KR20240046089A - Pharmaceutical composition containing abhd6 antagonist - Google Patents

Abstract

[Problem] To provide a pharmaceutical composition containing a compound with ABHD6 inhibitory activity in the prevention and/or treatment of diseases associated with ABHD6.
[Solution] The compound represented by the general formula (IA) or a pharmaceutically acceptable salt thereof has ABHD6 inhibitory activity, and therefore contains the compound represented by the general formula (IA) or a pharmaceutically acceptable salt thereof. The pharmaceutical compositions are useful as agents for the prevention and/or treatment of diseases associated with ABHD6:

(In the formula, all symbols have the same meaning as the symbols described in the specification).

Description

Pharmaceutical composition containing ABHD6 antagonist {PHARMACEUTICAL COMPOSITION CONTAINING ABHD6 ANTAGONIST}

The present invention relates to a pharmaceutical composition containing a compound having ABHD6 inhibitory activity or a pharmaceutically acceptable salt thereof. Specifically, the present invention relates to a pharmaceutical composition containing a compound represented by the general formula (I-A) or a pharmaceutically acceptable salt thereof (hereinafter, the compound is referred to as the compound of the present invention):

(In the formula, all symbols have the same meaning as the symbols listed later).

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

In addition, inhibition of ABHD6 is known to significantly reduce neuroinflammation and exert neuroprotection in animal models of traumatic brain injury and multiple sclerosis. Inhibition of ABHD6 is believed to be useful in the prevention and/or treatment of various inflammatory and neurological diseases without causing central side effects caused by the cannabinoid system (Non-patent Document 2).

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

The general formula (A) is:

wherein ring A ^A represents a 5- to 6-membered heteroaryl ring having 1 to 3 heteroatoms selected from N, O and S,

Q ^A represents NR ^aA or O,

mA represents 0, 1 or 2,

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

nA represents 1 or 2,

R ^2A is selected from hydrogen, C1-4 alkyl group, halogen and -OR ^fA ,

R ^3A is selected from hydrogen and C1-4 alkyl groups,

R ^4A is selected from -(CR ^gA R ^hA ) _pA -Y ^A' , hydrogen, C1-8 alkyl group, and C1-8 alkenyl group,

R ^5A is selected from hydrogen, C1-4 alkyl group, halogen, C1-4 haloalkyl group, C1-4 alkoxy group, and C1-4 haloalkoxy group,

Y ^A' is selected from cycloalkyl, cycloalkenyl, heterocycle, aryl and heteroaryl,

p ^A represents an integer from 0 to 4, and the definition of the group is partially extracted.

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

The general formula (B) is:

where R ^2B represents hydrogen, fluorine, hydroxyl, cyano, trifluoromethyl, C1-6 alkyl group, C1-6 alkoxy group, or NR ^8B R ^9B group,

m ^B , n ^B , o ^B and p ^B each independently represent a number ranging from 0 to 3, and each of m ^B + o ^B and n ^B + p ^B is 4 or less,

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

R ^1B represents R ^5B unsubstituted or substituted with one or more R ^6B and/or R ^7B ,

R ^5B is phenyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, naphthyl, quinolyl, isoquinolyl, phthalazinyl, quinazolinyl, quinoxalinyl, cinnolinyl, naphthyridi Represents a group selected from nyl, benzothiazolyl, benzoxazolyl, benzimidazolyl, benzisothiazolyl, benzisoxazolyl, indazolyl and benzotriazolyl,

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

R ^4B is a 5-membered hetero selected from furyl, pyrrolyl, thienyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyrazolyl, oxadiazolyl, thiadiazolyl, imidazole, triazolyl and tetrazolyl. Cyclic rings are shown, and the definitions of groups are partially extracted.

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

The general formula (C) is:

where L ^1C is C(O), S(O) ₂ , SO ₂ N(R ⁴ ), C(O)O, or -(CR ^aC R ^bC ) _mC -,

R ^1C is alkyl, G ^1C , -CH(G ^1C ) ₂ , -(CR ^aC R ^bC ) _mC -G ^1C , -(CR ^aC R ^bC ) _mC -CH(G ^1C ) ₂ , -(CR ^eC R ^fC ) _nC -N(R ^5C ) ₂ , -(CR ^eC R ^fC ) _nC -N(R ^5C )-C(O)O(alkyl), -(CR ^eC R ^fC ) _nC -N(R ^5C )-C (O)(alkyl) or -(CR ^eC R ^fC ) _nC -N(R ^5C )-SO ₂ R ^6C ,

or L ^1C -R ^1C together are hydrogen, alkyl, hydroxyalkyl, G ^1C , or -CH(G ^1C ) ₂ ;

L ^2C is -(CR ^cC R ^dC ) _pC -, C(O), C(O)N(R ^4C ), S(O) ₂ , SO ₂ N(R ^5C ), or C(O)O;

R ^2C is alkyl, G ^2C , -C(R ^cC )(G ^2C )(G ^3C ), -(CR ^cC R ^dC ) _pC -G ^2C , -(CR ^cC R ^dC ) _pC -CH(G ^2C )( G ^3C ), -(CR ^gC R ^hC ) _qC -N(R ^5C )-C(O)O(alkyl), -(CR ^gC R ^hC ) _qC -N(R ^5C )-C(O)OG ^2C , -(CR ^gC R ^hC ) _qC -N(R ^5C )-C(O)(alkyl), -(CR ^gC R ^hC ) _qC -N(R ^5C )-SO ₂ R ^6C , -(CR ^gC R ^hC ) _qC -N(R ^4C )(R ^5C ), -(CR ^gC R ^hC ) _qC -N(R ^5C )-C(O)N(R ^5C )-(alkyl) or -(CR ^gC R ^hC ) _qC - N(R ^5C )-C(O)N(R ^5C )-G ^2C ,

or L ^2C -R ^2C together are alkyl, G ^2C or -C(R ^cC )(G ^2C )(G ^3C );

G ^1C , G ^2C , and G ^3C are each independently aryl, cycloalkyl, cycloalkenyl, heteroaryl, or heterocyclic; G ^1C , G ^2C and G ^3C are each independently unsubstituted or substituted with 1, 2, 3, 4 or 5 substituents; G ^1C is other than quinoline, quinazolinedione or pyridopyrimidinedione;

R ^3C represents hydrogen, alkyl, haloalkyl, cycloalkyl or cycloalkylalkyl, and the definitions of the groups are partially extracted.

However, none of the prior art documents describe or suggest that the compounds of the present invention have ABHD6 inhibitory activity.

WO 2019/089676 A WO 2010/130944 A WO 2010/062927 A

European Journal of Medicinal Chemistry, Vol. 198, article No. 112353, 2020 Journal of Neuroinflammation, Vol. 15, article No. 9, 2018

The object of the present invention is to provide a pharmaceutical composition containing a compound having inhibitory activity against ABHD6.

As a result of intensive research to solve the above problems, the present inventors discovered that a pharmaceutical composition containing a compound represented by the general formula (I-A) described later has a strong inhibitory activity against ABHD6.

That is, one aspect of the present invention provides the following embodiments, etc.:

[1] A pharmaceutical composition containing a compound represented by general formula (I-A) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier:

During the ceremony,

X ^{1 and} X ^{2 each} independently represent (1) CH, (2) ^CR

R ¹ represents a halogen atom,

^R Represents a haloalkyl group, (7) C2-6 haloalkenyl group, (8) C2-6 haloalkynyl group, (9) C1-6 haloalkoxy group, or (10) cyano group,

R ² is (1) a halogen atom, (2) C1-6 alkyl group, (3) C2-6 alkenyl group, (4) C2-6 alkynyl group, (5) C1-6 alkoxy group, (6) C1-6 Represents a haloalkyl group, (7) C2-6 haloalkenyl group, (8) C2-6 haloalkynyl group, (9) C1-6 haloalkoxy group, or (10) cyano group,

When m is 2 or more, a plurality of R ² may be the same or different,

R ³ is (1) a hydrogen atom, (2) C1-6 alkyl group, (3) C1-6 haloalkyl group, (4) 3- to 10-membered cyclic group, (5) -(C1-6 alkylene) -(3- to 10-membered cyclic group), (6) -(C1-6 haloalkylene)-(3- to 10-membered cyclic group), where C1-6 alkyl group, C1-6 halo 1 to 2 carbon atoms in alkyl groups, C1-6 alkylene and C1-6 haloalkylene may be replaced by oxygen atoms or optionally oxidized sulfur atoms,

The 3- to 10-membered cyclic group of R ³ may be substituted with 1 to 5 R ³⁰¹ ,

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

When two or more R ³⁰¹ are substituted, the plurality of R ³⁰¹ may be the same or different,

R ³⁰² , R ³⁰³ , R ³⁰⁴ , R ³⁰⁵ , R ³⁰⁶ , R ³⁰⁷ , R ³⁰⁸ , or R ³⁰⁹ each independently represents (1) a hydrogen atom or (2) a C1-4 alkyl group,

When R ² represents ( ² ) to (9) in R 2 and R ³ represents a C1-6 alkyl group, R ² and R ³ together with the atoms to which R ² and R ³ are bonded represent 5- to Can form a 6-membered cyclic group,

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

When n is 2 or more, a plurality of R ⁴ may be the same or different,

When two R ⁴ existing on the same carbon atom represent a C1-6 alkyl group, the two R ⁴ may form a C3-6 cycloalkyl group together with the carbon atom to which the two R ⁴ are bonded,

ring 1 represents a 3- to 15-membered cyclic group,

R ^5-A is (1) a halogen atom, (2) C1-6 alkyl group, (3) C2-6 alkenyl group, (4) C2-6 alkynyl group, (5) C1-6 alkoxy group, (6) C1 -6 alkylthio group, (7) C1-6 alkylsulfinyl group, (8) C1-6 alkylsulfonyl group, (9) C2-6 acyl group, (10) 3- to 6-membered cyclic group, (11) ) -L ^R5 -(3- to 6-membered cyclic group), (12) hydroxyl group, (13) nitro group, (14) cyano group, (15) oxo group, (16) -NR ⁵⁰¹ R ⁵⁰² , (17) -COOR ⁵⁰³ , (18) -CONR ⁵⁰⁴ R ⁵⁰⁵ , or (19) -SO ₂ NR ⁵⁰⁶ R ⁵⁰⁷ , C1-6 alkyl group, C2-6 alkenyl group, C2-6 alkynyl group, C1- 1 to 2 carbon atoms in the 6 alkoxy group, C1-6 alkylthio group, C1-6 alkylsulfinyl group, C1-6 alkylsulfonyl group, and C2-6 acyl group may be substituted with an oxygen atom or an optionally oxidized sulfur atom. There is,

When p is 2 or more, a plurality of R ^5-A may be the same or different,

Groups (2) to (11) of R ^5-A may be substituted with 1 to 9 R ⁵⁰⁸ ,

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

When two or more R ⁵⁰⁸ are substituted, the plurality of R ⁵⁰⁸ may be the same or different,

L ^R5 is (1) -O-, (2) -(C1-4 alkylene)-, (3) -O-(C1-4 alkylene)-, (4) -(C1-4 alkylene)- O-, (5) -NR ⁵¹¹ -, or (6) -SO _0-2 -,

R ⁵⁰¹ , R ⁵⁰² , R ⁵⁰³ , R ⁵⁰⁴ , R ⁵⁰⁵ , R ⁵⁰⁶ , R ⁵⁰⁷ , R ⁵⁰⁹ , R ⁵¹⁰ , or R ⁵¹¹ each independently represents (1) a hydrogen atom, (2) a C1-6 alkyl group, (3) ) C2-6 acyl group, or (4) C1-6 alkylsulfonyl group,

m represents an integer from 0 to 2,

n represents an integer from 0 to 5,

p represents an integer from 0 to 5.

[2] A pharmaceutical composition containing a compound represented by general formula (I) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier:

In the formula, R ⁵ is (1) a halogen atom, (2) a C1-6 alkyl group, (3) a C2-6 alkenyl group, (4) a C2-6 alkynyl group, (5) a C1-6 alkoxy group, (6) C1-6 alkylthio group, (7) C1-6 alkylsulfinyl group, (8) C1-6 alkylsulfonyl group, (9) C2-6 acyl group, (10) 3- to 6-membered cyclic group, ( 11) -L ^R5 -(3- to 6-membered cyclic group), (12) hydroxyl group, (13) nitro group, (14) cyano group, (15) oxo group, (16) -NR ⁵⁰¹ R ⁵⁰² , (17) -COOR ⁵⁰³ , (18) -CONR ⁵⁰⁴ R ⁵⁰⁵ , or (19) -SO ₂ NR ⁵⁰⁶ R ⁵⁰⁷ ,

When p is 2 or more, a plurality of R ⁵ may be the same or different,

Groups (2) to (11) of R ⁵ may be substituted with 1 to 9 R ⁵⁰⁸ ,

Other symbols have the same meaning as the symbols described in [1].

[3] The pharmaceutical composition according to [1] or [2] above, which is an ABHD6 inhibitor.

Since the compounds of the present invention have inhibitory activity against ABHD6, pharmaceutical compositions containing the compounds of the present invention are useful as agents for the prevention and/or treatment of diseases associated with ABHD6.

Below, the present invention will be explained in detail.

As used herein, examples of halogen atoms include fluorine, chlorine, bromine, and iodine atoms.

In this specification, examples of C1-4 alkyl groups include methyl, ethyl, propyl, butyl groups, and isomers thereof.

As used herein, examples of C1-6 alkyl groups include methyl, ethyl, propyl, butyl, pentyl, hexyl groups, and isomers thereof.

As used herein, examples of C2-6 alkenyl groups include ethenyl, propenyl, butenyl, butadienyl, pentenyl, pentadienyl, hexenyl, hexadienyl groups, and isomers thereof.

As used herein, examples of C2-6 alkynyl groups include ethynyl, propynyl, butynyl, butadiynyl, pentynyl, pentadiynyl, hexynyl, hexadiinyl groups, and isomers thereof.

As used herein, examples of C1-4 alkylene include methylene, ethylene, propylene, butylene, and isomers thereof.

As used herein, examples of C1-6 alkylene include methylene, ethylene, propylene, butylene, pentylene, hexylene, and isomers thereof.

In this specification, a C1-4 haloalkyl group means, for example, an alkyl group substituted with one or more halogen atoms. Specific examples of C1-4 haloalkyl groups include fluoromethyl group, chloromethyl group, bromomethyl group, iodomethyl group, difluoromethyl group, trifluoromethyl group, 1-fluoroethyl group, 2-fluoroethyl group, and 2-chloroethyl group. , pentafluoroethyl group, 1-fluoropropyl group, 2-chloropropyl group, 3-fluoropropyl group, 3-chloropropyl group, 4,4,4-trifluorobutyl group, 4-bromobutyl group , and their isomers.

In this specification, a C1-6 haloalkyl group means, for example, an alkyl group substituted with one or more halogen atoms. Specific examples of C1-6 haloalkyl groups include fluoromethyl group, chloromethyl group, bromomethyl group, iodomethyl group, difluoromethyl group, trifluoromethyl group, 1-fluoroethyl group, 2-fluoroethyl group, and 2-chloroethyl group. , pentafluoroethyl group, 1-fluoropropyl group, 2-chloropropyl group, 3-fluoropropyl group, 3-chloropropyl group, 4,4,4-trifluorobutyl group, 4-bromobutyl group , 5,5,5-trifluoropentyl group, 6,6,6-trifluorohexyl group, and isomers thereof.

In this specification, C1-6 haloalkylene means, for example, alkylene substituted with one or more halogen atoms. Specific examples of C1-6 haloalkylene include fluoromethylene, chloromethylene, bromomethylene, iodomethylene, difluoromethylene, 1-fluoroethylene, 2-fluoroethylene, 2-chloroethylene, pentafluoro. Ethylene, 1-fluoropropylene, 2-chloropropylene, 3-fluoropropylene, 3-chloropropylene, 4-bromobutylene, 5-fluoropentylene, 6-fluorohexylene, and isomers thereof Includes.

In this specification, a C2-6 haloalkenyl group refers to an alkenyl group substituted with, for example, one or more halogen atoms. Specific examples of the C2-6 haloalkenyl group include 1-fluoroethenyl group, 2-fluoroethenyl group, 2-chloroethenyl group, 1-fluoropropenyl group, 2-chloropropenyl group, and 3-fluoro It includes propenyl group, 3-chloropropenyl group, 4-bromobutenyl group, 5,5,5-trifluoropentenyl group, 6,6,6-trifluorohexenyl group, and isomers thereof.

In this specification, C2-6 haloalkynyl group refers to, for example, an alkynyl group substituted with one or more halogen atoms. Specific examples of the C2-6 haloalkynyl group include 2-fluoroethynyl group, 2-chloroethynyl group, 3-fluoropropynyl group, 3-chloropropynyl group, 4-bromobutynyl group, 5,5,5 -Includes trifluoropentinyl group, 6,6,6-trifluorohexynyl group, and isomers thereof.

As used herein, examples of C1-4 alkoxy groups include methoxy, ethoxy, propoxy, butoxy groups, and isomers thereof.

As used herein, examples of C1-6 alkoxy groups include methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy groups, and isomers thereof.

In this specification, a C1-4 haloalkoxy group means, for example, an alkoxy group substituted with one or more halogen atoms. Specific examples of C1-4 haloalkoxy groups include fluoromethoxy group, chloromethoxy group, bromomethoxy group, iodomethoxy group, difluoromethoxy group, trifluoromethoxy group, 1-fluoroethoxy group, 2 -Fluoroethoxy group, 2-chloroethoxy group, pentafluoroethoxy group, 1-fluoropropoxy group, 2-chloropropoxy group, 3-fluoropropoxy group, 3-chloropropoxy group , 4,4,4-trifluorobutoxy group, 4-bromobutoxy group, and isomers thereof.

In this specification, C1-6 haloalkoxy group means, for example, an alkoxy group substituted with one or more halogen atoms. Specific examples of C1-6 haloalkoxy groups include fluoromethoxy group, chloromethoxy group, bromomethoxy group, iodomethoxy group, difluoromethoxy group, trifluoromethoxy group, 1-fluoroethoxy group, 2 -Fluoroethoxy group, 2-chloroethoxy group, pentafluoroethoxy group, 1-fluoropropoxy group, 2-chloropropoxy group, 3-fluoropropoxy group, 3-chloropropoxy group , 4,4,4-trifluorobutoxy group, 4-bromobutoxy group, 5,5,5-trifluoropentyloxy group, 6,6,6-trifluorohexyloxy group, and isomers thereof. Includes.

As used herein, examples of C1-6 alkylthio groups include methylthio, ethylthio, propylthio, butylthio, pentylthio, hexylthio, and isomers thereof.

As used herein, examples of C1-6 alkylsulfinyl groups include methylsulfinyl, ethylsulfinyl, propylsulfinyl, butylsulfinyl, pentylsulfinyl, hexylsulfinyl groups, and isomers thereof.

As used herein, examples of C1-6 alkylsulfonyl groups include methylsulfonyl, ethylsulfonyl, propylsulfonyl, butylsulfonyl, pentylsulfonyl, hexylsulfonyl groups, and isomers thereof.

As used herein, examples of C3-6 cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl groups.

As used herein, examples of C2-6 acyl groups include ethanoyl, propanoyl, butanoyl, pentanoyl, hexanoyl groups, and isomers thereof.

In this specification, 3- to 6-membered cyclic groups refer to C3-6 carbocyclic rings and 3- to 6-membered heterocyclic rings.

As used herein, examples of C3-6 carbocyclic rings include cyclopropane, cyclobutane, cyclopentane, cyclohexane, cyclobutene, cyclopentene, cyclohexene, cyclobutadiene, cyclopentadiene, cyclohexadiene, and benzene rings. Includes.

As used herein, examples of 3- to 6-membered heterocyclic rings include aziridine, azetidine, oxirane, oxetane, thiirane, thiethane, pyrrole, imidazole, triazole, tetrazole, pyrazole, pyridine. , pyrazine, pyrimidine, pyridazine, furan, pyran, thiophene, thiopyran, oxazole, isoxazole, thiazole, isothiazole, furazane, oxadiazole, oxazine, oxadiazine, thiadiazole, Thiazine, thiadiazine, pyrroline, pyrrolidine, imidazoline, imidazolidine, triazoline, triazolidine, tetrazoline, tetrazolidine, pyrazoline, pyrazolidine, dihydropyridine, tetrahydro Pyridine, piperidine, dihydropyrazine, tetrahydropyrazine, piperazine, dihydropyrimidine, tetrahydropyrimidine, perhydropyrimidine, dihydropyridazine, tetrahydropyridazine, perhydropyridazine, dihydrofuran , tetrahydrofuran, dihydropyran, tetrahydropyran, dihydrothiophene, tetrahydrothiophene, dihydrothiopyran, tetrahydrothiopyran, dihydroxazole, ??, dihydroxazole (oxazolidine) , dihydroisoxazole, tetrahydroisoxazole (isoxazolidine), dihydrothiazole, tetrahydrothiazole (thiazolidine), dihydroisothiazole, tetrahydroisothiazole (isothiazolidine), Dihydrofurazan, tetrahydrofurazan, dihydroxadiazole, tetrahydroxadiazole (oxadiazolidine), dihydroxazine, tetrahydroxadiazine, dihydroxadiazine, tetrahydroxadiazine , dihydrothiadiazole, tetrahydrothiadiazole (thiadiazolidine), dihydrothiazine, tetrahydrothiazine, dihydrothiadiazine, tetrahydrothiadiazine, morpholine, thiomorpholine, oxathiane , dioxolane, dioxane, dithiolane and dithian rings.

In this specification, 5- to 6-membered cyclic group refers to C5-6 carbocyclic ring and 5- to 6-membered heterocyclic ring.

As used herein, examples of C5-6 carbocyclic rings include cyclopentane, cyclohexane, cyclopentene, cyclohexene, cyclopentadiene, cyclohexadiene, and benzene rings.

As used herein, examples of 5- to 6-membered heterocyclic rings include pyrrole, imidazole, triazole, tetrazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, furan, pyran, thiophene, thiopyran. , oxazole, isoxazole, thiazole, isothiazole, furazane, oxadiazole, oxazine, oxadiazine, thiadiazole, thiazine, thiadiazine, pyrroline, pyrrolidine, imidazoline, imidazolidine, triazoline, triazolidine, tetrazoline, tetrazolidine, pyrazoline, pyrazolidine, dihydropyridine, tetrahydropyridine, piperidine, dihydropyrazine, tetrahydropyrazine, piperazine, dihydropyridine Hydropyrimidine, tetrahydropyrimidine, perhydropyrimidine, dihydropyridazine, tetrahydropyridazine, perhydropyridazine, dihydrofuran, tetrahydrofuran, dihydropyran, tetrahydropyran, dihydrothiophene, Tetrahydrothiophene, dihydrothiopyran, tetrahydrothiopyran, dihydroxazole, ??, dihydroxazole (oxazolidine), dihydroisoxazole, tetrahydroisoxazole (isoxazolidine), Hydrothiazole, tetrahydrothiazole (thiazolidine), dihydroisothiazole, tetrahydroisothiazole (isothiazolidine), dihydrofurazan, tetrahydrofurazan, dihydroxadiazole, tetrahydro Oxadiazole (oxadiazolidine), dihydroxazine, tetrahydroxadiazine, dihydroxadiazine, tetrahydroxadiazine, dihydrothiadiazole, tetrahydrothiadiazole (thiadiazolidine) , dihydrothiazine, tetrahydrothiazine, dihydrothiadiazine, tetrahydrothiadiazine, morpholine, thiomorpholine, oxathiane, dioxolane, dioxane, dithiolane and dithian rings.

In this specification, 3- to 10-membered cyclic groups refer to C3-10 carbocyclic rings and 3- to 10-membered heterocyclic rings.

As used herein, examples of C3-10 carbocyclic rings include cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, cyclooctane, cyclononane, cyclodecane, cyclobutene, cyclopentene, cyclohexene, cycloheptene, Cyclooctene, cyclononene, cyclodecene, cyclobutadiene, cyclopentadiene, cyclohexadiene, cycloheptadiene, cyclooctadiene, benzene, pentalene, perhydropentalene, azulene, perhydroazulene, indene, perhydro indene, indane, naphthalene, dihydronaphthalene, tetrahydronaphthalene, perhydronaphthalene, bicyclo[1.1.1]pentane, bicyclo[2.1.1]hexane, bicyclo[2.1.1]hexene, bicyclo[2.2] .1]heptane, bicyclo[2.2.1]heptene, bicyclo[3.1.1]heptane, bicyclo[3.1.1]heptene, bicyclo[2.2.2]octane, bicyclo[2.2.2]octene, Bicyclo[3.2.1]octane, and bicyclo[3.2.1]octene rings.

