3-azabicyclo(3.1.0)hexane derivative having KDM5 inhibitory action and pharmaceutical use thereof

Abstract

To provide a compound having KDM5 inhibitory activity for treating or preventing diseases such as cancer, Huntington's disease, and Alzheimer's disease.SOLUTION: Disclosed are compounds represented by formula (I) or salts thereof. (In the formula, R1 is a substituted / unsubstituted C5-C9 aromatic heterocycle, a 5-membered non-aromatic heterocycle, a CO-substituted / unsubstituted C3-C12 monocyclic / bicyclic carbocycle, or the like; R2 to R8 are each H, C1-C4 alkyl, halogen, or C1-C4 alkoxy; and R9 is substituted / unsubstituted imidazole, or substituted / unsubstituted pyrazole.)SELECTED DRAWING: None

Description

Technical Field

[0001] The present invention relates to a compound represented by the following general formula (I) having a KDM5 inhibitory action, a salt thereof, and its pharmaceutical use.

Background Art

[0002] Eukaryotic DNA is in the cell nucleus in the state of chromatin structure, which is a complex with histone proteins. Histone proteins are modified by various enzymes such as methylation, acetylation, and phosphorylation, and it is known that the changes due to this modification induce chromatin remodeling and transcriptional changes. Epigenetic modifications including histone methylation reversibly control gene expression without changing the nucleic acid sequence and play an important role in physiological processes.

[0003] The KDM5 protein belongs to the JARID histone demethylase protein group and demethylates the trimethylation of the fourth lysine residue in the histone H3 protein (H3K4me3). In mammals including humans, there are four subfamilies of KDM5A, KDM5B, KDM5C, and KDM5D, which have five conserved domains, namely JmjN, ARID, JmjC, PHDs, and C5HC2 zinc fingers. The KDM5 family is widely distributed in blood cells and various organs in vivo and is known to be highly expressed particularly in cancer tissues. Epigenetic abnormalities in cancer cells are known to be involved in the proliferation and metastasis of cancer cells, and it has been reported that KDM5 inhibitors are effective against cancer cells. The involvement of epigenetic abnormalities including histone modification has also been reported in other pathological fields such as mental and neurological diseases and metabolic diseases. Therefore, a compound having KDM5 inhibitory activity improves epigenetic pathological abnormalities and is useful for the prevention and treatment of these diseases.

[0004] As a related art of the present invention, International Publication No. 2016057924 reports that a compound of formula (A) is useful as an inhibitor of one or more demethylases such as KDM5. Formula (A): [Chemical formula] (In the formula, A A is selected from the following: [Chemical formula] R 1A is alkyl, a cyclic group, etc.; R 2A is an optionally substituted cyclic group, -OR aA , -C(O)N(R aA ) 2 or NR aA R bA ; R aA and R bA are each independently H, an optionally substituted alkyl group, an optionally substituted cyclic group, etc.; R 3A is H or alkyl; R 4A is H, alkyl, or a cyclic group; and R 5A is H, halogen, or alkyl, and R 6A is H, alkyl, or a cyclic group; or, R 5A and R 6A together form a cyclic group (extract of the group definition).), or a salt thereof.

[0005] Furthermore, in International Publication No. 2000 / 039089, it is reported that a compound represented by the following formula (B) is useful as an opioid receptor ligand. Formula (B) [Chemical formula] (In the formula, Ar B ring represents a phenyl ring which may be benzo-fused or a 5-6 membered heteroaryl ring; R 1B is selected from various substituents; R2B is H or a halogen; R 3B is H, a halogen, an alkyl group, a cyclic group, etc., R 4B is optionally substituted alkyl, alkenyl, or alkynyl, R 5B and R 8B are each independently H or C 1-6 alkyl, R 6B 、R 7B 、R 9 and R 10B are each H when alone, X is a halogen, an alkyl, an alkoxy, etc. (excerpt of the group definition) or a pharmaceutically or veterinarily acceptable derivative or prodrug thereof.

[0006] Furthermore, in International Publication No. 2021010492, it is reported that the compound of formula (C) is useful as a KDM5 inhibitor. Formula (C):

Chemical formula

Prior Art Documents

Patent Documents

[0007]

Patent Document 1

Patent Document 2

Patent Document 3

Summary of the Invention

Problems to be Solved by the Invention

[0008] For example, compounds having KDM5 inhibitory activity for the treatment or prevention of diseases such as cancer, Huntington's disease, Alzheimer's disease, etc. are desired.

Means for Solving the Problems

[0009] As a result of intensive studies to solve the above problems, the inventors of the present invention have found that the above object can be achieved by a compound represented by the following general formula (I) or a salt thereof. The inventors have conducted further research and completed the present invention.

[0010] That is, the present invention relates to the following: [1] General formula (I):

Chemical Formula

Chemical Formula

Chemical formula

[10] R 1 is -CONR 10 R 11The compound or a salt thereof according to [1] above, which represents;

[11] R 10 The compound or a salt thereof according to the preceding [1] or

[10] , wherein R represents isopropyl, tert-butyl, 1,1,1-trifluoro-2-methylpropan-2-yl, 1-methylcyclopropyl, 1-(trifluoromethyl)cyclopropyl or 1-cyanocyclopropyl; [11-1] When the compound represented by the general formula (I) is the general formula (I-02) [Chemical formula] (wherein R 10-1 represents isopropyl, tert-butyl, 1,1,1-trifluoro-2-methylpropan-2-yl, 1-methylcyclopropyl, 1-(trifluoromethyl)cyclopropyl, or 1-cyanocyclopropyl, and the other symbols have the same meanings as in [1] above), the compound or a salt thereof according to

[11] above;

[12] R 9 represents imidazole which may be substituted with 1 to 3 R 14 , the compound or a salt thereof according to the preceding

[10] ,

[11] or [11-1];

[13] When the compound represented by the general formula (I) is the general formula (I-3) [Chemical formula] (wherein R 10-1 represents isopropyl, tert-butyl, 1,1,1-trifluoro-2-methylpropan-2-yl, 1-methylcyclopropyl, 1-(trifluoromethyl)cyclopropyl, or 1-cyanocyclopropyl, and the other symbols have the same meanings as in [1] or [5] above), the compound or a salt thereof according to any one of the preceding [1],

[10] to

[12] and [11-1];

[14] The compound is (1)(1R,5S,6r)-N-tert-butyl-6-methyl-3-[1-(propan-2-yl)-1H-imidazole-4-carbonyl]-3-azabicyclo[3.1.0]hexane-6-carboxamide; (2)(1R,5S,6r)-N-tert-butyl-3-[1-(propan-2-yl)-1H-imidazole-4-carbonyl]-3-azabicyclo[3.1.0]hexane-6-carboxamide; (3)(1R,5S,6r)-N-(propan-2-yl)-3-[1-(propan-2-yl)-1H-imidazole-4-carbonyl]-3-azabicyclo[3.1.0]hexane-6-carboxamide, or (4)(1R,5S,6r)-N-(1-cyanocyclopropyl)-3-[1-(propan-2-yl)-1H-imidazole-4-carbonyl]-3-azabicyclo[3.1.0]hexane-6-carboxamide, the compound or a salt thereof according to any one of [1],

[10] to

[13] and [11-1];

[15] R 9 wherein R is from 1 to 3 R 15 which represents pyrazole which may be substituted with, the compound or a salt thereof according to

[10] ,

[11] and [11-1];

[16] The compound represented by the general formula (I) is the general formula (I-4)

Chemical formula

[13] ), the compound or a salt thereof according to any one of [1],

[10] ,

[11] , [11-1] and

[15] ;

[17] The compound is (1)(1R,5S,6r)-N-(propan-2-yl)-3-[5-(propan-2-yl)-1H-pyrazole-3-carbonyl]-3-azabicyclo[3.1.0]hexane-6-carboxamide; (2)(1R,5S,6r)-N-tert-butyl-6-methyl-3-[5-(propan-2-yl)-1H-pyrazole-3-carbonyl]-3-azabicyclo[3.1.0]hexane-6-carboxamide; (3) (1R,5S,6r)-N-tert-butyl-N-methyl-3-[5-(propan-2-yl)-1H-pyrazole-3-carbonyl]-3-azabicyclo[3.1.0]hexane-6-carboxamide, or (4) The compound or a salt thereof according to any one of the above [1],

[10] ,

[11] , [11-1],

[15] and

[16] , which is (1R,5S,6r)-N-methyl-N-(1-methylcyclopropyl)-3-[5-(propan-2-yl)-1H-pyrazole-3-carbonyl]-3-azabicyclo[3.1.0]hexane-6-carboxamide;

[18] A pharmaceutical composition comprising the compound represented by the general formula (I) according to the above [1] or a salt thereof, and a pharmaceutically acceptable carrier;

[19] The pharmaceutical composition according to the above

[18] , which is a KDM5 inhibitor;

[20] The pharmaceutical composition according to the above

[18] or

[19] , which is a prophylactic and / or therapeutic agent for KDM5-related diseases; [21-1] The pharmaceutical composition according to the above

[20] , wherein the KDM5-related disease is hyperproliferative disease, cancer, stroke, diabetes, hepatomegaly, cardiovascular disease, multiple sclerosis, Huntington's disease, Alzheimer's disease, cystic fibrosis, viral disease, autoimmune disease, atherosclerosis, restenosis, psoriasis, rheumatoid arthritis, inflammatory bowel disease, asthma, allergic disease, inflammation, neuropathy, hormone-related disease, symptoms associated with organ transplantation, immunodeficiency disease, destructive bone disorder, proliferative disease, infectious disease, symptoms associated with cell death, thrombin-induced platelet aggregation, liver disease, pathological immune state associated with T cell activity, central nervous system disorder, myeloproliferative disease, Parkinson's disease, Lewy body disease, frontotemporal lobar degeneration, mild cognitive impairment, dementia, cerebrovascular disease, schizophrenia, depression, anxiety disorder, bipolar disorder, autism spectrum disorder, attention deficit / hyperactivity disorder, learning disorder, movement disorder, obsessive-compulsive disorder, personality disorder, sleep disorder, delirium, amyotrophic lateral sclerosis, developmental disorder, intellectual disability, post-traumatic stress disorder, or hepatitis; [21-2] The pharmaceutical composition according to the above

[20] , wherein the KDM5-related disease is cancer or Alzheimer's disease;

[22] A prophylactic and / or therapeutic agent for KDM5-related diseases containing, as an active ingredient, the compound represented by the general formula (I) described in [1] above or a salt thereof, wherein the prophylactic and / or therapeutic agent is co-administered with at least one agent selected from the group consisting of donepezil hydrochloride, galantamine hydrobromide, fupirtine A, idebenone, levacecarnine hydrochloride, memantine hydrochloride, memantine hydrochloride / donepezil hydrochloride, a peptide decomposition peptide fraction derived from porcine brain protein, rivastigmine tartrate, tacrine hydrochloride, and aducanumab;

[23] A method for preventing and / or treating KDM5-related diseases, comprising administering an effective amount of the compound represented by the general formula (I) described in [1] above or a salt thereof to a mammal (preferably a patient in need of treatment);

[24] The compound represented by the general formula (I) described in [1] above or a salt thereof, which is used for the prevention and / or treatment of KDM5-related diseases; and

[25] Use of the compound represented by the general formula (I) described in [1] above or a salt thereof for the manufacture of a prophylactic and / or therapeutic agent for KDM5-related diseases. [Effects of the Invention]

[0011] The compound represented by the general formula (I) described in this specification, or a salt thereof (hereinafter collectively referred to as the present compound), has KDM5 inhibitory activity. Therefore, the present compound can be used as a prophylactic and / or therapeutic agent for diseases such as hyperproliferative diseases, cancer, stroke, diabetes, hepatomegaly, cardiovascular diseases, multiple sclerosis, Huntington's disease, Alzheimer's disease, cystic fibrosis, viral diseases, autoimmune diseases, atherosclerosis, restenosis, psoriasis, rheumatoid arthritis, inflammatory bowel disease, asthma, allergic diseases, inflammation, neuropathy, hormone-related diseases, symptoms associated with organ transplantation, immunodeficiency diseases, destructive bone disorders, proliferative diseases, infectious diseases, symptoms associated with cell death, thrombin-induced platelet aggregation, liver diseases, pathological immune states associated with T cell activity, central nervous system disorders, myeloproliferative diseases, Parkinson's disease, Lewy body disease, frontotemporal lobar degeneration, mild cognitive impairment, dementia, cerebrovascular diseases, schizophrenia, depression, anxiety disorders, bipolar disorder, autism spectrum disorder, attention deficit / hyperactivity disorder, learning disorders, movement disorders, obsessive-compulsive disorder, personality disorders, sleep disorders, delirium, amyotrophic lateral sclerosis, developmental disorders, intellectual disabilities, post-traumatic stress disorder, hepatitis, etc.

Mode for Carrying Out the Invention

[0012] In this specification, examples of halogen include fluorine, chlorine, bromine, and iodine atoms.

[0013] In this specification, C1-4 alkyl includes methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, and isobutyl groups.

[0014] In this specification, "1 to 9 deuterated C1-4 alkyl" means CH 2 D-, CHD 2 -, CD 3 -, CD 3 CD 2 -, CD 3 CD 2 CD 2 -, (CD 3 ) 2 CD-, CD 3 CD 2 CD 2 CD 2 -, CD3 CD 2 CD (CD 3 )-, (CD 3 ) 3 C-, (CD 3 ) 2 CDCD 2 - etc. are included (D means deuterium).

[0015] In this specification, "C1-8 alkyl" includes methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, isobutyl, pentyl, 1,2-dimethylpropyl, 1-ethylpropyl, hexyl, 1,3-dimethylbutyl, heptyl, and octyl groups.

[0016] In this specification, "C1-4 alkoxy" includes methoxy, ethoxy, propoxy, isopropoxy, butoxy, sec-butoxy, tert-butoxy, and isobutoxy groups.

[0017] In this specification, "C1-4 haloalkyl" includes fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, 2,2,2-trifluoroethyl, perfluoroethyl, perfluoropropyl, perfluoro(isopropyl), perfluorobutyl, perfluoro(sec-butyl), perfluoro(tert-butyl), and perfluoro(isobutyl) groups, etc.

[0018] In this specification, "C1-8 haloalkyl" includes fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, 2,2,2-trifluoroethyl, perfluoroethyl, perfluoropropyl, perfluoro(isopropyl), perfluorobutyl, perfluoro(sec-butyl), perfluoro(tert-butyl), perfluoro(isobutyl), perfluoropentyl, perfluorohexyl, perfluoroheptyl, and perfluorooctyl groups, etc.

[0019] As used herein, "C3-5 cycloalkyl" includes, for example, cyclopropyl, cyclobutyl, and cyclopentyl groups.

[0020] As used herein, "C3-5 cycloalkane" includes, for example, cyclopropane, cyclobutane, and cyclopentane rings.

[0021] As used herein, "C3-5 cycloalkane in which one or two carbon atoms of the C3-5 cycloalkane may be replaced by a heteroatom selected from N, O, and S" includes, for example, cyclopropane, cyclobutane, cyclopentane, aziridine, oxirane, thiirane, azetidine, oxetane, thietane, pyrrolidine, tetrahydrofuran, tetrahydrothiophene, pyrazolidine, isoxazolidine, isothiazolidine, imidazolidine, oxazolidine, thiazolidine, and 1,3-dioxolane rings, etc.

[0022] As used herein, "C3-7 cycloalkyl" includes, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, bicyclo[1.1.0]butyl, bicyclo[2.1.0]pentyl, bicyclo[1.1.1]pentyl, bicyclo[3.1.0]hexyl, bicyclo[2.2.0]hexyl, bicyclo[2.1.1]hexyl, bicyclo[4.1.0]heptyl, bicyclo[3.2.0]heptyl, bicyclo[2.2.1]heptyl, and bicyclo[3.1.1]heptyl groups, etc.

[0023] In this specification, examples of the "5- to 9-membered aromatic heterocycle" include the "5- to 9-membered aromatic heterocycle containing 1 to 4 nitrogen atoms, 1 oxygen atom and / or 1 sulfur atom", etc. Examples of the "5- to 9-membered aromatic heterocycle containing 1 to 4 nitrogen atoms, 1 oxygen atom and / or 1 sulfur atom" include 1,2,5-oxadiazole, 1,2,5-thiadiazole, 1,2,4-oxadiazole, 1,2,4-thiadiazole, isothiazole, 1,3,4-thiadiazole, benzo[d]isothiazole, isoxazole, 1,3,4-oxadiazole, 1,2,4-triazole, tetrazole, benzo[d]isoxazole, [1,2,3]triazolo[1,5-a]pyridine, or [1,2,4]triazolo[4,3-a]pyridine ring, etc.

[0024] In this specification, examples of the "5-membered non-aromatic heterocycle" include a "5-membered non-aromatic heterocycle containing 1 to 4 nitrogen atoms, 1 oxygen atom and / or 1 sulfur atom", etc. Examples of the "5-membered non-aromatic heterocycle containing 1 to 4 nitrogen atoms, 1 oxygen atom and / or 1 sulfur atom" include 2,3-dihydro-1,2,3-oxadiazole, 2,3-dihydro-1,2,3-thiadiazole, 2,3-dihydro-1,2,4-oxadiazole, 2,3-dihydro-1,2,4-thiadiazole, 2,3-dihydro-1,2,5-oxadiazole, 2,3-dihydro-1,2,5-thiadiazole, 2,3-dihydro-1,3,4-oxadiazole, 2,3-dihydro-1,3,4-thiadiazole, 2,3-dihydro-1,3,4-oxadiazole, 2,3-dihydro-1H-1,2,3-triazole, 2,3-dihydro-1H-1,2,4-triazole, 2,3-dihydro-1H-imidazole, 2,3-dihydro-1H-pyrazole, 2,3-dihydro-1H-pyrrole, 2,3-dihydro-1H-tetrazole, 2,3-dihydrofuran, 2,3-dihydroisothiazole, 2,3-dihydroisoxazole, 2,3-dihydrooxazole, 2,3-dihydrothiazole, 2,3-dihydrothiophene, 4,5-dihydro-1,2,3-oxadiazole, 4,5-dihydro-1,2,3-thiadiazole, 4,5-dihydro-1,2,4-thiadiazole, 4,5-dihydro-1H-1,2,3-triazole, 4,5-dihydro-1H-1,2,4-triazole, 4,5-dihydro-1H-imidazole, 4,5-dihydro-1H-pyrazole, 4,5-dihydro-1H-tetrazole, 4,5-dihydroisothiazole, 4,5-dihydroisoxazole, 4,5-dihydrooxazole ring, and 4,5-dihydrothiazole ring, etc.

[0025] In this specification, examples of the "C3-12 monocyclic or bicyclic carbocyclic ring" include cyclopropane, cyclobutane, cyclopentane, cyclohexane, cyclopentene, cyclohexene, cyclopentadiene, cyclohexadiene, benzene, indene, dihydroindene, naphthalene, dihydronaphthalene, and tetrahydronaphthalene ring, etc.

[0026] In this specification, examples of "a 5- to 9-membered monocyclic or bicyclic heterocyclic ring" include "a 5- to 9-membered monocyclic or bicyclic heterocyclic ring containing 1 to 4 nitrogen atoms, 1 to 2 oxygen atoms, and / or 1 sulfur atom".Examples of "a 5- to 9-membered monocyclic or bicyclic heterocyclic ring containing 1 to 4 nitrogen atoms, 1 to 2 oxygen atoms, and / or 1 sulfur atom" include pyrrole, imidazole, triazole, tetrazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, furan, pyran, thiophene, thiopyran, oxazole, isoxazole, thiazole, isothiazole, furazan, oxadiazole, oxazine, oxadiazine, thiadiazole, thiazine, thiadiazine, pyrroline, pyrrolidine, imidazoline, imidazolidine, triazoline, triazolidine, tetrazoline, tetrazolidine, pyrazoline, pyrazolidine, dihydropyridine, tetrahydropyridine, piperidine, dihydropyrazine, tetrahydropyrazine, piperazine, dihydropyrimidine, tetrahydropyrimidine, perhydropyrimidine, dihydropyridazine, tetrahydropyridazine, perhydropyridazine, dihydrofuran, tetrahydrofuran, dihydropyran, tetrahydropyran, dihydrothiophene, tetrahydrothiophene, dihydrothiopyran, tetrahydrothiopyran, dihydrooxazole, tetrahydrooxazole (oxazolidine), dihydroisoxazole, tetrahydroisoxazole (isoxazolidine), dihydrothiazole, tetrahydrothiazole (thiazolidine), dihydroisothiazole, tetrahydroisothiazole (isothiazolidine), dihydrofurazan, tetrahydrofurazan, dihydrooxadiazole, tetrahydrooxadiazole (oxadiazolidine), dihydrooxazine, tetrahydrooxazine, dihydrooxadiazine, tetrahydrooxadiazine, dihydrothiadiazole, tetrahydrothiadiazole (thiadiazolidine), dihydrothiazine, tetrahydrothiazine, dihydrothiadiazine, tetrahydrothiadiazine, morpholine, thiomorpholine, oxathiane, dioxolane, dioxane, dioxole, indole, benzimidazole, benzotriazole, indazole, benzofuran, benzothiophene, benzoxazole, indoline, dihydrobenzimidazole, dihydrobenzotriazole, dihydroindazole, dihydrobenzofuran, dihydrobenzothiophene, and dihydrobenzoxazole rings, etc.

[0027] In the present invention, unless otherwise specified, the following symbols:

Chem.

Chem.

Chem.

[0028] In the present invention, R 1 is preferably, for example, Cyc1, or -CONR 10 R 11 and more preferably, for example, Cyc1, and particularly preferably, for example, a 5-membered non-aromatic heterocyclic ring.

[0029] In the present invention, Cyc1 is preferably, for example, a 5-membered non-aromatic heterocyclic ring which may be substituted with, for example, 1 to 5 R 12 and more preferably, for example, 2,3-dihydro-1,2,5-oxadiazole, 2,3-dihydro-1,2,5-thiadiazole, 4,5-dihydro-1,2,3-oxadiazole, 4,5-dihydro-1,2,3-thiadiazole, 4,5-dihydro-1,2,4-oxadiazole, 4,5-dihydro-1,2,4-thiadiazole, 4,5-dihydro-1H-1,2,3-triazole, 4,5-dihydroisothiazole, or 4,5-dihydroisoxazole, each of which may be substituted with, for example, 1 to 5 R 12 and particularly preferably, for example, each of which may be substituted with 1 to 5 R 12It may be replaced with 4,5-dihydro-1,2,4-oxadiazole or 4,5-dihydroisoxazole, and particularly preferably, 1 to 5 Rs 12 It is 4,5-dihydroisoxazole which may be substituted with 12 .

[0030] In the present invention, Cyc1 is similarly preferably, for example, a 5- to 9-membered aromatic heterocyclic ring which may be substituted with 1 to 5 Rs 12 and more preferably, for example, 1,2,5-oxadiazole, 1,2,5-thiadiazole, 1,2,4-oxadiazole, 1,2,4-thiadiazole, isothiazole, 1,3,4-thiadiazole, benzo[d]isothiazole, isoxazole, 1,3,4-oxadiazole, 1,2,4-triazole, tetrazole, benzo[d]isoxazole, [1,2,3]triazolo[1,5-a]pyridine, or [1,2,4]triazolo[4,3-a]pyridine, each of which may be substituted with 1 to 5 Rs 12 and particularly preferably, for example, isoxazole, 1,3,4-oxadiazole, 1,2,4-triazole, tetrazole, benzo[d]isoxazole, [1,2,3]triazolo[1,5-a]pyridine, or [1,2,4]triazolo[4,3-a]pyridine, each of which may be substituted with 1 to 5 Rs 12 In the present invention, R

[0031] is preferably, for example, (1) C1-4 alkyl, (2) C3-7 cycloalkyl, (3) C1-4 haloalkyl, (4) C1-4 alkoxy, (5) phenyl which may be substituted with 1 to 3 Rs 12 (6) C1-4 alkyl which may be substituted with phenyl, (7) dimethylamino, (8) pyridyl, or (9) 1-(cyclopropylmethyl)pyrazol-3-yl, or (10) 2 Rs 17 wherein these Rs 12 are these Rs 12It may be a group that forms a C3-5 cycloalkane together with the atom to which it is bonded. More preferably, for example, (1) C1-4 alkyl, (2) C3-7 cycloalkyl, (3) phenyl optionally substituted with 1 to 3 R 17 or (4) 2 R 12 where these R 12 is a group that may form a C3-5 cycloalkane together with the atom to which it is bonded. Particularly preferably, for example, C1-4 alkyl, or 2 R 12 where these R 12 is a group that may form a C3-5 cycloalkane together with the atom to which it is bonded.

[0032] In the present invention, R 17 is preferably, for example, C1-4 alkyl or C1-4 alkoxy. In the present invention, Cyc2 is preferably, for example, cyclopropane, cyclobutane, cyclopentane, cyclohexane, cyclopentene, cyclohexene, cyclopentadiene, cyclohexadiene, benzene, pyrrole, imidazole, triazole, tetrazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, furan, pyran, thiophene, thiopyran, oxazole, isoxazole, thiazole, isothiazole, furazan, oxadiazole, oxazine, oxadiazine, thiadiazole, thiazine, thiadiazine, indole, benzimidazole, benzotriazole, indazole, benzofuran, benzothiophene, benzoxazole, indoline, dihydrobenzimidazole, dihydrobenzotriazole, dihydroindazole, dihydrobenzofuran, dihydrobenzothiophene, or dihydrobenzoxazole, each optionally substituted with 1 to 5 R 13 and more preferably, for example, cyclopropane, benzene, pyridine, thiophene, thiazole, or indole, each optionally substituted with 1 to 5 R 13

[0033] In the present invention, R 10is preferably, for example, isopropyl, tert-butyl, 1,1,1-trifluoro-2-methylpropan-2-yl, 1-methylcyclopropyl, 1-(trifluoromethyl)cyclopropyl, or 1-cyanocyclopropyl.

[0034] In the present invention, R 13 is preferably, for example, C1-4 alkyl, or C1-4 alkoxy. In the present invention, R 11 is preferably, for example, a hydrogen atom, or C1-4 alkyl. In the present invention, R 2 is preferably, for example, a hydrogen atom, or C1-4 alkyl. In the present invention, R 3 is preferably, for example, a hydrogen atom, or C1-4 alkyl. In the present invention, R 4 is preferably, for example, a hydrogen atom, or C1-4 alkyl. In the present invention, R 5 is preferably, for example, a hydrogen atom, or C1-4 alkyl. In the present invention, R 6 is preferably, for example, a hydrogen atom, or C1-4 alkyl. In the present invention, R 7 is preferably, for example, a hydrogen atom, or C1-4 alkyl. In the present invention, R 8 is preferably, for example, a hydrogen atom, or C1-4 alkyl. In the present invention, R 9 is preferably, for example, imidazole which may be substituted with 1 to 3 R 14 groups. In the present invention, R 9 is likewise preferably, for example, pyrazole which may be substituted with 1 to 3 R 15 groups.

[0035] In the present invention, R 14is preferably, for example, (1) C1-8 alkyl, (2) C3-7 cycloalkyl optionally substituted with C1-4 alkyl, (3) C1-8 alkyl substituted with Cyc3 which may be substituted with 1 to 3 R 16 or (4) C1-8 alkyl substituted with phenoxy, and more preferably, for example, (1) C1-8 alkyl, or (2) C3-7 cycloalkyl optionally substituted with C1-4 alkyl.

[0036] In the present invention, Cyc3 is preferably, for example, phenyl or C3-7 cycloalkyl. In the present invention, R 16 is preferably, for example, C1-4 alkyl or cyano.

[0037] In the present invention, R 15 is preferably, for example, (1) C1-8 alkyl, (2) C3-7 cycloalkyl optionally substituted with C1-4 alkyl, (3) C1-8 alkyl substituted with Cyc3 which may be substituted with 1 to 3 R 21 and more preferably, for example, (1) C1-8 alkyl, or (2) C3-7 cycloalkyl optionally substituted with C1-4 alkyl.

[0038] In the present invention, Cyc4 is preferably, for example, phenyl or C3-7 cycloalkyl. In the present invention, R 21 is preferably, for example, C1-4 alkyl or cyano.

[0039] In the present invention, examples of the general formula (I) preferably include the general formula (I-1A):

Chemical formula

[0040] In the present invention, examples of the general formula (I) preferably include the general formula (I-1): [Chemical formula] (wherein all symbols have the same meanings as defined above),

[0041] General formula (I-1A-1): [Chemical formula] (wherein R 2 represents a hydrogen atom or C1-4 alkyl; R 14 represents (1) C1-8 alkyl, (2) C3-7 cycloalkyl optionally substituted with C1-4 alkyl, or (5) C1-8 alkyl substituted with phenoxy; R 12-1 and R 12-2 each represent C1-4 alkyl; and, R 12-1 and R 12-2 are such that together with the atom to which R 12-1 and R 12-2 are attached, may form a C3-5 cycloalkane),

[0042] General formula (I-2): [Chemical formula] (wherein all symbols have the same meanings as defined above),

[0043] General formula (I-2-1): [Chemical formula] (wherein R 2 represents a hydrogen atom, C1-4 alkyl, halogen, or C1-4 alkoxy; R 15 represents (1) C1-8 alkyl, or (3) C1-8 haloalkyl; R 12-1 and R 12-2 each independently represent C1-4 alkyl; and, R 12-1 and R12-2 is, together with the atom to which R 12-1 and R 12-2 are bonded, may form a C3-5 cycloalkane);

[0044] General formula (I-3A):

Chemical formula

[0045] General formula (I-3):

Chemical formula

[0046] General formula (I-4):

Chemical formula

[0047] General formula (I-5):

Chemical formula

[0048] General formula (I-6):

Chemical formula

[0049] General formula (I-7):

Chem.

[0050] General formula (I-7-1):

Chem.

[0051] General formula (I-8): [Chemical formula] (wherein all symbols have the same meanings as described above),

[0052] General formula (I-8-1): [Chemical formula] (wherein R 15 represents (1) C1-8 alkyl, or (3) C1-8 haloalkyl; R 12H1 represents (2) C1-4 alkyl, (3) C3-7 cycloalkyl, (4) C1-4 haloalkyl, (5) C1-4 alkoxy, (6) phenyl optionally substituted with 1 to 3 R 17 , (7) C1-4 alkyl substituted with phenyl, (8) dimethylamino, (9) pyridyl, or (10) 1-(cyclopropylmethyl)pyrazol-3-yl (preferably, R 12H1 represents (2) C1-4 alkyl, (3) C3-7 cycloalkyl, (4) C1-4 haloalkyl, (6) phenyl optionally substituted with 1 to 3 R 17 , (7) C1-4 alkyl substituted with phenyl, (9) pyridyl, or (10) 1-(cyclopropylmethyl)pyrazol-3-yl); R 12H2 represents (1) a hydrogen atom, (2) C1-4 alkyl, (3) C3-7 cycloalkyl, (4) C1-4 haloalkyl, (5) C1-4 alkoxy, (6) phenyl optionally substituted with 1 to 3 R 17 , (7) C1-4 alkyl substituted with phenyl, (8) dimethylamino, (9) pyridyl, or (10) 1-(cyclopropylmethyl)pyrazol-3-yl (preferably, R 12H2represents (1) a hydrogen atom, (2) C1-4 alkyl, (4) C1-4 haloalkyl, (7) C1-4 alkyl substituted with phenyl, (8) dimethylamino); and R 17 represents C1-4 alkyl, C1-4 alkoxy, or halogen),

[0053] General formula (I-9): [Chemical formula] (wherein all symbols represent the same meaning as described above),

[0054] General formula (I-10): [Chemical formula] (wherein all symbols represent the same meaning as described above),

[0055] General formula (I-11): [Chemical formula] (wherein all symbols represent the same meaning as described above),

[0056] General formula (I-11-1): [Chemical formula] (wherein R 14 represents (1) C1-8 alkyl, or (3) C1-8 haloalkyl; R 12H1 represents (2) C1-4 alkyl, (3) C3-7 cycloalkyl, (4) C1-4 haloalkyl, (5) C1-4 alkoxy, (6) phenyl optionally substituted with 1 to 3 R 17 represents phenyl optionally substituted with (7) phenyl, (8) dimethylamino, (9) pyridyl, or (10) 1-(cyclopropylmethyl)pyrazol-3-yl (preferably, R 12H1 represents (2) C1-4 alkyl, (3) C3-7 cycloalkyl, (4) C1-4 haloalkyl, (6) 1 to 3 R 17phenyl which may be substituted, C1-4 alkyl substituted with (7) phenyl, (9) pyridyl, or (10) 1-(cyclopropylmethyl)pyrazol-3-yl); R 12H2 is (1) a hydrogen atom, (2) C1-4 alkyl, (3) C3-7 cycloalkyl, (4) C1-4 haloalkyl, (5) C1-4 alkoxy, (6) phenyl optionally substituted with 1 to 3 R 17 phenyl which may be substituted, (7) C1-4 alkyl optionally substituted with phenyl, (8) dimethylamino, (9) pyridyl, or (10) 1-(cyclopropylmethyl)pyrazol-3-yl (preferably, R 12H2 is (1) a hydrogen atom, (2) C1-4 alkyl, (4) C1-4 haloalkyl, (7) C1-4 alkyl substituted with phenyl, (8) dimethylamino); and R 17 is C1-4 alkyl, C1-4 alkoxy, or halogen),

[0057] General formula (I-12):

Chemical formula

Chemical formula

[0058] General formula (I-13):

Chemical formula

[0059] General formula (I-13-1):

Chemical formula

[0060] General formula (I-14): [Chemical formula] (wherein all symbols represent the same meaning as above),

[0061] General formula (I-14-1): [Chemical formula] In the formula, R 15 represents (1) C1-8 alkyl, or (3) C1-8 haloalkyl; R 12H represents (1) a hydrogen atom, (2) C1-4 alkyl, (3) C3-7 cycloalkyl, (4) C1-4 haloalkyl, (5) C1-4 alkoxy, (6) phenyl which may be substituted with 1 to 3 R 17 phenyl which may be substituted with, (7) C1-4 alkyl substituted with phenyl, (8) dimethylamino, (9) pyridyl, or (10) 1-(cyclopropylmethyl)pyrazol-3-yl (preferably, R 12H represents (1) a hydrogen atom, (2) C1-4 alkyl, (4) C1-4 haloalkyl); and R 17 represents C1-4 alkyl, C1-4 alkoxy, or halogen),

[0062] General formula (I-15): [Chemical formula] (In the formula, n represents an integer from 0 to 4, and other symbols represent the same meanings as above),

[0063] General formula (I-15-1):

Chemical formula

[0064] General formula (I-16):

Chemical formula

[0065] General formula (I-16-1):

Chemical formula

[0066] General formula (I-17):

Chemical formula

Chemical formula

[0067] General formula (I-18):

Chemical formula

[0068] General formula (I-18-1): [Chemical formula] (wherein, R 15 is (1) C1-8 alkyl, or (3) C1-8 haloalkyl; R 12 is (1) C1-4 alkyl, (2) C3-7 cycloalkyl, (3) C1-4 haloalkyl, (4) C1-4 alkoxy, (5) phenyl optionally substituted with one to three R 17 , (6) C1-4 alkyl substituted with phenyl, (7) dimethylamino, (8) pyridyl, or (9) 1-(cyclopropylmethyl)pyrazol-3-yl (preferably, R 12 is (1) C1-4 alkyl, (2) C3-7 cycloalkyl, (3) C1-4 haloalkyl, (4) C1-4 alkoxy; n represents an integer from 0 to 4, preferably, n is 1; and R 17 represents C1-4 alkyl, C1-4 alkoxy, or halogen),

[0069] General formula (I-19): [Chemical formula] (wherein, all symbols represent the same meaning as above),

[0070] General formula (I-20): [Chemical formula] (wherein, all symbols represent the same meaning as above),

[0071] General formula (I-21): [Chemical formula] (wherein, m represents an integer from 0 to 2, and other symbols represent the same meaning as above),

[0072] General formula (I-21-1): [Chemical formula] (wherein, R 14 is (1) C1-8 alkyl, or (3) C1-8 haloalkyl; R 13 represents C1-4 alkyl, C1-4 alkoxy, or halogen; and m represents an integer from 0 to 2),

[0073] General formula (I-22):

Chemical formula

[0074] General formula (I-23):

Chemical formula

[0075] General formula (I-24):

Chemical formula

[0076] General formula (I-25):

Chemical formula

[0077] General formula (I-26):

Chemical formula

[0078] General formula (I-27):

Chemical formula

[0079] General formula (I-28): [Chemical formula] (wherein all symbols represent the same meaning as above),

[0080] General formula (I-29): [Chemical formula] (wherein all symbols represent the same meaning as above),

[0081] General formula (I-30): [Chemical formula] (wherein all symbols represent the same meaning as above),

[0082] General formula (I-31): [Chemical formula] (wherein all symbols represent the same meaning as above),

[0083] General formula (I-32): [Chemical formula] (wherein all symbols represent the same meaning as above),

[0084] General formula (I-33): [Chemical formula] (wherein all symbols represent the same meaning as above),

[0085] General formula (I-33-1): [Chemical formula] (wherein, R 14 is (1) C1-8 alkyl, or (3) C1-8 haloalkyl; R 12H1 is (2) C1-4 alkyl, (3) C3-7 cycloalkyl, (4) C1-4 haloalkyl, (5) C1-4 alkoxy, (6) phenyl which may be substituted with 1 to 3 R 17 , (7) C1-4 alkyl substituted with phenyl, (8) dimethylamino, (9) pyridyl, or (10) 1-(cyclopropylmethyl)pyrazol-3-yl (preferably, R 12H1 is (2) C1-4 alkyl, (3) C3-7 cycloalkyl, (4) C1-4 haloalkyl, (6) phenyl which may be substituted with 1 to 3 R 17 , (7) C1-4 alkyl substituted with phenyl, (9) pyridyl, or (10) 1-(cyclopropylmethyl)pyrazol-3-yl); R 12H2 is (1) a hydrogen atom, (2) C1-4 alkyl, (3) C3-7 cycloalkyl, (4) C1-4 haloalkyl, (5) C1-4 alkoxy, (6) phenyl which may be substituted with 1 to 3 R 17 , (7) C1-4 alkyl substituted with phenyl, (8) dimethylamino, (9) pyridyl, or (10) 1-(cyclopropylmethyl)pyrazol-3-yl (preferably, R 12H2 is (1) a hydrogen atom, (2) C1-4 alkyl, (4) C1-4 haloalkyl, (7) C1-4 alkyl substituted with phenyl, (8) dimethylamino); and R 17 represent C1-4 alkyl, C1-4 alkoxy, or halogen),

[0086] General formula (I-34): [Chemical formula] (wherein, all symbols represent the same meaning as above),

[0087] General formula (I-34-1): [Chemistry] (In the formula, R 15 represents (1) C1-8 alkyl or (3) C1-8 haloalkyl; R 12H1 represents (2) C1-4 alkyl, (3) C3-7 cycloalkyl, (4) C1-4 haloalkyl, (5) C1-4 alkoxy, (6) phenyl optionally substituted by 1 to 3 R 17 , (7) C1-4 alkyl substituted by phenyl, (8) dimethylamino, (9) pyridyl, or (10) 1-(cyclopropylmethyl)pyrazol-3-yl (preferably, R 12H1 represents (2) C1-4 alkyl, (3) C3-7 cycloalkyl, (4) C1-4 haloalkyl, (6) phenyl optionally substituted by 1 to 3 R 17 , (7) C1-4 alkyl substituted by phenyl, (9) pyridyl, or (10) 1-(cyclopropylmethyl)pyrazol-3-yl; R 12H2 represents (1) hydrogen atom, (2) C1-4 alkyl, (3) C3-7 cycloalkyl, (4) C1-4 haloalkyl, (5) C1-4 alkoxy, (6) phenyl optionally substituted by 1 to 3 R 17 , (7) C1-4 alkyl substituted by phenyl, (8) dimethylamino, (9) pyridyl, or (10) 1-(cyclopropylmethyl)pyrazol-3-yl (preferably, R 12H2 represents (1) hydrogen atom, (2) C1-4 alkyl, (4) C1-4 haloalkyl, (7) C1-4 alkyl substituted by phenyl, (8) dimethylamino); and R 17 represent C1-4 alkyl, C1-4 alkoxy, or halogen),

[0088] General formula (I-35): [Chemistry] (wherein all symbols have the same meanings as described above),

[0089] General formula (I-35-1):

Chemical formula

[0090] General formula (I-36):

Chemical formula

[0091] and general formula (I-36-1-1):

Chemical formula

[0092] In the present invention, examples of the general formula (I) preferably include the general formula (I-37): [Chemical formula] (wherein all symbols have the same meanings as described above).

[0093] In the present invention, examples of the general formula (I) preferably include the general formula (I-01): [Chemical formula] (wherein all symbols have the same meanings as described above).

[0094] In the present invention, examples of the general formula (I) preferably include the general formula (I-02): [Chemical formula] (wherein all symbols have the same meanings as described above).

[0095] In the present invention, for the substituents represented by R, R, and R on the 3-azabicyclo[3.1.0]hexane ring of the general formulas (I-1) to (I-36), 1 , R 3 and R 4 the steric configurations of the corresponding substituents are preferably in the same direction, similar to the general formula (I-37).

[0096] In the present invention, or in the general formula (I) or (I-1), preferably as a compound, for example, (1) [(1R,5S,6r)-6-(5,5-dimethyl-4,5-dihydro-1,2-oxazol-3-yl)-3-azabicyclo[3.1.0]hex-3-yl](1-isopropyl-1H-imidazol-4-yl)methanone; (2) [(1R,5S,6r)-6-(5,5-dimethyl-4,5-dihydro-1,2-oxazol-3-yl)-3-azabicyclo[3.1.0]hex-3-yl][1-(1-methylcyclopropyl)-1H-imidazol-4-yl]methanone; (3) (1-Cyclopropyl-1H-imidazol-4-yl)[(1R,5S,6r)-6-(5,5-dimethyl-4,5-dihydro-1,2-oxazol-3-yl)-6-methyl-3-azabicyclo[3.1.0]hex-3-yl]methanone; (4) (1-Cyclopropyl-1H-imidazol-4-yl)[(1R,5S,6r)-6-methyl-6-(4-oxa-5-azaspiro[2.4]hept-5-en-6-yl)-3-azabicyclo[3.1.0]hex-3-yl]methanone; (5) {1-[(2S)-Butan-2-yl]-1H-imidazol-4-yl}[(1R,5S,6S)-6-(5,5-dimethyl-4,5-dihydro-1,2-oxazol-3-yl)-3-azabicyclo[3.1.0]hex-3-yl]methanone; (6) [(1R,5S,6r)-6-(5,5-dimethyl-4,5-dihydro-1,2-oxazol-3-yl)-6-methyl-3-azabicyclo[3.1.0]hex-3-yl](1-isopropyl-1H-imidazol-4-yl)methanone; (7) (1-Isopropyl-1H-imidazol-4-yl)[(1R,5S,6r)-6-methyl-6-(4-oxa-5-azaspiro[2.4]hept-5-en-6-yl)-3-azabicyclo[3.1.0]hex-3-yl]methanone; (8) (1-Cyclopropyl-1H-imidazol-4-yl)[(1R,5S,6r)-6-(4-oxa-5-azaspiro[2.4]hept-5-en-6-yl)-3-azabicyclo[3.1.0]hex-3-yl]methanone, or (9) [1-(1-Methylcyclopropyl)-1H-imidazol-4-yl][(1R,5S,6r)-6-(4-oxa-5-azaspiro[2.4]hept-5-en-6-yl)-3-azabicyclo[3.1.0]hex-3-yl]methanone, or a salt thereof.

