3-Azabicyclo(3.1.0)hexane derivatives having KDM5 inhibitory activity and their medical uses

Abstract

To provide KDM5 inhibitors.SOLUTION: Compounds represented by general formula (I) in the figure, where the definition of all symbols is as described in the specification, or salts thereof are useful as prophylactic and / or therapeutic agents for cancer, Huntington's disease, Alzheimer's disease, and the like.SELECTED DRAWING: None

Description

[Technical field]

[0001] The present invention relates to a compound represented by the following general formula (I) having KDM5 inhibitory activity, or a salt thereof, and medical use thereof. [Background technology]

[0002] Eukaryotic DNA is present in the cell nucleus in the form of chromatin, a complex with histone proteins. Histone proteins are modified by various enzymes, such as methylation, acetylation, and phosphorylation, and these modifications are known to induce chromatin reorganization 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] KDM5 protein belongs to the JARID histone demethylase protein group and demethylates the trimethylation of the fourth lysine residue in histone H3 protein (H3K4me3). In mammals, including humans, there are four subfamilies, KDM5A, KDM5B, KDM5C, and KDM5D, which have five conserved domains, namely JmjN, ARID, JmjC, PHDs, and C5HC2 zinc finger. The KDM5 family is widely distributed in blood cells and various organs in the body, and is known to be highly expressed in cancer tissues in particular. Epigenetic abnormalities in cancer cells are known to be involved in the proliferation and metastasis of cancer cells, and KDM5 inhibitors have been reported to be effective against cancer cells. The involvement of epigenetic abnormalities, including histone modifications, has also been reported in other pathological fields such as psychiatric and neurological disorders and metabolic disorders. Therefore, compounds with KDM5 inhibitory activity will improve epigenetic pathological abnormalities and be useful for the prevention and treatment of these diseases.

[0004] As a related art of the present invention, WO2016057924 reports that the compound of formula (A) is useful as an inhibitor of one or more demethylases such as KDM5. Formula (A): [ka] (In the formula, A A is selected from: [ka] R 1A is an alkyl group, a cyclic group, etc.; R 2A represents an optionally substituted cyclic group, -OR aA , -C(O)N(R aA ) 2 or NR aA R bA is; R aA and R bA each independently represents H, an optionally substituted alkyl group, an optionally substituted cyclic group, or the like; R 3A is H or alkyl; R 4A is H, an alkyl, or a cyclic group; and R 5A is H, halogen, or alkyl; and R 6A is H, an alkyl, or a cyclic group; Or, R 5A and R 6A together form a cyclic group (excerpt from the definition of the group). ), or a salt thereof.

[0005] Furthermore, International Publication No. 2000039089 reports that a compound represented by the following formula (B) is useful as an opiate receptor ligand. Formula (B) [ka] (In the formula, Ar B The ring represents an optionally benzo-fused phenyl ring or a 5- to 6-membered heteroaryl ring; R 1B is selected from a variety of substituents; R2B is H, or a halogen; R 3B is H, a halogen, an alkyl group, a cyclic group, etc. R 4B is an optionally substituted alkyl, alkenyl, or alkynyl; R 5B and R 8B are each independently H or C 1-6 is alkyl, R 6B , R 7B , R 9 and R 10B When alone, each is H, X is halogen, alkyl, alkoxy, etc. (excerpts from definitions of groups) or a pharma- ceutical or veterinary acceptable derivative or prodrug thereof.

[0006] Furthermore, WO 2021010492 reports that the compound of formula (C) is useful as a KDM5 inhibitor. Formula (C): [ka] (In the formula, ring C is a 3-10 membered monocyclic or bicyclic heterocycle containing 1 to 4 nitrogen atoms, 1 oxygen atom and / or 1 sulfur atom and optionally substituted with 1 to 3 substituents; A C is R 1-1C -L 1C - etc.; B C is R 2-1C -L 2C - etc.; R 1-1C is a C3-8 cycloalkyl optionally substituted by 1 to 4 substituents; L 1C is a bond or carbonyl (-C(=O)-); L 2C is a bond, carbonyl (-C(=O)-), etc.; R 2-1Crepresents a 5-6 membered monocyclic heterocycle optionally substituted by 1 to 4 substituents; R 3C is a hydrogen atom, etc.; rC is an integer between 0 and 1. Or its salt. [Prior art documents] [Patent documents]

[0007] [Patent Document 1] International Publication No. 2016 / 057924 [Patent Document 2] International Publication No. 2000 / 039089 [Patent Document 3] International Publication No. 2021 / 010492 Summary of the Invention [Problem to be solved by the invention]

[0008] For example, compounds having KDM5 inhibitory activity for treating or preventing diseases such as cancer, Huntington's disease, and Alzheimer's disease are desirable. [Means for solving the problem]

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

[0010] That is, the present invention relates to: [1] General formula (I): [ka] (In the formula, R 1 Cyc1, -CO-Cyc2 or -CONR 10 R 11 represents; Cyc1 contains one to five R 12a 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 with phenyl, (7) dimethylamino, (8) pyridyl, or (9) 1-(cyclopropylmethyl)pyrazol-3-yl; Multiple R 12 may be the same or different; 2 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, S; R 17 represents C1-4 alkyl, C1-4 alkoxy or halogen; Multiple R 17 may be the same or different; Cyc2 has 1 to 5 R 13 C3-12 monocyclic or bicyclic carbocycle or 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, [ka] (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, a C1-4 alkyl, a C1-4 haloalkyl or a nitrile; Within the group, the arrow indicates the bond of -CON< to the nitrogen atom; R 11 represents a hydrogen atom, a 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 1 to 3 R 14 imidazole optionally substituted with 1 to 3 R 15 represents an optionally substituted pyrazole; R 14 is (1) C alkyl, (2) C cycloalkyl optionally substituted with C alkyl, (3) C 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) C alkyl, (2) C cycloalkyl optionally substituted with C alkyl, (3) C 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-4-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 composed of 1 to 5 R 12 The compound according to the above [1], or a salt thereof, wherein [3] The compound according to the above [2], wherein the 5-membered non-aromatic heterocycle represents 4,5-dihydroisoxazole or 4,5-dihydro-1,2,4-oxadiazole, or a salt thereof; [3-1] The compound represented by general formula (I) is represented by general formula (I-01) [ka] (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 bonded, and the other symbols have the same meanings as in the above [1]), or a salt thereof according to the above [3]; [4]R 9 But 1 to 3 R 14 represents an imidazole optionally substituted by the formula (I) or (II), or a salt thereof; [5] The compound represented by general formula (I) is represented by general formula (I-1) [ka] (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 other symbols have the same meanings as in [1]); a compound according to any one of [1] to [4] and [3-1] above, or a salt thereof; [6] The compound, (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 the preceding items [1] to [5] and [3-1], 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 15a compound according to any one of the above [1] to [3] and [3-1], or a salt thereof, which represents a pyrazole optionally substituted by [8] The compound represented by general formula (I) is represented by general formula (I-2): [ka] (wherein all symbols have the same meaning as in the above [1] or [5]), or a salt thereof according to any one of the above [1] to [3], [3-1] and [7]; [9] The compound, (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 the above [1] to [3], [3-1], [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 -CONR 10 R 11The compound according to the above [1] or a salt thereof;

[11] R 10 represents isopropyl, tert-butyl, 1,1,1-trifluoro-2-methylpropan-2-yl, 1-methylcyclopropyl, 1-(trifluoromethyl)cyclopropyl, or 1-cyanocyclopropyl; [11-1] The compound represented by general formula (I) is represented by general formula (I-02) [ka] (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 in the above [1]), or a salt thereof according to the above

[11] ;

[12] R 9 But 1 to 3 R 14 The compound according to the above

[10] ,

[11] or [11-1], or a salt thereof, wherein

[13] The compound represented by general formula (I) is represented by general formula (I-3) [ka] (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 other symbols have the same meanings as in [1] or [5] above), the compound according to any one of the above [1],

[10] to

[12] , and [11-1], or a salt thereof;

[14] The compound, (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 or salt thereof according to any one of [1],

[10] to

[13] and [11-1], 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;

[15] R 9 But 1 to 3 R 15 The compound according to the above

[10] ,

[11] and [11-1], or a salt thereof, wherein

[16] The compound represented by general formula (I) is represented by general formula (I-4) [ka] (wherein all symbols have the same meaning as in [1] or

[13] above), or a salt thereof;

[17] The compound (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 salt thereof according to any one of [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) or a salt thereof according to the preceding paragraph [1] and a pharma- ceutically acceptable carrier;

[19] The pharmaceutical composition according to the above

[18] , which is a KDM5 inhibitor;

[20] The pharmaceutical composition according to the preceding item

[18] or

[19] , which is an agent for preventing and / or treating a KDM5-related disease; [21-1] KDM5-related diseases include hyperproliferation, cancer, stroke, diabetes, hepatomegaly, cardiovascular disease, multiple sclerosis, Huntington's disease, Alzheimer's disease, cystic fibrosis, viral diseases, autoimmune diseases, atherosclerosis, restenosis, psoriasis, rheumatoid arthritis, inflammatory bowel disease, asthma, allergies, inflammation, neurological disorders, hormone-related diseases, conditions associated with organ transplantation, immunodeficiency diseases, destructive bone disorders, proliferative diseases, infectious diseases, conditions associated with cell death, thrombin-induced platelet aggregation, and liver diseases. the pharmaceutical composition according to the above

[20] , wherein the indication is a chronic idiopathic pulmonary disease, a pathological immune condition involving T cell activity, a central nervous system disorder, a myeloproliferative disorder, 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, a learning disability, a movement disorder, obsessive-compulsive disorder, a personality disorder, a sleep disorder, delirium, amyotrophic lateral sclerosis, a developmental disorder, an 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 a KDM5-associated disease, comprising the compound represented by general formula (I) or a salt thereof according to [1] above as an active ingredient, wherein the prophylactic and / or therapeutic agent is administered in combination with at least one agent selected from the group consisting of donepezil hydrochloride, galantamine hydrobromide, huperzine A, idebenone, levacecarnine 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, 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] A compound represented by the general formula (I) or a salt thereof according to [1] above, for use in the prevention and / or treatment of a KDM5-associated disease; and

[25] Use of a compound represented by the general formula (I) or a salt thereof according to [1] above for the manufacture of an agent for the prevention and / or treatment of a KDM5-associated disease. Effect of the Invention

[0011] The compound represented by the general formula (I) described in the present specification or a salt thereof (hereinafter collectively referred to as the present compound) has KDM5 inhibitory activity. Therefore, the present compound is effective in treating 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, neurological disorders, 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, T-cell disorders, and the like. The present invention may be used as a prophylactic and / or therapeutic agent for diseases such as pathological immune conditions associated with cellular activity, central nervous system disorders, myeloproliferative disorders, Parkinson's disease, Lewy body disease, frontotemporal lobar degeneration, mild cognitive impairment, dementia, cerebrovascular disease, schizophrenia, depression, anxiety disorders, bipolar disorder, autism spectrum disorder, attention-deficit / hyperactivity disorder, learning disabilities, movement disorders, obsessive-compulsive disorder, personality disorders, sleep disorders, delirium, amyotrophic lateral sclerosis, developmental disorders, intellectual disabilities, post-traumatic stress disorder, and hepatitis. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[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] As used herein, the term "1 to 9 deuterated C alkyl" refers to 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. (D means deuterium).

[0015] As used herein, "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] As used herein, "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.

[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 and the like.

[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] In the present specification, examples of "C3-5 cycloalkane in which carbon atoms of C3-5 cycloalkane may be replaced by 1 to 2 heteroatoms selected from N, O and S" include cyclopropane, cyclobutane, cyclopentane, aziridine, oxirane, thiirane, azetidine, oxetane, thietane, pyrrolidine, tetrahydrofuran, tetrahydrothiophene, pyrazolidine, isoxazolidine, isothiazolidine, imidazolidine, oxazolidine, thiazolidine, and 1,3-dioxolane rings.

[0022] In the present specification, "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.

[0023] In the present specification, examples of the "5- to 9-membered aromatic heterocycle" include "a 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 the present specification, examples of the "5-membered non-aromatic heterocycle" include "5-membered non-aromatic heterocycles containing 1 to 4 nitrogen atoms, 1 oxygen atom and / or 1 sulfur atom" and the like. Examples of the "5-membered non-aromatic heterocycles 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.

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

[0026] In this specification, examples of "5- to 9-membered monocyclic or bicyclic heterocycle" include "5- to 9-membered monocyclic or bicyclic heterocycle containing 1 to 4 nitrogen atoms, 1 to 2 oxygen atoms, and / or 1 sulfur atom."Examples of "5-9 membered monocyclic or bicyclic heterocycles containing 1 to 4 nitrogen atoms, 1 to 2 oxygen atoms, and / or 1 sulfur atom" are 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, triphenylphosphine, ... Azolidine, 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, tetrahydro Oxazole (Oxazolidine), Dihydroisoxazole, Tetrahydroisoxazole (Isoxazolidine), Dihydrothiazole, Tetrahydrothiazole (Thiazolidine), Dihydroisothiazole, Tetrahydroisothiazole (Isothiazolidine), Dihydrofurazan, Tetrahydrofurazan, Dihydrooxadiazole, Tetrahydrooxadiazole (Oxadiazolidine), Dihydrooxazine, Tetrahydrooxazine, Dihydrooxadiazine, Tetrahydrooxadiazine, Dihydrothiadiazole, Tetrahydrothiadiazine Examples of such rings include azole (thiadiazolidine), dihydrothiazine, tetrahydrothiazine, dihydrothiadiazine, tetrahydrothiadiazine, morpholine, thiomorpholine, oxathiane, dioxolane, dioxane, dioxole, indole, benzimidazole, benztriazole, indazole, benzofuran, benzothiophene, benzoxazole, indoline, dihydrobenzimidazole, dihydrobenzotriazole, dihydroindazole, dihydrobenzofuran, dihydrobenzothiophene, and dihydrobenzoxazole rings.

[0027] In the present invention, unless otherwise specified, the following symbols: [ka] represents a bond extending outward from the plane of the paper (i.e., β-configuration), and the symbol: [ka] represents a bond pointing towards the back of the page (i.e., the α-configuration), and the symbol: [ka] indicates that the bond is in the α-configuration, β-configuration, or a mixture of these in any proportion, as will be apparent to one of skill in the art.

[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 heterocycle.

[0029] In the present invention, Cyc1 preferably has, for example, 1 to 5 R 12 and more preferably, for example, each of 1 to 5 R 12 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 optionally substituted with, for example, 1 to 5 R 12and 4,5-dihydro-1,2,4-oxadiazole or 4,5-dihydroisoxazole, which may be substituted with 1 to 5 R 12 and optionally substituted 4,5-dihydroisoxazole.

[0030] In the present invention, Cyc1 is also preferably, for example, 1 to 5 R 12 and more preferably, for example, each of 1 to 5 R 12 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, for example, 1 to 5 R 12 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, optionally substituted with

[0031] In the present invention, R 12 is preferably, for example, (1) C alkyl, (2) C cycloalkyl, (3) C haloalkyl, (4) C alkoxy, (5) 1 to 3 R 17 (6) C alkyl optionally substituted with phenyl; (7) dimethylamino; (8) pyridyl; or (9) 1-(cyclopropylmethyl)pyrazol-3-yl; or (10) two R 12 However, these R 12is a group which may form a C3-5 cycloalkane together with the atom to which it is bonded, and more preferably, for example, (1) C1-4 alkyl, (2) C3-7 cycloalkyl, (3) 1 to 3 R 17 or (4) two R 12 However, these R 12 is a group which may form a C3-5 cycloalkane together with the atom to which it is bonded, and particularly preferred is, for example, C1-4 alkyl, or two R 12 However, these R 12 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 preferably has, for example, 1 to 5 R 13 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, benztriazole, indazole, benzofuran, benzothiophene, benzoxazole, indoline, dihydrobenzimidazole, dihydrobenzotriazole, dihydroindazole, dihydrobenzofuran, dihydrobenzothiophene, or dihydrobenzoxazole, each of which may be optionally substituted with, for example, 1 to 5 R 13 and n is 0 or 1; and n is 1 or 2; and n is 2 or 3; and n is 3 or 4. The n-type alkyl group is cyclopropane, benzene, pyridine, thiophene, thiazole, or indoline, optionally substituted with

[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, 1 to 3 R 14 is an imidazole which may be substituted with In the present invention, R 9 Also preferred are, for example, 1 to 3 R 15 and optionally substituted pyrazole.

[0035] In the present invention, R 14is preferably, for example, (1) C alkyl, (2) C cycloalkyl optionally substituted with C alkyl, (3) one to three 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) C alkyl, (2) C cycloalkyl optionally substituted with C alkyl, (3) one to three 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, the examples of the general formula (I) are preferably represented by the general formula (I-1A): [ka] (wherein all symbols have the same meaning as above).