In the present specification, examples of 3- to 10-membered heterocyclic rings include 3- to 6-membered heterocyclic rings, and azepine, diazepine, oxepin, thiepine, oxazepine, oxadiazepine, Thiazepine, thiadiazepine, indole, isoindole, indolizine, benzofuran, isobenzofuran, benzothiophene, isobenzothiophene, dithianaphthalene, indazole, quinoline, isoquinoline, quinolizine, purine, phosphorus Thalazine, pteridine, naphthyridine, quinoxaline, quinazoline, cinnoline, benzoxazole, benzothiazole, benzimidazole, chromene, benzofurazine, benzothiadiazole, benzotriazole, dihydrase Pin, tetrahydroazepine, perhydroazepine, dihydrodiazepine, tetrahydrodiazepine, perhydrodiazepine, dihydroxepin, tetrahydroxepin, perhydroxepin, dihydrothiepine, tetrahydrothiepine Pin, perhydrothiepine, dihydroxazepine, tetrahydroxazepine, perhydroxazepine, dihydroxadiazepine, tetrahydroxadiazepine, perhydroxadiazepine, dihydrothiazepine, tetrahydrothiazepine, Perhydrothiazepine, dihydrothiadiazepine, tetrahydrothiadiazepine, perhydrothiadiazepine, indoline, isoindoline, dihydrobenzofuran, perhydrobenzofuran, dihydroisobenzofuran, perhydroisobenzo Furan, dihydrobenzothiophene, perhydrobenzothiophene, dihydroisobenzothiophene, perhydroisobenzothiophene, dihydroindazole, perhydroindazole, dihydroquinoline, tetrahydroquinoline, perhydroquinoline, Dihydroisoquinoline, tetrahydroisoquinoline, perhydroisoquinoline, dihydrophthalazine, tetrahydrophthalazine, perhydrophthalazine, dihydronaphthyridine, tetrahydronaphthyridine, perhydronaphthyridine, dihydro Quinoxaline, tetrahydroquinoxaline, perhydroquinoxaline, dihydroquinazoline, tetrahydroquinazoline, perhydroquinazoline, dihydrocinnoline, tetrahydrocinnoline, perhydrocinnoline, dihydrobenzothiazine, pyra Zinomorpholine, dihydrobenzoxazole, perhydrobenzoxazole, dihydrobenzothiazole, perhydrobenzothiazole, dihydrobenzimidazole, perhydrobenzimidazole, dioxindan, benzodioxane, chroman , benzodithiolane, benzodithian, azaspiro[4.4]nonane, oxaspiro[4.4]nonane, dioxaspiro[4.4]nonane, azaspiro[4.5]decane, thiaspiro[4.5]decane, dithispiro[ 4.5]decane, dioxaspiro[4.5]decane, oxaspiro[4.5]decane, azabicyclo[3.2.1]octane, oxabicyclo[3.2.1]octane, thieno[3,2-c]pyra Sol, 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 Contains [3,2-c]thiopyran, tetrahydrothieno[3,2-b]pyridine, tetrahydrothieno[3,2-c]pyridine, and thieno[3,2-c]pyridine rings. do.

In this specification, 3- to 15-membered cyclic groups refer to C3-15 carbocyclic rings and 3- to 15-membered heterocyclic rings.

As used herein, examples of C3-15 carbocyclic rings include C3-10 carbocyclic rings, and heptalene, biphenylene, as-indacene, s-indacene, acenaphthylene, acenaphthene, fluorene, fe Includes nalene, phenanthrene, and anthracene rings.

As used herein, examples of 3- to 15-membered heterocyclic rings include 3- to 10-membered heterocyclic rings and benzoxadiazepines, benzothiadiazepines, benzoxazepines, benzothiazepines, benzodiazepines, dihydro Benzodiazepine, tetrahydrobenzodiazepine, benzodioxepane, dihydrobenzoxazepine, tetrahydrobenzoxazepine, benzoxepin, benzothiepine, benzazepine, dihydrobenzazepine, tetrahydrobenzazepine, perimidine, β -Carboline, dihydrocarbazole, tetrahydrocarbazole, dihydrodibenzofuran, dihydrodibenzothiophene, tetrahydrodibenzofuran, tetrahydrodibenzothiophene, carbazole, dibenzofuran, dibenzothiophene Ophen, phenothiazine, phenoxazine, phenoxathiine, thianthrene, phenazine, phenanthroline, xanthene, dihydroacridine, tetrahydroacridine, acridine, phenanthridine. and a dihydropyrrolo[1,2-b]thieno[2,3-d]pyrazole ring.

As used herein, "one to two carbon atoms may be replaced by oxygen atoms or optionally oxidized sulfur atoms" means that one or two carbon atoms (-CH ₂ -) are replaced by oxygen atoms (- O-) or optionally an oxidized sulfur atom (-S-, -SO-, or -SO ₂ -). For C1-6 alkyl groups, specific examples of such groups are CH ₃ -O-CH ₂ - group, CH ₃ -CH ₂ -O-CH ₂ - group, CH ₃ -O-CH ₂ -CH ₂ - group, CH ₃ -O-CH ₂ -CH ₂ -CH ₂ -group, CH ₃ -CH ₂ -O-CH ₂ -CH ₂ - group.

In the present invention, X ¹ and X ² are preferably N.

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

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

In the present invention, ^R It is cyano group.

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

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

In the present invention, ring 1 is preferably a 3- to 10-membered cyclic group or a ring structure selected from the group consisting of:

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

ring 1 is more preferably a ring structure selected from the group consisting of:

In the formula, * indicates the bonding position with the carbonyl group, and the hydrogen atom represented by NH may be replaced with R ^5-A or R ⁵ .

ring 1 is even more preferably a ring structure selected from the group consisting of:

In the formula, * indicates the bonding position with the carbonyl group, and the hydrogen atom represented by NH may be replaced with R ^5-A or R ⁵ .

In the present invention, R ⁵ is preferably a halogen atom, C1-6 alkyl group, C1-6 alkoxy group, C1-6 haloalkyl group, C1-6 haloalkoxy group, 3- to 6-membered cyclic group, oxo group, -NR ⁵⁰¹ R ⁵⁰² , or -COOR ⁵⁰³ , more preferably C1-6 alkyl group, C1-6 alkoxy group, C1-6 haloalkyl group, C1-6 haloalkoxy group, cyclopropyl group, furan ring, N-methylpyra A sol ring, an oxo group, a dimethylamino group, or -COOCH ₃ , and even more preferably a C1-6 alkyl group, a C1-6 haloalkyl group, a C1-6 haloalkoxy group, or a cyclopropyl group.

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

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

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

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

In the present invention, the compound represented by general formula (I-A) or general formula (I) is preferably a compound represented by general formula (I-1):

In the formula, R ^3-a represents (1) a hydrogen atom, (2) a C1-6 alkyl group, (3) a C1-6 haloalkyl group, (4) a cyclopropyl group, or (5) -CH ₂ -Q;

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

ring 1-a represents a ring structure selected from the group consisting of the following ring structures;

In the formula, * indicates the bonding position with the carbonyl group, and the hydrogen atom represented by NH can be replaced by R ^5-a ,

R ^5-a is (1) C1-6 alkyl group, (2) C1-6 alkoxy group, (3) C1-6 haloalkyl group, (4) C1-6 haloalkoxy group, (5) cyclopropyl group, (6) ) represents a furan ring, (7) N-methylpyrazole ring, (8) oxo group, (9) dimethylamino group, or (10) -COOCH ₃ ,

Other symbols have the same meaning as the above symbols.

^{In the} present invention, the compound represented by general formula (IA) ^{is preferably X 1 ,} It is a combination of desirable definitions.

In the present invention, the ^{compound represented} by general formula ^{( I} ) preferably has ^{the preferred compounds} of It is a combination of justice.

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

All isomers are included in the invention unless otherwise indicated. For example, alkyl groups, alkoxy groups, alkylene groups, etc. include straight chain groups and branched chain groups. In addition, isomers in double bonds, rings and fused rings (E-, Z-, cis- and trans-forms), isomers due to the presence of asymmetric carbons (R-, S-forms, α-, β-forms, mirror images isomers and diastereomers), optically active substances with optical rotation (D-, L-, d- and l-forms), polar substances obtained through chromatographic separation (highly polar substances and low polar substances), equilibrium compounds, Rotational isomers, mixtures thereof in appropriate ratios, and racemic mixtures are all encompassed by the present invention. Additionally, all isomers by tautomerism are also included in the present invention.

In this specification, compounds described as “rel-” in the compound name indicate that the stereoscopic configuration of a plurality of stereogenic centers is a relative configuration.

In the present invention, unless otherwise specified, the symbols:

indicates that the substituent is bonded to the back side of the paper surface (i.e. α-configuration), symbol:

indicates that the substituent is attached to the front side of the paper surface (i.e. β-configuration), and the symbol:

represents a mixture of α- and β-members in appropriate ratios, as will be clear to the person skilled in the art.

[salt]

Compounds represented by general formula (I-A) are converted into salts by known methods.

The salt is a pharmaceutically acceptable salt.

The salt is preferably water soluble.

Examples of pharmaceutically acceptable salts include acid addition salts, alkali metal salts, alkaline earth metal salts, ammonium salts, and amine salts.

Examples of acid addition salts include, for example, mineral acid salts such as hydrochloride, hydrobromide, hydroiodide, sulfate, phosphate, and nitrate, or acetate, lactate, tartrate, benzoate, citrate, and methane. Includes organic acid salts such as sulfonate, ethanesulfonate, trifluoroacetate, benzenesulfonate, toluenesulfonate, isethionate, glucuronate, and gluconate.

Examples of alkali metal salts include potassium salts and sodium salts.

Examples of alkaline earth metal salts include calcium salts and magnesium salts.

Examples of ammonium salts include tetramethylammonium salt.

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

Additionally, the compounds of the present invention can be converted to N-oxides by any method. N-oxide refers to a compound obtained by oxidizing the nitrogen atom of a compound represented by general formula (I-A).

The compound represented by general formula (I-A) and its pharmaceutically acceptable salt may exist in an unsolvated or solvated form with a pharmaceutically acceptable solvent such as water or ethanol. The solvate is preferably a hydrate. The compounds represented by general formula (I-A) and their pharmaceutically acceptable salts can be converted into solvates.

Compounds represented by general formula (I-A) are capable of forming cocrystals with suitable cocrystal formers. The co-crystal is preferably a pharmaceutically acceptable co-crystal formed with a pharmaceutically acceptable co-crystal former. A cocrystal is typically defined as a crystal in which two or more different molecules are formed by intermolecular interactions that are different from ionic bonding. A cocrystal may be a complex of a neutral molecule and a salt. Co-crystals can be prepared by known methods, for example by melt crystallization, recrystallization from a solvent, or by physically grinding the components together. Suitable co-crystal formers are those described in WO 2006/007448.

In the present invention, all references to compounds of the present invention refer to compounds represented by general formula (I-A), pharmaceutically acceptable salts thereof, N-oxides thereof, solvates (e.g., hydrates) thereof, or A co-crystal, or a pharmaceutically acceptable salt of a compound represented by formula (I-A), a solvate (e.g., a hydrate) thereof, or an N-oxide of a co-crystal thereof.

[Prodrug]

The prodrug of the compound represented by the general formula (I-A) refers to a compound that is converted to the compound represented by the general formula (I-A) by reacting with enzymes, stomach acid, etc. in vivo. Examples of prodrugs of the compound represented by general formula (I-A) include, when the compound represented by general formula (I-A) has an amino group, compounds in which the amino group is acylated, alkylated or phosphorylated (e.g., The amino group of the compound represented by (I-A) is eicosanoylated, alanylated, pentylaminocarbonylated, (5-methyl-2-oxo-1,3-dioxolen-4-yl)methoxycarbonylated, compounds that are tetrahydrofuranylated, pyrrolidyl methylated, pivaloyloxymethylated, acetoxymethylated, tert-butylated, etc.); When the compound represented by general formula (I-A) has a hydroxyl group, the hydroxyl group is acylated, alkylated, phosphorylated or boricated (e.g., the hydroxyl group of the compound represented by general formula (I-A) compounds in which the roxyl group is acetylated, palmitoylated, propanoylated, pivaloylated, succinylated, fumarylated, alanylated, dimethylaminomethylcarbonylated, etc.); and when the compound represented by the general formula (I-A) has a carboxyl group, a compound in which the carboxyl group is esterified or amidated (the carboxyl group in the compound represented by the general formula (I-A) is ethyl esterified, phenyl esterified, carboxymethyl Esterification, dimethylaminomethyl esterification, pivaloyloxymethyl esterification, 1-{(ethoxycarbonyl)oxy}ethyl esterification, phthalidyl esterification, (5-methyl-2-oxo-1,3 -dioxolen-4-yl)methyl esterification, 1-{[(cyclohexyloxy)carbonyl]oxy}ethyl esterification, methylamidation, etc.). These compounds can be produced by known methods. The prodrug of the compound represented by general formula (I-A) may be hydrated or non-hydrated. Additionally, prodrugs of compounds represented by general formula (I-A) are described in the literature ["Development of Pharmaceuticals", Vol. 7, “Molecular Design”, pp. 163 to 198, published by Hirokawa Shoten, 1990].

In addition, each atom constituting the compound represented by general formula (IA) is an isotope thereof (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, and ¹²⁵ I).

[Method for producing compounds of the present invention]

The compounds of the present invention can be prepared by appropriately improving known methods, for example, the method shown below, method equivalents thereof, Comprehensive Organic Transformations: A Guide to Functional Group Preparations, 3rd Edition (Richard C. Larock, John It can be manufactured using the method described in (Wiley & Sons Inc, 2018), the method described in the Examples, etc., and a combination thereof. Salt may be used as a starting material. The progress order of each reaction may be appropriately changed depending on the protecting group introduced and reaction conditions.

In addition, if necessary, after an appropriate reaction step, a known deprotection reaction can be performed to prepare a compound having an amino group, carboxyl group, or hydroxyl group using a compound protected with a protecting group commonly used for these groups. Protecting groups are described, for example, in [T. It is a protecting group described in W. Greene, Protective Groups in Organic Synthesis, Wiley, New York, 5th Edition, 2014.

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

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

Examples of protecting groups of hydroxyl groups or hydroxamic acids are methyl, trityl, methoxymethyl (MOM), 1-ethoxyethyl (EE), methoxyethoxymethyl (MEM), 2-tetrahydropyranyl (THP) ), trimethylsilyl (TMS), triethylsilyl (TES), tert-butyldimethylsilyl (TBDMS), tert-butyldiphenylsilyl (TBDPS), acetyl (Ac), pivaloyl, benzoyl, benzyl (Bn), Includes p-methoxybenzyl, allyloxycarbonyl (Alloc), and 2,2,2-trichloroethoxycarbonyl (Troc).

Deprotection reactions are known and can be performed, for example, by the following methods: (1) deprotection reaction by alkaline hydrolysis;

(2) deprotection reaction under acidic conditions;

(3) deprotection reaction by hydrogenolysis;

(4) Deprotection reaction of silyl group;

(5) deprotection reaction using metal; and

(6) Deprotection reaction using metal complex.

This method is specifically explained as follows.

(1) The deprotection reaction by alkaline hydrolysis is a hydroxide of an alkali metal in an organic solvent (e.g., methanol, tetrahydrofuran (hereinafter referred to as THF), and dioxane), for example, at 0°C to 40°C. This is accomplished using hydroxides of alkaline earth metals (e.g. sodium hydroxide, potassium hydroxide and lithium hydroxide), hydroxides of alkaline earth metals (e.g. barium hydroxide and calcium hydroxide), carbonates (e.g. sodium carbonate and potassium carbonate), or aqueous solutions or mixtures thereof. .

(2) The deprotection reaction under acidic conditions is, for example, at 0 to 100° C., in the presence or absence of 2,2,2-trifluoroethanol, in an organic solvent (e.g., dichloromethane, chloroform, dioxane, ethyl acetate, methanol, isopropyl alcohol, THF, and anisole), organic acids (e.g., acetic acid, trifluoroacetic acid, methanesulfonic acid, and p-tosylic acid) or inorganic acids (e.g., hydrochloric acid and sulfuric acid) , or mixtures thereof (e.g. hydrogen bromide/acetic acid).

(3) Deprotection reaction by hydrocracking, for example, at a temperature of 0 to 200° C., using catalysts (e.g., palladium-carbon, palladium black, palladium hydroxide-carbon, platinum oxide and Raney nickel) ), in a hydrogen atmosphere at normal or high pressure, or in the presence of ammonium formate, in the presence of a solvent (e.g., ether-based solvents such as THF, dioxane, dimethoxyethane and diethyl ether; methanol and ethanol, etc. Alcohol-based solvents; Benzene-based solvents such as benzene and toluene; Ketone-based solvents such as acetone and methyl ethyl ketone; Nitrile-based solvents such as acetonitrile; Amide-based solvents such as N,N-dimethylformamide (hereinafter referred to as DMF); It is carried out in water, ethyl acetate, acetic acid, or a mixed solvent of two or more thereof.

(4) The deprotection reaction of the silyl group is carried out, for example, using tetrabutylammonium fluoride in an organic solvent miscible with water (for example, THF and acetonitrile) at 0 to 40° C. Additionally, the deprotection reaction can be carried out, for example, at -10 to 100° C. using organic acids (e.g. acetic acid, trifluoroacetic acid, methanesulfonic acid and p-tosylic acid) or inorganic acids (e.g. hydrochloric acid and sulfuric acid) or these. (e.g. hydrogen bromide/acetic acid).

(5) The deprotection reaction using a metal is carried out, for example, at 0 to 40°C in an acidic solvent (e.g., a mixed solution of acetic acid, a buffer solution of pH 4.2 to 7.2, or a solution thereof and an organic solvent such as THF). It is performed in the presence of powdered zinc while applying ultrasonic waves as needed.

(6) The deprotection reaction using a metal complex is carried out, for example, at 0 to 40° C. in an organic solvent (e.g., dichloromethane, DMF, THF, ethyl acetate, acetonitrile, dioxane, and ethanol), water, or these In the mixed solvent, capture reagents (e.g., tributyltin hydride, triethylsilane, dimedone, morpholine, diethylamine, and pyrrolidine), organic acids (e.g., acetic acid, formic acid, and 2 -ethylhexanoic acid) and/or organic acid salts (e.g. sodium 2-ethylhexanoate and potassium 2-ethylhexanoate), in the presence of a phosphine-based reagent (e.g. triphenylphosphine) Under, metal complexes (e.g., tetrakistriphenylphosphine palladium(0), bis(triphenylphosphine)palladium(II) dichloride, palladium(II) acetate, and tris(triphenylphosphine)rhodium( I) It is carried out using chloride).

The compound represented by general formula (I-A) can be produced according to Scheme 1 below.

Scheme 1

In the formula, PG represents a protecting group of an amino group, Y represents a halogen atom, Z represents a halogen atom, and other symbols represent the same meanings as described above.

In Scheme 1, Scheme 1-1 is a halogen substitution reaction or cross-coupling reaction. Halogen substitution reactions are known, for example, in organic solvents (DMF, dimethyl sulfoxide, chloroform, dichloromethane, diethyl ether, THF, methyl t-butyl ether, etc.) at 0 to 200° C., in bases (sodium ethyl) sodium hydroxide, potassium hydroxide, triethylamine, diisopropylethylamine, sodium carbonate, sodium bicarbonate, potassium carbonate, cesium carbonate, tripotassium phosphate, cesium fluoride, barium hydroxide, tetrabutylammonium fluoride, etc.), or these It is carried out through a reaction in the presence of an aqueous solution or mixture.

Cross-coupling reactions are known, for example, at room temperature to 120°, in organic solvents (benzene, toluene, DMF, dioxane, THF, methanol, acetonitrile, dimethoxyethane, acetone, etc.), with bases ( sodium ethylate, sodium hydroxide, potassium hydroxide, triethylamine, sodium carbonate, sodium bicarbonate, potassium carbonate, cesium carbonate, thallium carbonate, tripotassium phosphate, cesium fluoride, barium hydroxide, tetrabutylammonium fluoride, etc.), or an aqueous solution thereof, or Mixtures and catalysts (tetrakis(triphenylphosphine)palladium (Pd(PPh ₃ ) ₄ ), bis(triphenylphosphine)palladium dichloride (PdCl ₂ (PPh ₃ ) ₂ ), palladium acetate (Pd(OAc) ₂ ) ), palladium black, 1,1'-bis(diphenylphosphinoferrocene)dichloropalladium (PdCl ₂ (dppf) ₂ ), diallylpalladium dichloride (PdCl ₂ (allyl) ₂ ), phenylbis(triphenylphosphine) ) is carried out through a reaction in the presence of palladium iodide (PhPdI(PPh ₃ ) ₂ ), etc.

In Scheme 1, Scheme 1-2 is the N-alkylation reaction. N-alkylation reactions are known, for example, in organic solvents (DMF, dimethyl sulfoxide, chloroform, dichloromethane, diethyl ether, THF, methyl t-butyl ether, etc.) at 0 to 100° C. of alkali metals. It is carried out through a reaction in the presence of hydroxides (sodium hydroxide, potassium hydroxide, lithium hydroxide, etc.), hydroxides of alkaline earth metal salts (barium hydroxide, calcium hydroxide, etc.), carbonates (sodium carbonate, potassium carbonate, etc.), or aqueous solutions or mixtures thereof.

In Scheme 1, Scheme 1-3 is a deprotection reaction and can be performed in the same manner as above.

In Scheme 1, Schemes 1-4 are amidation reactions. Amidation reactions are known and examples include:

(1) Method using acid halide;

(2) a method using mixed acid anhydrides; and

(3) Method of using condensing agent. This method is specifically explained as follows.

(1) A method using an acid halide is, for example, mixing a carboxylic acid and an acid halogenating agent (oxalyl chloride, thionyl chloride, etc.) in an organic solvent (chloroform, dichloromethane, diethyl ether, THF, etc.) at -20°C. Alternatively, the reaction is carried out to reflux temperature in the absence of a solvent, and the obtained acid halide is reacted with an organic solvent (chloroform, dichloroform, etc.) at 0 to 40° C. in the presence of a base (pyridine, triethylamine, dimethylaniline, dimethylaminopyridine, diisopropylethylamine, etc.). It is carried out by reacting with an amine in methane, diethyl ether, THF, etc.). Alternatively, the method may also be carried out by reacting the obtained acid halide with an amine using an aqueous alkaline solution (sodium bicarbonate water, sodium hydroxide solution, etc.) in an organic solvent (dioxane, THF, etc.) at 0 to 40° C. there is.

(2) Methods using mixed acid anhydrides include, for example, organic solvents (chloroform, dichloromethane, diethyl ether, THF, etc.) or bases (pyridine, triethylamine, dimethylaniline, dimethylaminopyridine, diisopropylethyl) Reacting carboxylic acids with acid halides (pivaloyl chloride, tosyl chloride, mesyl chloride, etc.) or acid derivatives (ethyl chloroformate, isobutyl chloroformate, etc.) at 0 to 40°C in the presence of amines, etc. This is carried out by reacting the obtained mixed acid anhydride with an amine in an organic solvent (chloroform, dichloromethane, diethyl ether, THF, etc.) at 0 to 40° C.

(3) A method of using a condensing agent is, for example, a base (pyridine, triethylamine, Carboxylic acids and amines are reacted in the presence or absence of dimethylaniline, dimethylaminopyridine, etc., and condensing agents (1,3-dicyclohexylcarbodiimide (DCC), 1-ethyl-3-[3-(dimethylamino )Propyl]carbodiimide (EDC), 1,1'-carbonyldiimidazole (CDI), 2-chloro-1-methylpyridinium iodine, 1-propylphosphonic acid cyclic anhydride (1-propanephosphonic acid) cyclic anhydrides, propyl phosphonic acid (PPA), etc.), and O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU) and the like, with or without 1-hydroxybenztriazole (HOBt).

These reactions (1), (2), and (3) are all preferably carried out in an anhydrous inert gas (argon, nitrogen, etc.) atmosphere.

The compound represented by General Formula 1a can be produced according to Scheme 2 below.

Scheme 2

In Scheme 2, all symbols have the same meaning as the symbols described above.

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

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

In Scheme 2, Scheme 2-3 is a tosylation reaction in which p-toluenesulfonyl chloride is reacted in an organic solvent (e.g., dichloromethane, diethyl ether, THF, acetonitrile, benzene, toluene) at 0 to 100°C. It can be performed by reacting in the presence of a base (e.g., pyridine, triethylamine, dimethylaniline, dimethylaminopyridine, and diisopropylethylamine).

In Scheme 2, Schemes 2-4 are azidation reactions, for example, in organic solvents (DMF, dimethyl sulfoxide, chloroform, dichloromethane, diethyl ether, THF, methyl t-butyl ether, etc.) at 0 to 100°C. It can be performed by reacting sodium azide in water.

In Scheme 2, Scheme 2-5 is the reduction reaction of the azide group, which is reacted with an organic solvent (e.g., THF, dioxane, dimethoxyethane, diethyl ether, methanol, ethanol, benzene, toluene, acetone, methyl ethyl ketone) , acetonitrile, DMF, ethyl acetate, acetic acid, or a mixed solvent of two or more thereof), a hydrogenation catalyst (palladium-carbon, palladium black, palladium, palladium hydroxide, platinum dioxide, platinum-carbon, nickel, Raney nickel, chloride) At normal pressure under a hydrogen atmosphere, 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.) or at 0 to 200° C. under pressure.

In each reaction of the present specification, the compounds represented by General Formula 1b, General Formula 1d, General Formula 1g, General Formula 2a, and General Formula 2b used as starting materials are known or can be obtained by using known methods, for example, in the literature [Comprehensive] Organic Transformations: A Guide to Functional Group Preparations, 3rd Edition (Richard C. Larock, John Wiley & Sons Inc, 2018)], etc., or methods obtained by partially modifying known methods can be easily combined. can be manufactured.

Among the compounds of the present invention, the optically active compounds can be prepared by using optically active starting materials or reagents, by optically separating the racemic intermediate and then converting it to the compound of the present invention, or by converting the racemic intermediate into the compound of the present invention. The semi-form can be manufactured by optically separating it.

Such optical separation is known, and examples include a method of forming a salt or complex with another optically active compound and then isolating the target compound after recrystallization or directly separating the target compound using a chiral column or the like.

In the reactions herein, reactions involving heating can be carried out using a water bath, oil bath, sand bath, or microwaves, as will be apparent to those skilled in the art.

In the reaction herein, a solid phase support reagent supported on a polymer (eg, polystyrene, polyacrylamide, polypropylene, polyethylene glycol, etc.) can be appropriately used.

In the reaction herein, the reaction product is purified by conventional purification means, such as distillation at normal or reduced pressure, high performance liquid chromatography using silica gel or magnesium silicate, thin layer chromatography, ion exchange resin, or scavenger resin. It can be purified by methods, column chromatography, washing and recrystallization. Purification may be performed for each reaction, or may be performed after completion of some reactions.

[toxicity]

Because the compounds of the present invention have low toxicity, pharmaceutical compositions containing the compounds of the present invention can be used safely.

[Pharmaceutical composition]

Since the compounds of the present invention have inhibitory activity against ABHD6, pharmaceutical compositions containing the compounds of the present invention can be used to treat diseases associated with ABHD6, such as pain, neurological diseases, inflammatory diseases, autoimmune diseases, metabolic diseases, and It is useful as an agent for the prevention and/or treatment of malignant tumors.