[0097] In the present invention, or in general formula (I) or (I-2), the compound is preferably, for example, (1)[(1R,5S,6r)-6-(5,5-dimethyl-4,5-dihydro-1,2-oxazol-3-yl)-3-azabicyclo[3.1.0]hexan-3-yl](5-isopropyl-1H-pyrazol-3-yl)methanone; (2)(5-isopropyl-1H-pyrazol-3-yl)[(1R,5S,6r)-6-(2-oxa-3-azabicyclo[3.1.0]hex-3-en-4-yl)-3-azabicyclo[3.1.0]hexan-3-yl]methanone; (3)[5-(1-cyclopropylethyl)-1H-pyrazol-3-yl][(1R,5S,6r)-6-(5,5-dimethyl-4,5-dihydro-1,2-oxazol-3-yl)-3-azabicyclo[3.1.0]hexan-3-yl]methanone; (4)[(1R,5S,6r)-6-(5,5-dimethyl-4,5-dihydro-1,2-oxazol-3-yl)-6-methyl-3-azabicyclo[3.1.0]hexan-3-yl](5-isopropyl-1H-pyrazol-3-yl)methanone, or (5)(5-cyclopropyl-1H-pyrazol-3-yl)[(1R,5S,6r)-6-methyl-6-(4-oxa-5-azaspiro[2.4]hept-5-en-6-yl)-3-azabicyclo[3.1.0]hexan-3-yl]methanone, or a salt thereof.

[0098] In the present invention, or in general formula (I) or (I-3), the compound is preferably, for example, (1)(1R,5S,6r)-N-tert-butyl-6-methyl-3-[1-(propan-2-yl)-1H-imidazole-4-carbonyl]-3-azabicyclo[3.1.0]hexane-6-carboxamide; (2)(1R,5S,6r)-N-tert-butyl-3-[1-(propan-2-yl)-1H-imidazole-4-carbonyl]-3-azabicyclo[3.1.0]hexane-6-carboxamide; (3) (1R,5S,6r)-N-(propan-2-yl)-3-[1-(propan-2-yl)-1H-imidazole-4-carbonyl]-3-azabicyclo[3.1.0]hexane-6-carboxamide, or (4) (1R,5S,6r)-N-(1-cyanocyclopropyl)-3-[1-(propan-2-yl)-1H-imidazole-4-carbonyl]-3-azabicyclo[3.1.0]hexane-6-carboxamide, or a salt thereof.

[0099] In the present invention, or in general formula (I) or (I-4), the compound is preferably, for example, (1) (1R,5S,6r)-N-(propan-2-yl)-3-[5-(propan-2-yl)-1H-pyrazole-3-carbonyl]-3-azabicyclo[3.1.0]hexane-6-carboxamide; (2) (1R,5S,6r)-N-tert-butyl-6-methyl-3-[5-(propan-2-yl)-1H-pyrazole-3-carbonyl]-3-azabicyclo[3.1.0]hexane-6-carboxamide; (3) (1R,5S,6r)-N-tert-butyl-N-methyl-3-[5-(propan-2-yl)-1H-pyrazole-3-carbonyl]-3-azabicyclo[3.1.0]hexane-6-carboxamide, or (4) (1R,5S,6r)-N-methyl-N-(1-methylcyclopropyl)-3-[5-(propan-2-yl)-1H-pyrazole-3-carbonyl]-3-azabicyclo[3.1.0]hexane-6-carboxamide, or a salt thereof. [Isomer]

[0100] The present invention includes all isomers unless otherwise specified. For example, an alkyl group, an alkoxy group, etc. include linear and branched chain groups. Further, the present invention includes isomers of double bonds, rings and condensed rings (E-type, Z-type, cis-type, trans-type), isomers of asymmetric carbon atoms (R and S forms, α and β configurations, enantiomers and diastereomers), optically active substances having optical activity (D, L, d and l forms), polar substances separated by chromatography (highly polar substances and lowly polar substances), equilibrium compounds, rotational isomers, mixtures of any ratios thereof, and racemic mixtures. The present invention also includes tautomers. [Salts and Solvates]

[0101] The salts of the compounds represented by general formula (I) described in the present specification include all pharmacologically acceptable salts. All pharmacologically acceptable salts are preferably low-toxic water-soluble salts. Examples of suitable salts include acid addition salts (e.g., inorganic acid salts [e.g., hydrochloride, hydrobromide, hydroiodide, sulfate, phosphate, nitrate, etc.], organic acid salts [e.g., acetate, trifluoroacetate, lactate, tartrate, oxalate, fumarate, maleate, benzoate, citrate, methanesulfonate, ethanesulfonate, benzenesulfonate, toluenesulfonate, isethionate, glucuronate, gluconate, etc.], salts with acidic natural amino acids [e.g., aspartic acid, glutamic acid, etc.], etc.).

[0102] The salts also include quaternary ammonium salts. A quaternary ammonium salt represents a compound in which the nitrogen atom of the compound represented by general formula (I) is quaternized by an 0 R group. The R 0 group described in the present specification represents a C1-8 alkyl group which may be substituted with, for example, a phenyl group.

[0103] The compounds represented by general formula (I) can be converted into salts, N-oxides and solvates by known methods.

[0104] The N-oxide form of the compound represented by the general formula (I) refers to the one in which the nitrogen atom of the compound represented by the general formula (I) is oxidized. The N-oxide form may form salts such as the acid addition salts described above.

[0105] The compound represented by the general formula (I), its salt, or N-oxide may form a solvate with, for example, water or an alcohol solvent (such as ethanol). The solvate is preferably low-toxic and water-soluble.

[0106] The compound represented by the general formula (I) and its salt may exist in a non-solvated form, or may be in a solvated form with a pharmaceutically acceptable solvent such as water and ethanol. The solvate is preferably a hydrate. The compound represented by the general formula (I) or its salt can be converted into a solvate by a known method.

[0107] The compound represented by the general formula (I) and its salt may form a co-crystal with a suitable co-crystal former. The co-crystal is preferably pharmaceutically acceptable and is formed with a pharmaceutically acceptable co-crystal former. A co-crystal is usually defined as a crystal formed by two or more molecules through intermolecular interactions that are not ionic bonds. The co-crystal may be a complex of a neutral molecule and a salt. The co-crystal can be prepared according to known methods such as melt crystallization, recrystallization from a solvent, or physical grinding of the components. Suitable co-crystal formers include those disclosed in WO 2006 / 007448.

[0108] In the present invention, all descriptions regarding the present compound include the compound represented by the general formula (I), its salt, its solvate (such as hydrate), its N-oxide or its co-crystal, or the solvate (such as hydrate), N-oxide or co-crystal of the salt of the compound represented by the general formula (I).

[0109] That is, in the present invention, the compound represented by the general formula (I) or a salt thereof includes a solvate (e.g., hydrate), N-oxide or co-crystal of the compound represented by the general formula (I), or a solvate (e.g., hydrate), N-oxide or co-crystal of the salt of the compound represented by the general formula (I).

[0110] [Prodrug] The prodrug of the compound represented by the general formula (I) means a compound that is converted into the compound represented by the general formula (I) by reaction with enzymes, gastric acid, etc. in vivo. Examples of the prodrug of the compound represented by the general formula (I) include, when the compound represented by the general formula (I) has an amino group, a compound in which the amino group is acylated, alkylated, or phosphorylated (e.g., a compound represented by the general formula (I) in which the amino group in the formula is converted to eicosanoyl, alanyl, pentylaminocarbonyl, (5-methyl-2-oxo-1,3-dioxolen-4-yl)methoxycarbonyl, tetrahydrofuranyl, pyrrolidylmethyl, pivaloyloxymethyl, acetoxymethyl, tert-butyl, etc.); when the compound represented by the general formula (I) has a hydroxyl group, a compound acylated, alkylated, phosphorylated, or converted to a borate (e.g., a compound represented by the general formula (I) in which the hydroxyl group in the formula is converted to acetyl, palmitoyl, propanoyl, pivaloyl, succinyl, fumaroyl, alanyl, dimethylaminomethylcarbonyl, etc.). Examples of the prodrug of the compound represented by the general formula (I) include those disclosed in "Drug Development", Volume 7, "Molecular Design", 1990, Hirokawa Shoten, pages 163-198, which are converted into the compound represented by the general formula (I) under physiological conditions. The prodrug of the compound represented by the general formula (I) can be produced by a method known per se. The prodrug of the compound represented by the general formula (I) may form a salt such as an acid addition salt, or a solvate with water or an alcoholic solvent (ethanol, etc.) in the same manner as the compound represented by the general formula (I). [Labeled compound]

[0111] In the present invention, the compound represented by the general formula (I) or a salt thereof includes a so-called labeled compound in which some or all of the atoms constituting the compound are substituted with their isotopes. The labeled compound can be produced by a method known per se. Examples of the isotope that can be used for labeling include, but are not limited to, 2 H, 3 H, 13 C, 14 C, 15 N, 16 N, 17 O, 18 O, 35 S, 36 Cl, 77 Br, 125 I and the like. [Production Method] [Production Method of the Compound of the Present Invention]

[0112] The compound represented by the general formula (I) or a salt thereof can be produced by a known method, for example, the methods described below shown in Schemes I to XII, methods equivalent thereto, the methods described in the Examples, methods equivalent to the methods described in the Examples, or the methods described in Comprehensive Organic Transformations: A Guide to Functional Group Preparations 2nd Edition (Richard C. Larock, John Wiley & Sons Inc., 1999), methods applying them, or methods combining them. In the production methods described below, the starting compound may be a salt. Examples of the salt include those described above as salts of the compound represented by the general formula (I).

[0113] [Chemical Formula] In the formula, the compound represented by the general formula (I) can be produced by subjecting the compound represented by the general formula (III) and the compound represented by the general formula (IV) to an amidation reaction.

[0114] Amidation is known. For example, it includes the following methods. (1) Method via acyl halide (2) Method via mixed acid anhydride (3) Use of condensing agent

[0115] These methods will be described below. (1) As the method via acyl halide, for example, a carboxylic acid and an acyl halide (e.g., oxalyl chloride or thionyl chloride) are reacted in an organic solvent (e.g., chloroform, dichloromethane, diethyl ether, tetrahydrofuran) or without a solvent at about -20°C to the reflux temperature. Next, the obtained acyl halide derivative and an amine are reacted in an organic solvent (e.g., chloroform, dichloromethane, diethyl ether, tetrahydrofuran) at about 0°C to 40°C in the presence of a base (e.g., pyridine, triethylamine, dimethylaniline, dimethylaminopyridine, diisopropylethylamine, etc.). Alternatively, the obtained acyl halide derivative and an amine may be reacted in an organic solvent (e.g., dioxane, tetrahydrofuran) using an aqueous alkali solution (e.g., sodium hydrogen carbonate, sodium hydroxide) at about -78°C to 40°C.

[0116] (2) The method via mixed acid anhydride can be carried out, for example, by reacting a carboxylic acid with an acyl halide (e.g., pivaloyl chloride, p-toluenesulfonyl chloride or methanesulfonyl chloride), or an acid derivative (e.g., ethyl chloroformate or isobutyl chloroformate) in an organic solvent (e.g., chloroform, dichloromethane, diethyl ether, tetrahydrofuran) or without a solvent at about 0°C to 40°C in the presence of a base (e.g., pyridine, triethylamine, dimethylaniline, dimethylaminopyridine, diisopropylethylamine, etc.). The obtained mixed acid anhydride derivative can be reacted with an amine in an organic solvent (e.g., chloroform, methylene chloride, diethyl ether, or tetrahydrofuran) at about 0°C to 40°C.

[0117] (3) As a method using a condensing agent, for example, in the presence or absence of a base (e.g., pyridine, triethylamine, dimethylaniline or dimethylaminopyridine), a carboxylic acid and an amine are reacted in an organic solvent (e.g., chloroform, dichloromethane, dimethylformamide, diethyl ether, tetrahydrofuran) or without a solvent, with a condensing agent (e.g., 1,3-dicyclohexylcarbodiimide (DCC), 1-ethyl-3-[3-(dimethylamino)propyl]carbodiimide (EDC), 1,1'-carbodiimidazole (CDI), 2-chloro-1-methylpyridinium iodide, or 1-propanephosphonic acid cyclic anhydride (PPA)) in the presence or absence of 1-hydroxybenzotriazole (HOBt) at about 0 °C to 40 °C.

[0118] (1), (2) and (3) The reactions described can be carried out under anhydrous conditions and under an inert gas (e.g., argon, nitrogen) to obtain favorable results.

[0119] The compound represented by the general formula (III) can be produced by subjecting the compound represented by the general formula (II) to a deprotection reaction of the protecting group of the amino group. In the general formula (II), P represents a protecting group of the amino group. P includes benzyloxycarbonyl (Z), tert-butoxycarbonyl (Boc), allyloxycarbonyl (Alloc), 1-methyl-1-(4-biphenyl)ethoxycarbonyl (Bpoc), trifluoroacetyl, 9-fluorenylmethoxycarbonyl (Fmoc), benzyl (Bn), p-methoxybenzyl, benzyloxymethyl (BOM), or 2-(trimethylsilyl)ethoxymethyl (SEM), etc.

[0120] The deprotection reaction of the protecting group of the amino group can be carried out under appropriate conditions for each protecting group. For example, the deprotection of the t-butoxycarbonyl (Boc) group can be carried out using an acidic reagent (e.g., hydrogen chloride / dioxane, TFA, or MsOH) in a solvent (e.g., dioxane or dichloromethane) at 0 °C to 40 °C. For example, the deprotection of the benzyloxycarbonyl (Z) group can be carried out under hydrogenation conditions such as hydrogen and a catalyst Pd-C at 20 °C to 60 °C in a solvent (e.g., methanol (MeOH) or ethanol (EtOH), etc.).

[0121] The deprotection reaction of the protecting group of the amino group is well-known and is described in detail in T.W. Greene, Protective Group in Organic Synthesis, Wiley, New York, 1999.

[0122]

Chemical formula

Chemical formula

[0123] The compound represented by the general formula (II)-1 can be produced by subjecting the compound represented by the general formula (VII) and the compound represented by the general formula (VIII) to an isoxazoline cyclization reaction.

[0124] The isoxazoline cyclization reaction can be carried out at 0 °C to 80 °C using a base (e.g., trimethylamine or DIPEA) and a solvent (e.g., DMF, etc.). The compound represented by the general formula (VII) can be produced by subjecting the compound represented by the general formula (VI) to a chlorination reaction.

[0125] The chlorination reaction can be carried out using a chlorination reagent (e.g., N-chlorosuccinimide) at about 0 °C to 40 °C in a solvent (e.g., DMF, etc.). The compound represented by the general formula (VI) can be produced by subjecting the compound represented by the general formula (V) to an oxime formation reaction.

[0126] The oxime formation reaction can be carried out using hydroxylamine hydrochloride, potassium acetate, and acetic acid at about 20 °C to 40 °C in a solvent (e.g., EtOH, etc.).

[0127] [Chemical formula] R in the general formula (II) in Scheme I 1 is [Chemical formula] and the general formula (II) is represented as the general formula (II)-2 in Scheme III.

[0128] The compound represented by the general formula (II)-2 can be produced by subjecting the compound represented by the general formula (IX) and the compound represented by the general formula (X) to an amidation reaction.

[0129] The amidation can be carried out in the same manner as the preparation of the general formula (I) in Scheme 1 described above. The compound represented by the general formula (II)-2 can be produced by subjecting the compound represented by the general formula (XII) and the compound represented by the general formula (XIII) to an alkylation reaction.

[0130] The alkylation reaction can be carried out using a base (e.g., sodium hydride, potassium hydride, lithium hydride, sodium methoxide, sodium ethoxide, potassium tert-butoxide, butyllithium, LDA, LHMDS, NaHMDS, KHMDS, etc.) at -78 °C to 40 °C in a solvent (e.g., THF, DMF, DMA, diethyl ether, etc.).

[0131] The compound represented by the general formula (XII) can be produced by subjecting the compound represented by the general formula (IX) and the compound represented by the general formula (XI) to an amidation reaction.

[0132] The amidation can be carried out in the same manner as the preparation of the general formula (I) in Scheme I described above.

[0133]

Chemical formula

Chemical formula

[0134] The compound represented by the general formula (II)-3 can be produced by subjecting the compound represented by the general formula (XV) to an oxidation reaction of the hydroxyl group.

[0135] The oxidation of the hydroxyl group is known. For example, it includes the following methods. (1) Dess-Martin oxidation (2) DMSO oxidation (3) Chromium reagent oxidation

[0136] These methods will be described below. (1) Dess-Martin oxidation can be carried out at 0 °C to 40 °C using Dess-Martin periodinane in a solvent (for example, methylene chloride). (2) DMSO oxidation can be carried out at -78 °C to 40 °C using dimethyl sulfoxide and its activator (for example, oxalyl chloride, thionyl chloride, or sulfur trioxide pyridinium complex, etc.) and a base (for example, trimethylamine or DIPEA, etc.). (3) Chromium reagent oxidation is carried out at -20 °C to 40 °C using a chromium oxidizing agent (for example, PCC, PDC) in a solvent (for example, dichloromethane).

[0137] The compound represented by the general formula (XV) can be produced by subjecting the compound represented by the general formula (V) and the compound represented by the general formula (XIV) to an addition reaction. M in the general formula (XIV) represents a metal (for example, Li, Na or K) or a metal halide (MgCl, MgBr, MgI, ZnCl, ZnBr or ZnI).

[0138] The addition reaction can be carried out in a solvent (for example, tetrahydrofuran) under an inert atmosphere (for example, dry nitrogen or argon) at a temperature from -78 °C to 0 °C.

[0139]

Chemical formula

Chemical formula

[0140] The compound represented by the general formula (II)-4 can be produced by subjecting the compound represented by the general formula (VII) and the compound represented by the general formula (XVI) to an isoxazole cyclization reaction.

[0141] The isoxazole cyclization reaction can be carried out in a solvent (for example, dichloromethane, etc.) using a base (for example, trimethylamine, etc.) at a temperature from -20 °C to 40 °C.

[0142] The compound represented by the general formula (II)-4a can be produced by subjecting the compound represented by the general formula (XVII) and the compound represented by the general formula (XVIII) to a coupling reaction.

[0143] The coupling reaction is known. For example, in an organic solvent (e.g., benzene, toluene, dimethylformamide, 1,4-dioxane, tetrahydrofuran, methanol, acetonitrile, dimethoxyethane, acetone, or a mixed solvent thereof), in the presence of a catalyst (e.g., bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) ((A-taPhos) 2 PdCl 2 ), 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 ), iodophenylbis(triphenylphosphine)palladium (PhPdI(PPh 3 ) 2 ), etc.), at a temperature from room temperature to 150 °C, in the presence of a base (e.g., sodium ethoxide, sodium hydroxide, potassium hydroxide, triethylamine, sodium carbonate, sodium bicarbonate, potassium carbonate, cesium carbonate, thallium carbonate, tripotassium phosphate, cesium fluoride, barium hydroxide, tetrabutylammonium fluoride, etc.) or an aqueous solution thereof, or a mixture of these, the reaction can be carried out by reacting.

[0144] The compound represented by the general formula (XVII) can be produced by subjecting the compound represented by the general formula (II)-4 to a bromination reaction.

[0145] The bromination reaction can be carried out at a temperature from -20 °C to 40 °C using a bromination reagent (e.g., NBS, bromine, etc.) in a solvent (e.g., DMF, etc.).

[0146] [Chemical formula] R in general formula (II) in Scheme I 1 represents [Chemical formula] and general formula (II) can be represented as general formula (II)-5 in Scheme VI.

[0147] The compound represented by general formula (II)-5 can be produced by subjecting the compound represented by general formula (VII) and the compound represented by general formula (XIX) to a 1,2,4-oxadiazoline cyclization reaction.

[0148] The 1,2,4-oxadiazoline cyclization reaction can be carried out at 0 °C to 40 °C using a base (such as trimethylamine, etc.) in a solvent (such as tetrahydrofuran, toluene, DMF, etc.).

[0149] [Chemical formula] R in general formula (II) in Scheme I 1 represents [Chemical formula] and general formula (II) can be described as general formula (II)-6 in Scheme VII.

[0150] The compound represented by general formula (II)-6 can be produced by subjecting the compound represented by general formula (XXII) to a 1,3,4-oxadiazole cyclization reaction.

[0151] The 1,3,4-oxadiazole cyclization reaction can be carried out at 80 °C to 120 °C using a dehydrating agent (such as POCl 3 etc.). The compound represented by the general formula (XXII) can be produced by subjecting the compound represented by the general formula (XX) and the compound represented by the general formula (XXI)-1 or (XXI)-2 to an amidation reaction.

[0152] The amidation can be carried out in the same manner as the preparation of the general formula (I) in Scheme I described above. The compound represented by the general formula (XX) can be produced by subjecting the compound represented by the general formula (IX) to an amidation reaction. The amidation can be carried out in the same manner as the preparation of the general formula (I) in Scheme I described above.

[0153] [Chemical formula] R in the general formula (II) in Scheme I 1 is [Chemical formula] and the general formula (II) can be described as the general formula (II)-7 in Scheme VIII.

[0154] The compound represented by the general formula (II)-7 can be produced by subjecting the compound represented by the general formula (II)-6 and the compound represented by the general formula (XXIII) to a substitution reaction.

[0155] The substitution reaction can be carried out at 120°C to 150°C using an acidic catalyst (e.g., TsOH, etc.) in a solvent (e.g., xylene, etc.). The compound represented by the general formula (II)-7 can be produced by subjecting the compound represented by the general formula (XXIV) and the compound represented by the general formula (XXIII) to a 1,3,4-triazole cyclization reaction. The 1,3,4-triazole cyclization reaction can be carried out at 0°C to 100°C using acetic acid. The compound represented by the general formula (XXIV) can be produced by subjecting the compound represented by the general formula (XX) to a hydrazonohydroformamide formation reaction.

[0156] The hydrazonohydroformamide formation reaction can be carried out at 100 °C to 120 °C using 1,1-dimethoxy-N,N-dimethylmethanamine in a solvent (e.g., acetonitrile, DMF, etc.).

[0157]

Chem.

Chem.

[0158] The compound represented by the general formula (II)-8 can be produced by subjecting the compound represented by the general formula (XXVI) to a dehydrative tetrazole cyclization reaction. The dehydrative tetrazole cyclization reaction can be carried out at 0 °C to 30 °C using Tf 2 O and TMSN 3 in a solvent (e.g., dichloromethane, etc.).

[0159] The compound represented by the general formula (XXVI) can be produced by subjecting the compound represented by the general formula (IX) and the compound represented by the general formula (XXV) to an amidation reaction. The amidation can be carried out in the same manner as the preparation of the general formula (I) in Scheme I described above. In the formula, R 12 represents a hydrogen atom (H), and the compound represented by the general formula (II)-8 can be produced by subjecting the compound represented by the general formula (XXVIII) to a tetrazole cyclization reaction. The tetrazole cyclization reaction can be carried out at 100 °C to 140 °C using sodium azide and ammonium chloride in a solvent (e.g., DMF, etc.).

[0160] The compound represented by the general formula (XXVIII) can be produced by subjecting the compound represented by the general formula (XXVII) to a nitrile formation reaction. The nitrile formation reaction can be carried out at 100 °C to 140 °C using a dehydrating agent (such as cyanuric chloride, thionyl chloride, or phosphorus pentoxide, etc.) in a solvent (such as DMF, benzene, toluene, or xylene, etc.).

[0161] The compound represented by the general formula (XXVII) can be produced by subjecting the compound represented by the general formula (IX) and ammonia to an amidation reaction. The amidation can be carried out in the same manner as the preparation of the general formula (I) in Scheme I described above.

[0162] [Chemical formula] R in the general formula (II) in Scheme I 1 is [Chemical formula] and the general formula (II) can be described as the general formula (II)-9 in Scheme X.

[0163] The compound represented by the general formula (II)-9 can be produced by subjecting the compound represented by the general formula (XXX) to a [1,2,4]triazolo[4,3-a]pyridine cyclization reaction. The [1,2,4]triazolo[4,3-a]pyridine cyclization reaction can be carried out at 100 °C to 140 °C using a Burgess reagent in a solvent (such as acetonitrile, etc.).

[0164] The compound represented by the general formula (XXX) can be produced by subjecting the compound represented by the general formula (IX) and the compound represented by the general formula (XXIX) to an amidation reaction. The amidation can be carried out in the same manner as the preparation of the general formula (I) in Scheme I above.

[0165] [Chemical formula] R in General Formula (II) in Scheme I 1 is

Chemical Formula

[0166] The compound represented by General Formula (II)-10 can be produced by subjecting the compound represented by General Formula (XXXIII) to a [1,2,3]triazolo[1,5-a]pyridine cyclization reaction. The [1,2,4]triazolo[4,3-a]pyridine cyclization reaction is carried out using hydrazine hydrate at 50°C to 70°C, and then treating copper acetate in a solvent (e.g., ethyl acetate, etc.) at 20°C to 40°C.

[0167] The compound represented by General Formula (XXXIII) can be produced by subjecting the compound represented by General Formula (XXXII) to an oxidation reaction of the hydroxyl group. The oxidation reaction of the hydroxyl group can be carried out in the same manner as the preparation of General Formula (II)-3 in Scheme IV above.

[0168] The compound represented by General Formula (XXXII) can be produced by subjecting the compound represented by General Formula (V) and the compound represented by General Formula (XXXI) to an addition reaction. The addition reaction can be carried out in the same manner as the preparation of General Formula (XV) in Scheme IV above.

[0169] In the formula, the compounds represented by general formulas (IV), (VIII), (X), (XI), (XIII), (XIV), (XVI), (XVIII), (XIX), (XXI)-1, (XXI)-2, (XXIII), (XXV), (XXVII), (XXIX), and (XXXI) can be obtained as commercial products, and can also be easily prepared from commercial products by known methods described in, for example, Comprehensive Organic Transformations: A Guide to Functional Group Preparations, 2nd Edition (Richard C. Larock, John Wiley & Sons, 1999).

[0170] In the formula, the compound represented by general formula (V) can be obtained as a commercial product and can also be prepared by the method described in Scheme XII.

[0171] [Chemical formula] In the formula, the compound represented by general formula (V) can be produced by subjecting the compound represented by general formula (XXXIX) to an oxidation reaction of the hydroxyl group.

[0172] The oxidation reaction of the hydroxyl group can be carried out in the same manner as the preparation of general formula (II)-3 in Scheme IV above.

[0173] The compound represented by general formula (XXXIX) can be produced by subjecting the compound represented by general formula (XXXVIII) to a protecting group exchange reaction. The protecting group exchange reaction can be carried out at 20°C to 40°C using hydrogen gas, a Pd catalyst (e.g., Pd-C or Pd(OH) 2 -C, etc.) and (Boc) 2 O in a solvent (e.g., methanol, EtOH, or THF, etc.).

[0174] The compound represented by general formula (XXXVIII) can be produced by subjecting the compound represented by general formula (XXXVII) to an ester reduction reaction. The reduction reaction of the ester can be carried out at -20°C to 20°C using a reducing agent (e.g., LiAlH 4 , DIBAL-H, Red-Al, etc.) in a solvent (e.g., THF, diethyl ether, DME, etc.).

[0175] The compound represented by the general formula (XXXVII) can be produced by subjecting the compound represented by the general formula (XXXVIII) to an imide reduction reaction. The imide reduction reaction can be carried out at 20°C to 80°C using a borane reducing agent (e.g., BH 3 THF complex, BH 3 Me 2 S complex or B 2 H 6 , etc.) in a solvent (e.g., THF, diethyl ether, DME, etc.).

[0176] The compound represented by the general formula (XXXVII) can be produced by subjecting the compound represented by the general formula (XXXV) and the compound represented by the general formula (XXXVI) to a cyclopropanation reaction. The cyclopropanation reaction can be carried out at 20°C to 100°C using manganese dioxide in a solvent (e.g., dioxane, etc.).

[0177] The compound represented by the general formula (XXXV) can be produced by subjecting the compound represented by the general formula (XXXIV) to a hydrazone formation reaction. The hydrazone formation reaction can be carried out using hydrazine hydrate and acetic acid in water at 0°C to 40°C.

[0178] The compounds represented by the general formulas (XXXIV) and (XXXVI) can be obtained as commercially available products, and can also be easily prepared from commercially available products by known methods described, for example, in Comprehensive Organic Transformations: A Guide to Functional Group Preparations, 2nd Edition (Richard C. Larock, John Wiley & Sons, 1999), etc.

[0179] In the reactions exemplified herein, heating means such as a water bath, an oil bath, a sand bath, and microwaves may be used.

[0180] In the reactions exemplified herein, a solid-phase supported reagent supported on a polymer (such as polystyrene, polyacrylamide, polypropylene, and polyethylene glycol) may be used as necessary.

[0181] The product obtained by the reaction exemplified herein can be purified by ordinary purification methods, for example, distillation under normal pressure or reduced pressure, chromatography using silica gel, an ion exchange resin, a scavenger resin, or magnesium silicate (such as high-performance liquid chromatography, thin-layer chromatography, or column chromatography), or washing or recrystallization. Purification can be carried out after each reaction step or after a series of reactions. [Toxicity]

[0182] This compound has low toxicity and can therefore be safely used as a pharmaceutical. [Application to Pharmaceuticals]

[0183] Since this compound has KDM5 inhibitory activity, it can be used as a prophylactic and / or therapeutic agent for KDM5-related diseases in mammals, particularly humans.

[0184] Examples of such diseases include hyperproliferative diseases, cancer, stroke, diabetes, hepatomegaly, cardiovascular diseases, multiple sclerosis, Huntington's disease, Alzheimer's disease, cystic fibrosis, viral diseases, autoimmune diseases, atherosclerosis, restenosis, psoriasis, rheumatoid arthritis, inflammatory bowel disease, asthma, allergic diseases, inflammation, neuropathy, hormone-related diseases, symptoms associated with organ transplantation, immunodeficiency diseases, destructive bone disorders, proliferative diseases, infectious diseases, symptoms associated with cell death, thrombin-induced platelet aggregation, liver diseases, pathological immune states associated with T cell activity, central nervous system disorders, myeloproliferative diseases, Parkinson's disease, Lewy body disease, frontotemporal dementia, mild cognitive impairment, dementia, cerebrovascular diseases, schizophrenia, depression, anxiety disorders, bipolar disorder, autism spectrum disorder, attention deficit / hyperactivity disorder, learning disorders, movement disorders, obsessive-compulsive disorder, personality disorders, sleep disorders, delirium, amyotrophic lateral sclerosis, developmental disorders, intellectual disabilities, post-traumatic stress disorder, hepatitis, and the like.

[0185] In particular, the present compound is useful for the prevention and / or treatment of cancer, Huntington's disease, Alzheimer's disease, Parkinson's disease, Lewy body disease, frontotemporal dementia, mild cognitive impairment, dementia, cerebrovascular diseases, schizophrenia, depression, anxiety disorders, bipolar disorder, autism spectrum disorder, attention deficit / hyperactivity disorder, learning disorders, movement disorders, obsessive-compulsive disorder, personality disorders, sleep disorders, delirium, amyotrophic lateral sclerosis, developmental disorders, intellectual disabilities, post-traumatic stress disorder, or hepatitis. The present compound is particularly suitable for the prevention and / or treatment of cancer and Alzheimer's disease.

[0186] In addition to having strong KDM5 inhibitory activity, the present compound has excellent metabolic stability and can be present at high concentrations in the brain.

[0187] Examples of test methods for evaluating the pharmacological activity of the present compound include an evaluation system for improving cognitive impairment in mice. For example, the improvement of cognitive impairment by the present compound can be evaluated using the following method.

[0188] Mice (male C57BL / 6 mice aged 16 to 23 months (Charles River Laboratories Japan, Inc.)) are used. The test substance and its solvent are orally administered once a day for two weeks. Then, a plastic cage (ECON cage, CL-0107, 345 mm × 403 mm × 177 mm, CLEA Japan, Inc.) equipped with a video camera as the experimental apparatus is used to evaluate the cognitive function by the novel object recognition (NOR) test. The evaluation is performed in a dark room, and the light intensity is adjusted to approximately 20 lux near the experimental apparatus. To acclimatize the animals to the evaluation environment, the mice are moved to the evaluation room more than 1 hour before the start of the test. This test is carried out over three days. For acclimatization to the experimental apparatus on the first day, the mice are placed in the cage and allowed to move freely for 10 minutes. In the acquisition trial on the second day, two identical objects (known objects) are placed on the cage, and the same procedure is carried out for 10 minutes. The two objects are placed apart on a line parallel to the long side of the cage. The distance between the object and the inner walls of the two adjacent sides is 10 cm. In the test trial on the third day, one of the objects used in the acquisition trial is replaced with a new object of a different color and shape, and the animals are allowed to behave in the same way for 10 minutes. The test trial starts 24 hours (tolerance range: 23 to 25 hours) after the acquisition trial. From the video images recorded in the test trial, the exploration time of each object is measured. From the exploration times of the known and novel objects, the total exploration time and the novel object recognition rate are calculated by the following formulas.

[0189] Total exploration time (seconds) = Exploration time of known object + Exploration time of novel object Recognition index (%) = 100 × (Exploration time of novel object / Total exploration time)

[0190] Examples of test methods for evaluating the pharmacological activity of this compound include a clonogenicity test and a cytotoxicity test in cancer cells. For example, the effectiveness of this compound in cancer cells can be evaluated by the following method.

[0191] MCF-7, T47D, and MBA-MB231 human breast cancer cells are purchased from ATCC upon authentication. The cells are passaged up to 10 - 12 times at most and then replaced with the initial passage cells stored in liquid nitrogen since purchase. The cells are adhered and grown in high-glucose Dulbecco's modified Eagle's medium (DMEM) containing 1% penicillin / streptomycin, 2 mM L-glutamine, and 10% inactivated fetal bovine serum. The cells are maintained in an incubator at 37 °C and 5% CO 2 and removed DMEM, washed with PBS, detached with an appropriate amount of trypsin / EDTA, and passaged regularly.

[0192] In the clonogenicity test, 1 hour after treatment with the compound, cells are exposed to X-rays using an MLG300 / 6-D device (Gilardoni) set at 200 V and 6 mA to obtain an equivalent absorbed dose of 1 cGy / s. Then, the cells are collected, counted, and diluted in growth medium containing the compound. Appropriate numbers of cells are seeded in quadruplicate according to the doubling time of the cell line and the irradiation dose. 24 hours after this seeding, the medium containing the compound is replaced with fresh DMEM, and the cells are cultured for 14 days (a time sufficient for at least 6 cell divisions). After this growth period, the cells are washed twice with PBS, then fixed and stained at room temperature for 30 minutes with an appropriate solution consisting of 0.3% methylene blue and 80% ethanol. After washing the cells twice with dd water, the plates are imaged colorimetrically using a ChemiDoc XRS+ imaging system (Bio-Rad). The radiation dose-response curves for DMSO and the compound samples are calculated using the survival rate. The colony formation rate and survival rate are calculated as follows. Colony formation rate = Number of counted colonies / Number of seeded cells Survival rate = Colony formation rate / Colony formation rate of the mock sample

[0193] In the cytotoxicity test, Cell Counting Kit-8 (#CK04, DOJINDO) is used according to the manufacturer's instructions. An MCF-7 T47D or MDA-MB 231 cell suspension (5000 cells / 100 μL / well) is dispensed into a 96-well plate. After 24 hours, the compound or DMSO is added to the growth medium and the cells are irradiated with radiation. 48 hours after irradiation, 10 μL of CCK-8 solution is added to each well of the plate and the cells are cultured for another 1 hour. The absorbance at 450 nm is measured using a VICTOR2 1420 reader (Perkin Elmer).

[0194] Examples of test methods for evaluating the pharmacological activity of this compound include tests using primary cultured human hepatocytes (PHH) related to the inhibition of hepatitis B virus antigen (HbsAg). For example, the efficacy of this compound in the PHH assay can be evaluated using the following method.

[0195] Primary human hepatocytes (PHH) (Bioresclamation IVT) are seeded onto collagen-coated flasks using plate medium (Life Technologies) containing William's Medium E supplemented with 1% penicillin / streptomycin, 4 pg / mL human recombinant insulin, 2 mM GlutaMAX, 15 mM HEPES, 1 μM dexamethasone, 5% fetal bovine serum, and 0.2% antibiotic mixture. After incubation at 37 °C for 4 hours, the cells are switched to maintenance medium (Life Technologies) containing William's Medium E supplemented with 0.5% penicillin / streptomycin, 6.25 pg / mL human recombinant insulin, 6.25 pg / mL human transferrin, 6.25 ng / mL selenious acid, 1.25 mg / mL bovine serum albumin, 5.35 pg / mL linoleic acid, 2 mM GlutaMAX, 15 mM HEPES, 0.1 μM dexamethasone, 2% fetal bovine serum, 2% DMSO, and 0.2% antibiotic mixture. The next day, genotype D (derived from AD38) HBV is infected into PHH at a concentration of 500 genome equivalents per cell in maintenance medium supplemented with 4% PEG8000 (Promega). After incubation for 24 hours, the cells are washed three times with William's Medium E and fresh maintenance medium is added. On day 3 post-infection, the infected PHH cells are seeded at a concentration of 65,000 cells / well onto collagen-precoated 96-well plates in a final volume of 125 μL of maintenance medium (Life Technologies) containing the most diluted compound or DMSO (final concentration 1%). The medium containing the compound is replenished every 2 to 3 days. After 12 days of incubation, HBsAg secreted into the supernatant is measured by multiplex chemiluminescence (Mesoscale discovery, MSD) assay using an HBsAg-specific capture antibody and detection antibody pair. The EC50 value is calculated by fitting the dose-response curve to a four-parameter equation.

[0196] Examples of test methods for evaluating the pharmacological activity of the present compound include an evaluation system for improvement of depressive symptoms in a social defeat stress model. For example, the efficacy of the present compound in a social defeat model can be evaluated using the following method.

[0197] Eight-week-old male DBA / 2 mice are used in the experiment. Social defeat stress is imposed on the mice. The test mice are placed in a cage with highly aggressive CD-1 mice for 5 minutes. At this time, the CD-1 mice unilaterally attack the test mice (physical stress). After 5 minutes, the CD-1 mice and the test mice are separated by a transparent acrylic plate and maintained for 24 hours (psychological stress load). This process is continued for 5 days. The compound or solvent is orally administered daily 2 hours before the social defeat stress. Then, a social interaction test and a sucrose preference test are conducted.

[0198] In the social interaction test, CD-1 mice are placed as novel mice in a 42 cm square box (target area). The test mice (DBA / 2 mice) are placed in the box, and the staying time in the target area for 3 minutes is measured with a video tracking system (Any-Maze software). In depressive animals, the contact time with novel mice decreases.

[0199] In the sucrose preference test, bottles containing 1% sucrose solution and tap water are given simultaneously. The amounts of sucrose solution and tap water consumed over 4 hours are measured, and the consumption ratio of sucrose water (sucrose preference) is used as an index of anhedonia. Animals usually prefer sweet sucrose, but in animals in an anhedonic state with depression, sucrose preference decreases.

[0200] When this compound is used for pharmaceutical purposes, this compound can be used not only as a single agent but also, for example, (1) for the purpose of assisting and / or enhancing the effect of this compound for the prevention, treatment, and / or improvement of symptoms, (2) for the purpose of improving pharmacokinetics and absorption, reducing the dosage of this compound, and / or (3) for the purpose of reducing the side effects of this compound, it can also be used as a formulated agent added with active ingredients listed below.

[0201] When using this compound for the prevention and / or treatment of Alzheimer's disease, drugs that can be used in combination with this compound include, for example, symptomatic therapeutic agents, such as M1 and M3 muscarinic receptor agonists, or drugs known to modify cholinergic transmission, such as allosteric modulators, M2 muscarinic antagonists, M4 agonists or positive allosteric modulators (PAMs), acetylcholinesterase inhibitors (e.g., tetrahydroaminoacridine, donepezil hydrochloride, rivastigmine), nicotinic receptor agonists, or allosteric modulators (e.g., α7 agonists, or allosteric modulators, or α4β2 agonists, or allosteric modulators), PPAR agonists (e.g., PPARy agonists), 5-HT4 receptor agonists or partial agonists, histamine H3 antagonists, 5-HT6 receptor antagonists, or 5-HT1A receptor ligands, and NMDA receptor antagonists or modulators, 5-HT 2A antagonists, 5-HT 7Antagonists, Dl agonists or PAMs, D4 agonists or PAMs, D5 agonists or PAMs, GABA-Aa5 inverse agonists or negative allosteric modulators (NAMs), GABA-Aa2 / 3 agonists or PAMs, mGluR2 modulators (PAMs or NAMs), mGluR3 PAMs, mGluR5 PAMs, PDE1 inhibitors, PDE2 inhibitors, PDE4 inhibitors, PDE5 inhibitors, PDE9 inhibitors, PDE10 inhibitors, GlyT1 inhibitors, DAAO inhibitors, ASCI inhibitors, AMPA modulators, SIRT1 activators or inhibitors, AT4 antagonists, GalR1 antagonists, GalR3 ligands, adenosine A1 antagonists, adenosine A2a antagonists, a2A antagonists or agonists, selective and non-selective norepinephrine reuptake inhibitors (SNRIs), or potential disease modifying agents such as gamma-secretase inhibitors or modulators, alpha-secretase activators or modulators, amyloid aggregation inhibitors, amyloid antibodies, tau aggregation inhibitors, or tau phosphorylation / kinase inhibitors, tau dephosphorylation / phosphatase activators, mitogen-activated protein kinase kinase 4 (MKK4 / MEK4 / MAP2K4) inhibitors, c-Jun N-terminal kinase (JNK) inhibitors, casein kinase inhibitors, MK2 (mitogen-activated protein kinase 2) inhibitors, MARK (microtubule affinity regulating kinase) inhibitors, CDK5 (cyclin-dependent kinase 5) inhibitors, GSK-3 (glycogen synthase kinase 3) inhibitors and tau-tubulin kinase 1 (TTBK1) inhibitors are included.As further examples of combination drugs, there are calcium channel blockers, HMG-CoA (3-hydroxy-3-methyl-glutaryl-CoA) reductase inhibitors (statins) and lipid-lowering drugs, NGF (nerve growth factor) mimetics, antioxidants, GPR3 ligands, plasmin activators, neprilysin (NEP) activators, IDE (insulin-degrading enzyme) activators, melatonin MT1 and / or MT2 agonists, TLX / NR2E1 (tailless X receptor) ligands, GluR1 ligands, RAGE (receptor for advanced glycation end products) antagonists, EGFR (epidermal growth factor receptor) inhibitors, FPRL-1 (formyl peptide-like receptor-1) ligands, GABA antagonists, and MICAL (molecule interacting with casL) inhibitors, such as redox enzyme inhibitors, CB1 antagonists / inverse agonists, non-steroidal anti-inflammatory drugs (NSAIDs), anti-inflammatory drugs (e.g., drugs that can be used for the treatment of neuroinflammation by enhancing or reducing neuroinflammation), amyloid precursor protein (APP) ligands, anti-amyloid vaccines and / or antibodies, drugs that promote or enhance the excretion and / or removal of amyloid, histone deacetylase (HDAC) inhibitors, EP2 antagonists, 11βHSD1 (hydroxysteroid dehydrogenase) inhibitors, liver X receptor (LXR) agonists or PAMs, lipoprotein receptor-related protein (LRP) mimetics, ligands, enhancers and / or inhibitors, butyrylcholinesterase inhibitors, quinolinic acid antagonists and / or quinurenine aminotransferase (KAT) inhibitors, orphanin FQ / nociceptin (NOP) / opioid-like receptor 1 (ORL1) antagonists, excitatory amino acid transporter (EAAT) ligands (activators or inhibitors), plasminogen activator inhibitor-1 (PAI-1) inhibitors, cholesterol-lowering drugs and / or niacin used in combination with HMGCoA reductase inhibitors (statins) and / or GPR109 agonists or PAMs, dimebolin or similar drugs, antihistamines, metal-binding / chelating drugs, antibiotics, growth hormone secretagogues, cholesterol-lowering drugs, vitamin E, cholesterol absorption inhibitors, cholesterol excretion promoters and / or activators, and insulin-increasing drugs, etc.