[0040] In the present invention, the examples of the general formula (I) are preferably the general formula (I-1): [ka] (wherein all symbols have the same meaning as above),

[0041] General formula (I-1A-1): [ka] (In the formula, R 2 represents a hydrogen atom or a C1-4 alkyl group; R 14 represents (1) C1-8 alkyl, (2) C3-7 cycloalkyl optionally substituted by C1-4 alkyl, or (5) C1-8 alkyl substituted by phenoxy; R 12-1 and R 12-2 each represents C1-4 alkyl; and 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),

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

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

[0044] General formula (I-3A): [ka] (wherein all symbols have the same meaning as above),

[0045] General formula (I-3): [ka] (wherein all symbols have the same meaning as above),

[0046] General formula (I-4): [ka] (wherein all symbols have the same meaning as above),

[0047] General formula (I-5): [ka] (In the formula, R 12H is (1) a hydrogen atom, (2) a C1-4 alkyl, (3) a C3-7 cycloalkyl, (4) a C1-4 haloalkyl, (5) a C1-4 alkoxy, or (6) one to three R 17 (7) C1-4 alkyl substituted with phenyl, (8) dimethylamino, (9) pyridyl, or (10) 1-(cyclopropylmethyl)pyrazol-3-yl, and the other symbols have the same meanings as above),

[0048] General formula (I-6): [ka] (wherein all symbols have the same meaning as above),

[0049] General formula (I-7): [ka] (wherein all symbols have the same meaning as above),

[0050] General formula (I-7-1): [ka] (In the formula, R 14 represents (1) C1-8 alkyl, or (3) C1-8 haloalkyl; R 12H1 (2) C1-4 alkyl, (3) C3-7 cycloalkyl, (4) C1-4 haloalkyl, (5) C1-4 alkoxy, (6) 1 to 3 R 17 (7) C alkyl substituted with phenyl; (8) dimethylamino; (9) pyridyl; or (10) 1-(cyclopropylmethyl)pyrazol-3-yl (preferably, R 12H1 (2) C1-4 alkyl, (3) C3-7 cycloalkyl, (4) C1-4 haloalkyl, (6) 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) a C1-4 alkyl, (3) a C3-7 cycloalkyl, (4) a C1-4 haloalkyl, (5) a C1-4 alkoxy, or (6) one to three R 17 (7) C alkyl substituted with phenyl; (8) dimethylamino; (9) pyridyl; or (10) 1-(cyclopropylmethyl)pyrazol-3-yl (preferably, R 12H2 represents (1) a hydrogen atom, (2) a C1-4 alkyl, (4) a C1-4 haloalkyl, (7) a C1-4 alkyl substituted with phenyl, or (8) a dimethylamino; and R 17represents C1-4 alkyl, C1-4 alkoxy, or halogen);

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

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

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

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

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

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

[0057] General formula (I-12): [ka] (wherein all symbols have the same meaning as above), General formula (I-12-1): [ka] (In the formula, R 15 represents (1) C1-8 alkyl, or (3) C1-8 haloalkyl; R 12H1 (2) C1-4 alkyl, (3) C3-7 cycloalkyl, (4) C1-4 haloalkyl, (5) C1-4 alkoxy, (6) 1 to 3 R 17 (7) C alkyl substituted with phenyl; (8) dimethylamino; (9) pyridyl; or (10) 1-(cyclopropylmethyl)pyrazol-3-yl (preferably, R 12H1(2) C1-4 alkyl, (3) C3-7 cycloalkyl, (4) C1-4 haloalkyl, (6) 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) a C1-4 alkyl, (3) a C3-7 cycloalkyl, (4) a C1-4 haloalkyl, (5) a C1-4 alkoxy, or (6) one to three R 17 (7) C alkyl substituted with phenyl; (8) dimethylamino; (9) pyridyl; or (10) 1-(cyclopropylmethyl)pyrazol-3-yl (preferably, R 12H2 represents (1) a hydrogen atom, (2) a C1-4 alkyl, (4) a C1-4 haloalkyl, (7) a C1-4 alkyl substituted with phenyl, or (8) dimethylamino; and R 17 represents C1-4 alkyl, C1-4 alkoxy, or halogen);

[0058] General formula (I-13): [ka] (wherein all symbols have the same meaning as above),

[0059] General formula (I-13-1): [ka] (In the formula, R 14 represents (1) C1-8 alkyl, or (3) C1-8 haloalkyl; R 12H is (1) a hydrogen atom, (2) a C1-4 alkyl, (3) a C3-7 cycloalkyl, (4) a C1-4 haloalkyl, (5) a C1-4 alkoxy, or (6) one to three R 17(7) C alkyl substituted with phenyl, (8) dimethylamino, (9) pyridyl, or (10) 1-(cyclopropylmethyl)pyrazol-3-yl (preferably, R 12H represents (1) a hydrogen atom, (2) a C1-4 alkyl, or (4) a C1-4 haloalkyl; and R 17 represents C1-4 alkyl, C1-4 alkoxy, or halogen);

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

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

[0062] General formula (I-15): [ka] (wherein n represents an integer of 0 to 4, and the other symbols have the same meanings as above),

[0063] General formula (I-15-1): [ka] (In the formula, R 14 represents (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) 1 to 3 R 17 (6) C1-4 alkyl substituted with phenyl, (7) dimethylamino, (8) pyridyl, or (9) 1-(cyclopropylmethyl)pyrazol-3-yl; n represents an integer from 0 to 4, preferably n is 0; and R 17 represents C1-4 alkyl, C1-4 alkoxy, or halogen);

[0064] General formula (I-16): [ka] (wherein all symbols have the same meaning as above),

[0065] General formula (I-16-1): [ka] (In the formula, R 15 represents (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) 1 to 3 R 17(6) C1-4 alkyl substituted with phenyl, (7) dimethylamino, (8) pyridyl, or (9) 1-(cyclopropylmethyl)pyrazol-3-yl; n represents an integer from 0 to 4, preferably n is 0; and R 17 represents C1-4 alkyl, C1-4 alkoxy, or halogen);

[0066] General formula (I-17): [ka] (wherein all symbols have the same meaning as above), General formula (I-17-1): [ka] (In the formula, R 14 represents (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) 1 to 3 R 17 (6) C1-4 alkyl substituted with phenyl, (7) dimethylamino, (8) pyridyl, or (9) 1-(cyclopropylmethyl)pyrazol-3-yl; n represents an integer from 0 to 4, preferably n is 0; and R 17 represents C1-4 alkyl, C1-4 alkoxy, or halogen);

[0067] General formula (I-18): [ka] (wherein all symbols have the same meaning as above),

[0068] General formula (I-18-1): [ka] (In the formula, 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) 1 to 3 R 17 (6) C alkyl substituted with phenyl; (7) dimethylamino; (8) pyridyl; or (9) 1-(cyclopropylmethyl)pyrazol-3-yl (preferably, R 12 represents (1) C1-4 alkyl, (2) C3-7 cycloalkyl, (3) C1-4 haloalkyl, or (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): [ka] (wherein all symbols have the same meaning as above),

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

[0071] General formula (I-21): [ka] (wherein m represents an integer of 0 to 2, and the other symbols have the same meanings as above),

[0072] General formula (I-21-1): [ka] (In the formula, 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): [ka] (wherein all symbols have the same meaning as above),

[0074] General formula (I-23): [ka] (wherein all symbols have the same meaning as above),

[0075] General formula (I-24): [ka] (wherein all symbols have the same meaning as above),

[0076] General formula (I-25): [ka] (wherein all symbols have the same meaning as above),

[0077] General formula (I-26): [ka] (wherein all symbols have the same meaning as above),

[0078] General formula (I-27): [ka] (In the formula, R13H represents a hydrogen atom, a C1-4 alkyl group, a C1-4 alkoxy group, or a halogen atom, and the other symbols have the same meanings as above),

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

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

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

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

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

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

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

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

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

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

[0089] General formula (I-35-1): [ka] (In the formula, R 2 represents a hydrogen atom, a C1-4 alkyl, a halogen, or a C1-4 alkoxy; R 14 represents (1) C1-8 alkyl, or (3) C1-8 haloalkyl; R 10 represents C1-8 alkyl or C1-8 haloalkyl (preferably, R 10 represents isopropyl, tert-butyl, or 1,1,1-trifluoro-2-methylpropan-2-yl); and R 11 represents a hydrogen atom or a C1-4 alkyl group,

[0090] General formula (I-36): [ka] (wherein all symbols have the same meaning as above),

[0091] and general formula (I-36-1-1): [ka] (In the formula, R 2 represents a hydrogen atom, a C1-4 alkyl, a halogen, or a C1-4 alkoxy; R 15 represents (1) C1-8 alkyl, or (3) C1-8 haloalkyl; R 10 represents C1-8 alkyl or C1-8 haloalkyl (preferably, R 10 represents isopropyl, tert-butyl, or 1,1,1-trifluoro-2-methylpropan-2-yl); and R 11 represents a hydrogen atom or a C1-4 alkyl.

[0092] In the present invention, the examples of general formula (I) are preferably general formula (I-37): [ka] (wherein all symbols have the same meaning as above).

[0093] In the present invention, the examples of the general formula (I) are preferably the general formula (I-01): [ka] (wherein all symbols have the same meaning as above).

[0094] In the present invention, the examples of the general formula (I) are preferably the general formula (I-02): [ka] (wherein all symbols have the same meaning as above).

[0095] In the present invention, R on the 3-azabicyclo[3.1.0]hexane ring of general formulas (I-1) to (I-36) 1 , R 3 and R 4 The configuration of the substituents corresponding to the substituent represented by the following formula (I-37) is preferably in the same direction as the substituent represented by the following formula (I-37).

[0096] In the present invention or in the general formula (I) or (I-1), 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]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 the 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]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) (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.

[0098] In the present invention or in the 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 the 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. [Isomers]

[0100] The present invention includes all isomers unless otherwise stated. For example, alkyl groups, alkoxy groups, etc. include linear and branched groups. Furthermore, the present invention includes isomers of double bonds, rings and fused rings (E-, Z-, cis-, trans-), isomers of asymmetric carbon atoms (R- and S-forms, α- and β-configurations, enantiomers and diastereomers), optically active substances with optical rotation (D-, L-, d-, and l-forms), polar substances separated by chromatography (high polarity substances and low polarity substances), equilibrium compounds, rotational isomers, mixtures of these in any ratio, and racemic mixtures. The present invention also includes tautomers. [Salts and solvates]

[0101] The salts of the compounds represented by the general formula (I) described herein include all pharmacologically acceptable salts. All pharmacologically acceptable salts are preferably water-soluble salts with low toxicity. 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 salt also includes quaternary ammonium salts. Quaternary ammonium salts are salts in which the nitrogen atom of the compound represented by formula (I) is R 0 The R 0 The group represents, for example, a C1-8 alkyl group which may be substituted with a phenyl group.

[0103] The compound represented by the general formula (I) can be converted into a salt, N-oxide, or solvate by a known method.

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

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

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

[0107] The compound of formula (I) and its salt may form a co-crystal with a suitable co-crystal former. The co-crystal is preferably a pharma- ceutically acceptable one formed with a pharma- ceutically acceptable co-crystal former. A co-crystal is generally 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 may 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 references to the compound include the compound represented by general formula (I), a salt thereof, a solvate (e.g., hydrate), an N-oxide or a co-crystal thereof, or a solvate (e.g., hydrate), an N-oxide or a co-crystal of a salt of the compound represented by general formula (I).

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

[0110] [Prodrug] The prodrug of the compound represented by the general formula (I) means a compound which is converted into the compound represented by the general formula (I) by reaction with an enzyme, gastric acid, or the like in a living body. Examples of the prodrug of the compound represented by general formula (I) include, when the compound represented by general formula (I) has an amino group, a compound in which the amino group has been acylated, alkylated or phosphorylated (for example, a compound represented by general formula (I) in which the amino group has been converted to eicosanoyl, alanyl, pentylaminocarbonyl, (5-methyl-2-oxo-1,3-dioxolen-4-yl)methoxycarbonyl, tetrahydrofuranyl, pyrrolidylmethyl, pivaloyloxymethyl, acetoxymethyl, tert-butyl, or the like); when the compound represented by general formula (I) has a hydroxyl group, a compound in which the compound represented by general formula (I) has been acylated, alkylated, phosphorylated or converted to a borate (for example, a compound represented by general formula (I) in which the hydroxyl group has been converted to acetyl, palmitoyl, propanoyl, pivaloyl, succinyl, fumaryl, alanyl, dimethylaminomethylcarbonyl, or the like), and the like. Examples of prodrugs of the compound represented by general formula (I) include those that are converted to the compound represented by general formula (I) under physiological conditions as disclosed in "Drug Development", Vol. 7, "Molecular Design", 1990, Hirokawa Publishing Co., Ltd., pp. 163-198. Prodrugs of the compound represented by general formula (I) can be produced by methods known per se. The prodrugs of the compound represented by general formula (I) may form salts such as acid addition salts, as with the compound represented by general formula (I), or may form solvates with water or alcoholic solvents (ethanol, etc.). [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 isotopes that can be used for labeling include: 2 H, 3 H, 13 C. 14 C. 15 N, 16 N, 17 O. 18 O. 35 S, 36 Cl, 77 Br, 125 These include, but are not limited to, I. [Manufacturing method] [Method of producing the compound of the present invention]

[0112] The compound represented by general formula (I) or its salt can be produced by known methods, such as the methods described below in schemes I to XII, methods equivalent thereto, methods described in the Examples, methods equivalent thereto, or methods described in Comprehensive Organic Transformations: A Guide to Functional Group Preparations 2nd Edition (Richard C. Larock, John Wiley & Sons Inc., 1999), methods that apply them, or methods that combine them. In the production methods described below, the raw material compound may be a salt. Examples of salts include those described above as salts of the compound represented by general formula (I).

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

[0114] Amidation is known and includes, for example, the following methods: (1) Acyl halide route (2) Mixed acid anhydride method (3) Use of a condensation agent

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

[0116] (2) The method via a 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 the presence of a base (e.g., pyridine, triethylamine, dimethylaniline, dimethylaminopyridine, diisopropylethylamine, etc.) in an organic solvent (e.g., chloroform, dichloromethane, diethyl ether, tetrahydrofuran) or without a solvent at about 0° C. to 40° C. The resulting 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) The method using a condensing agent can be carried out, for example, by reacting a carboxylic acid with an amine in an organic solvent (e.g., chloroform, dichloromethane, dimethylformamide, diethyl ether, tetrahydrofuran) or without a solvent in the presence or absence of a base (e.g., pyridine, triethylamine, dimethylaniline, or dimethylaminopyridine) using 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-hydroxybenzothiazole (HOBt) at about 0°C to 40°C.

[0118] The reactions described in (1), (2) and (3) can be carried out under anhydrous conditions and under an inert gas (eg, 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 for an 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), and the like.

[0120] The deprotection reaction of the amino protecting group can be carried out under appropriate conditions for each protecting group. For example, deprotection of a 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, deprotection of a benzyloxycarbonyl (Z) group can be carried out using hydrogenation conditions such as hydrogen and catalytic Pd-C in a solvent such as methanol (MeOH) or ethanol (EtOH) at 20° C. to 60° C.

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

[0122] [ka] R in general formula (II) of Scheme I 1 teeth, [ka] and general formula (II) is represented as general formula (II)-1 in scheme II.

[0123] The compound represented by general formula (II)-1 can be produced by subjecting a compound represented by general formula (VII) and a compound represented by 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 (eg, trimethylamine, or DIPEA) and a solvent (eg, 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 chlorinating reagent (eg, N-chlorosuccinimide) in a solvent (eg, DMF, etc.) at about 0° C. to 40° C. 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 in a solvent such as EtOH at about 20° C. to 40° C.

[0127] [ka] R in general formula (II) of Scheme I 1 teeth, [ka] and general formula (II) is represented as general formula (II)-2 in scheme III.

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

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

[0130] The alkylation reaction can be carried out in a solvent (e.g., THF, DMF, DMA, diethyl ether, etc.) 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.

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

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

[0133] [ka] R in general formula (II) in scheme I 1 teeth, [ka] and general formula (II) can be represented as general formula (II)-3 in Scheme IV.

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

[0135] Oxidation of hydroxyl groups is well known and includes, for example, the following methods: (1) Dess-Martin oxidation (2) DMSO oxidation (3) Chromium Reagent Oxidation

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

[0137] The compound represented by the general formula (XV) can be produced by addition reaction of the compound represented by the general formula (V) with the compound represented by the general formula (XIV). In the general formula (XIV), M represents a metal (e.g., 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 such as tetrahydrofuran under an inert atmosphere such as dry nitrogen, or argon at -78°C to 0°C.

[0139] [ka] R in general formula (II) in scheme I 1 teeth, [ka] and general formula (II) can be depicted in Scheme V as general formula (II)-4 and (II)-4a.

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

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

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

[0143] The coupling reaction is known and can be carried out, for example, in an organic solvent (e.g., benzene, toluene, dimethylformamide, 1,4-dioxane, tetrahydrofuran, methanol, acetonitrile, dimethoxyethane, acetone, or a mixture thereof) using 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 ) or the like) at room temperature to 150° C. using a base (e.g., sodium ethylate, sodium hydroxide, potassium hydroxide, triethylamine, sodium carbonate, sodium hydrogencarbonate, potassium carbonate, cesium carbonate, thallium carbonate, tripotassium phosphate, cesium fluoride, barium hydroxide, tetrabutylammonium fluoride or the like) or an aqueous solution thereof, or a mixture thereof.

[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 in a solvent (eg, DMF, etc.) using a brominating reagent (eg, NBS, bromine, etc.) at -20°C to 40°C.

[0146] [ka] R in general formula (II) in scheme I 1 teeth, [ka] 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 a compound represented by general formula (VII) and a 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 in a solvent such as tetrahydrofuran, toluene or DMF using a base such as trimethylamine at a temperature between 0°C and 40°C.

[0149] [ka] R in general formula (II) in scheme I 1 teeth, [ka] and general formula (II) can be depicted 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 using a dehydrating agent (e.g., POCl). 3 etc.) at 80°C to 120°C. The compound represented by general formula (XXII) can be produced by subjecting a compound represented by general formula (XX) and a compound represented by general formula (XXI)-1 or (XXI)-2 to an amidation reaction.

[0152] The amidation can be carried out in a similar manner to the preparation of 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 a similar manner to the preparation of general formula (I) in Scheme I described above.

[0153] [ka] R in general formula (II) in scheme I 1 teeth, [ka] and general formula (II) can be depicted as general formula (II)-7 in Scheme VIII.

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

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

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

[0157] [ka] R in general formula (II) in scheme I 1 teeth, [ka] and general formula (II) can be depicted as general formula (II)-8 in Scheme IX.

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

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

[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-forming reaction. The nitrile-forming reaction can be carried out in a solvent (eg, DMF, benzene, toluene, or xylene) using a dehydrating agent (eg, cyanuric chloride, thionyl chloride, or diphosphorus pentoxide) at 100° C. to 140° C.

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

[0162] [ka] R in general formula (II) in scheme I 1 teeth, [ka] In Scheme X, general formula (II) can be represented as general formula (II)-9.

[0163] The compound represented by general formula (II)-9 can be produced by subjecting the compound represented by 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 using Burgess reagent in a solvent (e.g., acetonitrile) at temperatures ranging from 100°C to 140°C.

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

[0165] [ka] R in general formula (II) in scheme I 1 teeth, [ka] In Scheme XI, general formula (II) can be represented as general formula (II)-10.

[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 can be carried out using hydrazine hydrate at 50-70° C., followed by treatment with copper acetate in a solvent (e.g., ethyl acetate) at 20-40° C.

[0167] The compound represented by the general formula (XXXIII) can be produced by subjecting the compound represented by the 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 in the preparation of the compound of general formula (II)-3 in Scheme IV above.

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

[0169] In the formula, the compounds represented by general formula (IV), (VIII), (X), (XI), (XIII), (XIV), (XVI), (XVIII), (XIX), (XXI)-1, (XXI)-2, (XXIII), (XXV), (XXVII), (XXIX) and (XXXI) can be obtained as commercially available products, or can be easily prepared from commercially available 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) and the like.

[0170] In the formula, the compound represented by general formula (V) is commercially available, or can be prepared by the method described in Scheme XII.

[0171] [ka] 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 in the preparation of the compound of general formula (II)-3 in Scheme IV above.

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

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

[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 is carried out using a borane reducing agent (e.g., BH 3 THF complex, BH 3 Me 2 S complex or B 2 H 6 etc.) at temperatures between 20°C and 80°C.

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

[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 temperatures between 0°C and 40°C.

[0178] The compounds represented by the general formulae (XXXIV) and (XXXVI) are commercially available, and can also be easily prepared from commercially available 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) and the like.