More specifically, examples of pain include pain associated with osteoarthritis, cancer pain, pain associated with chemotherapy, chronic back pain, back pain associated with osteoporosis, fracture pain, pain associated with rheumatoid arthritis, neuropathic pain, post-herpetic pain, and diabetic nerves. Includes pain associated with a condition, pain associated with fibromyalgia, pain associated with pancreatitis, pain associated with interstitial cystitis or bladder pain syndrome, pain associated with endometriosis, pain associated with irritable bowel syndrome, migraine, and pain associated with pulpitis. .

Examples of neurological disorders include tremors, dyskinesias, dystonia, rigidity, pressure and obsessive-compulsive behavior, depression, and psychiatric disorders including anxiety disorders (e.g., panic disorder, acute stress disorder, post-traumatic stress disorder, obsessive-compulsive disorder). , agoraphobia, social phobia), mood disorders, epilepsy, traumatic brain injury, spinal cord injury, multiple sclerosis, encephalomyelitis, Parkinson's disease, Huntington's disease, Alzheimer's disease, and sleep disorders.

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

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

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

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, and head and neck cancer (e.g., oral squamous cell carcinoma, head and neck squamous cell carcinoma). cancer, pharyngeal cancer, laryngeal cancer, tongue cancer, thyroid cancer, and acoustic schwannoma), lymphomas (e.g., B-cell lymphoma and T-cell lymphoma), uveal malignant melanoma, thymoma, mesothelioma, esophageal cancer, stomach cancer, duodenal cancer, and hepatocellular cancer , bile duct cancer, gallbladder cancer, pancreatic cancer, renal cell cancer, renal pelvic and ureteral cancer, bladder cancer, penile cancer, testicular cancer, uterine cancer, vaginal cancer, vulvar cancer, skin cancer (e.g., malignant melanoma), malignant bone tumor, soft tissue sarcoma, chondrosarcoma , leukemia (e.g., acute myeloid leukemia, acute lymphocytic leukemia, chronic myeloid leukemia, and chronic lymphocytic leukemia), myelodysplastic syndrome, brain tumor, or multiple myeloma.

In the present specification, prevention and/or treatment of malignant tumors include, for example, (a) treatment to reduce the proliferation of cancer cells, (b) treatment to alleviate symptoms caused by cancer and improve the quality of life of cancer patients, ( c) treatment that reduces the dose of other anticancer drugs or cancer treatment adjuvants already administered, (d) treatment that suppresses the progression of cancer, (e) treatment that suppresses recurrence of cancer, and/or (f) survival of cancer patients. Includes treatment that prolongs. Additionally, “inhibiting the progression of cancer” means slowing the progression of cancer, stabilizing symptoms associated with cancer, and reversing the progression of symptoms. “Inhibition of recurrence” means preventing recurrence of cancer in patients whose cancerous lesions have been completely or substantially eliminated or removed by cancer treatment or surgical resection of cancer.

Pharmaceutical compositions containing the compounds of the present invention typically contain a pharmaceutically acceptable carrier. When a pharmaceutical composition containing a compound of the present invention is used for the purpose of preventing and/or treating the above-mentioned diseases, the compound of the present invention is usually formulated with a pharmaceutically acceptable carrier such as various additives or solvents to or administered topically, orally, or parenterally. Here, a pharmaceutically acceptable carrier refers to a substance other than the active ingredient commonly used in pharmaceutical preparations. It is desirable that the pharmaceutically acceptable carrier does not exhibit pharmacological action at the dosage of the preparation, is harmless, and does not inhibit the therapeutic effect of the active ingredient. Pharmaceutically acceptable carriers can also be used for the purpose of, for example, improving the usefulness of active ingredients and preparations, promoting formulation, stabilizing quality, or improving usefulness. Specifically, substances listed in the "Japanese Pharmaceutical Excipients Directory" published in 2000, authored by Yakuji Nippo Limited (edited by the International Pharmaceutical Excipients Council Japan), etc. can be appropriately selected depending on the purpose.

A pharmaceutical composition containing a compound of the invention may be a pharmaceutical composition administered to a subject (preferably a mammal, more preferably a human, even more preferably a human patient) in a pharmaceutically effective amount of the compound of the invention. there is.

Since the dosage of the compound of the present invention varies depending on age, body weight, symptoms, desired therapeutic effect, administration route, treatment period, etc., the dosage inevitably varies. The compounds of the invention are generally administered orally in the range of 0.1 ng to 1,000 mg per patient per dose, or parenterally in the range of 0.01 ng to 100 mg per patient per dose or administered intravenously continuously.

Of course, the dosage of the compounds of the present invention varies depending on various conditions as described above. Therefore, a capacity smaller than the above capacity may be sufficient, and a capacity exceeding the above range may also be necessary.

Pharmaceutical compositions containing the compounds of the present invention may be in the form of various formulations. Examples of its dosage forms include preparations for oral administration (e.g., tablets, capsules, granules, powders, oral solutions, syrups, and oral jellies), oral preparations (e.g., oral tablets, oral sprays, oral semi-solids, and oral rinses), injectable formulations (e.g., injectables), dialysis formulations (e.g., dialysis agents), inhalable formulations (e.g., inhalants), ophthalmic formulations (e.g., eye drops and ophthalmic ointments), otological preparations (e.g., ear drops), nasal preparations (e.g., nasal drops), rectal preparations (e.g., suppositories, rectal semisolids, and rectal enemas) ), vaginal preparations (e.g., vaginal tablets and vaginal suppositories), and dermal preparations (e.g., solid preparations for external use, liquid preparations for external use, sprays, ointments, creams, gels, and patches).

[Preparations for oral administration]

Examples of preparations for oral administration include tablets, capsules, granules, powders, oral solutions, syrups, and oral jellies. Formulations for oral administration include rapidly disintegrating formulations in which the release of the active ingredient from the formulation is not particularly controlled; and controlled-release preparations such as enteric-coated preparations, and sustained-release preparations whose release is adjusted to suit the purpose through unique formulation design and formulation methods. Enteric-coated preparations refer to preparations designed to release the active ingredient mainly in the small intestine without releasing the active ingredient in the stomach, with the purpose of preventing decomposition of the active ingredient in the stomach or reducing stimulation of the active ingredient in the stomach. Enteric coating preparations can usually be prepared by coating with an acid-insoluble enteric coating base. Sustained-release preparations refer to preparations in which the release rate, release time, and release location of the active ingredient from the preparation are controlled for the purpose of reducing the number of administrations or reducing side effects. Sustained-release preparations can usually be prepared using an appropriate sustained-release agent. Among preparations for oral administration, capsules, granules, tablets, etc. may be coated with an appropriate coating agent such as sugars, sugar alcohols, or polymer compounds, for example, for the purpose of facilitating ingestion or preventing decomposition of the active ingredient.

(1) Tablets

Tablets are solid preparations that are administered orally and have a definite form. Tablets include those commonly called tablets, such as uncoated tablets, film-coated tablets, dragee tablets, multilayer tablets, and dry-coated tablets, and orally rapidly disintegrating tablets, chewable tablets, effervescent tablets, dispersible tablets, and soluble tablets. In the production of uncoated tablets, the following methods (a), (b) or (c) are usually used:

(a) Add and mix additives such as excipients, binders, and disintegrants to the active ingredient to prepare a homogeneous mixture, granulate the mixture in an appropriate manner using water or a solution containing the binder, and then granulate A lubricant, etc. was added to the product and mixed, and the resulting mixture was compression molded;

(b) adding and mixing additives such as excipients, binders, and disintegrants to the active ingredients to prepare a homogeneous mixture, and compression molding the mixture directly; Alternatively, the active ingredient, lubricant, etc. are added to pre-prepared granules along with additives to prepare a homogeneous mixture, and then the mixture is compression molded; and

(c) Add and mix additives such as excipients and binders to the active ingredients to prepare a homogeneous mixture, wet the mixture with a solvent, pour the kneaded product into a predetermined mold and mold it, and then mold the molded product using an appropriate method. Dry with

Film-coated tablets can usually be manufactured by thinly coating an uncoated tablet with a suitable coating agent such as a polymer compound. Sugar-coated tablets can usually be manufactured by coating uncoated tablets with a coating agent containing sugars or sugar alcohols. Multilayer tablets can be manufactured by forming layers of powder particles with different compositions and compression molding the layered powder particles by an appropriate method. Dry coated tablets can be manufactured by coating an inner core tablet with an outer layer that has a different composition from the inner core tablet. The tablets may also be enteric-coated tablets or sustained-release tablets by known suitable methods. Orally rapidly disintegrating tablets, masticating tablets, effervescent tablets, dispersion tablets, and soluble tablets are those in which unique functions are imparted to tablets by appropriate selection of additives, and can be manufactured according to the tablet manufacturing method described above. In addition, oral rapidly disintegrating tablets refer to tablets that dissolve or disintegrate quickly in the oral cavity and can be taken; Masticating tablets refer to tablets that are chewed and taken; Effervescent tablets refer to tablets that rapidly foam and dissolve or disperse in water; Dispersible tablets refer to tablets that are dispersed in water and taken; Soluble tablets are tablets that are taken by dissolving them in water. Effervescent tablets can be produced by using appropriate acidic substances, carbonates, bicarbonates, etc. as additives.

(2) Capsule

Capsules are preparations in which ingredients are filled in a capsule or encapsulated in a capsule base, and include hard capsules, soft capsules, etc. Hard capsules are made by mixing the active ingredients with additives such as excipients to produce a homogeneous mixture, or by manufacturing the mixture into particles or molded bodies by an appropriate method and filling the capsules with the mixture, particles, or molded bodies as is or by slightly molding each content. It can be manufactured. Soft capsules can be manufactured by encapsulating a mixture of active ingredients and additives in a predetermined shape with a suitable capsule base such as gelatin whose plasticity is increased by adding glycerin, D-sorbitol, etc. The capsule may be an enteric-coated capsule or a sustained-release capsule manufactured by a known suitable method, and colorants, preservatives, etc. may be added to the capsule base.

(3) Granules

Granules are preparations granulated in the form of granules, and include foamable granules in addition to those generally referred to as granules. For the production of granules, the following methods (a), (b) or (c) are usually used:

(a) Add excipients, binders, disintegrants or other additives to the powdered active ingredient and mix to prepare a homogeneous mixture, and then granulate the mixture by an appropriate method;

(b) Add additives such as excipients to the active ingredient previously prepared in granule form and mix to prepare a homogeneous mixture; and

(c) After adding and mixing additives such as excipients to the active ingredient previously prepared in granule form, the mixture is formed into granules by an appropriate method.

The granules may be coated as needed, and may be enteric-coated granules or sustained-release granules prepared by a known appropriate method. Foamable granules can be produced by using appropriate acidic substances, carbonates, bicarbonates, etc. as additives. Foamable granules refer to granules that rapidly foam and dissolve or disperse in water. Granules can also be made into fine granules by controlling the particle size.

(4) powder

Powder is a powder preparation, and can usually be manufactured by adding excipients or other additives to the active ingredient and mixing them to prepare a homogeneous mixture.

(5) Oral solution

Oral solutions are liquid or fluid viscous gel preparations and, in addition to those commonly referred to as oral solutions, include elixirs, suspensions, emulsions, lemonades, etc. Oral solutions can usually be prepared by adding excipients and purified water to the active ingredient, followed by mixing, uniformly dissolving, emulsifying or suspending as necessary, and filtering. Elixir refers to a clear liquid oral solution containing sweet, aromatic ethanol. Elixirs can typically be prepared by adding ethanol, purified water, flavoring agents, and white sugar or other sugars or sweeteners to the solid active ingredient or its leachate, dissolving the ingredients, and producing a clear liquid by filtration or other methods. Solution refers to an oral solution in which the active ingredient is finely and homogeneously suspended. Suspensions can usually be prepared by adding suspending agents or other additives and purified water or oil to the solid active ingredients and suspending them by a suitable method to homogenize the entire active ingredient. Emulsion refers to an oral solution in which the active ingredient is finely and homogeneously emulsified. Emulsions can usually be prepared by adding an emulsifier and purified water to the liquid active ingredient and emulsifying it by a suitable method to homogenize the mixture. Lemonade is a clear liquid oral solution with a sweet and sour taste.

(6) Syrup

Syrup is a viscous liquid or solid preparation containing sugars or sweeteners, and includes preparations such as syrup. Syrups can generally be prepared by adding the active ingredients to solutions of white sugar, other sugars or sweeteners, or to a single syrup, dissolving, mixing, suspending or emulsifying them, boiling the mixed liquid as needed, and then heat filtering. Syrup preparations refer to granular or powder-type preparations that turn into syrup when water is added, and are also called dry syrup. Syrup preparations can be manufactured using sugars or sweeteners as additives according to the usual granule or powder manufacturing method.

(7) Oral jelly

Oral jelly is a formed gel preparation that does not have fluidity, and can usually be prepared by adding and mixing the active ingredient with additives and a polymer gel base, gelling the mixture by an appropriate method, and forming the resulting gel in a certain form.

[Injectable preparation]

(1) Injectable medication

Injectables are solutions, suspensions or emulsions administered subcutaneously, intramuscularly, or directly to body tissues such as blood vessels or organs, or solid sterile preparations that are dissolved or suspended upon use. Injectables include, in addition to those commonly referred to as injectables, lyophilized injectables, powder injectables, filled syringes, cartridges, injectables, embedded injectables, long-acting injectables, and the like. In the preparation of injectables, the following methods (a), (b) or (c) are usually used:

(a) A homogeneous solution is prepared by dissolving, suspending, or emulsifying the active ingredient as is or by adding additives to the active ingredient in water for injection, another aqueous solvent, or non-aqueous solvent. Next, the prepared solution is filled into a container for injection, and then the container is sealed and sterilized; and

(b) A homogeneous solution is prepared by dissolving, suspending, or emulsifying the active ingredient as is or by adding additives to the active ingredient in water for injection, another aqueous solvent, non-aqueous solvent, etc. Next, the prepared solution is aseptically filtered or prepared, and then the calculated solution is filled into a container for injection, and the container is sealed.

Freeze-dried injectables are usually manufactured by dissolving the active ingredient as is or a mixture of the active ingredient and excipients, etc., in water for injection, or by filtering the solution aseptically, filling the solution into a container for injection, and then freeze-drying the solution. The solution can be prepared by lyophilizing it in a dedicated container and then filling the solution directly into the container. Powder injections can usually be prepared by crystallizing sterile-filtered powder to produce a powder, adding sterilized additives to the prepared powder as needed, and filling the powder into a container for injection. Filled syringes can generally be manufactured by preparing a solution, suspension, or emulsion with the active ingredient as is or using the active ingredient and additives, and then filling the prepared solution, suspension, or emulsion into a glass syringe. A cartridge is an injection that is used by inserting a cartridge filled with a drug solution into a dedicated syringe. Cartridges filled with drug solutions can generally be prepared by preparing a solution, suspension, or emulsion with the active ingredient as is or using the active ingredient and additives, and then filling the prepared solution, suspension, or emulsion into the cartridge. Infusion refers to injectable volumes of 100 mL or more, typically administered intravenously. Embedded injection refers to a solid or gel-like injection that is applied subcutaneously, intramuscularly, etc. using an implantable tool or surgically for the purpose of releasing the active ingredient over a long period of time. Embedded injections can usually be manufactured using biodegradable polymer compounds and forming the compounds into pellets, microspheres, or gels. Long-acting injections refer to injections applied intramuscularly, etc., with the purpose of releasing the active ingredient over a long period of time. Long-acting injectables can usually be prepared by dissolving or suspending the active ingredient in vegetable oil, etc., or by preparing a microsphere suspension containing a biodegradable polymer compound.

Pharmaceutical compositions containing the compounds of the present invention may also be pharmaceutical compositions (or combination drugs) administered in combination with another drug for:

1) Complementing and/or enhancing the preventive and/or therapeutic effects of the compounds of the present invention;

2) improvement of kinetics and absorption, and reduction of dosage; and/or

3) Alleviating side effects of the compounds of the present invention.

The pharmaceutical composition (or combination drug) described above may be administered in the form of a blended drug in which both components are blended in one formulation, or may be administered in the form of a separate formulation. Administration in these separate preparations includes simultaneous administration and staggered administration. Additionally, administration by time difference can be performed by first administering the compound of the present invention and then administering another drug later, or by administering another drug first and then administering the compound of the present invention later. The method of administering the drug may be the same or different.

The disease for which the pharmaceutical composition (or combination drug) has a preventive and/or therapeutic effect is not particularly limited as long as it is a disease in which the preventive and/or therapeutic effect of the compound of the present invention is complemented and/or improved.

Other drugs to complement and/or enhance the preventive and/or therapeutic effect of the compounds of the invention on pain include, for example, acetaminophen, non-steroidal anti-inflammatory drugs, opioid drugs, antidepressant drugs, antiepileptic drugs, N- Includes methyl-D-aspartate antagonists, muscle relaxants, antiarrhythmic drugs, steroid drugs, and bisphosphonate drugs.

Examples of nonsteroidal anti-inflammatory drugs include sasaspirin, sodium salicylate, aspirin, and aspirin-dialuminate formulations, diflunisal, indomethacin, suprofen, upenamate, dimethylisoppropyl azulene, and bupexamak. , felvinac, diclofenac, tolmetin sodium, clinoril, fenbufen, nabumetone, proglumethacin, indomethacin farnesyl, acemetacin, proglumethacin maleate, amfenac sodium, mofezolac, etodolac. , ibuprofen, ibuprofen piconol, naproxen, flurbiprofen, flurbiprofen axetil, ketoprofen, fenoprofen calcium, thiaprofen, oxaprozine, planoprofen, loxoprofen sodium. , Alminoprofen, zaltoprofen, mefenamic acid, aluminum mefenamate, tolfenamic acid, floctafenine, ketophenylbutazone, oxyphenbutazone, piroxicam, tenoxicam, ampyroxicam, Napageln ointment, Epirizole, tiaramide hydrochloride, tinolidine hydrochloride, emorpazone, sulphyline, Migrenin, Saridon, Sedes G, Amipylo-N, Solvon, pyrin cryotherapy agent, acetaminophen, phenacetin, dimethothiazine mesylate, Includes meloxicam, celecoxib, rofecoxib, valdecoxib, symetrid blended drugs, and non-pyrinic cryotherapeutics.

Opioid drugs include codeine, fentanyl, hydromorphone, levorphanol, meperidine, methadone, morphine, oxycodone, oxymorphone, propoxyphene, and tramadol.

Examples of antidepressant drugs include tricyclic antidepressant drugs (e.g., amitriptyline hydrochloride, imipramine hydrochloride, clomipramine hydrochloride, dosulepine hydrochloride, nortriptyline hydrochloride, rofepramine hydrochloride, trimipramine maleate and amoxapine), tetracyclic antidepressant drugs (e.g., maprotiline hydrochloride, mianserin hydrochloride, and cetiptyline maleate), monoamine oxidase (MAO) inhibitors (saf razine hydrochloride), serotonin and noradrenaline reuptake inhibitors (SNRIs) (e.g., milnacipran hydrochloride and venlafaxine hydrochloride), selective serotonin reuptake inhibitors (SSRIs) (e.g., fluvoxamine maleate, paroxetine hydrochloride, fluoxetine hydrochloride, and citalopram hydrochloride), and serotonin reuptake inhibitors (e.g., trazodone hydrochloride).

Examples of antiepileptic drugs include phenobarbital, primidone, phenytoin, ethoxyimide, zonisamide, nitrazepam, clonazepam, carbamazepine, sodium valproate, acetozolamide, and sultiam.

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

Examples of muscle relaxants include succinylcholine, suxamethonium, vecuronium bromide, pancuronium bromide, and dantrolene sodium.

Examples of antiarrhythmic drugs include procainamide, disopyramide, cibenzoline, firmenol, lidocaine, mexiletine, aprindin, pilsicainide, flecainide, propafenone, propranolol, atenolol, bisoprolol, and amiodarone. , sotalol, verapamil, diltiazem, and bepridil.

Examples of steroid drugs include, as topical agents, clobetasol propionate, diflorasone acetate, flucinonide, mometasone furoate, betamethasone dipropionate, betamethasone butyrate propionate, betamethasone valerate, and diflupred. Nate, budesonide, diflucortolone valerate, amcinonide, halcinonide, dexamethasone, dexamethasone propionate, dexamethasone valerate, dexamethasone acetate, hydrocortisone acetate, hydrocortisone butyrate, hydrocortisone butyrate propionate, Depro Don propionate, prednisolone valerate acetate, flucocinolone acetonide, beclomethasone dipropionate, triamcinolone acetonide, flumethasone pivalate, alclomethasone dipropionate, clobetasone butyrate, prednisolone. , beclomethasone dipropionate, and fludroxycortide.

Examples of oral or injectable drugs include cortisone acetate, hydrocortisone, hydrocortisone sodium phosphate, hydrocortisone sodium succinate, fluorocortisone acetate, prednisolone, prednisolone acetate, prednisolone sodium succinate, prednisolone butylacetate, prednisolone sodium phosphate, and halopredone acetate. , methylprednisolone, methylprednisolone acetate, methylprednisolone sodium succinate, triamcinolone, triamcinolone acetate, triamcinolone acetonide, dexamethasone, dexamethasone acetate, dexamethasone sodium phosphate, dexamethasone palmitate, paramethasone acetate, and betamethasone.

Examples of inhalants include beclomethasone dipropionate, fluticasone propionate, budesonide, flunisolide, triamcinolone, ST-126P, ciclesonide, dexamethasone palomithionate, and mometasone furancarbonate. , prasterone sulfonate, defrazacort, methylprednisolone suleptanate, and methylprednisolone sodium succinate.

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

Any two or more different drugs may be administered in combination.

Additionally, other drugs that complement and/or enhance the preventive and/or therapeutic effects of the compounds of the present invention include those discovered to date as well as those discovered in the future based on the mechanisms described above.

Unless otherwise defined, all technical and scientific terms and abbreviations used herein have the same meaning as commonly understood by a person skilled in the art to which the present invention pertains.

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

In one aspect, the invention provides the following embodiments.

[1] A pharmaceutical composition containing a compound represented by general formula (I-A) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier:

During the ceremony,

X ^{1 and} X ^{2 each} independently represent (1) CH, (2) ^CR

R ¹ represents a halogen atom,

^R Represents a haloalkyl group, (7) C2-6 haloalkenyl group, (8) C2-6 haloalkynyl group, (9) C1-6 haloalkoxy group, or (10) cyano group,

R ² is (1) a halogen atom, (2) C1-6 alkyl group, (3) C2-6 alkenyl group, (4) C2-6 alkynyl group, (5) C1-6 alkoxy group, (6) C1-6 Represents a haloalkyl group, (7) C2-6 haloalkenyl group, (8) C2-6 haloalkynyl group, (9) C1-6 haloalkoxy group, or (10) cyano group,

When m is 2 or more, a plurality of R ² may be the same or different,

R ³ is (1) a hydrogen atom, (2) C1-6 alkyl group, (3) C1-6 haloalkyl group, (4) 3- to 10-membered cyclic group, (5) -(C1-6 alkylene) -(3- to 10-membered cyclic group), (6) -(C1-6 haloalkylene)-(3- to 10-membered cyclic group), where C1-6 alkyl group, C1-6 halo 1 to 2 carbon atoms in alkyl groups, C1-6 alkylene and C1-6 haloalkylene may be replaced by oxygen atoms or optionally oxidized sulfur atoms,

The 3- to 10-membered cyclic group of R ³ may be substituted with 1 to 5 R ³⁰¹ ,

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

When two or more R ³⁰¹ are substituted, the plurality of R ³⁰¹ may be the same or different,

R ³⁰² , R ³⁰³ , R ³⁰⁴ , R ³⁰⁵ , R ³⁰⁶ , R ³⁰⁷ , R ³⁰⁸ , or R ³⁰⁹ each independently represents (1) a hydrogen atom or (2) a C1-4 alkyl group,

When R ² represents ( ² ) to (9) in R 2 and R ³ represents a C1-6 alkyl group, R ² and R ³ together with the atoms to which R ² and R ³ are bonded represent 5- to Can form a 6-membered cyclic group,

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

When n is 2 or more, a plurality of R ⁴ may be the same or different,

When two R ⁴ existing on the same carbon atom represent a C1-6 alkyl group, the two R ⁴ may form a C3-6 cycloalkyl group together with the carbon atom to which the two R ⁴ are bonded,

ring 1 represents a 3- to 15-membered cyclic group,

R ^5-A is (1) a halogen atom, (2) C1-6 alkyl group, (3) C2-6 alkenyl group, (4) C2-6 alkynyl group, (5) C1-6 alkoxy group, (6) C1 -6 alkylthio group, (7) C1-6 alkylsulfinyl group, (8) C1-6 alkylsulfonyl group, (9) C2-6 acyl group, (10) 3- to 6-membered cyclic group, (11) ) -L ^R5 -(3- to 6-membered cyclic group), (12) hydroxyl group, (13) nitro group, (14) cyano group, (15) oxo group, (16) -NR ⁵⁰¹ R ⁵⁰² , (17) -COOR ⁵⁰³ , (18) -CONR ⁵⁰⁴ R ⁵⁰⁵ , or (19) -SO ₂ NR ⁵⁰⁶ R ⁵⁰⁷ , C1-6 alkyl group, C2-6 alkenyl group, C2-6 alkynyl group, C1- 1 to 2 carbon atoms in the 6 alkoxy group, C1-6 alkylthio group, C1-6 alkylsulfinyl group, C1-6 alkylsulfonyl group, and C2-6 acyl group may be replaced by an oxygen atom or an optionally oxidized sulfur atom. There is,

When p is 2 or more, a plurality of R ^5-A may be the same or different,

Groups (2) to (11) of R ^5-A may be substituted with 1 to 9 R ⁵⁰⁸ ,

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

When two or more R ⁵⁰⁸ are substituted, the plurality of R ⁵⁰⁸ may be the same or different,

L ^R5 is (1) -O-, (2) -(C1-4 alkylene)-, (3) -O-(C1-4 alkylene)-, (4) -(C1-4 alkylene)- O-, (5) -NR ⁵¹¹ -, or (6) -SO _0-2 -,

R ⁵⁰¹ , R ⁵⁰² , R ⁵⁰³ , R ⁵⁰⁴ , R ⁵⁰⁵ , R ⁵⁰⁶ , R ⁵⁰⁷ , R ⁵⁰⁹ , R ⁵¹⁰ , or R ⁵¹¹ each independently represents (1) a hydrogen atom, (2) a C1-6 alkyl group, (3) ) C2-6 acyl group, or (4) C1-6 alkylsulfonyl group,

m represents an integer from 0 to 2,

n represents an integer from 0 to 5,

p represents an integer from 0 to 5.

