo group, R 301 When replacing more than two, multiple R 301 They can be the same or different. R 302 R 303 R 304 R 305 R 306 R 307 R 308 、or R 309 Each can be independently represented as (1) a hydrogen atom or (2) a C1-4 alkyl group. R 2 R represents 2 In (2), (5), (6), (9), R 3 When representing C1-6 alkyl groups, it can be combined with R 2 and R 3 The bonded atoms together form a 5-6 membered cyclic group. R 4 This indicates (1) a halogen atom, (2) a C1-6 alkyl group, (5) a C1-6 alkoxy group, (6) a C1-6 haloalkyl group, or (9) a C1-6 haloalkoxy group. When n is 2 or more, multiple R 4 They can be the same or different. Two Rs on the same carbon atom 4 When representing C1-6 alkyl groups, they can form C3-6 cycloalkyl groups together with the bonded carbon atoms. ring1 is a ring structure selected from the following ring structures. [Chemical Formula 4] ， In the formula, * indicates the bonding position with the carbonyl group, and the hydrogen atom represented by NH is optionally bonded to R. 5 replace, R 5 It represents (1) a halogen atom, (2) a C1-6 alkyl group, (5) a C1-6 alkoxy group, or (10) a cyclopropyl group. When p is 2 or higher, multiple R 5 They can be the same or different. R 5 The groups (2), (5), and (10) can be optionally substituted with 1 to 9 R groups. 508 , R 508 This indicates (1) a halogen atom, (2) a C1-4 alkyl group, (3) a C1-4 alkoxy group, (4) a C2-6 acyl group, (5) a C3-6 cycloalkyl group, (6) a hydroxyl group, or (7) -NR. 509 R 510 , When R 508 When replacing more than two, multiple R 508 They can be the same or different. R 509 or R 510 Each of the following can be independently represented: (1) a hydrogen atom, (2) a C1-6 alkyl group, (3) a C2-6 acyl group, or (4) a C1-6 alkylsulfonyl group. m represents an integer between 0 and 2. n represents an integer from 0 to 5. p represents an integer from 0 to 5.

3. The compound according to claim 1 or 2, or a pharmaceutically permissible salt thereof, wherein, R 3 It represents (1) a hydrogen atom, (2) a C1-6 alkyl group, (3) a C1-6 haloalkyl group, or (5) -CH2-Q. Q represents (1) benzene.

4. The compound according to claim 1, 2 or 3, or a pharmaceutically permissible salt thereof, wherein, Compounds represented by general formula (IA) or general formula (I) are represented by general formula (I-1). [Chemical Formula 5] ， In the formula, R 3-a It represents (1) a hydrogen atom, (2) a C1-6 alkyl group, (3) a C1-6 haloalkyl group, or (5) -CH2-Q, where Q represents (1) benzene. ring1-a represents a ring structure selected from the following ring structures. [Chemical Formula 6] ， In the formula, * indicates the bonding position with the carbonyl group, and the hydrogen atom represented by NH is optionally bonded to R. 5-a replace, Other symbols have the same meaning as those described in claims 1, 2 or 3.

