Pharmaceutical composition containing a compound having KDM5 inhibitory activity

Abstract

To provide preventive and / or therapeutic agents for cancer, Huntington's disease, Alzheimer's disease, etc.SOLUTION: The invention provides a pharmaceutical composition containing a compound represented by the general formula (I) (where all symbols are as defined in descriptions in the specification) or a salt thereof.SELECTED DRAWING: None

Description

[Technical Field]

[0001] The present disclosure relates to a pharmaceutical composition containing a compound represented by the following general formula (I) or a salt thereof, which has a KDM5 inhibitory activity. [Background technology]

[0002] Eukaryotic DNA resides in the cell nucleus in the form of chromatin, a complex with histone proteins. Histone proteins undergo modifications such as methylation, acetylation, and phosphorylation by various enzymes, and these modifications are known to induce chromatin reorganization and transcriptional changes. Epigenetic modifications, including histone methylation, reversibly regulate gene expression without altering the nucleic acid sequence and play an important role in physiological processes.

[0003] KDM5 proteins belong to the JARID histone demethylase family and demethylate the trimethylated lysine 4 residue of histone H3 (H3K4me3). Mammals, including humans, have four subfamily members: KDM5A, KDM5B, KDM5C, and KDM5D. Each subfamily contains five conserved domains: JmjN, ARID, JmjC, PHDs, and the C5HC2 zinc finger. The KDM5 family is widely distributed in blood cells and various organs in the body, and is particularly highly expressed in cancer tissues. Epigenetic abnormalities in cancer cells are known to contribute to their proliferation and metastasis, 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 neuropsychiatric and metabolic disorders. Therefore, compounds with KDM5 inhibitory activity may be useful for ameliorating epigenetic abnormalities and preventing and treating these diseases.

[0004] As a related art of the present invention, WO 2016 / 057924 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, 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 are each independently 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, alkyl, or a cyclic group; Or, R 5A and R 6A are taken together to form a cyclic group (excerpt from the definition of the group). ) or a salt thereof.

[0005] Furthermore, WO 2000 / 039089 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- or 6-membered heteroaryl ring; R 1B is selected from a variety of substituents; R 2Bis H, or a halogen; R 3B is H, halogen, alkyl group, 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. (extract of definition of group) or a pharmaceutically or veterinarily acceptable derivative or prodrug thereof.

[0006] Furthermore, WO 2021 / 010492 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 heterocyclic ring 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, etc.; L 1C is a bond or carbonyl (-C(=O)-); L 2C is a bond, carbonyl (-C(=O)-), etc.; R 2-1Crepresents a 5- or 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, pharmaceutical compositions containing compounds having KDM5 inhibitory activity for treating or preventing diseases such as cancer, Huntington's disease, and Alzheimer's disease are desired. [Means for solving the problem]

[0009] As a result of intensive research conducted by the inventors of the present invention to solve the above-mentioned problems, they have found that the above-mentioned object can be achieved by a pharmaceutical composition containing a compound represented by the following general formula (I) or a salt thereof:

[0010] Thus, one aspect of 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- to 9-membered aromatic heterocycle or a 5-membered non-aromatic heterocycle optionally substituted by R 12 is (1) C alkyl, (2) C cycloalkyl, (3) C haloalkyl, (4) C alkoxy, (5) 1 to 3 R 17 (6) phenyl optionally substituted with C alkyl, (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 to 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 has 1 to 5 R 13 C3-12 mono- or bi-carbocyclic ring or 5-9-membered mono- or bi-heterocyclic ring 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, C1-4 alkyl, C1-4 haloalkyl or nitrile; Within the group, the arrow indicates the bond of -CON< to the nitrogen atom; 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 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 Cyc4, which may be substituted with (Cyc4), or (6) 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 [(1S,5R)-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 consists of 1 to 5 R 12 the compound according to the above [1] or a salt thereof; [3] The compound according to the above [2], wherein the 5-membered non-aromatic heterocycle is 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 C 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 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 the compound according to any one of [1] to [3] and [3-1] above, or a salt thereof, wherein the compound represents imidazole optionally substituted by [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 C 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, and R 14-1 represents C1-4 alkyl or C3-5 cycloalkyl optionally substituted by C1-4 alkyl, and other symbols have the same meanings as defined 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 or salt thereof 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; [7]R 9 But 1 to 3 R 15the compound according to any one of [1] to [3] and [3-1] above, or a salt thereof, wherein the compound 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 [1] or [5] above), or a salt thereof according to any one of [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 or salt thereof according to any one of [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;

[10] R 1 -CONR 10 R 11the compound according to [1] above, 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 other symbols have the same meanings as in the above [1]), the compound according to the above

[11] , or a salt thereof;

[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 or salt thereof according to any one of [1],

[10] to

[12] , and [11-1];

[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 or salt thereof according to the above

[10] ,

[11] and [11-1], wherein the compound represents a pyrazole optionally substituted by

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

[10] ,

[11] , [11-1] and

[15] ;