[2] A pharmaceutical composition containing a compound represented by general formula (I) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier:

During the ceremony,

X ^{1 and} X ^{2 each} independently represent (1) CH, (2) ^CR

R ¹ represents a halogen atom,

^R Represents a haloalkyl group, (7) C2-6 haloalkenyl group, (8) C2-6 haloalkynyl group, (9) C1-6 haloalkoxy group, or (10) cyano group,

R ² is (1) a halogen atom, (2) C1-6 alkyl group, (3) C2-6 alkenyl group, (4) C2-6 alkynyl group, (5) C1-6 alkoxy group, (6) C1-6 Represents a haloalkyl group, (7) C2-6 haloalkenyl group, (8) C2-6 haloalkynyl group, (9) C1-6 haloalkoxy group, or (10) cyano group,

When m is 2 or more, a plurality of R ² may be the same or different,

R ³ is (1) a hydrogen atom, (2) C1-6 alkyl group, (3) C1-6 haloalkyl group, (4) 3- to 10-membered cyclic group, (5) -(C1-6 alkylene) -(3- to 10-membered cyclic group), (6) -(C1-6 haloalkylene)-(3- to 10-membered cyclic group), where C1-6 alkyl group, C1-6 halo 1 to 2 carbon atoms in alkyl groups, C1-6 alkylene and C1-6 haloalkylene may be replaced by oxygen atoms or optionally oxidized sulfur atoms,

The 3- to 10-membered cyclic group of R ³ may be substituted with 1 to 5 R ³⁰¹ ,

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

When two or more R ³⁰¹ are substituted, the plurality of R ³⁰¹ may be the same or different,

R ³⁰² , R ³⁰³ , R ³⁰⁴ , R ³⁰⁵ , R ³⁰⁶ , R ³⁰⁷ , R ³⁰⁸ , or R ³⁰⁹ each independently represents (1) a hydrogen atom or (2) a C1-4 alkyl group,

When R ² represents ( ² ) to (9) in R 2 and R ³ represents a C1-6 alkyl group, R ² and R ³ together with the atoms to which R ² and R ³ are bonded represent 5- to Can form a 6-membered cyclic group,

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

When n is 2 or more, a plurality of R ⁴ may be the same or different,

When two R ⁴ existing on the same carbon atom represent a C1-6 alkyl group, the two R ⁴ may form a C3-6 cycloalkyl group together with the carbon atom to which the two R ⁴ are bonded,

ring 1 represents a 3- to 15-membered cyclic group,

R ⁵ is (1) a halogen atom, (2) C1-6 alkyl group, (3) C2-6 alkenyl group, (4) C2-6 alkynyl group, (5) C1-6 alkoxy group, (6) C1-6 Alkylthio group, (7) C1-6 alkylsulfinyl group, (8) C1-6 alkylsulfonyl group, (9) C2-6 acyl group, (10) 3- to 6-membered cyclic group, (11) - L ^R5 -(3- to 6-membered cyclic group), (12) hydroxyl group, (13) nitro group, (14) cyano group, (15) oxo group, (16) -NR ⁵⁰¹ R ⁵⁰² , ( 17) -COOR ⁵⁰³ , (18) -CONR ⁵⁰⁴ R ⁵⁰⁵ , or (19) -SO ₂ NR ⁵⁰⁶ R ⁵⁰⁷ ,

When p is 2 or more, a plurality of R ⁵ may be the same or different,

Groups (2) to (11) of R ⁵ may be substituted with 1 to 9 R ⁵⁰⁸ ,

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

When two or more R ⁵⁰⁸ are substituted, the plurality of R ⁵⁰⁸ may be the same or different,

L ^R5 is (1) -O-, (2) -(C1-4 alkylene)-, (3) -O-(C1-4 alkylene)-, (4) -(C1-4 alkylene)- O-, (5) -NR ⁵¹¹ -, or (6) -SO _0-2 -,

R ⁵⁰¹ , R ⁵⁰² , R ⁵⁰³ , R ⁵⁰⁴ , R ⁵⁰⁵ , R ⁵⁰⁶ , R ⁵⁰⁷ , R ⁵⁰⁹ , R ⁵¹⁰ , or R ⁵¹¹ each independently represents (1) a hydrogen atom, (2) a C1-6 alkyl group, (3) ) C2-6 acyl group, or (4) C1-6 alkylsulfonyl group,

m represents an integer from 0 to 2,

n represents an integer from 0 to 5,

p represents an integer from 0 to 5.

[3] The method of [1] or [2] above, wherein ring 1 is a 3- to 10-membered cyclic group, or

(wherein * indicates the bonding position with the carbonyl group).

[4] The pharmaceutical composition of [1] or [3] above, wherein ring 1 represents a ring structure selected from the group consisting of the following ring structures;

In the formula, * indicates the bonding position with the carbonyl group, and the hydrogen atom represented by NH can be replaced with R ^5-A .

[5] The pharmaceutical composition of [2] or [3] above, wherein ring 1 represents a ring structure selected from the group consisting of the following ring structures;

In the formula, * indicates the bonding position with the carbonyl group, and the hydrogen atom represented by NH may be replaced with R ⁵ .

[6] The pharmaceutical composition according to any one of [1] to [5] above, wherein ring 1 represents a ring structure selected from the group consisting of the following ring structures;

In the formula, * indicates the bonding position with the carbonyl group, and the hydrogen atom represented by NH may be replaced with R ^5-A or R ⁵ .

[7] In any one of [1] to [6] above, R ^5-A or R ⁵ is (1) a halogen atom, (2) a C1-6 alkyl group, (3) a C1-6 alkoxy group, (4) ) C1-6 haloalkyl group, (5) C1-6 haloalkoxy group, (6) 3- to 6-membered cyclic group, (7) oxo group, (8) -NR ⁵⁰¹ R ⁵⁰² , or (9) - Pharmaceutical composition which is COOR ⁵⁰³ .

[8] In any one of [1] to [7] above, R ^5-A or R ⁵ is (1) C1-6 alkyl group, (2) C1-6 alkoxy group, (3) C1-6 haloalkyl group. , (4) C1-6 haloalkoxy group, (5) cyclopropyl group, (6) furan ring, (7) N-methylpyrazole ring, (8) oxo group, (9) dimethylamino group, or (10) -COOCH ₃ phosphorus pharmaceutical composition.

[9] In any one of [1] to [8] above, R ³ is (1) a hydrogen atom, (2) a C1-6 alkyl group, (3) a C1-6 haloalkyl group, (4) 3- to 10 -One cyclic group, or (5) -CH ₂ -(3- to 10-membered cyclic group).

[10] The method according to any one of [1] to [9] above, wherein R ³ is (1) a hydrogen atom, (2) a C1-6 alkyl group, (3) a C1-6 haloalkyl group, (4) a cyclopropyl group, or (5) -CH ₂ -Q, and Q is (1) benzene, (2) pyridine, or (3) imidazo[2,1-b]thiazole.

[11] The pharmaceutical composition according to any one of [1] to [10] above, wherein both X ¹ and X ² are N.

[12] In any one of the above [1] to [11], the compound represented by general formula (I-A) or general formula (I), or a pharmaceutically acceptable salt thereof, has general formula (I-1) A pharmaceutical composition that is a compound represented by or a pharmaceutically acceptable salt thereof:

In the formula, R ^3-a represents (1) a hydrogen atom, (2) a C1-6 alkyl group, (3) a C1-6 haloalkyl group, (4) a cyclopropyl group, or (5) -CH ₂ -Q;

ring 1-a represents a ring structure selected from the group consisting of the following ring structures;

In the formula, * indicates the bonding position with the carbonyl group, and the hydrogen atom represented by NH can be replaced by R ^5-a ,

R ^5-a is (1) C1-6 alkyl group, (2) C1-6 alkoxy group, (3) C1-6 haloalkyl group, (4) C1-6 haloalkoxy group, (5) cyclopropyl group, (6) ) represents a furan ring, (7) N-methylpyrazole ring, (8) oxo group, (9) dimethylamino group, or (10) -COOCH ₃ ,

Other symbols have the same meaning as the symbols described in [1], [2], or [10] above.

[13] The pharmaceutical composition of [12] above, wherein ring 1-a represents a ring structure selected from the group consisting of the following ring structures;

In the formula, * indicates the bonding position with the carbonyl group, and the hydrogen atom represented by NH may be replaced with R ^5-a .

[14] In [1] or [2] above, the compound represented by general formula (I-A) or general formula (I), or a pharmaceutically acceptable salt thereof, is a pharmaceutical compound selected from the group consisting of Composition:

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

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

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

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

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

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

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

(8) rel-6-chloro-3-({(3aS,4R,6aR)-2-[(5-methyl-2-thienyl)carbonyl]octahydrocyclopenta[c]pyrrol-4-yl} Amino)-4-pyridazinecarbonitrile,

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

(10) [(3aR,6R,6aS)-6-[(6-bromo-3-pyridazinyl)amino]-4,4-difluorohexahydrocyclopenta[c]pyrrole-2(1H) -yl], (6,7-dihydro-4H-thieno[3,2-c]pyran-2-yl)methanone, or a pharmaceutically acceptable salt thereof.

[15] In [1] or [2] above, the compound represented by general formula (I-A) or general formula (I), or a pharmaceutically acceptable salt thereof, is a pharmaceutical compound selected from the group consisting of Composition:

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

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

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

(4) [(3aS,4R,6aR)-4-{(6-bromo-3-pyridazinyl)[2-(2-fluoroethoxy)ethyl]amino}hexahydrocyclopenta[c]pyrrole -2(1H)-yl](5-methyl-2-thienyl)methanone, or a pharmaceutically acceptable salt thereof.

[16] The pharmaceutical composition according to any one of [1] to [15] above, which is an ABHD6 inhibitor.

[17] The pharmaceutical composition according to any one of [1] to [16] above, which is an agent for the treatment and/or prevention of diseases associated with ABHD6.

[18] The pharmaceutical composition according to [17] above, wherein the disease associated with ABHD6 is pain, neurological disease, inflammatory disease, autoimmune disease, metabolic disease, or malignant tumor.

[19] In [17] or [18] above, the disease associated with ABHD6 is pain, and the pain is pain associated with osteoarthritis, cancer pain, pain associated with chemotherapy, chronic back pain, back pain associated with osteoporosis, fracture pain, and rheumatism. Pain associated with arthritis, neuropathic pain, post-herpetic pain, pain associated with diabetic neuropathy, pain associated with fibromyalgia, pain associated with pancreatitis, pain associated with interstitial cystitis or bladder pain syndrome, pain associated with endometriosis, irritability. A pharmaceutical composition for pain associated with intestinal syndrome, migraine, or pain associated with pulpitis.

[20] In [17] or [18] above, the disease associated with ABHD6 is a neurological disease, and the neurological disease is tremor, dyskinesia, dystonia, rigidity, pressure and compulsive behavior, depression, anxiety disorder, and panic. disorders, acute stress disorder, post-traumatic stress disorder, obsessive-compulsive disorder, agoraphobia, social phobia, mood disorders, epilepsy, traumatic brain injury, spinal cord injury, multiple sclerosis, encephalomyelitis, Parkinson's disease, Huntington's disease, Alzheimer's disease, and sleep disorders. Composition.

[21] The pharmaceutical composition according to any one of [16] to [20] above, wherein the pharmaceutical composition includes acetaminophen, a non-steroidal anti-inflammatory drug, an opioid drug, an antidepressant drug, an antiepileptic drug, and an N-methyl-D-aspartate antagonist. , a pharmaceutical composition administered in combination with one or more selected from the group consisting of muscle relaxants, anti-arrhythmic drugs, steroid drugs, and bisphosphonate drugs.

[22] An agent for the treatment and/or prevention of diseases associated with ABHD6, containing the compound according to any one of [1] to [15] above or a pharmaceutically acceptable salt thereof.

[23] Administering a pharmaceutical composition containing the compound according to any one of [1] to [15] above or a pharmaceutically acceptable salt thereof to a patient in need of prevention and/or treatment of a disease associated with ABHD6. A method of preventing and/or treating diseases associated with ABHD6, including:

[24] A pharmaceutical composition comprising the compound according to any one of [1] to [15] above or a pharmaceutically acceptable salt thereof, wherein the pharmaceutical composition is used for the prevention and/or treatment of diseases associated with ABHD6. .

[25] Use of the compound according to any one of [1] to [15] above, or a pharmaceutically acceptable salt thereof, for the production of an agent for the prevention and/or treatment of diseases associated with ABHD6.

[Synthesis example]

In the description of separation by chromatography and TLC, the solvent listed in parentheses indicates the elution solvent or developing solvent used, and the ratio indicates the volume ratio.

The solvent in parentheses shown in the description of NMR indicates the solvent used in the measurement.

Compound names used herein are generally named according to the IUPAC nomenclature, either by the computer program ACD/Name (registered trademark), which performs nomenclature according to the IUPAC nomenclature, or by Chemdraw Ultra (Version 12.0, manufactured by Cambridge Soft).

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

TFA terms;

Column: YMC Triart C ₁₈ (particle size: 1.9 x 10 ^-6 m; column length: 30 x 2.0 mm ID); Flow rate: 1.0 mL/min; Column temperature: 30°C; Mobile phase (A): 0.1% aqueous trifluoroacetic acid solution; Mobile phase (B): 0.1% trifluoroacetic acid-acetonitrile solution; Gradient (ratio of mobile phase (A):mobile phase (B)): [0 min] 95:5; [0.1 min] 95:5; [1.2 min] 5:95; [1.6 min] 5:95; Detectors: UV (PDA), ELSD, MS.

Formic acid conditions;

Column: YMC Triart C ₁₈ (particle size: 1.9 x 10 ^-6 m; column length: 30 x 2.0 mm ID); Flow rate: 1.0 mL/min; Column temperature: 30°C; Mobile phase (A): 0.1% aqueous formic acid solution; Mobile phase (B): 0.1% formic acid-acetonitrile solution; Gradient (ratio of mobile phase (A):mobile phase (B)): [0 min] 95:5; [0.1 min] 95:5; [1.2 min] 5:95; [1.6 min] 5:95; Detectors: UV (PDA), ELSD, MS.

HPLC retention times refer to retention times under conditions described in LC-MS/ELSD unless otherwise stated. The description in parentheses for HPLC retention times indicates measurement conditions.

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

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

HPLC retention time (min): 0.65 (TFA);

MS (ESI, Pos.): 226 (M+H) ⁺ .

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

To a solution of the compound prepared in Reference Example 1 (20 g) in THF (300 mL) was added titanium(IV) ethoxide (CAS No.: 3037-36-3, 46.6 g) and (R)-(+)-2. -Methyl-2-propanesulfinamide (CAS No.: 196929-78-9, 11.8 g) was added, and the mixture was stirred at 60°C for 15 hours. The reaction solution was slowly poured into saturated aqueous sodium bicarbonate solution and dichloromethane and filtered. The mixture was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound (12.4 g).

HPLC retention time (min): 0.80 (TFA);

MS (ESI, Pos.): 319 (M+H) ⁺ .

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

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

Reference Example 4: 2-Methyl-2-propanyl (3aS, 6aR)-4-oxohexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate

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

¹ H-NMR (CD ₃ OD): δ 3.66-3.53, 3.14, 3.06-2.98, 2.76-2.71, 2.39-2.35, 2.21-2.12, 1.87 1.45.

Reference Example 5: 2-Methyl-2-propanyl (3aS, 4S, 6aR)-4-hydroxyhexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate

1 M lithium tri-sec-butylborohydride THF solution (CAS No.: 38721-52-7, 49 mL) was added to a solution of the compound prepared in Reference Example 4 (7.3 g) in THF (200 mL) - 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 solution at 0°C until foaming stopped, and then extracted with dichloromethane. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound (6.5 g).

¹ H-NMR (CDCl ₃ ): δ 4.30-4.25, 3.63-3.50, 3.38-3.30, 3.17-3.15, 2.67, 1.90-1.73, 1.73-1.54, 1.47.

Reference Example 6: 2-Methyl-2-propanyl (3aS, 4S, 6aR)-4-{[(4-methylphenyl)sulfonyl]oxy}hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate

To a solution of the compound prepared in Reference Example 5 (6.5 g) in dichloromethane (100 mL) was added triethylamine (12 mL), p-toluenesulfonyl chloride (CAS No.: 98-59-9, 8.2 g), and trimethylamine hydrochloride (CAS No.: 75-50-3, 820 mg) were added, and the mixture was stirred at room temperature for 6 hours. Saturated aqueous sodium bicarbonate solution was added to the reaction solution, and then extracted with dichloromethane. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound (9.3 g).

HPLC retention time (min): 1.2 (TFA);

MS (ESI, Pos.): 382 (M+H) ⁺ .

Reference Example 7: 2-Methyl-2-propanyl (3aS, 4R, 6aR)-4-azidohexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate

Sodium azide (CAS No.: 26628-22-8, 3.2 g) was added to a solution of the compound prepared in Reference Example 6 (9.3 g) in dimethyl sulfoxide (72 mL) and the mixture was incubated at 60° C. for 6 hours. It was stirred for a while. After adding water to the reaction solution, it was extracted with dichloromethane. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and used in the next reaction without purification.

Reference Example 8: 2-Methyl-2-propanyl (3aS, 4R, 6aR)-4-aminohexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate

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

HPLC retention time (min): 0.77 (TFA);

MS (ESI, Pos.): 227 (M+H) ⁺ .

Reference Example 9: 2-Methyl-2-propanyl (3aS,4R,6aR)-4-[(6-chloro-3-pyridazinyl)amino]hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate

N,N-diisopropylethylamine (hereinafter referred to as DIPEA) (6.9 mL) and 3,6-dichloropyridazine (CAS No.: 141-30-0, 1.5 g) were mixed with N,N-dimethylacetamide ( Hereinafter, it was added to a solution of the compound (1.5 g) prepared in Reference Example 8 in DMA) (25 mL), and the mixture was stirred at 160° C. for 1 hour. After adding water to the reaction solution, it was extracted with dichloromethane. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound (1.5 g).

HPLC retention time (min): 0.89 (formic acid);

MS (ESI, Pos.): 339 (M+H) ⁺ .

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

4 N hydrochloric acid (1,4 dioxane solution, 12 mL) was added to the compound prepared in Reference Example 9 (1.2 g), 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).

HPLC retention time (min): 0.59 (formic acid);

MS (ESI, Pos.): 239 (M+H) ⁺ .

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

The same procedure as in Reference Example 4 → Reference Example 5 → Reference Example 6 → Reference Example 7 → Reference Example 8 → Reference Example 9 → Reference Example 10 was performed using the compound prepared in Reference Example 1 instead of the compound prepared in Reference Example 3. This was carried out to obtain the title compound.

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

To a solution of the compound prepared in Reference Example 10 (30 mg) in DMA (0.5 mL) was added DIPEA (0.083 mL), 5-(difluoromethyl)thiophene-2-carboxylic acid (CAS No.: 189330-23) -2, 19 mg), and O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (hereinafter HATU) (CAS No. : 148893-10-1, 38 mg) was added, and the mixture was stirred at room temperature for 3 hours. After adding water to the reaction solution, it was extracted with dichloromethane. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound (32 mg).

HPLC retention time (min): 0.88 (TFA);

MS (ESI, Pos.): 399 (M+H) ⁺ ;

¹ H-NMR (CDCl ₃ ): δ 7.43, 7.18, 6.83, 6.63, 4.78-4.52, 4.12, 3.88, 3.67, 3.49, 2.99-2.80, 2.79-2.61, 2.36, 2.13, 1.69-1.57.

Examples 1-1 to 1-6

Instead of 5-(difluoromethyl)thiophene-2-carboxylic acid, use the corresponding carboxylic acid compound, and replace the compound prepared in Reference Example 10 or the compound prepared in Reference Example 10-1 with Reference Example 10-1. Each title compound was obtained in the same process as Example 1 using the compound prepared in .

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

HPLC retention time (min): 1.10 (formic acid);

MS (ESI, Pos.): 400 (M+H) ⁺ ;

¹ H-NMR (DMSO-d ₆ ): δ 8.23-8.14, 7.64-7.55, 7.42-7.30, 6.92, 4.44-4.27, 4.14-4.07, 4.24-4.03, 3.93-3.81, 3.78-3.66, 3.55-3.47, 3.35-3.24, 3.23-3.05, 3.00-2.70, 2.61-2.54, 2.26-2.16, 2.13-1.97, 1.66-1.49.

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

HPLC retention time (min): 0.85 (TFA);

MS (ESI, Pos.): 363 (M+H) ⁺ ;

¹ H-NMR (CDCl ₃ ): δ 7.35-7.28, 7.16, 6.76-6.71, 6.65, 4.96, 4.14-3.96, 3.96-3.86, 3.82, 3.65, 2.88, 2.79-2.62, 2.50, 2.41-2.27, 2.18- 2.04, 1.72-1.54.

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

HPLC retention time (min): 0.74 (formic acid);

MS (ESI, Pos.): 400 (M+H) ⁺ ;

¹ H-NMR (DMSO-d ₆ ): δ 9.46-9.25, 8.63-8.43, 8.40-8.30, 8.29-8.14, 7.43-7.30, 6.97-6.83, 4.20-4.00, 3.99-3.65, 3.15-3.04, 3.04- 2.79, 2.77-2.57, 2.27-2.15, 2.14-1.98, 1.70-1.58, 1.58-1.48.

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

HPLC retention time (min): 0.83 (TFA);

MS (ESI, Pos.): 405 (M+H) ⁺ ;

¹ H-NMR (CDCl ₃ ): δ 7.22-7.13, 6.66, 5.04, 4.76-4.65, 4.12, 3.98, 3.86, 3.64, 2.89, 2.70, 2.39-2.28, 2.17-2.07, 1.69-1.55.

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

HPLC retention time (min): 1.00 (formic acid);

MS (ESI, Pos.): 409 (M+H) ⁺ ;

¹ H-NMR (DMSO-d ₆ ): δ 8.14-8.07, 8.07-7.93, 7.73-7.47, 7.43-7.22, 6.98-6.88, 6.88-6.78, 4.11-3.99, 3.99-3.88, 3.76-3.65, 3.10, 2.86-2.70, 2.21-2.09, 2.09-1.98, 1.98-1.84, 1.65-1.43, 1.43-1.29.

Examples 1-6: 1-benzofuran-2-yl[(3aS,4R,6aR)-4-[(6-chloro-3-pyridazinyl)amino]hexahydrocyclopenta[c]pyrrol-2(1H)-yl]meta rice paddy

HPLC retention time (min): 1.00 (formic acid);

MS (ESI, Pos.): 383 (M+H) ⁺ ;

¹ H-NMR (DMSO-d ₆ ): δ 7.79-7.74, 7.71-7.65, 7.57-7.49, 7.49-7.43, 7.41-7.32, 7.31-7.25, 6.96-6.84, 4.14-4.01, 3.83-3.72, 3.34- 3.25, 2.97-2.76, 2.73-2.66, 2.64-2.53, 2.25-2.15, 2.10-1.98, 1.65-1.57, 1.56-1.46.

Reference Example 11: 2-Methyl-2-propanyl (3aS,4R,6aR)-4-[(6-bromo-3-pyridazinyl)amino]hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate

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

HPLC retention time (min): 0.91 (formic acid);

MS (ESI, Pos.): 383 (M+H) ⁺ .

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

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

HPLC retention time (min): 0.59 (formic acid);

MS (ESI, Pos.): 283 (M+H) ⁺ .

Reference Example 12-1: rel-(3aS,4R,6aR)-N-(6-bromo-3-pyridazinyl)octahydrocyclopenta[c]pyrrol-4-amine dihydrochloride racemic mixture

The same procedure as in Reference Example 4 → Reference Example 5 → Reference Example 6 → Reference Example 7 → Reference Example 8 → Reference Example 11 → Reference Example 12 was performed using the compound prepared in Reference Example 1 instead of the compound prepared in Reference Example 3. This was carried out to obtain the title compound.

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

DIPEA (2.9 mL) and 5-methyl-2-thiophenecarboxylic acid (CAS No.: 1918-79-2, 6.6 g), and HATU (3.8 g) were prepared in Reference Example 12 in DMA (20 mL). was added to the solution of the compound (3.0 g), and the mixture was stirred at room temperature for 3 hours. After adding water to the reaction solution, it was extracted with dichloromethane. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound (1.8 g).

HPLC retention time (min): 0.87 (TFA);

MS (ESI, Pos.): 407 (M+H) ⁺ ;

¹ H-NMR (CDCl ₃ ): δ 7.33-7.27, 6.75-6.72, 6.54, 5.00, 4.15-3.99, 3.98-3.78, 3.66, 2.88, 2.68, 2.50, 2.39-2.29, 2.14-2.03, 1.68-1 .59.

Examples 2-1 to 2-14

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

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

HPLC retention time (min): 0.93 (TFA);

MS (ESI, Pos.): 451 (M+H) ⁺ ;

¹ H-NMR (CDCl ₃ ): δ 7.32-7.27, 7.17, 6.54, 4.77-4.63, 4.10, 4.04-3.93, 3.87, 3.65, 2.89, 2.69, 2.40-2.29, 2.17-2.07, 1.68-1.57.

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

HPLC retention time (min): 1.00 (formic acid);

MS (ESI, Pos.): 443 (M+H) ⁺ ;

¹ H-NMR (DMSO-d ₆ ): δ 7.63-7.56, 7.50-7.47, 7.46-7.43, 7.34-7.27, 7.32, 6.86-6.73, 4.11-3.87, 3.87-3.70, 3.71-3.54, 2.96-2.72, 2.71-2.56, 2.23-2.11, 2.09-1.95, 1.59, 1.51.

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

HPLC retention time (min): 0.96 (formic acid);

MS (ESI, Pos.): 408 (M+H) ⁺ ;

¹ H-NMR (DMSO-d ₆ ): δ 7.77-7.68, 7.50-7.41, 7.41-7.28, 6.87-6.77, 4.29-3.93, 3.84-3.62, 3.18-3.04, 2.97-2.60, 2.24-2.11, 2.11- 1.95, 1.66-1.54, 1.54-1.43.