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

[0180] In the reactions exemplified here, solid-phase supported reagents supported on polymers (polystyrene, polyacrylamide, polypropylene, polyethylene glycol, etc.) may be used, if necessary.

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

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

[0183] Since the present compound has KDM5 inhibitory activity, it can be used as an agent for the prevention and / or treatment of KDM5-associated diseases in mammals, particularly humans.

[0184] Examples of such diseases include hyperproliferative diseases, cancer, stroke, diabetes, hepatomegaly, cardiovascular disease, 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, neurological disorders, hormone-related diseases, conditions associated with organ transplants, immunodeficiency diseases, destructive bone disorders, proliferative diseases, infectious diseases, conditions associated with cell death, and thrombin-induced These conditions include: platelet aggregation, liver disease, pathological immune conditions involving T cell activity, central nervous system disorders, myeloproliferative disorders, Parkinson's disease, disease with Lewy bodies, frontotemporal lobar degeneration, mild cognitive impairment, dementia, cerebrovascular disease, schizophrenia, depression, anxiety disorders, bipolar disorder, autism spectrum disorder, attention-deficit / hyperactivity disorder, learning disabilities, movement disorders, obsessive-compulsive disorder, personality disorders, sleep disorders, delirium, amyotrophic lateral sclerosis, developmental disabilities, intellectual disabilities, post-traumatic stress disorder, and hepatitis.

[0185] In particular, the compounds are useful for the prevention and / or treatment of cancer, Huntington's disease, Alzheimer's 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 disability, movement disorder, obsessive-compulsive disorder, personality disorder, sleep disorder, delirium, amyotrophic lateral sclerosis, developmental disorder, intellectual disability, post-traumatic stress disorder or hepatitis. The compounds are particularly suitable for the prevention and / or treatment of cancer and Alzheimer's disease.

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

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

[0188] Mice (male C57BL / 6 mice aged 16 to 23 months (Charles River Japan Co., Ltd.)) are used. The test substance and its solvent are orally administered once a day for two weeks. After that, cognitive function is evaluated by the novel object recognition (NOR) test using a plastic cage equipped with a video camera (ECON cage, CL-0107, 345 mm x 403 mm x 177 mm, CLEA Japan Co., Ltd.) as the experimental apparatus. The evaluation is performed in a dark room, and the light intensity is adjusted to about 20 lux near the experimental apparatus. To allow the animals to acclimate to the evaluation environment, the mice are moved to the evaluation room at least one hour before the start of the test. This test is performed over three days. For acclimatization to the experimental apparatus on the first day, the mice are placed in a cage and allowed to move freely for 10 minutes. For the acquisition trial on the second day, two identical objects (known objects) are placed on the cage and the experiment is performed in the same way 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 faces 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 animal is made to behave in the same way for 10 min. The test trial begins 24 hours after the acquisition trial (tolerance range: 23 to 25 hours). The exploration time of each object is measured from the video images recorded in the test trial. The total exploration time and novel object recognition rate are calculated from the exploration times of the known and novel objects using the following formula:

[0189] Total exploration time (sec) = exploration time of known objects + exploration time of novel objects Recognition index (%) = 100 × (new object search time / total search time)

[0190] Examples of test methods for evaluating the pharmacological activity of the present compound include clonogenicity tests and cytotoxicity tests in cancer cells. For example, the effectiveness of the present 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 with certification. Cells are cultured for a maximum of 10–12 passages and then replaced with cells from earlier passages that have been stored in liquid nitrogen since purchase. Cells are grown adherently in high glucose Dulbecco's modified Eagle's medium (DMEM) containing 1% penicillin / streptomycin, 2 mM L-glutamine and 10% inactivated fetal bovine serum. Cells are maintained in an incubator at 37°C and 5% CO. 2 The cells are maintained at 4°C for 24 hours and passaged periodically by removing the DMEM, washing with PBS, and detaching the cells with an appropriate amount of trypsin / EDTA.

[0192] For clonogenicity testing, one hour after treatment with the compound, cells are exposed to X-rays using an MLG300 / 6-D instrument (Gilardoni) set at 200V and 6mA to obtain an equivalent absorbed dose of 1cGy / s. Cells are then harvested, counted, and diluted in growth medium containing the compound. Depending on the doubling time of the cell line and the radiation dose, an appropriate number of cells are seeded in quadruplicate. 24 hours after this seeding, the medium containing the compound is replaced with fresh DMEM, and the cells are cultured for 14 days (sufficient time for at least six cell divisions). After this growth period, the cells are washed twice with PBS, then fixed and stained with an appropriate amount of a solution consisting of 0.3% methylene blue and 80% ethanol for 30 minutes at room temperature. After washing the cells twice with dd water, the plates are imaged colorimetrically using a ChemiDoc XRS+ imaging system (Bio-Rad). Radiation dose response curves to X-rays for DMSO and compound samples are calculated using the survival rate. The plating efficiency and survival rate are calculated as follows: Plating efficiency = number of colonies counted / number of cells seeded Viability = plating efficiency / plating efficiency of mock sample

[0193] For cytotoxicity testing, Cell Counting Kit-8 (#CK04, DOJINDO) is used according to the manufacturer's instructions. MCF-7T47D or MDA-MB231 cell suspension (5000cells / 100μL / well) is dispensed into 96-well plates. After 24 hours, compounds or DMSO are added to the growth medium and the cells are irradiated. 48 hours after irradiation, 10μL of CCK-8 solution is added to each well of the plate and incubated again for 1 hour. The absorbance at 450nm is measured using a VICTOR2 1420 reader (Perkin Elmer).

[0194] An example of a test method for evaluating the pharmacological activity of the present compounds includes a test using primary cultured human hepatocytes (PHH) for the inhibition of hepatitis B virus antigen (HbsAg). For example, the effectiveness of the present compounds in the PHH assay can be evaluated using the following method.

[0195] Primary cultured human hepatocytes (PHH) (Bioreclaimation IVT) are seeded onto collagen-coated flasks using plating 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 4 h of incubation at 37 °C, switch the cells 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 selenium 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, infect PHH with genotype D (AD38-derived) HBV at 500 genome equivalents per cell in maintenance medium supplemented with 4% PEG8000 (Promega). After 24 h of incubation, wash the cells three times with William's medium E and add fresh maintenance medium. Three days after infection, infected PHH cells are seeded at a concentration of 65,000 cells / well in a final volume of 125 μl of maintenance medium (Life Technologies) containing serially diluted compounds or DMSO (final concentration 1%) onto collagen-precoated 96-well plates. Compound-containing medium is replenished every 2 to 3 days. After 12 days of culture, HBsAg secreted into the supernatant is measured by a multiplex chemiluminescence (Mesoscale discovery, MSD) assay using an HBsAg-specific capture and detection antibody pair. EC50 values ​​are calculated by fitting the dose-response curve to a four-parameter equation:

[0196] The test method for evaluating the pharmacological activity of the present compound can be exemplified by the evaluation system of the improvement of depressive symptoms in social defeat stress model.For example, the effectiveness of the present compound in social defeat model can be evaluated by the following method.

[0197] Eight-week-old male DBA / 2 mice are used in the experiment. Social defeat stress is applied to the mice. The test mice are placed in a highly aggressive CD-1 mouse cage for 5 minutes. During 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 board and maintained for 24 hours (psychological stress loading). This process is carried out for 5 consecutive days. Compounds or solvents are orally administered 2 hours before social defeat stress every day. Then, social interaction tests and sucrose preference tests are performed.

[0198] In the social interaction test, a CD-1 mouse is placed in a 42 cm square box (target area) as a novel mouse. A test mouse (DBA / 2 mouse) is placed in the box, and the time spent in the target area for 3 minutes is measured using a video tracking system (Any-Maze software). Depressed animals show a decrease in contact time with the novel mouse.

[0199] In the sucrose preference test, a bottle containing 1% sucrose solution and regular water is given simultaneously. The amount of sucrose solution and regular water consumed over a 4-hour period is measured, and the percentage of sucrose water consumed (sucrose preference) is used as an index of anhedonia. Animals normally prefer sweet sucrose, but sucrose preference is reduced in animals in anhedonia, a state of depression.

[0200] When the present compound is used for medical purposes, the present compound can be used as a single agent, and can also be used as a combination agent to which the active ingredients listed below are added for the purposes of, for example, (1) supplementing and / or enhancing the effects of the present compound for the prevention, treatment and / or amelioration of symptoms, (2) improving the pharmacokinetics and absorption, reducing the dosage of the present compound, and / or (3) reducing the side effects of the present compound.

[0201] When the present compound is used for the prevention and / or treatment of Alzheimer's disease, examples of drugs that can be used in combination with the present compound include, for example, symptomatic drugs, for example, drugs known to modify cholinergic transmission, such as M1 and M3 muscarinic receptor agonists or 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, 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 5HT1A receptor ligands, and NMDA receptor antagonists or modulators, 5-HT 2A Antagonist, 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), mGluR3PAMs, mGluR5 Potential disease modifying agents such as PAMs, PDE1 inhibitors, PDE2 inhibitors, PDE4 inhibitors, PDE5 inhibitors, PDE9 inhibitors, PDE10 inhibitors, GlyTl inhibitors, DAAO inhibitors, ASCI inhibitors, AMPA modulators, SIRT1 activators or inhibitors, AT4 antagonists, GalRl antagonists, GalR3 ligands, adenosine Al antagonists, adenosine A2a antagonists, a2A antagonists or agonists, selective and nonselective norepinephrine reuptake inhibitors (SNRIs), or 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 These include 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.Further examples of concomitant medications include 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, GluRl ligands, RAGE (receptor for advanced glycation end products) antagonists, EGFR (upregulatory receptor antagonists), and EGFR-associated vasopressins. epidermal growth factor receptor (EFR) inhibitors, FPRL-1 (formyl peptide-like receptor-1) ligands, GABA antagonists, and MICAL (molecule that interacts with casL) inhibitors, e.g., oxidoreductase inhibitors, CB1 antagonists / inverse agonists, nonsteroidal anti-inflammatory drugs (NSAIDs), anti-inflammatory drugs (e.g., drugs that can be used to treat neuroinflammation by enhancing or reducing neuroinflammation), amyloid precursor protein (APP) ligands, anti-amyloid vaccines and / or antibodies, drugs that promote or enhance amyloid clearance and / or removal, histone deacetylase inhibitors, anti-amyloid drugs, anti-inflammatory ... HDAC inhibitors, EP2 antagonists, 11βHSD1 (hydroxysteroid dehydrogenase) inhibitors, liver X receptor (LXR) agonists or PAMs, lipoprotein receptor-related protein (LRP) mimetics, ligands, potentiators and / or inhibitors, butyrylcholinesterase inhibitors, kynuric acid antagonists and / or kynurenine 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, niacin and / or GPR109 agonists or PAMs used in combination with cholesterol-lowering drugs and / or HMGCoA reductase inhibitors (statins), dimebolins or similar drugs, antihistamines, metal binding / chelating drugs, antibiotics, growth hormone secretagogues, cholesterol-lowering drugs, vitamin E, cholesterol absorption inhibitors, cholesterol efflux promoters and / or activators, and insulin-increasing drugs.

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

[0203] The combination of the present compound and other drugs may be administered as a compounded drug containing both ingredients in one drug, or may be administered as separate preparations by the same or different administration route. Separate preparations do not need to be administered simultaneously, and may be administered sequentially with a time difference. When administering sequentially, the order or method of administration is not particularly limited, and can be appropriately adjusted to obtain the expected efficacy.

[0204] The dose of the additional drug used in combination with the present compound can be appropriately increased or decreased depending on its clinical dose or similar drug. The ratio of the present compound to the additional drug can be appropriately adjusted taking into consideration the subject's age, body weight, administration method, administration time, target disease, pathology, etc. Usually, the other drug can be combined with 1 part by weight of the present compound in the range of 0.01 to 100 parts by weight. A plurality of other drugs may be used. In addition to the above drugs, the other drugs may have the same mechanism of action as the above drugs. The other drugs include not only known drugs but also those to be discovered in the future.

[0205] The dosage of the compound varies depending on age, body weight, pathology, therapeutic effect, administration method, administration period, etc. The compound may be orally administered to an adult in the range of 0.1 mg to 300 mg once to several times a day, or may be parenterally administered to an adult in the range of 0.1 mg to 150 mg once to several times a day, or may be continuously administered intravenously for 1 to 24 hours a day.

[0206] As described above, the dosage varies depending on various conditions, and therefore, in some cases, a dosage less than the above-mentioned amount is sufficient, whereas in other cases, an amount exceeding the above-mentioned amount is required.

[0207] When the compound is used as a single agent or a combination drug with other drugs for the prevention and / or treatment of the above diseases, the compound, which is an active ingredient, is usually formulated using pharma- ceutical acceptable carriers such as various additives or solvents, and the resulting formulation is administered systemically or locally, orally or parenterally. Here, the pharma- ceutical acceptable carrier means a substance other than the active ingredient that is generally used in pharmaceutical preparations. The pharma- ceutical acceptable carrier preferably does not show pharmacological activity at the dosage of the preparation, is harmless, and does not interfere with the therapeutic effect of the active ingredient. The pharma- ceutical acceptable carrier may be used to enhance the usefulness of the active ingredient and the preparation, to facilitate formulation, to stabilize the quality, and to improve the usability. Specifically, the substances listed in the "Dictionary of Pharmaceutical Additives" 2000, Yakuji Nipposha (IPEC JAPAN edition) can be appropriately selected as needed.

[0208] Examples of dosage forms include oral administration agents (e.g., tablets, capsules, granules, powders, oral liquid agents, syrups, oral jellies, etc.), oral agents (e.g., oral tablets, oral sprays, oral semisolid agents, oral gargles, etc.), injectable preparations (e.g., injections, etc.), dialysis preparations (e.g., dialysis agents, etc.), inhalation agents (e.g., inhalants, etc.), ophthalmic agents (e.g., eye drops, eye ointments, etc.), otorhinological agents (e.g., ear drops, etc.), nasal agents (e.g., nasal drops, etc.), rectal agents (e.g., suppositories, rectal semisolid agents, enemas, etc.), vaginal agents (e.g., vaginal tablets, vaginal suppositories, etc.), and dermatological agents (e.g., solid topical agents, liquid topical agents, sprays, ointments, creams, gels, patches, etc.). [Oral administration]

[0209] Oral preparations include, for example, tablets, capsules, granules, powders, oral liquids, syrups, and oral jellies. Oral preparations are classified into fast-disintegrating preparations in which the release of the active ingredient from the preparation is not particularly controlled, and controlled-release preparations, such as enteric preparations and sustained-release preparations, in which the release is controlled according to the purpose by adjusting the formulation design and manufacturing method. An enteric preparation is a preparation 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. An enteric preparation is generally produced by coating an acid-insoluble enteric base. A sustained-release preparation is a preparation in which the release rate, release time, and release site of the active ingredient are adjusted for the purpose of reducing the frequency of administration or reducing side effects. A sustained-release preparation is usually produced using an appropriate sustained-release agent. Among the oral preparations, capsules, granules, and tablets may be coated with an appropriate coating film made of sugars, sugar alcohols, polymeric compounds, etc., for the purpose of facilitating administration and preventing decomposition of the active ingredient. (1) Tablets

[0210] Tablets are solid preparations for oral administration in a certain shape. Examples of tablets include plain tablets, film-coated tablets, sugar-coated tablets, multi-layer tablets, dry-coated tablets, etc., which are generally called tablets, as well as orally disintegrating tablets, chewable tablets, effervescent tablets, dispersible tablets, soluble tablets, etc. Plain tablets can usually be manufactured by the following operation methods (a), (b), or (c). (a) Additives such as excipients, binders, and disintegrants to the active ingredient, granulate using water or a solution containing a binder in an appropriate manner, mix with lubricants, etc., and compress into a homogeneous mixture. (b) The active ingredient is mixed with additives such as a diluent, binder, disintegrant, etc., and then homogenized, and then directly compressed and molded, or the active ingredient, lubricant, etc. are added to the granules to which the additives have been added, and then mixed with them to homogenize, and then compressed and molded. (c) The active ingredient is mixed with additives such as excipients and binders to form a homogeneous mixture, then wet-kneaded with a solvent, molded into a certain shape, and dried by an appropriate method. Film-coated tablets can usually be produced by applying a suitable thin film of a polymer compound or the like to a plain tablet. Sugar-coated tablets can usually be produced by applying a coating film containing sugars or sugar alcohols to a plain tablet. Multi-layer tablets can be produced by stacking powder granules of different compositions in layers and compressing them by an appropriate method. Dry-coated tablets can be produced by coating an inner core tablet with an outer layer of different composition. Tablets can be made into enteric tablets or sustained-release tablets by an appropriate known method. Orally disintegrating tablets, chewable tablets, effervescent tablets, dispersible tablets, and dissolving tablets are tablets that are given unique functions by appropriately selecting additives, and can be produced according to the above-mentioned manufacturing method of tablets. Orally disintegrating tablets refer to tablets that dissolve or disintegrate quickly in the oral cavity and are taken. Chewable tablets refer to tablets that are taken by chewing. An effervescent tablet is a tablet that dissolves or disperses in water while effervescently releasing heat. A dispersible tablet is a tablet that is dispersed in water and taken. A dissolving tablet is a tablet that is dissolved in water and taken. Effervescent tablets can be produced using additives such as suitable acidic substances, carbonates, and bicarbonates. (2) Capsules

[0211] A capsule is a preparation in which an active ingredient is filled in a capsule shell or in which the active ingredient is coated with a capsule base. Examples of capsules include hard capsules and soft capsules. Hard capsules can be produced by adding an additive such as an excipient to the active ingredient, mixing them to make them homogeneous, or by obtaining granules or molded products by an appropriate method, and then adding them directly or after appropriate molding to the capsule shell. Soft capsules can be produced by encapsulating a mixture of the active ingredient and additives in a suitable capsule base such as gelatin whose plasticity has been increased by adding glycerin, D-sorbitol, etc., and molding the mixture into a certain shape. The capsule can be made into an enteric capsule or a sustained-release capsule by an appropriate known method. A coloring agent, a preservative, 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 manufactured by the following methods (a), (b), or (c). (a) The active ingredient is mixed with excipients such as diluents, binders, disintegrants, etc. to obtain a homogeneous mixture, and then granulated by a suitable method; (b) The granulated active ingredient is mixed with additives such as excipients to obtain a homogeneous mixture; (c) The granulated active ingredient is mixed with additives such as excipients to obtain a homogeneous mixture, and then granulated by an appropriate method. The granules may be coated with a film as necessary, or may be made into enteric granules or sustained-release granules by an appropriate known method. Effervescent granules can be produced using appropriate additives such as acidic substances, carbonates, and bicarbonates. Effervescent granules are granules that dissolve or disperse in water while effervescently generating foam. They can also be made into fine particles by adjusting the particle size. (4) Powders