[0202] Alternatively, it can be used in combination with, for example, donepezil hydrochloride, galantamine hydrobromide, fupirtine A, idebenone, levocarnitine hydrochloride, memantine hydrochloride, memantine hydrochloride / donepezil hydrochloride, porcine brain protein-derived proteolytic peptide fraction, rivastigmine tartrate, tacrine hydrochloride, aducanumab (recombinant), etc.

[0203] The combination agent of this compound and other drugs may be administered as a formulated drug containing both components in one dosage form, or separate formulations may be administered by the same or different administration routes. It is not necessary to administer the separate formulations simultaneously, and they may be administered sequentially with a time interval. When administering sequentially, the order of administration or the method of administration is not particularly limited and can be appropriately adjusted so as to obtain the expected effectiveness.

[0204] The dosage of the additional drug used in combination with this compound can be appropriately increased or decreased according to its clinical dosage or similar drugs. The ratio of this compound to the additional drug can be appropriately adjusted in consideration of the age, body weight, administration method, administration time, target disease, disease state, etc. of the subject. Usually, other drugs can be combined in the range of 0.01 to 100 parts by weight with respect to 1 part by weight of this compound. A plurality of other drugs may be used. In addition to the above drugs, other drugs having the same mechanism of action as the above drugs may also be used. Such other drugs include not only known ones but also those to be discovered in the future.

[0205] The dosage of this compound varies depending on age, body weight, disease state, treatment effect, administration method, administration period, etc. This compound may be orally administered once a day to several times a day to adults in the range of 0.1 mg to 300 mg per dose, or may be parenterally administered once a day to several times a day to adults in the range of 0.1 mg to 150 mg per dose, or may be continuously administered intravenously to adults over 1 hour to 24 hours per day.

[0206] As described above, since the dosage varies depending on various conditions, there may be cases where it is sufficient even below the above dosage, and there may be cases where an amount exceeding the above dosage is required.

[0207] When this compound is used as a single agent or in combination with other drugs for the prevention and / or treatment of the above diseases, the compound as the active ingredient is usually formulated using pharmaceutically acceptable carriers such as various additives or solvents, and the resulting formulation is administered systemically or locally, orally or parenterally. Here, pharmaceutically acceptable carriers mean substances other than the active ingredient commonly used in pharmaceutical preparations. Pharmaceutically acceptable carriers preferably do not exhibit pharmacological activity at the dosage of the formulation, are harmless, and do not interfere with the therapeutic effect of the active ingredient. Pharmaceutically acceptable carriers may be used to enhance the usefulness of the active ingredient and the formulation, facilitate formulation, stabilize quality, or improve usability. Specifically, substances described in the "Dictionary of Pharmaceutical Additives" 2000, Yakujihosha (IPEC JAPAN edition) can be appropriately selected as needed.

[0208] Examples of dosage forms include, for example, oral dosage forms (e.g., tablets, capsules, granules, powders, oral liquids, syrups, oral jellies, etc.), oral preparations (e.g., oral tablets, oral sprays, oral semi-solid preparations, oral gargles, etc.), injectable preparations (e.g., injections, etc.), preparations for dialysis (e.g., dialysis agents, etc.), inhalants (e.g., inhalers, etc.), ophthalmic preparations (e.g., eye drops, eye ointments, etc.), otolaryngological preparations (e.g., ear drops, etc.), nasal preparations (e.g., nasal drops, etc.), rectal preparations (e.g., suppositories, rectal administration semi-solid preparations, enemas, etc.), vaginal preparations (e.g., vaginal tablets, vaginal suppositories, etc.), skin preparations (e.g., solid external preparations, liquid external preparations, sprays, ointments, creams, gels, patches, etc.), and the like. [Oral Dosage Forms]

[0209] Examples of oral dosage forms include tablets, capsules, granules, powders, oral solutions, syrups, oral jellies, and the like. Oral dosage forms are classified into rapidly disintegrating dosage forms in which the release of the active ingredient from the dosage form is not particularly controlled, and release-controlled dosage forms in which the release is controlled according to the purpose by adjusting the formulation design and manufacturing method, such as enteric-coated dosage forms and sustained-release dosage forms. Enteric-coated dosage forms are those designed to release the active ingredient mainly in the small intestine rather than in the stomach for the purpose of suppressing the decomposition of the active ingredient in the stomach or reducing the irritation to the stomach caused by the active ingredient. Enteric-coated dosage forms are generally manufactured by coating with an acid-insoluble enteric base. Sustained-release dosage forms are those in which the release rate, release time, and release site of the active ingredient are adjusted for the purpose of reducing the dosing frequency or side effects. Sustained-release dosage forms are usually manufactured using appropriate sustained-release agents. Among oral dosage forms, capsules, granules, and tablets may be provided with an appropriate coating film such as saccharides, sugar alcohols, and high molecular compounds for the purpose of facilitating administration or preventing the decomposition of the active ingredient. (1) Tablets

[0210] Tablets are solid oral dosage forms having a certain shape. Examples of tablets include not only those generally called tablets such as plain tablets, film-coated tablets, sugar-coated tablets, multilayer tablets, dry-coated tablets, etc., but also orally disintegrating tablets, chewable tablets, effervescent tablets, dispersible tablets, soluble tablets, and the like. Plain tablets can usually be manufactured by the following operation methods (a), (b), or (c). (a) Additives such as excipients, binders, and disintegrants are added to the active ingredient, granulated by an appropriate method using water or a solution containing a binder, and mixed with a lubricant or the like and compression molded into a homogeneous mixture. (b) Additives such as excipients, binders, and disintegrants are added to the active ingredient and mixed to make it homogeneous, and then directly compression molded, or the active ingredient, lubricant, etc. are added to the granules with additives and mixed to make it homogeneous, and then compression molded. (c) After mixing the active ingredient with additives such as excipients and binders to form a homogeneous mixture, it is wet-kneaded with a solvent, molded into a certain shape, and dried by an appropriate method. Film-coated tablets can usually be manufactured by applying an appropriate thin film such as a polymer compound to the core tablets. Sugar-coated tablets can usually be manufactured by applying a coating film containing saccharides or sugar alcohols to the core tablets. Multilayer tablets can be manufactured by stacking powder granules with different compositions in layers and compression-molding them by an appropriate method. Dry-coated tablets can be manufactured by coating the core tablets with outer layers having different compositions. Tablets can be made into enteric-coated tablets or sustained-release tablets by appropriate known methods. Orally disintegrating tablets, chewable tablets, effervescent tablets, dispersible tablets, and soluble tablets are tablets imparted with unique functions by appropriately selecting additives and can be manufactured according to the above manufacturing methods of tablets. Orally disintegrating tablets refer to tablets that dissolve or disintegrate rapidly in the oral cavity for administration. Chewable tablets refer to tablets that are chewed for administration. Effervescent tablets refer to tablets that dissolve or disperse in water while rapidly foaming. Dispersible tablets refer to tablets that are dispersed in water for administration. Soluble tablets refer to tablets that are dissolved in water for administration. Effervescent tablets can be manufactured using appropriate additives such as acidic substances, carbonates, and bicarbonates. (2) Capsules

[0211] Capsules are preparations in which the active ingredient is filled in a capsule shell or the active ingredient is coated with a capsule base. Examples of capsules include hard capsules, soft capsules, etc. Hard capsules can be manufactured by adding additives such as excipients to the active ingredient and mixing to make it homogeneous, or after obtaining granules or molded products by an appropriate method, adding them directly or after appropriate molding to the capsule shell. Soft capsules can be manufactured by encapsulating a mixture of the active ingredient and additives with an appropriate capsule base such as gelatin with increased plasticity by adding glycerin, D-sorbitol, etc., and molding it into a certain shape. Capsules can be made into enteric-coated capsules or sustained-release capsules by appropriate known methods. Colorants, preservatives, etc. may be added to the capsule base. (3) Granules

[0212] Granules are granular preparations. Examples of granules include those generally called granules and effervescent granules. Granules can usually be produced by the following methods (a), (b) or (c). (a) After mixing the active ingredient with additives such as excipients, binders, disintegrants, etc. to form a homogeneous mixture, granulate by an appropriate method; (b) In order to obtain a homogeneous mixture, the granulated active ingredient is mixed with additives such as excipients; (c) After mixing the granulated active ingredient with additives such as excipients to form a homogeneous mixture, granulate by an appropriate method. Films may be attached to the granules as needed, or they may be made into enteric-coated granules or sustained-release granules by appropriate known methods. Effervescent granules can be produced using additives such as appropriate acidic substances, carbonates, bicarbonates, etc. Effervescent granules are granules that dissolve or disperse in water while rapidly foaming. Also, they can be made finer by adjusting the particle size. (4) Powders

[0213] Powders are powdery preparations and can usually be produced by mixing additives such as excipients with the active ingredient to form a homogeneous mixture. (5) Oral liquids

[0214] An oral liquid preparation is a liquid preparation or a fluid viscous gel preparation. Examples of trending liquid preparations include, in addition to those generally called oral liquid preparations, elixirs, suspensions, emulsions, lemonade preparations, etc. Oral liquid preparations are generally manufactured by adding additives and purified water to the active ingredient, mixing them, and dissolving, emulsifying, or suspending the active ingredient homogeneously, and filtering the preparation as necessary. An elixir is a clear oral liquid preparation containing ethanol, with a sweet taste and aroma. An elixir can usually be manufactured by dissolving a solid active ingredient or its leaching solution in ethanol, purified water, flavoring, sucrose, saccharides, or a sweetening agent, etc., and obtaining a clear liquid by filtration or other methods. A suspension refers to an oral liquid preparation in which the active ingredient is finely and homogeneously suspended. A suspension can usually be manufactured by suspending a solid active ingredient in a suspending agent or additive and purified water or oil, and homogenizing the whole by an appropriate method. An emulsion refers to an oral liquid preparation in which the active ingredient is finely and homogeneously emulsified. An emulsion can usually be manufactured by adding an emulsifier and purified water to a liquid active ingredient and emulsifying and homogenizing the whole by an appropriate method. A lemonade preparation is a transparent oral liquid preparation having a sweet and sour taste. (6) Syrup preparation

[0215] Preparations include, for example, syrup preparations. A syrup preparation is a viscous liquid or solid preparation containing saccharides or a sweetening agent. Examples thereof include syrup agents. A syrup preparation is usually prepared by dissolving, mixing, suspending, or emulsifying the active ingredient in a solution of sucrose, other saccharides, or a sweetening agent, or in a syrup preparation alone, boiling if necessary, and then filtering while heating. A syrup agent is a granular or powdery dosage form to which water is added to make a syrup, and is sometimes called a dry syrup preparation. A syrup agent can usually be manufactured using saccharides or a sweetening agent as an additive, according to the above manufacturing method for granules or powders. (7) Oral jelly preparation

[0216] An oral jelly preparation is a non-fluid shaped gel preparation. An oral jelly preparation can usually be manufactured by adding additives and a polymer gel base to an active ingredient, mixing them to form a gel, and shaping it into a certain shape by an appropriate method. [Oral preparations] (1) Oral tablets

[0217] An oral tablet is a preparation having a certain shape administered in the oral cavity. Examples of oral tablets include troches, sublingual tablets, buccal tablets, adhesive tablets, chewing gums, etc. Oral tablets can usually be manufactured according to the tablet manufacturing method. A troche refers to an oral tablet that gradually dissolves or disintegrates in the oral cavity and is topically applied in the oral cavity or pharynx. A sublingual tablet refers to an oral tablet that rapidly dissolves under the tongue to absorb the active ingredient from the oral mucosa. A buccal tablet refers to an oral tablet that gradually dissolves between the molar and the cheek to absorb the active ingredient from the oral mucosa. An adhesive tablet refers to an oral tablet that adheres to the oral mucosa. A chewing gum refers to an oral tablet that releases the active ingredient by chewing. (2) Oral sprays

[0218] An oral spray is a preparation that sprays an active ingredient in a mist, powder, foam, or paste form. An oral spray can usually be manufactured by dissolving or suspending an active ingredient and an additive in a solvent or the like, filtering if necessary, and filling it into a container together with a liquefied gas or a compressed gas, or by preparing a solution or suspension containing an active ingredient and an additive and filling it into a container equipped with a spray pump. (3) Oral semi-solid preparations

[0219] Oral semi-solid preparations are preparations used for the oral mucosa. Examples of oral semi-solid preparations include creams, gels, ointments, etc. Oral semi-solid preparations are usually manufactured by emulsifying the active ingredient together with additives in an oily component such as purified water or petrolatum, or by mixing the active ingredient and additives with a base such as a polymer gel or fats and oils to form a homogeneous mixture. A cream preparation refers to a semi-solid preparation of an oil-in-water or water-in-oil emulsion. A lipophilic preparation of a water-in-oil emulsion is also called an oily cream preparation. A cream preparation is usually prepared by preparing an oil phase from petrolatum or a higher alcohol or a mixture of these and additives such as an emulsifier, preparing an aqueous phase from purified water or a mixture of these and additives such as an emulsifier, adding the active ingredient to the oil phase or the aqueous phase, heating both phases, and mixing them until homogeneous to obtain an emulsion. A gel refers to a gel preparation, and examples include aqueous gels and oily gels. An aqueous gel can be manufactured by dissolving or suspending the active ingredient in a polymer compound and additives such as purified water, and crosslinking by heating and cooling, or by adding a gelling agent. An oily gel can be manufactured by mixing the active ingredient with a liquid oil base such as glycol or a higher alcohol and additives. An ointment preparation refers to a semi-solid preparation in which the active ingredient is dissolved or dispersed in a base. Examples of ointment preparations include oleaginous ointment preparations and water-soluble ointment preparations. An oleaginous ointment preparation can usually be manufactured by dissolving an oleaginous base such as fats, waxes, hydrocarbons containing paraffin, heating, dissolving or dispersing the active ingredient therein, and mixing and kneading to form a homogeneous mixture. A water-soluble ointment preparation can usually be manufactured by dissolving a water-soluble base such as macrogol, heating, mixing and kneading the active ingredient therein to form a homogeneous mixture. (4) Gargle

[0220] An oral gargle is a liquid preparation for topical use in the oral cavity or pharynx, and may include a solid preparation that dissolves during use. An oral gargle can usually be manufactured by homogeneously dissolving the active ingredient in a solvent and additives, and filtering if necessary. A solid preparation that dissolves during use can usually be manufactured according to the above manufacturing methods for tablets and granules. [Injectable preparation] (1) Injectable

[0221] An injectable is a sterile solid preparation that is a solution, suspension or emulsion, or a solid that is dissolved or suspended at the time of use, and is directly administered to body tissues and organs such as subcutaneous, intramuscular or blood vessels. Examples thereof include, in addition to those generally called injectables, freeze-dried injectables, powder injectables, prefilled syringes, cartridges, infusions, implantable injectables, sustained-release injectables, and the like. Injectables can generally be manufactured by the following method (a) or (b). (a) Dissolve, suspend or emulsify the active ingredient or a mixture of the active ingredient and additives in water for injection or other aqueous or non-aqueous solvents, fill the injectable container, and then sterilize; (b) The active ingredient or a mixture of the active ingredient and an additive is dissolved, suspended or emulsified in water for injection or other aqueous or non-aqueous solvents, and then aseptically filtered or aseptically and homogeneously prepared, filled into a container for injection and sealed. To manufacture a freeze-dried injection, usually, the active ingredient or the active ingredient together with additives such as solvents is dissolved in water for injection, aseptically filtered, then the injection solution is filled into a container for injection and freeze-dried, or freeze-dried in a container dedicated for freeze-drying and then filled into a container for injection. A powder injection is usually manufactured by using aseptic filtration and crystallization to obtain a powder, and filling the powder directly or a mixture of the powder and a sterile additive into a container for injection. A prefilled syringe can usually be manufactured by filling a solution, suspension or emulsion of the active ingredient or a mixture of the active ingredient and an additive into the syringe. A cartridge refers to a cartridge-type injection containing a drug solution filled in a dedicated syringe. A cartridge containing a drug solution can usually be manufactured by filling a solution, suspension or emulsion of the active ingredient or the active ingredient and an additive into the cartridge. An infusion refers to an injection of usually 100 mL or more administered intravenously. An implantable injection is a solid or gel-like injection, which is used by using an implantable device or through subcutaneous or intramuscular surgery to release the active ingredient over a long period of time. An implantable injection can usually be manufactured by using a biodegradable polymer compound to form pellets, microspheres or gels. A sustained-release injection is an injection administered intramuscularly to release the active ingredient over a long period of time, and generally can be manufactured by dissolving or suspending the active ingredient in a vegetable oil or obtaining a microsphere suspension by using a biodegradable polymer compound. [Formulations for dialysis] (1) Agent for dialysis

[0222] The dialysis agent is a liquid agent or solid preparation that is used for peritoneal dialysis or hemodialysis and dissolves during use. For example, peritoneal dialysis agents, hemodialysis agents, etc. may be mentioned. The peritoneal dialysis agent refers to a sterile dialysis agent used for peritoneal dialysis. Usually, a solution in which an active ingredient and an additive are dissolved in a certain amount of solvent, or a mixture of an active ingredient and an additive is filled into a container, sealed, and sterilized as necessary can be manufactured. The solid preparation that dissolves during use can usually be manufactured according to the manufacturing methods of tablets and granules described above. The hemodialysis agent refers to a dialysis agent used for hemodialysis. Usually, a solution in which an active ingredient and an additive are dissolved in a certain amount of solvent, or a mixture of an active ingredient and an additive can be manufactured by filling it into a container. The solid preparation that dissolves during use can usually be manufactured according to the manufacturing methods of tablets and granules described above. [Inhalation preparation] (1) Inhalant

[0223] An inhalant is a preparation that is administered to the bronchus or lung by inhaling an aerosol of an active ingredient. For example, inhaled powders, inhaled liquid agents, inhaled aerosols, etc. may be mentioned. An inhaled powder is a preparation that causes a predetermined amount of solid particles to be inhaled in an aerosol form. Usually, fine particles of an active ingredient are prepared and, if necessary, mixed with an additive such as lactose to make it homogeneous, and then it can be manufactured. An inhaled liquid agent refers to an inhaled liquid agent that is administered by a nebulizer or the like. Usually, an active ingredient is homogeneously dissolved or suspended in a solvent, a suitable tonicity agent, a pH adjuster, etc., and filtered as necessary to manufacture it. An inhaled aerosol agent refers to a metered-dose inhaler that sprays a certain amount of an active ingredient filled in a container together with a propellant. [Ophthalmic preparation] (1) Eye drops

[0224] Eye drops are a sterile liquid agent or a sterile solid preparation that dissolves or suspends during use and is administered to eye tissues such as the conjunctival sac. Eye drops can usually be manufactured by dissolving or suspending an active ingredient and an additive in a certain amount of solvent or the like, or by filling a container with a mixture of an active ingredient and an additive. (2) Ophthalmic ointment

[0225] An eye ointment is a semi-solid sterile preparation administered to eye tissues such as the conjunctival sac, etc., and can usually be manufactured by filling a container with a homogeneous mixture of a base such as petrolatum and a solution or fine powder of an active ingredient. [Preparations for otology] (1) Ear drops

[0226] An ear drop is a liquid preparation, semi-solid preparation or solid preparation that is administered to the outer ear or middle ear and is dissolved or suspended during use. Ear drops can usually be manufactured by dissolving or suspending an active ingredient and additives in a certain amount of a solvent, etc., or by filling a container with a mixture of an active ingredient and additives. [Nasal preparations] (1) Nasal drops

[0227] A nasal preparation is a preparation administered to the nasal cavity or nasal mucosa, and examples include nasal powder preparations, nasal drops, etc. A nasal powder preparation is a fine powder nasal preparation for nasal administration, and can usually be manufactured by making an active ingredient into an appropriate fine powder and, if necessary, mixing the active ingredient and additives to form a homogeneous mixture. A nasal drop is a liquid or solid nasal preparation that dissolves or suspends during use and is administered to the nasal cavity. A nasal drop can usually be manufactured by dissolving or suspending an active ingredient in a solvent and additives and filtering if necessary. Additives for nasal drops that can be used include tonicity agents, pH adjusters, etc. [Rectal preparations] (1) Suppository

[0228] A suppository is a semi-solid preparation of a certain shape that is administered rectally and releases an active ingredient by melting at body temperature or by gradually dissolving or dispersing in water. A suppository can usually be manufactured by dissolving or homogeneously dispersing a homogeneous mixture of an active ingredient and additives such as a dispersant and an emulsifier in a base liquefied by heating, etc., filling a container with a predetermined amount, and solidifying / molding. Bases commonly used for suppositories include oily bases and hydrophilic bases. (2) Semi-solid preparation for rectal administration

[0229] Semi-solid preparations for rectal administration are preparations administered around or into the anus, and examples include rectal creams, rectal gels, rectal ointments, etc. Semi-solid preparations for rectal administration are usually manufactured by emulsifying the active ingredient together with additives in purified water and an oily ingredient such as petrolatum, or by homogeneously mixing the active ingredient and additives with a base composed of a polymer gel or fats and oils. A rectal cream usually prepares an oil phase from petrolatum, a higher alcohol or a mixture of these and additives such as an emulsifier, prepares an aqueous phase from purified water or a mixture of these and additives such as an emulsifier, adds the active ingredient to the oil phase or the aqueous phase and heats it, mixes the oil phase and the aqueous phase to make it homogeneous, and forms an emulsion. A rectal gel is a gel preparation, and examples include aqueous gels, oily gels, etc. An aqueous gel can be manufactured by dissolving or suspending the active ingredient in additives such as a polymer compound and purified water, and crosslinking by heating and cooling, or by adding a gelling agent. An oily gel can be manufactured by mixing the active ingredient with a liquid oil base such as glycols or a higher alcohol and additives. A rectal ointment is a semi-solid preparation in which the active ingredient is dissolved or suspended in a base, and examples include oily ointments, water-soluble ointments, etc. An oily ointment can usually be manufactured by heating, dissolving or suspending the active ingredient in an oily base such as fats and oils, waxes, hydrocarbons containing paraffin, and mixing and kneading to form a homogeneous mixture. A water-soluble ointment can generally be manufactured by melting a water-soluble base such as macrogol by heating, mixing and kneading the active ingredient to form a homogeneous mixture. (3) Enemas

[0230] An enema is a liquid or viscous gel preparation administered through the anus. An enema can usually be manufactured by dissolving or suspending the active ingredient in a certain amount of solvent, etc. using purified water or an appropriate aqueous solvent, and filling it into a container. Additives that can be used in enemas include dispersants, stabilizers, pH adjusters, etc. [Vaginal preparations] (1) Vaginal tablets

[0231] Vaginal tablets are solid preparations with a certain shape, which are administered intravaginally and release the active ingredient by gradually dissolving or dispersing in water. Vaginal tablets can usually be manufactured according to the above-mentioned tablet manufacturing method.

[0232] Vaginal suppositories are semi-solid preparations with a certain shape, which are administered intravaginally and release the active ingredient by melting at body temperature or gradually dissolving or dispersing in water. Vaginal suppositories can usually be manufactured according to the manufacturing methods of the above-mentioned rectal suppositories, etc. [Skin preparations] (1) External solid preparations External solid preparations are solid preparations administered or applied to the skin including the scalp or nails, and examples include external powder preparations. External powder preparations refer to external solid powder preparations, and can usually be manufactured by mixing the active ingredient and additives such as a base and making it into a homogeneous mixture and then powdering. (2) External liquid preparations

[0233] External liquid preparations are liquid preparations administered to the skin including the scalp or nails, and examples include liniments, lotions, etc. External liquid preparations can usually be manufactured by dissolving, emulsifying or suspending the active ingredient in a solvent, additives, etc. and filtering if necessary. Liniments refer to liquid or muddy external liquid preparations rubbed on the skin. Lotions refer to external liquid preparations in which the active ingredient is dissolved, emulsified or finely dispersed in an aqueous liquid. Lotions can usually be manufactured by preparing a solution, suspension or emulsion of the active ingredient, additives and purified water and making it into a homogeneous preparation. (3) Sprays

[0234] A spray agent is a preparation that sprays an active ingredient onto the skin in the form of a mist, powder, foam, or paste. Examples include topical aerosol agents, pump spray agents, etc. A spray agent can usually be manufactured by preparing a solution or suspension of the active ingredient, filtering it if necessary, and filling it into a container. A topical aerosol agent refers to a spray agent that sprays the active ingredient together with a liquefied gas or compressed gas filled in a container. A topical aerosol can usually be manufactured by preparing a solution or suspension of the active ingredient and filling it into a pressure-resistant container equipped with a continuous injection valve together with a liquid propellant. Additives such as dispersants and stabilizers may be optionally added to the topical aerosol. A pump spray agent refers to a spray agent that sprays the active ingredient in the container by means of a pump. A pump spray agent can usually be manufactured by dissolving or suspending the active ingredient and additives and filling it into a container equipped with a pump. (4) Ointment

[0235] An ointment is a semi-solid preparation that dissolves or disperses the active ingredient in a base and applies it to the skin. Examples include oily ointments, water-soluble ointments, etc. An oily ointment can usually be manufactured by melting an oily base such as fats, waxes, hydrocarbons containing paraffin by heating, dissolving or suspending the active ingredient, and mixing and kneading to form a homogeneous mixture. A water-soluble ointment can usually be manufactured by melting a water-soluble base such as macrogol by heating, mixing and kneading the active ingredient to form a homogeneous mixture. (5) Cream

[0236] A cream is a semi-solid preparation in the form of an oil-in-water or water-in-oil emulsion, which is applied to the skin. A fat-soluble preparation of a water-in-oil emulsion is also called an oily cream. A cream can usually be manufactured by preparing an oil phase from petrolatum, higher alcohols or a mixture of these and additives such as emulsifiers, preparing an aqueous phase from purified water or a mixture of these and additives such as emulsifiers, adding the active ingredient to the oil phase or aqueous phase, heating both phases, and mixing and emulsifying until the oil phase and aqueous phase become homogeneous. (6) Gel

[0237] The gel preparation is a gel preparation for application to the skin, and examples thereof include aqueous gel preparations, oily gel preparations, and the like. An aqueous gel preparation can usually be produced by dissolving or suspending an active ingredient in additives such as a polymer compound and purified water, and crosslinking by heating and cooling, or by adding a gelling agent. An oily gel can be produced by mixing an active ingredient with a liquid oil base such as glycol or a higher alcohol and an additive. (7) Patch

[0238] A patch is a preparation for application to the skin, and examples thereof include tapes, cataplasms, and the like. A patch can usually be produced by homogeneously mixing an active ingredient with a base that is a polymer compound or a mixture thereof, and spreading and molding it on a support or a liner (release material). A patch can be made into a transdermal absorption preparation using a release control film. Additives such as an adhesive or an absorption promoter may be used in the patch. A tape preparation refers to a patch containing a base containing a small amount of water, and examples thereof include adhesive plasters and the like. A tape preparation can usually be produced using a natural or synthetic polymer compound insoluble in water such as resin, plastic, or rubber as a base, and spreading an active ingredient or a homogeneous mixture of an active ingredient and an additive on cloth or spreading or encapsulating it on a plastic film and molding it. A tape preparation can also be produced by incorporating a mixture of an active ingredient and a base or other additives into a release material composed of a release control film, a support, and a liner (release material) and molding it. A cataplasm is a patch containing a base containing water, and it can usually be produced by mixing a liquid substance such as purified water or glycerin with an active ingredient to make it homogeneous, or by kneading purified water in addition to an active ingredient into a natural or synthetic polymer compound such as a water-soluble polymer or a water-absorbing polymer to make it homogeneous, and spreading and molding it on cloth or the like.

[0239] Unless otherwise defined, all technical and scientific terms and abbreviations used herein have the same meaning as commonly understood by those skilled in the art to which the present invention pertains.

[0240] The content of all patent documents, non-patent documents or reference documents explicitly cited in this specification can be incorporated as part of this specification.

Examples

[0241] The present invention will be described in detail below by way of examples and biological examples, but the present invention is not limited thereto. The compound names of the present invention and the compounds shown in the examples are named according to the IUPAC nomenclature. Naming according to the IUPAC nomenclature can be performed using, for example, ACD / Name (version 2019.2.0, Advanced Chemistry Development Inc.), ACD / Name Batch (version 12.02.45356, Advanced Chemistry Development Inc.) or ChemDraw Professional (version 17.1.0.105 or 18.0.0.231, available from PerkinElmer Inc.). In each of the following examples, the name of the target compound of the example is described after the example number, and the compound may also be referred to as the "marked compound". Analysis method

[0242] 1 The 1H NMR spectrum was recorded on a Bruker DRX-400 instrument and calibrated using the remaining non-deuterated solvent ( 1 In 1H NMR, CHCl at 7.26, 2.50, and 3.31 ppm respectively 3 , DMSO, methanol). The chemical shift (δ) is shown in parts per million (ppm), and based on the corresponding NMR solvent peak, it is shown in a numbered chart as s (singlet), d (doublet), t (triplet), q (quartet), combinations thereof (i.e., td represents a triplet of doublets) or m (multiplet) and br s (broad singlet).

[0243] The liquid chromatography MS analysis method (LCMS) used is as follows.; General LCMS procedure Method 1 Simadzu LC20-MS2010, Agilent Pursit5 C at 50 °C 18 Equipped with 20×2.0 mm. Mobile phase (A): 1.5 mL of TFA - 4 L of water; Mobile phase (B): 0.75 mL of TFA - acetonitrile solution. Gradient: Gradient - Time Flow rate mL / min %A %B 0.00 1.5 95 5 0.70 1.5 5 95 1.10 1.5 5 95 1.11 1.5 95 5 1.50 1.5 95 5 Detection: MS, UV220, 254 nm. MS ionization method: Electrospray (positive ion). Method 2 Simadzu LC20-MS2010, equipped with Xbridge Shield RP-18, 5um, 2.1x50mm at 50 °C. Mobile phase (A): 0.8 mL of NH 3 - water - 4 L of water; Mobile phase (B): Acetonitrile. Gradient: Gradient - Time Flow rate mL / min %A %B 0.00 1.0 50 50 2.00 1.0 0 100 2.48 1.0 0 100 2.49 1.0 5 50 3.00 1.0 50 50 Detection: MS, UV220, 254 nm. MS ionization method: Electrospray (positive ion). Column: XBridge C 18 3.5um, 2.1x50mm;

[0244] The high performance liquid chromatography (HPLC) used is as follows. General HPLC procedure Method 1 SHIMADZU 20A, Ultimate C at 40 °C18 It has 3.0x50mm and 3um. Mobile phase (A): 2.75 mL of TFA - 4 L of water; Mobile phase (B): 2.5 mL of TFA - acetonitrile. Gradient: Gradient - Time Flow rate mL / min %A %B 0.00 1.2 70 30 6.00 1.2 10 90 8.00 1.2 10 90 8.01 1.2 70 30 10.00 1.2 70 30 Detection: MS, UV220, 254 nm. MS ionization method: Electrospray (positive ion). Method 2 SHIMADZU 20A, Ultimate C at 40 °C 18 It has 3.0x50mm and 3um. Mobile phase (A): 2.75 mL of TFA - 4 L of water; Mobile phase (B): 2.5 mL of TFA - acetonitrile. Gradient: Gradient - Time Flow rate mL / min %A %B 0.00 1.2 90 10 6.00 1.2 20 80 8.00 1.2 20 80 8.01 1.2 90 10 10.00 1.2 90 10 Detection: MS, UV220, 254 nm. MS ionization method: Electrospray (positive ion). Method 3 SHIMADZU LC20 - MS2020, Xbridge Shield RP - 18, 5 um, 2.1 x 50 mm at 50 °C. Elution with A: 0.8 mL of NH 3 · water in 4 L water; B: Acetonitrile. Gradient: SHIMADZU LC20 - MS2020, equipped with Xbridge Shield RP - 18 2.1x50mm, 5um at 50 °C. 0.8 mL of NH3 - Water - 4 L of water; Mobile phase (B): Acetonitrile. Gradient: Gradient - Time Flow rate mL / min %A %B 0.00 0.8 90 10 6.00 0.8 20 80 6.50 0.8 20 80 6.51 0.8 90 10 7.00 0.8 90 10 Detection: MS, UV220, 254 nm. MS ionization method: Electrospray (positive ion).

[0245] The chiral supercritical fluid chromatography (SFC) used is as follows.; Chiral SFC procedure Method 1 Column: ChiralPak AD - 3 150×4.6 mm I.D., 3 um Mobile phase: A: CO 2 , B: IPA (0.05% DEA) Isocratic: 40% B Flow rate: 2.5 mL / min, Column temperature: 40 °C Back pressure: 100 bar Method 2 Column: Chiralcel OJ - 3 150×4.6 mm I.D., 3 um Mobile phase: A: CO 2 , B: EtOH (0.05% DEA) Gradient: 5% to 40% of B for 5 min, 40% to 5% of B for 0.5 min, hold at 5% of B for 1.5 min Flow rate: 2.5 mL / min Column temperature: 35 °C ABPR: 1500 psi Method 3 Column: Chiralcel OD - 3 150×4.6 mm I.D., 3 um Mobile phase: A: CO 2 , B: EtOH (0.05% DEA) Gradient: 5% to 40% B for 5 minutes, 40% to 5% B for 0.5 minutes, hold at 5% B for 1.5 minutes Flow rate: 2.5 mL / min Column temperature: 35 °C ABPR: 1500 psi

[0246] Abbreviations 2-MeTHF = 2-methyltetrahydrofuran; 4A MS = Molecular sieves, 4A; DAST = N,N-diethylaminosulfur trifluoride; DCM = Dichloromethane; DE = Diethyl ether; DEA = Diethylamine; DIPEA = Diisopropylethylamine; DMF = N,N-dimethylformamide; DMP = Dess-Martin periodinane; DMSO = Dimethyl sulfoxide; dppf = 1,1’-ferrocenediylbis(diphenylphosphine); EA = Ethyl acetate; EDCI = 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide; HATU = 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate; MTBE = Methyl tert-butyl ether; NBS = N-bromosuccinimide; NCS = N-chlorosuccinimide; PE = Petroleum ether; TBHP = tert-butyl hydroperoxide; TEA = Triethylamine; TFA = Trifluoroacetic acid; THF = Tetrahydrofuran; TLC = Thin layer chromatography X-Phos = 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl.

[0247] Example 1 [(1R,5S,6r)-6-(5,5-dimethyl-4,5-dihydro-1,2-oxazol-3-yl)-3-azabicyclo[3.1.0]hexan-3-yl](1-isopropyl-1H-imidazol-4-yl)methanone

Chem.

[0248] tert-Butyl (1R,5S,6r)-6-[(Z)-chloro-(hydroxyimino)methyl]-3-azabicyclo[3.1.0]hexane-3-carboxylate To a solution of tert-butyl (1R,5S,6r)-6-[(E)-(hydroxyimino)methyl]-3-azabicyclo[3.1.0]hexane-3-carboxylate (2.2 g, 9.72 mmol) in DMF (18.4 mL) was added N-chlorosuccinimide (1363 mg, 10.21 mmol), and the mixture was stirred at 20 °C for 2 hours. The mixture was poured into water (90 mL) and extracted with ethyl acetate (50 mL × 3). The organic layer was washed with saturated brine (50 mL × 3), dried over anhydrous sodium sulfate, and concentrated to obtain the title compound as a white solid. LC-MS Method1 0.780 min, MS (m / z) 245.9 (M + H + ) 1 1H NMR (400 MHz, chloroform-d) δ ppm 8.42 (s, 1 H), 3.75 (d, J = 11.2 Hz, 1 H), 3.64 (d, J = 10.8 Hz, 1 H), 3.38 (d, J = 10.8 Hz, 2 H), 2.06 (s, 2 H), 1.76 (t, J = 3.2 Hz, 1 H), 1.45 (s, 9 H).

[0249] tert-Butyl (1R,5S,6r)-6-(5,5-dimethyl-4,5-dihydro-1,2-oxazol-3-yl)-3-azabicyclo[3.1.0]hexane-3-carboxylate To a solution of tert-butyl (1R,5S,6r)-6-[(Z)-chloro(hydroxyimino)methyl]-3-azabicyclo[3.1.0]hexane-3-carboxylate (100 mg, 0.38 mmol) and triethylamine (0.19 mL, 1.15 mmol) in DMF (1.0 mL) was added 2-methylprop-1-ene (0.72 mL, 1.15 mmol) (15% isopropyl ether solution), and the mixture was stirred at 20 °C for 16 hours. The reaction mixture was poured into water (20 mL) and extracted with ethyl acetate (20 mL × 3). The organic layer was washed with brine (20 mL × 3), dried over anhydrous sodium sulfate, and concentrated to obtain the title compound (100 mg, 0.356 mmol, yield 92.9%) as a yellow oil. LC-MS Method1 0.852 min, MS (m / z): 281 (M + H + ) 1 1H NMR (400 MHz, dimethyl sulfoxide-d6) δ ppm 3.50 (d, J = 11.1 Hz, 2H), 3.30 (d, J = 10.8 Hz, 2H), 2.61 (s, 2H), 1.91 (t, J = 2.7 Hz, 2H), 1.40 - 1.38 (m, 1H), 1.37 (s, 9H), 1.23 (s, 6H).

[0250] (1R,5S,6r)-6-(5,5-Dimethyl-4,5-dihydro-1,2-oxazol-3-yl)-3-azabicyclo[3.1.0]hexane hydrochloride tert-Butyl (1R,5S,6R)-6-(5,5-dimethyl-4,5-dihydro-1,2-oxazol-3-yl)-3-azabicyclo[3.1.0]hexane-3-carboxylate (100 mg, 0.36 mmol) was stirred in a hydrochloric acid / dioxane (2.0 mL, 8.0 mmol, 4.0 M) mixture at 20 °C for 0.5 h. The mixture was concentrated to give the title compound (100 mg, 0.46 mmol, yield 129%, crude) as a yellow oil. LC-MS Method1 0.232 min, MS (m / z): 181 (M - HCl + H + ). 1 1H NMR (400 MHz, dimethyl sulfoxide-d6) δ ppm 9.53 (brs, 1H), 9.06 (brs, 1H), 3.40 - 3.26 (m, 4H), 2.60 (s, 2H), 2.12 (brs, 2H), 1.99 (m, 1H), 1.23 (s, 6H).

[0251] [(1R,5S,6r)-6-(5,5-Dimethyl-4,5-dihydro-1,2-oxazol-3-yl)-3-azabicyclo[3.1.0]hex-3-yl](1-isopropyl-1H-imidazol-4-yl)methanone (1R,5S,6r)-6-(5,5-Dimethyl-4,5-dihydro-1,2-oxazol-3-yl)-3-azabicyclo[3.1.0]hexane hydrochloride (100 mg, 0.46 mmol), 1-isopropylimidazole-4-carboxylic acid (92 mg, 0.6 mmol), and DIPEA (0.38 mL, 2.31 mmol) in DMF (3.0 mL) were added HATU (194 mg, 0.51 mmol), and the mixture was stirred at 20 °C for 16 h. The mixture was poured into water (30 mL) and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated to obtain a residue. The residue was purified by Prep-HPLC (NH 3 ) to give the title compound (4 mg, 0.012 mmol, 2.7% yield) as a white solid. 1 1H NMR (400 MHz, CDCl 3 -d): δ ppm 1.38 (s, 6 H) 1.46 (t, J = 3.5 Hz, 1 H) 1.51 (d, J = 6.8 Hz, 6 H) 1.98 (br d, J = 3.5 Hz, 1 H) 2.08 (br d, J = 3.0 Hz, 1 H) 2.64 (s, 2 H) 3.62 (dd, J = 12.5, 4.5 Hz, 1 H) 3.95 (dd, J = 11.9, 3.6 Hz, 1 H) 4.20 (d, J = 12.5 Hz, 1 H) 4.36 (dt, J = 13.5, 6.7 Hz, 1 H) 4.75 (d, J = 12.0 Hz, 1 H) 7.47 (d, J = 1.3 Hz, 1 H) 7.67 (d, J = 1.5 Hz, 1 H) LCMS Method 1 0.65 min, MS (m / z) 317.0 [M+H + .

[0252] Example 2 [(1R,5S,6r)-6-(5,5-Dimethyl-4,5-dihydro-1,2-oxazol-3-yl)-3-azabicyclo[3.1.0]hexan-3-yl](1-methyl-1H-imidazol-4-yl)methanone [(1R,5S,6r)-6-(5,5-Dimethyl-4,5-dihydro-1,2-oxazol-3-yl)-3-azabicyclo[3.1.0]hex-3-yl](1-methyl-1H-imidazol-4-yl)methanone A mixture of 1-methyl-1H-imidazole-4-carboxylic acid (52.47 mg, 0.42 mmol) and EDCI (79.76 mg, 0.42 mmol) in pyridine (1.0 mL) was added to (1R,5S,6r)-6-(5,5-dimethyl-4,5-dihydro-1,2-oxazol-3-yl)-3-azabicyclo[3.1.0]hexane hydrochloride (91 mg, 0.42 mmol). The suspension was stirred at 20 °C for 8 hours. The reaction mixture was concentrated under reduced pressure. The residue was purified by Prep-HPLC (NH 3 ) and freeze-dried to obtain the title compound (17.45 mg, yield 21.8%) as a yellow solid. LC-MS Method1: 0.691 min, MS (m / z): 289.2 (M + H + ). 1 H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.56 (d, J = 1.25 Hz, 1 H), 7.38 (s, 1 H), 4.70 (d, J = 12.05 Hz, 1 H), 4.19 (d, J = 12.30 Hz, 1 H), 3.94 (dd, J = 12.05, 4.02 Hz, 1 H), 3.72 (s, 3 H), 3.61 (dd, J = 12.55, 4.27 Hz, 1 H), 2.64 (s, 2 H), 2.05 - 2.11 (m, 1 H), 1.95 - 2.01 (m, 1 H), 1.46 (t, J = 3.39 Hz, 1 H), 1.38 (s, 6 H).

[0253] Example 3 [((1R,5S,6r)-6-(5,5-dimethyl-4,5-dihydro-1,2-oxazol-3-yl)-3-azabicyclo[3.1.0]hex-3-yl](1-ethyl-1H-imidazol-4-yl)methanone Ethyl 1-ethyl-1H-imidazole-4-carboxylate A mixture of ethyl (2Z)-3-(dimethylamino)-2-isocyanatoacrylate and ethylamine (1608.2 mg, 35.67 mmol, 1.60 mL, 20 eq) was stirred at 40 °C for 16 h. The solution was then concentrated under reduced pressure. The residue was purified by prep-TLC (PE:ethyl acetate = 0:1, Rf = 0.2) to give the title compound (126 mg, crude) as a yellow oil. LC-MS Method1: 0.259 min, MS (m / z): 168.8(M + H + ). 1 H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.64 (s, 1H), 7.51 (s, 1H), 4.37 (q, J = 7.2 Hz, 2H), 4.04 (q, J = 7.2 Hz, 2H), 1.39 (t, J = 7.2 Hz, 3H), 1.26 (t, J = 7.2 Hz, 3H).