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

HPLC retention time (min): 0.75 (formic acid);

MS (ESI, Pos.): 444 (M+H) ⁺ ;

¹ H-NMR (DMSO-d ₆ ): δ 9.42-9.26, 8.60, 8.44-8.31, 8.31-8.17, 7.52-7.42, 7.42-7.31, 6.88-6.74, 4.17-4.00, 3.89-3.67, 3.14-3.06, 2.87, 2.28-2.14, 2.13-1.97, 1.70-1.45.

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

HPLC retention time (min): 0.84 (TFA);

MS (ESI, Pos.): 452 (M+H) ⁺ ;

¹ H-NMR (CDCl ₃ ): δ 7.31-7.27, 6.54, 4.85-4.78, 4.73, 4.34-4.27, 4.21, 4.15-3.97, 3.95-3.84, 3.78, 3.65, 2.97, 2.90-2.71, 2.69-2 .59; 2.39-2.28, 2.18-2.01, 1.69-1.61.

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

HPLC retention time (min): 0.74 (TFA);

MS (ESI, Pos.): 438 (M+H) ⁺ ;

¹ H-NMR (CDCl ₃ ): δ 7.57, 7.26, 6.55, 4.92, 4.15-4.02, 3.98-3.89, 3.87, 3.78, 3.61, 3.15, 2.89, 2.69, 2.39-2.29, 2.17-2.07, 1.62 -1.55.

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

HPLC retention time (min): 0.88 (formic acid);

MS (ESI, Pos.): 497 (M+H) ⁺ ;

¹ H-NMR (DMSO-D ₆ ): δ 7.46, 7.33, 6.82, 4.39, 4.11-3.99, 3.97-3.83, 3.81-3.65, 3.18-3.05, 2.99-2.72, 2.70-2.09, 2.24-2.09, 2.09- 1.96, 1.58, 1.49.

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

HPLC retention time (min): 1.00 (formic acid);

MS (ESI, Pos.): 465 (M+H) ⁺ ;

¹ H-NMR (DMSO-d ₆ ): δ 7.46, 7.41-7.31, 6.86-6.77, 4.11-4.02, 4.02-3.86, 3.71, 3.69-3.58, 3.46, 3.15-3.05, 3.04-2.96, 2.94-2.88, 2.88-2.71, 2.25-2.12, 2.10-1.94, 1.68-1.54, 1.54-1.39.

Example 2-9: [(3aS,4R,6aR)-4-[(6-bromo-3-pyridazinyl)amino]hexahydrocyclopenta[c]pyrrol-2(1H)-yl](1-methyl-1H-thi No[2,3c]pyrazol-5-yl)methanone

HPLC retention time (min): 0.90 (formic acid);

MS (ESI, Pos.): 447 (M+H) ⁺ ;

¹ H-NMR (DMSO-d ₆ ): δ 7.85, 7.69-7.57, 7.52-7.43, 7.43-7.28, 6.89-6.70, 4.12-4.00, 3.96, 3.92-3.67, 3.15-3.05, 2.96-2.75, 2.75- 2.57, 2.26-2.11, 2.09-1.94, 1.66-1.55, 1.55-1.44.

Example 2-10: [(3aS,4R,6aR)-4-[(6-bromo-3-pyridazinyl)amino]hexahydrocyclopenta[c]pyrrol-2(1H)-yl][2-(dimethylamino)thi no[2,3-d][1,3]thiazol-5-yl]methanone

HPLC retention time (min): 0.88 (TFA);

MS (ESI, Pos.): 493 (M+H) ⁺ ;

¹ H-NMR (DMSO-d ₆ ): δ 7.79, 7.44, 7.25, 6.79, 4.16-3.94, 3.86, 3.74, 3.56, 3.44-3.36, 3.31-3.23, 3.13, 2.87, 2.61, 2.19, 2.07-1. 98, 1.63-1.47.

Example 2-11: [(3aS,4R,6aR)-4-[(6-bromo-3-pyridazinyl)amino]hexahydrocyclopenta[c]pyrrol-2(1H)-yl](3-methyl-3H-thi no[2,3-d][1,2,3]triazol-5-yl)methanone

HPLC retention time (min): 0.87 (formic acid);

MS (ESI, Pos.): 448 (M+H) ⁺ ;

¹ H-NMR (DMSO-D ₆ ): δ 7.91, 7.46, 7.44-7.36, 6.84, 4.24, 4.14-3.98, 3.95-3.61, 3.00-2.79, 2.77-2.59, 2.27-2.16, 2.11-1.98, 1.65- 1.57, 1.57-1.50.

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

HPLC retention time (min): 0.80 (TFA);

MS (ESI, Pos.): 407 (M+H) ⁺ ;

¹ H-NMR (CDCl ₃ ): δ 7.31-7.27, 7.05, 6.54, 5.31, 4.81-4.66, 4.12, 3.92, 3.94-3.77, 3.76-3.58, 2.95-2.76, 2.72-2.52, 2.34, 2.05, 1.66- 1.56.

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

HPLC retention time (min): 0.93 (formic acid);

MS (ESI, Pos.): 461 (M+H) ⁺ ;

¹ H-NMR (DMSO-d ₆ ): δ 7.62, 7.51-7.44, 7.45-7.36, 6.88-6.79, 4.13-4.04, 3.85, 4.01-3.66, 3.36-3.24, 2.95-2.80, 2.71-2.58, 2.37, 2.26-2.15, 2.11-2.00, 1.64-1.57, 1.56-1.48.

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

HPLC retention time (min): 1.10 (formic acid);

MS (ESI, Pos.): 419 (M+H) ⁺ ;

¹ H-NMR (DMSO-d ₆ ): δ 7.51-7.39, 7.38-7.25, 6.85-6.74, 4.07-3.85, 3.73-3.51, 3.29-3.16, 2.87-2.59, 2.18-1.82, 1.72-1.14.

Reference Example 13: Methyl 5-[(1E)-3-ethoxy-3-oxo-1-propen-1-yl]-4-nitro-2-thiophenecarboxylate

DIPEA (0.083 mL) and tripotasium phosphate (CAS No.: 7778-53-2, 1730 mg), (E)-ethyl 3-(4,4,5,5-tetramethyl-1,3,2-di) Oxaborolan-2-yl)acrylate (CAS No.: 1009307-13-4, 300 mg), and bis(triphenylphosphine)palladium(II) chloride (CAS No.: 13965-03-2, 63) mg) was added to a solution of methyl 5-bromo-4-nitrothiophene-2-carboxylate (CAS No.: 38239-32-6, 120 mg) in 1,2-dimethoxyethane (3 mL). And the mixture was stirred at 55°C for 3 hours. After adding water to the reaction solution, it was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound (97 mg).

HPLC retention time (min): 1.20 (formic acid);

MS (ESI, Pos.): 286 (M+H) ⁺ .

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

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

HPLC retention time (min): 0.80 (formic acid);

MS (ESI, Pos.): 258 (M+H) ⁺ .

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

To a solution of the compound prepared in Reference Example 14 (20 mg) in methanol (1 mL) was added p-toluenesulfonic acid monohydrate (CAS No.: 6192-52-5, 1.5 mg) and the mixture was incubated for 15 minutes at 60°C. Stirred for an hour. Saturated sodium bicarbonate water was added to the reaction solution, and then extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound (5 mg).

HPLC retention time (min): 0.81 (formic acid);

MS (ESI, Pos.): 212 (M+H) ⁺ .

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

Sodium hydride (CAS No.: 7646-69-7, 2.9 mg) and iodomethane (CAS No.: 74-88-4, 22 mg) were reacted with the compound prepared in Reference Example 15 (5 mg) was added to the solution and the mixture was stirred at room temperature for 3 hours. Afterwards, 2N hydrochloric acid was added to the reaction solution, and then extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound (7 mg).

HPLC retention time (min): 0.88 (formic acid);

MS (ESI, Pos.): 225 (M+H) ⁺ .

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

A 2 N aqueous sodium hydroxide solution (0.5 mL) was added to a solution of the compound prepared in Reference Example 6 (7 mg) in methanol (1 mL), and the mixture was stirred at 60° C. for 1 hour. Then, 1 N hydrochloric acid was added to the reaction solution, and the precipitate was collected by filtration to obtain the title compound (5.0 mg).

Reference Example 18: 5-chloro-3,4-dihydro-2H-pyran-6-carbaldehyde

DMF (0.70 mL) was added to a solution of phosphoryl chloride (CAS No.: 10025-87-3, 1,400 mg) in dichloromethane (5 mL) at 0°C, and the mixture was stirred at 0°C for 1 hour. Dihydro-2H-pyran-3(4H)-one (CAS No.: 23462-75-1, 900 mg) was added to the mixed solution, and the mixture was stirred at room temperature for 2 hours. Saturated aqueous sodium bicarbonate solution was added to the reaction solution, and then extracted with dichloromethane. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained title compound was used in the next reaction without purification.

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

Triethylamine (2.5 mL) and methyl thioglycolate (CAS No.: 2365-48-2, 1,100 mg) were added to a solution of the compound prepared in Reference Example 18 in dichloroethane (20 mL) and the mixture was incubated at 70 mL. It was stirred at ℃ for 15 hours. The reaction solution was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography to obtain the title compound (300 mg).

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

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

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

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

HPLC retention time (min): 1.00 (formic acid);

MS (ESI, Pos.): 449 (M+H) ⁺ ;

¹ H-NMR (DMSO-D ₆ ): δ 7.55-7.43, 7.10, 6.89-6.60, 4.67-4.62, 4.17-4.07, 4.05-3.87, 3.73, 3.67, 3.42-3.40, 3.37-3.33, 3.22- 3.04, 2.79-2.70, 2.58-2.53, 2.17, 2.09-1.85, 1.71-1.37.

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

Triethylamine (0.11 mL) and methyl chloroformate (CAS No.: 79-22-1, 72 mg) were reacted with methyl 4,5,6,7-tetrahydrothieno[3, 2-c]pyridine-2-carboxylate (CAS No.: 221316-61-6, 50 mg) was added to the solution, and the mixture was stirred at room temperature for 15 hours. Afterwards, 2N hydrochloric acid was added to the reaction solution, and then extracted with dichloromethane. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained title compound was used in the next reaction without purification.

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

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

Reference Example 24: 4,4-dimethyl-6,7-dihydrothieno[3,2-c]pyran

2,2-dimethoxypropane (CAS No.: 77-76-9, 0.38 mL) and iron(III) trifluoromethanesulfonate (CAS No.: 63295-48-7, 15.7 mg) were added, and the mixture was stirred at 70° C. for 17 hours. Triethylamine (0.22 mL) was added to the reaction solution, and the mixture was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound (284 mg).

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

HPLC retention time (min): 1.07 (TFA);

MS (ESI, Pos.): 169 (M+H) ⁺ .

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

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

HPLC retention time (min): 0.89 (TFA);

MS (ESI, Pos.): 213 (M+H) ⁺ .

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

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

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

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

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

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

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

To a solution of the compound prepared in Reference Example 27 in methanol (1.8 mL) was added 20% palladium hydroxide (10 mg), 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 resulting residue was purified by silica gel column chromatography to obtain the title compound (40 mg).

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

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

HPLC retention time (min): 0.76 (TFA);

MS (ESI, Pos.): 200 (M+H) ⁺ .

Reference Example 30: Methyl 5-hydroxy-2-thiophenecarboxylate

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

HPLC retention time (min): 0.84 (TFA);

MS (ESI, Pos.): 171(M+Na) ⁺ .

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

Chlorodifluoroacetic acid (CAS No.: 76-04-0, 0.027 mL) and cesium carbonate (CAS No.: 534-17-8, 142 mg) were reacted with the compound prepared in Reference Example 30 in DMF (0.2 mL). (23 mg) was added to the solution and the mixture was stirred at 100° C. for 10 minutes. After adding water to the reaction solution, it was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound (31 mg).

HPLC retention time (min): 1.06 (TFA);

MS (ESI, Pos.): 209 (M+H) ⁺ .

Reference Example 32: 5-(difluoromethoxy)-2-thiophenecarboxylic acid

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

HPLC retention time (min): 0.91 (TFA);

MS (ESI, Pos.): 195 (M+H) ⁺ .

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

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

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

Propargyl alcohol (CAS No.: 107-19-7, 11 mg), copper(I) iodide (CAS No.: 7681-65-4, 2.5 mg), tetrakis(triphenylphosphine)palladium (0) (CAS No.: 14221-01-3, 15 mg), and triethylamine (0.09 mL) were added to a solution of the compound prepared in Reference Example 33 (40 mg) in THF (1 mL), The mixture was stirred at 60° C. for 1 hour. After adding water to the reaction solution, it was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound (23 mg).

HPLC retention time (min): 0.84 (formic acid);

MS (ESI, Pos.): 237 (M+H) ⁺ .

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

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

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

Cyanomethylene tributylphosphorane (CAS No.: 157141-27-0, 27 mg) was added to a solution of the compound prepared in Reference Example 35 (18 mg) in toluene (0.5 mL) and the mixture was incubated at 60°C. Stirred for 1 hour. The mixture was purified by silica gel column chromatography to obtain the title compound (10 mg).

¹ H-NMR (CDCl ₃ ): δ 7.85, 4.38, 3.83, 3.10, 2.73.

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

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

Reference Example 38: Methyl 5-methyl-4-(1-methyl-1H-pyrazol-4-yl)-2-thiophenecarboxylate

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) was added to a solution of methyl 4-bromo-5-methylthiophene-2-carboxylate (CAS No.: 237385-15-8, 30 mg) in toluene (0.75 mL). And the mixture was stirred at 80°C for 13 hours. The reaction solution was subjected to extraction with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound (10 mg).

HPLC retention time (min): 1.00 (formic acid);

MS (ESI, Pos.): 237 (M+H) ⁺ .

Reference Example 39: 5-methyl-4-(1-methyl-1H-pyrazol-4-yl)-2-thiophenecarboxylic acid

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

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

Sodium hydride (2.9 mg) and iodomethane (22 mg) were dissolved in methyl 3-methyl-1H-thieno[2,3-c]pyrazole-5-carboxylate (CAS No. 5-carboxylate) in DMF (1.0 mL). : 873072-42-5, 20 mg) was added to the solution, and the mixture was stirred at room temperature for 3 hours. Afterwards, 2N hydrochloric acid was added to the reaction solution, and then extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound (10 mg).

¹ H-NMR (CDCl ₃ ): δ 7.69, 3.95, 3.89, 2.52.

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

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

Reference Example 42: Methyl 2-methyl-2H-thieno[3,2-c]pyrazole-5-carboxylate

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

¹ H-NMR (CDCl ₃ ): δ 7.70, 7.66, 4.06, 3.93.

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

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

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

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

HPLC retention time (min): 1.00 (formic acid);

MS (ESI, Pos.): 223 (M+H) ⁺ .

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

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

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

Sodium chlorodifluoroacetate (CAS No.: 1895-39-2, 2,100 mg) and potassium carbonate (1,900 mg) were dissolved in methyl 1H-thieno[3,2-c]pyrazole-5 in DMF (10 mL). -carboxylate (500 mg) was added to the solution and the mixture was stirred at 100° C. for 20 hours. After adding water to the reaction solution, it was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound (85 mg).

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

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

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

(2) Methyl 1-(2,2,2-trifluoroethyl)-2H-thieno[3,2-c]pyrazole-5-carboxylate

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

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

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

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

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

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

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

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

Instead of methyl 3-methyl-1H-thieno[2,3-c]pyrazole-5-carboxylate, methyl 3-methyl-1H-thieno[3,2-c]pyrazole-5-carboxylate ( CAS No.: 1379258-29-3) was used to obtain the title compound by carrying out the same procedure as in Reference Example 40 → Reference Example 41.

Example 3: 2-{[(3aS,4R,6aR)-4-[(6-bromo-3-pyridazinyl)amino]hexahydrocyclopenta[c]pyrrol-2(1H)-yl]carbonyl}-4 -Methyl-6,7-dihydrothieno[3,2-b]pyridin-5(4H)-one

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

HPLC retention time (min): 0.89 (formic acid);

MS (ESI, Pos.): 476 (M+H) ⁺ ;

¹ H-NMR (DMSO-d ₆ ): δ 7.44, 7.38, 7.28, 6.80, 4.10-3.96, 3.24, 3.18-3.03, 3.01-2.87, 2.85, 2.71-2.57, 2.25-2.10, 2.10-1.96, 1.62 - 1.45.

Examples 3-1 to 3-14

Instead of the compound prepared in Reference Example 17, 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, using instead of the compound prepared in Reference Example 49, Reference Example 50, or Reference Example 51, and using the compound prepared in Reference Example 10 instead of the compound prepared in Reference Example 12 or the compound prepared in Reference Example 12. The same procedure as in Example 3 was performed to obtain each title compound.

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

HPLC retention time (min): 0.74 (formic acid);

MS (ESI, Pos.): 400 (M+H) ⁺ ;

¹ H-NMR (DMSO-d ₆ ): δ 9.46-9.25, 8.63-8.43, 8.40-8.30, 8.29-8.14, 7.43-7.30, 6.97-6.83, 4.20-4.00, 3.99-3.65, 3.15-3.04, 3.04- 2.79, 2.77-2.57, 2.27-2.15, 2.14-1.98, 1.70-1.58, 1.58-1.48.

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

HPLC retention time (min): 0.97 (formic acid);

MS (ESI, Pos.): 506 (M+H) ⁺ ;

¹ H-NMR (DMSO-d ₆ ): δ 7.49-7.44, 7.44-7.31, 6.86-6.78, 4.57-4.41, 4.07-4.00, 3.67, 3.64, 3.20-3.05, 2.81, 2.71-2.45, 2.27-2.12, 2.09-1.95, 1.64-1.54, 1.54-1.42.

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

HPLC retention time (min): 0.88 (TFA);

MS (ESI, Pos.): 435 (M+H) ⁺ ;

¹ H-NMR (CDCl ₃ ): δ 7.23, 7.18, 6.63, 4.70, 4.11, 3.98, 3.95-3.83, 3.66, 3.49, 2.89, 2.83, 2.69, 2.40-2.30, 2.17-2.08, 1.68-1.58 , 1.48.

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

HPLC retention time (min): 0.88 (TFA);

MS (ESI, Pos.): 420 (M+H) ⁺ ;

¹ H-NMR (CDCl ₃ ): δ 7.18, 6.63, 4.85-4.66, 4.25-4.17, 4.15-4.02, 3.85, 3.55-3.46, 3.22, 3.03-2.55, 2.35, 2.13, 1.68-1.57, 1.29.

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

HPLC retention time (min): 0.91 (TFA);

MS (ESI, Pos.): 415 (M+H) ⁺ ;

¹ H-NMR (CDCl ₃ ): δ 7.32-7.28, 7.26-7.16, 6.67-6.61, 6.64, 4.69, 4.16-4.06, 4.02, 3.87, 3.66, 3.66, 2.88, 2.70, 2.41-2.31, 2.18- 2.08, 1.69-1.58.

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

HPLC retention time (min): 0.92 (formic acid);

MS (ESI, Pos.): 473 (M+H) ⁺ ;

¹ H-NMR (DMSO-d ₆ ): δ 7.63, 7.50-7.42, 7.41-7.28, 6.88-6.76, 4.32-4.21, 4.10-3.95, 3.91-3.61, 3.07-2.96, 2.96-2.77, 2.68-2.58, 2.24-2.14, 2.10-1.92, 1.69-1.55, 1.55-1.46.

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

HPLC retention time (min): 0.88 (formic acid);

MS (ESI, Pos.): 487 (M+H) ⁺ ;

¹ H-NMR (DMSO-d ₆ ): δ 8.05-7.98, 7.78-7.70, 7.59, 7.49-7.42, 7.42-7.32, 6.87-6.76, 4.09-4.00, 3.88, 3.34-3.18, 2.94-2.75, 2.72- 2.57, 2.48, 2.26-2.14, 2.09-1.95, 1.64-1.55, 1.55-1.46.

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

HPLC retention time (min): 0.83 (TFA);

MS (ESI, Pos.): 461 (M+H) ⁺ ;

¹ H-NMR (CDCl ₃ ): δ 7.33-7.27, 7.26, 6.55, 4.80, 4.15-4.06, 4.02-3.93, 3.91, 3.69, 2.88, 2.70, 2.55-2.47, 2.39-2.24, 2.18-2.02, 1.69- 1.61.

Example 3-9: [(3aS,4R,6aR)-4-[(6-bromo-3-pyridazinyl)amino]hexahydrocyclopenta[c]pyrrol-2(1H)-yl](2-methyl-2H-thi No[3,2-c]pyrazol-5-yl)methanone

HPLC retention time (min): 0.87 (TFA);

MS (ESI, Pos.): 447 (M+H) ⁺ ;

¹ H-NMR (CDCl ₃ ): δ 7.57, 7.43, 7.33-7.27, 6.54, 4.83, 4.17-4.10, 4.10-4.02, 3.94, 3.91-3.80, 3.69, 2.92, 2.71, 2.40-2.30, 2.18- 2.04, 1.70-1.61.

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

HPLC retention time (min): 0.86 (TFA);

MS (ESI, Pos.): 473 (M+H) ⁺ ;

¹ H-NMR (CDCl ₃ ): δ 7.67, 7.40, 7.34-7.27, 6.55, 4.92, 4.15-3.95, 3.93, 3.90-3.78, 3.68, 2.90, 2.70, 2.39-2.28, 2.18-2.03, 1.71- 1.65, 1.30-1.09.

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

HPLC retention time (min): 0.90 (TFA);

MS (ESI, Pos.): 483 (M+H) ⁺ ;

¹ H-NMR (CDCl ₃ ): δ 8.02, 7.48, 7.42, 7.35-7.27, 7.18, 6.71-6.49, 4.14-3.98, 3.89, 3.69, 3.05-2.83, 2.74, 2.40-2.31, 2.15, 2.05, 1.68.

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

HPLC retention time (min): 1.00 (formic acid);

MS (ESI, Pos.): 515 (M+H) ⁺ ;

¹ H-NMR (DMSO-d ₆ ): δ 7.97, 7.89-7.81, 7.52-7.43, 7.43-7.33, 6.90-6.72, 5.48-5.31, 4.19-4.05, 4.04-3.92, 3.92-3.71, 3.01-2.63, 2.27-2.15, 2.12-2.00, 1.66-1.57, 1.57-1.47.

Example 3-13: [(3aS,4R,6aR)-4-[(6-bromo-3-pyridazinyl)amino]hexahydrocyclopenta[c]pyrrol-2(1H)-yl][2-(2,2, 2-trifluoroethyl)-12-thieno[3,2-c]pyrazol-5-yl]methanone

HPLC retention time (min): 0.90 (TFA);

MS (ESI, Pos.): 515 (M+H) ⁺ ;

¹ H-NMR (CDCl ₃ ): δ 7.71, 7.42, 7.26, 6.55, 4.90, 4.16-3.97, 3.94, 3.86, 3.68, 2.92, 2.72, 2.40-2.30, 2.15-2.07, 1.71-1.55.

Example 3-14: [(3aS,4R,6aR)-4-[(6-bromo-3-pyridazinyl)amino]hexahydrocyclopenta[c]pyrrol-2(1H)-yl](2,3-dimethyl-2H -thieno[3,2-c]pyrazol-5-yl)methanone

HPLC retention time (min): 0.91 (formic acid);

MS (ESI, Pos.): 461 (M+H) ⁺ .

Reference Example 52: 1-(5-((3aS,4R,6aR)-4-((6-bromopyridazin-3-yl)amino)octahydrocyclopenta[c]pyrrole-2-carbonyl)thiophene-2- 1) Ethane-1-one

To a solution of the compound prepared in Reference Example 12 (10 mg) in DMA (0.25 mL) was added 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. After adding water to the reaction solution, it was extracted with dichloromethane. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound (15 mg).

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

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

HPLC retention time (min): 0.89 (formic acid);

MS (ESI, Pos.): 451 (M+H) ⁺ .

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

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

HPLC retention time (min): 0.88 (TFA);

MS (ESI, Pos.): 455 (M+H) ⁺ .

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

The same procedure as in Example 2 → Reference Example 16 was performed using the compound prepared in Reference Example 12-1 instead of the compound prepared in Reference Example 12 to obtain the title compound.

HPLC retention time (min): 1.10 (formic acid);

MS (ESI, Pos.): 421 (M+H) ⁺ ;

¹ H-NMR (DMSO-d ₆ ): δ 7.55, 7.38, 7.19-7.10, 6.83, 4.86, 3.62, 3.27, 3.22-3.05, 2.93, 2.81, 2.49-2.43, 2.06-1.96, 1.90-1.75, 1.5 8- 1.45.

Examples 6-1 to 6-9

Instead of iodomethane or iodomethane, use the corresponding halogen compound, and instead of 5-methyl-2-thiophenecarboxylic acid or 5-methyl-2-thiophenecarboxylic acid, use the corresponding carboxylic acid compound, Example 2 → Same procedure as in Reference Example 16, using 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 or the compound prepared in Reference Example 12. was performed to obtain each title compound.

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

HPLC retention time (min): 1.30 (formic acid);

MS (ESI, Pos.): 463 (M+H) ⁺ ;

¹ H-NMR (DMSO-d ₆ ): δ 7.51, 7.38, 7.12-7.05, 6.83, 4.66-4.58, 3.62, 3.47, 3.45-3.43, 3.35-3.25, 3.22-3.05, 2.84, 2.45, 2.06-1.91 , 1.83-1.75, 1.54-1.40, 1.38-1.23, 1.18, 0.92.

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

HPLC retention time (min): 1.20 (TFA);

MS (ESI, Pos.): 497 (M+H) ⁺ ;

¹ H-NMR (CDCl ₃ ): δ 7.36-7.27, 7.21-7.16, 6.73, 6.48, 5.09, 4.60, 3.92-3.73, 3.62, 2.82, 2.50, 2.29-2.21, 2.14-2.03, 1.89, 1.62- 1.56.