[0213] A powder is a powdered preparation, and can usually be produced by mixing an active ingredient with additives such as excipients to form a homogeneous mixture. (5) Oral liquid

[0214] Oral liquids are liquids or viscous gels with fluidity. Examples of oral liquids include elixirs, suspensions, emulsions, and lemonades, in addition to those generally called oral liquids. Oral liquids are generally produced by adding additives and purified water to the active ingredient, mixing, dissolving, emulsifying, or suspending the active ingredient homogeneously, and filtering the preparation as necessary. Elixirs are clear oral liquids containing ethanol, sweet in taste, and aromatic. Elixirs can usually be produced by dissolving a solid active ingredient or its exudate in ethanol, purified water, flavorings, white sugar, sugars, or sweeteners, and obtaining a clear liquid by filtering or other methods. Suspensions refer to oral liquids in which the active ingredient is finely and homogeneously suspended. Suspensions can usually be produced 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. Emulsions refer to oral liquids in which the active ingredient is finely and homogeneously emulsified. Emulsions can usually be produced by adding an emulsifier and purified water to a liquid active ingredient, and emulsifying and homogenizing the whole by a suitable method. Limonades are transparent oral liquids that have a sweet and sour taste. (6) Syrups

[0215] The preparation includes, for example, syrups. Syrups are viscous liquid or solid preparations containing sugars or sweeteners. Examples include syrup preparations. Syrups are usually prepared by dissolving, mixing, suspending or emulsifying the active ingredient in a solution of white sugar, other sugars or sweeteners, or a syrup alone, boiling it as necessary, and then filtering it while heating. Syrup preparations are syrups made by adding water to a granular or powdered dosage form, and are sometimes called dry syrups. Syrup preparations usually use sugars or sweeteners as additives, and can be manufactured in accordance with the above-mentioned manufacturing method for granules or powders. (7) Oral jelly preparations

[0216] Oral jelly preparations are non-fluid, molded gel preparations. Oral jelly preparations can usually be produced by mixing an active ingredient with an additive and a polymer gel base to form a gel, and then molding the gel into a certain shape using an appropriate method. [Oral preparations] (1) Oral tablets

[0217] Oral tablets are preparations having a certain shape that are administered into the oral cavity. Examples of oral tablets include lozenges, sublingual tablets, buccal tablets, adhesive tablets, gum tablets, etc. Oral tablets can usually be manufactured in accordance with the manufacturing method of tablets. A lozenge is an oral tablet that gradually dissolves or disintegrates in the oral cavity and is applied locally to the oral cavity or pharynx. A sublingual tablet is an oral tablet that quickly dissolves under the tongue and absorbs the active ingredient from the oral mucosa. A buccal tablet is an oral tablet that gradually dissolves between the molar and the cheek to absorb the active ingredient from the oral mucosa. An adhesive tablet is an oral tablet that adheres to the oral mucosa. A gum tablet is an oral tablet that is chewed to release the active ingredient. (2) Oral spray

[0218] Oral sprays are preparations that spray active ingredients in the form of mist, powder, foam, or paste. Oral sprays can usually be produced by dissolving or suspending active ingredients and additives in a solvent or the like, filtering the solution as necessary, and filling the solution into a container together with liquefied gas or compressed gas, or by preparing a solution or suspension containing active ingredients and additives, and filling the solution into a container equipped with a spray pump. (3) Semi-solid preparations for oral application

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

[0220] Oral mouthwash is a liquid preparation that is used locally in the oral cavity or pharynx, and may include a solid preparation that dissolves when used. Oral mouthwash can usually be produced by homogeneously dissolving an active ingredient in a solvent and an additive, and filtering as necessary. Solid preparations that dissolve when used can usually be produced according to the above-mentioned manufacturing method for tablets and granules. [Injectable preparations] (1) Injectables

[0221] Injections are solutions, suspensions, or emulsions, or solid sterile preparations that are dissolved or suspended when used, and are administered subcutaneously, intramuscularly, or directly into bodily tissues and organs such as blood vessels. Examples include those generally called injections, as well as freeze-dried injections, powder injections, pre-filled syringes, cartridges, infusions, implantable injections, sustained-release injections, etc. Injections can usually be manufactured by the following method (a) or (b). (a) dissolving, suspending or emulsifying an active ingredient or a mixture of an active ingredient and an excipient in water for injection or other aqueous or non-aqueous solvent, filling the container for injection with the drug, and then sterilizing the same; (b) The active ingredient or a mixture of the active ingredient and additives is dissolved, suspended or emulsified in water for injection or other aqueous or non-aqueous solvent, and then aseptically filtered or aseptically homogenized, and filled into an injection container and sealed. To produce a freeze-dried injection, the active ingredient or the mixture of the active ingredient and additives is usually dissolved in water for injection together with a solvent or other additives, and then aseptically filtered, and then the injection solution is filled into an injection container and freeze-dried, or freeze-dried in a dedicated freeze-drying container and filled into an injection container. Powder injections can usually be produced by using a sterile filtration method and crystallization to obtain a powder, and filling a container for injections with the powder directly or a mixture of the powder and a sterilized additive. A prefilled syringe can usually be produced by filling a syringe with a solution, suspension or emulsion of the active ingredient or the active ingredient and additives. A cartridge refers to a cartridge-type injection containing a drug solution filled into a dedicated syringe. A cartridge containing a drug solution can usually be produced by filling a cartridge with a solution, suspension or emulsion of the active ingredient or the active ingredient and additives. Infusion refers to an injection, usually 100mL or more, administered intravenously. Implantable injection refers to a solid or gel-like injection, which is used by implantation devices or subcutaneous or intramuscular surgery to release the active ingredient over a long period of time. Implantable injections can usually be produced by forming pellets, microspheres, or gels using biodegradable polymeric compounds. Sustained release injections are injections administered intramuscularly to release the active ingredient over a long period of time, and can generally be produced by dissolving or suspending the active ingredient in vegetable oil, or by obtaining a microsphere suspension using biodegradable polymeric compounds. [Dialysis preparations] (1) Dialysis agents

[0222] A dialysis agent is a liquid or solid preparation that dissolves when used and is used for peritoneal dialysis or hemodialysis. Examples include peritoneal dialysis agents and hemodialysis agents. A peritoneal dialysis agent refers to a sterile dialysis agent used for peritoneal dialysis, and can usually be produced by filling a container with a solution in which an active ingredient and an additive are dissolved in a certain amount of a solvent, or a mixture of an active ingredient and an additive, sealing the container, and sterilizing as necessary. A solid preparation that dissolves when used can usually be produced in accordance with the above-mentioned manufacturing method for tablets and granules. A hemodialysis agent refers to a dialysis agent used for hemodialysis, and can usually be produced by filling a container with a solution in which an active ingredient and an additive are dissolved in a certain amount of a solvent, or a mixture of an active ingredient and an additive. A solid preparation that dissolves when used can usually be produced in accordance with the above-mentioned manufacturing method for tablets and granules. [Inhalation preparations] (1) Inhalants

[0223] Inhalants are preparations administered to the bronchi or lungs by inhaling an aerosol of an active ingredient. Examples include powders for inhalation, liquids for inhalation, and aerosols for inhalation. Powders for inhalation are preparations that allow solid particles to be inhaled in a predetermined amount in the form of an aerosol, and can usually be produced by preparing fine particles of the active ingredient and mixing them with additives such as lactose as necessary to make them homogeneous. Liquids for inhalation refer to liquids for inhalation administered by a nebulizer or the like, and can usually be produced by dissolving or suspending the active ingredient homogeneously in a solvent, a suitable tonicity agent, a pH regulator, etc., and filtering as necessary. Aerosols for inhalation refer to metered-dose sprays for inhalation that spray a certain amount of the active ingredient filled in a container together with a propellant. [Ophthalmic preparations] (1) Eye drops

[0224] Eye drops are sterile liquid preparations administered to ocular tissues such as the conjunctival sac, or sterile solid preparations that are dissolved or suspended at the time of use. Eye drops can usually be produced by dissolving or suspending an active ingredient and an additive in a certain amount of a solvent or the like, or by filling a container with a mixture of the active ingredient and the additive. (2) Eye ointment

[0225] Eye ointments are semi-solid sterile preparations to be administered to eye tissues such as the conjunctival sac, and can usually be produced by filling a container with a homogeneous mixture of a base such as petrolatum and a solution or fine powder of an active ingredient. [Otalologic preparations] (1) Ear drops

[0226] Ear drops are liquid, semi-solid or solid preparations that are administered to the outer or middle ear and are dissolved or suspended when used. Ear drops are usually prepared by dissolving or suspending the active ingredient and additives in a certain amount of a solvent or the like, or by filling a container with a mixture of the active ingredient and additives. [Nasal spray preparation] (1) Nasal solution

[0227] Nasal drops are preparations administered to the nasal cavity or nasal mucosa, and examples thereof include nasal powders and nasal solutions. Nasal powders are fine powdered nasal drops administered to the nasal cavity, and can usually be produced by mixing the active ingredient as a suitable fine powder and, if necessary, the active ingredient and additives to form a homogeneous mixture. Nasal solutions are liquid or solid nasal drops that dissolve or suspend when used, and are administered to the nasal cavity. Nasal solutions can usually be produced by dissolving or suspending the active ingredient in a solvent and additives, and filtering if necessary. Examples of additives for nasal solutions that can be used include tonicity agents, pH regulators, and the like. [Rectal preparations] (1) Suppositories

[0228] Suppositories are semi-solid preparations of a certain shape that are administered rectally and release the active ingredient by melting at body temperature or gradually dissolving or dispersing in water. Suppositories can usually be produced by dissolving or dispersing a homogeneous mixture of the active ingredient and additives such as dispersants and emulsifiers in a base that has been liquefied by heating or the like, filling a specified amount into a container, and solidifying / molding it. Commonly used suppository bases include oily bases and hydrophilic bases. (2) Semisolid preparations for rectal administration

[0229] Semi-solid preparations for rectal administration are preparations administered around or into the anus, and examples thereof include rectal creams, rectal gels, and rectal ointments. Semi-solid preparations for rectal administration can usually be produced by emulsifying an active ingredient together with an additive in purified water and oily ingredients such as petrolatum, or by homogeneously mixing an active ingredient and an additive with a base made of a polymer gel or oil. Rectal creams are usually produced by preparing an oil phase from petrolatum, higher alcohols, or a mixture of these with additives such as emulsifiers, preparing an aqueous phase from purified water or a mixture of these with additives such as emulsifiers, adding an active ingredient to the oil phase or aqueous phase, heating, and mixing the oil phase and aqueous phase to make a homogeneous emulsion. Rectal gels are gel preparations, and examples thereof include aqueous gels and oily gels. Aqueous gels can be produced by dissolving or suspending an active ingredient in additives such as polymer compounds and purified water, and crosslinking by heating and cooling, or by adding a gel-forming agent. Oily gels can be produced by mixing an active ingredient with a liquid oil base such as glycols or higher alcohols and additives. Rectal ointments are semi-solid preparations in which an active ingredient is dissolved or suspended in a base, and examples include oleaginous ointments and water-soluble ointments. Oleaginous ointments can be produced by heating, dissolving or suspending an active ingredient in an oleaginous base such as oils, waxes, and hydrocarbons including paraffin, and mixing and kneading the mixture to produce a homogeneous mixture. Water-soluble ointments can generally be produced by melting a water-soluble base such as macrogol by heating, and mixing and kneading the active ingredient to produce a homogeneous mixture. (3) Enema

[0230] An enema is a liquid or viscous gel that is administered through the anus. Enemas are usually produced by dissolving or suspending an active ingredient in a certain amount of solvent, such as purified water or an appropriate aqueous solvent, and filling the container. Examples of additives that can be used in enemas include dispersants, stabilizers, and pH adjusters. [Vaginal preparations] (1) Vaginal tablets

[0231] Vaginal tablets are solid preparations of a certain shape that are administered into the vagina and release the active ingredient by gradually dissolving or dispersing in water. Vaginal tablets can usually be manufactured in a similar manner to the tablet manufacturing method described above.

[0232] Vaginal suppositories are semi-solid preparations with a certain shape that are administered into the vagina and release the active ingredient by melting at body temperature or slowly dissolving or dispersing in water. Vaginal suppositories can usually be manufactured in a similar manner to the above-mentioned rectal suppositories. [Skin preparations] (1) Solid preparations for external use A solid preparation for external use is a solid preparation that is administered or applied to the skin, including the scalp or nails, and examples thereof include powders for external use. Powders for external use refer to solid powder preparations for external use, and can usually be produced by mixing an active ingredient with an additive such as a base to form a homogeneous mixture, and then powdering the mixture. (2) Liquid preparations for external use

[0233] The topical liquid is a liquid preparation administered to the skin, including the scalp or nails, and examples thereof include liniments, lotions, etc. The topical liquid can usually be produced by dissolving, emulsifying, or suspending the active ingredient in a solvent, additive, etc., and filtering as necessary. The topical liquid refers to a liquid or muddy topical liquid that is rubbed into the skin. The lotion refers to a topical liquid in which the active ingredient is dissolved, emulsified, or finely dispersed in an aqueous liquid. The lotion can usually be produced by preparing a solution, suspension, or emulsion of the active ingredient, additive, and purified water to form a homogeneous preparation. (3) Sprays

[0234] A spray is a preparation that sprays an active ingredient onto the skin in the form of a mist, powder, foam, or paste, and examples thereof include an aerosol for external use, a pump spray, and the like. A spray can usually be produced by preparing a solution or suspension of an active ingredient, filtering it as necessary, and filling it into a container. An aerosol for external use refers to a spray that sprays an active ingredient together with a liquefied gas or compressed gas filled in a container. An aerosol for external use can usually be produced by preparing a solution or suspension of an active ingredient and filling it together with a liquid propellant into a pressure-resistant container equipped with a continuous injection valve. Additives such as dispersants and stabilizers may be added to the aerosol for external use. A pump spray refers to a spray that sprays an active ingredient in a container by a pump. A pump spray can usually be produced by dissolving or suspending an active ingredient and an additive, and filling it into a container equipped with a pump. (4) Ointments

[0235] Ointments are semi-solid preparations in which an active ingredient is dissolved or dispersed in a base and applied to the skin. Examples include oleaginous ointments and water-soluble ointments. Oleaginous ointments can usually be produced by melting an oleaginous base such as fats and oils, waxes, and hydrocarbons including paraffin by heating, dissolving or suspending the active ingredient, and mixing and kneading the mixture to form a homogeneous mixture. Water-soluble ointments can usually be produced by melting a water-soluble base such as macrogol by heating, and mixing and kneading the active ingredient to form a homogeneous mixture. (5) Creams

[0236] Creams are semi-solid preparations in the form of oil-in-water or water-in-oil emulsions, which are applied to the skin, and fat-soluble preparations of water-in-oil emulsions are also called oily creams. Creams can usually be produced by preparing an oil phase from petrolatum, higher alcohols or a mixture of these with additives such as emulsifiers, preparing an aqueous phase from purified water or a mixture of these with additives such as emulsifiers, adding an active ingredient to the oil or aqueous phase, heating both phases, and mixing the oil and aqueous phases until they are homogeneous to form an emulsion. (6) Gels

[0237] Gels are gels to be applied to the skin, and include, for example, aqueous gels, oily gels, etc. An aqueous gel can usually be produced by dissolving or suspending an active ingredient in an additive such as a polymer compound and purified water, and crosslinking the mixture 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 higher alcohol, and an additive. (7) Patches

[0238] A patch is a preparation to be applied to the skin, and examples thereof include tapes and poultices. A patch can usually be produced by homogeneously mixing an active ingredient with a base which is a polymeric compound or a mixture thereof, spreading the mixture on a support or liner (release material) and molding the mixture. A patch can be made into a transdermal absorption preparation by using a release-controlled film. An additive such as an adhesive or an absorption enhancer may be used in the patch. A tape refers to a patch containing a base containing a small amount of water, and examples thereof include bandages. A tape can usually be produced by using a base made of a natural or synthetic polymeric compound insoluble in water, such as resin, plastic, or rubber, and spreading or sealing the active ingredient or a homogeneous mixture of the active ingredient and an additive on a cloth or a plastic film and molding the same. A tape can also be produced by incorporating a mixture of the active ingredient and a base or other additives into a release material consisting of a release-controlled film, a support, and a liner (release material) and molding the mixture. A cataplasm is a patch containing a water-containing base, and can usually be produced by mixing the active ingredient with a liquid substance such as purified water or glycerin to make it homogeneous, or by kneading the active ingredient and purified water into a natural or synthetic polymer compound such as a water-soluble polymer or water-absorbent polymer to make it homogeneous, and then spreading it on a cloth or the like to form it.

[0239] Unless otherwise defined, all technical and scientific terms and abbreviations used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.

[0240] The contents of all patent and non-patent literature or references expressly cited in this specification are hereby incorporated by reference. EXAMPLES

[0241] The present invention will be described in detail below with reference to 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, for example, using 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 written after the example number, and the compound may also be referred to as the "title compound". Analysis method

[0242] 1 H NMR spectra were recorded on a Bruker DRX-400 instrument and the residual deuterated solvent ( 1 H NMR shows CHCl at 7.26, 2.50, and 3.31 ppm, respectively. 3 , DMSO, methanol). Chemical shifts (δ) are given in parts per million (ppm) and are referenced to the corresponding NMR solvent peak and are designated on the numbered diagrams as s (singlet), d (doublet), t (triplet), q (quartet), combinations thereof (i.e., td stands for triplet of doublets) or m (multiplet) and br s (broad singlet).

[0243] The liquid chromatography MS analysis method (LCMS) used was as follows: General LCMS procedures Method 1 Simadzu LC20-MS2010, Agilent Pursit5 C at 50°C 18 Equipped with a 20 x 2.0 mm. Mobile phase (A): 1.5 mL TFA-4 L water; Mobile phase (B): 0.75 mL 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, UV 220, 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): 0.8mL of NH 3 - Water - 4 L 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, UV 220, 254 nm. MS ionization method: electrospray (positive ion). Column: XBridge C 18 3.5um, 2.1x50mm;

[0244] The high performance liquid chromatography (HPLC) used was as follows: General HPLC procedure Method 1 SHIMADZU 20A, 40℃ Ultimate C18 Mobile phase (A): 2.75 mL TFA-4 L water; Mobile phase (B): 2.5 mL 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, UV 220, 254 nm. MS ionization method: electrospray (positive ion). Method 2 SHIMADZU 20A, 40℃ Ultimate C 18 Mobile phase (A): 2.75 mL TFA-4 L water; Mobile phase (B): 2.5 mL 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, UV 220, 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 A: water in 4 L water; B: acetonitrile. Gradient: SHIMADZU LC20-MS2020, equipped with Xbridge Shield RP-18 2.1x50mm, 5um at 50°C. 0.8mL of NH3 - Water - 4 L 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, UV 220, 254 nm. MS ionization method: electrospray (positive ion).