[0254] 1-Ethyl-1H-imidazole-4-carboxylic acid To a solution of ethyl 1-ethyl-1H-imidazole-4-carboxylate in water (0.5 mL) and THF (1.5 mL) was added lithium hydroxide monohydrate (47.16 mg, 1.12 mmol, 1.5 eq). The suspension was stirred at 40 °C for 6 h. The residue was diluted with water (1 mL) and extracted with ethyl acetate (5 mL x 4). The combined aqueous layers were acidified to pH = 5 with aqueous hydrochloric acid (1N). The combined organic layers were concentrated and then lyophilized to give the title compound (70 mg, crude) as a yellow solid. 1 H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.69 (s, 1H), 7.45 (s, 1H), 3.98 (q, J = 7.2 Hz, 2H), 1.33 (t, J = 7.2 Hz, 3H).

[0255] [(1R,5S,6r)-6-(5,5-Dimethyl-4,5-dihydro-1,2-oxazol-3-yl)-3-azabicyclo[3.1.0]hex-3-yl](1-ethyl-1H-imidazol-4-yl)methanone To a mixture of pyridine (1 mL) of 1-ethyl-1H-imidazole-4-carboxylic acid, EDCI (95.54 mg, 0.50 mmol) and (1R,5S,6r)-6-(5,5-dimethyl-4,5-dihydro-1,2-oxazol-3-yl)-3-azabicyclo[3.1.0]hexane hydrochloride (72 mg, 0.33 mmol) were added. The suspension was stirred at 20 °C for 16 hours. The solution was purified by Prep-HPLC(NH 3 ) and lyophilized to obtain the title compound (23.69 mg, yield 23.58%) as a yellow solid. LC-MS Method1: 2.045 min, MS (m / z): 303.2 (M + H + ). 1 H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.54 (d, J = 1.25 Hz, 1 H) 7.35 (d, J = 1.25 Hz, 1 H) 4.65 (d, J = 12.05 Hz, 1 H) 4.12 (d, J = 12.30 Hz, 1 H) 3.94 (q, J = 7.28 Hz, 2 H) 3.87 (dd, J = 12.05, 4.02 Hz, 1 H) 3.54 (dd, J = 12.55, 4.27 Hz, 1 H) 2.57 (s, 2 H) 2.00 (dt, J = 7.47, 3.92 Hz, 1 H) 1.91 (br d, J = 3.76 Hz, 1 H) 1.37 - 1.44 (m, 4 H) 1.30 (s, 7 H).

[0256] Example 4 (1-Cyclopropyl-1H-imidazol-4-yl)[((1R,5S,6r)-6-(5,5-dimethyl-4,5-dihydro-1,2-oxazol-3-yl)-3-azabicyclo[3.1.0]hexan-3-yl]methanone Methyl 1-cyclopropyl-1H-imidazole-4-carboxylate A suspension of 2,2'-bipyridine (618.79 mg, 3.96 mmol), copper(II) acetate (720.01 mg, 3.96 mmol), and sodium carbonate (840.54 mg, 7.93 mmol) in DCE (30 mL) was added with methyl 1H-imidazole-4-carboxylate (500 mg, 3.96 mmol) and cyclopropylboronic acid (681.15 mg, 7.93 mmol). The mixture was stirred at 70 °C under an oxygen atmosphere for 16 h. TLC (PE:ethyl acetate = 1:4) indicated the completion of the reaction. The reaction mixture was cooled to 23 °C. The solid was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by flash column (PE → 20% ethyl acetate in PE). The combined organic layers were concentrated under reduced pressure to afford the title compound (140 mg, 0.8425 mmol, yield 21.249%) as a brown oil. 1 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.66 (s, 1H), 7.60 (s, 1H), 3.87 (s, 3H), 3.42 - 3.36 (m, 1H), 1.10 - 0.90 (m, 4H).

[0257] 1-Cyclopropyl-1H-imidazole-4-carboxylic acid To a solution of methyl 1-cyclopropyl-1H-imidazole-4-carboxylate (140 mg, 0.84 mmol) in THF (3 mL) and water (1 mL) was added lithium hydroxide monohydrate (0.06 mL, 1.1 mmol). The resulting mixture was stirred at 20 - 25 °C for 2 h to obtain a white suspension. TLC (PE:ethyl acetate = 1:4) indicated the completion of the reaction (Rf = 0). The reaction solution was directly concentrated. The residue was acidified with aqueous hydrochloric acid (1 M), and then the obtained organic layer was lyophilized to afford the title compound (120 mg, 0.7887 mmol, yield 93.618%) as a white solid.

[0258] (1-Cyclopropyl-1H-imidazol-4-yl)[((1R,5S,6r)-6-(5,5-dimethyl-4,5-dihydro-1,2-oxazol-3-yl)-3-azabicyclo[3.1.0]hex-3-yl]methanone To a solution of 1-cyclopropyl-1H-imidazole-4-carboxylic acid (120 mg, 0.79 mmol) in DMF (3 mL) were added HATU (361.82 mg, 0.95 mmol), triethylamine (0.51 mL, 3.94 mmol), and (1R,5S,6r)-6-(5,5-dimethyl-4,5-dihydro-1,2-oxazol-3-yl)-3-azabicyclo[3.1.0]hexane hydrochloride (142.16 mg, 0.79 mmol). The resulting mixture was stirred at 20 - 25 °C for 14 hours. The residue was purified by Prep-HPLC (hydrochloric acid). The combined organic layers were concentrated and then lyophilized to give the title compound (4.8 mg, 0.0137 mmol, yield 1.7347%) as a pale yellow gum. LC-MS Method1: 315.0 [M+H + 1 H NMR (400MHz, METHANOL-d 4 ) δ = 8.68 - 8.33 (m, 1H), 7.91 (br s, 1H), 4.10 - 3.84 (m, 3H), 3.60 (br d, J=4.8 Hz, 2H), 2.63 (s, 2H), 2.16 - 1.99 (m, 2H), 1.44 (br s, 1H), 1.24 (s, 7H), 1.07 (d, J=6.5 Hz, 4H).

[0259] Example 5 (1-Cyclobutyl-1H-imidazol-4-yl)[((1R,5S,6r)-6-(5,5-dimethyl-4,5-dihydro-1,2-oxazol-3-yl)-3-azabicyclo[3.1.0]hexan-3-yl]methanone Ethyl 1-cyclobutyl-1H-imidazole-4-carboxylate ​A mixture of ethyl (2Z)-3-(dimethylamino)-2-isocyanoacrylate (400 mg, 2.38 mmol) and cyclobutanamine (1.02 mL, 11.89 mmol) was heated at 50 °C for 16 h. After concentrating the mixture under reduced pressure, the residue was purified by flash column (0 - 100% ethyl acetate in PE, 0.5% aqueous ammonia solution) to give the title compound (420 mg, 2.1624 mmol, 90.923% yield) as a yellow oil. LC-MS Method1 0.568 min, MS (M / Z) 194.9 (M + H + )。

[0260] 1-Cyclobutyl-1H-imidazole-4-carboxylic acid To a mixture of ethyl 1-cyclobutyl-1H-imidazole-4-carboxylate (100 mg, 0.5100 mmol) in THF (0.8578 mL) and water (1.0722 mL), lithium hydroxide monohydrate (0.09 mL, 1.54 mmol) was added. The resulting suspension was stirred at 20 °C for 3.5 h. TLC (100% ethyl acetate) showed a new spot (Rf = 0), and the reactant was completely consumed. The aqueous layer was washed with DCM (3 mL × 2) and acidified to pH = 2 with aqueous hydrochloric acid (1N). The residual aqueous solution was lyophilized to give the title compound (160 mg, 0.9628 mmol, 187.01% yield) as a pale yellow solid. 1 H NMR(400 MHz,D 2 O)δ ppm 8.77(s, 1 H), 8.03(s, 1 H), 4.85 - 4.75(m, 1 H), 2.50 - 2.40(m, 2 H), 2.40 - 2.30(m, 2 H), 1.90 - 1.75(m, 2 H).

[0261] (1-Cyclobutyl-1H-imidazol-4-yl)[((1R,5S,6r)-6-(5,5-dimethyl-4,5-dihydro-1,2-oxazol-3-yl)-3-azabicyclo[3.1.0]hex-3-yl]methanone To a mixture of ethyl 1-cyclobutyl-1H-imidazole-4-carboxylate (110 mg, 0.5400 mmol) in DMF (0.9736 mL) were added HATU (247.8 mg, 0.6500 mmol), DIPEA (0.45 mL, 2.7 mmol), and (1R,5S,6r)-6-(5,5-dimethyl-4,5-dihydro-1,2-oxazol-3-yl)-3-azabicyclo[3.1.0]hexane hydrochloride (97.36 mg, 0.5400 mmol). The resulting mixture was stirred at 20 °C for 4 h. The reaction solution was diluted with water (5 mL) and extracted with ethyl acetate (5 mL × 2). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure to obtain a crude oil. The crude oil was purified by Prep-TLC (ethyl acetate / methanol = 10 / 1), then by Prep-HPLC (NH 3 ) and freeze-dried to obtain the title compound (12.15 mg, 0.0370 mmol, yield 6.8494%) as a pale yellow solid. LC-MS Method1: 328.9 1 1H NMR (400 MHz, DMSO-d 6 ) δ = 8.03 (d, J = 1.3 Hz, 1H), 7.99 (s, 1H), 4.96 - 4.89 (m, 1H), 4.75 (br d, J = 12.0 Hz, 1H), 4.12 (br d, J = 12.3 Hz, 1H), 3.99 (br d, J = 9.0 Hz, 1H), 3.66 (br s, 1H), 2.83 (s, 2H), 2.57 (t, J = 8.7 Hz, 4H), 2.25 (br d, J = 11.3 Hz, 1H), 2.17 (br s, 1H), 2.00 - 1.90 (m, 2H), 1.60 - 1.57 (m, 1H), 1.44 (s, 6H).

[0262] Example 6 [(1-(Bicyclo[1.1.1]pentan-1-yl)-1H-imidazol-4-yl)][((1R,5S,6r)-6-(5,5-dimethyl-4,5-dihydro-1,2-oxazol-3-yl)-3-azabicyclo[3.1.0]hexan-3-yl]methanone Ethyl 1-(bicyclo[1.1.1]pentan-1-yl)-1H-imidazole-4-carboxylate To a solution of ethyl (2Z)-3-(dimethylamino)-2-isocyanoacrylate (100 mg, 0.5900 mmol) in 1-butanol (0.40 mL) were added bicyclo[1.1.1]pentan-1-amine (284.42 mg, 2.38 mmol) and triethylamine (0.58 mL, 4.46 mmol). The resulting mixture was heated at 76 °C for 16 h. The reaction solution was diluted with water (5 mL) and extracted with ethyl acetate (5 mL × 3). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure to obtain the title compound (100 mg, crude product) as a yellow oil.

[0263] 1-(bicyclo[1.1.1]pentan-1-yl)-1H-imidazole-4-carboxylic acid To a solution of ethyl 1-(bicyclo[1.1.1]pentan-1-yl)-1H-imidazole-4-carboxylate (100 mg, 0.4800 mmol) in water (1 mL) and methanol (0.80 mL) was added lithium hydroxide monohydrate (0.06 mL, 0.9700 mmol). The reaction solution was stirred at 25 °C for 16 h. The aqueous layer was washed with DCM (3 mL × 2) and acidified to pH = 2 with HCl (1N). The aqueous solution was lyophilized to obtain the title compound (50 mg, 0.2806 mmol, crude product) as a pale yellow solid.

[0264] [1-(bicyclo[1.1.1]pentan-1-yl)-1H-imidazol-4-yl][((1R,5S,6r)-6-(5,5-dimethyl-4,5-dihydro-1,2-oxazol-3-yl)-3-azabicyclo[3.1.0]hex-3-yl]methanone To a solution of 1-(bicyclo[1.1.1]pentan-1-yl)-1H-imidazole-4-carboxylic acid (59.54 mg, 0.2800 mmol) in DMF (0.50 mL) were added HATU (137.86 mg, 0.3600 mmol), DIPEA (0.18 mL, 1.11 mmol), and (1R,5S,6r)-6-(5,5-dimethyl-4,5-dihydro-1,2-oxazol-3-yl)-3-azabicyclo[3.1.0]hexane hydrochloride (50 mg, 0.2800 mmol). The resulting mixture was stirred at 20 °C for 4 h. The reaction solution was diluted with water (5 mL) and extracted with ethyl acetate (5 mL × 2). The organic layer was separated, washed with brine (8 mL), dried over sodium sulfate, and concentrated under reduced pressure to obtain a crude oil. The crude oil was purified by prep-HPLC (NH 3 ) to give the title compound (2.4 mg, 0.0071 mmol, 2.5416% yield) as a yellow solid. 1 H NMR (400 MHz, DMSO-d 6 ) δ = 7.76 (d, J = 1.0 Hz, 1H), 7.71 (d, J = 1.3 Hz, 1H), 4.53 (br d, J = 11.8 Hz, 1H), 3.93 (br d, J = 12.0 Hz, 1H), 3.81 (br dd, J = 3.6, 11.9 Hz, 1H), 3.47 (br dd, J = 3.6, 11.9 Hz, 1H), 2.65 (s, 2H), 2.24 (s, 6H), 2.08 - 1.93 (m, 3H), 1.40 (t, J = 3.4 Hz, 1H), 1.26 - 1.25 (m, 1H), 1.25 (s, 5H).

[0265] Example 7 (1-Cyclopentyl-1H-imidazol-4-yl)[((1R,5S,6r)-6-(5,5-dimethyl-4,5-dihydro-1,2-oxazol-3-yl)-3-azabicyclo[3.1.0]hexan-3-yl]methanone Ethyl 1-cyclopentyl-1H-imidazole-4-carboxylate A mixture of ethyl (2Z)-3-(dimethylamino)-2-isocyanatoacrylate (200 mg, 1.19 mmol) and cyclopentylamine (0.58 mL, 5.95 mmol) was heated at 50 °C for 16 h. The mixture was concentrated under reduced pressure. The residue was purified by flash column (0 - 100% ethyl acetate in PE, 0.5% aqueous ammonia solution) to give the title compound (240 mg, 1.1524 mmol, 96.912% yield) as a yellow oil. LC-MS Method1 0.668 min, MS (M / Z) 209.1 (M+H + )。

[0266] 1-cyclopentyl-1H-imidazole-4-carboxylic acid To a solution of ethyl 1-cyclopentyl-1H-imidazole-4-carboxylate (100 mg, 0.4800 mmol) in THF (0.80 mL) and water (1 mL), lithium hydroxide monohydrate (0.08 mL, 1.44 mmol) was added. The mixture was stirred at 25 °C for 3.5 h. The aqueous layer was washed with DCM (3 mL×2) and acidified to pH = 2 with aqueous hydrochloric acid (1N). The remaining aqueous solution was lyophilized to give the title compound (150 mg, crude product) as a pale yellow solid. 1 H NMR (400 MHz, D 2 O) δ ppm 8.73 (s, 1H), 7.90 (s, 1H), 4.75 - 4.70 (m, 1H), 2.25 - 2.10 (m, 2H), 1.90 - 1.60 (m, 6H).

[0267] (1-cyclopentyl-1H-imidazol-4-yl)[((1R,5S,6r)-6-(5,5-dimethyl-4,5-dihydro-1,2-oxazol-3-yl)-3-azabicyclo[3.1.0]hex-3-yl]methanone To a solution of 1-cyclopentyl-1H-imidazole-4-carboxylic acid (60.38 mg, 0.2800 mmol) in DMF (0.50 mL) were added HATU (137.86 mg, 0.3600 mmol), DIPEA (0.18 mL, 1.11 mmol), and (1R,5S,6r)-6-(5,5-dimethyl-4,5-dihydro-1,2-oxazol-3-yl)-3-azabicyclo[3.1.0]hexane hydrochloride (50 mg, 0.2800 mmol). The mixture was stirred at 20 °C for 4 h. The reaction solution was diluted with water (5 mL) and extracted with ethyl acetate (5 mL × 2). The organic layer was separated, washed with brine (8 mL), dried over sodium sulfate, and concentrated under reduced pressure to obtain a crude oil. The crude oil was purified by prep-TLC (ethyl acetate / methanol = 10 / 1), and then by Prep-HPLC (NH 3 ) to give the title compound (11 mg, 0.0321 mmol, yield 4.6614%) as a white solid. 1 H NMR (400 MHz, DMSO-d6) δ = 7.78 (d, J = 1.3 Hz, 1H), 7.73 (d, J = 1.3 Hz, 1H), 4.66 - 4.51 (m, 2H), 3.93 (br d, J = 12.3 Hz, 1H), 3.81 (br d, J = 6.5 Hz, 1H), 3.47 (br d, J = 11.8 Hz, 1H), 2.65 (s, 2H), 2.19 - 2.03 (m, 3H), 1.99 (br d, J = 6.0 Hz, 1H), 1.79 (br s, 4H), 1.64 (br s, 152H), 1.25 (s, 7H).

[0268] Example 8 (1-Cyclohexyl-1H-imidazol-4-yl)[((1R,5S,6r)-6-(5,5-dimethyl-4,5-dihydro-1,2-oxazol-3-yl)-3-azabicyclo[3.1.0]hexan-3-yl]methanone Ethyl 1-cyclohexyl-1H-imidazole-4-carboxylate A mixture of ethyl (2Z)-3-(dimethylamino)-2-isocyanoacrylate (200 mg, 1.19 mmol) and cyclohexylamine (0.68 mL, 5.95 mmol) was heated at 50 °C for 16 h. The mixture was concentrated under reduced pressure. The residue was purified by flash column (0 - 100% ethyl acetate in PE, 0.5% aqueous ammonia solution) to give the title compound (280 mg, 1.2597 mmol, 105.93% yield) as a yellow oil. LC-MS Method1 0.719 min, MS (m / z) 223.1 (M + H + ).

[0269] 1-cyclohexyl-1H-imidazole-4-carboxylic acid To a solution of ethyl 1-cyclohexyl-1H-imidazole-4-carboxylate (110 mg, 0.4900 mmol) in THF (0.80 mL) and water (1 mL), lithium hydroxide monohydrate (0.09 mL, 1.48 mmol) was added and stirred at 25 °C for 5 h. TLC (100% ethyl acetate) showed a new spot (Rf = 0) and the reaction solution was completely consumed. The aqueous layer was washed with DCM (3 mL × 2) and acidified to pH = 2 with aqueous hydrochloric acid (1 N). The remaining aqueous solution was lyophilized to give the title compound (190 mg, crude product) as a pale yellow solid. 1 H NMR (400 MHz, MethanoL-d 4 ) δ ppm 9.05 (s, 1H), 8.30 (s, 1H), 4.36 - 4.30 (m, 1H), 2.20 - 2.17 (m, 2H), 1.92 - 1.82 (m, 2H), 1.80 - 1.73 (m, 3H), 1.60 - 1.40 (m, 2H), 1.40 - 1.25 (m, 1H).

[0270] (1-cyclohexyl-1H-imidazol-4-yl)[((1R,5S,6r)-6-(5,5-dimethyl-4,5-dihydro-1,2-oxazol-3-yl)-3-azabicyclo[3.1.0]hex-3-yl]methanone To a solution of 1-cyclohexyl-1H-imidazole-4-carboxylic acid (64.27 mg, 0.2800 mmol) in DMF (0.50 mL) were added HATU (106.05 mg, 0.2800 mmol), DIPEA (0.18 mL, 1.11 mmol), and (1R,5S,6r)-6-(5,5-dimethyl-4,5-dihydro-1,2-oxazol-3-yl)-3-azabicyclo[3.1.0]hexane hydrochloride (50 mg, 0.2800 mmol). The mixture was stirred at 20 °C for 4 h. The reaction solution was diluted with water (5 mL) and extracted with ethyl acetate (5 mL × 2). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure to obtain a crude oil. The crude oil was purified by prep-TLC (ethyl acetate / methanol = 10 / 1) and then lyophilized to give the title compound (9.5 mg, 0.0267 mmol, yield 9.6077%) as a white powder. 1 H NMR (400MHz, DMSO-d 6 ) δ = 7.77 (d, J=5.5 Hz, 2H), 4.58 (br d, J=12.0 Hz, 1H), 4.14-4.02 (m, 1H), 3.93 (br d, J=12.0 Hz, 1H), 3.80 (br d, J=8.5 Hz, 1H), 3.51-3.43 (m, 1H), 2.64 (s, 2H), 2.05 (br s, 1H), 1.95 (br d, J=12.3 Hz, 3H), 1.80 (br d, J=13.3 Hz, 2H), 1.72-1.61 (m, 3H), 1.41 - 1.29 (m, 3H), 1.25 (s, 7H).

[0271] Example 9 [((1R,5S,6r)-6-(5,5-dimethyl-4,5-dihydro-1,2-oxazol-3-yl)-3-azabicyclo[3.1.0]hex-3-yl][1-(1,1,1-trifluoropropan-2-yl)-1H-imidazol-4-yl]methanone Ethyl 1-(1,1,1-trifluoropropan-2-yl)-1H-imidazole-4-carboxylate A solution of 1,1,1-trifluoro-2-propanamine (403.4 mg, 3.57 mmol) in 2-MeTHF (3 mL, 1.19 mmol) was added dropwise with n-butyllithium (1.43 mL, 3.57 mmol) at -78 °C. After stirring at -78 °C for 15 minutes, ethyl (2Z)-3-(dimethylamino)-2-isocyanoacrylate (200 mg, 1.19 mmol) was added. The mixture was warmed to 25 °C for 0.5 hour to obtain a black solution. The reaction solution was poured into ethanol (5 mL) and concentrated. The crude product was purified by flash column (PE → 100% ethyl acetate in PE). The obtained residue was purified by prep-TLC (ethyl acetate) to give the title compound (50 mg, 0.2117 mmol, yield 17.802%) as a brown oil.

[0272] 1-(1,1,1-trifluoropropan-2-yl)-1H-imidazole-4-carboxylic acid To a solution of ethyl 1-(1,1,1-trifluoropropan-2-yl)-1H-imidazole-4-carboxylate (50 mg, 0.2100 mmol) in THF (1.5 mL) and water (0.3 mL, 16.67 mmol) was added lithium hydroxide monohydrate (26.65 mg, 0.6400 mmol). The mixture was stirred at 20 °C for 3 hours to obtain a black solution. As a result of LCMS, the starting material (50 mg, 0.2100 mmol) remained. The mixture was stirred at 40 °C for 12 hours to obtain a black solution. The reaction solution was directly concentrated. The obtained aqueous layer was acidified to pH = 5 - 6 with 1N HCl aqueous solution. After freeze-drying, the title compound (30 mg, 0.1441 mmol, yield 68.086%) was obtained as a brown solid.

[0273] [((1R,5S,6r)-6-(5,5-dimethyl-4,5-dihydro-1,2-oxazol-3-yl)-3-azabicyclo[3.1.0]hex-3-yl][1-(1,1,1-trifluoropropan-2-yl)-1H-imidazol-4-yl]methanone A solution of 1-(1,1,1-trifluoropropan-2-yl)-1H-imidazole-4-carboxylic acid (30 mg, 0.1400 mmol) in DMF (1.5 mL) was added with HATU (66.12 mg, 0.1700 mmol) and DIPEA (0.12 mL, 0.7200 mmol). The mixture was stirred for 30 minutes. Then, (1R,5S,6r)-6-(5,5-dimethyl-4,5-dihydro-1,2-oxazol-3-yl)-3-azabicyclo[3.1.0]hexane hydrochloride (36.48 mg, 0.1400 mmol) was added. The mixture was stirred at 25 °C for 3 hours to obtain a brown solution. The reaction solution was directly concentrated. The residue was purified by Prep-HPLC (NH 3 ) to obtain the title compound (16.87 mg, 0.0455 mmol, yield 17.802%) as a white powder. LC-MS Method1: 371.1 [M+H + 1 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.72 (1 H, s) 7.53 (1 H, s) 4.59 - 4.78 (2 H, m) 4.19 (1 H, dd, J=12.80, 5.77 Hz) 3.95 (1 H, dd, J=12.05, 7.91, 4.14 Hz) 3.63 (1 H, br d, J=12.30 Hz) 2.65 (2 H, s) 2.09 (1 H, m d, J=3.76 Hz) 2.01 (1 H, m d, J=6.53 Hz) 1.76 (3 H, d, J=7.28 Hz) 1.44 - 1.50 (1 H, m) 1.38 (6 H, s).

[0274] Example 10 [((1R,5S,6S)-6-(5,5-dimethyl-4,5-dihydro-1,2-oxazol-3-yl)-3-azabicyclo[3.1.0]hex-3-yl]{1-[(2S)-3-methylbutan-2-yl]-1H-imidazol-4-yl}methanone (R)-2-methyl-N-[(1E)-2-methylpropylidene]-2-propanesulfinamide (R)-t-BuS(O)NH 2 ​To a solution of (8403.83 mg, 69.34 mmol) in THF (36.369 mL) at 20 °C were added 2-methylpropanal (6.3 mL, 69.34 mmol) and titanium(IV) ethoxide (21.57 mL, 104.01 mmol). The resulting mixture was stirred at 60 °C for 0.5 h to obtain a yellow solution. Water (3 mL) was added dropwise, and after stirring at 20 °C for 5 min, the mixture was filtered through celite and concentrated under reduced pressure to obtain the title compound (8330 mg, 47.521 mmol, yield 68.535%) as a white solid. It was used directly in the next step. LC-MS Method1 0.825 min, MS (m / z) 176.2 (M + H + )。

[0275] (R)-2-methyl-N-[(2S)-3-methyl-2-butanyl]-2-propanesulfinamide To a solution of (R)-2-methyl-N-[(1E)-2-methylpropylidene]-2-propanesulfinamide (2500 mg, 14.26 mmol) in THF (30 mL) cooled to -40 °C was added methylmagnesium bromide (5.7 mL, 17.11 mmol) dropwise. The reaction mixture was stirred at -40 °C for 3 h and then gradually warmed to 20 °C over 13 h. TLC (DCM / ethyl acetate = 6 / 1, RF = 0.3) showed two new spots. Water (30 mL) was added, and the mixture was extracted with ethyl acetate (30 mL x 2). The organic layer was dried over sodium sulfate and concentrated under reduced pressure to obtain a yellow oil. 1 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 3.35 - 3.10 (m, 1H), 2.90 - 2.75 (m, 1H), 1.80 - 1.60 (m, 1H), 1.21 (d, J = 6.8 Hz, 3H), 1.20 (s, 9H), 0.886 (d, J = 6.8 Hz, 3H), 0.871 (d, J = 6.8 Hz, H).

[0276] (2S)-3-methyl-2-butanamine (R)-2-Methyl-N-[(2S)-3-methyl-2-butanyl]-2-propanesulfinamide (2200 mg, 11.5 mmol) in hydrochloric acid / methanol solution (10 mL, 40 mmol) was stirred at 20 °C for 4 h to obtain a colorless solution. The reaction mixture was distilled under reduced pressure to obtain a white solid. It was triturated with toluene / PE = 1 / 6 to obtain the title compound (1350 mg, 10.921 mmol) as a white solid.

[0277] Ethyl 1-[(2S)-3-methylbutan-2-yl]-1H-imidazole-4-carboxylate To a 5 mL microwave vial were added (2S)-3-methyl-2-butanamine (500 mg, 4.04 mmol), ethyl (2Z)-3-(dimethylamino)-2-isocyanoacrylate (680.27 mg, 4.04 mmol), 1-butanol (3 mL), and triethylamine (0.84 mL, 6.07 mmol). The reaction mixture was irradiated with microwave at 130 °C for 1 h to obtain a brown solution. Water (30 mL) was added. It was extracted with ethyl acetate (30 mL x 2). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure to obtain a yellow oil. The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure to obtain a yellow oil. The crude product was purified by silica gel chromatography (PE / ethyl acetate = 10 / 1 → 3 / 2) to obtain the title compound (161 mg, 0.7657 mmol, yield 18.931%) as a brown oil. LC-MS Method1 0.691 min, MS(m / z)211.2(M+H + )。

[0278] 1-[(2S)-3-methylbutan-2-yl]-1H-imidazole-4-carboxylic acid To a stirred solution of ethyl 1-[(2S)-3-methylbutan-2-yl]-1H-imidazole-4-carboxylate (150.0 mg, 0.7600 mmol) in 1,4-dioxane (3 mL) was added a solution of lithium hydroxide monohydrate (48.11 mg, 1.15 mmol). The mixture was stirred at 20 °C for 4 h to obtain a yellow solution. Water (10 mL) was added and the mixture was extracted with ethyl acetate (10 mL x 2). After lyophilization, the title compound (110 mg, 0.6037 mmol, yield 78.98%) was obtained as a brown solid. LC-MS Method1: 0.306 min, MS (m / z) 183.0 (M+H+).

[0279] [((1R,5S,6S)-6-(5,5-dimethyl-4,5-dihydro-1,2-oxazol-3-yl)-3-azabicyclo[3.1.0]hex-3-yl]{1-[(2S)-3-methylbutan-2-yl]-1H-imidazol-4-yl}methanone To a stirred solution of 1-[(2S)-3-methylbutan-2-yl]-1H-imidazole-4-carboxylic acid (1 mg, 0.5500 mmol) and HATU (251.76 mg, 0.6600 mmol) in DMF (3 mL) was added N-ethyl-N-isopropylpropan-2-amine (0.47 mg, 2.74 mmol). After stirring for 30 min, (1R,5S,6r)-6-(5,5-dimethyl-4,5-dihydro-1,2-oxazol-3-yl)-3-azabicyclo[3.1.0]hexane hydrochloride (138.94 mg, 0.5500 mmol) was added and the mixture was stirred at 20 °C for 16 h to obtain a yellow solution. Water (30 mL) was added and the mixture was extracted with ethyl acetate (30 mL x 2). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure to obtain a yellow oil. The crude product was purified by Prep-HPLC (NH 3 ) and then lyophilized to obtain the title compound (108.71 mg, 0.3156 mmol, yield 57.509%) as a white solid. LC-MS Method1: 345.3 [M+H + 1 ​1H NMR (400 MHz, CHLOROFORM-d) δ 7.61 (d, J=1.00 Hz, 1H), 7.40 (d, J=1.25 Hz, 1H), 4.76 (br d, J=12.05 Hz, 1H), 4.18 (d, J=12.55 Hz, 1H), 3.94 (br dd, J=4.02, 11.80 Hz, 1H), 3.84 (quin, J=7.09 Hz, 1H), 3.61 (dd, J=4.27, 12.55 Hz, 1H), 2.64 (s, 2H), 2.07 (br dd, J=3.51, 7.28 Hz, 1H), 1.95-1.99 (m, 1H), 1.87-1.94 (m, 1H), 1.47 (d, J=6.78 Hz, 4H), 1.36 (s, 6H), 0.96 (d, J=6.78 Hz, 3H), 0.78 (d, J=6.53 Hz, 3H).

[0280] Example 11 {1-[(2R)-butan-2-yl]-1H-imidazol-4-yl}[((1R,5S,6r)-6-(5,5-dimethyl-4,5-dihydro-1,2-oxazol-3-yl)-3-azabicyclo[3.1.0]hex-3-yl]methanone Ethyl 1-[(2R)-butan-2-yl]-1H-imidazole-4-carboxylate A mixture of ethyl (2Z)-3-(dimethylamino)-2-isocyanoacrylate (300 mg, 1.78 mmol) and (2R)-2-butylamine (0.54 mL, 5.35 mmol) was stirred at 50 °C for 16 h to give a brown mixture. TLC (PE: ethyl acetate = 1:1) detected a new spot (Rf = 0.2). The mixture was concentrated to give a residue. The residue was purified by flash column (PE: ethyl acetate = 1:0 → 1:4) to give the title compound (240 mg, 1.2229 mmol, yield 68.562%) as a brown solid. LC-MS Method1 0.586 min, MS (m / z) 196.9 (M + H + )

[0281] 1-[(2R)-butan-2-yl]-1H-imidazole-4-carboxylic acid To a mixture of ethyl 1-[(2R)-butan-2-yl]-1H-imidazole-4-carboxylate (240 mg, 1.22 mmol) in THF (3 mL) and water (1.5 mL), lithium hydroxide monohydrate (0.11 mL, 1.83 mmol) was added. The reaction mixture was stirred at 25 °C for 16 h to obtain a yellow mixture. TLC (PE: ethyl acetate = 1:1) indicated that most of the starting material was consumed. The reaction mixture was diluted with water (15 mL) and extracted with ethyl acetate (8 mL × 5). The aqueous layer was acidified to pH = 4 with aqueous hydrochloric acid (1 N). The resulting aqueous layer was dried under reduced pressure to obtain the title compound (200 mg, 1.1891 mmol, yield 97.236%) (crude) as a yellow oil.

[0282] {1-[(2R)-butan-2-yl]-1H-imidazol-4-yl}[((1R,5S,6r)-6-(5,5-dimethyl-4,5-dihydro-1,2-oxazol-3-yl)-3-azabicyclo[3.1.0]hex-3-yl]methanone (1R,5S,6r)-6-(5,5-Dimethyl-4,5-dihydro-1,2-oxazol-3-yl)-3-azabicyclo[3.1.0]hexane hydrochloride (70 mg, 0.3900 mmol) in DMF (1 mL) was added 1-[(2R)-butan-2-yl]-1H-imidazole-4-carboxylic acid (65.32 mg, 0.3900 mmol), DIPEA (0.26 mL, 1.55 mmol), and HATU (178.16 mg, 0.4700 mmol). The reaction mixture was stirred at 25 °C for 16 h to obtain a brown mixture. The reaction mixture was concentrated under reduced pressure to obtain a residue. The residue was purified by Prep-HPLC (NH 3 ). The obtained fractions were combined, concentrated to remove most of the acetonitrile, freeze-dried, and lyophilized to obtain the title compound (4.09 mg, 0.0108 mmol, yield 2.7864%) as a yellow solid. LC-MS Method1: 331.1 [M+H + 1 ​1H NMR (400 MHz, DMSO-d6) δ ppm 8.91 (br s, 1 H), 8.19 (br s, 1 H), 4.31 - 4.44 (m, 1 H), 4.15 (br d, J=11.3 Hz, 1 H), 3.96 (br d, J=12.8 Hz, 1 H), 3.90 (br d, J=9.0 Hz, 1 H), 3.50 - 3.65 (m, 1 H), 2.65 (s, 2 H), 2.16 (br d, J=3.3 Hz, 1 H), 2.07 (br d, J=3.5 Hz, 1 H), 1.82 (quin, J=7.2 Hz, 2 H), 1.55 (t, J=3.4 Hz, 1 H), 1.48 (d, J=6.8 Hz, 3 H), 1.26 (s, 6 H), 0.76 (t, J=7.4 Hz, 3 H).

[0283] Example 12 {1-[(2S)-butan-2-yl]-1H-imidazol-4-yl}[((1R,5S,6S)-6-(5,5-dimethyl-4,5-dihydro-1,2-oxazol-3-yl)-3-azabicyclo[3.1.0]hex-3-yl]methanone [Chemical formula] Ethyl 1-[(2S)-butan-2-yl]-1H-imidazole-4-carboxylate A mixture of ethyl (2Z)-3-(dimethylamino)-2-isocyanoacrylate (300 mg, 1.78 mmol) and (S)-butan-2-amine (0.54 mL, 5.35 mmol) was stirred at 50 °C for 12 hours to obtain a brown mixture. TLC (PE:ethyl acetate = 1:1) detected a new spot (Rf = 0.2). The mixture was concentrated to obtain a residue. The residue was purified by flash column (PE:ethyl acetate = 1:0 → 1:4) to obtain the title compound (160 mg, 0.8153 mmol, yield 45.708%) as a yellow solid. LC-MS Method1 0.580 min, MS (m / z) 196.1 (M + H + ).

[0284] 1-[(2S)-butan-2-yl]-1H-imidazole-4-carboxylic acid To a mixture of ethyl 1-[(2S)-butan-2-yl]-1H-imidazole-4-carboxylate (160 mg, 0.8200 mmol) in THF (4 mL) and water (2 mL) was added lithium hydroxide monohydrate (0.07 mL, 1.22 mmol). The reaction mixture was stirred at 20 °C for 16 h to obtain a yellow mixture. The reaction mixture was diluted with water (15 mL) and extracted with ethyl acetate (8 mL × 5). The aqueous layer was acidified to pH = 4 with aqueous hydrochloric acid (1 N). The resulting aqueous layer was dried under reduced pressure to give the title compound (150 mg, 0.8918 mmol, yield 109.39%) (crude) as a yellow solid.

[0285] {1-[(2S)-butan-2-yl]-1H-imidazol-4-yl}[((1R,5S,6S)-6-(5,5-dimethyl-4,5-dihydro-1,2-oxazol-3-yl)-3-azabicyclo[3.1.0]hex-3-yl]methanone (1R,5S,6S)-6-(5,5-Dimethyl-4,5-dihydro-1,2-oxazol-3-yl)-3-azabicyclo[3.1.0]hexane hydrochloride (70 mg, 0.3900 mmol) in DMF (1.5 mL) was mixed with 1-[(2S)-butan-2-yl]-1H-imidazole-4-carboxylic acid (65.32 mg, 0.3900 mmol), DIPEA (0.26 mL, 1.55 mmol), and HATU (178.16 mg, 0.4700 mmol). The reaction mixture was stirred at 25 °C for 16 h to obtain a brown mixture. LCMS indicated consumption of the starting material. The reaction mixture was filtered. The filtrate was purified by Prep-HPLC (NH 3 ) and the resulting fractions were combined, concentrated to remove most of the acetonitrile, and lyophilized to give the title compound (34.59 mg, 0.1002 mmol, yield 25.797%) as a white solid. LC-MS Method2 1.516 min, MS (m / z) 331.2 [M+H + 1 ​1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.64 (s, 1 H), 7.44 (s, 1 H), 4.76 (br d, J=12.0 Hz, 1 H), 4.19 (br d, J=12.5 Hz, 1 H), 4.02 - 4.10 (m, 1 H), 3.95 (br d, J=7.8 Hz, 1 H), 3.58 - 3.65 (m, 1 H), 2.64 (s, 2 H), 2.08 (br s, 1 H), 1.93 - 2.01 (m, 1 H), 1.93 - 2.01 (m, 1 H), 1.74 - 1.84 (m, 2 H), 1.49 (d, J=6.8 Hz, 3 H), 1.47 (br s, 1 H), 1.37 (s, 6 H), 0.85 (t, J=7.4 Hz, 3 H).

[0286] Example 13 [((1R,5S,6S)-6-(5,5-Dimethyl-4,5-dihydro-1,2-oxazol-3-yl)-3-azabicyclo[3.1.0]hex-3-yl]{1-[(2S)-4-methylpentan-2-yl]-1H-imidazol-4-yl}methanone (R)-2-methyl-N-[(2E)-1,3-dimethylbutan-2-ylidene]-2-propanesulfinamide To a mixed solution of 4-methyl-2-pentanone (1.25 mL, 9.98 mmol) in THF (10 mL), (R)-2-methylpropane-2-sulfinamide (1210.06 mg, 9.98 mmol) and titanium(IV) ethoxide (3414.54 mg, 14.98 mmol) were added. The reaction mixture was stirred at 60 °C for 2 hours to obtain a colorless mixture. The reaction mixture was diluted with ethyl acetate (30 mL). The mixture was added to water (10 mL) and stirred for 1 minute to obtain a yellow suspension. The suspension was filtered. The filtrate was washed with water (20 mL×3), dried over anhydrous sodium sulfate, filtered, and then concentrated under reduced pressure to obtain the title compound (900 mg, 4.4261 mmol, yield 44.332%) as a colorless oil. LC-MS Method1 0.778 min, MS (m / z) 204.0 (M + H + )。

[0287] (R)-2-methyl-N-[(2S)-4-methylpentan-2-yl]-2-propanesulfinamide (R)-2-Methyl-N-[(2E)-1,3-dimethylbutan-2-ylidene]-2-propanesulfinamide (900 mg, 4.43 mmol) in THF (9 mL) was added dropwise with L-selectride (13.28 mL, 13.28 mmol) at 0 °C. The reaction mixture was stirred at 25 °C for 2 h to obtain a colorless mixture. By TLC (PE:ethyl acetate = 2:1), one new spot (Rf = 0.2) was detected. The reaction was quenched with water (3 mL). The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by flash column (PE → 30% ethyl acetate in PE) to give the title compound (260 mg, 1.026 mmol, yield 45.252%) as a colorless oil. 1 H NMR (400 MHz, CHLOROFORM-d) δ ppm 3.50 - 3.30 (m, 1H), 2.81 (d, J = 8.0 Hz, 1H), 1.80 - 1.60 (m, 1H), 1.60 - 1.30 (m, 2H), 1.28 (d, J = 6.4 Hz, 3H), 1.21 (s, 9H), 0.90 (d, J = 6.8 Hz, 3H), 0.88 (d, J = 6.8 Hz, 3H).

[0288] (2S)-4-methyl-2-pentanamine hydrochloride (R)-2-Methyl-N-[(2S)-4-methylpentan-2-yl]-2-propanesulfinamide (610 mg, 2.97 mmol) in methanol / hydrochloric acid (10 mL, 2.97 mmol) was stirred at 25 °C for 2 h to obtain a colorless mixture. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was triturated with PE (20 mL) and dried under reduced pressure to give the title compound (240 mg, 1.7436 mmol, yield 58.698%) as a white solid.

[0289] Ethyl 1-[(2S)-4-methylpentan-2-yl]-1H-imidazole-4-carboxylate (2S)-4-Methyl-2-pentanamine hydrochloride (240 mg, 1.74 mmol) in 1-butanol (2.5 mL) was mixed with ethyl (2Z)-3-(dimethylamino)-2-isocyanoacrylate (293.25 mg, 1.74 mmol) and triethylamine (0.34 mL, 2.62 mmol). The reaction mixture was stirred at 130 °C for 1 hour by microwave to obtain a brown mixture. One new spot (Rf = 0.2) was detected by TLC (PE: ethyl acetate = 1:1). The reaction mixture was concentrated under reduced pressure to obtain a residue. The residue was purified by prep-TLC (PE: ethyl acetate = 1:1) to obtain the title compound (60 mg, 0.2675 mmol, yield 15.342%) as a yellow oil. LC-MS Method1 0.681 min, MS (m / z) 225.0 (M + H + )。

[0290] 1-[(2S)-4-methylpentan-2-yl]-1H-imidazole-4-carboxylic acid Lithium hydroxide monohydrate (0.02 mL, 0.4000 mmol) was added to a mixture of ethyl 1-[(2S)-4-methylpentan-2-yl]-1H-imidazole-4-carboxylate (60 mg, 0.2700 mmol) in THF (1.5 mL) and water (0.50 mL). The reaction solution was stirred at 40 °C for 16 hours to obtain a yellow mixture. TLC (PE: ethyl acetate = 1:1) indicated that the starting material was completely consumed. The reaction solution was diluted with water (5 mL) and extracted with ethyl acetate (3 mL × 2). The aqueous layer was acidified to pH = 5 with hydrochloric acid aqueous solution (1N) and lyophilized to obtain the title compound (50 mg, 0.2548 mmol, yield 95.244%) as a yellow solid.