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

HPLC retention time (min): 1.00 (formic acid);

MS (ESI, Pos.): 463 (M+H) ⁺ ;

¹ H-NMR (DMSO-D ₆ ): δ 7.61-7.49, 7.32, 7.21-7.06, 4.95-4.81, 4.59, 3.87, 3.82-3.56, 3.37-3.29, 3.14-3.03, 2.92, 2.09-1.93, 1.84- 1.71, 1.57-1.45.

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

HPLC retention time (min): 1.10 (formic acid);

MS (ESI, Pos.): 471 (M+H) ⁺ ;

¹ H-NMR (DMSO-d ₆ ): δ 7.68-7.54, 7.52-7.42, 7.43-7.21, 7.25-7.15, 4.71-4.59, 4.04-3.84, 3.64, 3.44-3.41, 3.31, 3.26, 3.24-3.15, 3.01-2.71, 2.07-1.91, 1.85-1.68, 1.58-1.44.

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

HPLC retention time (min): 0.98 (formic acid);

MS (ESI, Pos.): 535 (M+H) ⁺ ;

¹ H-NMR (DMSO-d ₆ ): δ 7.88-7.75, 7.71-7.53, 7.53-7.17, 5.03-4.78, 4.65, 4.03-3.59, 3.15-3.05, 2.97-2.74, 2.14-1.97, 1.96-1.79, 1.58-1.43.

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

HPLC retention time (min): 0.88 (formic acid);

MS (ESI, Pos.): 490 (M+H) ⁺ ;

¹ H-NMR (DMSO-d ₆ ): δ 8.61, 7.59, 7.53, 7.50-7.40, 7.24, 7.43-7.21, 4.93-4.83, 4.80, 3.95, 3.87, 3.66, 3.23-3.08, 3.00, 2.88, 2. 78, 2.67, 2.55, 2.10, 1.99, 1.77-1.63, 1.62-1.45, 1.32-1.22, 1.18.

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

HPLC retention time (min): 1.20 (formic acid);

MS (ESI, Pos.): 514 (M+H) ⁺ ;

¹ H-NMR (DMSO-d ₆ ): δ 7.91-7.84, 7.62, 7.56-7.51, 7.50-7.40, 7.43-7.22, 7.27-7.19, 4.95-4.85, 4.87-4.76, 4.02-3.87, 3.71, 3.42, 3.32-3.24, 3.14-3.05, 2.96-2.67, 2.16-2.07, 2.06-1.94, 1.57-1.38.

Example 6-8: [(3aS,4R,6aR)-4-[(6-bromo-3-pyridazinyl)(3-fluoropropyl)amino]hexahydrocyclopenta[c]pyrrol-2(1H)-yl]( 5-methyl-2-thienyl)methanone

HPLC retention time (min): 1.10 (TFA);

MS (ESI, Pos.): 467 (M+H) ⁺ ;

¹ H-NMR (CDCl ₃ ): δ 7.32-7.28, 6.79-6.72, 4.60, 4.48, 3.82, 3.71-3.52, 2.91, 2.51, 2.20-2.02, 1.98, 1.66-1.58, 1.50, 1.33-1.19, 0.82.

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

HPLC retention time (min): 0.93 (TFA);

MS (ESI, Pos.): 421 (M+H) ⁺ ;

¹ H-NMR (CDCl ₃ ): δ 7.32-7.23, 6.78-6.65, 4.92-4.75, 4.01-3.85, 3.85-3.77, 3.64, 2.98, 2.92-2.77, 2.50, 2.17-2.05, 1.91-1.79, 1. 61- 1.52.

Reference Example 53: rrel-(3aS, 6aR)-hexahydrocyclopenta[c]pyrrol-4(1H)-one hydrochloride racemic mixture

The title compound was obtained by carrying out the same procedure as in Example 4 → Reference Example 10, using the compound prepared in Reference Example 1 instead of the compound prepared in Reference Example 3.

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

The same procedure as in Reference Example 10 was performed using the compound prepared in Reference Example 3 instead of the compound prepared in Reference Example 9 to obtain the title compound.

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

DIPEA (22 mL) and HATU (17.6 g) were added to a solution of the compound prepared in Reference Example 53 (5.0 g) and 5-methyl-2-thiophenecarboxylic acid (6.6 g) in DMA (100 mL) , the mixture was stirred at room temperature for 3 hours. Afterwards, 2N hydrochloric acid was added to the reaction solution, and then extracted with dichloromethane. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound (7.0 g).

HPLC retention time (min): 0.88 (formic acid);

MS (ESI, Pos.): 250 (M+H) ⁺ .

Reference Example 54-1: (3aS, 6aR)-2-(5-methylthiophen-2-carbonyl)hexahydrocyclopenta[c]pyrrol-4(1H)-one

The same procedure as in Reference Example 54 was performed using the compound prepared in Reference Example 53-1 instead of the compound prepared in Reference Example 53 to obtain the title compound.

Reference Example 55: (rel-(3aS,4R,6aR)-4-(cyclopropylamino)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)(5-methylthiophen-2-yl)methanone racemic mixture

Cyclopropylamine (CAS: 765-30-0, 0.25 mL) and acetic acid (0.34 mL) were added to a solution of the compound prepared in Reference Example 54 (300 mg) in dichloromethane (10 mL) and the mixture was incubated at room temperature. Stirred for 10 minutes. Sodium triacetoxyborohydride (CAS: 56553-60-7, 760 mg) was added thereto, and the mixture was stirred at 40° C. for 3 hours. Afterwards, 2N sodium hydroxide was added to the reaction solution, and then extracted with dichloromethane. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound (22 mg).

HPLC retention time (min): 0.78 (formic acid);

MS (ESI, Pos.): 291 (M+H) ⁺ .

Example 7: rel-{(3aS,4R,6aR)-4-[(6-bromo-3-pyridazinyl)(cyclopropyl)amino]hexahydrocyclopenta[c]pyrrole-2(1H)- 1}(5-methyl-2-thienyl)methanone racemic mixture

To a solution of the compound prepared in Reference Example 55 (20 mg) in tert-amyl alcohol (CAS: 75-85-4, 0.3 mL) was added 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 closed tube. The reaction solution was concentrated under reduced pressure, and then the obtained residue was purified by silica gel column chromatography to obtain the title compound (1.0 mg).

HPLC retention time (min): 1.20 (formic acid);

MS (ESI, Pos.): 447 (M+H) ⁺ .

Reference Example 56: (rel-(3aS, 4S, 6aR)-4-hydroxyhexahydrocyclopenta[c]pyrrol-2(1H)-yl)(5-methylthiophen-2-yl)methanone racemic mixture

1 M lithium tri-sec-butylborohydride THF solution (8.5 mL) was added to a solution of the compound prepared in Reference Example 54 (1.4 g) in THF (42 mL) at -78°C and the mixture was cooled to -78°C. It was stirred at ℃ for 1 hour. A 35% aqueous hydrogen peroxide solution was slowly added to the reaction solution at 0°C until foaming stopped, and then extracted with dichloromethane. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound (600 mg).

HPLC retention time (min): 0.86 (TFA);

MS (ESI, Pos.): 252 (M+H) ⁺ .

Reference Example 57: rel-(3aS, 4S, 6aR)-2-(5-methylthiophene-2-carbonyl)octahydrocyclopenta[c]pyrrol-4-yl 4-methylbenzenesulfonate racemic mixture

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

HPLC retention time (min): 1.16 (TFA);

MS (ESI, Pos.): 406 (M+H) ⁺ .

Example 8: rel[(3aS,4R,6aR)-4-(3-chloro-5,6-dihydro-7H-pyrrolo[2,3-c]pyridazin-7-yl)hexahydrocyclopenta [c]pyrrol-2(1H)-yl](5-methyl-2-thienyl)methanone racemic mixture

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

HPLC retention time (min): 0.90 (formic acid);

MS (ESI, Pos.): 389 (M+H) ⁺ ;

¹ H-NMR (DMSO-d ₆ ): δ 7.45-7.38, 7.21-7.17, 6.88-6.80, 4.33-4.23, 3.67-3.59, 3.54-3.44, 3.08-2.99, 2.92-2.77, 2.29-2.14, 2.08- 1.94, 1.94-1.76, 1.68-1.54, 1.57-1.42.

Examples 8-1 to 8-4

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 each title compound.

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

HPLC retention time (min): 1.10 (TFA);

MS (ESI, Pos.): 387 (M+H) ⁺ ;

¹ H-NMR (CDCL ₃ ): δ 7.69, 7.55, 7.33, 6.74, 6.46, 5.14-4.96, 4.01-3.86, 3.73, 3.35-3.25, 3.13, 2.62, 2.51, 2.48-2.29, 1.80-1.65.

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

HPLC retention time (min): 0.89 (TFA);

MS (ESI, Pos.): 393 (M+H) ⁺ ;

¹ H-NMR (CDCl ₃ ): δ 7.35-7.28, 6.76-6.70, 6.56, 4.88, 4.34-4.26, 4.15-4.02, 3.94-3.73, 3.73-3.60, 2.85, 2.74, 2.50, 2.46-2.29, 2 .17- 1.99, 1.70-1.60.

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

HPLC retention time (min): 1.10 (formic acid);

MS (ESI, Pos.): 362 (M+H) ⁺ .

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

HPLC retention time (min): 1.20 (formic acid);

MS (ESI, Pos.): 396 (M+H) ⁺ .

Reference Example 58: rel-tert-butyl(3aS,4R,6aR)-4-((6-chloro-4-cyanopyridazin-3yl)amino)hexahydrocyclopenta[c]pyrrole-2(1H) -carboxylate racemic mixture

Instead of the compound prepared in Reference Example 3, the compound prepared in Reference Example 1 was used, and instead of 3,6-dichloropyridazine, 3,6-dichloropyridazine-4-carbonitrile (CAS No.: 35857-93-3, 45 mg), the same procedure 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.

Reference Example 59: rel-6-chloro-3-(((3aS,4R,6aR)-octahydrocyclopenta[c]pyrrol-4-yl)amino)pyridazine-4-carbonitrile racemic mixture

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

Example 9: rel-6-chloro-3-({(3aS,4R,6aR)-2-[(5-methyl-2-thienyl)carbonyl]octahydrocyclopenta[c]pyrrol-4-yl }Amino)-4-pyridazinecarbonitrile racemic mixture

The same procedure as in Example 2 was performed using the compound prepared in Reference Example 59 instead of the compound prepared in Reference Example 12 to obtain the title compound.

HPLC retention time (min): 1.10 (TFA);

MS (ESI, Pos.): 388 (M+H) ⁺ ;

¹ H-NMR (CDCl ₃ ): δ 7.42, 7.37-7.27, 6.75, 5.11, 4.47-4.39, 4.05, 3.99-3.82, 3.68, 2.91, 2.74, 2.53-2.50, 2.50-2.42, 2.21-1.98, 1.78- 1.54.

Example 9-1

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

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

HPLC retention time (min): 1.10 (formic acid);

MS (ESI, Pos.): 473 (M+H) ⁺ ;

¹ H-NMR (DMSO-d ₆ ): δ 7.94-7.83, 7.37-7.24, 6.85-6.70, 4.60, 4.48-4.37, 3.88, 3.82-3.63, 2.84-2.78, 2.97-2.67, 2.29-2.12, 2.10- 1.98, 1.83-1.70, 1.58-1.43.

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

(2) [(3aR, 6aS)-6-{[dimethyl(2-methyl-2-propanyl)silyl]oxy}-3,3a,4,6a-tetrahydrocyclopenta[c]pyrrole-2(1H )-yl](5-methyl-2-thienyl)methanone

Triethylamine (2.4 mL) and tert-butyldimethylsilyl trifluoromethanesulfonic acid (CAS No.: 69739-34-0, 2.0 mL) were reacted with the compound prepared in Reference Example 54-1 ( 4.3 g) was added to the solution and the mixture was stirred at 40° C. for 2 hours. Saturated aqueous sodium bicarbonate solution was added to the reaction solution, and then extracted with dichloromethane. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound (1) (1.9 g) and the title compound (2) (1.0 g).

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

To a solution of the compound prepared in Reference Example 60 (1) (1.9 g) in acetonitrile (38 mL) was added 1-chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane bis. (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 obtained residue was purified by silica gel column chromatography to obtain the title compound (540 mg).

HPLC retention time (min): 0.95 (TFA);

MS (ESI, Pos.): 268 (M+H) ⁺ .

Reference Example 62: [(3aR, 4S, 6aS)-3a-fluoro-4-hydroxy-1,3,4,5,6,6a-hexahydrocyclopenta[c]pyrrol-2-yl](5-methyl-2 -Thienyl)methanone

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

HPLC retention time (min): 0.88 (TFA);

MS (ESI, Pos.): 270 (M+H) ⁺ .

Reference Example 63: [(3aR,4R,6aS)-3a-fluoro-2-(5-methylthiophene-2-carbonyl)-1,3,4,5,6,6a-hexahydro-1H-cyclopenta[c ]pyrrol-4-yl]-4-methylbenzenesulfonate

Triethylamine (1.4 mL), p-toluenesulfonyl chloride (1.2 g), and trimethylamine hydrochloride (154 mg) were added to a solution of the compound prepared in Reference Example 62 (872 mg) in dichloromethane (13 mL). was added and the mixture was stirred at room temperature for 23 hours. After adding water to the reaction solution, it was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound (1.0 g).

HPLC retention time (min): 1.16 (TFA);

MS (ESI, Pos.): 424 (M+H) ⁺ .

Reference Example 64: [(3aR,4R,6aS)-4-azide-3a-fluoro-1,3,4,5,6,6a-hexahydrocyclopenta[c]pyrrol-2-yl]-(5-methyl- 2-thienyl)methanone

Sodium azide (560 mg) was added to a solution of the compound prepared in Reference Example 63 (1.4 g) in dimethyl sulfoxide (13 mL), and the mixture was stirred at 100° C. for 90 hours. After adding water to the reaction solution, it was extracted with dichloromethane. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained title compound was used in the next reaction without purification.

HPLC retention time (min): 1.08 (TFA);

MS (ESI, Pos.): 295 (M+H) ⁺ .

Reference Example 65: [(3aR,4R,6aS)-4-amino-3a-fluoro-1,3,4,5,6,6a-hexahydrocyclopenta[c]pyrrol-2-yl]-(5-methyl-2 -Thienyl)methanone

To a solution of the compound prepared in Reference Example 64 (892 mg) in ethanol (18 mL) was added 20% palladium hydroxide (1.8 g), and the mixture was stirred at room temperature for 15 minutes under a hydrogen atmosphere. The reaction solution was filtered and concentrated under reduced pressure, and the obtained title compound was used in the next reaction without purification.

HPLC retention time (min): 0.72 (TFA);

MS (ESI, Pos.): 269 (M+H) ⁺ .

Example 10: [(3aR,4R,6aS)-4-[(6-bromopyridazin-3-yl)amino]-3a-fluoro-1,3,4,5,6,6a-hexahydrocyclopenta[c ]pyrrol-2-yl]-(5-methyl-2-thienyl)methanone

DIPEA (0.91 mL) and 3-bromo-6-fluoropyridazine (619 mg) were added to a solution of the compound prepared in Reference Example 65 (470 mg) in 2-methyl-2-butanol (9.4 mL) , the mixture was stirred at 180°C for 3 hours. After adding water to the reaction solution, it was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound (141 mg).

HPLC retention time (min): 1.00 (TFA);

MS (ESI, Pos.): 427 (M+H) ⁺ .

Reference Example 66: (3aR,4R,6aS)-N-(6-bromo-3-pyridazinyl)-3a-fluorooctahydrocyclopenta[c]pyrrol-4-amine

Methanol (1 mL) and 5 N aqueous sodium hydroxide solution (1 mL) were added to a solution of the compound prepared in Reference Example 10 (40 mg) in THF (2 mL), and the mixture was stirred at 50° C. for 16 hours. After adding water to the reaction solution, it was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained title compound was used in the next reaction without purification.

Example 11: [(3aR,4R,6aS)-4-[(6-bromo-3-pyridazinyl)amino]-3a-fluorohexahydrocyclopenta[c]pyrrol-2(1H)-yl](6, 7-dihydro-4H-thieno[3,2-c]pyran-2-yl)methanone

DIPEA (0.02 mL) and HATU (31 mg) were mixed with the compound prepared in Reference Example 66 (5.0 g) and 6,7-dihydro-4H-thieno[3,2-c]pyran- in DMA (0.22 mL). 2-Carboxylic acid (14 mg) was added to the solution and the mixture was stirred at room temperature for 3 hours. Afterwards, 2N hydrochloric acid was added to the reaction solution, and then extracted with dichloromethane. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound (22 mg).

HPLC retention time (min): 0.89 (TFA);

MS (ESI, Pos.): 467 (M+H) ⁺ ;

¹ H-NMR (CDCl ₃ ): δ 7.29, 7.24-7.16, 6.59, 4.78, 4.75-4.67, 4.56, 4.28, 4.22-4.08, 4.01-3.89, 3.61, 2.89, 2.51-2.40, 2.26-2.17, 1.86- 1.75, 1.60, 1.52-1.34.

Examples 11-1 to 11-3

Each title compound was prepared by following the same procedure as in Example 11, using the corresponding carboxylic acid compound instead of 6,7-dihydro-4H-thieno[3,2-c]pyran-2-carboxylic acid. got it

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

HPLC retention time (min): 0.91 (TFA);

MS (ESI, Pos.): 491 (M+H) ⁺ ;

¹ H-NMR (DMSO-d ₆ ): δ 8.17, 7.64, 7.47, 7.30, 6.92, 4.55-4.41, 4.00, 2.89, 2.73-2.68, 2.56-2.53, 2.29-2.16, 2.14-2.01, 1.87-1.72 , 1.47-1.35, 1.28-1.12, 1.12-1.01.

Example 11-2: [(3aR,4R,6aS)-4-[(6-bromo-3-pyridazinyl)amino]-3a-fluorohexahydrocyclopenta[c]pyrrol-2(1H)-yl][5- (fluoromethyl)-2-thienyl]methanone

HPLC retention time (min): 0.92 (TFA);

MS (ESI, Pos.): 443 (M+H) ⁺ ;

¹ H-NMR (CDCl ₃ ): δ 7.40, 7.31, 7.28, 7.10, 6.60, 5.54, 5.42, 4.84-4.74, 4.62-4.48, 4.27-4.13, 4.01-3.93, 3.87, 3.61, 3.49, 3.00 -2.83, 2.50, 2.19, 2.28-2.14, 1.61-1.58, 1.53-1.36.

Example 11-3: [(3aR,4R,6aS)-4-[(6-bromo-3-pyridazinyl)amino]-3a-fluorohexahydrocyclopenta[c]pyrrol-2(1H)-yl][5- (2-fluoroethyl)-2-thienyl]methanone

HPLC retention time (min): 0.94 (TFA);

MS (ESI, Pos.): 457 (M+H) ⁺ ;

¹ H-NMR (CDCl ₃ ): δ 7.36-7.27, 6.87, 6.59, 4.71, 4.59, 4.19, 4.01, 3.63, 3.49, 3.28-3.17, 2.98-2.79, 2.57-2.41, 2.28-2.14, 1.87- 1.73, 1.61-1.57, 1.53-1.45.

Example 12: {(3aR,4R,6aS)-4-[(6-chloro-3-pyridazinyl)amino]-3a-fluorohexahydrocyclopenta[c]pyrrol-2(1H)-yl}(6,7 -dihydro-4H-thieno[3,2-c]pyran-2-yl)methanone

Instead of 3-bromo-6-fluoropyridazine, use 3,6-dichloropyridazine and replace 6,7-dihydro-4H-thieno[3,2-c]pyran-2-carboxylic acid with the corresponding The title compound was obtained in the same procedure as in Example 10 → Reference Example 66 → Example 11 using carboxylic acid.

HPLC retention time (min): 0.89 (TFA);

MS (ESI, Pos.): 423 (M+H) ⁺ ;

¹ H-NMR (CDCl ₃ ): δ 7.22-7.15, 6.70, 4.85, 4.71, 4.66-4.47, 4.27, 4.19-4.09, 4.03-3.90, 3.61, 2.96-2.82, 2.45, 2.27-2.15, 1.88-1 .66; 1.58-1.37.

Reference Example 67: (3aS, 5R, 6aR)-5-fluoro-2-(5-methylthiophene-2-carbonyl)-1,3,3a,5,6,6a-hexahydrocyclopenta[c]pyrrole-4 -on

To a solution of the compound prepared in Reference Example 60 (2) (1.3 g) in acetonitrile (25 mL) was added 1-chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane bis. (Tetrafluoroborate) (1.5 g) was added and the mixture was stirred at room temperature for 3 minutes. The reaction solution was concentrated under reduced pressure, water was added to the obtained residue, and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound (633 mg).

HPLC retention time (min): 0.81 (TFA);

MS (ESI, Pos.): 304 (M+H) ⁺ .

Reference Example 68: [(3aS, 4R, 5R, 6aR)-5-fluoro-4-hydroxy-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrol-2-yl]- (5-methyl-2-thienyl)methanone

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

Reference Example 69: [(3aS, 4R, 5R, 6aR)-5-fluoro-2-(5-methylthiophene-2-carbonyl)-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta [c]pyrrol-4-yl] 4-methylbenzenesulfonate

DIPEA (0.23 mL), p-toluenesulfonyl chloride (127 mg), and trimethylamine hydrochloride (21 mg) were added to a solution of the compound prepared in Reference Example 68 (120 mg) in acetonitrile (1.2 mL) , the mixture was stirred at room temperature for 24 hours. After adding water to the reaction solution, it was extracted with dichloromethane. After concentration, the obtained residue was purified by silica gel column chromatography to obtain the title compound (190 mg).

HPLC retention time (min): 1.13 (TFA);

MS (ESI, Pos.): 424 (M+H) ⁺ .

Reference Example 70: [(3aS, 4S, 5R, 6aR)-4-azide-5-fluorohexahydrocyclopenta[c]pyrrol-2(1H)-yl](5-methyl-2-thienyl)methanone

Sodium azide (145 mg) was added to a solution of the compound prepared in Reference Example 69 (190 mg) in dimethyl sulfoxide (0.8 mL), and the mixture was stirred at 100° C. for 17 hours. After adding water to the reaction solution, it was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained title compound was used in the next reaction without purification.

HPLC retention time (min): 1.05 (TFA);

MS (ESI, Pos.): 295 (M+H) ⁺ .

Reference Example 71: [(3aS, 4S, 5R, 6aR)-4-amino-5-fluoro-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrol-2-yl]-( 5-methyl-2-thienyl)methanone

To a solution of the compound prepared in Reference Example 70 in ethanol (2 mL) was added 20% palladium hydroxide (50 mg), 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 obtained title compound was used in the next reaction without purification.

HPLC retention time (min): 0.75 (TFA);

MS (ESI, Pos.): 269 (M+H) ⁺ .

Example 13: [(3aS, 4S, 5R, 6aR)-4-[(6-bromopyridazin-3-yl)amino]-5-fluoro-3,3a,4,5,6,6a-hexahydro-1H -Cyclopenta[c]pyrrol-2-yl]-(5-methyl-2-thienyl)methanone

DIPEA (0.19 mL) and 3-bromo-6-fluoropyridazine (132 mg) were added to a solution of the compound prepared in Reference Example 71 (50 mg) in 2-methyl-2-butanol (0.23 mL) , the mixture was stirred at 160°C for 1 hour. The reaction solution was purified by reverse-phase column chromatography to obtain the title compound (8.9 mg).

HPLC retention time (min): 0.94 (TFA);

MS (ESI, Pos.): 426 (M+H) ⁺ ;

¹ H-NMR (CDCl ₃ ): δ 7.32, 7.28-7.26, 6.73, 6.62, 5.42-5.10, 4.89, 4.51-4.38, 4.13-3.88, 3.63, 3.09-2.99, 2.82-2.75, 2.50, 1.95-1 .77.

Reference Example 72: (3aS, 6aR)-2-(6,7-dihydro-4H-thieno[3,2-c]pyran-2-ylcarbonyl)hexahydrocyclopenta[c]pyrrol-4(1H)-one

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

Reference Example 73: [(3aS, 6aR)-6-{[dimethyl(2-methyl-2-propanyl)silyl]oxy}-3,3a,4,6a-tetrahydrocyclopenta[c]pyrrol-2(1H)-yl ](6,7-dihydro-4H-thieno[3,2-c]pyran-2-yl)methanone

Triethylamine (2.8 mL) and tert-butyldimethylsilyl trifluoromethanesulfonate (2.3 mL) were added to a solution of the compound prepared in Reference Example 72 (2.0 g) in dichloromethane (40 mL) at 0° C. , the mixture was stirred at 50° C. for 22 hours. Saturated aqueous sodium bicarbonate solution was added to the reaction solution, and then extracted with dichloromethane. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained title compound was used in the next reaction without purification.

Reference Example 74: (3aS, 5R, 6aR)-2-(6,7-dihydro-4H-thieno[3,2-c]pyran-2-ylcarbonyl)-5-methylhexahydrocyclopenta[c]pyrrole- 4(1H)-on

A solution of the compound prepared in Reference Example 73 was prepared by adding iodomethane (9.5 g) and 1 M tetra-N-butylammonium fluoride (CAS No. 429-41-4, 0.74 mL, THF solution) in DMF (10 mL). was added, and the mixture was stirred at room temperature for 3 hours. The reaction solution was concentrated under reduced pressure, water was added to the obtained residue, and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound (100 mg).

Example 14: [(3aS, 4R, 5R, 6aR)-4-[(6-bromo-3-pyridazinyl)amino]-5-methylhexahydrocyclopenta[c]pyrrol-2(1H)-yl](6 ,7-dihydro-4H-thieno[3,2-c]pyran-2-yl)methanone

The same procedure as in Reference Example 62 → Reference Example 63 → Reference Example 64 → Reference Example 65 → Example 10 was performed using the compound prepared in Reference Example 74 instead of the compound prepared in Reference Example 61 to obtain the title compound.

HPLC retention time (min): 0.86 (TFA);

MS (ESI, Pos.): 463 (M+H) ⁺ ;

¹ H-NMR (CDCl ₃ ): δ 7.33-7.28, 7.13, 6.65-6.58, 5.21, 4.70, 4.04-3.83, 3.66, 2.93-2.85, 2.76, 2.55, 1.88-1.69, 0.95.