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

[0246] Abbreviation 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 = Des-Martin Periodinane; DMSO = dimethyl sulfoxide; dppf = 1,1'-ferrocenebis(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]hex-3-yl](1-isopropyl-1H-imidazol-4-yl)methanone [ka] tert-Butyl (1R,5S,6r)-6-[(E)-(hydroxyimino)methyl]-3-azabicyclo[3.1.0]hexane-3-carboxylate To a solution of tert-butyl (1R,5S,6r)-6-formyl-3-azabicyclo[3.1.0]hexane-3-carboxylate (Pharmablock Inc., catalog No. PBG0012) (2 g, 9.47 mmol) in ethanol (20 mL), acetic acid (0.54 mL, 9.47 mmol, 1.0 eq) and potassium acetate (0.93 g, 9.47 mmol, 1.0 eq) were added. Ammonium chloride (0.47 mL, 11.36 mmol) was then added to the mixture. The mixture was stirred at 25°C for 2 hours to obtain a white suspension. The reaction mixture was poured into water (40 mL) and extracted with ethyl acetate (40 mL x 3). The combined organic layer was washed with brine (60 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to obtain the title compound as a white solid. TLC: Rf=0.4, PE:ethyl acetate=3:1; LC-MS Method1 0.694 min, MS (m / z) 170.8 (M -tBu, + H + ); 1 H NMR (400MHz, CHLOROFORM-d)δ=7.16(d, J=7.6 Hz, 0.5 H), 6.13(d, J=8.8 Hz, 0.5 H), 3.75-3.55(m, 2 H),3.50-3.35(m, 2 H), 2.23-2.15(m, 0.5 H), 2.10(s, 1.5H), 1.80(brs, 1H), 1.44(s, 9H).

[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), N-chlorosuccinimide (1363 mg, 10.21 mmol) was added, 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 saline (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 H 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 2-Methylprop-1-ene (0.72 mL, 1.15 mmol) (15% solution in isopropyl ether) was added 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), 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 H 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 added to a mixture of hydrochloric acid / dioxane (2.0 mL, 8.0 mmol, 4.0 M) and stirred for 0.5 hours at 20° C. The mixture was concentrated to give the title compound (100 mg, 0.46 mmol, 129% yield, crude) as a yellow oil. LC-MS Method1 0.232 min, MS (m / z): 181 (M -HCl+ H + ). 1 H 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 To a solution of (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), HATU (194 mg, 0.51 mmol) was added and stirred at 20°C for 16 hours. 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 obtain the title compound (4 mg, 0.012 mmol, yield 2.7%) as a white solid. 1 H 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]hex-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 To a mixture of 1-methyl-1H-imidazole-4-carboxylic acid (52.47 mg, 0.42 mmol), EDCI (79.76 mg, 0.42 mmol) and pyridine (1.0 mL), (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) was added. The suspension was stirred at 20°C for 8 hours. The reaction mixture was concentrated under reduced pressure. The residue was analyzed 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-isocyanoacrylate and ethylamine (1608.2 mg, 35.67 mmol, 1.60 mL, 20 eq) was stirred at 40° C. for 16 hours. 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× 4). The resulting aqueous layer was 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 1-ethyl-1H-imidazole-4-carboxylic acid in pyridine (1 mL), 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. Prep-HPLC (NH 3 ) and lyophilized to give the title compound (23.69 mg, 23.58% yield) 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=3.76Hz, 1H) 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]hex-3-yl]methanone Methyl 1-cyclopropyl-1H-imidazole-4-carboxylate To a suspension of 2,2'-bipyridine (618.79 mg, 3.96 mmol), copper acetate (720.01 mg, 3.96 mmol), and sodium carbonate (840.54 mg, 7.93 mmol) in DCE (30 mL) was added methyl 1H-imidazole-4-carboxylate (500 mg, 3.96 mmol), cyclopropylboronic acid (681.15 mg, 7.93 mmol). The mixture was stirred at 70°C under oxygen atmosphere for 16 h. TLC (PE:ethyl acetate = 1:4) showed the reaction was complete. The reaction mixture was cooled to 23°C. The solids were 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 give the title compound (140 mg, 0.8425 mmol, 21.249% yield) as a brown oil. 1 H 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 give a white suspension. TLC (PE:ethyl acetate=1:4) showed the reaction was complete (Rf=0). The reaction solution was directly concentrated. The residue was acidified with aqueous hydrochloric acid (1 M), and then the resulting organic layer was lyophilized to give the title compound (120 mg, 0.7887 mmol, 93.618% yield) 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) was 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 h. The residue was purified by Prep-HPLC (HCl). The combined organic layers were concentrated and then lyophilized to give the title compound (4.8 mg, 0.0137 mmol, 1.7347% yield) as a pale yellow gum. LC-MS Method 1: 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]hex-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 for 16 h at 50° C. After concentrating the mixture under reduced pressure, the residue was purified by flash column (0-100% ethyl acetate, 0.5% aqueous ammonia in PE) 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) was added lithium hydroxide monohydrate (0.09 mL, 1.54 mmol). 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 x 2) and acidified to pH = 2 with aqueous hydrochloric acid (1N). The remaining 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)δppm 8.77(s, 1H), 8.03(s, 1H), 4.85-4.75(m, 1H), 2.50-2.40(m, 2H), 2.40-2.30(m, 2H), 1.90-1.75(m, 2H).

[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), HATU (247.8 mg, 0.6500 mmol), DIPEA (0.45 mL, 2.7 mmol), (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) were added. The mixture was stirred at 20°C for 4 hours. The reaction mixture was diluted with water (5 mL) and extracted with ethyl acetate (5 mL x 2). The organic layers were combined, dried over sodium sulfate, and concentrated under reduced pressure to give a crude oil. The crude oil was analyzed by Prep-TLC (ethyl acetate / methanol = 10 / 1) and then Prep-HPLC (NH 3 ) and lyophilized to give the title compound (12.15 mg, 0.0370 mmol, 6.8494% yield) as a pale yellow solid. LC-MS Method 1: 328.9 1 H NMR (400MHz, 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, 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]pent-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 Ethyl 1-(bicyclo[1.1.1]pent-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), bicyclo[1.1.1]pentan-1-amine (284.42 mg, 2.38 mmol) and triethylamine (0.58 mL, 4.46 mmol) were added. The resulting mixture was heated at 76° C. for 16 hours. The reaction solution was diluted with water (5 mL) and extracted with ethyl acetate (5 mL×3). The organic layers were combined, dried over sodium sulfate, and concentrated under reduced pressure to give the title compound (100 mg, crude product) as a yellow oil.

[0263] 1-(Bicyclo[1.1.1]pent-1-yl)-1H-imidazole-4-carboxylic acid To a solution of ethyl 1-(bicyclo[1.1.1]pent-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 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 give the title compound (50 mg, 0.2806 mmol, crude) as a pale yellow solid.

[0264] [1-(bicyclo[1.1.1]pent-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 HATU (137.86 mg, 0.3600 mmol), DIPEA (0.18 mL, 1.11 mmol), (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) were added to a solution of 1-(bicyclo[1.1.1]pent-1-yl)-1H-imidazole-4-carboxylic acid (59.54 mg, 0.2800 mmol) in DMF (1.1.1 0.50 mL). The resulting mixture was stirred at 20° C. for 4 hours. 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 subjected to prep-HPLC (NH 3 ) to give the title compound (2.4 mg, 0.0071 mmol, yield 2.5416%) as a yellow solid. 1 H NMR (400MHz, 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]hex-3-yl]methanone Ethyl 1-cyclopentyl-1H-imidazole-4-carboxylate A mixture of ethyl (2Z)-3-(dimethylamino)-2-isocyanoacrylate (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) 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) was added lithium hydroxide monohydrate (0.08 mL, 1.44 mmol). The mixture was stirred at 25° C. for 3.5 hours. 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 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) were added to a solution of 1-cyclopentyl-1H-imidazole-4-carboxylic acid (60.38 mg, 0.2800 mmol) in DMF (0.50 mL). The mixture was stirred at 20°C for 4 hours. The reaction mixture was diluted with water (5 mL) and extracted with ethyl acetate (5 mL x 2). The organic layer was separated, washed with brine (8 mL), dried over sodium sulfate, and concentrated under reduced pressure to give a crude oil. The crude oil was analyzed by prep-TLC (ethyl acetate / methanol = 10 / 1) and then prep-HPLC (NH 3 ) to obtain the title compound (11 mg, 0.0321 mmol, yield 4.6614%) as a white solid. 1 H NMR (400MHz, 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]hex-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) 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 mixture was completely consumed. 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 (190 mg, crude) 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) was 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 hours. The reaction mixture 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 in vacuo to give 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, 9.6077% yield) 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 To a solution of 1,1,1-trifluoro-2-propanamine (403.4 mg, 3.57 mmol) in 2-MeTHF (3 mL, 1.19 mmol), n-butyllithium (1.43 mL, 3.57 mmol) was added at -78°C. After stirring for 15 minutes at -78°C, ethyl (2Z)-3-(dimethylamino)-2-isocyanoacrylate (200 mg, 1.19 mmol) was added. The mixture was heated at 25°C for 0.5 hours to obtain a black solution. The reaction mixture was poured into ethanol (5 mL) and concentrated. The crude product was purified by flash column (PE→100% ethyl acetate in PE). The residue obtained was purified by prep-TLC (ethyl acetate) to obtain the title compound (50 mg, 0.2117 mmol, 17.802% yield) as a brown oil.

[0272] 1-(1,1,1-trifluoropropan-2-yl)-1H-imidazole-4-carboxylic acid Lithium hydroxide monohydrate (26.65 mg, 0.6400 mmol) was added 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). Stir at 20° C. for 3 hours to give a black solution. LCMS showed that starting material (50 mg, 0.2100 mmol) remained. Stir the mixture at 40° C. for 12 hours to give a black solution. The reaction solution was directly concentrated. The resulting aqueous layer was acidified to pH=5-6 with 1N HCl aqueous solution. Lyophilization afforded the title compound (30 mg, 0.1441 mmol, 68.086% yield) 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 To 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), HATU (66.12 mg, 0.1700 mmol) and DIPEA (0.12 mL, 0.7200 mmol) were added. The mixture was stirred 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 (36.48 mg, 0.1400 mmol) was added. The mixture was stirred at 25° C. for 3 h to give a brown solution. The reaction solution was directly concentrated. The residue was analyzed 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 Method 1: 371.1 [M+H + ] 1 H 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, md, J=3.76 Hz) 2.01 (1 H, md, 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 2To a solution of (8403.83 mg, 69.34 mmol) in THF (36.369 mL) was added 2-methylpropanal (6.3 mL, 69.34 mmol) and titanium(IV) ethoxide (21.57 mL, 104.01 mmol) at 20° C. The resulting mixture was stirred at 60° C. for 0.5 h to give a yellow solution. Water (3 mL) was added dropwise, and the mixture was stirred at 20° C. for 5 min, filtered through Celite, and concentrated under reduced pressure to give the title compound (8330 mg, 47.521 mmol, yield 68.535%) as a white solid. Used as is 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 Methylmagnesium bromide (5.7 mL, 17.11 mmol) was added dropwise 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. The reaction 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 extracted with ethyl acetate (30 mLx 2). The organic layer was dried over sodium sulfate and concentrated in vacuo to give a yellow oil. 1 H 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 A solution of (R)-2-methyl-N-[(2S)-3-methyl-2-butanyl]-2-propanesulfinamide (2200 mg, 11.5 mmol) in hydrochloric acid / methanol (10 mL, 40 mmol) was stirred at 20°C for 4 hours to give a colorless solution. The reaction mixture was distilled under reduced pressure to give a white solid. Trituration with toluene / PE=1 / 6 gave the title compound (1350 mg, 10.921 mmol) as a white solid.

[0277] Ethyl 1-[(2S)-3-methylbutan-2-yl]-1H-imidazole-4-carboxylate In a 5 mL microwave vial, (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) were added. The reaction mixture was irradiated with microwaves at 130°C for 1 hour to obtain a brown solution. Water (30 mL) was added. Extraction was performed with ethyl acetate (30 mLx2). 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 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). Stirring at 20°C for 4 hours gave a yellow solution. Water (10 mL) was added and extracted with ethyl acetate (10 mLx 2). Lyophilization afforded the title compound (110 mg, 0.6037 mmol, 78.98% yield) 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 stirred at 20 °C for 16 h to give a yellow solution. Water (30 mL) was added and extracted with ethyl acetate (30 mLx 2). The combined organic layers were dried over sodium sulfate and concentrated in vacuo to give a yellow oil. The crude product was analyzed 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 Method 1: 345.3 [M+H + ] 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-butanamine (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) showed a new spot (Rf = 0.2). Concentration gave 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, 68.562% yield) 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) was added lithium hydroxide monohydrate (0.11 mL, 1.83 mmol). The reaction was stirred at 25° C. for 16 hours to give a yellow mixture. TLC (PE:ethyl acetate=1:1) showed that most of the starting material was consumed. The reaction 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 aqueous layer was dried under reduced pressure to give 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 To a solution of (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 hours to give a brown mixture. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by Prep-HPLC (NH 3 The resulting fractions were combined, concentrated to remove most of the acetonitrile, lyophilized, and freeze-dried to give the title compound (4.09 mg, 0.0108 mmol, 2.7864% yield) as a yellow solid. LC-MS Method 1: 331.1 [M+H + ] 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 [ka] 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 give a brown mixture. TLC (PE:ethyl acetate=1:1) showed 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 (160 mg, 0.8153 mmol, 45.708% yield) 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 Lithium hydroxide monohydrate (0.07 mL, 1.22 mmol) was added 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). The reaction mixture was stirred at 20° C. for 16 hours 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 (1N). The obtained aqueous layer was dried under reduced pressure to obtain 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 To a mixture of (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 added 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 give a brown mixture. LCMS showed that the starting material was consumed. The reaction mixture was filtered. The filtrate was purified by Prep-HPLC (NH 3 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, 25.797% yield) as a white solid. LC-MS Method2 1.516 min, MS (m / z) 331.2 [M+H + ] 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-dimethylbutanylidene]-2-propanesulfinamide To a mixture 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 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 To a mixture of (R)-2-methyl-N-[(2E)-1,3-dimethylbutanylidene]-2-propanesulfinamide (900 mg, 4.43 mmol) in THF (9 mL) was added L-selectride (13.28 mL, 13.28 mmol) at 0° C. The reaction was stirred at 25° C. for 2 h to give a colorless mixture. TLC (PE:ethyl acetate=2:1) ​​showed one new spot (Rf=0.2). 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, 45.252% yield) 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 / HCl (10 mL, 2.97 mmol) was stirred at 25° C. for 2 hours to give 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, 58.698% yield) as a white solid.