[0291] [(1R,5S,6S)-6-(5,5-dimethyl-4,5-dihydro-1,2-oxazol-3-yl)-3-azabicyclo[3.1.0]hex-3-yl]{1-[(2S)-4-methylpentan-2-yl]-1H-imidazol-4-yl}methanone To a mixture of 1-[(2S)-4-methylpentan-2-yl]-1H-imidazole-4-carboxylic acid (50 mg, 0.2500 mmol) in pyridine (2.5 mL), EDCI (58.61 mg, 0.3100 mmol) was added. The mixture was stirred at 25 °C for 10 minutes, then (1R,5S,6r)-6-(5,5-dimethyl-4,5-dihydro-1,2-oxazol-3-yl)-3-azabicyclo[3.1.0]hexane hydrochloride (55.21 mg, 0.2500 mmol) was added. The mixture was stirred at 25 °C for 16 hours to obtain a yellow mixture. LCMS indicated that the starting material was completely consumed. The reaction solution was concentrated under reduced pressure to obtain a residue. The residue was purified by prep-HPLC(NH 3 )). The obtained fractions were combined, concentrated to remove most of the acetonitrile, and lyophilized to obtain the title compound (16.26 mg, 0.0449 mmol, yield 17.643%) as a yellow solid. LC-MS Method1: 359.2 [M+H + 1 H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.64 (s, 1 H), 7.46 (s, 1 H), 4.76 (br d, J=12.0 Hz, 1 H), 4.13 - 4.33 (m, 2 H), 3.95 (dd, J=12.0, 3.8 Hz, 1 H), 3.62 (dd, J=12.3, 4.0 Hz, 1 H), 2.64 (s, 2 H), 2.08 (br d, J=3.5 Hz, 1 H), 1.98 (br d, J=3.5 Hz, 1 H), 1.68 - 1.78 (m, 1 H), 1.50 - 1.57 (m, 2 H), 1.47 (d, J=6.8 Hz, 4 H), 1.38 (s, 6 H), 0.92 (d, J=6.5 Hz, 3 H), 0.87 (d, J=6.8 Hz, 3 H).

[0292] ​Example 14 (1-((S)-1-Cyclopropylethyl)-1H-imidazol-4-yl)((1R,5S,6S)-6-(5,5-Dimethyl-4,5-dihydroisoxazol-3-yl)-3-azabicyclo[3.1.0]hexan-3-yl)methanone Ethyl 1-[(1S)-1-cyclopropylethyl]-1H-imidazole-4-carboxylate To a round-bottom flask were added (S)-1-cyclopropylethylamine hydrochloride (903.81 mg, 7.43 mmol), triethylamine (1.57 mL, 11.15 mmol), ethyl (2Z)-3-(dimethylamino)-2-isocyanoacrylate (250 mg, 1.49 mmol) and 1-butanol (0.50 mL). The resulting mixture was stirred at 70 °C for 36 hours to obtain a yellow solution. The reaction mixture was poured into water (30 mL) and extracted with ethyl acetate (30 mL × 2). The combined organic layers were washed with saturated brine (30 mL × 2), dried over sodium sulfate, filtered, and concentrated under reduced pressure to obtain a yellow oil. The crude product was purified by flash column (PE → 100% ethyl acetate in PE) to obtain the title compound (100 mg, 0.4802 mmol, yield 32.304%) as a yellow oil. LC-MS Method1 0.652 min, MS (m / z) 209.2 (M + H + ).

[0293] 1-[(1S)-1-cyclopropylethyl]-1H-imidazole-4-carboxylic acid To a solution of ethyl 1-[(1S)-1-cyclopropylethyl]-1H-imidazole-4-carboxylate (150 mg, 0.7200 mmol) in water (0.50 mL), THF (0.50 mL), and methanol (0.50 mL) was added lithium hydroxide monohydrate (60.44 mg, 1.44 mmol). The resulting mixture was stirred at 20 - 25 °C for 14 hours to obtain a white suspension. The reaction mixture was poured into water and extracted with ethyl acetate (20 mL × 4). The combined organic layers were washed with saturated brine (20 mL × 2), dried over sodium sulfate, filtered, and concentrated under reduced pressure to obtain the title compound (150 mg, crude product) as a yellow oil. LC-MS Method1: 0.227 min, MS (m / z) 180.9 (M + H + )。

[0294] (1-((S)-1-Cyclopropylethyl)-1H-imidazol-4-yl)((1R,5S,6S)-6-(5,5-dimethyl-4,5-dihydroisoxazol-3-yl)-3-azabicyclo[3.1.0]hexan-3-yl)methanone To a solution of 1-[(1S)-1-cyclopropylethyl]-1H-imidazole-4-carboxylic acid (70 mg, 0.3900 mmol) in DMF (3 mL) were added HATU (193.06 mg, 0.5000 mmol) and N-ethyl-N-isopropylpropan-2-amine (0.33 mL, 1.94 mmol) at 20 °C for 30 minutes. (1R,5S,6r)-6-(5,5-dimethyl-4,5-dihydro-1,2-oxazol-3-yl)-3-azabicyclo[3.1.0]hexane hydrochloride (98.35 mg, 0.3900 mmol) was added. The resulting mixture was stirred at 20 - 25 °C for 14 hours to obtain a yellow solution. The reaction solution was poured into a saturated aqueous ammonium chloride solution (50 mL) and extracted with ethyl acetate (50 mL × 4). The combined organic layers were washed with saturated brine (50 mL × 2), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by prep-HPLC (FA) to obtain the title compound (10.65 mg, 0.0311 mmol, yield 8.0061%) as a yellow oil. LC-MS Method1: 343.1 [M+H + 1 ​1H NMR (400 MHz, CHLOROFORM-d) δ = 7.70 (s, 1H), 7.64 (s, 1H), 4.63 (br d, J = 10.0 Hz, 1H), 4.19 (br d, J = 12.5 Hz, 1H), 3.95 (br dd, J = 3.4, 11.2 Hz, 1H), 3.63 (br d, J = 11.5 Hz, 1H), 3.48 - 3.43 (m, 1H), 2.64 (s, 2H), 2.08 (br s, 2H), 1.58 (d, J = 6.8 Hz, 3H), 1.47 (t, J = 3.4 Hz, 1H), 1.36 (s, 6H), 1.19 - 1.13 (m, 1H), 0.75 - 0.61 (m, 2H), 0.36 (q, J = 4.9 Hz, 2H).

[0295] Example 15 {1-[(1R)-1-cyclopropylethyl]-1H-imidazol-4-yl}[(1R,5S,6r)-6-(5,5-dimethyl-4,5-dihydro-1,2-oxazol-3-yl)-3-azabicyclo[3.1.0]hex-3-yl]methanone Ethyl 1-[(1R)-1-cyclopropylethyl]-1H-imidazole-4-carboxylate To a solution of ethyl (2Z)-3-(dimethylamino)-2-isocyanoacrylate (500 mg, 2.97 mmol) in 1-butanol (1 mL) was added (1R)-1-cyclopropylethylamine (253.14 mg, 2.97 mmol) at 20 °C. The reaction mixture was irradiated with microwave at 130 °C for 40 minutes to obtain a yellow solution. The reaction mixture was poured into a saturated aqueous ammonium chloride solution (50 mL) and extracted with ethyl acetate (50 mL × 4). The combined organic layers were washed with saturated brine (50 mL × 2), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica column (PE → PE:ethyl acetate = 1:1) to obtain the title compound (190 mg, 0.9123 mmol, yield 30.689%) as a yellow oil. LC-MS Method1 0.608 min, MS (m / z) 209.0 (M + H + ).

[0296] 1-[(1R)-1-cyclopropylethyl]-1H-imidazole-4-carboxylic acid To a solution of ethyl 1-[(1R)-1-cyclopropylethyl]-1H-imidazole-4-carboxylate (190 mg, 0.9100 mmol) in water (1.9 mL), THF (1.9 mL), and methanol (1.9 mL) was added lithium hydroxide monohydrate (76.56 mg, 1.82 mmol) at 20 °C. The resulting mixture was stirred at 20 - 25 °C for 2 h to obtain a white suspension. The reaction mixture was poured into water and extracted with ethyl acetate (20 mL × 4). The combined organic layers were washed with saturated brine (20 mL × 2), dried over sodium sulfate, filtered, and concentrated under reduced pressure to give the title compound (180 mg, 0.9989 mmol, yield 109.49%) as a yellow oil. LC-MS Method1 0.214 min, MS (m / z) 180.0 (M + H + )。

[0297] {1-[(1R)-1-cyclopropylethyl]-1H-imidazol-4-yl}[(1R,5S,6r)-6-(5,5-dimethyl-4,5-dihydro-1,2-oxazol-3-yl)-3-azabicyclo[3.1.0]hex-3-yl]methanone To a solution of 1-[(1R)-1-cyclopropylethyl]-1H-imidazole-4-carboxylic acid (70 mg, 0.3900 mmol) in DMF (2 mL) were added HATU (193.06 mg, 0.5000 mmol) and N-ethyl-N-isopropylpropan-2-amine (0.33 mL, 1.94 mmol) at 20 °C. The reaction mixture was stirred for 30 min. (1R,5S,6r)-6-(5,5-dimethyl-4,5-dihydro-1,2-oxazol-3-yl)-3-azabicyclo[3.1.0]hexane hydrochloride (98.35 mg, 0.3900 mmol) was added. The resulting mixture was stirred at 20 - 25 °C for 14 h to obtain a yellow solution. The reaction solution was poured into an aqueous saturated ammonium chloride solution (50 mL) and extracted with ethyl acetate (50 mL × 4). The combined organic layers were washed with an aqueous saturated solution (50 mL × 2), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by prep-HPLC (FA) to give the title compound (14.08 mg, 0.0411 mmol, yield 10.585%) as a yellow oil. LC-MS Method1: 343.3 [M+H+ 1 H NMR (400 MHz, CHLOROFORM-d) δ = 7.70 (d, J = 1.3 Hz, 1H), 7.64 (s, 1H), 4.65 (br d, J = 11.5 Hz, 1H), 4.19 (br d, J = 12.3 Hz, 1H), 3.94 (br dd, J = 3.8, 11.8 Hz, 1H), 3.62 (br dd, J = 4.1, 12.4 Hz, 1H), 3.45 (dd, J = 6.8, 8.8 Hz, 1H), 2.64 (s, 2H), 2.11 - 2.05 (m, 2H), 1.58 (d, J = 6.8 Hz, 3H), 1.46 (t, J = 3.4 Hz, 1H), 1.36 (s, 6H), 1.19 - 1.13 (m, 1H), 0.77 - 0.70 (m, 1H), 0.65 - 0.60 (m, 1H), 0.36 (q, J = 5.4 Hz, 2H).

[0298] Example 16 (1-((S)-1-cyclobutylethyl)-1H-imidazol-4-yl)((1R,5S,6S)-6-(5,5-dimethyl-4,5-dihydroisoxazol-3-yl)-3-azabicyclo[3.1.0]hexan-3-yl)methanone (R)-N-[(E)-Cyclobutylmethylene]-2-methyl-2-propanesulfinamide ​To a THF (15 mL) mixture of cyclobutanecarbaldehyde (1.07 mL, 11.89 mmol), (R)-2-methylpropane-2-sulfinamide (1.44 g, 11.89 mmol) and titanium(IV) ethoxide (4065.62 mg, 17.83 mmol) were added. The reaction mixture was stirred at 60 °C for 2 h to obtain a yellow mixture. As a result of TLC (PE:ethyl acetate = 10:1), the starting material was completely consumed and one new spot (Rf = 0.2) was detected. The reaction solution was diluted with ethyl acetate (40 mL). This mixture was added to water (10 mL) and stirred for 1 min to obtain a white suspension. This suspension was filtered. The filtrate was washed with water (20 mL×3), dried over anhydrous sodium sulfate, filtered, and then concentrated under reduced pressure to obtain the title compound (1.77 g, 9.4501 mmol, yield 79.494%) as a colorless oil. 1 1H NMR (400 MHz, CHLOROFORM-d) δ = 8.12 (d, J = 4.8 Hz, 1H), 3.45 - 3.30 (m, 1H), 2.35 - 2.10 (m, 4H), 2.10 - 2.00 (m, 1H), 2.00 - 1.90 (m, 1H), 1.20 (s, 9H).

[0299] (R)-N-[(1S)-1-cyclobutylethyl]-2-methyl-2-propanesulfinamide (R)-N-[(E)-Chlorobutylmethylene]-2-methyl-2-propanesulfinamide (0.5 g, 2.67 mmol) in THF (6 mL) was added with chloro(methyl)magnesium (2.67 mL, 8.01 mmol) at -40 °C. The reaction mixture was stirred at -40 °C for 2 hours to obtain a yellow mixture. TLC (DCM:ethyl acetate = 1:1) showed that the starting material was completely consumed and one new spot (Rf = 0.3) was detected. After quenching the reaction solution with ammonium chloride (eq., 25 mL), it was extracted with ethyl acetate (15 mL × 3). The combined organic layers were washed with brine (20 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to obtain a residue. The residue was purified by flash column (DCM → 20% ethyl acetate in DCM) to obtain the title compound (360 mg, 1.7704 mmol, yield 66.32%) as a colorless oil. 1 H NMR (400MHz, CHLOROFORM-d) δ = 3.35 - 3.15 (m, 1H), 2.84 (d, J = 8.0 Hz, 1H), 2.40 - 2.20 (m, 1H), 2.10 - 1.90 (m, 1H), 2.00 - 1.90 (m, 1H), 1.90 - 1.60 (m, 4H), 1.20 (s, 9H), 1.18 (d, J = 6.8 Hz, 3H).

[0300] (1S)-1-Cyclobutylethanamine hydrochloride (R)-N-[(1S)-1-Cyclobutylethyl]-2-methyl-2-propanesulfinamide (360 mg, 1.77 mmol) in methanol / hydrochloric acid (0.44 mL, 1.77 mmol) solution was stirred at 25 °C for 2 hours to obtain a colorless mixture. TLC (DCM:ethyl acetate = 1:1) indicated that the starting material was completely consumed. The reaction mixture was concentrated under reduced pressure to obtain the title compound (330 mg, 2.4329 mmol, yield 137.42%) as a yellow solid.

[0301] Ethyl 1-[(1S)-1-cyclobutylethyl]-1H-imidazole-4-carboxylate To a solution of (1S)-1-cyclobutylethanamine hydrochloride (240 mg, 1.77 mmol) in 1-butanol (2 mL) were added ethyl (2Z)-3-(dimethylamino)-2-isocyanoacrylate (297.59 mg, 1.77 mmol) and triethylamine (0.37 mL, 2.65 mmol). The reaction mixture was stirred at 130 °C for 1 h using microwave to obtain a brown mixture. LCMS indicated that the starting material was completely consumed. One new spot (Rf = 0.2) was detected by TLC (PE: ethyl acetate = 2:1). The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (100% ethyl acetate) to give the title compound (36 mg, 0.1620 mmol, yield 9.1533%) as a brown solid. 1 H NMR (400MHz, CHLOROFORM-d) δ = 7.61 (s, 1H), 7.50 (s, 1H), 4.37 (q, J = 6.8 Hz, 2H), 4.15 - 4.00 (m, 1H), 2.70 - 2.50 (m, 1H), 2.20 - 2.10 (m, 1H), 2.00 - 1.60 (m, 5H), 1.40 (d, J = 6.8 Hz, 3H), 1.39 (t, J = 6.8Hz, 3H).

[0302] 1-[(1S)-1-cyclobutylethyl]-1H-imidazole-4-carboxylic acid To a mixture of ethyl 1-[(1S)-1-cyclobutylethyl]-1H-imidazole-4-carboxylate (36 mg, 0.1600 mmol) in THF (1.5 mL) and water (0.50 mL) was added lithium hydroxide monohydrate (0.01 mL, 0.2400 mmol). The reaction mixture was stirred at 25 °C for 16 h to obtain a brown mixture. TLC (PE: ethyl acetate = 1:1) indicated that the starting material was completely consumed. The reaction solution was diluted with water (4 mL) and extracted with ethyl acetate (2 mL × 2). The aqueous layer was acidified with hydrochloric acid aqueous solution (1N) and freeze-dried to give the title compound (31 mg, 0.1596 mmol, yield 98.547%) as a brown solid. 11H NMR (400 MHz, DMSO-d 6 ) δ = 7.91 (s, 1H), 7.84 (s, 1H), 4.40 - 4.20 (m, 1H), 2.75 - 2.65 (m, 1H), 2.15 - 2.00 (m, 1H), 1.95 - 1.60 (m, 5H), 1.38 (d, J = 6.8 Hz, 3H).

[0303] (1-((S)-1-Cyclobutylethyl)-1H-imidazol-4-yl)((1R,5S,6S)-6-(5,5-dimethyl-4,5-dihydroisoxazol-3-yl)-3-azabicyclo[3.1.0]hexan-3-yl)methanone To a solution of 1-[(1S)-1-cyclobutylethyl]-1H-imidazole-4-carboxylic acid (30 mg, 0.1500 mmol) in DMF (1.5 mL) were added HATU (70.86 mg, 0.1900 mmol) and DIPEA (99.81 mg, 0.7700 mmol). After stirring the mixture for 10 minutes, (1R,5S,6r)-6-(5,5-dimethyl-4,5-dihydro-1,2-oxazol-3-yl)-3-azabicyclo[3.1.0]hexane hydrochloride (39.1 mg, 0.1500 mmol) was added. The mixture was stirred at 25 °C for 12 hours to obtain a brown solution. The reaction solution was concentrated directly. The residue was purified by prep-HPLC (NH 3 ) to give the title compound (25.52 mg, 0.0716 mmol, yield 46.352%) as a brown solid. LC-MS Method1: 357.1 [M+H + 1 ​1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.61 (1 H, d, J=1.25 Hz), 7.42 (1 H, d, J=1.25 Hz), 4.76 (1 H, d, J=12.05 Hz), 4.19 (1 H, d, J=12.55 Hz), 3.99 - 4.08 (1 H, m), 3.94 (1 H, dd, J=12.17, 4.14 Hz), 3.61 (1 H, dd, J=12.55, 4.27 Hz), 2.64 (2 H, s), 2.53 - 2.63 (1 H, m), 2.05 - 2.18 (2 H, m), 1.94 - 2.01 (1 H, m), 1.85 - 1.94 (2 H, m), 1.67 - 1.84 (3 H, m), 1.46 (1 H, br s), 1.36 - 1.41 (9 H, m).

[0304] Example 17 {1-[(1R)-1-Cyclobutylethyl]-1H-imidazol-4-yl}[(1R,5S,6r)-6-(5,5-dimethyl-4,5-dihydro-1,2-oxazol-3-yl)-3-azabicyclo[3.1.0]hex-3-yl]methanone Ethyl 1-[(1R)-1-cyclobutylethyl]-1H-imidazole-4-carboxylate To a solution of ethyl (2Z)-3-(dimethylamino)-2-isocyanoacrylate (100 mg, 0.5900 mmol) in triethylamine (0.58 mL, 4.46 mmol) was added a mixture of (1R)-1-cyclobutylethanamine hydrochloride (241.94 mg, 1.78 mmol) in 1-butanol (0.30 mL). The resulting mixture was stirred at 70 °C for 16 h to obtain a yellow mixture. One new spot (Rf = 0.3) was detected by TLC (PE:ethyl acetate = 1:1). The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (PE:ethyl acetate = 1:1) to give the title compound (25 mg, 0.1125 mmol, yield 18.916%) as a yellow oil. LC-MS Method1 0.667 min, MS (m / z) 222.9 (M + H + )

[0305] 1-[(1R)-1-cyclobutylethyl]-1H-imidazole-4-carboxylic acid To a mixture of ethyl 1-[(1R)-1-cyclobutylethyl]-1H-imidazole-4-carboxylate (25 mg, 0.1100 mmol) in THF (0.75 mL) and water (0.25 mL) was added lithium hydroxide monohydrate (0.01 mL, 0.1700 mmol). The reaction mixture was stirred at 40 °C for 16 h to give a yellow mixture. TLC (PE:ethyl acetate = 1:1) indicated complete consumption of the starting material. The reaction mixture was diluted with water (6 mL) and concentrated to remove most of the THF. The aqueous layer was acidified to pH = 5 with aqueous hydrochloric acid (1 N) and lyophilized to give the title compound (21 mg, 0.1081 mmol, 96.131% yield) as a yellow solid. LC-MS Method1 0.414 min, MS (m / z) 194.9 (M + H + )。

[0306] {1-[(1R)-1-cyclobutylethyl]-1H-imidazol-4-yl}[(1R,5S,6r)-6-(5,5-dimethyl-4,5-dihydro-1,2-oxazol-3-yl)-3-azabicyclo[3.1.0]hex-3-yl]methanone To a mixture of 1-[(1R)-1-cyclobutylethyl]-1H-imidazole-4-carboxylic acid (21 mg, 0.1100 mmol) in DMF (0.50 mL) were added HATU (49.6 mg, 0.1300 mmol) and DIPEA (0.09 mL, 0.5400 mmol). The mixture was stirred at 50 °C for 30 min, then (1R,5S,6r)-6-(5,5-dimethyl-4,5-dihydro-1,2-oxazol-3-yl)-3-azabicyclo[3.1.0]hexane hydrochloride (29.23 mg, 0.1600 mmol) was added. The mixture was stirred at 25 °C for 16 h to give a yellow mixture. The reaction solution was purified by prep-HPLC (NH 3 ). The obtained fractions were combined, concentrated to remove most of the acetonitrile, and lyophilized to give the title compound (1.64 mg, 0.0046 mmol, 4.2553% yield) as a yellow solid. LC-MS Method1: 357.1 [M+H + 1 ​1H NMR (400 MHz, METHANOL-d4) δ ppm 7.73 (s, 1 H), 7.68 (s, 1 H), 4.42 (br d, J=11.3 Hz, 1 H), 4.18 - 4.29 (m, 1 H), 4.11 (br d, J=12.8 Hz, 1 H), 3.94 (br dd, J=12.2, 3.9 Hz, 1 H), 3.60 (br dd, J=12.4, 3.6 Hz, 1 H), 2.73 (s, 2 H), 2.62 - 2.71 (m, 1 H), 2.10 - 2.20 (m, 2 H), 2.03 - 2.10 (m, 1 H), 1.78 - 1.94 (m, 4 H), 1.72 (br t, J=8.5 Hz, 1 H), 1.49 (t, J=3.4 Hz, 1 H), 1.40 (d, J=6.5 Hz, 3 H), 1.34 (s, 6 H), 0.89 (br d, J=9.8 Hz, 1 H).

[0307] Example 18 (1-((S)-1-cyclopentylethyl)-1H-imidazol-4-yl)((1R,5S,6S)-6-(5,5-dimethyl-4,5-dihydroisoxazol-3-yl)-3-azabicyclo[3.1.0]hexan-3-yl)methanone A solution of 1-[(1S)-1-cyclopentylethyl]-1H-imidazole-4-carboxylic acid (50 mg, 0.2400 mmol, prepared according to the same protocol as Example 19 using (R)-2-methylpropane-2-sulfinamide instead of (S)-2-methylpropane-2-sulfinamide) in DMF (5 mL) was added with HATU (137.68 mg, 0.3600 mmol) and triethylamine (0.12 mL, 0.9600 mmol). The mixture was stirred at 25 °C for 30 minutes. Then, (1R,5S,6r)-6-(5,5-dimethyl-4,5-dihydro-1,2-oxazol-3-yl)-3-azabicyclo[3.1.0]hexane hydrochloride (43.28 mg, 0.2400 mmol) was added. The resulting mixture was stirred at 25 °C for 3 hours to obtain a brown solution. The reaction mixture was concentrated under reduced pressure to remove most of the DMF. The crude product was purified by Prep-HPLC (NH 3 ) and then lyophilized to obtain the title compound (70 mg, 0.1889 mmol, yield 78.697%) as a white solid. LC-MS Method1: 371.3 [M+H + 1 ​1H NMR (400 MHz, CHLOROFORM-d) δ = 7.65 (d, J = 1.1 Hz, 1H), 7.44 (d, J = 0.9 Hz, 1H), 4.76 (br d, J = 11.9 Hz, 1H), 4.19 (br d, J = 12.6 Hz, 1H), 3.95 (br dd, J = 3.9, 11.9 Hz, 1H), 3.87 (qd, J = 6.8, 9.5 Hz, 1H), 3.62 (br dd, J = 4.1, 12.5 Hz, 1H), 3.66 - 3.57 (m, 1H), 2.64 (s, 2H), 2.20 - 2.04 (m, 2H), 2.02 - 1.94 (m, 1H), 1.88 (dtd, J = 3.9, 7.6, 11.7 Hz, 1H), 1.64 - 1.55 (m, 3H), 1.49 (d, J = 6.8 Hz, 6H), 1.38 (s, 6H), 1.23 (qd, J = 8.8, 12.6 Hz, 1H), 1.14 - 1.01 (m, 1H).

[0308] Example 19 {1-[(1R)-1-Cyclopentylethyl]-1H-imidazol-4-yl}[(1R,5S,6r)-6-(5,5-Dimethyl-4,5-dihydro-1,2-oxazol-3-yl)-3-azabicyclo[3.1.0]hex-3-yl]methanone (S)-N-[(E)-Cyclopentylmethylene]-2-methyl-2-propanesulfinamide To a mixture of cyclopentylaldehyde (20 mL) in THF, (S)-2-Methylpropane-2-sulfinamide (2.47 g, 20.38 mmol) and titanium(IV) ethoxide (6.97 g, 30.57 mmol) were added. The suspension was stirred at 20 °C for 16 hours. The reaction mixture was diluted with ethyl acetate (60 mL). This was added to water (10 mL) and stirred for 1 minute to obtain a white suspension. The suspension was filtered. The filtrate was washed with water (30 mL x 3), dried over anhydrous sodium sulfate, filtered, and then concentrated under reduced pressure to obtain the title compound (3.6 g, crude) as a yellow liquid. LC-MS Method1: 0.833 min, MS (m / z): 201.9 (M + H + ). 1 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.92 (t, d = 4.8 Hz, 1H), 2.90 - 2.80 (m, 1H), 1.90 - 1.75 (m, 3H), 1.75 - 1.50 (m, 5H), 1.15 (s, 9H).

[0309] (S)-N-[(1R)-1-cyclopentylethyl]-2-methyl-2-propanesulfinamide (S)-N-[(E)-Cyclopentylmethylene]-2-methyl-2-propanesulfinamide (742.96 mg, 9.93 mmol, 3.31 mL) in THF (20 mL) was added dropwise with chloromagnesium methyl at -40 °C for 10 minutes under a nitrogen atmosphere. The suspension was stirred at 20 °C for 16 hours. The residue was diluted with an aqueous ammonium chloride solution (15 mL), extracted with ethyl acetate (30 mL x 4), washed with saturated brine (30 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Purification by flash column (PE → 30% ethyl acetate in PE) gave the title compound (595 mg, crude) as a yellow liquid. LC-MS Method1: 0.827 min, MS (m / z): 218 (M + H + ). 1 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 3.20 - 3.05 (m, 1H), 2.82 (brd, J = 8.4 Hz, 1H), 1.90 - 1.40 (m, 8H), 1.20 (d, J = 7.2 Hz, 3H), 1.14 (s, 9H).

[0310] (1R)-1-Cyclopentylethanamine hydrochloride Methanol / hydrochloric acid (5 mL) was added to a mixture of (S)-N-[(1R)-1-cyclopentylethyl]-2-methyl-2-propanesulfinamide. The suspension was stirred at 25 °C for 1 hour. The residue was concentrated under reduced pressure to give the title compound (257 mg, crude) as a yellow solid.

[0311] Ethyl 1-[(1R)-1-cyclopentylethyl]-1H-imidazole-4-carboxylate (1R)-1-Cyclopentylethanamine hydrochloride (52.0 mg, 0.35 mmol) was added to a mixture of 1-butanol (0.5 mL). Then, ethyl (2Z)-3-(dimethylamino)-2-isocyanoacrylate (58.44 mg, 0.35 mmol) and triethylamine (52.64 mg, 0.52 mmol, 0.07 mL) were added to the solution. The suspension was reacted in a microwave reactor (time: 1 hour, reaction temperature: 130 °C). The residue was concentrated under reduced pressure to obtain the title compound (77 mg, crude) as a yellow oil. LC-MS Method1: 0.690 min, MS (m / z): 237.0 (M + H + ). 1 H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.57 (s, 1H), 7.43 (s, 1H), 4.30 (q, J = 6.8 Hz, 2H), 3.80 - 3.70 (m, 1H), (q, J = 7.2 Hz, 2H), 1.70 - 1.40 (m, 8H), 1.42 (d, J = 6.8 Hz, 2H), 1.32 (t, J = 7.2 Hz, 3H).

[0312] 1-[(1R)-1-Cyclopentylethyl]-1H-imidazole-4-carboxylic acid Lithium hydroxide monohydrate (20.5 mg, 0.49 mmol, 1.5 eq) was added to a mixture of water (0.5 mL) and THF (1.5 mL) of ethyl 1-[(1R)-1-cyclopentylethyl]-1H-imidazole-4-carboxylate. The suspension was stirred at 20 °C for 2 hours. The residue was diluted with water (1 mL) and extracted with ethyl acetate (5 mL x 4). The obtained aqueous layer was acidified to pH = 5 with aqueous hydrochloric acid (1N). The combined organic layers were concentrated and then lyophilized to obtain the title compound (39 mg, crude) as a yellow solid. LC-MS Method1: 0.571 min, MS (m / z): 209 (M + H + )。

[0313] {1-[(1R)-1-Cyclopentylethyl]-1H-imidazol-4-yl}[(1R,5S,6r)-6-(5,5-Dimethyl-4,5-dihydro-1,2-oxazol-3-yl)-3-azabicyclo[3.1.0]hex-3-yl]methanone To a mixture of pyridine (0.5 mL) and 1-[(1R)-1-cyclopentylethyl]-1H-imidazole-4-carboxylic acid (30.0 mg, 0.14 mmol), EDCI (27.6 mg, 0.14 mmol) and (1R,5S,6r)-6-(5,5-dimethyl-4,5-dihydro-1,2-oxazol-3-yl)-3-azabicyclo[3.1.0]hexane hydrochloride (26.0 mg, 0.14 mmol) were added. The suspension was stirred at 20 °C for 16 hours. Water (10 mL) was added to the reaction mixture to quench the reaction. The residue was diluted with ethyl acetate (20 mL x 3), washed with saturated brine (5 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The solution was purified by prep-HPLC (NH 3 ), and freeze-dried to obtain the title compound (1.88 mg, yield 3.5%) as a white solid. LC-MS Method1: 3.486 min, MS (m / z): 371.3 (M + H + ). 1 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.58 (d, J = 1.25 Hz, 1 H), 7.36 (s, 1 H), 4.70 (br d, J = 12.30 Hz, 1 H), 4.12 (d, J = 12.30 Hz, 1 H), 3.87 (br d, J = 12.30 Hz, 1 H), 3.79 (dd, J = 9.41, 6.65 Hz, 1 H), 3.54 (br d, J = 8.53 Hz, 1 H), 2.57 (s, 2 H), 1.80 - 2.10 (m, 4 H), 1.51 - 1.60 (m, 2 H), 1.41 (br d, J = 6.78 Hz, 9 H), 1.30 (s, 7 H), 1.18 (s, 7 H).

[0314] Example 20 [(1R,5S,6S)-6-(5,5-Dimethyl-4,5-dihydro-1,2-oxazol-3-yl)-3-azabicyclo[3.1.0]hex-3-yl]{1-[(1S)-1-(tetrahydro-2H-pyran-4-yl)ethyl]-1H-imidazol-4-yl}methanone (R)-2-Methyl-N-[(E)-tetrahydro-2H-pyran-4-ylmethylene]-2-propanesulfinamide To a 100 mL round-bottom flask were added tetrahydro-2H-pyran-4-carbaldehyde (5000 mg, 43.81 mmol), (R)-2-methylpropane-2-sulfinamide (5309.27 mg, 43.81 mmol), titanium(IV) ethoxide (13.5 mL, 65.71 mmol) and THF (25 mL). The reaction solution was heated at 60 °C for 30 minutes under a nitrogen atmosphere to obtain a yellow solution. A new spot was detected by TLC (PE / ethyl acetate = 3 / 1, Rf = 0.4). Water (3 mL) was added dropwise, and after stirring at 20 °C for 5 minutes, it was filtered through celite, and the filtrate was concentrated under reduced pressure to obtain the title compound (8700 mg, 40.031 mmol, yield 91.383%) as a white solid. LC-MS Method1 0.745 min, MS (m / z) 218.1 (M + H + )。

[0315] (R)-2-Methyl-N-[(1S)-1-(tetrahydro-2H-pyran-4-yl)ethyl]-2-propanesulfinamide (R)-2-Methyl-N-[(E)-tetrahydro-2H-pyran-4-ylmethylene]-2-propanesulfinamide (3000 mg, 13.8 mmol) and THF (30 mL) were placed in a round-bottom flask and cooled to -48 °C, and methylmagnesium bromide (5.06 mL, 15.18 mmol) was added dropwise to the mixture. The reaction solution was stirred at the same temperature for 2 hours to obtain a yellow solution. Water (30 mL) was added, and it was extracted with ethyl acetate (30 mL x 2). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure to obtain a yellow oil. The crude product was purified by silica gel chromatography (DCM / ethyl acetate = 3 / 1 → 1 / 1) to obtain the title compound (1700 mg, 7.2846 mmol, yield 52.772%) as a colorless oil. 11H NMR (400 MHz, CHLOROFORM-d) δ ppm 4.05 - 3.95 (m, 2H), 3.40 (dt, J = 4.0, 1.6 Hz, 2H), 3.25 - 3.10 (m, 1H), 2.90 (d, J = 7.6 Hz, 1H), 1.85 - 1.75 (m, 1H), 1.70 - 1.20 (m, 4H), 1.29 (d, J = 6.8 Hz, 3H), 1.25 (s, 9H).

[0316] (1S)-1-(Tetrahydro-2H-pyran-4-yl)ethanamine hydrochloride (R)-2-Methyl-N-[(1S)-1-(tetrahydro-2H-pyran-4-yl)ethyl]-2-propanesulfinamide (1700 mg, 7.28 mmol) and hydrochloric acid / methanol (10 mL, 7.28 mmol) were placed in a 100 mL round-bottom flask. The reaction mixture was stirred at 25 °C for 3 hours to obtain a colorless oil. The solvent was removed under reduced pressure to obtain the title compound (1250 mg, 7.5456 mmol, yield 103.58%) as a colorless oil.

[0317] (R)-Ethyl 1-[(1S)-1-(tetrahydro-2H-pyran-4-yl)ethyl]-1H-imidazole-4-carboxylate Ethyl (2Z)-3-(dimethylamino)-2-isocyanoacrylate (400.29 mg, 2.38 mmol), (1S)-1-(tetrahydro-2H-pyran-4-yl)ethanamine hydrochloride (394.27 mg, 2.38 mmol), triethylamine (0.5 mL, 3.57 mmol), and 1-butanol (0.6004 mL) were added to a microwave tube. The mixture was irradiated with microwave at 130 °C for 1 hour to obtain a brown solution. Water (15 mL) was added, and the mixture was extracted with ethyl acetate (15 mL x 2). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure to obtain a yellow oil. The crude product was purified by silica gel chromatography (PE / ethyl acetate = 1 / 1 → 0 / 1) to obtain the title compound (135 mg, 0.5351 mmol, yield 22.481%) as a yellow oil. LC-MS Method1 0.638, MS (m / z) 253.2 (M + H + )

[0318] 1-[(1S)-1-(Tetrahydro-2H-pyran-4-yl)ethyl]-1H-imidazole-4-carboxylic acid To a 100 mL round-bottom flask were added ethyl 1-[(1S)-1-(tetrahydro-2H-pyran-4-yl)ethyl]-1H-imidazole-4-carboxylate (130 mg, 0.5200 mmol), lithium hydroxide hydrate (43.24 mg, 1.03 mmol), and THF (3 mL). The mixture was stirred at 20 °C for 3 hours to obtain a yellow solution. Water (15 mL) was added, and the mixture was extracted with ethyl acetate (15 mL × 2). The aqueous layer was lyophilized to obtain the title compound (110 mg, 0.4905 mmol, yield 95.199%) as a yellow solid, which was used directly in the next step.

[0319] [(1R,5S,6S)-6-(5,5-Dimethyl-4,5-dihydro-1,2-oxazol-3-yl)-3-azabicyclo[3.1.0]hex-3-yl]{1-[(1S)-1-(tetrahydro-2H-pyran-4-yl)ethyl]-1H-imidazol-4-yl}methanone To a DMF (5 mL) mixture of 1-[(1S)-1-(tetrahydro-2H-pyran-4-yl)ethyl]-1H-imidazole-4-carboxylic acid (110 mg, 0.4900 mmol) and HATU (243.77 mg, 0.6400 mmol) was added N-ethyl-N-isopropylpropan-2-amine (0.59 mL, 3.43 mmol). After stirring for 30 minutes, (1R,5S,6r)-6-(5,5-dimethyl-4,5-dihydro-1,2-oxazol-3-yl)-3-azabicyclo[3.1.0]hexane hydrochloride (384.3 mg, 0.7400 mmol) was added. The mixture was further stirred for 16 hours to obtain a yellow solution. Water (30 mL) was added, and the mixture was extracted with ethyl acetate (30 mL × 2). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure to obtain a yellow oil. The crude product was purified by Prep-HPLC (NH 3 ) and the obtained fractions were concentrated in vacuo to remove most of the acetonitrile and lyophilized to obtain the title compound (9.57 mg, 0.0248 mmol, yield 5.0482%) as a white solid. LC-MS Method1: 387.3 [M+H + 1 ​1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.12 - 1.17 (m, 1 H) 1.23 (dd, J=12.30, 4.02 Hz, 1 H) 1.37 (s, 6 H) 1.46 (br d, J=3.01 Hz, 1 H) 1.50 (d, J=6.78 Hz, 3 H) 1.68 (br d, J=13.05 Hz, 1 H) 1.78 (br d, J=8.78 Hz, 1 H) 1.94 - 1.99 (m, 1 H) 2.04 - 2.11 (m, 1 H) 2.63 (s, 2 H) 3.25 (td, J=11.80, 2.26 Hz, 1 H) 3.36 (td, J=11.92, 2.01 Hz, 1 H) 3.61 (dd, J=12.42, 3.89 Hz, 1 H) 3.81 - 3.88 (m, 1 H) 3.92 (br t, J=11.80 Hz, 2 H) 4.02 (br dd, J=11.54, 3.76 Hz, 1 H) 4.18 (br d, J=13.05 Hz, 1 H) 4.75 (dd, J=12.05, 4.27 Hz, 1 H) 7.40 (s, 1 H) 7.62 (s, 1 H).

[0320] Example 21 [(1R,5S,6S)-6-(5,5-Dimethyl-4,5-dihydro-1,2-oxazol-3-yl)-3-azabicyclo[3.1.0]hex-3-yl]{1-[(1S)-1-phenylethyl]-1H-imidazol-4-yl}methanone (R)-Ethyl 1-[(1S)-1-phenylethyl]-1H-imidazole-4-carboxylate A mixture of ethyl isocyanoacetate (1.0 g, 8.84 mmol) and 1,1-dimethoxy-N,N-dimethylmethanamine (1.53 mL, 11.49 mmol) was stirred at 0 °C for 3 h. As a result of TLC (PE: ethyl acetate = 3:1), ethyl 2-isocyanoacetate (1. g, 8.84 mmol) (Rf = 0.6) was completely consumed and a new spot (Rf = 0.4) was detected. (S)-1-Phenylethylamine (4.5 mL, 35.36 mmol) was added. The resulting mixture was stirred at 50 °C for 16 h to obtain a brown mixture. A new spot (Rf = 0.1) was detected by TLC (PE: ethyl acetate = 1:1). The mixture was concentrated to obtain a residue. The residue was purified by flash column (PE: ethyl acetate = 1:0→0:1) to obtain the title compound (0.9300 g, 3.807 mmol, yield 43.06%) (PE: ethyl acetate = 1:1, Rf = 0.1) as a brown oil. LC-MS Method1 0.685 min, MS (m / z) 244.9 (M + H + )。

[0321] 1-[(1S)-1-Phenylethyl]-1H-imidazole-4-carboxylic acid To a mixture of ethyl 1-[(1S)-1-phenylethyl]-1H-imidazole-4-carboxylate (930 mg, 3.81 mmol) in THF (6 mL) and water (3 mL), lithium hydroxide monohydrate (0.33 mL, 5.71 mmol) was added. The reaction mixture was stirred at 20 °C for 16 h to obtain a yellow mixture. TLC (PE: ethyl acetate = 1:1) indicated that the starting material was completely consumed. The reaction mixture was diluted with water (15 mL) and extracted with ethyl acetate (8 mL×5). The aqueous layer was acidified to pH = 4 with aqueous hydrochloric acid (1N). The resulting aqueous layer was dried under reduced pressure to obtain the title compound (900 mg, 4.162 mmol, yield 109.33%) (crude) as a brown solid. LC-MS Method1 0.539 min, MS (m / z) 216.9 (M + H + )。

[0322] [(1R,5S,6S)-6-(5,5-Dimethyl-4,5-dihydro-1,2-oxazol-3-yl)-3-azabicyclo[3.1.0]hex-3-yl]{1-[(1S)-1-phenylethyl]-1H-imidazol-4-yl}methanone (1R,5S,6r)-6-(5,5-Dimethyl-4,5-dihydro-1,2-oxazol-3-yl)-3-azabicyclo[3.1.0]hexane hydrochloride (100 mg, 0.5500 mmol) in DMF (2 mL) was mixed with 1-[(1S)-1-phenylethyl]-1H-imidazole-4-carboxylic acid (143.96 mg, 0.6700 mmol), DIPEA (0.37 mL, 2.22 mmol), and HATU (254.51 mg, 0.6700 mmol). The reaction mixture was stirred at 25 °C for 16 h to give a brown mixture. One new spot (Rf = 0.5) was detected by TLC (DCM:methanol = 40:1 with 1 drop of triethylamine added). The reaction solution was diluted with water (10 mL). The resulting mixture was extracted with ethyl acetate (5 mL × 4). The combined organic layers were dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (DCM: methanol = 40:1, 1% triethylamine added to the solvent) to give a crude product. The crude product was purified by prep-HPLC (NH 3 ) and the fractions obtained were combined, concentrated to remove most of the acetonitrile, freeze-dried to give the title compound (3.85 mg, 0.0102 mmol, yield 1.8336%) as a white solid. LC-MS Method1: 379.1 [M+H + 1 ​1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.67 (br s, 1 H), 7.48 (s, 1 H), 7.31 - 7.40 (m, 3 H), 7.18 (br d, J=6.5 Hz, 2 H), 5.35 (q, J=6.9 Hz, 1 H), 4.75 (br d, J=8.0 Hz, 1 H), 4.18 (br d, J=12.3 Hz, 1 H), 3.88 - 4.01 (m, 1 H), 3.61 (br d, J=8.8 Hz, 1 H), 2.64 (s, 2 H), 2.07 (br s, 1 H), 1.98 (br s, 1 H), 1.88 (d, J=7.0 Hz, 3 H), 1.46 (br s, 1 H), 1.38 (s, 6 H), 1.26 (s, 1 H).