Reference Example 75: (3aS, 6aR)-2-(6,7-dihydro-4H-thieno[3,2-c]pyran-2-carbonyl)spiro[3,3a,6,6a-tetrahydro-1H-cyclo penta[c]pyrrole-5,1'-cyclopropane]-4-one

To a solution of the compound prepared in Reference Example 72 (300 mg) in dimethyl sulfoxide (7.5 mL) was added 1,8-diazabicyclo[5.4.0]undec-7-ene (CAS No.: 6674-22- 2, 0.31 mL) and diphenyl vinyl sulfonium triflate (CAS No.: 247129-88-0, 410 mg) were added, and the mixture was stirred at room temperature for 1 hour. Water and 1 N aqueous hydrochloric acid solution were added to the reaction solution, and then extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound (100 mg).

HPLC retention time (min): 0.90 (TFA);

MS (ESI, Pos.): 318 (M+H) ⁺ .

Reference Example 76: [(3aS,4R,6aR)-4-hydroxyspiro[1,3,3a,4,6,6a-hexahydrocyclopenta[c]pyrrole-5,1'-cyclopropan]-2-yl]- (6,7-dihydro-4H-thieno[3,2-c]pyran-2-yl)methanone

Sodium borohydride (25 mg) was added to a solution of the compound prepared in Reference Example 75 (138 mg) in methanol (2.8 mL), and the mixture was stirred at 0° C. for 30 minutes. After adding water to the reaction solution, it was extracted with dichloromethane. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound (95 mg).

HPLC retention time (min): 0.91 (TFA);

MS (ESI, Pos.): 320 (M+H) ⁺ .

Reference Example 77: [(3aS, 4S, 6aR)-4-azidospiro[1,3,3a,4,6,6a-hexahydrocyclopenta[c]pyrrole-5,1'-cyclopropane]-2-yl]- (6,7-dihydro-4H-thieno[3,2-c]pyran-2-yl)methanone

Triphenylphosphine (CAS No.: 603-35-0, 102 mg), 2.2 M diethyl azodicarboxylate solution (CAS No.: 1972-28-7, 0.18 mL), and diphenylphosphoryl acetate Zide (CAS No.: 26386-88-9, 82 mg) was added to a solution of the compound prepared in Reference Example 76 (95 mg) in THF (0.2 mL), and the mixture was stirred at room temperature for 30 minutes. The reaction solution was purified by silica gel column chromatography to obtain the title compound (43 mg).

HPLC retention time (min): 1.08 (TFA);

MS (ESI, Pos.): 345 (M+H) ⁺ .

Reference Example 78: [(3aS, 4S, 6aR)-4-aminospiro[1,3,3a,4,6,6a-hexahydrocyclopenta[c]pyrrole-5,1'-cyclopropan]-2-yl]-( 6,7-dihydro-4H-thieno[3,2-c]pyran-2-yl)methanone

To a solution of the compound (43 mg) prepared in Reference Example 77 in methanol (1 mL) was added 20% palladium hydroxide (20 mg), and the mixture was stirred at room temperature 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).

HPLC retention time (min): 0.73 (TFA);

MS (ESI, Pos.): 319 (M+H) ⁺ .

Example 15: [(3aS, 4S, 6aR)-4-[(6-bromopyridazin-3-yl)amino]spiro[1,3,3a,4,6,6a-hexahydrocyclopenta[c]pyrrole-5 ,1'-cyclopropane]-2-yl]-(6,7-dihydro-4H-thieno[3,2-c]pyran-2-yl)methanone

DIPEA (0.92 mL) and 3-bromo-6-fluoropyridazine (18.9 mg) were added to a solution of the compound prepared in Reference Example 78 (17 mg) in 2-methyl-2-butanol (0.5 mL) , the mixture was stirred at 180°C for 4 hours. After adding water to the reaction solution, it was extracted with dichloromethane. The organic layer was purified by silica gel column chromatography to obtain the title compound (13 mg).

HPLC retention time (min): 0.97 (TFA);

MS (ESI, Pos.): 477 (M+H) ⁺ ;

¹ H-NMR (CD ₃ OD): δ 7.37, 7.34-7.18, 6.84, 4.68, 4.12-3.91, 3.80, 2.97, 2.93-2.81, 2.36, 2.07-1.95, 1.50, 1.41-1.17, 0.74-0.65, 0.60 , 0.53-0.35.

Reference Example 79: 2-methyl-2-propanyl rel-[(3aS,4R,6aR)-2-benzyl-6-oxooctahydrocyclopenta[c]pyrrol-4-yl]carbamate racemic mixture

tert-Butyl N-(4-oxocyclopenta-2-en-1-yl)carbamate (CAS No.: 657396-97-9, 17 g) and trifluoroacetic acid (58 mg) were combined with N-benzyl- N-(methoxymethyl)-N-trimethylsilylmethylamine (3.6 g) was added to a dichloromethane solution (20 mL), and the mixture was stirred at room temperature for 16 hours. Triethylamine (430 mg) was added to the reaction solution, and the mixture was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound (300 mg).

HPLC retention time (min): 0.86 (TFA);

MS (ESI, Pos.): 331 (M+H) ⁺ .

Reference Example 80: 2-methyl-2-propanyl rel-[(3aS,4R,6aR)-2-benzyl-6,6-difluorooctahydrocyclopenta[c]pyrrol-4-yl]carbamate racemic mixture

Bis(2-methoxyethyl)aminosulfur trifluoride (CAS No.: 202289-38-1, 1.2 g) was added to a solution of the compound prepared in Reference Example 79 (300 mg) in dichloromethane (5 mL). And the mixture was stirred at room temperature for 15 hours. Saturated aqueous sodium bicarbonate solution was added to the reaction solution, and then extracted with dichloromethane. The mixture was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound (120 mg).

HPLC retention time (min): 0.91 (TFA);

MS (ESI, Pos.): 353 (M+H) ⁺ .

Reference Example 81: 2-Methyl-2-propanyl rel-[(3aS,4R,6aR)-6,6-difluorooctahydrocyclopenta[c]pyrrol-4-yl]carbamate racemic mixture

To a solution of the compound (120 mg) prepared in Reference Example 80 in ethanol (10 mL) was added 20% palladium hydroxide (120 mg), 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 obtained residue was used in the next reaction without purification.

Reference Example 82: 2-methyl-2-propanyl rel-[(3aS,4R,6aR)-2-(6,7-dihydro-4H-thieno[3,2-c]pyran-2-ylcarbonyl)-6 ,6-difluorooctahydrocyclopenta[c]pyrrol-4-yl]carbamate racemic mixture

To a solution of the compound prepared in Reference Example 81 in DMA (3 mL) was added 6,7-dihydro-4H-thieno[3,2-c]pyran-2-carboxylic acid (112 mg), DIPEA (0.26 mL) ), and HATU (210 mg) were added, and the mixture was stirred at room temperature for 3 hours. After adding water to the reaction solution, it was extracted with dichloromethane. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound (100 mg).

HPLC retention time (min): 1.00 (formic acid);

MS (ESI, Pos.): 429 (M+H) ⁺ .

Reference Example 83: rel-[(3aR,6R,6aS)-6-amino-4,4-difluorohexahydrocyclopenta[c]pyrrol-2(1H)-yl](6,7-dihydro- 4H-thieno[3,2-c]pyran-2-yl)methanone racemic mixture

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

Example 16: [(3aR,6R,6aS)-6-[(6-bromo-3-pyridazinyl)amino]-4,4-difluorohexahydrocyclopenta[c]pyrrol-2(1H)-yl] (6,7-dihydro-4H-thieno[3,2-c]pyran-2-yl)methanone

DIPEA (0.24 mL) and 3,6-dibromopyridazine (120 mg) were added to a solution of the compound prepared in Reference Example 83 (80 mg) in DMA (1 mL) and the mixture was incubated at 160° C. for 1 hour. It was stirred for a while. After adding water to the reaction solution, it was extracted with dichloromethane. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography, and then the two diastereomers were separated by supercritical fluid chromatography (CHIRALPAK IC, CO ₂ : methanol = 70 : 30) to obtain a low polar substance (19 mg). got it

HPLC retention time (min): 1.00 (TFA);

MS (ESI, Pos.): 485 (M+H) ⁺ ;

¹ H-NMR (DMSO-d ₆ ): δ 7.54-7.45, 7.36-7.35, 7.40-7.32, 6.85, 4.62, 4.23-4.15, 3.88, 3.57-3.50, 3.38-3.31, 3.31-3.16, 2.99-2.88, 2.83, 2.30-2.17.

Reference Example 84: 2-Bromo-5-[2-(2-fluoroethoxy)ethyl]thiophene

1-iodo-2- in a solution of 2-(5-bromothiophen-2-yl)ethan-1-ol (CAS No.: 57070-78-7, 653 mg) in dimethylacetamide (15 mL) Fluoroethane (CAS No.: 762-51-6, 1.52 mL) and sodium hydride (757 mg) were added and the mixture was stirred at room temperature for 17 hours. Thereafter, the mixture was stirred at 60° C. for 24 hours. After adding water to the reaction solution, it was extracted with a mixed solvent of ethyl acetate and n-hexane. The organic layer was washed with water, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound (396 mg).

HPLC retention time (min): 0.828 (TFA);

¹ H-NMR (CDCl ₃ ): δ 6.86, 6.61, 4.66-4.61, 4.54-4.49, 3.77-3.66, 3.04.

Reference Example 85: 5-[2-(2-fluoroethoxy)ethyl]-2-thiophene carboxylic acid

Water (0.135 mL), trans-bis(acetato)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) was added to a solution of the compound prepared in Reference Example 84 (396 mg) in THF (1 mL). The reaction solution was heated at 120°C for 1 hour. 1 M aqueous hydrochloric acid solution and ethyl acetate were added to the reaction solution, and the mixture was filtered. The organic layer was washed with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound (190 mg).

¹ H-NMR (CDCl ₃ ): δ 7.72, 6.91, 4.72-4.61, 4.55-4.49, 3.84-3.68, 3.15, 2.50.

Reference Example 86: [(3aS,4R,6aR)-4-[(6-bromo-3-pyridazinyl)amino]hexahydrocyclopenta[c]pyrrol-2(1H)-yl]{5-[2-(2 -fluoroethoxy)ethyl]-2-thienyl}methanone

DIPEA (0.024 mL) and 1H-benzotriazol-1-yloxytripyrrolidinophosphonium hexafluorophosphate (hereinafter referred to as PyBOP, 22 mg, CAS No.: 128625-52-5) were dissolved in DMA (1.0 mL). was added to a solution of the compound prepared in Reference Example 12 (10 mg) and the compound prepared in Reference Example 85 (9.2 mg), and the mixture was stirred at room temperature for 1 hour. After adding water to the reaction solution, it was extracted with dichloromethane. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound (5.0 mg).

HPLC retention time (min): 0.88 (TFA);

MS (ESI, Pos.): 483 (M+H) ⁺ .

Example 17: [(3aS,4R,6aR)-4-[(6-bromo-3-pyridazinyl)(methyl)amino]hexahydrocyclopenta[c]pyrrol-2(1H)-yl]{5-[2 -(2-fluoroethoxy)ethyl]-2-thienyl}methanone

Sodium hydride (4.1 mg) was added to a solution of the compound prepared in Reference Example 86 (5.0 mg) in DMF (1.0 mL). After stirring at room temperature for 15 minutes, iodomethane (0.003 mL) was added thereto, and the mixture was further stirred at room temperature for 1 hour. After adding water to the reaction solution, it was extracted with dichloromethane. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound (3.9 mg).

HPLC retention time (min): 0.95 (TFA);

MS (ESI, Pos.): 497 (M+H) ⁺ ;

¹ H-NMR (CDCl ₃ ): δ 7.34-7.27, 6.82, 6.70, 4.84, 4.64-4.61, 4.53-4.49, 3.91, 3.83, 3.80-3.63, 3.11, 2.98, 2.92-2.77, 2.17-2.08, 1.90- 1.80.

Reference Example 87: 5-(2-fluoroethoxy)-2-thiophenecarboxylic acid

Sodium hydride (1,313 mg) was added to a solution of 2-fluoroethanol (CAS No.: 371-62-0, 1,578 mg) in DMA (15 mL) at room temperature, then 5-fluorothiophene-2-car Boxylic acid (CAS No.: 4377-58-6, 600 mg) was added thereto. The reaction solution was stirred at 100°C for 2 days. After adding water to the reaction solution, it was extracted with a mixed solvent of ethyl acetate and n-hexane. The organic layer was washed with water, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The obtained residue was dissolved in methanol (4 mL), trimethylsilyldiazomethane (CAS No.: 18107-18-1, 1 mL) was added thereto, and the mixture was stirred at room temperature for 1 hour. The reaction solution was purified by silica gel column chromatography to obtain a methyl ester compound (60 mg). The methyl ester compound (60 mg) thus obtained was dissolved in methanol (4 mL), and then 2 M aqueous sodium hydroxide solution (1.5 mL) was added thereto. The reaction solution was stirred at 50°C for 18 hours. Afterwards, 1 M hydrochloric acid was added to the reaction solution, and then extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure to obtain the title compound (57 mg).

HPLC retention time (min): 0.83 (TFA);

MS (ESI, Pos.): 191 (M+H) ⁺ ;

¹ H-NMR (CDCl ₃ ): δ 7.53, 6.28, 4.84-4.79, 4.72-4.67, 4.38-4.27.

Reference Example 88: [(3aS,4R,6aR)-4-[(6-bromo-3-pyridazinyl)amino]hexahydrocyclopenta[c]pyrrol-2(1H)-yl][5-(2-fluoro Ethoxy)-2-thienyl]methanone

DIPEA (0.024 mL) and PyBOP (22 mg) were added to a solution of the compound prepared in Reference Example 12 (10 mg) and the compound prepared in Reference Example 87 (8.1 mg) in DMA (1.0 mL) and the mixture was cooled to room temperature. It was stirred for 1 hour. After adding water to the reaction solution, it was extracted with dichloromethane. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound (7.0 mg).

HPLC retention time (min): 0.89 (TFA);

MS (ESI, Pos.): 455 (M+H) ⁺ .

Example 18: [(3aS,4R,6aR)-4-[(6-bromo-3-pyridazinyl)(methyl)amino]hexahydrocyclopenta[c]pyrrol-2(1H)-yl][5-(2 -fluoroethoxy)-2-thienyl]methanone

Sodium hydride (6.1 mg) was added to a solution of the compound prepared in Reference Example 88 (7.0 mg) in DMF (1.0 mL), and the mixture was stirred at room temperature for 15 minutes. Then, iodomethane (0.005 mL) was added thereto and the mixture was further stirred at room temperature for 1 hour. After adding water to the reaction solution, it was extracted with dichloromethane. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound (3.9 mg).

HPLC retention time (min): 0.95 (TFA);

MS (ESI, Pos.): 469 (M+H) ⁺ ;

¹ H-NMR (CDCl ₃ ): δ 7.28, 7.19, 6.71, 6.24, 4.91-4.78, 4.71-4.66, 4.37-4.33, 4.30-4.26, 3.95-3.78, 3.63, 2.98, 2.92-2.77, 2.17-2 .09; 1.91-1.80, 1.60.

Reference Example 89: 2-{2-[(6-bromo-3-pyridazinyl){(3aS,4R,6aR)-2-[(5-methyl-2-thienyl)carbonyl]octahydrocyclopenta[c] pyrrol-4-yl}amino]ethoxy}ethyl 4-methylbenzenesulfonate

Sodium hydride (88 mg) was added to a solution of the compound prepared in Example 2 (300 mg) in DMF (7.4 mL), and the mixture was stirred at room temperature for 30 minutes. Then Diethylene glycol ditosylate (CAS No.: 7460-82-4, 305 mg) was added thereto, and the mixture was stirred at room temperature for 4 hours. An aqueous sodium bicarbonate solution was added to the reaction solution, and then extracted with dichloromethane. The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound (100 mg).

HPLC retention time (min): 1.18 (TFA);

MS (ESI, Pos.): 649 (M+H) ⁺ .

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

Potassium fluoride (27 mg) and 4,7,13,16,21,24-hexaoxa-1,10-diazabicyclo[8.8.8]hexacosane (CAS No.: 23978-09-8, 174 mg ) was added to a solution of the compound prepared in Reference Example 89 (100 mg) in acetonitrile (1.5 mL), and the mixture was stirred at 80° C. for 40 minutes. The reaction solution was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography to obtain the title compound (41.6 mg).

HPLC retention time (min): 1.05 (TFA);

MS (ESI, Pos.): 497 (M+H) ⁺ ;

¹ H-NMR (CDCl ₃ ): δ 7.37-7.30, 7.28-7.21, 6.85, 6.73, 4.60-4.53, 4.48-4.41, 4.32-4.23, 3.89, 3.87-3.79, 3.78-3.61, 3.04-2.83, 2. 50, 2.20-2.01, 1.98-1.87.

Pharmacological Experimental Example 1: Evaluation of ABHD6 enzyme inhibitory activity

First, 1-arachidonoyl glycerol (Cayman Chemical) was used as a substrate to have a final concentration of 10 μmol/L using an assay buffer containing 50 mM tris-HCl (pH 7.4), 100 mM NaCl, and 0.05% BSA. It was prepared as. Thereafter, compounds were added thereto to a final concentration of 0.0003, 0.001, 0.003, 0.01, 0.03, 0.1, 0.3, 1, 3, or 10 μmol/L (DMSO: final concentration 0.3%). In addition, a solution in which DMSO was added to a final concentration of 0.3% was prepared as a group in which no compound was added. The enzyme reaction was started by adding recombinant human ABHD6 (33-337) prepared in the same assay buffer to the mixed solution of substrate and compound to a final concentration of 300 μg/mL. Recombinant human ABHD6 (33-337) was GST-tagged ABHD6, expressed in E. coli, purified with glutathione-Sepharose 4B resin, and then concentrated. The enzyme reaction was performed at room temperature using a 384-well microplate made of polypropylene, and wells to which no enzyme was added were designated as the blank group.

One hour after the start of the enzymatic reaction, the enzymatic reaction was stopped by adding arachidonic acid-d8 (Cayman Chemical) and methanol containing 1% formic acid as internal standards. The top of the enzyme reaction plate was sealed with aluminum, and centrifugation was performed at 560 g for 5 minutes at room temperature. Afterwards, arachidonic acid, an enzyme reaction product, and arachidonic acid-d ₈ , an internal standard, were quantified using the RapidFire (registered trademark)-Mass Spectrometry system. By taking the ratio of the quantitative values of each substance, taking the average of the blank group as 100% inhibition and the average of the group without adding a compound as 0% inhibition, the arachidonic acid production inhibition rate at each compound concentration was calculated to obtain the IC ₅₀ value. decided.

From the above pharmacological experiments, it was confirmed that the compound of the present invention has strong ABHD6 inhibitory activity. For example, the IC ₅₀ values of some compounds of the present invention are shown in Table 1 below.

[Table 1]

Pharmacological Experimental Example 2: Binding affinity measurements for human ABHD6

The binding affinity of the test compound to human ABHD6 was measured using bioluminescence resonance energy transfer (hereinafter abbreviated as BRET) as an indicator. Bioluminescence resonance energy transfer is induced by the proximity of the probe molecule to the NanoLuc-human ABHD6 fusion protein, which is caused by competitive action of the fluorescent probe molecule and the test compound using HEK293 cells forcefully expressing the NanoLuc-human ABHD6 fusion protein. do.

<Compound treatment>

The test compound and the compound described in Example 2 were each dissolved in dimethyl sulfoxide (DMSO) as a control material to prepare a 10 mmol/L solution. The prepared 10 mmol/L solution was thawed upon use, sequentially diluted with DMSO, and applied to the experiment.

<Cell culture>

Inactivate HEK293 cells expressing the Nanoluc-human ABHD6 fusion protein (56°C, 30 min) using 9.8 vol% non-dialyzed FBS (containing 0.5 vol% GENETICIN and 1% penicillin-streptomycin) in 5% CO. ₂ was cultured statically at 37°C in the presence of . Subculture was performed by the following method.

Culture medium was removed and cells were washed once with phosphate buffered saline without Ca ²⁺ and Mg ²⁺ . An appropriate amount of trypsin-EDTA was added, and the cells were incubated at room temperature. After cells were detached, the enzymatic reaction was stopped by adding 10 volumes of culture medium with trypsin-EDTA (0.05%). Cells were collected in a centrifuge tube, centrifuged at 120 g for 3 minutes at room temperature, and the supernatant was removed. Cells were suspended in an appropriate amount of culture medium and seeded into culture flasks.

HEK293 cells expressing the NanoLuc-human ABHD6 fusion protein were prepared, then cryopreserved in CELLBANKER2 at 5.0 x 10 ⁶ cells/mL/vial, and the cells were subjected to experiments. HBSS (+) containing 20 mmol/L HEPES (pH 7.3) and 0.1% BSA was prepared and used as an assay buffer. Cells were thawed and suspended in assay buffer to prepare a cell suspension of 2 x 10 ⁵ cells/mL. The reaction was started by adding the cell suspension (25 μL) to a 384-well assay plate to which the test compound had been previously added. The plate was left in the presence of 5% CO ₂ for 30 minutes at 37°C. Next, probe molecules with fluorophores (10 mmol/L in DMSO) were diluted with assay buffer to a final concentration of 100 nmol/L and added to the assay plates in an amount of 15 μL each. Additionally, it was left to stand in the presence of 5% CO ₂ at 37° C. for 30 minutes. Next, Nano-Glo (registered trademark) Vivazine (trade name) substrate (Promega Corporation) was diluted with assay buffer according to the method described in the protocol, added to the assay plates in an amount of 10 μL each, and incubated at room temperature. Let stand for 1 hour. Thereafter, luminescence and fluorescence intensity were measured using the GloMax (registered trademark) Discover system. The ratio between the emission intensity through a 450 nm bandpass filter and the fluorescence intensity through a 600 nm longpass filter was defined as the measured value for each sample. The measured value of the group containing control material at a final concentration of 30 μmol/L was defined as 100% inhibition. The measured value for the group containing no compound was defined as 0% inhibition. IC ₅₀ values of test compounds were determined from measurements at each test compound concentration.

In a cell assessment system, it was observed that the compounds of the present invention have strong ABHD6 binding activity. For example, the IC ₅₀ values of some compounds of the present invention are shown in Table 2 below.

[Table 2]

Pharmacological Experimental Example 3: ABHD6 selectivity evaluation

Rat brain membrane fraction was used to react with fluorescent probe molecules and test compounds, and then proteins were separated by electrophoresis. Next, the binding affinity of the test compounds was measured using the fluorescence intensity of ABHD6, MAGL, and FAAH as indicators.

<Compound treatment>

The test compound was dissolved in dimethyl sulfoxide (DMSO) to prepare a 10 mmol/L solution. The prepared 10 mmol/L solution was thawed upon use, sequentially diluted with DMSO, and adjusted to a concentration 50 times higher than the final concentration.

<Preparation of rat brain membrane fraction>

Rats were killed under anesthesia and their brains were removed. Then, 1 mL of ice-cold phosphate buffered saline (PBS, pH 7.5) was added per 200 mg of brain, and homogenized using a homogenizer. The homogenate solution was centrifuged at 1,000 g and 4°C for 10 minutes, and then the supernatant was collected. The obtained supernatant was centrifuged at 100,000 g and 4°C for 45 minutes, ice-cold PBS was added to the precipitate, and the mixture was resuspended to obtain a membrane fraction. The protein concentration in the prepared brain membrane fraction solution was quantified, and the fraction solution was stored in a freezer at -80°C until use.

<ABPP>

Brain membrane fraction solutions were prepared up to 3 mg/mL in PBS. Afterwards, 1 μL of DMSO or compound solution was added to 50 μL of the 3 mg/mL membrane fraction solution, and reacted at 37°C for 30 minutes. Afterwards, 1 μL of a probe molecule having a fluorophore (ActivX (trade name) TAMRA-FP Serine Hydrolase Probe, final concentration: 1 μmol/L, DMSO solution) was added thereto, and reacted at room temperature for 30 minutes. The reaction was stopped with 4x sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE) loading buffer. The sample was heat treated at 95°C for 5 minutes, and then protein separation was performed by SDS-PAGE using a 10% acrylamide gel. In the gel after SDS-PAGE, fluorescence was visualized with a chemiluminescence imaging system.

In each band of ABHD6, MAGL, and FAAH, the IC ₅₀ value of the test compound was determined from the fluorescence intensity at each test compound concentration by setting the fluorescence band intensity of the control group (DMSO-treated group) as 0% inhibition. As a result, it was confirmed that the compound of the present invention has selective inhibitory activity against ABHD6 with respect to MAGL and FAAH.

Pharmacological Experimental Example 4: Sodium monoiodoacetate-induced analgesic effects on rat model

The analgesic effect of the compounds of the present invention was evaluated using sodium monoiodoacetate (hereinafter abbreviated as MIA) (Sigma-Aldrich Japan)-induced model rats.

(1) Preparation of MIA-induced model rats

The area around the knee of the rat's right hind limb was shaved under isoflurane anesthesia, and 25 μL of 120 mg/mL MIA solution was administered into the joint space of the right hind limb using a glass syringe with a 29 G needle (BD Roads, Becton, Dickinson). and Company, Japan). The normal control group received 25 μL of physiological saline.

(2) Group composition and grouping

Rats were divided into groups consisting of normal control group, disease control group, test substance administration group, and tramadol administration group or morphine administration group. Excluding the normal control group, the right hind limb load-to-weight ratio of model rats (the measurement method will be described later) was measured 13 or 14 days after MIA-induction prepared by the method of (1) above, and the right hind limb load-to-weight ratio was calculated for each group. Rats were divided into groups to avoid bias.

(3) Administration of test substance, tramadol or morphine

The compounds of the present invention as test substances were dissolved in solubilization medium (7:3 Kolliphor solution: PEG) to prepare 0.4 or 8 mg/mL solutions. The prepared solution was diluted 4-fold with distilled water to prepare a 0.1 or 2 mg/mL solution (final concentration of solubilization medium: 25%). As a positive control drug, tramadol was dissolved in physiological saline to prepare a 2 mg/mL solution. Alternatively, morphine as a positive control drug was dissolved in physiological saline to prepare a 0.6 mg/mL solution. Test substances were 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.