5. The compound according to claim 1 or 2, or a pharmaceutically permissible salt thereof, wherein, The compounds represented by general formula (IA) or general formula (I) are selected from the following compounds: (1){(3aS,4R,6aR)-4-[(6-chloro-3-pyridazinyl)amino]hexahydrocyclopentano[c]pyrrolo-2(1H)-yl}[5-(difluoromethyl)-2-thienyl]methyl ketone, (2){(3aS,4R,6aR)-4-[(6-chloro-3-pyridazinyl)amino]hexahydrocyclopentano[c]pyrrolo-2(1H)-yl}(5-methyl-2-thienyl)methyl ketone, (3)[(3aS,4R,6aR)-4-[(6-chloro-3-pyridazinyl)amino]hexahydrocyclopentano[c]pyrrolo-2(1H)-yl](6,7-dihydro-4H-thieno[3,2-c]pyran-2-yl) methyl ketone, (4)[(3aS,4R,6aR)-4-[(6-bromo-3-pyridazinyl)amino]hexahydrocyclopentano[c]pyrrolo-2(1H)-yl](5-methyl-2-thienyl)methyl ketone, (5) [(3aS,4R,6aR)-4-[(6-bromo-3-pyridazinyl)amino]hexahydrocyclopentano[c]pyrrolo-2(1H)-yl](6,7-dihydro-4H-thieno[3,2-c]pyran-2-yl) methyl ketone, (6)[(3aS,4R,6aR)-4-[(6-bromo-3-pyridazinyl)amino]hexahydrocyclopentano[c]pyrrolo-2(1H)-yl](2-methyl-2H-thieno[3,2-c]pyrazol-5-yl) methyl ketone, (7)[(3aS,4R,6aR)-4-[benzyl(6-bromo-3-pyridazinyl)amino]hexahydrocyclopentan[c]pyrrolo-2(1H)-yl](5-methyl-2-thienyl)methyl ketone, (8) rel-6-chloro-3-({(3aS,4R,6aR)-2-[(5-methyl-2-thienyl)carbonyl]octahydrocyclopentano[c]pyrrolo-4-yl}amino)-4-pyridazine carboxynitrile, (9) {(3aR,4R,6aS)-4-[(6-chloro-3-pyridazinyl)amino]-3a-fluorohexahydrocyclopentano[c]pyrrolo-2(1H)-yl}(6,7-dihydro-4H-thieno[3,2-c]pyran-2-yl) ketone, and (10)[(3aR,6R,6aS)-6-[(6-bromo-3-pyridazinyl)amino]-4,4-difluorohexahydrocyclopentano[c]pyrrolo-2(1H)-yl](6,7-dihydro-4H-thieno[3,2-c]pyran-2-yl) methyl ketone.

6. [(3aS,4R,6aR)-4-[(6-bromo-3-pyridazinyl)amino]hexahydrocyclopentano[c]pyrrolo-2(1H)-yl](5-methyl-2-thienyl) methyl ketone, or a pharmaceutically permissible salt thereof.

7. A pharmaceutical composition comprising, as an active ingredient, any one of claims 1 to 6, the compound or a pharmaceutically permissible salt thereof. The pharmaceutical composition also includes a pharmaceutically permissible carrier.

8. The pharmaceutical composition according to claim 7, wherein it is an ABHD6 inhibitor.

9. The pharmaceutical composition according to claim 7 or 8, which is a therapeutic and / or preventive agent for diseases associated with ABHD6.

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

11. The pharmaceutical composition according to claim 9, wherein, The diseases associated with ABHD6 include pain, such as pain associated with osteoarthritis, cancer pain, chemotherapy pain, chronic low back pain, low back pain associated with osteoporosis, fracture pain, pain associated with rheumatoid arthritis, neuropathic pain, postherpetic neuralgia, pain associated with diabetic neuropathy, fibromyalgia, pain associated with pancreatitis, pain associated with interstitial cystitis and cystic dysplasia syndrome, pain associated with endometritis, pain associated with irritable bowel syndrome, migraine, or pain associated with pulpitis.

12. The pharmaceutical composition according to claim 7 or 8, wherein it is administered in combination with at least one of the following ingredients: Acetaminophen, nonsteroidal anti-inflammatory drugs, opioids, antidepressants, antiepileptics, N-methyl-D-aspartate antagonists, muscle relaxants, antiarrhythmic drugs, steroids, and bisphosphonates.

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

14. The compound or a pharmaceutically permissible salt thereof according to any one of claims 1 to 6, for the prevention and / or treatment of diseases associated with ABHD6.

15. Use of any compound of claims 1 to 6 or a pharmaceutically permissible salt thereof for the manufacture of a preventive and / or therapeutic agent for diseases associated with ABHD6.

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