[0323] Example 22 2-[(1S)-1-(4-{[(1R,5S,6S)-6-(5,5-Dimethyl-4,5-dihydro-1,2-oxazol-3-yl)-3-azabicyclo[3.1.0]hex-3-yl]carbonyl}-1H-imidazol-1-yl)ethyl]benzonitrile (R)-N-[(E)-(2-Bromophenyl)methylene]-2-methyl-2-propanesulfinamide 2-Bromobenzaldehyde (2000 mg, 10.81 mmol), (R)-2-methylpropane-2-sulfinamide (1310.13 mg, 10.81 mmol), titanium(IV) ethoxide (3.33 mL, 16.21 mmol) and THF (9.2536 mL) were added to a 100 mL round-bottom flask. The reaction solution was heated at 60 °C for 30 minutes under a nitrogen atmosphere to obtain a yellow solution. A new spot was detected by TLC (PE / ethyl acetate = 3 / 1, Rf = 0.4). Water (3 mL) was added dropwise, and after stirring at 20 °C for 5 minutes, the mixture was filtered through a Celite pad and then concentrated under reduced pressure to obtain the title compound (3050 mg, 10.583 mmol, yield 97.903%) as a white solid.

[0324] (R)-N-[(1S)-1-(2-Bromophenyl)ethyl]-2-methyl-2-propanesulfinamide (R)-N-[(E)-(2-Bromophenyl)methylene]-2-methyl-2-propanesulfinamide (3000 mg, 10.41 mmol) and THF (25 mL) were placed in a round-bottom flask and cooled to -48 °C. Chloro(methyl)magnesium (4.16 mL, 12.49 mmol) was added dropwise. The mixture was stirred at this temperature for 2 hours to obtain a yellow solution. Water (30 mL) was added, and the mixture was extracted with ethyl acetate (30 mL x 2). The organic layer was dried over sodium sulfate and concentrated under reduced pressure to obtain a yellow oil. The crude product was purified by silica gel chromatography (DCM / ethyl acetate = 10 / 1 → 3 / 1) to obtain the title compound (960 mg, 3.1553 mmol, yield 30.312%) as a white solid. 1 H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.54 (d, J = 8.0 Hz, 1H), 7.43 (dd, J = 8.0, 0.8 Hz, 1H), 7.40 - 7.20 (m, 1H), 7.20 - 7.10 (m, 1H), 5.05 - 4.95 (m, 1H), 3.37 (d, J = 4.0 Hz, 1H), 1.54 (d, J = 6.8 Hz, 3H), 1.21 (s, 9H).

[0325] (1S)-1-(2-Bromophenyl)ethanamine hydrochloride (R)-N-[(1S)-1-(2-Bromophenyl)ethyl]-2-methyl-2-propanesulfinamide (900 mg, 2.96 mmol) in hydrochloric acid / methanol (105.31 mg, 2.96 mmol) solution was stirred at 30 °C for 16 hours to obtain a colorless solution. The solvent of the reaction mixture was removed under reduced pressure to obtain the title compound (700 mg, 2.95 mmol, yield 100.04%) as a yellow oil. It was used directly in the next step. LC-MS Method1 0.592 min, MS (m / z) 202.1 (M + H + )。

[0326] (R)-Ethyl 1-[(1S)-1-(2-bromophenyl)ethyl]-1H-imidazole-4-carboxylate To an 8 mL microwave vial were added (1S)-1-(2-bromophenyl)ethanamine hydrochloride (780 mg, 3.3 mmol), ethyl (2Z)-3-(dimethylamino)-2-isocyanoacrylate (554.61 mg, 3.3 mmol), triethylamine (0.69 mL, 4.95 mmol), and 1-butanol (3 mL). The reaction mixture was irradiated with microwave at 130 °C for 1 hour to obtain a brownish red solution. The reaction solution was diluted with saturated aqueous sodium carbonate solution (10 mL) and extracted with ethyl acetate (20 mL × 2). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure to obtain a yellow oil. The crude product was purified by silica gel chromatography (DCM / ethyl acetate = 10 / 1 → 6 / 1) to obtain the title compound (230 mg, 0.7117 mmol, yield 21.581%) as a yellow oil. LC-MS Method1 0.726 min, MS (m / z) 324.9 (M + H + )。

[0327] (R)-Ethyl 1-[(1S)-1-(2-cyanophenyl)ethyl]-1H-imidazole-4-carboxylate To a 50 mL round-bottom flask were added ethyl 1-[(1S)-1-(2-bromophenyl)ethyl]-1H-imidazole-4-carboxylate (180 mg, 0.5600 mmol), zinc cyanide (130.78 mg, 1.11 mmol), tris(dibenzylideneacetone)dipalladium(0) (25.5 mg 0.0300 mmol), tri-t-butylphosphonium tetrafluoroborate (32.32 mg, 0.1100 mmol), zinc (14.57 mg, 0.2200 mmol), and DMF (2 mL). The reaction mixture was stirred at 120 °C for 16 hours to obtain a yellow solution. Water (15 mL) was added and the mixture was extracted with ethyl acetate (20 mL x 2). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure to obtain a yellow oil. The solvent of the reaction mixture was removed under reduced pressure to obtain the title compound (60 mg, 0.2228 mmol, yield 40.004%) as a yellow oil. It was used as such in the next step.

[0328] 1-[(1S)-1-(2-Cyanophenyl)ethyl]-1H-imidazole-4-carboxylic acid To a mixture of ethyl 1-[(1S)-1-(2-cyanophenyl)ethyl]-1H-imidazole-4-carboxylate (150 mg, 0.5600 mmol) in 1,4-dioxane (5 mL) was added a solution of lithium hydroxide monohydrate (46.74 mg, 1.11 mmol) in water (1.5 mL, 0.5600 mmol). The mixture was reacted at 20 °C for 16 h to obtain a yellow solution. The solvent of the reaction mixture was removed under reduced pressure to obtain the title compound (160 mg, 0.6632 mmol, yield 119.07%) as a white solid. LC-MS Method1 0.688 min, MS (m / z) 242.2 (M + H + )。

[0329] 2-[(1S)-1-(4-{[(1R,5S,6S)-6-(5,5-Dimethyl-4,5-dihydro-1,2-oxazol-3-yl)-3-azabicyclo[3.1.0]hex-3-yl]carbonyl}-1H-imidazol-1-yl)ethyl]benzonitrile To a solution of 1-[(1S)-1-(2-cyanophenyl)ethyl]-1H-imidazole-4-carboxylic acid (50 mg, 0.2100 mmol) in DMF (2 mL) were added N-ethyl-N-isopropylpropan-2-amine (0.18 mL, 1.04 mmol) and HATU (118.85 mg, 0.3100 mmol) at 20 °C. After stirring for 30 min, (1R,5S,6r)-6-(5,5-dimethyl-4,5-dihydro-1,2-oxazol-3-yl)-3-azabicyclo[3.1.0]hexane hydrochloride (52.47 mg, 0.21 mmol) was stirred for 16 h to obtain a black suspension. Water (30 mL) was added and the mixture was extracted with ethyl acetate (30 mL x 2). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure to obtain a yellow oil. The crude product was purified by Prep-HPLC (NH 3 ) to obtain the fraction concentrated in vacuo to remove most of the acetonitrile and freeze-dried to obtain the title compound (37.35 mg, 0.0926 mmol) as a white solid. LC-MS Method1: 404.3 [M+H + 1 ​1H NMR (400 MHz, CHLOROFORM-d) δ 7.70 (dd, J=1.00, 7.53 Hz, 1H), 7.67 (d, J=1.51 Hz, 1H), 7.56-7.63 (m, 2H), 7.41-7.48 (m, 1H), 7.20 (d, J=8.03 Hz, 1H), 5.78 (q, J=7.03 Hz, 1H), 4.73 (dd, J=2.89, 12.17 Hz, 1H), 4.16 (d, J=12.55 Hz, 1H), 3.93 (br d, J=10.29 Hz, 1H), 3.60 (dd, J=4.14, 12.42 Hz, 1H), 2.63 (d, J=2.26 Hz, 2H), 2.07 (br d, J=3.51 Hz, 1H), 1.95-1.99 (m, 1H), 1.94 (d, J=7.03 Hz, 3H), 1.45 (br d, J=3.26 Hz, 1H), 1.36 (s, 6H).

[0330] Example 23 3-[(1S)-1-(4-{[(1R,5S,6S)-6-(5,5-Dimethyl-4,5-dihydro-1,2-oxazol-3-yl)-3-azabicyclo[3.1.0]hex-3-yl]carbonyl}-1H-imidazol-1-yl)ethyl]benzonitrile (R)-N-[(E)-(3-Cyanophenyl)methylene]-2-methyl-2-propanesulfinamide (R)-2-Methylpropan-2-sulfinamide (4621.37 mg, 38.13 mmol) in THF (20 mL) was added with 3-formylbenzonitrile (5000 mg, 38.13 mmol) and titanium(IV) ethoxide (11.86 mL, 57.2 mmol) at 60 °C. The resulting mixture was stirred at 60 °C for 0.5 h to obtain a yellow solution. Water (3 mL) was added dropwise and stirred for 5 min. Then, the solid was filtered through a pad of celite, and the filtrate was concentrated under reduced pressure to obtain the title compound (7630 mg, 32.562 mmol, yield 85.398%) as a white solid. It was used in the next step without further purification as it was. LC-MS Method1 0.858 min, MS (m / z) 235.2 (M + H +)。

[0331] (R)-N-[(1S)-1-(3-Cyanophenyl)ethyl]-2-methyl-2-propanesulfinamide (R)-N-[(E)-(3-Cyanophenyl)methylene]-2-methyl-2-propanesulfinamide (3000 mg, 12.8 mmol) in THF (32.054 mL) was added with chloro(methyl)magnesium (4.69 mL, 14.08 mmol) at -48 °C. The resulting mixture was stirred at -40 °C for 14 hours to obtain a yellow solution. The reaction solution was added to a saturated aqueous ammonium chloride solution (30 mL) and extracted with ethyl acetate (30 mL × 4). The combined organic layers were washed with saturated brine (30 mL × 2), dried over sodium sulfate, filtered, and concentrated under reduced pressure to obtain the title compound (960 mg, 3.8345 mmol, yield 29.95%) as a yellow solid. LC-MS Method1 0.845 min, MS (m / z) 251.2 (M + H + )。

[0332] 3-[(1S)-1-Aminoethyl]benzonitrile hydrochloride (R)-N-[(1S)-1-(3-Cyanophenyl)ethyl]-2-methyl-2-propanesulfinamide (960 mg, 3.83 mmol) was added with hydrochloric acid / methanol (10 mL, 3.83 mmol) at 20 °C. The resulting mixture was stirred at 20 - 25 °C for 0.5 hour to obtain a yellow solution. The solvent of the reaction mixture was removed under reduced pressure to obtain the title compound (643 mg, crude product) as a yellow oil. LC-MS Method1 0.258 min, MS (m / z) 147. (M -HCl + H + )。

[0333] Ethyl 1-[(1S)-1-(3-cyanophenyl)ethyl]-1H-imidazole-4-carboxylate To a solution of 3-[(1S)-1-aminoethyl]benzonitrile hydrochloride (250 mg, 1.49 mmol) in 1-butanol (2.5 mL) were added triethylamine (0.31 mL, 2.23 mmol) and ethyl (2Z)-3-(dimethylamino)-2-isocyanoacrylate (271.49 mg, 1.49 mmol). The reaction mixture was irradiated with microwave at 130 °C for 60 minutes to obtain a yellow solution. The reaction solution was poured into a saturated aqueous ammonium chloride solution (30 mL) and extracted with ethyl acetate (30 mL × 2). The combined organic layers were combined, washed with saturated brine (30 mL × 2), dried over sodium sulfate, filtered, and concentrated under reduced pressure to obtain the title compound (90 mg, 0.3342 mmol, yield 22.484%) as a yellow oil. LC-MS Method1 0.732 min, MS (m / z) 270.2 (M + H + )。

[0334] 1-[(1S)-1-(3-Cyanophenyl)ethyl]-1H-imidazole-4-carboxylic acid To a solution of ethyl 1-[(1S)-1-(3-cyanophenyl)ethyl]-1H-imidazole-4-carboxylate (90 mg, 0.3300 mmol) was added a solution of lithium hydroxide monohydrate (28.05 mg, 0.6700 mmol) in THF (0.90 mL), water (0.90 mL), and methanol (0.90 mL) at 20 °C. The resulting mixture was stirred at 20 - 25 °C for 14 hours to obtain a yellow solution. The reaction mixture was poured into water and extracted with ethyl acetate (20 mL × 4). The aqueous layer was concentrated and lyophilized to obtain the title compound (132 mg, crude product) as a white solid. LC-MS Method1 0.468 min, MS (m / z) 241.9 (M + H + )。

[0335] 3-[(1S)-1-(4-{[(1R,5S,6S)-6-(5,5-Dimethyl-4,5-dihydro-1,2-oxazol-3-yl)-3-azabicyclo[3.1.0]hex-3-yl]carbonyl}-1H-imidazol-1-yl)ethyl]benzonitrile A solution of 1-[(1S)-1-(3-cyanophenyl)ethyl]-1H-imidazole-4-carboxylic acid (60 mg, 0.2500 mmol) in DMF (1.8 mL) was added with HATU (123.6 mg, 0.3200 mmol) and N-ethyl-N-isopropylpropan-2-amine (0.3 mL, 1.74 mmol) at 20 °C. The reaction mixture was stirred at 20 °C for 30 minutes. Then, (1R,5S,6r)-6-(5,5-dimethyl-4,5-dihydro-1,2-oxazol-3-yl)-3-azabicyclo[3.1.0]hexane hydrochloride (62.96 mg, 0.2500 mmol) was added. The resulting mixture was stirred from 20 °C to 25 °C for 14 hours to obtain a yellow solution. The reaction solution was poured into a saturated aqueous ammonium chloride solution (80 mL) and extracted with ethyl acetate (50 mL × 4). The combined organic layers were washed with saturated brine (50 mL × 2), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by prep-HPLC (FA) to obtain the title compound (10 mg, 0.0248 mmol, yield 9.9654%) as a white solid. LC-MS Method1: 404.2 [M+H + 1 1H NMR (400 MHz, CHLOROFORM-d) δ = 7.63 (br d, J = 7.8 Hz, 2H), 7.52 - 7.46 (m, 2H), 7.44 (s, 1H), 7.37 (br d, J = 8.0 Hz, 1H), 5.40 (q, J = 6.9 Hz, 1H), 4.73 (br d, J = 12.3 Hz, 1H), 4.17 (br d, J = 12.3 Hz, 1H), 3.98 - 3.91 (m, 1H), 3.64 - 3.58 (m, 1H), 2.64 (s, 2H), 2.08 (br s, 1H), 1.98 (br d, J = 3.3 Hz, 1H), 1.90 (d, J = 7.0 Hz, 3H), 1.46 (t, J = 3.3 Hz, 1H), 1.36 (s, 6H).

[0336] ​Example 24 4-[(1S)-1-(4-{[(1R,5S,6S)-6-(5,5-Dimethyl-4,5-dihydro-1,2-oxazol-3-yl)-3-azabicyclo[3.1.0]hex-3-yl]carbonyl}-1H-imidazol-1-yl)ethyl]benzonitrile (R)-N-[(E)-(4-Cyanophenyl)methylene]-2-methyl-2-propanesulfinamide (R)-2-Methylpropane-2-sulfinamide (4621.37 mg, 38.13 mmol) in THF (20 mL) was added to 4-formylbenzonitrile (5000 mg, 38.13 mmol) and titanium(IV) ethoxide (13.05 g, 57.2 mmol) at 60 °C. The resulting mixture was stirred at 60 °C for 0.5 h to obtain a yellow solution. Water (3 mL) was added dropwise and stirred for 5 min. Then, the solid was removed by filtration through a pad of Celite, and the filtrate was concentrated under reduced pressure to obtain the title compound (8340 mg, 35.592 mmol, 93.345% yield) as a white solid. LC-MS Method1 0.858 min, MS (m / z) 234.8 (M + H + )。

[0337] (R)-N-[(1S)-1-(4-Cyanophenyl)ethyl]-2-methyl-2-propanesulfinamide (R)-N-[(E)-(4-Cyanophenyl)methylene]-2-methyl-2-propanesulfinamide (2340 mg, 9.99 mmol) in THF (30 mL) was added with chloro(methyl)magnesium (4.99 mL, 14.98 mmol) at -48 °C. The resulting mixture was stirred at -40 °C for 14 h to obtain a yellow solution. The mixture was cooled with aqueous ammonium chloride solution, and the aqueous layer was extracted with ethyl acetate (30 mL × 3). The combined organic layers were washed with saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The crude product was purified by silica column (PE → PE:ethyl acetate = 1:1). The obtained solid was triturated with ethyl acetate / hexane (20 mL / 10 mL) and air-dried to obtain the title compound (1310 mg, 5.2325 mmol, 52.396% yield) as a yellow solid. LC-MS Method1 0.732 min, MS (m / z) 250.9 (M + H+ )。

[0338] 4-[(1S)-1-Aminoethyl]benzonitrile hydrochloride (R)-N-[(1S)-1-(4-Cyanophenyl)ethyl]-2-methyl-2-propanesulfinamide (1310 mg, 5.23 mmol) was added with hydrochloric acid / methanol (10 mL, 5.23 mmol) at 20 °C. The resulting mixture was stirred at 20 - 25 °C for 0.5 hour to obtain a yellow solution. The solvent of the reaction mixture was removed under reduced pressure to obtain the title compound (1 g, crude product) as a yellow oil. LC-MS Method1 0.302 min, MS (m / z) 146.8 (M + H + )。

[0339] Ethyl 1-[(1S)-1-(4-cyanophenyl)ethyl]-1H-imidazole-4-carboxylate To a solution of ethyl (2Z)-3-(dimethylamino)-2-isocyanoacrylate (300 mg, 1.78 mmol) in 1-butanol (3 mL) were added triethylamine (0.38 mL, 2.68 mmol) and 4-[(1S)-1-aminoethyl]benzonitrile hydrochloride (300 mg, 1.78 mmol). The reaction mixture was irradiated with microwave at 130 °C for 60 minutes to obtain a yellow solution. The reaction solution was poured into a saturated aqueous ammonium chloride solution (30 mL) and extracted with ethyl acetate (30 mL × 2). The combined organic layers were washed with saturated brine (30 mL × 2), dried over sodium sulfate, filtered, and concentrated under reduced pressure to obtain the title compound (110 mg, 0.4085 mmol, yield 22.9%) as a yellow oil. LC-MS Method1 0.732 min, MS (m / z) 270.2 (M + H + )。

[0340] 1-[(1S)-1-(4-Cyanophenyl)ethyl]-1H-imidazole-4-carboxylic acid To a solution of ethyl 1-[(1S)-1-(4-cyanophenyl)ethyl]-1H-imidazole-4-carboxylate (110 mg, 0.4100 mmol) in THF (1.1 mL), water (1.1 mL), and methanol (1.1 mL) was added lithium hydroxide monohydrate (34.28 mg, 0.8200 mmol) at 20 °C. The resulting mixture was stirred at 20 - 25 °C for 14 hours to obtain a yellow solution. The reaction mixture was poured into water and extracted with ethyl acetate (20 mL × 4). After concentrating the aqueous layer, it was lyophilized to obtain the title compound (130 mg, crude product) as a yellow solid. LC-MS Method1 0.443 min, MS (m / z) 241.9 (M + H + )。

[0341] 4-[(1S)-1-(4-{[(1R,5S,6S)-6-(5,5-Dimethyl-4,5-dihydro-1,2-oxazol-3-yl)-3-azabicyclo[3.1.0]hex-3-yl]carbonyl}-1H-imidazol-1-yl)ethyl]benzonitrile To a solution of 1-[(1S)-1-(4-cyanophenyl)ethyl]-1H-imidazole-4-carboxylic acid (100 mg, 0.4100 mmol) in DMF (3 mL) were added HATU (206.01 mg, 0.5400 mmol) and N-ethyl-N-isopropylpropan-2-amine (0.5 mL, 2.9 mmol) at 20 °C. The reaction mixture was stirred for 30 minutes. Then, (1R,5S,6r)-6-(5,5-dimethyl-4,5-dihydro-1,2-oxazol-3-yl)-3-azabicyclo[3.1.0]hexane hydrochloride (104.94 mg, 0.4100 mmol) was added. The resulting mixture was stirred at 20 °C to 25 °C for 14 hours to obtain a yellow solution. The reaction solution was poured into a saturated aqueous ammonium chloride solution (20 mL) and extracted with ethyl acetate (20 mL × 3). The crude product was purified by Prep-HPLC (FA) to obtain the title compound (2 mg, 0.0050 mmol, yield 1.1958%) as a yellow solid. LC-MS Method1: 404.2 [M+H + 1 ​1H NMR (400 MHz, CHLOROFORM-d) δ = 7.66 (br d, J = 8.0 Hz, 3H), 7.51 (br d, J = 9.0 Hz, 1H), 7.23 (br s, 2H), 5.42 (br d, J = 7.0 Hz, 1H), 4.72 (br s, 1H), 4.17 (br d, J = 12.8 Hz, 1H), 3.93 (br d, J = 12.0 Hz, 1H), 3.61 (br d, J = 14.8 Hz, 1H), 2.63 (s, 2H), 2.08 (br s, 1H), 1.98 (br s, 1H), 1.90 (br d, J = 7.0 Hz, 3H), 1.47 (br s, 1H), 1.37 (s, 6H).

[0342] Example 25 [(1R,5S,6S)-6-(5,5-Dimethyl-4,5-dihydro-1,2-oxazol-3-yl)-3-azabicyclo[3.1.0]hex-3-yl]{1-[(1S)-1-(2-pyridinyl)ethyl]-1H-imidazol-4-yl}methanone Ethyl 1-[(1S)-1-(2-pyridinyl)ethyl]-1H-imidazole-4-carboxylate (1S)-1-(2-Pyridinyl)ethanamine (500 mg, 4.09 mmol) and ethyl (2Z)-3-(dimethylamino)-2-isocyanoacrylate (137.67 mg, 0.8200 mmol) were stirred at 50 °C for 16 h. The reaction mixture was concentrated directly. The residue was purified by prep-TLC (PE:ethyl acetate = 0:1) to give the title compound as a brown oil. 1 1H NMR (400 MHz, CHLOROFORM-d) δ = 8.61 (d, J = 4.0 Hz, 1H), 7.78 (d, J = 1.2 Hz, 1H), 7.70 - 7.60 (m, 2H), 7.30 - 7.20 (m, 1H), 7.02 (d, J = 8.0 Hz, 1H), 5.50 - 5.35 (m, 1H), 4.36 (q, J = 6.8 Hz, 2H), 1.94 (d, J = 7.6 Hz, 3H), 1.38 (t, J = 6.8 Hz, 3H).

[0343] 1-[(1S)-1-(2-Pyridinyl)ethyl]-1H-imidazole-4-carboxylic acid To a solution of ethyl 1-[(1S)-1-(2-pyridinyl)ethyl]-1H-imidazole-4-carboxylate (160 mg, 0.6500 mmol) in THF (5 mL) and water (1 mL, 55.56 mmol) was added lithium hydroxide monohydrate (0.11 mL, 1.96 mmol). The mixture was stirred at 20 °C for 12 h to obtain a brown suspension. LCMS indicated complete consumption of the starting material. The reaction mixture was concentrated. The resulting aqueous layer was acidified to pH = 5 - 7 with aqueous hydrochloric acid (1 N) and then lyophilized to give the title compound (130 mg, 0.5985 mmol, 91.746% yield) as a white solid.

[0344] [(1R,5S,6S)-6-(5,5-dimethyl-4,5-dihydro-1,2-oxazol-3-yl)-3-azabicyclo[3.1.0]hex-3-yl]{1-[(1S)-1-(2-pyridinyl)ethyl]-1H-imidazol-4-yl}methanone To a solution of 1-[(1S)-1-(2-pyridinyl)ethyl]-1H-imidazole-4-carboxylic acid (130 mg, 0.6000 mmol) in DMF (2 mL) were added HATU (274.55 mg, 0.7200 mmol), DIPEA (0.49 mL, 2.99 mmol), and (1R,5S,6r)-6-(5,5-dimethyl-4,5-dihydro-1,2-oxazol-3-yl)-3-azabicyclo[3.1.0]hexane hydrochloride (108 mg, 0.6000 mmol). The mixture was stirred at 30 °C for 3 h to obtain a brown solution. The reaction mixture was concentrated directly. The residue was purified by prep-HPLC (NH 3 ) and the combined fractions were concentrated to remove most of the acetonitrile and then lyophilized to give the title compound (48.15 mg, 0.1269 mmol, 21.202% yield) as a pale yellow solid. LC-MS Method1: 380.0 [M+H + 1 ​1H NMR (400 MHz, CHLOROFORM-d) δ ppm 8.60 (1 H, d, J=4.63 Hz), 7.74 (1 H, br d, J=2.38 Hz), 7.67 (1 H, td, J=7.75, 1.50 Hz), 7.60 (1 H, s), 7.24 (1 H, dd, J=7.44, 4.82 Hz), 7.03 (1 H, d, J=7.88 Hz), 5.43 (1 H, q, J=7.00 Hz), 4.74 (1 H, dd, J=12.07, 3.69 Hz), 4.18 (1 H, d, J=12.51 Hz), 3.90 - 4.01 (1 H, m), 3.61 (1 H, dd, J=12.51, 4.13 Hz), 2.64 (2 H, s), 2.07 (1 H, br d, J=3.38 Hz), 1.97 (1 H, br dd, J=7.13, 3.50 Hz), 1.92 (3 H, d, J=7.00 Hz), 1.45 (1 H, t, J=3.31 Hz), 1.31 - 1.43 (6 H, m).

[0345] Example 26 [(1R,5S,6S)-6-(5,5-Dimethyl-4,5-dihydro-1,2-oxazol-3-yl)-3-azabicyclo[3.1.0]hex-3-yl]{1-[(1S)-1-(4-pyridinyl)ethyl]-1H-imidazol-4-yl}methanone (1R)-1-(4-pyridinyl)ethyl 4-methylbenzenesulfonate To a solution of (1R)-1-(4-pyridinyl)ethanol (5 mL) in THF, sodium hydride (148.11 mg, 6.17 mmol) was added at 0 °C. The mixture was stirred at 0 °C for 0.5 h. 4-Methylbenzene-1-sulfonyl chloride (0.29 mL, 1.95 mmol) was added, and the mixture was stirred at 20 - 25 °C for 16 h. The reaction mixture was poured into water (10 mL) and extracted with ethyl acetate (10 mL × 4). The combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by flash column (PE → 30% ethyl acetate in PE) to obtain the title compound (330 mg, 1.1899 mmol, yield 73.267%) as a white solid. 1 H NMR (400 MHz, CHLOROFORM-d) δ = 8.54 - 8.48 (m, 2H), 7.69 (d, J = 8.5 Hz, 2H), 7.25 (d, J = 8.0 Hz, 2H), 7.13 - 7.10 (m, 2H), 5.54 (q, J = 6.6 Hz, 1H), 2.42 (s, 3H), 1.59 (d, J = 6.8 Hz, 3H).

[0346] (1S)-1-(4-pyridinyl)ethyl 1H-imidazole-4-carboxylate To a solution of (1R)-1-(4-pyridinyl)ethyl 4-methylbenzenesulfonate (280 mg, 1.01 mmol) in DMF (11.2 mL), methyl 1H-imidazole-5-carboxylate (127.32 mg, 1.01 mmol) and cesium carbonate (164.47 mg, 0.50 mmol) were added. The mixture was stirred at 40 °C for 16 h. The reaction mixture was poured into water (10 mL) and extracted with ethyl acetate (15 mL × 4). The combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by prep-TLC (DCM:methanol = 10:1) to obtain the target compound (28 mg, 0.1211 mmol, yield 11.993%) as a yellow oil. LC-MS Method1: 232.1 [M+H] + 11H NMR (400 MHz, CHLOROFORM-d) δ = 8.64 - 8.60 (m, 2H), 7.68 - 7.59 (m, 2H), 7.05 - 7.01 (m, 2H), 5.39 (q, J=7.0 Hz, 1H), 3.95 - 3.84 (m, 3H), 1.91 (d, J=7.3 Hz, 3H).

[0347] (1S)-1-(4-pyridinyl)ethyl 1H-imidazole-4-carboxylic acid To a solution of ethyl 1-[(1S)-1-(4-pyridinyl)ethyl]-1H-imidazole-4-carboxylate (50 mg, 0.22 mmol) in THF (2 mL) and water (1 mL) was added lithium hydroxide monohydrate (13.61 mg, 0.32 mmol). The mixture was stirred at 20 - 25 °C for 2 hours. The reaction solution was concentrated directly. The reaction solution was acidified to pH = 6 with aqueous hydrochloric acid (1N), and then lyophilized to obtain the title compound (40 mg, 0.1841 mmol, 85.167% yield) as a yellow oil. 1 1H NMR (400 MHz, DMSO-d 6 ) δ = 8.59 - 8.50 (m, 2H), 7.95 (s, 1H), 7.83 (s, 1H), 7.25 (d, J = 6.3 Hz, 2H), 5.66 (q, J = 7.1 Hz, 1H), 1.81 (d, J = 7.3 Hz, 3H).

[0348] [(1R,5S,6S)-6-(5,5-dimethyl-4,5-dihydro-1,2-oxazol-3-yl)-3-azabicyclo[3.1.0]hex-3-yl]{1-[(1S)-1-(4-pyridinyl)ethyl]-1H-imidazol-4-yl}methanone To a solution of 1-[(1S)-1-(4-pyridinyl)ethyl]-1H-imidazole-4-carboxylic acid (20 mg, 0.09 mmol) in pyridine (1 mL) were added EDCI (26.48 mg, 0.14 mmol) and (1R,5S,6r)-6-(5,5-dimethyl-4,5-dihydro-1,2-oxazol-3-yl)-3-azabicyclo[3.1.0]hexane hydrochloride (19.95 mg, 0.0900 mmol). The resulting mixture was stirred at 20 - 25 °C for 16 hours. The resulting mixture was stirred at 20 - 25 °C for 16 hours. The residue was purified by prep-HPLC (NH 3) was purified. The obtained fractions were combined, concentrated to remove most of the acetonitrile, freeze-dried, and the title compound (24.99 mg, 0.0659 mmol, yield 71.527%) was obtained as a yellow solid. LC-MS Method1: 380.1 [M+H] + 1 H NMR (400 MHz, CHLOROFORM-d) δ = 8.61 (d, J = 5.8 Hz, 2H), 7.68 (s, 1H), 7.51 (s, 1H), 7.03 (d, J = 5.8 Hz, 2H), 5.36 (q, J = 6.9 Hz, 1H), 4.76 (dd, J = 2.9, 12.2 Hz, 1H), 4.19 (br d, J = 12.3 Hz, 1H), 4.02 - 3.89 (m, 1H), 3.62 (dd, J = 4.1, 12.7 Hz, 1H), 2.64 (s, 2H), 2.13 - 1.96 (m, 2H), 1.90 (d, J = 7.3 Hz, 3H), 1.48 (t, J = 3.4 Hz, 1H), 1.38 (s, 6H).

[0349] Example 27 [(1R,5S,6S)-6-(5,5-Dimethyl-4,5-dihydro-1,2-oxazol-3-yl)-3-azabicyclo[3.1.0]hex-3-yl]{1-[(1S)-1-(1,3-thiazol-2-yl)ethyl]-1H-imidazol-4-yl}methanone (1S)-1-(1,3-thiazol-2-yl)ethyl 1H-imidazole-4-carboxylate To a solution of (1S)-1-(1,3-thiazol-2-yl)ethanamine (131.19 mg, 0.7800 mmol) in 1-butanol (1.4 mL) were added ethyl (2Z)-3-(dimethylamino)-2-isocyanoacrylate (100 mg, 0.7800 mmol) and triethylamine (0.16 mL, 1.17 mmol) at 25 °C. The resulting mixture was reacted in a microwave reactor (time: 1 hour, temperature: 130 °C). The reaction mixture was poured into water (5 mL) and extracted with ethyl acetate (5 mL × 3). The combined organic layers were washed with saturated brine (10 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by Prep-TLC (ethyl acetate) to obtain the title compound (50 mg, 0.1990 mmol, yield 25.507%) as a yellow oil.

[0350] (1S)-1-(1,3-thiazol-2-yl)ethyl 1H-imidazole-4-carboxylic acid To a solution of ethyl 1-[(1S)-1-(1,3-thiazol-2-yl)ethyl]-1H-imidazole-4-carboxylate (50 mg, 0.2000 mmol) in THF (3 mL) and water (1 mL) was added lithium hydroxide monohydrate (41.75 mg, 0.9900 mmol). The reaction solution was stirred at 25 °C for 16 hours to obtain a yellow mixture. The reaction mixture was concentrated in vacuo to remove most of the THF. The residue was diluted with water (5 mL) and acidified to pH = 6 with aqueous hydrochloric acid (0.5 M). Then, the solution was lyophilized to obtain the title compound as a yellow solid.

[0351] [(1R,5S,6S)-6-(5,5-dimethyl-4,5-dihydro-1,2-oxazol-3-yl)-3-azabicyclo[3.1.0]hex-3-yl]{1-[(1S)-1-(1,3-thiazol-2-yl)ethyl]-1H-imidazol-4-yl}methanone A solution of 1-[(1S)-1-(1,3-thiazol-2-yl)ethyl]-1H-imidazole-4-carboxylic acid (44 mg, 0.2000 mmol) in pyridine (2 mL) was added with EDCI (56.67 mg, 0.3000 mmol). The mixture was stirred at 25 °C for 10 minutes under a nitrogen atmosphere. Then, (1R,5S,6r)-6-(5,5-dimethyl-4,5-dihydro-1,2-oxazol-3-yl)-3-azabicyclo[3.1.0]hexane hydrochloride (42.71 mg, 0.2000 mmol) was added. The resulting mixture was stirred at 25 °C for 2 hours to obtain a yellow solution. The reaction mixture was poured into water (5 mL) and extracted with ethyl acetate (5 mL×3). The obtained organic layers were combined, washed with saturated brine (20 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to obtain a residue. The crude product was purified by Prep-HPLC(NH 3 ) to obtain the title compound (60 mg, 0.1557 mmol, yield 78.975%) as a white solid. LC-MS Method1: 386.2 [M+H + 1 H NMR (400MHz, CHLOROFORM-d) δ = 7.79 (d, J=3.3 Hz, 1H), 7.75 (s, 1H), 7.62 (s, 1H), 7.35 (d, J=3.3 Hz, 1H), 5.70 (q, J=6.9 Hz, 1H), 4.73 (dd, J=8.8, 11.9 Hz, 1H), 4.18 (br d, J=12.3 Hz, 1H), 3.99 - 3.91 (m, 1H), 3.61 (dd, J=4.2, 12.7 Hz, 1H), 2.64 (s, 2H), 2.11 - 2.06 (m, 1H), 2.03 (d, J=7.0 Hz, 3H), 2.00 - 1.95 (m, 1H), 1.37 (s, 6H).

[0352] ​Example 28 [(1R,5S,6S)-6-(5,5-dimethyl-4,5-dihydro-1,2-oxazol-3-yl)-3-azabicyclo[3.1.0]hex-3-yl]{1-[(1S)-1-(1,3-thiazol-5-yl)ethyl]-1H-imidazol-4-yl}methanone (R)-2-methyl-N-[(E)-1,3-thiazol-5-ylmethylene]-2-propanesulfinamide To a mixture of 5-formylthiazole (2.14 mL, 17.68 mmol) in THF (20 mL) were added (R)-2-methylpropane-2-sulfinamide (2142.48 mg, 17.68 mmol) and titanium(IV) ethoxide (6045.61 mg, 26.52 mmol). The mixture was stirred at 60 °C for 2 h to give a yellow mixture. By TLC (PE:ethyl acetate = 2:1), the starting materials were completely consumed and one new spot (Rf = 0.5) was detected. The reaction solution was diluted with ethyl acetate (30 mL). Water (10 mL) was added and the mixture was stirred for 1 min to give a yellow suspension. The suspension was filtered. The filtrate was washed with water (20 mL×3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the title compound (3.77 g, 17.428 mmol, yield 98.59%) as a yellow solid.

[0353] (R)-2-methyl-N-[(1S)-1-(1,3-thiazol-5-yl)ethyl]-2-propanesulfinamide A solution of (R)-2-methyl-N-[(E)-1,3-thiazol-5-ylmethylene]-2-propanesulfinamide (3.77 g, 17.43 mmol) in THF (37 mL) was added with chloro(methyl)magnesium (9.88 mL, 29.63 mmol) at -40 °C. The mixture was stirred at 25 °C for 16 h, turning the reaction solution black-brown. TLC (100% ethyl acetate) indicated complete consumption of the starting material and detected one new spot (Rf = 0.3). Ammonium chloride (60 mL) was added to the reaction solution to stop the reaction. The resulting mixture was extracted with ethyl acetate (40 mL × 4). The combined organic layers were washed with brine (80 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a residue. The residue was purified by flash column (10% ethyl acetate in PE → 100% ethyl acetate) to obtain the title compound (1.7 g, 7.3159 mmol, yield 41.978%) as a brown oil. 1 1H NMR (400 MHz, CHLOROFORM-d) δ = 8.77 (s, 1H), 7.84 (s, 1H), 5.00 - 4.60 (m, 1H), 3.52 (d, J = 3.2 Hz, 1H), 1.69 (d, J = 6.4 Hz, 3H), 1.23 (s, 9H).

[0354] (1S)-1-(1,3-thiazol-5-yl)ethanamine A solution of (R)-2-methyl-N-[(1S)-1-(1,3-thiazol-5-yl)ethyl]-2-propanesulfinamide (500 mg, 2.15 mmol) in methanol / hydrochloric acid (8 mL, 2.15 mmol) was stirred at 25 °C for 2 h to obtain a brown mixture. TLC (100% ethyl acetate) indicated complete consumption of the starting material. The reaction mixture was concentrated under reduced pressure to obtain a residue. The residue was triturated with MTBE (20 mL) and dried under reduced pressure to obtain the title compound (504 mg, 3.0609 mmol, yield 142.25%) (crude) as a brown solid.

[0355] (1S)-1-(1,3-thiazol-5-yl)ethyl 1H-imidazole-4-carboxylate (1S)-1-(1,3-Thiazol-5-yl)ethanamine (350 mg, 2.13 mmol) in 1-butanol (3.5 mL) was added to ethyl (2Z)-3-(dimethylamino)-2-isocyanoacrylate (357.5 mg, 2.13 mmol) and triethylamine (0.41 mL, 3.19 mmol). The mixture was stirred at 130 °C for 1 hour using microwave to obtain a brown mixture. The reaction mixture was concentrated under reduced pressure to obtain a residue. The residue was purified by prep-TLC (100% ethyl acetate) to obtain the title compound (46 mg, 0.1830 mmol, yield 8.6116%) as a brown solid. 1 H NMR (400 MHz, CHLOROFORM-d) δ = 8.83 (s, 1H), 7.81 (s, 1H), 7.66 (s, 1H), 7.62 (s, 1H), 5.75 - 5.60 (m, 1H), 4.37 (q, J = 7.6 Hz, 2H), 2.00 (d, J = 7.2 Hz, 3H), 1.39 (t, J = 7.6 Hz, 3H).

[0356] (1S)-1-(1,3-thiazol-5-yl)ethyl 1H-imidazole-4-carboxylic acid To a mixture of ethyl 1-[(1S)-1-(1,3-thiazol-5-yl)ethyl]-1H-imidazole-4-carboxylate (46 mg, 0.1800 mmol) in THF (1.5 mL) and water (0.50 mL) was added lithium hydroxide monohydrate (0.02 mL, 0.2700 mmol). The reaction mixture was stirred at 25 °C for 16 hours to obtain a yellow mixture. The reaction mixture was diluted with water (4 mL) and extracted with ethyl acetate (2 mL × 3). The aqueous layer was acidified to pH = 5 with aqueous hydrochloric acid (1N) and freeze-dried to obtain the title compound (40 mg, 0.1792 mmol, yield 97.882%) as a brown solid. 1 H NMR (400 MHz, DMSO-d 6) δ = 9.06 (s, 1H), 7.93 (s, 1H), 7.90 (s, 1H), 7.76 (s, 1H), 6.05 - 5.95 (m, 1H), 1.89 (d, J = 6.8 Hz, 3H).

[0357] [(1R,5S,6S)-6-(5,5-dimethyl-4,5-dihydro-1,2-oxazol-3-yl)-3-azabicyclo[3.1.0]hex-3-yl]{1-[(1S)-1-(1,3-thiazol-5-yl)ethyl]-1H-imidazol-4-yl}methanone To a mixed solution of 1-[(1S)-1-(1,3-thiazol-5-yl)ethyl]-1H-imidazole-4-carboxylic acid (40 mg, 0.1800 mmol) in DMF (0.8286 mL), HATU (82.2 mg, 0.2200 mmol) and DIPEA (0.15 mL, 0.9000 mmol) were added. After stirring the mixture at 50 °C for 30 minutes, (1R,5S,6r)-6-(5,5-dimethyl-4,5-dihydro-1,2-oxazol-3-yl)-3-azabicyclo[3.1.0]hexane hydrochloride (48.44 mg, 0.2700 mmol) was added. The mixture was stirred at 25 °C for 16 hours to obtain a yellow mixture. The reaction solution was purified by prep-HPLC (NH 3 ) and the obtained fractions were combined, concentrated to remove most of the acetonitrile, and freeze-dried to obtain the title compound (14.11 mg, 0.0366 mmol, yield 20.34%) as a yellow solid. LC-MS Method1: 386.1 [M+H + 1 ​1H NMR (400 MHz, CHLOROFORM-d) δ ppm 8.80 (s, 1 H), 7.79 (s, 1 H), 7.67 (s, 1 H), 7.52 (d, J=1.4 Hz, 1 H), 5.68 (d, J=7.0 Hz, 1 H), 4.71 (t, J=11.3 Hz, 1 H), 4.16 (dd, J=12.6, 1.9 Hz, 1 H), 3.87 - 3.99 (m, 1 H), 3.60 (dd, J=12.6, 4.2 Hz, 1 H), 2.63 (s, 2 H), 2.08 (dt, J=7.3, 3.7 Hz, 1 H), 1.98 (d, J=7.0 Hz, 4 H), 1.45 (br d, J=4.0 Hz, 1 H), 1.37 (s, 6 H).

[0358] Example 29 [(1R,5S,6S)-6-(5,5-Dimethyl-4,5-dihydro-1,2-oxazol-3-yl)-3-azabicyclo[3.1.0]hex-3-yl]{1-[(2S)-1-phenylpropan-2-yl]-1H-imidazol-4-yl}methanone (2R)-1-phenyl-2-propanyl 4-methylbenzenesulfonate (2R)-1-Phenyl-2-propanol (400 mg, 2.94 mmol) in DCM (5 mL) was added with triethylamine (0.45 mL, 3.23 mmol) and 4-methylbenzene-1-sulfonyl chloride (0.44 mL, 2.94 mmol). The reaction solution was stirred at 20 °C for 16 hours to obtain a yellow solution. TLC (PE / ethyl acetate = 10 / 1, rf = 0.3) showed a new major spot. Water (30 mL) was added and extracted with DCM (30 mL x 2). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure to obtain a yellow oil. The crude was purified by silica gel chromatography (PE / ethyl acetate = 1 / 0 → 10 / 1) to obtain the title compound (680 mg, 2.3418 mmol, yield 79.731%) as a white solid.