(4) Measurement of right hind limb load-to-weight ratio

The load-to-weight ratio of the left and right hind limbs was measured using the Linton Incapacitance Tester (MJS Technology INC., UK). Specifically, the rat was moved to the dedicated cage of the Linton Incapacitance Tester, and the rat's posture was adjusted so that its left and right hind legs could ride on two pairs of weight measurement sensors, respectively. After confirming that the rat's posture was not biased left and right and forward and backward, the load weight of each left and right hind limb was measured for 3 seconds. Measurement of load weight was repeated three times for each individual rat. To obtain stable measurements, rats were housed in dedicated cages for at least 5 days and acclimatized for at least 20 min between the day of MIA induction and 14 days after induction. Moreover, rats were also acclimatized for approximately 10 min immediately prior to load weighing to determine load weight. Left and right hindlimbs before grouping 14 days after MIA induction, and 14 days later normal control group, initiation control group, test substance-treated group (5 hours after administration), tramadol-treated group (1 hour after administration), and morphine-treated group (1 hour after administration). The load weight was measured. The ratio of the loaded weight of the right hind leg to the loaded weight of both hind legs was calculated based on the average of the loaded weight of the left and right hind legs from Equation 1 below. When the compound of the present invention was administered as a test substance, the improvement rate of the right hind limb load ratio was calculated from the following equation 2, based on the right hind limb load ratio of each group 14 days after MIA induction. Next, the analgesic effect of the test substance (compound of the present invention) was evaluated.

[Equation 1]

Right hind limb load-to-weight ratio B (%) = {A _R /(A _R + A _L ) × 100}

A _R : Load weight of the right hind limb (average of values obtained by measuring the same individual three times)

A _L : Load weight of the left hind limb (average of values obtained by measuring the same individual three times)

[Equation 2]

Improvement rate of test material (%) = {1 - (B _T - B _C )/(B _N - B _C )} × 100

B _C : Average right hind limb load-to-weight ratio of normal controls

B _N : Average of right hind limb load-to-weight ratio of starting control group

B _T : Average load-to-weight ratio of the right hind limb in the test substance administration group

As a result, the analgesic effect of the compound of the present invention was shown to be equal to or better than that of tramadol and morphine, which are widely used as analgesics.

Pharmacological Experimental Example 5: Antidepressant action in rat forced swimming test

The antidepressant activity of compounds of the invention was evaluated using the rat forced swim test.

(1) Group composition and grouping

Rats were divided into groups consisting of a vehicle-administered group, a test substance-administered group, and an imipramine-administered group. Rats were divided into five groups by stratified randomization based on body weight on the day of grouping.

(2) Administration of test substance and imipramine

The compound of the present invention as a test substance was dissolved in solubilization medium (7:3 Kolliphor solution: PEG) to prepare a 4 mg/mL solution. The prepared solution was diluted 4-fold with distilled water to prepare a 1 mg/mL solution (final concentration of solubilization medium: 25%). Additionally, the 1 mg/mL solution was diluted 10-fold or 100-fold with 25% solubilization medium to prepare a 0.1 mg/mL or 0.01 mg/mL solution. As a positive control drug, imipramine was dissolved in physiological saline to prepare a 15 mg/mL solution. The test substance was administered orally at 5 mL/kg 5 hours before evaluation, and imipramine was administered subcutaneously at 2 mL/kg 0.5 hours before evaluation.

(3) Measurement of dead-state time

Rats were forced to swim for 15 minutes in a water tank (water depth: 20 cm, water temperature: 24 ± 1°C) the day before measurement (measurement acclimatization). After 24 hours, the rats were placed back in the water tank (water depth: 20 cm, water temperature: 24 ± 1°C) and forced to swim for 5 minutes. During this time, immobility time was measured as depressive behavior. The floating state time was measured using a stopwatch, and the measured value was recorded as an integer value rounded to 1 decimal place.

As a result, the compound of the present invention was shown to have an antidepressant effect comparable to that of imipramine, an antidepressant drug.

Pharmacological Experimental Example 6: Anxiolytic action in rat social interaction test

The anxiolytic activity of the compounds of the invention was assessed using the rat social interaction test.

(1) Group composition and grouping

Rats were divided into groups consisting of a vehicle-administered group, a test substance-administered group, and a diazepam-administered group. Rats were divided into five groups by stratified randomization based on body weight on the day of grouping.

(2) Administration of test substance and diazepam

The compound of the present invention as a test substance was dissolved in solubilization medium (7:3 Kolliphor solution: PEG) to prepare a 4 mg/mL solution. The prepared solution was diluted 4-fold with distilled water to prepare a 1 mg/mL solution (final concentration of solubilization medium: 25%). Additionally, the 1 mg/mL solution was diluted 10-fold or 100-fold with 25% solubilization medium to prepare a 0.1 mg/mL or 0.01 mg/mL solution. As a positive control drug, diazepam was suspended in 0.5% methylcellulose solution to prepare a 0.6 mg/mL suspension. The test substance was orally administered at 5 mL/kg 2 hours before evaluation, and diazepam was orally administered at 5 mL/kg 1 hour before evaluation.

(3) Measurement of social interaction time

2 hours after administration of the test substance or 1 hour after administration of the positive control substance, two rats (pair) with a body weight difference of 20 g or less were placed in an open-field device and incubated for 10 minutes. The rat's behavior was recorded on a video recorder. From 10 minutes of behavior, the time corresponding to the social behavior analysis items shown in Table 3 was measured. If this action time is prolonged, it can be confirmed that the test substance exhibits an anxiety-relieving effect.

[Table 3]

As a result, the compound of the present invention was found to have an anxiolytic effect comparable to that of diazepam, an anxiolytic drug.

[Formulation example]

Formulation example

The following ingredients are mixed and compressed in the usual manner to obtain about 10,000 tablets containing 10 mg of the active ingredient per tablet.

· {(3aS,4R,6aR)-4-[(6-chloro-3-pyridazinyl)amino]hexahydrocyclopenta[c]pyrrol-2(1H)-yl}[5-(difluoromethyl )-2-thienyl]methanone......100 g

· Carboxymethylcellulose calcium (disintegrant) ...... 20 g

· Magnesium stearate (lubricant)......10 g

· Microcrystalline cellulose ...... 870 g

Since the compound of the present invention has ABHD6 inhibitory activity, a pharmaceutical composition containing the compound of the present invention as an active ingredient is useful as a preventive and/or therapeutic agent for ABHD6-related diseases.

Claims (20)

A pharmaceutical composition comprising a compound represented by general formula (IA) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier:

During the ceremony,
X ^{1 and} X ^{2 each} independently represent (1) CH, (2) ^CR
R ¹ represents a halogen atom,
^R Represents a haloalkyl group, (7) C2-6 haloalkenyl group, (8) C2-6 haloalkynyl group, (9) C1-6 haloalkoxy group, or (10) cyano group,
R ² is (1) a halogen atom, (2) C1-6 alkyl group, (3) C2-6 alkenyl group, (4) C2-6 alkynyl group, (5) C1-6 alkoxy group, (6) C1-6 Represents a haloalkyl group, (7) C2-6 haloalkenyl group, (8) C2-6 haloalkynyl group, (9) C1-6 haloalkoxy group, or (10) cyano group,
When m is 2 or more, a plurality of R ² may be the same or different,
R ³ is (1) a hydrogen atom, (2) C1-6 alkyl group, (3) C1-6 haloalkyl group, (4) 3- to 10-membered cyclic group, (5) -(C1-6 alkylene) -(3- to 10-membered cyclic group), (6) -(C1-6 haloalkylene)-(3- to 10-membered cyclic group), where C1-6 alkyl group, C1-6 halo 1 to 2 carbon atoms in alkyl groups, C1-6 alkylene and C1-6 haloalkylene may be replaced by oxygen atoms or optionally oxidized sulfur atoms,
The 3- to 10-membered cyclic group of R ³ may be substituted with 1 to 5 R ³⁰¹ ,
R ³⁰¹ is (1) a halogen atom, (2) C1-4 alkyl group, (3) C1-4 alkoxy group, (4) C1-4 haloalkyl group, (5) C1-4 haloalkoxy group, (6) COOR ³⁰² , (7) CONR ³⁰³ R ³⁰⁴ , (8) C3-6 cycloalkyl group, (9) hydroxyl group, (10) nitro group, (11) cyano group, (12) -NR ³⁰⁵ R ³⁰⁶ , (13) - SR ³⁰⁷ , (14) -SOR ³⁰⁸ , (15) -SO ₂ R ³⁰⁹ , or (16) represents an oxo group,
When two or more R ³⁰¹ are substituted, the plurality of R ³⁰¹ may be the same or different,
R ³⁰² , R ³⁰³ , R ³⁰⁴ , R ³⁰⁵ , R ³⁰⁶ , R ³⁰⁷ , R ³⁰⁸ , or R ³⁰⁹ each independently represents (1) a hydrogen atom or (2) a C1-4 alkyl group,
When R ² represents ( ² ) to (9) in R 2 and R ³ represents a C1-6 alkyl group, R ² and R ³ together with the atoms to which R ² and R ³ are bonded represent 5- to Can form a 6-membered cyclic group,
R ⁴ is (1) a halogen atom, (2) C1-6 alkyl group, (3) C2-6 alkenyl group, (4) C2-6 alkynyl group, (5) C1-6 alkoxy group, (6) C1-6 Represents a haloalkyl group, (7) C2-6 haloalkenyl group, (8) C2-6 haloalkynyl group, or (9) C1-6 haloalkoxy group,
When n is 2 or more, a plurality of R ⁴ may be the same or different,
When two R ⁴ existing on the same carbon atom represent a C1-6 alkyl group, the two R ⁴ may form a C3-6 cycloalkyl group together with the carbon atom to which the two R ⁴ are bonded,
ring 1 represents a 3- to 15-membered cyclic group,
R ^5-A is (1) a halogen atom, (2) C1-6 alkyl group, (3) C2-6 alkenyl group, (4) C2-6 alkynyl group, (5) C1-6 alkoxy group, (6) C1 -6 alkylthio group, (7) C1-6 alkylsulfinyl group, (8) C1-6 alkylsulfonyl group, (9) C2-6 acyl group, (10) 3- to 6-membered cyclic group, (11) ) -L ^R5 -(3- to 6-membered cyclic group), (12) hydroxyl group, (13) nitro group, (14) cyano group, (15) oxo group, (16) -NR ⁵⁰¹ R ⁵⁰² , (17) -COOR ⁵⁰³ , (18) -CONR ⁵⁰⁴ R ⁵⁰⁵ , or (19) -SO ₂ NR ⁵⁰⁶ R ⁵⁰⁷ , C1-6 alkyl group, C2-6 alkenyl group, C2-6 alkynyl group, C1- 1 to 2 carbon atoms in the 6 alkoxy group, C1-6 alkylthio group, C1-6 alkylsulfinyl group, C1-6 alkylsulfonyl group, C2-6 acyl group may be replaced by an oxygen atom or an optionally oxidized sulfur atom; ,
When p is 2 or more, a plurality of R ^5-A may be the same or different,
Groups (2) to (11) of R ^5-A may be substituted with 1 to 9 R ⁵⁰⁸ ,
R ⁵⁰⁸ is (1) a halogen atom, (2) C1-4 alkyl group, (3) C1-4 alkoxy group, (4) C2-6 acyl group, (5) C3-6 cycloalkyl group, (6) hydroxyl group , or (7) -NR ⁵⁰⁹ R ⁵¹⁰ ,
When two or more R ⁵⁰⁸ are substituted, the plurality of R ⁵⁰⁸ may be the same or different,
L ^R5 is (1) -O-, (2) -(C1-4 alkylene)-, (3) -O-(C1-4 alkylene)-, (4) -(C1-4 alkylene)- O-, (5) -NR ⁵¹¹ -, or (6) -SO _0-2 -,
R ⁵⁰¹ , R ⁵⁰² , R ⁵⁰³ , R ⁵⁰⁴ , R ⁵⁰⁵ , R ⁵⁰⁶ , R ⁵⁰⁷ , R ⁵⁰⁹ , R ⁵¹⁰ , or R ⁵¹¹ each independently represents (1) a hydrogen atom, (2) a C1-6 alkyl group, (3) ) C2-6 acyl group, or (4) C1-6 alkylsulfonyl group,
m represents an integer from 0 to 2,
n represents an integer from 0 to 5,
p represents an integer from 0 to 5. A pharmaceutical composition comprising a compound represented by general formula (I) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier:

During the ceremony,
X ^{1 and} X ^{2 each} independently represent (1) CH, (2) ^CR
R ¹ represents a halogen atom,
^R Represents a haloalkyl group, (7) C2-6 haloalkenyl group, (8) C2-6 haloalkynyl group, (9) C1-6 haloalkoxy group, or (10) cyano group,
R ² is (1) a halogen atom, (2) C1-6 alkyl group, (3) C2-6 alkenyl group, (4) C2-6 alkynyl group, (5) C1-6 alkoxy group, (6) C1-6 Represents a haloalkyl group, (7) C2-6 haloalkenyl group, (8) C2-6 haloalkynyl group, (9) C1-6 haloalkoxy group, or (10) cyano group,
When m is 2 or more, a plurality of R ² may be the same or different,
R ³ is (1) a hydrogen atom, (2) C1-6 alkyl group, (3) C1-6 haloalkyl group, (4) 3- to 10-membered cyclic group, (5) -(C1-6 alkylene) -(3- to 10-membered cyclic group), (6) -(C1-6 haloalkylene)-(3- to 10-membered cyclic group), where C1-6 alkyl group, C1-6 halo 1 to 2 carbon atoms in alkyl groups, C1-6 alkylene and C1-6 haloalkylene may be replaced by oxygen atoms or optionally oxidized sulfur atoms,
The 3- to 10-membered cyclic group of R ³ may be substituted with 1 to 5 R ³⁰¹ ,
R ³⁰¹ is (1) a halogen atom, (2) C1-4 alkyl group, (3) C1-4 alkoxy group, (4) C1-4 haloalkyl group, (5) C1-4 haloalkoxy group, (6) COOR ³⁰² , (7) CONR ³⁰³ R ³⁰⁴ , (8) C3-6 cycloalkyl group, (9) hydroxyl group, (10) nitro group, (11) cyano group, (12) -NR ³⁰⁵ R ³⁰⁶ , (13) - SR ³⁰⁷ , (14) -SOR ³⁰⁸ , (15) -SO ₂ R ³⁰⁹ , or (16) represents an oxo group,
When two or more R ³⁰¹ are substituted, the plurality of R ³⁰¹ may be the same or different,
R ³⁰² , R ³⁰³ , R ³⁰⁴ , R ³⁰⁵ , R ³⁰⁶ , R ³⁰⁷ , R ³⁰⁸ , or R ³⁰⁹ each independently represents (1) a hydrogen atom or (2) a C1-4 alkyl group,
When R ² represents ( ² ) to (9) in R 2 and R ³ represents a C1-6 alkyl group, R ² and R ³ together with the atoms to which R ² and R ³ are bonded represent 5- to Can form a 6-membered cyclic group,
R ⁴ is (1) a halogen atom, (2) C1-6 alkyl group, (3) C2-6 alkenyl group, (4) C2-6 alkynyl group, (5) C1-6 alkoxy group, (6) C1-6 Represents a haloalkyl group, (7) C2-6 haloalkenyl group, (8) C2-6 haloalkynyl group, or (9) C1-6 haloalkoxy group,
When n is 2 or more, a plurality of R ⁴ may be the same or different,
When two R ⁴ existing on the same carbon atom represent a C1-6 alkyl group, the two R ⁴ may form a C3-6 cycloalkyl group together with the carbon atom to which the two R ⁴ are bonded,
ring 1 represents a 3- to 15-membered cyclic group,
R ⁵ is (1) a halogen atom, (2) C1-6 alkyl group, (3) C2-6 alkenyl group, (4) C2-6 alkynyl group, (5) C1-6 alkoxy group, (6) C1-6 Alkylthio group, (7) C1-6 alkylsulfinyl group, (8) C1-6 alkylsulfonyl group, (9) C2-6 acyl group, (10) 3- to 6-membered cyclic group, (11) - L ^R5 -(3- to 6-membered cyclic group), (12) hydroxyl group, (13) nitro group, (14) cyano group, (15) oxo group, (16) -NR ⁵⁰¹ R ⁵⁰² , ( 17) -COOR ⁵⁰³ , (18) -CONR ⁵⁰⁴ R ⁵⁰⁵ , or (19) -SO ₂ NR ⁵⁰⁶ R ⁵⁰⁷ ,
When p is 2 or more, a plurality of R ⁵ may be the same or different,
Groups (2) to (11) of R ⁵ may be substituted with 1 to 9 R ⁵⁰⁸ ,
R ⁵⁰⁸ is (1) a halogen atom, (2) C1-4 alkyl group, (3) C1-4 alkoxy group, (4) C2-6 acyl group, (5) C3-6 cycloalkyl group, (6) hydroxyl group , or (7) -NR ⁵⁰⁹ R ⁵¹⁰ ,
When two or more R ⁵⁰⁸ are substituted, the plurality of R ⁵⁰⁸ may be the same or different,
L ^R5 is (1) -O-, (2) -(C1-4 alkylene)-, (3) -O-(C1-4 alkylene)-, (4) -(C1-4 alkylene)- O-, (5) -NR ⁵¹¹ -, or (6) -SO _0-2 -,
R ⁵⁰¹ , R ⁵⁰² , R ⁵⁰³ , R ⁵⁰⁴ , R ⁵⁰⁵ , R ⁵⁰⁶ , R ⁵⁰⁷ , R ⁵⁰⁹ , R ⁵¹⁰ , or R ⁵¹¹ each independently represents (1) a hydrogen atom, (2) a C1-6 alkyl group, (3) ) C2-6 acyl group, or (4) C1-6 alkylsulfonyl group,
m represents an integer from 0 to 2,
n represents an integer from 0 to 5,
p represents an integer from 0 to 5. The pharmaceutical composition according to claim 1, wherein ring 1 represents a ring structure selected from the group consisting of the following ring structures;

In the formula, * indicates the bonding position with the carbonyl group, and the hydrogen atom represented by NH can be replaced with R ^5-A . The pharmaceutical composition according to claim 2, wherein ring 1 represents a ring structure selected from the group consisting of the following ring structures;

In the formula, * indicates the bonding position with the carbonyl group, and the hydrogen atom represented by NH may be replaced with R ⁵ . The method according to claim 1 or 3, wherein R ^5-A is (1) C1-6 alkyl group, (2) C1-6 alkoxy group, (3) C1-6 haloalkyl group, (4) C1-6 haloalkoxy group. , (5) cyclopropyl group, (6) furan ring, (7) N-methylpyrazole ring, (8) oxo group, (9) dimethylamino group, or (10) -COOCH ₃ . The method according to claim 2 or 4, wherein R ⁵ is (1) C1-6 alkyl group, (2) C1-6 alkoxy group, (3) C1-6 haloalkyl group, (4) C1-6 haloalkoxy group, ( 5) a cyclopropyl group, (6) a furan ring, (7) an N-methylpyrazole ring, (8) an oxo group, (9) a dimethylamino group, or (10) -COOCH ₃ . The method according to any one of claims 1 to 4, wherein R ³ is (1) a hydrogen atom, (2) a C1-6 alkyl group, (3) a C1-6 haloalkyl group, (4) a cyclopropyl group, or (5) ) -CH ₂ -Q,
A pharmaceutical composition wherein Q is (1) benzene, (2) pyridine, or (3) imidazo[2,1-b]thiazole. The pharmaceutical composition according to any one of claims 1 to 4, wherein both X ¹ and X ² are N. The compound according to any one of claims 1 to 4, wherein the compound represented by general formula (IA) or general formula (I), or a pharmaceutically acceptable salt thereof, is represented by general formula (I-1). A pharmaceutical composition wherein is a compound or a pharmaceutically acceptable salt thereof:

In the formula, R ^3-a represents (1) a hydrogen atom, (2) a C1-6 alkyl group, (3) a C1-6 haloalkyl group, (4) a cyclopropyl group, or (5) -CH ₂ -Q;
ring 1-a represents a ring structure selected from the group consisting of the following ring structures;

In the formula, * indicates the bonding position with the carbonyl group, and the hydrogen atom represented by NH can be replaced by R ^5-a ,
R ^5-a is (1) C1-6 alkyl group, (2) C1-6 alkoxy group, (3) C1-6 haloalkyl group, (4) C1-6 haloalkoxy group, (5) cyclopropyl group, (6) ) represents a furan ring, (7) N-methylpyrazole ring, (8) oxo group, (9) dimethylamino group, or (10) -COOCH ₃ ,
Other symbols have the same meaning as the symbols described in paragraphs 1, 2, or 7. The compound according to claim 1 or 2, wherein the compound represented by formula (IA) or formula (I), or a pharmaceutically acceptable salt thereof, is selected from the group consisting of:
(1) {(3aS,4R,6aR)-4-[(6-chloro-3-pyridazinyl)amino]hexahydrocyclopenta[c]pyrrol-2(1H)-yl}[5-(difluoro Romethyl)-2-thienyl]methanone,
(2) {(3aS,4R,6aR)-4-[(6-chloro-3-pyridazinyl)amino]hexahydrocyclopenta[c]pyrrol-2(1H)-yl}(5-methyl-2 -thienyl)methanone,
(3) [(3aS,4R,6aR)-4-[(6-chloro-3-pyridazinyl)amino]hexahydrocyclopenta[c]pyrrol-2(1H)-yl](6,7-di hydro-4H-thieno[3,2-c]pyran-2-yl)methanone,
(4) [(3aS,4R,6aR)-4-[(6-bromo-3-pyridazinyl)amino]hexahydrocyclopenta[c]pyrrol-2(1H)-yl](5-methyl- 2-thienyl)methanone,
(5) [(3aS,4R,6aR)-4-[(6-bromo-3-pyridazinyl)amino]hexahydrocyclopenta[c]pyrrol-2(1H)-yl](6,7- dihydro-4H-thieno[3,2-c]pyran-2-yl)methanone,
(6) [(3aS,4R,6aR)-4-[(6-bromo-3-pyridazinyl)amino]hexahydrocyclopenta[c]pyrrol-2(1H)-yl](2-methyl- 2H-thieno[3,2-c]pyrazol-5-yl)methanone,
(7) [(3aS,4R,6aR)-4-[benzyl(6-bromo-3-pyridazinyl)amino]hexahydrocyclopenta[c]pyrrol-2(1H)-yl](5-methyl -2-thienyl)methanone,
(8) rel-6-chloro-3-({(3aS,4R,6aR)-2-[(5-methyl-2-thienyl)carbonyl]octahydrocyclopenta[c]pyrrol-4-yl} Amino)-4-pyridazinecarbonitrile,
(9) {(3aR,4R,6aS)-4-[(6-chloro-3-pyridazinyl)amino]-3a-fluorohexahydrocyclopenta[c]pyrrol-2(1H)-yl}( 6,7-dihydro-4H-thieno[3,2-c]pyran-2-yl)methanone, and
(10) [(3aR,6R,6aS)-6-[(6-bromo-3-pyridazinyl)amino]-4,4-difluorohexahydrocyclopenta[c]pyrrole-2(1H) -yl](6,7-dihydro-4H-thieno[3,2-c]pyran-2-yl)methanone, or a pharmaceutically acceptable salt thereof
phosphorus pharmaceutical composition. The pharmaceutical composition according to any one of claims 1 to 4, which is an ABHD6 inhibitor. The pharmaceutical composition according to any one of claims 1 to 4, which is an agent for the treatment and/or prevention of diseases associated with ABHD6. The pharmaceutical composition according to claim 12, wherein the disease associated with ABHD6 is pain, neurological disease, inflammatory disease, autoimmune disease, metabolic disease, or malignant tumor. The method of claim 12, wherein the condition associated with ABHD6 is pain, and the pain is pain associated with osteoarthritis, cancer pain, pain associated with chemotherapy, chronic back pain, back pain associated with osteoporosis, fracture pain, pain associated with rheumatoid arthritis, neuropathic pain. , post-herpetic pain, pain associated with diabetic neuropathy, pain associated with fibromyalgia, pain associated with pancreatitis, pain associated with interstitial cystitis or bladder pain syndrome, pain associated with endometriosis, pain associated with irritable bowel syndrome, migraine, or a pharmaceutical composition for pain associated with pulpitis. The method of claim 12, wherein the disease associated with ABHD6 is a neurological disease, and the neurological disease is tremor, dyskinesia, dystonia, rigidity, pressure and compulsive behavior, depression, anxiety disorder, panic disorder, acute stress disorder, and post-traumatic disorder. Pharmaceutical compositions for stress disorders, obsessive-compulsive disorder, agoraphobia, social phobia, mood disorders, epilepsy, traumatic brain injury, spinal cord injury, multiple sclerosis, encephalomyelitis, Parkinson's disease, Huntington's disease, Alzheimer's disease, and sleep disorders. 12. The method of claim 11, wherein the pharmaceutical composition is from the group consisting of acetaminophen, non-steroidal anti-inflammatory drugs, opioid drugs, antidepressants, antiepileptic drugs, N-methyl-D-aspartate antagonists, muscle relaxants, anti-arrhythmic drugs, steroid drugs and bisphosphonate drugs. A pharmaceutical composition administered in combination with one or more selected substances. An agent for the treatment and/or prevention of diseases associated with ABHD6, comprising a compound according to any one of claims 1 to 4 or a pharmaceutically acceptable salt thereof. Comprising administering a pharmaceutical composition containing the compound according to any one of claims 1 to 4 or a pharmaceutically acceptable salt thereof to a patient in need of prevention and/or treatment of a disease associated with ABHD6, Methods for preventing and/or treating diseases associated with ABHD6. A pharmaceutical composition comprising the compound according to any one of claims 1 to 4 or a pharmaceutically acceptable salt thereof, wherein the pharmaceutical composition is used for the prevention and/or treatment of diseases associated with ABHD6. Use of a compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, for the manufacture of an agent for the prevention and/or treatment of diseases associated with ABHD6.