[0289] Ethyl 1-[(2S)-4-methylpentan-2-yl]-1H-imidazole-4-carboxylate To a mixture of (2S)-4-methyl-2-pentanamine hydrochloride (240 mg, 1.74 mmol) in 1-butanol (2.5 mL), ethyl (2Z)-3-(dimethylamino)-2-isocyanoacrylate (293.25 mg, 1.74 mmol) and triethylamine (0.34 mL, 2.62 mmol) were added. The reaction mixture was stirred at 130° C. for 1 h in a microwave oven to give a brown mixture. TLC (PE:ethyl acetate=1:1) showed one new spot (Rf=0.2). 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 (60 mg, 0.2675 mmol, 15.342% yield) 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 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) was added lithium hydroxide monohydrate (0.02 mL, 0.4000 mmol). The reaction was stirred at 40° C. for 16 hours to give a yellow mixture. TLC (PE:ethyl acetate=1:1) showed complete consumption of the starting material. The reaction 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 (1N) and lyophilized to give the title compound (50 mg, 0.2548 mmol, 95.244% yield) 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) was added EDCI (58.61 mg, 0.3100 mmol). The mixture was stirred at 25° C. for 10 minutes, and 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 give a yellow mixture. LCMS showed that the starting material was completely consumed. The reaction was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (NH 3 The resulting 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 Method 1: 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, (S)-1-cyclopropylethanamine 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) were added. The resulting mixture was stirred at 70° C. for 36 hours to give a yellow solution. The reaction mixture was poured into water (30 mL) and extracted with ethyl acetate (30 mL×2). The combined organic layer was washed with saturated brine (30 mL×2), dried over sodium sulfate, filtered and concentrated under reduced pressure to give a yellow oil. The crude product was purified by flash column (PE→100% ethyl acetate in PE) to give the title compound (100 mg, 0.4802 mmol, 32.304% yield) 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 Lithium hydroxide monohydrate (60.44 mg, 1.44 mmol) was added to a solution of ethyl 1-[(1 S)-1-cyclopropylethyl]-1H-imidazole-4-carboxylate (150 mg, 0.7200mmol) in water (0.50 mL), THF (0.50 mL), and methanol (0.50 mL). 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 x 4). The combined organic layer was washed with saturated brine (20 mL x 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), HATU (193.06 mg, 0.5000 mmol) and N-ethyl-N-isopropylpropan-2-amine (0.33 mL, 1.94 mmol) were added at 20 °C 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 mixture was poured into saturated aqueous ammonium chloride solution (50 mL) and extracted with ethyl acetate (50 mL x 4). The combined organic layer was 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 Method 1: 343.1 [M+H + ] 1H NMR (400MHz, 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 (1R)-1-cyclopropylethanamine (253.14 mg, 2.97 mmol) was added to a solution of ethyl (2Z)-3-(dimethylamino)-2-isocyanoacrylate (500 mg, 2.97 mmol) in 1-butanol (1 mL) at 20°C. The reaction mixture was irradiated with microwaves 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 x 4). The combined organic layer was washed with saturated brine (50 mL x 2), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified on a 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 Lithium hydroxide monohydrate (76.56 mg, 1.82 mmol) was added 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) at 20° C. The resulting mixture was stirred at 20-25° C. for 2 hours to obtain a white suspension. The reaction mixture was poured into water and extracted with ethyl acetate (20 mL×4). The combined organic layer was washed with saturated brine (20 mL×2), dried over sodium sulfate, filtered, and concentrated under reduced pressure to obtain the title compound (180 mg, 0.9989 mmol, 109.49% yield) 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 HATU (193.06 mg, 0.5000 mmol) and N-ethyl-N-isopropylpropan-2-amine (0.33 mL, 1.94 mmol) were added to a solution of 1-[(1R)-1-cyclopropylethyl]-1H-imidazole-4-carboxylic acid (70 mg, 0.3900 mmol) in DMF (2 mL) at 20°C. The reaction mixture was stirred 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 mixture was poured into a saturated aqueous ammonium chloride solution (50 mL) and extracted with ethyl acetate (50 mL x 4). The combined organic layer was washed with a saturated aqueous solution (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 (14.08 mg, 0.0411 mmol, yield 10.585%) as a yellow oil. LC-MS Method 1: 343.3 [M+H+ ] 1 H NMR (400MHz, 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 mixture of cyclobutanaldehyde (1.07 mL, 11.89 mmol) in THF (15 mL) was added (R)-2-methylpropane-2-sulfinamide (1.44 g, 11.89 mmol) and titanium(IV) ethoxide (4065.62 mg, 17.83 mmol). The reaction mixture was stirred at 60° C. for 2 hours to give a yellow mixture. TLC (PE:ethyl acetate=10:1) showed complete consumption of the starting material and one new spot (Rf=0.2). The reaction was diluted with ethyl acetate (40 mL). The mixture was added to water (10 mL) and stirred for 1 minute to give a white 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 obtain the title compound (1.77 g, 9.4501 mmol, yield 79.494%) as a colorless oil. 1 H NMR (400MHz, 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 To (R)-N-[(E)-chlorobutylmethylene]-2-methyl-2-propanesulfinamide (0.5 g, 2.67 mmol) in THF (6 mL) was added chloro(methyl)magnesium (2.67 mL, 8.01 mmol) at -40°C. The reaction mixture was stirred at -40°C for 2 hours to give a yellow mixture. TLC (DCM:ethyl acetate = 1:1) showed complete consumption of the starting material and one new spot (Rf = 0.3). The reaction was quenched with ammonium chloride (eq., 25 mL) and extracted with ethyl acetate (15 mL x 3). The combined organic layer was washed with brine (20 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by flash column (DCM → 20% ethyl acetate in DCM) to give the title compound (360 mg, 1.7704 mmol, 66.32% yield) 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 A solution of (R)-N-[(1S)-1-cyclobutylethyl]-2-methyl-2-propanesulfinamide (360 mg, 1.77 mmol) in methanol / HCl (0.44 mL, 1.77 mmol) was stirred at 25 °C for 2 h to give a colorless mixture. TLC (DCM:ethyl acetate=1:1) showed complete consumption of the starting material. The reaction mixture was concentrated under reduced pressure to give the title compound (330 mg, 2.4329 mmol, 137.42% yield) 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) was 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 give a brown mixture. LCMS showed complete consumption of starting material. TLC (PE:ethyl acetate=2:1) ​​showed one new spot (Rf=0.2). 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, 9.1533% yield) 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 give a brown mixture. TLC (PE:ethyl acetate=1:1) showed complete consumption of the starting material. The reaction was diluted with water (4 mL) and extracted with ethyl acetate (2 mL×2). The aqueous layer was acidified with aqueous hydrochloric acid (1N) and lyophilized to give the title compound (31 mg, 0.1596 mmol, 98.547% yield) as a brown solid. 1H NMR (400MHz, 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), HATU (70.86 mg, 0.1900 mmol) and DIPEA (99.81 mg, 0.7700 mmol) were added. 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 directly concentrated. The residue was analyzed by prep-HPLC (NH 3 ) to obtain the title compound (25.52 mg, 0.0716 mmol, yield 46.352%) as a brown solid. LC-MS Method 1: 357.1 [M+H + ] 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 (1H, 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 A mixture of (1R)-1-cyclobutylethanamine hydrochloride (241.94 mg, 1.78 mmol) in 1-butanol (0.30 mL) was added to a solution of ethyl (2Z)-3-(dimethylamino)-2-isocyanoacrylate (100 mg, 0.5900 mmol) in triethylamine (0.58 mL, 4.46 mmol). The resulting mixture was stirred at 70° C. for 16 hours to give a yellow mixture. TLC (PE:ethyl acetate=1:1) showed one new spot (Rf=0.3). 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, 18.916% yield) 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) showed complete consumption of 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 (1N) 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 HATU (49.6 mg, 0.1300 mmol) and DIPEA (0.09 mL, 0.5400 mmol) were added to a mixture of 1-[(1R)-1-cyclobutylethyl]-1H-imidazole-4-carboxylic acid (21 mg, 0.1100 mmol) and DMF (0.50 mL). The mixture was stirred at 50°C for 30 minutes, and 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 hours to obtain a yellow mixture. The reaction solution was analyzed by prep-HPLC (NH 3 The resulting 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 Method 1: 357.1 [M+H + ] 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 To a solution of 1-[(1S)-1-cyclopentylethyl]-1H-imidazole-4-carboxylic acid (50 mg, 0.2400 mmol, prepared using the same protocol as in Example 19, but using (R)-2-methylpropane-2-sulfinamide instead of (S)-2-methylpropane-2-sulfinamide) in DMF (5 mL), HATU (137.68 mg, 0.3600 mmol) and triethylamine (0.12 mL, 0.9600 mmol) were added. The mixture was stirred at 25° 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 (43.28 mg, 0.2400 mmol) was added. The resulting mixture was stirred at 25° C. for 3 hours to give 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 Method 1: 371.3 [M+H + ] 1H NMR (400MHz, 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. 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 in THF (20 mL) was added (S)-2-methylpropane-2-sulfinamide (2.47 g, 20.38 mmol) and titanium(IV) ethoxide (6.97 g, 30.57 mmol). 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 give a white suspension. The suspension was filtered. The filtrate was washed with water (30 mLx 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 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 H 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 To a mixture of (S)-N-[(E)-cyclopentylmethylene]-2-methyl-2-propanesulfinamide (742.96 mg, 9.93 mmol, 3.31 mL) in THF (20 mL) was added chloro(methyl)magnesium dropwise over 10 min at -40°C under nitrogen atmosphere. The suspension was stirred at 20°C for 16 h. The residue was diluted with aqueous ammonium chloride solution (15 mL), extracted with ethyl acetate (30 mLx 4), washed with saturated brine (30 mLx 2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification by flash column (PE→30% ethyl acetate in PE) afforded the title compound (595 mg, crude) as a yellow liquid. LC-MS Method1: 0.827 min, MS (m / z): 218 (M + H + ). 1 H 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 obtain the title compound (257 mg, crude) as a yellow solid.

[0311] Ethyl 1-[(1R)-1-cyclopentylethyl]-1H-imidazole-4-carboxylate 1-Butanol (0.5 mL) was added to a mixture of (1R)-1-cyclopentylethanamine hydrochloride (52.0 mg, 0.35 mmol). 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 To a mixture of ethyl 1-[(1R)-1-cyclopentylethyl]-1H-imidazole-4-carboxylate in water (0.5 mL) and THF (1.5 mL) was added lithium hydroxide monohydrate (20.5 mg, 0.49 mmol, 1.5 eq). The turbid solution was stirred at 20° C. for 2 hours. The residue was diluted with water (1 mL) and extracted with ethyl acetate (5 mL×4). The resulting aqueous layer was acidified to pH=5 with aqueous hydrochloric acid (1N). The combined organic layers were concentrated and then lyophilized to give 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 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 to a mixture of 1-[(1R)-1-cyclopentylethyl]-1H-imidazole-4-carboxylic acid (30.0 mg, 0.14 mmol) in pyridine (0.5 mL). 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 mLx 3), washed with saturated saline (5 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The solution was analyzed by prep-HPLC (NH 3 ) and lyophilized to give the title compound (1.88 mg, 3.5% yield) as a white solid. LC-MS Method1: 3.486 min, MS (m / z): 371.3 (M + H + ). 1 H 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, 7H), 1.18 (s, 7H).

[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 A 100 mL round bottom flask was charged with 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 was heated at 60° C. for 30 min under nitrogen to give a yellow solution. A new spot was detected by TLC (PE / ethyl acetate=3 / 1, Rf=0.4). Water (3 mL) was added dropwise, stirred at 20° C. for 5 min, then filtered through Celite, and the filtrate was concentrated under reduced pressure to give the title compound (8700 mg, 40.031 mmol, 91.383% yield) 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 A round-bottom flask containing (R)-2-methyl-N-[(E)-tetrahydro-2H-pyran-4-ylmethylene]-2-propanesulfinamide (3000 mg, 13.8 mmol) and THF (30 mL) was 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 extracted with ethyl acetate (30 mL x 2). The combined organic layer was dried over sodium sulfate and concentrated under reduced pressure to obtain a yellow oil. The crude 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. 1H 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 A 100 mL round bottom flask was charged with (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). The reaction mixture was stirred at 25° C. for 3 hours to give a colorless oil. The solvent was removed under reduced pressure to give the title compound (1250 mg, 7.5456 mmol, 103.58% yield) as a colorless oil.

[0317] 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 microwaves 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 mLx 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 / 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 was 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). Stirred at 20 °C for 3 h to give a yellow solution. Water (15 mL) was added and extracted with ethyl acetate (15 mL x 2). The aqueous layer was lyophilized to give the title compound (110 mg, 0.4905 mmol, 95.199% yield) as a yellow solid. 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 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) in DMF (5 mL), N-ethyl-N-isopropylpropan-2-amine (0.59 mL, 3.43 mmol) was added. 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 (384.3 mg, 0.7400 mmol) was added. After stirring for an additional 16 h, a yellow solution was obtained. Water (30 mL) was added and the mixture was extracted with ethyl acetate (30 mLx 2). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure to give a yellow oil. The crude was purified by Prep-HPLC (NH 3 The resulting fraction was concentrated in vacuo to remove most of the acetonitrile and lyophilized to give the title compound (9.57 mg, 0.0248 mmol, 5.0482% yield) as a white solid. LC-MS Method 1: 387.3 [M+H + ] 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, 2.26Hz, 1H) 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 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 hours. TLC (PE:ethyl acetate=3:1) showed that 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-phenylethanamine (4.5 mL, 35.36 mmol) was added. The resulting mixture was stirred at 50°C for 16 hours to give a brown mixture. TLC (PE:ethyl acetate=1:1) showed a new spot (Rf=0.1). The mixture was concentrated to give a residue. The residue was purified by flash column (PE:ethyl acetate=1:0→0:1) to give the title compound (0.9300 g, 3.807 mmol, 43.06% yield) (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) was added lithium hydroxide monohydrate (0.33 mL, 5.71 mmol). The reaction mixture was stirred at 20° C. for 16 hours to give a yellow mixture. TLC (PE:ethyl acetate=1:1) showed 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 obtained aqueous layer was dried under reduced pressure to give 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 To a mixture of (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 added 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. TLC (DCM:methanol=40:1 with 1 drop of triethylamine) showed one new spot (Rf=0.5). The reaction was diluted with water (10 mL). The resulting mixture was extracted with ethyl acetate (5 mL×4). The combined organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a residue. The residue was purified by prep-TLC (DCM:methanol=40:1, 1% triethylamine in the solvent was added) to obtain a crude product. The crude product was purified by prep-HPLC (NH 3 The resulting fractions were combined, concentrated to remove most of the acetonitrile, and lyophilized to give the title compound (3.85 mg, 0.0102 mmol, 1.8336% yield) as a white solid. LC-MS Method 1: 379.1 [M+H + ] 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 A 100 mL round bottom flask was charged with 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). The reaction was heated at 60 °C under nitrogen for 30 min to give 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 stirred at 20 °C for 5 min, then filtered through a Celite pad and concentrated under reduced pressure to give the title compound (3050 mg, 10.583 mmol, 97.903% yield) as a white solid.

[0324] (R)-N-[(1S)-1-(2-bromophenyl)ethyl]-2-methyl-2-propanesulfinamide A round-bottom flask containing (R)-N-[(E)-(2-bromophenyl)methylene]-2-methyl-2-propanesulfinamide (3000 mg, 10.41 mmol) and THF (25 mL) was cooled to -48°C, and chloro(methyl)magnesium (4.16 mL, 12.49 mmol) was added dropwise. Stirring at this temperature for 2 hours gave a yellow solution. Water (30 mL) was added and extracted with ethyl acetate (30 mLx 2). The organic layer was dried over sodium sulfate and concentrated under reduced pressure to give a yellow oil. The crude was purified by silica gel chromatography (DCM / ethyl acetate = 10 / 1 → 3 / 1) to give 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 A solution of (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) was stirred at 30° C. for 16 hours to give a colorless solution. The reaction mixture was removed from the solvent under reduced pressure to give the title compound (700 mg, 2.95 mmol, 100.04% yield) as a yellow oil. Used directly in the next step. LC-MS Method1 0.592 min, MS (m / z) 202.1 (M + H + ).

[0326] Ethyl 1-[(1S)-1-(2-bromophenyl)ethyl]-1H-imidazole-4-carboxylate Into an 8 mL microweave vial, (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) were added. The reaction solution was irradiated with a microwave at 130 °C for 1 hour to obtain a brown-red solution. The reaction solution was diluted with saturated aqueous sodium carbonate solution (10 mL) and extracted with ethyl acetate (20 mL x 2). The combined organic layer was dried over sodium sulfate and concentrated under reduced pressure to obtain a yellow oil. The crude 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] Ethyl 1-[(1S)-1-(2-cyanophenyl)ethyl]-1H-imidazole-4-carboxylate To a 50 mL round bottom flask was 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 was stirred at 120° C. for 16 hours to give a yellow solution. Water (15 mL) was added and extracted with ethyl acetate (20 mLx 2). The combined organic layers were dried over sodium sulfate and concentrated in vacuo to give a yellow oil. The solvent of the reaction mixture was removed under reduced pressure to give the title compound (60 mg, 0.2228 mmol, 40.004% yield) as a yellow oil, which was used as such in the next step.

[0328] 1-[(1S)-1-(2-cyanophenyl)ethyl]-1H-imidazole-4-carboxylic acid A solution of lithium hydroxide monohydrate (46.74 mg, 1.11 mmol) in water (1.5 mL, 0.5600 mmol) was added 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). The mixture was reacted at 20° C. for 16 hours 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, 119.07% yield) 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) was 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 added and stirred for 16 h to obtain a black suspension. Water (30 mL) was added and extracted with ethyl acetate (30 mLx 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 Prep-HPLC (NH 3 ) The resulting fraction was concentrated in vacuo to remove most of the acetonitrile and lyophilized to give the title compound (37.35 mg, 0.0926 mmol) as a white solid. LC-MS Method 1: 404.3 [M+H + ] 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 To a solution of (R)-2-methylpropane-2-sulfinamide (4621.37 mg, 38.13 mmol) in THF (20 mL) was added 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 give a yellow solution. Water (3 mL) was added dropwise and stirred for 5 min. The solid was then filtered through a pad of Celite and the filtrate was concentrated under reduced pressure to give the title compound (7630 mg, 32.562 mmol, 85.398% yield) as a white solid. It was used directly in the next step without further purification. 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 To a solution of (R)-N-[(E)-(3-cyanophenyl)methylene]-2-methyl-2-propanesulfinamide (3000 mg, 12.8 mmol) in THF (32.054 mL), chloro(methyl)magnesium (4.69 mL, 14.08 mmol) was added 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 x 4). The combined organic layer was washed with saturated brine (30 mL x 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 To (R)-N-[(1S)-1-(3-cyanophenyl)ethyl]-2-methyl-2-propanesulfinamide (960 mg, 3.83 mmol) was added hydrochloric acid / methanol (10 mL, 3.83 mmol) at 20° C. The resulting mixture was stirred at 20-25° C. for 0.5 hours 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), triethylamine (0.31 mL, 2.23 mmol) and ethyl (2Z)-3-(dimethylamino)-2-isocyanoacrylate (271.49 mg, 1.49 mmol) were added. The reaction mixture was irradiated with microwaves 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 x 2). The combined organic layers were combined, washed with saturated brine (30 mL x 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), 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) was added at 20 °C. The resulting mixture was stirred at 20-25 °C for 14 h to give a yellow solution. The reaction mixture was poured into water and extracted with ethyl acetate (20 mL x 4). The aqueous layer was concentrated and lyophilized to give the title compound (132 mg, crude) 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 at 20° C. to 25° C. for 14 hours to give a yellow solution. The reaction mixture was poured into a saturated aqueous solution of ammonium chloride (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 Method 1: 404.2 [M+H + ] 1 H NMR (400MHz, 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 A solution of (R)-2-methylpropane-2-sulfinamide (4621.37 mg 38.13 mmol) in THF (20 mL) was added with 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 hours to obtain a yellow solution. Water (3 mL) was added dropwise and stirred for 5 minutes. Then, the solid was removed by filtration using a pad of Celite, and the filtrate was concentrated under reduced pressure to obtain the title compound (8340 mg, 35.592 mmol, yield 93.345%) 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 To a solution of (R)-N-[(E)-(4-cyanophenyl)methylene]-2-methyl-2-propanesulfinamide (2340 mg, 9.99 mmol) in THF (30 mL), chloro(methyl)magnesium (4.99 mL, 14.98 mmol) was added at -48°C. The resulting mixture was stirred at -40°C for 14 hours to obtain a yellow solution. The mixture was cooled with an aqueous ammonium chloride solution, and the aqueous layer was extracted with ethyl acetate (30 mL x 3). The combined organic layers were washed with saturated saline, dried over sodium sulfate, and concentrated under reduced pressure. The crude product was purified on a silica column (PE → PE: ethyl acetate = 1:1). The resulting solid was triturated with ethyl acetate / hexane (20 mL / 10 mL) and air-dried to obtain the title compound (1310 mg, 5.2325 mmol, yield 52.396%) as a yellow solid. LC-MS Method1 0.732 min, MS (m / z) 250.9 (M + H+ ).