[0359] Methyl 1-[(2S)-1-phenylpropan-2-yl]-1H-imidazole-4-carboxylate A solution of methyl 1H-imidazole-4-carboxylate (300 mg, 2.38 mmol) and (2R)-1-phenyl-2-propanyl 4-methylbenzenesulfonate (690.78 mg, 2.38 mmol) in DMF (4 mL) was stirred at 80 °C for 16 h to obtain a yellow solution. Water (30 mL) was added, and the mixture was extracted with ethyl acetate (30 mL x 2). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure to obtain a yellow oil. The crude product was purified by silica gel chromatography (DCM / ethyl acetate = 10 / 1 → 3 / 1) to obtain the title compound (120 mg, 0.4912 mmol, yield 20.649%). 1 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.61 (s, 1H), 7.35 - 7.15 (m, 5H), 6.95 - 6.85 (m, 2H), 4.45 - 4.35 (m, 1H), 3.88 (s, 3H), 3.10 - 2.90 (m, 2H), 1.56 (d, J = 6.8 Hz, 3H).

[0360] 1-[(2S)-1-phenylpropan-2-yl]-1H-imidazole-4-carboxylic acid A solution of lithium hydroxide monohydrate (41.22 mg, 0.9800 mmol) in water (1 mL, 0.4900 mmol) was added to a stirred solution of methyl 1-[(2S)-1-phenylpropan-2-yl]-1H-imidazole-4-carboxylate (120 mg, 0.4900 mmol) in 1,4-dioxane (3 mL). The reaction mixture was stirred at 20 °C for 16 h to obtain a colorless oil. TLC (PE / ethyl acetate = 1 / 1, Rf = 0) showed a new spot. After removing the solvent under reduced pressure, the reaction mixture was lyophilized to obtain the title compound (110 mg, 0.4777 mmol, yield 97.252%) as a white solid.

[0361] [(1R,5S,6S)-6-(5,5-dimethyl-4,5-dihydro-1,2-oxazol-3-yl)-3-azabicyclo[3.1.0]hex-3-yl]{1-[(2S)-1-phenylpropan-2-yl]-1H-imidazol-4-yl}methanone To a stirred solution of 1-[(2S)-1-phenylpropan-2-yl]-1H-imidazole-4-carboxylic acid (100 mg, 0.4300 mmol) and HATU (199.24 mg, 0.5200 mmol) in DMF (3 mL), N-ethyl-N-isopropylpropan-2-amine (0.37 mL, 2.17 mmol) was added. After stirring for 30 minutes, (1R,5S,6r)-6-(5,5-dimethyl-4,5-dihydro-1,2-oxazol-3-yl)-3-azabicyclo[3.1.0]hexane hydrochloride (109.95 mg, 0.4300 mmol) was added and the mixture was stirred at 20 °C for 16 hours to obtain a yellow solution. Water (30 mL) was added and the mixture was extracted with ethyl acetate (30 mL x 2). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure to obtain a yellow oil. The crude product was purified by Prep-HPLC(NH 3 ). The obtained fractions were concentrated in vacuo to remove most of the acetonitrile and freeze-dried to obtain the title compound (104.7 mg, 0.2668 mmol, 61.424% yield) as a white solid. LC-MS Method1: 393.3 [M+H + 1 1H NMR (400 MHz, CHLOROFORM-d) δ 7.64 (s, 1H), 7.21-7.26 (m, 3H), 7.17 (br s, 1H), 6.96 (br d, J=7.03 Hz, 2H), 4.69 (br d, J=12.05 Hz, 1H), 4.30-4.38 (m, 1H), 4.18 (br d, J=10.54 Hz, 1H), 3.86-3.95 (m, 1H), 3.60 (br dd, J=3.89, 12.42 Hz, 1H), 2.94-3.04 (m, 2H), 2.63 (s, 2H), 2.06 (br d, J=3.51 Hz, 1H), 1.97 (br d, J=3.51 Hz, 1H), 1.54 (d, J=6.78 Hz, 3H), 1.46 (br d, J=11.29 Hz, 1H), 1.37 (s, 6H).

[0362] ​Example 30 [(1R,5S,6S)-6-(5,5-dimethyl-4,5-dihydro-1,2-oxazol-3-yl)-3-azabicyclo[3.1.0]hex-3-yl]{1-[(2S)-4-phenylbutan-2-yl]-1H-imidazol-4-yl}methanone (R)-2-Methyl-N-[(1E)-1-methyl-3-phenylpropylidene]-2-propanesulfinamide To 4-phenyl-2-butanone (1.01 mL, 6.75 mmol), a mixed solution of (R)-2-methylpropan-2-sulfinamide (817.81 mg, 6.75 mmol) in THF (10 mL) and titanium(IV) ethoxide (2307.69 mg, 10.12 mmol) were added. The reaction solution was diluted with ethyl acetate (30 mL). Water (10 mL) was added and stirred for 1 minute to obtain a yellow suspension. This suspension was filtered. The filtrate was washed with water (20 mL × 3), dried over anhydrous sodium sulfate, filtered, and then concentrated under reduced pressure to obtain a residue. The residue was purified by flash column (PE → 30% ethyl acetate in PE) to obtain the title compound (570 mg, 2.2674 mmol, yield 33.603%) as a yellow oil. LC-MS Method1 0.823 min, MS (m / z) 252 (M + H + )。

[0363] (R)-2-Methyl-N-[(2S)-4-phenylbutan-2-yl]-2-propanesulfinamide (R)-2-Methyl-N-[(1E)-1-methyl-3-phenylpropylidene]-2-propanesulfinamide (570 mg, 2.27 mmol) in a mixed solution of THF (6 mL) was added with L-selectride (6.8 mL, 6.8 mmol) at 0 °C. The mixture was stirred at 25 °C for 3 hours to obtain a colorless mixture. One new spot (Rf = 0.3) was detected by TLC (PE: ethyl acetate = 2:1). The reaction solution was quenched with water (3 mL). The reaction mixture was concentrated under reduced pressure to obtain a residue. The residue was purified by flash column (PE → 30% ethyl acetate in PE) to obtain the title compound (260 mg, 1.026 mmol, yield 45.252%) as a yellow oil. 11H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.40 - 7.25 (m, 2H), 7.25 - 7.10 (m, 3H), 3.41 (qn, J = 6.8 Hz, 1H), 2.93 (d, J = 7.2 Hz, 1H), 2.80 - 2.55 (m, 2H), 1.95 - 1.75 (m, 2H), 1.33 (d, J = 6.8 Hz, 3H), 1.24 (s, 9H).

[0364] (2S)-4-Phenyl-2-butanamine (R)-2-Methyl-N-[(2S)-4-phenylbutan-2-yl]-2-propanesulfinamide (260 mg, 1.03 mmol) in methanol / hydrochloric acid (5 mL, 1.03 mmol) was stirred at 25 °C for 1 h to obtain a yellow mixture. The mixture was concentrated under reduced pressure to give the title compound (190 mg, 1.0232 mmol, yield 99.724%) (crude) as a yellow solid.

[0365] Ethyl 1-[(2S)-4-phenylbutan-2-yl]-1H-imidazole-4-carboxylate (2S)-4-Phenyl-2-butanamine (190 mg, 1.02 mmol) in 1-butanol (2 mL) was mixed with ethyl (2Z)-3-(dimethylamino)-2-isocyanoacrylate (172.09 mg, 1.02 mmol) and triethylamine (0.2 mL, 1.53 mmol). The reaction mixture was heated at 130 °C for 1 h in a microwave reactor to obtain a brown mixture. One new spot (Rf = 0.2) was detected by TLC (PE:ethyl acetate = 1:1). The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (PE:ethyl acetate = 1:1) to give the title compound (40 mg, 0.1469 mmol, yield 14.354%) as a brown oil. LC-MS Method1 0.718 min, MS (m / z) 273 (M + H + ).

[0366] 1-[(2S)-4-phenylbutan-2-yl]-1H-imidazole-4-carboxylic acid To a solution of ethyl 1-[(2S)-4-phenylbutan-2-yl]-1H-imidazole-4-carboxylate (40 mg, 0.1500 mmol) in THF (1.5 mL) and water (0.50 mL) was added lithium hydroxide monohydrate (0.01 mL, 0.2200 mmol). The reaction mixture was stirred at 40 °C for 16 h to give a yellow mixture. TLC (PE: ethyl acetate = 1:1) indicated complete consumption of the starting material. The reaction mixture was diluted with water (5 mL) and extracted with ethyl acetate (3 mL×2). The aqueous layer was acidified to pH = 5 with aqueous hydrochloric acid (1 N). Lyophilization gave the title compound (30 mg, 0.1228 mmol, 83.612% yield) as a yellow solid. LC-MS Method1 0.677 min, MS (m / z) 245 (M + H + )。

[0367] [(1R,5S,6S)-6-(5,5-dimethyl-4,5-dihydro-1,2-oxazol-3-yl)-3-azabicyclo[3.1.0]hex-3-yl]{1-[(2S)-4-phenylbutan-2-yl]-1H-imidazol-4-yl}methanone To a mixture of 1-[(2S)-4-phenylbutan-2-yl]-1H-imidazole-4-carboxylic acid (30 mg, 0.1200 mmol) in pyridine (1.5 mL) was added EDCI (28.25 mg 0.1500 mmol). The mixture was stirred at 25 °C for 10 min, then (1R,5S,6r)-6-(5,5-dimethyl-4,5-dihydro-1,2-oxazol-3-yl)-3-azabicyclo[3.1.0]hexane hydrochloride (26.61 mg, 0.1200 mmol) was added. The mixture was stirred at 25 °C for 16 h to give a yellow mixture. LCMS indicated complete consumption of the starting material. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (NH 3 ) to give the fractions were combined, concentrated to remove most of the acetonitrile, and lyophilized to give the title compound (16.26 mg, 0.0449 mmol, 17.643% yield) as a yellow solid. LC-MS Method1: 407.2 [M+H + 1 ​1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.68 (s, 1 H), 7.43 (s, 1 H), 7.28 - 7.32 (m, 2 H), 7.19 - 7.24 (m, 1 H), 7.12 (s, 1 H), 7.10 (s, 1 H), 4.78 (dd, J=11.8, 3.8 Hz, 1 H), 4.21 (br d, J=12.5 Hz, 1 H), 4.04 - 4.15 (m, 1 H), 3.97 (br d, J=11.5 Hz, 1 H), 3.63 (dd, J=12.4, 3.9 Hz, 1 H), 2.65 (s, 2 H), 2.39 - 2.60 (m, 2 H), 2.05 - 2.19 (m, 3 H), 1.99 (br d, J=3.5 Hz, 1 H), 1.50 (d, J=6.8 Hz, 3 H), 1.46 - 1.49 (m, 1 H), 1.38 (s, 6 H).

[0368] Example 31 [(1R,5S,6S)-6-(5,5-Dimethyl-4,5-dihydro-1,2-oxazol-3-yl)-3-azabicyclo[3.1.0]hex-3-yl]{1-[(2S)-1-phenoxypropan-2-yl]-1H-imidazol-4-yl}methanone tert-Butyl [(2S)-1-phenoxypropan-2-yl]carbamate A solution of phenol (0.51 mL, 5.84 mmol), tert-butyl [(2S)-1-hydroxypropan-2-yl]carbamate (1024.08 mg, 5.84 mmol), and triphenylphosphine (2299.32 mg, 8.77 mmol) in toluene (12 mL) was slowly added with diisopropyl azodicarboxylate (1.73 mL, 8.77 mmol). The reaction mixture was stirred at 20 °C for 16 h to obtain a yellow solution. TLC (PE / ethyl acetate = 10 / 1, Rf = 0.8) showed a new spot. Water (30 mL) was added and the mixture was extracted with ethyl acetate (30 mL x 2). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure to obtain a yellow oil. The crude product was purified by silica gel chromatography (PE / ethyl acetate = 10 / 1 → 3 / 1) to obtain the title compound (600 mg, 2.3874 mmol, 40.85% yield) as a white solid.

[0369] (2S)-1-Phenoxy-2-propanamine hydrochloride To a solution of tert-butyl [(2S)-1-phenoxypropan-2-yl]carbamate (1100 mg, 4.38 mmol) in methanol (1 mL) was added hydrochloric acid / dioxane (5 mL, 20 mmol), and the reaction solution was stirred at 20 °C for 3 h to obtain a colorless solution. LCMS showed a new peak at the target MS. The reaction mixture was distilled under reduced pressure to obtain the title compound (800 mg, 4.2628 mmol, 97.393% yield) as a yellow solid. It was used as such in the next step. LC-MS Method1 0.498 min, MS (m / z) 151.8 (M + H + )。

[0370] Ethyl 1-[(2S)-1-phenoxypropan-2-yl]-1H-imidazole-4-carboxylate To a 5 mL microwave vial were added (2S)-1-phenoxy-2-propanamine hydrochloride (1100 mg, 5.86 mmol), ethyl (2Z)-3-(dimethylamino)-2-isocyanoacrylate (985.82 mg, 5.86 mmol), 1-butanol (3 mL) and triethylamine (1.22 mL, 8.79 mmol). The reaction solution was irradiated with microwave at 130 °C for 1 hour to obtain a brown solution. LCMS showed a new peak in the target MS. The reaction solution was diluted with saturated aqueous sodium carbonate solution (20 mL). Water (30 mL) was added and the mixture was extracted with ethyl acetate (30 mL x 2). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure to obtain a yellow oil. The crude product was purified by silica gel chromatography (PE / ethyl acetate = 10 / 1 → 1 / 1) to obtain the title compound (310 mg, 1.1301 mmol, yield 19.28%) as a white solid. LC-MS Method1 0.765 min, MS (m / z) 275.2 (M + H + )。

[0371] 1-[(2S)-1-phenoxypropan-2-yl]-1H-imidazole-4-carboxylic acid A stirred solution of ethyl 1-[(2S)-1-phenoxypropan-2-yl]-1H-imidazole-4-carboxylate (310 mg, 1.13 mmol) in 1,4-dioxane (3 mL) was added to a solution of lithium hydroxide monohydrate (61.64 mg, 1.47 mmol) in water (mg, 1.13 mmol). The mixture was stirred at 20 °C for 16 hours to obtain a yellow solution. LCMS showed a new peak in the target MS. Water (30 mL) was added and the mixture was extracted with ethyl acetate (30 mL). Then the aqueous layer was acidified with 1M aqueous hydrochloric acid and lyophilized to obtain the title compound (240 mg, 0.9746 mmol, yield 86.241%) as a yellow solid. LC-MS Method1 0.645 min, MS (m / z) 247.2 (M + H + )。

[0372] [(1R,5S,6S)-6-(5,5-dimethyl-4,5-dihydro-1,2-oxazol-3-yl)-3-azabicyclo[3.1.0]hex-3-yl]{1-[(2S)-1-phenoxypropan-2-yl]-1H-imidazol-4-yl}methanone 1-[(2S)-1-Phenoxypropan-2-yl]-1H-imidazole-4-carboxylic acid (130 mg, 0.5300 mmol) and N-ethyl-N-isopropylpropan-2-amine (0.45 mL, 2.64 mmol) in DMF (2 mL) were added to HATU (300.9 mg, 0.7900 mmol) with stirring. After stirring for 30 minutes, (1R,5S,6r)-6-(5,5-dimethyl-4,5-dihydro-1,2-oxazol-3-yl)-3-azabicyclo[3.1.0]hexane hydrochloride (114.4 mg, 0.5300 mmol) was added to obtain a brown solution. Water (30 mL) was added and the mixture was extracted with ethyl acetate (30 mL x 2). The organic layer was dried over sodium sulfate and concentrated under reduced pressure to obtain a yellow oil. The crude product was purified by prep-HPLC (NH 3 )). The obtained fractions were concentrated in vacuo to remove most of the acetonitrile and freeze-dried to obtain the title compound (51.22 mg, 0.1254 mmol, 23.752% yield) as a white solid. LC-MS Method1: 409.3 [M+H + 1 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.33 (s, 6 H) 1.47 (br s, 1 H) 1.64 (d, J=7.03 Hz, 3 H) 2.00 - 2.15 (m, 2 H) 2.72 (s, 2 H) 3.53 - 3.67 (m, 1 H) 3.92 (br d, J=8.53 Hz, 1 H) 4.10 (br d, J=12.30 Hz, 1 H) 4.15 - 4.28 (m, 2 H) 4.37 (br d, J=10.79 Hz, 1 H) 4.75 (br dd, J=11.04, 6.78 Hz, 1 H) 6.88 (br d, J=8.03 Hz, 2 H) 6.92 (br t, J=7.53 Hz, 1 H) 7.24 (br t, J=7.65 Hz, 2 H) 7.82 (br d, J=6.78 Hz, 2 H).

[0373] ​Example 32 [(1R,5S,6r)-6-(5,5-dimethyl-4,5-dihydro-1,2-oxazol-3-yl)-3-azabicyclo[3.1.0]hexan-3-yl][1-(pentan-3-yl)-1H-imidazol-4-yl]methanone Ethyl 1-(pentan-3-yl)-1H-imidazole-4-carboxylate A mixture of pentan-3-amine (1.73 mL, 14.86 mmol) and ethyl (2Z)-3-(dimethylamino)-2-isocyanoacrylate (500 mg, 2.97 mmol) was stirred at 80 °C for 16 h. The crude product was purified by flash column (PE: ethyl acetate = 2:1) to give the title compound (500 mg, 2.3779 mmol, 79.988% yield) as a brown oil.

[0374] 1-(pentan-3-yl)-1H-imidazole-4-carboxylic acid Lithium hydroxide monohydrate (0.41 mL, 7.13 mmol) was added to a solution of ethyl 1-(pentan-3-yl)-1H-imidazole-4-carboxylate (500 mg, 2.3779 mmol) in THF (15 mL) and water (5 mL). The mixture was stirred at 40 °C for 16 h to obtain a yellow mixture. The reaction mixture was concentrated under reduced pressure to remove most of THF. The residue was diluted with water (5 mL) and acidified to pH = 6 with aqueous hydrochloric acid (0.5 M). Then the solution was lyophilized to give the title compound as a yellow solid.

[0375] [(1R,5S,6r)-6-(5,5-dimethyl-4,5-dihydro-1,2-oxazol-3-yl)-3-azabicyclo[3.1.0]hex-3-yl][1-(pentan-3-yl)-1H-imidazol-4-yl]methanone HATU (157.35 mg, 0.4100 mmol) and triethylamine (0.14 mL, 1.1 mmol) were added to a solution of 1-(pentan-3-yl)-1H-imidazole-4-carboxylic acid (50 mg, 0.2700 mmol) in DMF (5 mL), and the mixture was stirred at 25 °C for 15 min. Then, (1R,5S,6r)-6-(5,5-dimethyl-4,5-dihydro-1,2-oxazol-3-yl)-3-azabicyclo[3.1.0]hexane hydrochloride (49.46 mg, 0.2700 mmol) was added. The resulting mixture was stirred at 25 °C for 2 h to obtain a brown solution, which was then concentrated under reduced pressure to remove most of DMF, giving a crude product. The crude product was purified by Prep-HPLC (NH 3) It was purified to obtain the title compound as a white solid. LC-MS Method1: 345.3 [M+H + 1 1H NMR (400 MHz, CHLOROFORM-d) δ = 7.61 (d, J = 1.3 Hz, 1H), 7.40 (d, J = 1.3 Hz, 1H), 4.80 (d, J = 12.0 Hz, 1H), 4.20 (d, J = 12.5 Hz, 1H), 3.95 (dd, J = 4.0, 11.8 Hz, 1H), 3.74 (tt, J = 4.8, 9.5 Hz, 1H), 3.62 (dd, J = 4.3, 12.3 Hz, 1H), 2.65 (s, 2H), 2.13 - 2.05 (m, 1H), 2.02 - 1.95 (m, 1H), 1.91 - 1.79 (m, 2H), 1.78 - 1.69 (m, 2H), 1.48 (t, J = 3.4 Hz, 1H), 1.38 (s, 6H), 0.82 (t, J = 7.3 Hz, 6H).

[0376] Example 33 [(1R,5S,6r)-6-(5,5-Dimethyl-4,5-dihydro-1,2-oxazol-3-yl)-3-azabicyclo[3.1.0]hex-3-yl][1-(1-methylcyclopropyl)-1H-imidazol-4-yl]methanone

Chemical Structure

[0377] 1-(1-Methylcyclopropyl)-1H-imidazole-4-carboxylic acid To a solution of ethyl 1-(1-methylcyclopropyl)-1H-imidazole-4-carboxylate (118 mg, 0.61 mmol) in THF (1.5 mL) and water (0.50 mL) was added lithium hydroxide monohydrate (0.05 mL, 0.79 mmol). The resulting mixture was stirred at 20 - 25 °C for 2 hours. The reaction solution was concentrated directly. The residue was acidified to pH = 6 with aqueous hydrochloric acid (1 M). Lyophilization gave the target compound (100 mg, 0.6018 mmol, yield 99.05%) as a yellow solid. 1 1H NMR (400 MHz, DMSO-d 6) δ = 7.81 (d, J=1.0 Hz, 1H), 7.65 (s, 1H), 1.55-1.47 (m, 3H), 1.13-1.07 (m, 2H), 0.91 - 0.85 (m, 2H).

[0378] [(1R,5S,6r)-6-(5,5-Dimethyl-4,5-dihydro-1,2-oxazol-3-yl)-3-azabicyclo[3.1.0]hex-3-yl][1-(1-methylcyclopropyl)-1H-imidazol-4-yl]methanone To a solution of 1-(1-methylcyclopropyl)-1H-imidazole-4-carboxylic acid (100 mg, 0.60 mmol) in DMF (2 mL), HATU (276.06 mg, 0.72 mmol) and triethylamine (0.39 mL, 3.01 mmol) were added. The mixture was stirred at 20 - 25 °C for 0.5 h, and (1R,5S,6r)-6-(5,5-dimethyl-4,5-dihydro-1,2-oxazol-3-yl)-3-azabicyclo[3.1.0]hexane hydrochloride (108.47 mg, 0.60 mmol) was added. The reaction solution was stirred at 20 - 25 °C for 1 h. LCMS showed the target MS (as the major peak). The residue was purified by prep-HPLC (NH 3 ) and the obtained fractions were combined, concentrated to remove most of the acetonitrile, and freeze-dried to obtain the title compound (60.45 mg, 0.1841 mmol, yield 30.589%) as a yellow solid. 1 H NMR (400MHz, CHLOROFORM-d) δ = 7.68 (d, J=1.5 Hz, 1H), 7.52 (d, J=1.3 Hz, 1H), 4.70 (d, J=11.8 Hz, 1H), 4.18 (d, J=12.5 Hz, 1H), 3.92 (dd, J=4.0, 12.0 Hz, 1H), 3.60 (dd, J=4.1, 12.4 Hz, 1H), 2.63 (s, 2H), 2.07 (br dd, J=3.5, 7.0 Hz, 1H), 2.01 - 1.92 (m, 1H), 1.57 (s, 3H), 1.45 (t, J=3.4 Hz, 1H), 1.37 (s, 6H), 1.16 - 1.10 (m, 2H), 0.95 - 0.89 (m, 2H) LC-MS Method1 0.606 min, MS (m / z) 329.0 [M+H + 。

[0379] Example 34 [(1R,5S,6r)-6-(5,5-Dimethyl-4,5-dihydro-1,2-oxazol-3-yl)-3-azabicyclo[3.1.0]hex-3-yl][1-(1-methylcyclobutyl)-1H-imidazol-4-yl]methanone Ethyl 1-(1-methylcyclobutyl)-1H-imidazole-4-carboxylate To a mixture of ethyl (2Z)-3-(dimethylamino)-2-isocyanoacrylate (200 mg, 1.19 mmol) in 1-butanol (0.50 mL), 1-methylcyclobutanamine (583.25 mg, 4.76 mmol) and triethylamine (1.15 mL, 8.92 mmol) were added. The resulting mixture was heated at 76 °C for 16 h. The reaction solution was diluted with water (5 mL) and extracted with ethyl acetate (5 mL × 3). The combined organic layers were washed with brine (10 mL), dried over sodium sulfate, and concentrated under reduced pressure to obtain a crude oil. The crude oil was purified by prep-TLC (100% ethyl acetate) to give the title compound (50 mg, 0.2401 mmol, yield 20.19%) as a yellow oil. LC-MS Method1 0.665 min, MS (m / z) 209.2 (M + H + )。

[0380] 1-(1-Methylcyclobutyl)-1H-imidazole-4-carboxylic acid To a mixture of ethyl 1-(1-methylcyclobutyl)-1H-imidazole-4-carboxylate (50 mg, 0.2400 mmol) in water (0.4952 mL) and methanol (0.3961 mL), lithium hydroxide monohydrate (0.04 mL, 0.7200 mmol) was added. The resulting mixture was stirred at 25 °C for 5 h. The aqueous layer was washed with DCM (3 mL × 2) and acidified to pH = 2 with aqueous hydrochloric acid (1 N). The aqueous solution was lyophilized to give the title compound (50 mg, 0.2775 mmol, yield 115.57%) as a pale yellow solid.

[0381] [(1R,5S,6r)-6-(5,5-Dimethyl-4,5-dihydro-1,2-oxazol-3-yl)-3-azabicyclo[3.1.0]hex-3-yl][1-(1-methylcyclobutyl)-1H-imidazol-4-yl]methanone To a mixture of 1-(1-methylcyclobutyl)-1H-imidazole-4-carboxylic acid (48.08 mg, 0.2200 mmol) in DMF (0.40 mL), HATU (137.86 mg, 0.3600 mmol), DIPEA (0.18 mL, 1.11 mmol) and (1R,5S,6r)-6-(5,5-dimethyl-4,5-dihydro-1,2-oxazol-3-yl)-3-azabicyclo[3.1.0]hexane hydrochloride (40 mg, 0.2200 mmol) were added. The resulting mixture was stirred at 20 °C for 4 hours. The reaction solution was diluted with water (5 mL), extracted with ethyl acetate (5 mL × 2), and then washed with brine (8 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure to obtain a crude oil. The crude oil was purified by prep-HPLC (NH 3 ) and then lyophilized to obtain the title compound (3 mg, 0.0088 mmol, yield 3.9478%) as a pale yellow solid. 1 H NMR (400 MHz, CD 3 OD) δ = 7.74 (s, 1H), 7.67 (s, 1H), 4.41 (br d, J = 12.0 Hz, 1H), 4.09 (br d, J = 12.3 Hz, 1H), 3.93 (br dd, J = 3.8, 11.8 Hz, 1H), 3.59 (br dd, J = 3.9, 12.4 Hz, 1H), 2.71 (s, 2H), 2.63 - 2.52 (m, 2H), 2.30 (tt, J = 3.0, 8.9 Hz, 2H), 2.14 - 2.08 (m, 1H), 2.07 - 1.92 (m, 3H), 1.68 (s, 3H), 1.48 (t, J = 3.4 Hz, 1H), 1.32 (s, 6H).

[0382] Example 35 [(1R,5S,6r)-6-(5,5-Dimethyl-4,5-dihydro-1,2-oxazol-3-yl)-3-azabicyclo[3.1.0]hex-3-yl](1-propyl-1H-imidazol-4-yl)methanone Ethyl 1-propyl-1H-imidazole-4-carboxylate To a solution of ethyl (2Z)-3-(dimethylamino)-2-isocyanoacrylate (500 mg, 2.97 mmol) in 1-butanol (0.5 M, 64.98 mmol) were added propan-1-amine (2.97 mL, 1.78 mmol, 1.0 eq) and triethylamine (0.25 mL, 1.78 mmol, 0.6 eq). After stirring at 130 °C for 6 h, the mixture was concentrated to give a residue. The residue was purified by silica gel chromatography (n-hexane / ethyl acetate = 60 / 40 → 0 / 100, then methanol / ethyl acetate = 5 / 95) to afford the title compound (214 mg, 1.17 mmol, 39.5% yield) as a brown oil. LC-MS Method1 0.662 min, MS (m / z) 183.0 (M + H + ). 1 H NMR (400 MHz, CHLOROFORM-d) δ 7.60 (d, J = 1.2 Hz, 1H), 7.47 (d, J = 1.2 Hz, 1H), 4.36 (q, J = 7.2 Hz, 2H), 3.93 (t, J = 6.9 Hz, 2H), 1.90 - 1.80 (m, 2H), 1.39 (t, J = 6.9 Hz, 3H), 0.94 (t, J = 9.6 Hz, 3H).

[0383] 1-Propyl-1H-imidazole-4-carboxylic acid To a stirred solution of ethyl 1-propyl-1H-imidazole-4-carboxylate (214 mg, 1.17 mmol) in THF (1.7 mL, 660 mM) was added an aqueous solution (0.6 mL) of lithium hydroxide (70.3 mg, 2.94 mmol, 2.5 eq). The reaction mixture was stirred at 40 °C for 12 h. The reaction mixture was diluted with water and extracted with DCM. The aqueous layer was acidified to pH = 5 with aqueous hydrochloric acid (1N). The resulting aqueous layer was dried under reduced pressure to afford the title compound (133 mg, 0.86 mmol, 73.4% yield) (crude) as a beige solid. 1 H NMR (400 MHz, DMSO-d 6) δ 7.81 (d, J = 1.5 Hz, 1H), 7.72 (d, J = 1.5 Hz, 1H), 3.94 (t, J = 6.9 Hz, 2H), 1.80-1.60 (m, 2H), 0.78 (t, J = 7.5 Hz, 3H).

[0384] [(1R,5S,6r)-6-(5,5-Dimethyl-4,5-dihydro-1,2-oxazol-3-yl)-3-azabicyclo[3.1.0]hex-3-yl](1-propyl-1H-imidazol-4-yl)methanone To a stirred solution of 1-propyl-1H-imidazole-4-carboxylic acid (45.0 mg, 0.14 mmol) and HATU (53.2 mg, 0.14 mmol, 1.0 eq) in THF (0.7 mL, 200 mM) was added DIPEA (0.12 mL, 0.7 mmol, 5.0 eq). After stirring at 50 °C for 30 minutes, (1R,5S,6r)-6-(5,5-dimethyl-4,5-dihydro-1,2-oxazol-3-yl)-3-azabicyclo[3.1.0]hexane hydrochloride (33.4 mg, 0.154 mmol, 1.1 eq) was added and the mixture was stirred at 20 °C for 16 hours to obtain a yellow solution. Water was added and the mixture was extracted with DCM. The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure to give a yellow oil. The crude product was purified by silica gel chromatography (ethyl acetate / DCM = 99 / 1 → 70 / 30) to give the title compound (23 mg, 0.072 mmol, 51.9% yield) as a beige powder. LC-MS Method1 0.757 min, MS (m / z) 317.0 (M + H + ). 11H NMR (400 MHz, CHLOROFORM-d) δ 7.59 (d, J = 1.5 Hz, 1H), 7.39 (d, J = 1.5 Hz, 1H), 4.73 (d, J = 11.2 Hz, 1H), 4.18 (d, J = 11.2 Hz, 1H), 4.00 - 3.85 (m, 1H), 3.91 (t, J = 7.2 Hz, 2H), 3.65 - 3.55 (m, 1H), 2.64 (s, 2H), 2.10 - 2.05 (m, 1H), 2.05 - 1.90 (m, 1H), 1.90 - 1.70 (m, 2H), 1.50 - 1.45 (m, 1H), 1.37 (s, 6H), 0.91 (t, 3H, J = 7.2 Hz, 3H).

[0385] Example 36 [(1R,5S,6r)-6-(5,5-Dimethyl-4,5-dihydro-1,2-oxazol-3-yl)-3-azabicyclo[3.1.0]hex-3-yl](1-isobutyl-1H-imidazol-4-yl)methanone Ethyl 1-isobutyl-1H-imidazole-4-carboxylate To a solution of ethyl (2Z)-3-(dimethylamino)-2-isocyanoacrylate (1.50 g, 8.92 mmol) in 1-butanol (17.8 mL, 0.5 M) were added 2-methylpropan-1-amine (1.0 mL, 9.8 mmol, 1.1 eq) and triethylamine (0.74 mL, 5.35 mmol, 0.6 eq). The mixture was stirred at 130 °C for 6 hours and then concentrated to obtain a residue. The residue was purified by silica gel chromatography (n-hexane / ethyl acetate = 60 / 40 → 0 / 100, then methanol / ethyl acetate = 5 / 95) to give the title compound (455 mg, 2.3 mmol, 26.0% yield) as a brown oil. LC-MS Method1 0.743 min, MS (m / z) 197.0 (M + H + ). 11H NMR (300 MHz, CHLOROFORM-d) δ ppm 7.58 (d, J = 1.2 Hz, 1H), 7.44 (d, J = 1.2 Hz, 1H), 4.36 (q, J = 7.2 Hz, 2H), 3.75 (d, J = 7.8 Hz, 2H), 2.15-1.95 (m, 1H), 1.39 (t, J = 7.2 Hz, 3H), 0.93 (d, J = 6.6 Hz, 6H).

[0386] 1-Isobutyl-1H-imidazole-4-carboxylic acid To a stirred solution of ethyl 1-isobutyl-1H-imidazole-4-carboxylate (450 mg, 2.3 mmol) in THF (3.5 mL, 660 mM) was added a solution of lithium hydroxide (137 mg, 5.7 mmol, 2.5 eq) in water (1.2 mL). After stirring the reaction mixture at 40 °C for 12 h, it was diluted with water and extracted with DCM. The aqueous layer was acidified to pH = 5 with aqueous hydrochloric acid (1N). The resulting aqueous layer was dried under reduced pressure to give the title compound (440 mg, 2.15 mmol, 93.8% yield) (crude) as a yellow solid. 1 1H NMR (400 MHz, DMSO-d 6 ) δ ppm 9.50 brs, 1H), 8.10 (d, J = 1.2 Hz, 1H), 3.91 (d, J = 6.9 Hz, 2H), 2.15-1.95 (m, 1H), 0.82 (d, J = 6.6 Hz, 6H).

[0387] [(1R,5S,6r)-6-(5,5-Dimethyl-4,5-dihydro-1,2-oxazol-3-yl)-3-azabicyclo[3.1.0]hex-3-yl](1-isobutyl-1H-imidazol-4-yl)methanone A solution of 1-isobutyl-1H-imidazole-4-carboxylic acid (65.0 mg, 0.15 mmol) and HATU (56.8 mg, 0.15 mmol, 1.0 eq) in THF (0.7 mL, 200 mM) was stirred and DIPEA (0.13 mL, 0.75 mmol, 5.0 eq) was added. After stirring at 50 °C for 30 minutes, (1R,5S,6r)-6-(5,5-dimethyl-4,5-dihydro-1,2-oxazol-3-yl)-3-azabicyclo[3.1.0]hexane hydrochloride (35.6 mg, 0.164 mmol, 1.1 eq) was added and the mixture was stirred at 50 °C for 1 hour to obtain a yellow solution. Water was added and the mixture was extracted with DCM. The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure to obtain a yellow oil. The crude product was purified by silica gel chromatography (ethyl acetate / DCM = 99 / 1 → 80 / 20) to obtain the title compound (36.2 mg, 0.11 mmol, yield 73.4%) as a white powder. LC-MS Method1 0.800 min, MS (m / z) 331.1 (M + H + ). 1 1H NMR (300 MHz, CHLOROFORM-d) δ 7.57 (d, J = 1.8 Hz, 1H), 7.36 (d, J = 1.8Hz, 1H), 4.74 (d, J = 12.3 Hz, 1H), 4.18 (d, J = 12.3 Hz, 1H), 3.93 (dd, J = 12.3, 4.2 Hz, 1H), 3.73 (d, J = 7.2 Hz, 2H), 3.61 (dd, J = 12.3, 4.2 Hz, 1H), 2.64 (s, 2H), 2.15 - 1.95 (m, 3H), 1.50 - 1.40 (m, 1H), 1.37 (s, 6H), 0.92 (d, J = 6.6 Hz, 6H).

[0388] Example 37 (1-Isopropyl-1H-imidazol-4-yl)[(1R,5S,6r)-6-(5-methyl-4,5-dihydro-1,2-oxazol-3-yl)-3-azabicyclo[3.1.0]hexan-3-yl]methanone tert-Butyl (1R,5S,6r)-6-(5-methyl-4,5-dihydro-1,2-oxazol-3-yl)-3-azabicyclo[3.1.0]hexane-3-carboxylate To a solution of tert-butyl (1R,5S,6r)-6-[(Z)-chloro(hydroxyimino)methyl]-3-azabicyclo[3.1.0]hexane-3-carboxylate (200 mg, 0.77 mmol) in DMF (2 mL) were added 1-propene (4.6 mL, 2.3 mmol) and triethylamine (0.38 mL, 2.3 mmol). The resulting mixture was stirred at 20 °C for 16 h to give a pale yellow mixture. The reaction solution was diluted with water (10 mL) and extracted with ethyl acetate (10 mL × 2). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure to give the title compound (130 mg, crude) as a pale yellow oil. LC-MS Method1 0.825 min, MS (m / z) 267.0 (M + H + )。

[0389] (1R,5S,6r)-6-(5-Methyl-4,5-dihydro-1,2-oxazol-3-yl)-3-azabicyclo[3.1.0]hexane hydrochloride To tert-butyl (1R,5S,6r)-6-(5-methyl-4,5-dihydro-1,2-oxazol-3-yl)-3-azabicyclo[3.1.0]hexane-3-carboxylate (130 mg, 0.49 mmol) was added hydrochloric acid / dioxane (3 mL, 0.49 mmol). The reaction solution was stirred at 0 °C for 30 min to give a pale yellow mixture. The reaction mixture was directly concentrated to dryness to give the title compound (90 mg, crude).

[0390] (1-Isopropyl-1H-imidazol-4-yl)[(1R,5S,6r)-6-(5-methyl-4,5-dihydro-1,2-oxazol-3-yl)-3-azabicyclo[3.1.0]hex-3-yl]methanone (1R,5S,6r)-6-(5-Methyl-4,5-dihydro-1,2-oxazol-3-yl)-3-azabicyclo[3.1.0]hexane hydrochloride (50 mg, 0.30 mmol) in DMF (0.50 mL) was added with DIPEA (0.2 mL, 1.2 mmol), 1-isopropylimidazole-4-carboxylic acid (46.38 mg, 0.30 mmol) and HATU (148.6 mg, 0.39 mmol). The resulting mixture was stirred at 20 °C for 16 h to obtain a brown mixture. TLC (PE / ethyl acetate = 0 / 1) showed a series of new spots and complete consumption of 1-isopropylimidazole-4-carboxylic acid (46.38 mg, 0.30 mmol). LCMS detected the desired MS. The reaction solution was diluted with water (5 mL) and extracted with ethyl acetate (5 mL × 2), and then washed with water (5 mL) and brine (5 mL × 2). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure to obtain a crude product. The crude product was purified by prep-HPLC (NH 3 ) to obtain the title compound (5 mg, 0.0165 mmol, yield 5.4972%) as a white solid. 1 H NMR (400 MHz, CH 3 OH) δ = 7.69 (br d, J = 14.6 Hz, 2H), 4.76 - 4.73 (m, 1H), 4.74 - 4.73 (m, 1H), 4.42 (td, J = 6.6, 13.4 Hz, 1H), 4.26 (br d, J = 11.4 Hz, 1H), 4.08 - 3.98 (m, 1H), 3.86 (br dd, J = 3.6, 11.6 Hz, 1H), 3.54 (br d, J = 9.9 Hz, 1H), 3.02 - 2.89 (m, 1H), 2.44 (dd, J = 8.1, 16.9 Hz, 1H), 2.13 - 1.95 (m, 2H), 1.42 (d, J = 6.6 Hz, 6H), 1.18 (d, J = 6.3 Hz, 3H).

[0391] Example 38 (1-Isopropyl-1H-imidazol-4-yl)[(1R,5S,6r)-6-(4-oxa-5-azaspiro[2.4]hept-5-en-6-yl)-3-azabicyclo[3.1.0]hex-3-yl]methanone tert-Butyl (1R,5S,6r)-6-(4-oxa-5-azaspiro[2.4]hept-5-en-6-yl)-3-azabicyclo[3.1.0]hexane-3-carboxylate Methylenecyclopropane (300 mg, 1.22 mmol) was added to a solution of tert-butyl (1R,5S,6r)-6-[(Z)-chloro(hydroxyimino)methyl]-3-azabicyclo[3.1.0]hexane-3-carboxylate (0.24 mL, 24.32 mmol) in THF (15 mL) and triethylamine (0.51 mL, 3.65 mmol). The reaction mixture was stirred at 0 °C for 16 hours to obtain a yellow solution. LCMS showed a new peak at the target MS. The reaction mixture was diluted with water (30 mL) and extracted with ethyl acetate (30 mL × 2). The combined organic layers were dried over sodium sulfate and concentrated to obtain the title compound (260 mg, 0.9341 mmol, yield 76.809%) as a yellow oil. LC-MS Method1 0.845 min, MS (m / z) 279 (M + H + )。

[0392] 6-[(1R,5S,6r)-3-Azabicyclo[3.1.0]hex-6-yl]-4-oxa-5-azaspiro[2.4]hept-5-ene trifluoroacetate 2,2,2-Trifluoroacetic acid (0.07 mL, 0.93 mmol) was added to a solution of tert-butyl (1R,5S,6r)-6-(4-oxa-5-azaspiro[2.4]hept-5-en-6-yl)-3-azabicyclo[3.1.0]hexane-3-carboxylate (260 mg, 0.93 mmol) in DCM (16.25 mL). The reaction mixture was stirred at 10 °C for 3 hours to obtain a yellow solution. LCMS showed a new peak at the target MS. The solvent of the reaction mixture was removed under reduced pressure to obtain the title compound (272 mg, 0.9307 mmol, yield 99.64%) as a yellow oil. Used in the next step. LC-MS Method1 0.178 min, MS (m / z) 179.1 (M + H + )。

[0393] (1-Isopropyl-1H-imidazol-4-yl)[(1R,5S,6r)-6-(4-oxa-5-azaspiro[2.4]hept-5-en-6-yl)-3-azabicyclo[3.1.0]hex-3-yl]methanone To a 100 mL round-bottom flask were added 1-isopropylimidazole-4-carboxylic acid (143.49 mg, 0.93 mmol), HATU (426.97 mg, 1.12 mmol), DMF (4.5916 mL), and N-ethyl-N-isopropylpropan-2-amine (0.48 mL, 2.79 mmol). After stirring for 30 minutes, 6-[(1R,5S,6r)-3-azabicyclo[3.1.0]hex-6-yl]-4-oxa-5-azaspiro[2.4]hept-5-ene trifluoroacetate (272 mg, 0.93 mmol) was added. The reaction solution was stirred at 10 °C for 16 hours to obtain a yellow solution. LCMS indicated that the reactant was completely consumed and it was the desired MS. The reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (30 mL × 2). The combined organic layers were dried over sodium sulfate and concentrated to obtain a yellow oil. The crude obtained was purified by prep-HPLC (FA). The fractions obtained were concentrated in vacuo to remove most of the acetonitrile and freeze-dried to obtain the title compound (14.67 mg, 0.0467 mmol, yield 5.0137%) as a white solid. LC-MS Method1: 315.1 [M+H + 1 H NMR (400 MHz, CHLOROFORM-d) δ = 7.67 (s, 1H), 7.48 (s, 1H), 4.73 (br d, J = 12.0 Hz, 1H), 4.41 - 4.27 (m, 1H), 4.20 (br d, J = 12.4 Hz, 1H), 3.95 (br dd, J = 4.0, 12.0 Hz, 1H), 3.62 (br dd, J = 4.0, 12.0 Hz, 1H), 2.96 (s, 2H), 2.80 (s, 1H), 2.12 (br d, J = 3.0 Hz, 1H), 2.03 (br d, J = 3.5 Hz, 1H), 1.50 (d, J = 6.4 Hz, 6H), 1.14 - 1.08 (m, 2H), 0.73 - 0.67 (m, 2H).

[0394] ​Example 39 (1-Isopropyl-1H-imidazol-4-yl)[(1R,5S,6r)-6-(5-oxa-6-azaspiro[3.4]oct-6-en-7-yl)-3-azabicyclo[3.1.0]hex-3-yl]methanone tert-Butyl (1R,5S,6r)-6-(5-oxa-6-azaspiro[3.4]oct-6-en-7-yl)-3-azabicyclo[3.1.0]hexane-3-carboxylate To a DMF (1.5 mL) mixture of tert-butyl (1R,5S,6r)-6-[(E)-(hydroxyimino)methyl]-3-azabicyclo[3.1.0]hexane-3-carboxylate, methylenecyclobutane (78.4 mg, 1.15 mmol) was added. The turbid solution was stirred at 20 °C for 16 hours. Water (10 mL) was added to the reaction mixture to stop the reaction. The residue was diluted with ethyl acetate (20 mL x 3), washed with saturated brine (5 mL), dried over anhydrous sodium sulfate, filtered, and then concentrated under reduced pressure to obtain the title compound (46 mg, crude) as a yellow powder. LC-MS Method1: 0.818 min, MS (m / z): 237.0 (M - 56 + H + )。

[0395] 7-[(1R,5S,6r)-3-Azabicyclo[3.1.0]hex-6-yl]-5-oxa-6-azaspiro[3.4]oct-6-ene trifluoroacetate To a DCM (1.5 mL) mixture of tert-butyl (1R,5S,6r)-6-(5-oxa-6-azaspiro[3.4]oct-6-en-7-yl)-3-azabicyclo[3.1.0]hexane-3-carboxylate (46.0 mg, 0.16 mmol), 2,2,2-trifluoroacetic acid (17.9 mg, 0.16 mmol) was added. The suspension was stirred at 20 °C for 2 hours. The reaction mixture was concentrated under reduced pressure to obtain the title compound. LC-MS Method1: 0.822 min, MS (m / z): 193.0 (M + H + )。

[0396] (1-Isopropyl-1H-imidazol-4-yl)[(1R,5S,6r)-6-(5-oxa-6-azaspiro[3.4]oct-6-en-7-yl)-3-azabicyclo[3.1.0]hex-3-yl]methanone To a mixture of 7-[(1R,5S,6r)-3-azabicyclo[3.1.0]hex-6-yl]-5-oxa-6-azaspiro[3.4]oct-6-ene trifluoroacetate (30.0 mg, 0.16 mmol) in pyridine (0.5 mL), EDCI (29.9 mg, 0.16 mmol) and 1-isopropylimidazole-4-carboxylic acid (24.1 mg, 0.16 mmol) were added. The suspension was stirred at 20 °C for 16 h. The reaction mixture was quenched by the addition of water (10 mL). The residue was diluted with ethyl acetate (20 mL × 3), washed with saturated brine (5 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. It was purified by prep-HPLC(NH 3 ), and freeze-dried to obtain the title compound (6.49 mg, yield 12.7%) as a yellow solid. LC-MS Method1: 2.386 min, MS (m / z): 329.2 (M + H + ). 1 H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.69 (d, J = 1.51 Hz, 1 H), 7.49 (d, J = 1.51 Hz, 1 H), 4.75 (d, J = 12.05 Hz, 1 H), 4.37 (dt, J = 13.43, 6.84 Hz, 1 H), 4.20 (d, J = 12.80 Hz, 1 H), 3.93 - 3.99 (m, 1 H), 3.63 (dd, J = 12.92, 3.89 Hz, 1 H), 2.96 (s, 2 H), 2.48 (dt, J = 12.55, 9.66 Hz, 2 H), 2.07 - 2.18 (m, 4 H), 2.02 (br d, J = 9.03 Hz, 1 H), 1.76 - 1.85 (m, 1 H), 1.52 (d, J = 6.78 Hz, 7 H), 1.49 (t, J = 3.51 Hz, 1 H).

[0397] Example 40 {(1R,5S,6r)-6-[5-(Difluoromethyl)-5-methyl-4,5-dihydro-1,2-oxazol-3-yl]-3-azabicyclo[3.1.0]hex-3-yl}(1-isopropyl-1H-imidazol-4-yl)methanone tert-Butyl (1R,5S,6r)-6-[5-(dihydroxymethyl)-5-methyl-4,5-dihydro-1,2-oxazol-3-yl]-3-azabicyclo[3.1.0]hexane-3-carboxylate To a solution of tert-butyl (1R,5S,6r)-6-[(Z)-chloro(hydroxyimino)methyl]-3-azabicyclo[3.1.0]hexane-3-carboxylate (200 mg, 0.77 mmol) and methacrolein (0.32 mL, 3.84 mmol) in DMF (3 mL) was added triethylamine (0.22 mL, 1.53 mmol). The reaction mixture was stirred at 20 °C for 12 h to obtain a pale yellow solution. The reaction mixture was diluted with ethyl acetate (15 mL), and saturated aqueous sodium hydrogen carbonate solution (10 mL) was added and stirred for 5 min. The aqueous layer was extracted with ethyl acetate (10 mL × 2). The combined DCM layers were dried over sodium sulfate and concentrated under reduced pressure to obtain the title compound (240 mg, 0.7683 mmol, crude) as a pale brown oil.

[0398] tert-Butyl (1R,5S,6r)-6-[5-(difluoromethyl)-5-methyl-4,5-dihydro-1,2-oxazol-3-yl]-3-azabicyclo[3.1.0]hexane-3-carboxylate To a solution of tert-butyl (1R,5S,6r)-6-[5-(dihydroxymethyl)-5-methyl-4,5-dihydro-1,2-oxazol-3-yl]-3-azabicyclo[3.1.0]hexane-3-carboxylate (240 mg, 0.77 mmol) in DCM (10 mL) was added DAST (371.11 mg, 2.31 mmol) at -78 °C. The reaction mixture was warmed to 20 °C and stirred for an additional 12 hours to obtain a light brown solution. After cooling the reaction mixture to 0 °C, it was diluted with DCM (20 mL), and the reaction was quenched with saturated aqueous sodium bicarbonate solution (8 mL). The organic layer was collected, dried over sodium sulfate, and concentrated under reduced pressure. The crude oil obtained was purified by prep-HPLC (hydrochloric acid). The eluate obtained was washed with saturated aqueous sodium bicarbonate solution (2 mL) and concentrated to remove acetonitrile. The residue was extracted with ethyl acetate (10 mL × 2). The combined ethyl acetate layers were dried over sodium sulfate and concentrated under reduced pressure to obtain the title compound (55 mg, 0.1739 mmol, yield 22.628%) as a light brown gum. 1 H NMR (400MHz, CHLOROFORM-d) δ = 5.58 (t, J=56 Hz, 1H), 3.65 (d, J = 11.2 Hz, 1H), 3.56 (d, J = 11.2 Hz, 1H), 3.36-3.32 (m, 2H), 3.04 (dd, J = 17.2, 6.0 Hz, 1H), 2.60 (d, J = 17.2 Hz, 1H), 2.00-1.85 (m, 3H), 1.37 (s, 9H). 1.37 (s, 3H).

[0399] {(1R,5S,6r)-6-[5-(Difluoromethyl)-5-methyl-4,5-dihydro-1,2-oxazol-3-yl]-3-azabicyclo[3.1.0]hex-3-yl}(1-isopropyl-1H-imidazol-4-yl)methanone tert-Butyl (1R,5S,6r)-6-[5-(difluoromethyl)-5-methyl-4,5-dihydro-1,2-oxazol-3-yl]-3-azabicyclo[3.1.0]hexane-3-carboxylate (55 mg, 0.17 mmol) in DCM (2 mL) was added methanesulfonic acid (33.38 mg, 0.35 mmol). The reaction mixture was stirred at 20 °C for 1 h to obtain a pale yellow solution. After addition of DMF (1 mL), 1-isopropylimidazole-4-carboxylic acid (32.17 mg, 0.21 mmol), HATU (66.47 mg, 0.17 mmol), and triethylamine (0.12 mL, 0.87 mmol) were added. The resulting mixture was stirred at 20 °C for 12 h to obtain a yellow mixture. The reaction solution was concentrated and purified by prep-HPLC (NH 3 )). The eluate obtained was concentrated and lyophilized to give the title compound (7.01 mg, 0.0199 mmol, 11.442% yield) as a pale yellow solid. LC-MS Method1: 353.0 [M+H + 1 1H NMR (400 MHz, CHLOROFORM-d) δ = 7.60 (d, J = 1.4 Hz, 1H), 7.40 (d, J = 1.4 Hz, 1H), 5.78 - 5.37 (m, 1H), 4.70 (d, J = 12.1 Hz, 1H), 4.28 (quin, J = 6.7 Hz, 1H), 4.13 (d, J = 12.4 Hz, 1H), 3.87 (br d, J = 10.0 Hz, 1H), 3.54 (dd, J = 3.9, 12.4 Hz, 1H), 3.05 (d, J = 17.4 Hz, 1H), 2.61 (br dd, J = 7.8, 17.6 Hz, 1H), 2.04 (br s, 1H), 1.99 - 1.89 (m, 1H), 1.43 (d, J = 6.6 Hz, 6H), 1.38 (m, 3H).

[0400] ​Example 41 [(1R,5S,6r)-6-(5-Ethyl-5-methyl-4,5-dihydro-1,2-oxazol-3-yl)-3-azabicyclo[3.1.0]hexan-3-yl](1-isopropyl-1H-imidazol-4-yl)methanone tert-Butyl (1R,5S,6r)-6-(5-ethyl-5-methyl-4,5-dihydro-1,2-oxazol-3-yl)-3-azabicyclo[3.1.0]hexane-3-carboxylate To a DMF (1.5 mL) solution of tert-butyl (1R,5S,6r)-6-[(Z)-chloro(hydroxyimino)methyl]-3-azabicyclo[3.1.0]hexane-3-carboxylate, 2-methylbut-1-ene (403.48 mg, 5.75 mmol) and triethylamine (116.4 mg, 1.15 mmol, 0.16 mL) were added, and the mixture was stirred at 20 °C for 16 hours. Water (10 mL) was added to the reaction mixture to stop the reaction. The residue was extracted with ethyl acetate (20 mL × 3). The combined organic layers were washed with saturated brine (5 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by prep-TLC (PE:ethyl acetate = 2:1, Rf = 0.5) to obtain the title compound (76 mg, crude) as a yellow powder. LC-MS Method1: 0.833 min, MS (m / z): 239.0 (M - 56 + H + )。

[0401] (1R,5S,6r)-6-(5-Ethyl-5-methyl-4,5-dihydro-1,2-oxazol-3-yl)-3-azabicyclo[3.1.0]hexane trifluoroacetate A mixture of tert-butyl (1R,5S,6r)-6-(5-ethyl-5-methyl-4,5-dihydro-1,2-oxazol-3-yl)-3-azabicyclo[3.1.0]hexane-3-carboxylate (76.0 mg, 0.26 mmol) and 2,2,2-trifluoroacetic acid (29.4 mg, 0.16 mmol) in DCM (1 mL) was stirred at 20 °C for 2 hours. The reaction mixture was concentrated under reduced pressure to obtain the title compound as a brown oil. LC-MS Method1: 0.357 min, MS (m / z): 195.0 (M + H + )。

[0402] [(1R,5S,6r)-6-(5-Ethyl-5-methyl-4,5-dihydro-1,2-oxazol-3-yl)-3-azabicyclo[3.1.0]hexan-3-yl](1-isopropyl-1H-imidazol-4-yl)methanone (1R,5S,6r)-6-(5-Ethyl-5-methyl-4,5-dihydro-1,2-oxazol-3-yl)-3-azabicyclo[3.1.0]hexane trifluoroacetate (50.0 mg, 0.26 mmol) in pyridine (2 mL) was added with EDCI (49.3 mg, 0.26 mmol) and 1-isopropylimidazole-4-carboxylic acid (39.7 mg, 0.26 mmol). The suspension was stirred at 20 °C for 16 h. Water (10 mL) was added to the reaction mixture to stop the reaction. The residue was extracted with ethyl acetate (20 mL × 3), washed with saturated brine (5 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by prep-HPLC (NH 3 ) and lyophilized to obtain the title compound (5.77 mg, yield 6.8%) as a yellow solid. LC-MS Method1: 2.693 min, MS (m / z): 331.2 (M + H + ). 1 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.59 (s, 1 H), 7.40 (s, 1 H), 4.64 (s, 1 H), 4.28 (s, 1 H), 4.12 (br d, J = 12.63 Hz, 1 H), 3.86 (br d, J = 12.38 Hz, 1 H), 3.51 - 3.57 (m, 1 H), 2.59 - 2.65 (m, 1 H), 2.44 - 2.51 (m, 1 H), 2.00 (br s, 1 H), 1.90 (br s, 1 H), 1.54 - 1.61 (m, 3 H), 1.46 - 1.50 (m, 7 H), 1.43 (d, J = 6.63 Hz, 7 H), 1.38 (t, J = 3.25 Hz, 1 H), 1.25 (s, 4 H), 1.18 (s, 3 H), 0.85 (t, J = 7.44 Hz, 4 H).

[0403] Example 42 {(1R,5S,6r)-6-[(5R)-5-Ethyl-5-methyl-4,5-dihydro-1,2-oxazol-3-yl]-3-azabicyclo[3.1.0]hex-3-yl}(1-isopropyl-1H-imidazol-4-yl)methanone Example 43 {(1R,5S,6r)-6-[(5S)-5-Ethyl-5-methyl-4,5-dihydro-1,2-oxazol-3-yl]-3-azabicyclo[3.1.0]hex-3-yl}(1-isopropyl-1H-imidazol-4-yl)methanone Example 42 and Example 43 were each obtained in the production process of Example 41. Isolated by SFC purification from the final step of Example 41, {(1R,5S,6r)-6-[(5R)-5-Ethyl-5-methyl-4,5-dihydro-1,2-oxazol-3-yl]-3-azabicyclo[3.1.0]hex-3-yl}(1-isopropyl-1H-imidazol-4-yl)methanone (63.41 mg, 0.19 mmol, yield 9.3%) and {(1R,5S,6r)-6-[(5S)-5-Ethyl-5-methyl-4,5-dihydro-1,2-oxazol-3-yl]-3-azabicyclo[3.1.0]hex-3-yl}(1-isopropyl-1H-imidazol-4-yl)methanone (69.78 mg, 0.21 mmol, yield 10.2%) were white solids. 11H NMR (400 MHz, CHLOROFORM-d) δ = 7.66 (s, 1H), 7.48 (s, 1H), 4.74 (br d, J = 11.8 Hz, 1H), 4.36 (spt, J = 6.7 Hz, 1H), 4.19 (d, J = 12.5 Hz, 1H), 3.94 (dd, J = 4.0, 12.0 Hz, 1H), 3.61 (dd, J = 4.1, 12.4 Hz, 1H), 2.74 - 2.63 (m, 1H), 2.60 - 2.48 (m, 1H), 2.15 - 2.02 (m, 1H), 2.01 - 1.90 (m, 1H), 1.66 - 1.58 (m, 2H), 1.50 (d, J = 6.8 Hz, 6H), 1.45 (t, J = 3.4 Hz, 1H), 1.32 (s, 3H), 0.92 (t, J = 7.5 Hz, 3H).

[0404] Example 44 (1-Isopropyl-1H-imidazol-4-yl)[(1R,5S,6r)-6-(2-oxa-3-azabicyclo[3.1.0]hex-3-en-4-yl)-3-azabicyclo[3.1.0]hex-3-yl]methanone Ethyl (1R,5S,6r)-3-azabicyclo[3.1.0]hexane-6-carboxylate hydrochloride Hydrochloric acid / dioxane (50 mL, 3 mmol) was added to 6-ethyl 3-(tert-butyl) (1R,5S,6r)-3-azabicyclo[3.1.0]hexane-3,6-dicarboxylate (3.5 g, 13.71 mmol). The mixture was stirred at 30 °C for 2 h to give a brown solution. TLC (PE:ethyl acetate = 5:1) showed a new spot. The reaction mixture was concentrated directly to afford the title compound (2.5 g, 13.044 mmol, 95.15% yield) as a black solid. 6-Ethyl 3-[2-(trimethylsilyl)ethyl] (1R,5S,6r)-3-azabicyclo[3.1.0]hexane-3,6-dicarboxylate To a solution of ethyl (1R,5S,6r)-3-azabicyclo[3.1.0]hexane-6-carboxylate hydrochloride (2.5 g, 13.04 mmol) in DCM (20.27 mL) at 0 °C was added DIPEA (10.78 mL, 65.22 mmol). Then, DCM (20.27 mL) of 2,5-dioxopyrrolidin-1-yl (2-(trimethylsilyl)ethyl) carbonate (4.06 g, 15.65 mmol) was added, and the mixture was stirred at 30 °C for 12 hours to obtain a brown suspension. TLC (PE:ethyl acetate = 3:1) showed a new spot. The reaction solution was directly concentrated. The crude product was purified by flash column (PE → 20% ethyl acetate in PE) to obtain the title compound (3.5 g, 11.688 mmol, yield 89.609%) as a yellow oil. 1 1H NMR (400 MHz, CHLOROFORM-d) δ = 4.20 - 4.10 (m, 4H), 3.73 (d, J = 11.2 Hz, 1H), 3.65 (d, J = 11.2 Hz, 1H), 3.49 (t, J = 11.2 Hz, 2H), 2.12 (s, 2H), 1.48 (d, J = 3.2 Hz, 1H), 1.28 (t, J = 6.8 Hz, 3H), 1.00 - 0.90 (, 2H), 0.03 (s, 9H).

[0405] 2-(Trimethylsilyl)ethyl (1R,5S,6r)-6-(hydroxymethyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate To a solution of 6-ethyl 3-[2-(trimethylsilyl)ethyl] (1R,5S,6r)-3-azabicyclo[3.1.0]hexane-3,6-dicarboxylate (3.5 g, 11.69 mmol) in THF (40 mL) was added lithium aluminum hydride (0.67 g, 17.53 mmol) at 0 °C. The mixture was stirred at 0 °C for 20 minutes to obtain a white suspension. TLC (PE:ethyl acetate = 1:1) indicated the completion of the reaction. The reaction mixture was poured into water (0.6 mL), 1N aqueous sodium hydroxide solution (0.6 mL), and water (1.8 mL), and then filtered. The filtrate was concentrated to obtain a yellow oil. The crude product was purified by flash column (PE → 40% ethyl acetate) to obtain the title compound (1.2 g, 4.662 mmol, yield 39.885%) as a colorless oil. 1 1H NMR (400 MHz, CHLOROFORM-d) δ = 4.15 (dd, J = 8.8, 7.6 Hz, 2H), 3.67 (d, J = 10.8 Hz, 1H), 3.60 (d, J = 10.8 Hz, 1H), 3.60 - 3.45 (m, 2H), 3.41 (dt, J = 8.0, 4.0 Hz, 2H), 1.50 - 1.40 (m, 3H), 1.00 - 0.85 (m, 3H), 0.03 (s, 9H).

[0406] 2-(Trimethylsilyl)ethyl (1R,5S,6r)-6-formyl-3-azabicyclo[3.1.0]hexane-3-carboxylate To a solution of 2-(trimethylsilyl)ethyl (1R,5S,6r)-6-(hydroxymethyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate (1.2 g, 4.66 mmol) in DCM (15 mL) were added DMP (2.97 g, 6.99 mmol) and sodium hydrogen carbonate (979.14 mg, 11.66 mmol) at 0 °C, and the mixture was stirred at 30 °C for 2 h. TLC (PE:ethyl acetate = 1:1) indicated the completion of the reaction. The reaction mixture was poured into water (40 mL) and extracted with ethyl acetate (30 mL × 4). The combined organic layers were washed with an aqueous sodium hydrogen carbonate solution (50 mL) and an aqueous sodium sulfite solution (50 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by flash column (PE → 30% ethyl acetate in PE) to give the title compound (0.8200 g, 3.2108 mmol, yield 68.871%) as a brown oil. 1 H NMR (400 MHz, CHLOROFORM-d) δ = 9.46 (d, J = 4.0 Hz, 1H), 4.17 (dd, J = 7.6, 4.0 Hz, 2H), 3.80 (d, J = 11.6 Hz, 1H), 3.60 (d, J = 11.6 Hz, 1H), 3.54 (t, J = 11.6 Hz, 2H), 2.24 S, 2H), 1.83 (dd, J = 6.4, 3.2 Hz, 1H), 0.99 (dd, J = 7.6, 4.0 Hz, 2H), 0.03 (s, 9H).

[0407] 2-(Trimethylsilyl)ethyl (1R,5S,6r)-6-[(E)-(hydroxyimino)methyl]-3-azabicyclo[3.1.0]hexane-3-carboxylate To a solution of 2-(trimethylsilyl)ethyl (1R,5S,6r)-6-formyl-3-azabicyclo[3.1.0]hexane-3-carboxylate (820 mg, 3.21 mmol) in ethanol (10 mL) were added potassium acetate (315.11 mg, 3.21 mmol), acetic acid (0.18 mL, 3.21 mmol), and hydroxylamine hydrochloride (0.17 mL, 4.17 mmol). The mixture was stirred at 25 °C for 3 h to obtain a white suspension. TLC (PE: ethyl acetate = 2:1) indicated the completion of the reaction. The residue obtained by removing the reaction mixture under reduced pressure was added with water (40 mL) and extracted with ethyl acetate (30 mL × 4). The combined organic layers were washed with saturated aqueous sodium bicarbonate solution (30 mL × 2) and saturated brine (40 mL × 2), and dried over sodium sulfate. The solvent was distilled off under reduced pressure to obtain the title compound (850 mg, 3.1435 mmol, yield 97.904%) as a brown oil.

[0408] 2-(Trimethylsilyl)ethyl (1R,5S,6r)-6-[(Z)-chloro(hydroxyimino)methyl]-3-azabicyclo[3.1.0]hexane-3-carboxylate To a solution of 2-(trimethylsilyl)ethyl (1R,5S,6r)-6-[(E)-(hydroxyimino)methyl]-3-azabicyclo[3.1.0]hexane-3-carboxylate (850 mg, 3.14 mmol) in DMF (9 mL) was added N-chlorosuccinimide (503.7 mg, 3.77 mmol). The mixture was stirred at 25 °C for 3 h to obtain a brown solution. TLC (PE: ethyl acetate = 2:1) indicated the completion of the reaction. The reaction mixture was poured into water (40 mL) and extracted with ethyl acetate (30 mL × 4). The combined organic layers were washed with brine (50 mL × 2), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by flash column (PE → 30% ethyl acetate in PE) to obtain the title compound (750 mg, 2.4602 mmol, yield 78.264%) as a colorless oil.

[0409] 2-(Trimethylsilyl)ethyl (1R,5S,6r)-6-[5-(chloromethyl)-4,5-dihydro-1,2-oxazol-3-yl]-3-azabicyclo[3.1.0]hexane-3-carboxylate To a solution of 2-(trimethylsilyl)ethyl (1R,5S,6r)-6-[(Z)-chloro(hydroxyimino)methyl]-3-azabicyclo[3.1.0]hexane-3-carboxylate (400 mg, 1.31 mmol) in DMF (5.3333 mL) were added 3-chloroprop-1-ene (0.54 mL, 6.56 mmol) and triethylamine (0.51 mL, 3.94 mmol). The mixture was stirred at 25 °C for 12 h to obtain a brown solution. TLC (PE:ethyl acetate = 3:1) indicated the completion of the reaction. Water (40 mL) was added to the mixture, and the mixture was extracted with ethyl acetate (30 mL × 4). The combined organic layers were washed with saturated brine (40 mL × 2) and dried over sodium sulfate. The solvent was distilled off under reduced pressure. The crude product was purified by flash column (PE → 20% ethyl acetate in PE) to obtain the title compound (160 mg, 0.4639 mmol, yield 35.354%) as a colorless oil. 1 H NMR (400 MHz, CHLOROFORM-d) δ = 4.85 - 4.75 (m, 1H), 4.16 (dd, J = 9.2, 7.2 Hz, 2H), 3.76 (d, J = 11.2 Hz, 1H), 3.70 (d, J = 11.2 Hz, 1H), 3.61 (dd, J = 7.2, 4.0 Hz, 1H), 3.55 - 3.40 (m, 3H), 3.15 - 3.05 (m, 1H), 2.95 - 2.80 (m, 1H), 52.00 (brs, 2H), 1.50 (brs, 1H), 1.00 (dd, J = 9.2, 7.2 Hz, 2H), 0.05 (s, 9H).

[0410] 4-[(1R,5S,6r)-3-azabicyclo[3.1.0]hex-6-yl]-2-oxa-3-azabicyclo[3.1.0]hex-3-ene To a solution of 2-(trimethylsilyl)ethyl (1R,5S,6r)-6-[5-(chloromethyl)-4,5-dihydro-1,2-oxazol-3-yl]-3-azabicyclo[3.1.0]hexane-3-carboxylate (20 mg, 0.06 mmol) in DMSO (1 mL) was added potassium t-butoxide (13.01 mg, 0.12 mmol). The mixture was stirred at 20 °C for 30 minutes to obtain a brown solution. The reaction mixture was directly freeze-dried to obtain the title compound (8 mg, 0.0487 mmol, yield 84.022%) as a brown solid. 1 H NMR (400 MHz, CHLOROFORM-d) δ = 4.90 - 4.80 (m, 1H), 4.04 (d, J = 12.4 Hz, 1H), 3.80 - 3.60 (m, 2H), 3.40 - 3.30 (m, 1H), 2.40 - 2.30 (m, 1H), 2.20 - 1.90 (m, 2H), 1.60 - 1.50 (m, 1H), 1.00 - 0.85 (m, 2H), 0.40 - 0.30 (m, 1H).

[0411] (1-Isopropyl-1H-imidazol-4-yl)[(1R,5S,6r)-6-(2-oxa-3-azabicyclo[3.1.0]hex-3-en-4-yl)-3-azabicyclo[3.1.0]hexan-3-yl]methanone To a solution of 4-[(1R,5S,6r)-3-azabicyclo[3.1.0]hex-6-yl]-2-oxa-3-azabicyclo[3.1.0]hex-3-ene (30 mg, 0.18 mmol) and 1-isopropylimidazole-4-carboxylic acid (27.75 mg, 0.18 mmol) in pyridine (2.9557 mL) was added EDCI (44.86 mg, 0.23 mmol). The mixture was stirred at 25 °C for 3 hours to obtain a yellow solution. LCMS showed the target MS as the major peak. The reaction solution was directly concentrated. The residue was purified by prep-HPLC (NH 3 ) to obtain the title compound (7.58 mg, 0.0252 mmol, yield 14.02%) as a yellow solid. LC-MS Method1: 301.2 [M+H + 1 ​1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.68 (1 H, d, J=1.51 Hz), 7.48 (1 H, d, J=1.25 Hz), 4.85 (1 H, td, J=5.33, 2.13 Hz), 4.78 (1 H, br d, J=10.79 Hz), 4.36 (1 H, m, J=13.49, 6.68 Hz), 4.23 (1 H, br d, J=11.80 Hz), 3.98 (1 H, br dd, J=12.05, 4.52 Hz), 3.60 - 3.70 (1 H, m), 2.36 (1 H, dt, J=8.85, 4.49 Hz), 1.98 - 2.15 (2 H, m), 1.66 (1 H, br d, J=3.51 Hz), 1.51 (6 H, d, J=6.78 Hz), 0.85 - 0.89 (1 H, m), 0.31 (1 H, br s).

[0412] Example 45 (1-Isopropyl-1H-imidazol-4-yl)[(1R,5S,6r)-6-(1-methyl-2-oxa-3-azabicyclo[3.1.0]hex-3-en-4-yl)-3-azabicyclo[3.1.0]hex-3-yl]methanone 2-(Trimethylsilyl)ethyl (1R,5S,6r)-6-[5-(chloromethyl)-5-methyl-4,5-dihydro-1,2-oxazol-3-yl]-3-azabicyclo[3.1.0]hexane-3-carboxylate To a solution of 2-(trimethylsilyl)ethyl (1R,5S,6r)-6-[(Z)-chloro(hydroxyimino)methyl]-3-azabicyclo[3.1.0]hexane-3-carboxylate (150 mg, 0.49 mmol) in DMF (2 mL) were added 3-chloro-2-methylprop-1-ene (0.24 mL, 2.46 mmol) and triethylamine (0.19 mL, 1.48 mmol). The mixture was stirred at 25 °C for 12 hours. A brown mixture was obtained. The reaction mixture was poured into water (10...

Claims

1. General formula (I): 【Chemistry 1】 (In the formula, R １ is Cyc1, -CO-Cyc2 or -CONR １０ R １１ represents; Cyc1 is a 1 to 5 R １２ represents a 5-9 membered aromatic heterocycle or a 5 membered non-aromatic heterocycle, optionally substituted by R １２ is (1) C1-4 alkyl, (2) C3-7 cycloalkyl, (3) C1-4 haloalkyl, (4) C1-4 alkoxy, (5) 1 to 3 R １７ (6) C1-4 alkyl substituted by phenyl, (7) dimethylamino, (8) pyridyl, or (9) 1-(cyclopropylmethyl)pyrazol-3-yl; Multiple R １２ may be the same or different; Two R's １２ These R １２ together with the atom to which it is attached, may form a C3-5 cycloalkane, the carbon atoms of which may be replaced by 1 to 2 heteroatoms selected from N, O, and S; R １７ represents C1-4 alkyl, C1-4 alkoxy or halogen; Multiple R １７ may be the same or different; Cyc2 contains 1 to 5 R １３ represents a C3-12 monocyclic or bicyclic carbocycle or a 5-9 membered monocyclic or bicyclic heterocycle optionally substituted by R １３ represents C1-4 alkyl, C1-4 alkoxy or halogen; Multiple R １３ may be the same or different; R １０ teeth, 【Chemistry 2】 (In the formula, R １８ and R １９ each independently represents a C1-4 alkyl; R １８ and R １９ is R １８ and R １９ together with the carbon atom to which it is attached may form a C3-5 cycloalkane; R ２０ represents a hydrogen atom, C1-4 alkyl, C1-4 haloalkyl or nitrile; Within the group, the arrow indicates the bond to the nitrogen atom of -CON<; R １１ represents a hydrogen atom, C1-4 alkyl, or 1 to 9 deuterated C1-4 alkyl; R ２ , R ３ , R ４ , R ５ , R ６ , R ７ and R ８ independently represent a hydrogen atom, C1-4 alkyl, halogen or C1-4 alkoxy; R ９ is one to three R １４ or 1 to 3 R １５ represents an optionally substituted pyrazole; R １４ is (1) C1-8 alkyl, (2) C3-7 cycloalkyl optionally substituted with C1-4 alkyl, (3) C1-8 haloalkyl, (4) 1 to 3 R １６ (5) C1-8 alkyl substituted with phenoxy; Cyc3 represents phenyl, C3-7 cycloalkyl, pyridyl, thiazolyl or tetrahydropyranyl; R １６ represents C1-4 alkyl, halogen, C1-4 alkoxy or cyano; Multiple R １４ may be the same or different; Multiple R １６ may be the same or different; R １５ is (1) C1-8 alkyl, (2) C3-7 cycloalkyl optionally substituted with C1-4 alkyl, (3) C1-8 haloalkyl, (4) 1 to 3 R ２１ (5) C1-8 alkyl substituted with phenoxy; Cyc4 represents phenyl, C3-7 cycloalkyl, pyridyl, thiazolyl or tetrahydropyranyl; R ２１ represents C1-4 alkyl, halogen, C1-4 alkoxy or cyano; Multiple R １５ may be the same or different; Multiple R ２１ may be the same or different; Each hydrogen molecule may be a deuterium or tritium atom; However, ((1R,5S,6r)-6-(cyclopropanecarbonyl)-3-azabicyclo[3.1.0]hexan-3-yl)(5-isopropyl-1H-pyrazol-3-yl)methanone, (5-isopropyl-1H-pyrazol-3-yl)-[(1R,5S)-6-[(2R)-2-methylpyrrolidine-1-carbonyl]-3-azabicyclo[3.1.0]hexan-3-yl]methanone, (5-isopropyl-1H-pyrazol-3-yl)-[(1S,5R)-6-[(2S)-2-methylpyrrolidine-1-carbonyl a compound represented by the formula (I)-6-(2,2-dimethylpyrrolidine-1-carbonyl)-3-azabicyclo[3.1.0]hexan-3-yl]-methanone, [(1S,5R)-6-(2,2-dimethylpyrrolidine-1-carbonyl)-3-azabicyclo[3.1.0]hexan-3-yl]-(5-isopropyl-1H-pyrazol-3-yl)methanone, and (5-isopropyl-1H-pyrazol-3-yl)-[(1S,5R)-6-(5-methyl-4-phenyl-isoxazol-3-yl)-3-azabicyclo[3.1.0]hexan-3-yl]methanone, or a salt thereof.

2. R １ represents Cyc1, and Cyc1 is 1 to 5 R １２ 2. The compound according to claim 1, wherein R represents a 5-membered non-aromatic heterocycle optionally substituted by R, or a salt thereof.

3. The compound according to claim 2, wherein the 5-membered non-aromatic heterocycle is 4,5-dihydroisoxazole or 4,5-dihydro-1,2,4-oxadiazole, or a salt thereof.

4. R ９ But 1 to 3 R １４ The compound according to any one of claims 1 to 3, wherein R represents an optionally substituted imidazole, or a salt thereof.

5. The compound represented by the general formula (I) is represented by the general formula (I-1) 【Chemistry 3】 (In the formula, R １２－１ and R １２－２ each independently represents C1-4 alkyl; R １２－１ and R １２－２ is R １２－１ and R １２－２ may form a C3-5 cycloalkane together with the atom to which it is attached, R １４－１ represents C1-4 alkyl, or C3-5 cycloalkyl optionally substituted with C1-4 alkyl, and the other symbols have the same meanings as those in claim 1, or a salt thereof.

6. The compound is (1) [(1R,5S,6r)-6-(5,5-dimethyl-4,5-dihydro-1,2-oxazol-3-yl)-3-azabicyclo[3.1.0]hex-3-yl](1-isopropyl-1H-imidazol-4-yl)methanone; (2) [(1R,5S,6r)-6-(5,5-dimethyl-4,5-dihydro-1,2-oxazol-3-yl)-3-azabicyclo[3.1.0]hex-3-yl][1-(1-methylcyclopropyl)-1H-imidazol-4-yl]methanone; (3) (1-cyclopropyl-1H-imidazol-4-yl)[(1R,5S,6r)-6-(5,5-dimethyl-4,5-dihydro-1,2-oxazol-3-yl)-6-methyl-3-azabicyclo[3.1.0]hex-3-yl]methanone; (4) (1-cyclopropyl-1H-imidazol-4-yl)[(1R,5S,6r)-6-methyl-6-(4-oxa-5-azaspiro[2.4]hept-5-en-6-yl)-3-azabicyclo[3.1.0]hex-3-yl]methanone; (5) {1-[(2S)-butan-2-yl]-1H-imidazol-4-yl}[(1R,5S,6S)-6-(5,5-dimethyl-4,5-dihydro-1,2-oxazol-3-yl)-3-azabicyclo[3.1.0]hex-3-yl]methanone; (6) [(1R,5S,6r)-6-(5,5-dimethyl-4,5-dihydro-1,2-oxazol-3-yl)-6-methyl-3-azabicyclo[3.1.0]hex-3-yl](1-isopropyl-1H-imidazol-4-yl)methanone; (7) (1-isopropyl-1H-imidazol-4-yl)[(1R,5S,6r)-6-methyl-6-(4-oxa-5-azaspiro[2.4]hept-5-en-6-yl)-3-azabicyclo[3.1.0]hex-3-yl]methanone; (8) (1-cyclopropyl-1H-imidazol-4-yl)[(1R,5S,6r)-6-(4-oxa-5-azaspiro[2.4]hept-5-en-6-yl)-3-azabicyclo[3.1.0]hex-3-yl]methanone, or (9) The compound according to any one of claims 1 to 5, which is [1-(1-methylcyclopropyl)-1H-imidazol-4-yl][(1R,5S,6r)-6-(4-oxa-5-azaspiro[2.4]hept-5-en-6-yl)-3-azabicyclo[3.1.0]hex-3-yl]methanone, or a salt thereof.

7. R ９ But 1 to 3 R １５ The compound according to any one of claims 1 to 3, wherein the compound represents an optionally substituted pyrazole, or a salt thereof.

8. The compound represented by general formula (I) is represented by general formula (I-2): 【Chemistry 4】 8. The compound according to any one of claims 1 to 3 and 7, wherein the compound is represented by the formula: (wherein all symbols have the same meaning as defined in claim 1 or claim 5), or a salt thereof.

9. The compound is (1) [(1R,5S,6r)-6-(5,5-dimethyl-4,5-dihydro-1,2-oxazol-3-yl)-3-azabicyclo[3.1.0]hex-3-yl](5-isopropyl-1H-pyrazol-3-yl)methanone; (2) (5-isopropyl-1H-pyrazol-3-yl)[(1R,5S,6r)-6-(2-oxa-3-azabicyclo[3.1.0]hex-3-en-4-yl)-3-azabicyclo[3.1.0]hex-3-yl]methanone; (3) [5-(1-cyclopropylethyl)-1H-pyrazol-3-yl][(1R,5S,6r)-6-(5,5-dimethyl-4,5-dihydro-1,2-oxazol-3-yl)-3-azabicyclo[3.1.0]hex-3-yl]methanone; (4) [(1R,5S,6r)-6-(5,5-dimethyl-4,5-dihydro-1,2-oxazol-3-yl)-6-methyl-3-azabicyclo[3.1.0]hex-3-yl](5-isopropyl-1H-pyrazol-3-yl)methanone, or (5) The compound according to any one of claims 1 to 3, 7 and 8, which is (5-cyclopropyl-1H-pyrazol-3-yl)[(1R,5S,6r)-6-methyl-6-(4-oxa-5-azaspiro[2.4]hept-5-en-6-yl)-3-azabicyclo[3.1.0]hex-3-yl]methanone, or a salt thereof.

10. R １ Ga-CONR １０ R １１ The compound according to claim 1 , wherein

11. R １０ The compound according to claim 10, wherein represents isopropyl, tert-butyl, 1,1,1-trifluoro-2-methylpropan-2-yl, 1-methylcyclopropyl, 1-(trifluoromethyl)cyclopropyl or 1-cyanocyclopropyl, or a salt thereof.

12. R ９ But 1 to 3 R １４ 12. The compound according to claim 10 or 11, wherein R represents an optionally substituted imidazole, or a salt thereof.

13. The compound represented by general formula (I) is represented by general formula (I-3) 【Chemistry 5】 (In the formula, R １０－１ represents isopropyl, tert-butyl, 1,1,1-trifluoro-2-methylpropan-2-yl, 1-methylcyclopropyl, 1-(trifluoromethyl)cyclopropyl, or 1-cyanocyclopropyl, and the other symbols have the same meanings as those in claim 1 or claim 5. The compound or salt thereof according to any one of claims 10 to 12.

14. The compound is (1) (1R,5S,6r)-N-tert-butyl-6-methyl-3-[1-(propan-2-yl)-1H-imidazole-4-carbonyl]-3-azabicyclo[3.1.0]hexane-6-carboxamide; (2) (1R,5S,6r)-N-tert-butyl-3-[1-(propan-2-yl)-1H-imidazole-4-carbonyl]-3-azabicyclo[3.1.0]hexane-6-carboxamide; (3) (1R,5S,6r)-N-(propan-2-yl)-3-[1-(propan-2-yl)-1H-imidazole-4-carbonyl]-3-azabicyclo[3.1.0]hexane-6-carboxamide, or (4) The compound according to any one of claims 1 and 10 to 13, which is (1R,5S,6r)-N-(1-cyanocyclopropyl)-3-[1-(propan-2-yl)-1H-imidazole-4-carbonyl]-3-azabicyclo[3.1.0]hexane-6-carboxamide, or a salt thereof.

15. R ９ But 1 to 3 R １５ 12. The compound according to claim 10 or 11, wherein R represents an optionally substituted pyrazole, or a salt thereof.

16. The compound represented by general formula (I) is represented by general formula (I-4) 【Chemistry 6】 16. A compound according to any one of claims 1, 10, 11 and 15, represented by the formula: (wherein all symbols have the same meaning as defined in claim 1 or claim 13), or a salt thereof.

17. The compound is (1) (1R,5S,6r)-N-(propan-2-yl)-3-[5-(propan-2-yl)-1H-pyrazole-3-carbonyl]-3-azabicyclo[3.1.0]hexane-6-carboxamide; (2) (1R,5S,6r)-N-tert-butyl-6-methyl-3-[5-(propan-2-yl)-1H-pyrazole-3-carbonyl]-3-azabicyclo[3.1.0]hexane-6-carboxamide; (3) (1R,5S,6r)-N-tert-butyl-N-methyl-3-[5-(propan-2-yl)-1H-pyrazole-3-carbonyl]-3-azabicyclo[3.1.0]hexane-6-carboxamide, or (4) The compound according to any one of claims 1, 10, 11, 15 and 16, which is (1R,5S,6r)-N-methyl-N-(1-methylcyclopropyl)-3-[5-(propan-2-yl)-1H-pyrazole-3-carbonyl]-3-azabicyclo[3.1.0]hexane-6-carboxamide, or a salt thereof.

18. A pharmaceutical composition comprising a compound represented by the general formula (I) according to claim 1 or a salt thereof, and a pharma- ceutically acceptable carrier.

19. The pharmaceutical composition according to claim 18, which is a KDM5 inhibitor.

20. The pharmaceutical composition according to claim 18 or 19, which is an agent for preventing and / or treating a KDM5-related disease.

21. The pharmaceutical composition according to claim 20, wherein the KDM5-related disease is cancer or Alzheimer's disease.

22. A preventive and / or therapeutic agent for KDM5-related diseases, comprising the compound represented by the general formula (I) according to claim 1 or a salt thereof as an active ingredient, said preventive and / or therapeutic agent being administered in combination with at least one agent selected from the group consisting of donepezil hydrochloride, galantamine hydrobromide, huperzine A, idebenone, rebasecarnine hydrochloride, memantine hydrochloride, memantine hydrochloride / donepezil hydrochloride, a proteolytic peptide fraction derived from porcine brain protein, rivastigmine tartrate, tacrine hydrochloride and aducanumab.

23. A method for preventing and / or treating a KDM5-associated disease, which comprises administering to a mammal an effective amount of a compound represented by the general formula (I) according to claim 1 or a salt thereof.

24. 2. The compound represented by the general formula (I) according to claim 1 or a salt thereof for use in the prevention and / or treatment of a KDM5-related disease.

25. Use of a compound represented by the general formula (I) according to claim 1 or a salt thereof for the manufacture of an agent for the prevention and / or treatment of a KDM5-related disease.

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