[0338] 4-[(1S)-1-Aminoethyl]benzonitrile hydrochloride To (R)-N-[(1S)-1-(4-cyanophenyl)ethyl]-2-methyl-2-propanesulfinamide (1310 mg, 5.23 mmol) was added hydrochloric acid / methanol (10 mL, 5.23 mmol) at 20° C. The resulting mixture was stirred at 20-25° C. for 0.5 h to give a yellow solution. The solvent of the reaction mixture was removed under reduced pressure to give 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 Triethylamine (0.38 mL, 2.68 mmol) and 4-[(1S)-1-aminoethyl]benzonitrile hydrochloride (300 mg, 1.78 mmol) were added to a solution of ethyl (2Z)-3-(dimethylamino)-2-isocyanoacrylate (300 mg, 1.78 mmol) in 1-butanol (3 mL). The reaction mixture was irradiated with microwaves 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 layer was 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). The aqueous layer was concentrated and then 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), HATU (206.01 mg, 0.5400 mmol) and N-ethyl-N-isopropylpropan-2-amine (0.5 mL, 2.9 mmol) were added at 20°C. The reaction mixture was stirred 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 (104.94 mg, 0.4100 mmol) was added. The resulting mixture was stirred at 20°C to 25°C for 14 h to obtain a yellow solution. The reaction mixture was poured into saturated aqueous ammonium chloride solution (20 mL) and extracted with ethyl acetate (20 mL x 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 Method 1: 404.2 [M+H + ] 1H NMR (400MHz, 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 A mixture of (1S)-1-(2-pyridinyl)ethanamine (500 mg, 4.09 mmol) and ethyl (2Z)-3-(dimethylamino)-2-isocyanoacrylate (137.67 mg, 0.8200 mmol) was stirred at 50° C. for 16 hours. The reaction mixture was directly concentrated. The residue was purified by prep-TLC (PE:ethyl acetate=0:1) to obtain the title compound as a brown oil. 1 H NMR (400MHz, 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). Stirring at 20° C. for 12 hours gave a brown suspension. LCMS showed that the starting material was completely consumed. The reaction solution was concentrated. The resulting aqueous layer was acidified with aqueous hydrochloric acid (1N) to pH=5-7, 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), HATU (274.55 mg, 0.7200 mmol), DIPEA (0.49 mL, 2.99 mmol), (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) were added. The mixture was stirred at 30°C for 3 hours to give a brown solution. The reaction solution was directly concentrated. The residue 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 (48.15 mg, 0.1269 mmol, 21.202% yield) as a pale yellow solid. LC-MS Method 1: 380.0 [M+H + ] 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 in THF (5 mL) was added sodium hydride (148.11 mg, 6.17 mmol) at 0°C. The mixture was stirred at 0°C for 0.5 h. 4-Methylbenzene-1-sulfonyl chloride (0.29 mL, 1.95mmol) was added and stirred at 20°C to 25°C for 16 h. The reaction mixture was poured into water (10 mL) and extracted with ethyl acetate (10 mL x 4). The combined organic layer was 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 (330 mg, 1.1899 mmol, 73.267% yield) as a white solid. 1 H NMR (400MHz, 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] Ethyl 1-[(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 hours. The reaction mixture was poured into water (10 mL) and extracted with ethyl acetate (15 mL x 4). The combined organic layer was 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 Method 1: 232.1 [M+H] + 1H NMR (400MHz, 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] 1-[(1S)-1-(4-pyridinyl)ethyl]-1-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 directly concentrated. 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 H NMR (400MHz, 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), 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) were added. The resulting mixture was stirred at 20-25 °C for 16 h. The resulting mixture was stirred at 20-25 °C for 16 h. The residue was purified by prep-HPLC (NH 3The resulting fractions were combined, concentrated to remove most of the acetonitrile, and lyophilized to give the title compound (24.99 mg, 0.0659 mmol, 71.527% yield) as a yellow solid. LC-MS Method 1: 380.1 [M+H] + 1 H NMR (400MHz, 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 Ethyl 1-[(1S)-1-(1,3-thiazol-2-yl)ethyl]-1H-imidazole-4-carboxylate Ethyl (2Z)-3-(dimethylamino)-2-isocyanoacrylate (100 mg, 0.7800 mmol) and triethylamine (0.16 mL, 1.17 mmol) were added to a solution of (1S)-1-(1,3-thiazol-2-yl)ethanamine (131.19 mg, 0.7800 mmol) in 1-butanol (1.4 mL) 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 layer was washed with saturated saline (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] 1-[(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 was stirred at 25° C. for 16 hours to give 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). The solution was then lyophilized to give 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 EDCI (56.67 mg, 0.3000 mmol) was added to 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). The mixture was stirred at 25° C. for 10 minutes under 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 resulting organic layers were combined, washed with saturated saline (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 Method 1: 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) was added (R)-2-methylpropane-2-sulfinamide (2142.48 mg, 17.68 mmol) and titanium(IV) ethoxide (6045.61 mg, 26.52 mmol). Stirring at 60°C for 2 hours gave a yellow mixture. TLC (PE:ethyl acetate = 2:1) showed complete consumption of the starting material and one new spot (Rf = 0.5). The reaction solution was diluted with ethyl acetate (30 mL). Water (10 mL) was added and stirred for 1 minute to give a yellow suspension. This suspension was filtered. The filtrate was washed with water (20 mL x 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the title compound (3.77 g, 17.428 mmol, 98.59% yield) as a yellow solid.

[0353] (R)-2-Methyl-N-[(1S)-1-(1,3-thiazol-5-yl)ethyl]-2-propanesulfinamide To a mixture 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 chloro(methyl)magnesium (9.88 mL, 29.63 mmol) at -40°C. The mixture was stirred at 25°C for 16 hours, and the reaction mixture turned dark brown. TLC (100% ethyl acetate) showed that the starting material was completely consumed, and one new spot (Rf=0.3) was detected. Ammonium chloride (60 mL) was added to the reaction mixture to quench the reaction. The resulting mixture was extracted with ethyl acetate (40 mL×4). The combined organic layer was 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 give the title compound (1.7 g, 7.3159 mmol, 41.978% yield) as a brown oil. 1 H NMR (400MHz, 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 give a brown mixture. TLC (100% ethyl acetate) showed complete consumption of the starting material. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was triturated with MTBE (20 mL) and dried under reduced pressure to give the title compound (504 mg, 3.0609 mmol, 142.25% yield) (crude) as a brown solid.

[0355] Ethyl 1-[(1S)-1-(1,3-thiazol-5-yl)ethyl]-1H-imidazole-4-carboxylate To a solution of (1S)-1-(1,3-thiazol-5-yl)ethanamine (350 mg, 2.13 mmol) in 1-butanol (3.5 mL), ethyl (2Z)-3-(dimethylamino)-2-isocyanoacrylate (357.5 mg 2.13 mmol) and triethylamine (0.41 mL, 3.19 mmol) were added. The mixture was stirred at 130° C. for 1 hour using a 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 (400MHz, 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] 1-[(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 give 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 lyophilized to give the title compound (40 mg, 0.1792 mmol, 97.882% yield) as a brown solid. 1 H NMR (400MHz, 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 HATU (82.2 mg, 0.2200 mmol) and DIPEA (0.15 mL, 0.9000 mmol) were added to a mixture 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). The mixture was stirred at 50° C. for 30 minutes, and then (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 analyzed by prep-HPLC (NH 3 The resulting fractions were combined, concentrated to remove most of the acetonitrile, and lyophilized to give the title compound (14.11 mg, 0.0366 mmol, 20.34% yield) as a yellow solid. LC-MS Method 1: 386.1 [M+H + ] 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 To a solution of (2R)-1-phenyl-2-propanol (400 mg, 2.94 mmol) in DCM (5 mL) was added triethylamine (0.45 mL, 3.23 mmol) and 4-methylbenzene-1-sulfonyl chloride (0.44 mL, 2.94 mmol). The reaction was stirred at 20°C for 16 h to give 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 mLx 2). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure to give a yellow oil. The crude was purified by silica gel chromatography (PE / ethyl acetate = 1 / 0 → 10 / 1) to give the title compound (680 mg, 2.3418 mmol, 79.731% yield) 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 hours to give a yellow solution. Water (30 mL) was added and extracted with ethyl acetate (30 mL x 2). The combined organic layer was dried over sodium sulfate and concentrated under reduced pressure to give a yellow oil. The crude was purified by silica gel chromatography (DCM / ethyl acetate = 10 / 1 → 3 / 1) to give the title compound (120 mg, 0.4912 mmol, yield 20.649%). 1 H 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 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) was added a solution of lithium hydroxide monohydrate (41.22 mg, 0.9800 mmol) in water (1 mL, 0.4900 mmol). The reaction was stirred at 20°C for 16 hours to give a colorless oil. TLC (PE / ethyl acetate = 1 / 1, Rf = 0) showed a new spot. The reaction was removed under reduced pressure and then lyophilized to give the title compound (110 mg, 0.4777 mmol, 97.252% yield) 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) was added N-ethyl-N-isopropylpropan-2-amine (0.37 mL, 2.17 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 (109.95 mg, 0.4300 mmol) was added and stirred at 20 °C for 16 h to give a yellow solution. Water (30 mL) was added and extracted with ethyl acetate (30 mLx 2). The combined organic layers were dried over sodium sulfate and concentrated in vacuo to give a yellow oil. The crude was purified by Prep-HPLC (NH 3 The resulting fraction was concentrated in vacuo to remove most of the acetonitrile and lyophilized to give the title compound (104.7 mg, 0.2668 mmol, 61.424% yield) as a white solid. LC-MS Method 1: 393.3 [M+H + ] 1 H 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-phenylpropanylidene]-2-propanesulfinamide A mixture of (R)-2-methylpropane-2-sulfinamide (817.81 mg, 6.75 mmol) in THF (10 mL) and titanium(IV) ethoxide (2307.69 mg, 10.12 mmol) was added to 4-phenyl-2-butanone (1.01 mL, 6.75 mmol). The reaction mixture 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 x 3), dried over anhydrous sodium sulfate, filtered, and 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, 33.603% yield) 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 To a mixture of (R)-2-methyl-N-[(1E)-1-methyl-3-phenylpropanylidene]-2-propanesulfinamide (570 mg, 2.27 mmol) in THF (6 mL) was added L-selectride (6.8 mL, 6.8 mmol) at 0° C. The mixture was stirred at 25° C. for 3 h to give a colorless mixture. TLC (PE:ethyl acetate=2:1) ​​showed one new spot (Rf=0.3). 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, 45.252% yield) as a yellow oil. 1H 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 A solution of (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 hour to obtain a yellow mixture. The mixture was concentrated under reduced pressure to obtain 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 To a mixture of (2S)-4-phenyl-2-butanamine (190 mg, 1.02 mmol) in 1-butanol (2 mL), ethyl (2Z)-3-(dimethylamino)-2-isocyanoacrylate (172.09 mg, 1.02 mmol) and triethylamine (0.2 mL, 1.53 mmol) were added. The reaction mixture was heated in a microwave reactor at 130° C. for 1 h to give a brown mixture. TLC (PE:ethyl acetate=1:1) showed one new spot (Rf=0.2). 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, 14.354% yield) 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 was stirred at 40° C. for 16 h to give a yellow mixture. TLC (PE:ethyl acetate=1:1) showed complete consumption of starting material. The reaction 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 (1N). Lyophilization afforded 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), EDCI (28.25 mg, 0.1500 mmol) was added. After stirring the mixture at 25° C. 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 (26.61 mg, 0.1200 mmol) was added. After stirring at 25° C. for 16 hours, a yellow mixture was obtained. LCMS showed that the starting material was completely consumed. The reaction mixture was concentrated under reduced pressure to obtain a residue. The residue was purified by prep-HPLC (NH 3 The resulting 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 Method 1: 407.2 [M+H + ] 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, 2H), 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 To 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 added diisopropyl azodicarboxylate (1.73 mL, 8.77 mmol) slowly. The reaction mixture was stirred at 20 °C for 16 h to give a yellow solution. TLC (PE / ethyl acetate = 10 / 1, Rf = 0.8) showed a new spot. Water (30 mL) was added and extracted with ethyl acetate (30 mL x 2). The combined organic layers were dried over sodium sulfate and concentrated in vacuo to give a yellow oil. The crude was purified by silica gel chromatography (PE / ethyl acetate=10 / 1→3 / 1) to obtain the title compound (600 mg, 2.3874 mmol, yield 40.85%) as a white solid.

[0369] (2S)-1-Phenoxy-2-propanamine hydrochloride A solution of tert-butyl [(2S)-1-phenoxypropan-2-yl]carbamate (1100 mg, 4.38 mmol) in methanol (1 mL) was added with hydrochloric acid / dioxane (5 mL, 20 mmol) and the reaction was stirred at 20 °C for 3 h to give a colorless solution. LCMS showed a new peak in the desired MS. The reaction mixture was distilled under reduced pressure to give the title compound (800 mg, 4.2628 mmol, 97.393% yield) as a yellow solid, which was used directly 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 was 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 was irradiated with microwaves at 130°C for 1 h to give a brown solution. LCMS showed a new peak in the MS of interest. The reaction was diluted with saturated aqueous sodium carbonate (20 mL). Water (30 mL) was added and extracted with ethyl acetate (30 mLx 2). The combined organic layers were dried over sodium sulfate and concentrated in vacuo to give a yellow oil. The crude 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). Stirring at 20° C. for 16 hours gave a yellow solution. LCMS showed a new peak in the MS of interest. Water (30 mL) was added and extracted with ethyl acetate (30 mL). The aqueous layer was then acidified with 1M aqueous hydrochloric acid and lyophilized to give the title compound (240 mg, 0.9746 mmol, 86.241% yield) 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 A stirred solution of 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) was added to HATU (300.9 mg, 0.7900 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 (114.4 mg, 0.5300 mmol) was added to give a brown solution. Water (30 mL) was added and the mixture was extracted with ethyl acetate (30 mLx 2). The organic layer was dried over sodium sulfate and concentrated under reduced pressure to give a yellow oil. The crude was purified by prep-HPLC (NH 3 The resulting fraction was concentrated in vacuo to remove most of the acetonitrile and lyophilized to give the title compound (51.22 mg, 0.1254 mmol, 23.752% yield) as a white solid. LC-MS Method 1: 409.3 [M+H + ] 1 H 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]hex-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 for 16 hours at 80° C. 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 and water (5 mL) in THF (15 mL). Stirring was continued at 40° C. for 16 hours to give a yellow mixture. The reaction mixture was concentrated under reduced pressure to remove most of the THF. The residue was diluted with water (5 mL) and acidified to pH=6 with aqueous hydrochloric acid (0.5M). The solution was then 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 minutes. 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 hours to give a brown solution, which was then concentrated under reduced pressure to remove most of the DMF and give the crude product. The crude product was purified by Prep-HPLC (NH 3) to give the title compound as a white solid. LC-MS Method 1: 345.3 [M+H + ] 1 H NMR (400MHz, 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 [ka] Ethyl 1-(1-methylcyclopropyl)-1H-imidazole-4-carboxylate To a solution of ethyl (2Z)-3-(dimethylamino)-2-isocyanoacrylate (469.02 mg, 2.79 mmol) in 1-butanol (5.5 mL), 1-methylcyclopropanamine (300 mg, 2.79 mmol) and triethylamine (0.54 mL, 4.18 mmol) were added. The resulting mixture was reacted in a microwave reactor (time: 1 h, temperature: 130 °C). TLC (PE:ethyl acetate = 0:1) showed the reaction was complete (Rf = 0.5). The reaction was concentrated directly. The crude product was purified by flash column (PE → 40% ethyl acetate in PE) to give the title compound (118 mg, 0.6075 mmol, 21.786% yield) as a brown oil. LC-MS Method1: 0.568 min, MS (m / z) 194.9 [M+H] + 1 H NMR (400MHz, CHLOROFORM-d) δ = 7.71 - 7.69 (m, 1H), 7.60 (s, 1H), 4.36 (q, J=7.0 Hz, 2H), 1.58 (s, 3H), 1.38 (t, J=7.2 Hz, 3H), 1.17 - 1.12 (m, 2H), 0.96 - 0.91 (m, 2H).

[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 h. The reaction was concentrated directly. The residue was acidified to pH=6 with aqueous hydrochloric acid (1M). Lyophilization afforded the desired compound (100 mg, 0.6018 mmol, 99.05% yield) as a yellow solid. 1 H NMR (400MHz, 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) was added HATU (276.06 mg, 0.72 mmol) and triethylamine (0.39 mL, 3.01 mmol). 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 was stirred at 20-25 °C for 1 h. LCMS showed the desired MS (as the major peak). The residue was purified by prep-HPLC (NH 3 The resulting fractions were combined, concentrated to remove most of the acetonitrile, and lyophilized to give the title compound (60.45 mg, 0.1841 mmol, 30.589% yield) 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) was added 1-methylcyclobutanamine (583.25 mg, 4.76 mmol) and triethylamine (1.15 mL, 8.92 mmol). The resulting mixture was heated at 76°C for 16 hours. The reaction mixture was diluted with water (5 mL) and extracted with ethyl acetate (5 mL x 3). The combined organic layers were washed with brine (10 mL), dried over sodium sulfate, and concentrated under reduced pressure to give a crude oil. The crude oil was purified by prep-TLC (100% ethyl acetate) to give the title compound (50 mg, 0.2401 mmol, 20.19% yield) 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) was added lithium hydroxide monohydrate (0.04 mL, 0.7200 mmol). 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 (1N). The aqueous solution was lyophilized to give the title compound (50 mg, 0.2775 mmol, 115.57% yield) 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 mixture was diluted with water (5 mL), extracted with ethyl acetate (5 mL x 2), and washed with brine (8 mL). The combined organic layer was dried over sodium sulfate and concentrated under reduced pressure to give 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 (400MHz, 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. 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), propan-1-amine (2.97 mL, 1.78 mmol, 1.0 eq) and triethylamine (0.25 mL, 1.78 mmol, 0.6 eq) were added. After stirring at 130°C for 6 hours, 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 give 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 a solution of lithium hydroxide (70.3 mg, 2.94 mmol, 2.5 eq) in water (0.6 mL). The reaction 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 give 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 min, (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 stirred at 20°C for 16 h to give a yellow solution. Water was added and extracted with DCM. The combined organic layers were dried over sodium sulfate and concentrated in vacuo to give a yellow oil. The crude was purified by silica gel chromatography (ethyl acetate / DCM=99 / 1→70 / 30) to obtain the title compound (23 mg, 0.072 mmol, yield 51.9%) as a beige powder. LC-MS Method1 0.757 min, MS (m / z) 317.0 (M + H + ). 1H 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, 0.5M), 2-methylpropan-1-amine (1.0 mL, 9.8 mmol, 1.1 eq) and triethylamine (0.74 mL, 5.35 mmol, 0.6 eq) were added. The mixture was stirred at 130°C for 6 hours and then 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 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 + ). 1H 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). The reaction mixture was stirred at 40° C. for 12 h, then 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 H 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 To a stirred 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 added DIPEA (0.13 mL, 0.75 mmol, 5.0 eq). After stirring at 50°C 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 (35.6 mg, 0.164 mmol, 1.1 eq) was added and stirred at 50°C for 1 h to give a yellow solution. Water was added and the mixture was extracted with DCM. The combined organic layers were dried over sodium sulfate and concentrated in vacuo to give a yellow oil. The crude 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 H 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]hex-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), 1-propene (4.6 mL, 2.3 mmol) and triethylamine (0.38 mL, 2.3 mmol) were added. The resulting mixture was stirred at 20°C for 16 hours to obtain a pale yellow mixture. The reaction solution was diluted with water (10 mL) and extracted with ethyl acetate (10 mL x 2). The combined organic layer was dried over sodium sulfate and concentrated under reduced pressure to obtain 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), hydrochloric acid / dioxane (3 mL, 0.49 mmol) was added. The reaction solution was stirred at 0° C. for 30 minutes to obtain a pale yellow mixture. The reaction mixture was directly concentrated to dryness to obtain 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 To a mixture of (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 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 give a brown mixture. TLC (PE / ethyl acetate = 0 / 1) showed a series of new spots and that 1-isopropylimidazole-4-carboxylic acid (46.38 mg, 0.30 mmol) was completely consumed. LCMS showed the desired MS. The reaction mixture was diluted with water (5 mL), 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 give the crude product. The crude product was purified by prep-HPLC (NH 3 ) to give the title compound (5 mg, 0.0165 mmol, yield 5.4972%) as a white solid. 1 H NMR (400MHz, 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 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) was added methylenecyclopropane (300 mg, 1.22 mmol). The reaction was stirred at 0°C for 16 hours to give a yellow solution. LCMS showed a new peak in the MS of interest. The reaction mixture was diluted with water (30 mL) and extracted with ethyl acetate (30 mL x 2). The combined organic layers were dried over sodium sulfate and concentrated to give the title compound (260 mg, 0.9341 mmol, 76.809% yield) 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 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) was added 2,2,2-trifluoroacetic acid (0.07 mL, 0.93 mmol). The reaction was stirred at 10° C. for 3 h to give a yellow solution. LCMS showed a new peak in the MS of interest. The reaction mixture was removed under reduced pressure to give the title compound (272 mg, 0.9307 mmol, 99.64% yield) 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 was 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 was stirred at 10° C. for 16 hours to give a yellow solution. LCMS showed complete consumption of the reactants and MS of interest. 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 give a yellow oil. The resulting crude was purified by prep-HPLC (FA). The resulting fraction was concentrated in vacuo to remove most of the acetonitrile and lyophilized to give the title compound (14.67 mg, 0.0467 mmol, yield 5.0137%) as a white solid. LC-MS Method 1: 315.1 [M+H + ] 1 H NMR (400MHz, 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 mixture of tert-butyl (1R,5S,6r)-6-[(E)-(hydroxyimino)methyl]-3-azabicyclo[3.1.0]hexane-3-carboxylate in DMF (1.5 mL), methylenecyclobutane (78.4 mg, 1.15 mmol) was added. The mixture 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 (20mLx 3), washed with saturated saline (5 mL), dried over anhydrous sodium sulfate, filtered, and 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 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) in DCM (1.5 mL) was added 2,2,2-trifluoroacetic acid (17.9 mg, 0.16 mmol). The suspension was stirred at 20° C. for 2 hours. The reaction mixture was concentrated under reduced pressure to give 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 EDCI (29.9 mg, 0.16 mmol) and 1-isopropylimidazole-4-carboxylic acid (24.1 mg, 0.16 mmol) were added 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). 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 saline (5 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Prep-HPLC (NH 3 ) and lyophilized to give the title compound (6.49 mg, 12.7% yield) 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, 4H), 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 methacrylaldehyde (0.32 mL, 3.84 mmol) in DMF (3 mL), triethylamine (0.22 mL, 1.53 mmol) was added. The reaction solution was stirred at 20°C for 12 hours to obtain a pale yellow solution. The reaction solution was diluted with ethyl acetate (15 mL), and a saturated aqueous solution of sodium bicarbonate (10 mL) was added and stirred for 5 minutes. The aqueous layer was extracted with ethyl acetate (10 mL x 2). The combined DCM layer was 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), DAST (371.11 mg, 2.31 mmol) was added at -78°C. The reaction solution was warmed to 20°C and stirred for another 12 hours to obtain a light brown solution. After cooling to 0°C, the reaction solution was diluted with DCM (20 mL) and quenched with saturated aqueous sodium bicarbonate (8 mL). The organic layer was collected, dried over sodium sulfate, and concentrated under reduced pressure to obtain a crude oily product, which was purified by prep-HPLC (hydrochloric acid). The resulting eluent was washed with saturated aqueous sodium bicarbonate (2 mL) and concentrated to remove acetonitrile. The residue was extracted with ethyl acetate (10 mL x 2). The combined ethyl acetate layers were dried over sodium sulfate and concentrated in vacuo to give the title compound (55 mg, 0.1739 mmol, 22.628% yield) 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).

[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 To a solution of 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 give a pale yellow solution. DMF (1 mL) was added, followed by 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). The resulting mixture was stirred at 20°C for 12 h to give a yellow mixture. The reaction mixture was concentrated and purified by prep-HPLC (NH 3 The resulting eluate was concentrated and freeze-dried to obtain the title compound (7.01 mg, 0.0199 mmol, yield 11.442%) as a pale yellow solid. LC-MS Method 1: 353.0 [M+H + ] 1 H NMR (400MHz, 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]hex-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 2-Methylbut-1-ene (403.48 mg, 5.75 mmol) and triethylamine (116.4 mg, 1.15 mmol, 0.16 mL) were added to a solution of tert-butyl (1R,5S,6r)-6-[(Z)-chloro(hydroxyimino)methyl]-3-azabicyclo[3.1.0]hexane-3-carboxylate in DMF (1.5 mL) and 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 x 3). The combined organic layer was washed with saturated saline (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 for 2 hours at 20° C. The reaction mixture was concentrated under reduced pressure to give 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]hex-3-yl](1-isopropyl-1H-imidazol-4-yl)methanone EDCI (49.3 mg, 0.26 mmol) and 1-isopropylimidazole-4-carboxylic acid (39.7 mg, 0.26 mmol) were added to a solution of (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). 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 extracted with ethyl acetate (20 mL x 3), washed with saturated saline (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 H 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 Examples 42 and 43 were obtained during the preparation of Example 41, respectively. The {(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, 9.3% yield) 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, 10.2% yield), isolated by SFC purification from the final step of Example 41, were white solids. 1H NMR (400MHz, 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 To 6-ethyl 3-(tert-butyl) (1R,5S,6r)-3-azabicyclo[3.1.0]hexane-3,6-dicarboxylate (3.5 g, 13.71 mmol) was added hydrochloric acid / dioxane (50 mL, 3 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 directly concentrated to give 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) was added DIPEA (10.78 mL, 65.22 mmol) at 0 °C. Then, 2,5-dioxopyrrolidin-1-yl(2-(trimethylsilyl)ethyl)carbonate (4.06 g, 15.65 mmol) in DCM (20.27 mL) was added and stirred at 30 °C for 12 h to give 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 give the title compound (3.5 g, 11.688 mmol, 89.609% yield) as a yellow oil. 1 H NMR (400MHz, 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, 2 H), 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 give a white suspension. TLC (PE:ethyl acetate=1:1) showed the reaction was complete. The reaction mixture was poured into water (0.6 mL), 1N aqueous sodium hydroxide solution (0.6 mL), and water (1.8 mL) and filtered. The filtrate was concentrated to give a yellow oil. The crude product was purified by flash column (PE→40% ethyl acetate) to give the title compound (1.2 g, 4.662 mmol, 39.885% yield) as a colorless oil. 1 H NMR (400MHz, 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), DMP (2.97 g, 6.99 mmol) and sodium bicarbonate (979.14 mg, 11.66 mmol) were added at 0°C and stirred at 30°C for 2 hours. TLC (PE:ethyl acetate = 1:1) showed the reaction was complete. The reaction solution was poured into water (40 mL) and extracted with ethyl acetate (30 mL x 4). The combined organic layer was washed with aqueous sodium bicarbonate (50 mL) and aqueous sodium sulfite (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, 68.871% yield) as a brown oil. 1 H NMR (400MHz, 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) was 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 hours to give a white suspension. TLC (PE:ethyl acetate=2:1) ​​showed the reaction was complete. The reaction mixture was removed under reduced pressure, and the residue was added with water (40 mL) and extracted with ethyl acetate (30 mL×4). The combined organic layer was washed with saturated aqueous sodium bicarbonate (30 mLx 2) and saturated brine (40 mLx 2), and dried over sodium sulfate. The solvent was removed 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 give a brown solution. TLC (PE:ethyl acetate = 2:1) showed the reaction was complete. The reaction mixture was poured into water (40 mL) and extracted with ethyl acetate (30 mL x 4). The combined organic layers were washed with brine (50 mL x 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 give the title compound (750 mg, 2.4602 mmol, 78.264% yield) 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) was 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 hours to give a brown solution. TLC (PE:ethyl acetate=3:1) showed the reaction was complete. The mixture was added with water (40 mL) and extracted with ethyl acetate (30 mL x 4). The combined organic layer was washed with saturated brine (40 mLx 2) and dried over sodium sulfate. The solvent was removed under reduced pressure. The crude product was purified by flash column (PE→20% ethyl acetate in PE) to give the title compound (160 mg, 0.4639 mmol, 35.354% yield) as a colorless oil. 1 H NMR (400MHz, 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 give a brown solution. The reaction mixture was directly lyophilized to give the title compound (8 mg, 0.0487 mmol, 84.022% yield) as a brown solid. 1 H NMR (400MHz, 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]hex-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 give a yellow solution. LCMS showed the desired MS as the major peak. The reaction 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 Method 1: 301.2 [M+H + ] 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 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) was added with 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 mL) and extracted with ethyl acetate (15 mL x 4). The combined organic layer was washed with saturated saline (50 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to obtain the title compound (150 mg, 0.4179 mmol, yield 84.931%) as a brown oil. 1H NMR (400MHz, CHLOROFORM-d) δ = 4.25-4.10 (m, 2H), 3.80-3.60 (m, 2H), 3.55-3.45 (m, 4H), 3.05 (d, J = 9.2 Hz, 1H), 2.65 (d, J = 9.2 Hz, 1H), 2.00-1.90 (m, 1H), 1.55-1.45 (m, 2H), 1.05 (s, 3H), 1.50-1.40 (m, 1H), 0.99 (t, J = 8.0 Hz, 2H), 0.04 (s, 9H).

[0413] 4-[(1R,5S,6r)-3-azabicyclo[3.1.0]hex-6-yl]-1-methyl-2-oxa-3-azabicyclo[3.1.0]hex-3-ene To a solution of (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 (130 mg, 0.36 mmol) in DMSO (4 mL), potassium t-butoxide (81.28 mg, 0.72 mmol) was added. The mixture was stirred at 20°C for 30 minutes to obtain a brown solution. The reaction mixture was directly lyophilized to obtain the title compound (60 mg, 0.3366 mmol, 92.95% yield) as a brown solid.

[0414] (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 EDCI (129.07 mg, 0.67 mmol) was added to a solution of 4-[(1R,5S,6r)-3-azabicyclo[3.1.0]hex-6-yl]-1-methyl-2-oxa-3-azabicyclo[3.1.0]hex-3-ene (60 mg, 0.34 mmol) and 1-isopropylimidazole-4-carboxylic acid (51.9 mg, 0.34 mmol) in pyridine (5 mL). The mixture was stirred at 25°C for 3 h to give a yellow solution, which was then directly concentrated. The residue was purified by prep-HPLC (NH 3 The obtained solid was purified by prep-TLC (DCM:methanol=15:1) to obtain the title compound (11.96 mg, 0.0380 mmol, yield 11.301%) as a pale yellow solid. LC-MS Method 1: 315.2 [M+H + ] 1 H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.67 (1 H, s), 7.48 (1 H, s), 4.75 (1 H, br d, J=12.05 Hz), 4.36 (1 H, m, J=13.43, 6.84 Hz), 4.22 (1 H, br d, J=12.30 Hz), 3.97 (1 H, br d, J=12.05 Hz), 3.64 (1 H, br d, J=12.30 Hz), 2.08 (2 H, br d, J=3.76 Hz), 2.01 (1 H, br s), 1.67 (3 H, s), 1.51 (6 H, d, J=6.78 Hz), 0.90 (1 H, dd, J=9.41, 5.14 Hz), 0.33 - 0.43 (1 H, m).

[0415] Example 46 (1-Isopropyl-1H-imidazol-4-yl)[(1R,5S,6r)-6-(4,5,5-trimethyl-4,5-dihydro-1,2-oxazol-3-yl)-3-azabicyclo[3.1.0]hex-3-yl]methanone tert-Butyl (1R,5S,6r)-6-(4,5,5-trimethyl-4,5-dihydro-1,2-oxazol-3-yl)-3-azabicyclo[3.1.0]hexane-3-carboxylate To a solution of triethylamine (0.36 mL, 2.18 mmol) and 2-methylbut-2-ene (1.16 mL, 10.92 mmol) in THF, tert-butyl (1R,5S,6r)-6-[(Z)-chloro(hydroxyimino)methyl]-3-azabicyclo[3.1.0]hexane-3-carboxylate (200 mg, 0.73 mmol) was added. The mixture was stirred at 20°C for 16 hours. It was diluted with water (15 mL) and extracted with ethyl acetate (15 mL x 3). The organic layer was washed with saturated saline (50 mL), dried over anhydrous sodium sulfate, and concentrated to obtain a residue. The residue was purified by flash column (PE:ethyl acetate = 1:0 → 0:1) to obtain the title compound (100 mg, 0.3397 mmol, yield 46.663%) as a yellow oil.

[0416] (1R,5S,6r)-6-(4,5,5-trimethyl-4,5-dihydro-1,2-oxazol-3-yl)-3-azabicyclo[3.1.0]hexane trifluoroacetate A mixture of tert-butyl (1R,5S,6r)-6-(4,5,5-trimethyl-4,5-dihydro-1,2-oxazol-3-yl)-3-azabicyclo[3.1.0]hexane-3-carboxylate (160 mg, 0.54 mmol), trifluoroacetic acid (0.5 mL, 0.54 mmol), and DCM (2 mL) was stirred for 40 minutes at 20° C. The reaction mixture was concentrated under reduced pressure and then lyophilized to give the title compound (100 mg, crude product) as a yellow oil. 1 H NMR (400MHz, CHLOROFORM-d) δ = 3.60-3.40 (m, 4H), 2.30-2.20 (m, 2H), 2.00-1.70 (m, 2H), 1.24 (s, 3H), 1.15 (s, 3H), 0.95 (d, J = 7.6 Hz, 3H).

[0417] (1-Isopropyl-1H-imidazol-4-yl)[(1R,5S,6r)-6-(4,5,5-trimethyl-4,5-dihydro-1,2-oxazol-3-yl)-3-azabicyclo[3.1.0]hex-3-yl]methanone HATU (127.91 mg, 0.33 mmol) and DIPEA (0.21 mL, 1.29 mmol) were added to a mixture of 1-isopropylimidazole-4-carboxylic acid (39.68 mg, 0.26 mmol) and DMF (1 mL). The mixture was heated at 50°C for 30 minutes, and (1R,5S,6r)-6-(4,5,5-trimethyl-4,5-dihydro-1,2-oxazol-3-yl)-3-azabicyclo[3.1.0]hexane trifluoroacetate (50 mg, 0.26 mmol) was added. The mixture was stirred at 20°C for 4 hours. The reaction mixture was diluted with water (10 mL), extracted with ethyl acetate (10 mL x 2), and washed with saturated saline (10 mL). The combined organic layer was 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 (6 mg, 0.0182 mmol, yield 7.0554%) as a white solid. 1H NMR (400MHz, DMSO) δ = 7.98 (d, J=2.8 Hz, 2H), 4.79 (br d, J=12.5 Hz, 1H), 4.65 (td, J=6.8, 13.2 Hz, 1H), 4.17 - 4.10 (m, 1H), 4.01 (br d, J=13.1 Hz, 1H), 3.65 (br s, 1H), 3.02 (br d, J=6.5 Hz, 1H), 2.30 - 2.07 (m, 2H), 1.60 (d, J=6.5 Hz, 6H), 1.47 (br s, 1H), 1.48 - 1.45 (m, 1H), 1.40 (s, 3H), 1.31 (s, 3H), 1.22 (d, J=7.5 Hz, 3H).

[0418] Example 47 (1-isopropyl-1H-imidazol-4-yl){(1R,5S,6r)-6-[(4S)-4,5,5-trimethyl-4,5-dihydro-1,2-oxazol-3-yl]-3-azabicyclo[3.1.0]hex-3-yl}methanone Example 48 (1-Isopropyl-1H-imidazol-4-yl){(1R,5S,6r)-6-[(4R)-4,5,5-trimethyl-4,5-dihydro-1,2-oxazol-3-yl]-3-azabicyclo[3.1.0]hex-3-yl}methanone To a solution of 1-isopropylimidazole-4-carboxylic acid (476.15 mg, 3.09 mmol) in pyridine (8 mL) was added EDCI (592.06 mg, 3.09 mmol) and (1R,5S,6r)-6-(4,5,5-trimethyl-4,5-dihydro-1,2-oxazol-3-yl)-3-azabicyclo[3.1.0]hexane (400 mg, 2.06 mmol). The resulting mixture was stirred at 20°C to 25°C for 2 hours. LCMS showed the desired MS (as the major peak). The reaction mixture was concentrated directly. The residue was purified by prep-HPLC (NH 3The resulting fractions were combined, concentrated to remove most of the acetonitrile, and lyophilized. The products were chiral separated by SFC and lyophilized to give (1-isopropyl-1H-imidazol-4-yl){(1R,5S,6r)-6-[(4S)-4,5,5-trimethyl-4,5-dihydro-1,2-oxazol-3-yl]-3-azabicyclo[3.1.0]hex-3-yl}methanone (48.84 mg, 0.15 mmol, 7.2% yield) and (1-isopropyl-1H-imidazol-4-yl){(1R,5S,6r)-6-[(4R)-4,5,5-trimethyl-4,5-dihydro-1,2-oxazol-3-yl]-3-azabicyclo[3.1.0]hex-3-yl}methanone (52.66 mg, 0.1594 mmol, 7.7403% yield), both as yellow gums. 1 H NMR (400MHz, CHLOROFORM-d) δ = 7.68 (br s, 1H), 7.49 (s, 1H), 4.85 - 4.64 (m, 1H), 4.48 - 4.29 (m, 1H), 4.27 - 4.12 (m, 1H), 4.03 - 3.88 (m, 1H), 3.71 - 3.54 (m, 1H), 2.78 (quin, J=7.2 Hz, 1H), 2.30 - 1.95 (m, 2H), 1.65 (br s, 3H), 1.52 (s, 6H), 1.31 (d, J=2.8 Hz, 3H), 1.28 - 1.18 (m, 4H), 1.10 (br d, J=7.3 Hz, 3H).

[0419] Example 49 (1-Isopropyl-1H-imidazol-4-yl)[(1R,5S,6r)-6-(4-methoxy-5,5-dimethyl-4,5-dihydro-1,2-oxazol-3-yl)-3-azabicyclo[3.1.0]hex-3-yl]methanone tert-Butyl (1R,5S,6S)-6-ethynyl-3-azabi...

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]-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]methanone, a compound represented by the formula (I)-1,2-diphenyl-1-carbonyl)-3-azabicyclo[3.1.0]hex-3-yl]-(5-isopropyl-1H-pyrazol-3-yl)methanone, (5-isopropyl-1H-pyrazol-3-yl)-[(1S,5R)-6-(5-methyl-4-phenyl-isoxazol-3-yl)-3-azabicyclo[3.1.0]hex-3-yl]methanone, and [(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 are excluded) 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) (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; (3) (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; (4) {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; (5) [(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; (6) (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; (7) (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 (8) 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 R 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.

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