[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; [A-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 12 a 5- to 9-membered aromatic heterocycle or a 5-membered non-aromatic heterocycle optionally substituted by R 12 is (1) C alkyl, (2) C cycloalkyl, (3) C haloalkyl, (4) C alkoxy, (5) 1 to 3 R 17 (6) phenyl optionally substituted with C alkyl, (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 to 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 17may be the same or different; Cyc2 has 1 to 5 R 13 C3-12 mono- or bi-carbocyclic ring or 5-9-membered mono- or bi-heterocyclic ring 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, C1-4 alkyl, C1-4 haloalkyl or nitrile; Within the group, the arrow indicates the bond of -CON< to the nitrogen atom; 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 1 to 3 R 14 imidazole optionally substituted with 1 to 3 R 15 represents an optionally substituted pyrazole; R 14is (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 Cyc4, which may be substituted with (Cyc4), or (6) 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]-3- a pharmaceutical composition containing a compound represented by the formula (1), (excluding 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; [A-2] The pharmaceutical composition according to the above [A-1], further comprising a pharmaceutically acceptable carrier; [A-3]R 1 represents Cyc1, and Cyc1 consists of 1 to 5 R 12 the pharmaceutical composition according to the above [A-1] or [A-2], wherein R represents an optionally substituted 5-membered non-aromatic heterocycle; [A-4] The pharmaceutical composition according to the above [A-3], wherein the 5-membered non-aromatic heterocycle is 4,5-dihydroisoxazole or 4,5-dihydro-1,2,4-oxadiazole; [A-5] The compound represented by general formula (I) or a salt thereof is represented by general formula (I-01) [ka] (In the formula, R 12-1 and R 12-2 each independently represents C alkyl; R 12-1 and R 12-2 is R 12-1 and R 12-2may 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 [A-1]), or a salt thereof; [A-6]R 9 But 1 to 3 R 14 the pharmaceutical composition according to any one of [A-1] to [A-5] above, wherein the imidazole optionally substituted by [A-7] The compound represented by general formula (I) or a salt thereof is represented by general formula (I-1) [ka] (In the formula, R 12-1 and R 12-2 each independently represents C 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, and 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 defined in [A-1]); or a salt thereof; [A-8] A compound represented by general formula (I) or a salt thereof, (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, and (9) The pharmaceutical composition according to any one of the preceding items [A-1] to [A-7], which is a compound selected from the group consisting of [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; [A-9]R 9 But 1 to 3 R 15the pharmaceutical composition according to any one of [A-1] to [A-5] above, wherein the compound represents a pyrazole optionally substituted by [A-10] The compound represented by general formula (I) or a salt thereof is represented by general formula (I-2): [ka] (wherein all symbols have the same meaning as in [A-1] or [A-7] above) or a salt thereof; [A-11] A compound represented by general formula (I) or a salt thereof, (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, and (5) The pharmaceutical composition according to any one of [A-1] to [A-5], [A-9] and [A-10] above, which is a compound selected from the group consisting of (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; [A-12]R 1 -CONR 10 R 11 the pharmaceutical composition according to the above [A-1], [A-13]R 10 represents isopropyl, tert-butyl, 1,1,1-trifluoro-2-methylpropan-2-yl, 1-methylcyclopropyl, 1-(trifluoromethyl)cyclopropyl, or 1-cyanocyclopropyl; [A-14] The compound represented by general formula (I) or a salt thereof 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 other symbols have the same meanings as in the above [A-1]), or a salt thereof; [A-15]R 9 But 1 to 3 R 14 the pharmaceutical composition according to any one of [A-12] to [A-14], wherein the imidazole optionally substituted by [A-16] The compound represented by general formula (I) or a salt thereof 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 [A-1] or [A-7] above), or a salt thereof; [A-17] A compound represented by general formula (I) or a salt thereof, (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, and (4) The pharmaceutical composition according to any one of [A-1] and [A-12] to [A-16] above, which is a compound selected from the group consisting of (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; [A-18]R 9 But 1 to 3 R 15 the pharmaceutical composition according to any one of [A-12] to [A-14], wherein the pyrazole is optionally substituted with [A-19] The compound represented by general formula (I) or a salt thereof is represented by general formula (I-4) [ka] (wherein all symbols have the same meaning as in [A-1] or [A-16] above), [A-20] A compound represented by general formula (I) or a salt thereof, (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, and (4) The compound or salt thereof according to any one of [A-1], [A-12] to [A-14], [A-18], and [A-19] above, which is a compound selected from the group consisting of (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; [A-21] The pharmaceutical composition according to any one of the above items [A-1] to [A-20], which is a KDM5 inhibitor; [A-22] The pharmaceutical composition according to any one of the preceding items [A-1] to [A-21], which is an agent for preventing and / or treating a KDM5-related disease; [A-23] 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, 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, and liver disease. the pharmaceutical composition according to the above [A-22], wherein the patient is suffering from a neurodegenerative disorder, a pathological immune condition accompanied by T cell activity, a central nervous system disorder, a myeloproliferative disorder, Parkinson's disease, disease with Lewy bodies, 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; [A-24] The pharmaceutical composition according to the above [A-22], wherein the KDM5-related disease is cancer or Alzheimer's disease; [A-25] A prophylactic and / or therapeutic agent for a KDM5-associated disease, comprising the compound represented by general formula (I) described in [A-1] above or a salt thereof 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; [A-26] A preventive and / or therapeutic agent for a KDM5-associated disease, comprising the compound represented by general formula (I) described in [A-1] above or a salt thereof; [A-27] The preventive and / or therapeutic agent according to the above [A-26], further comprising a pharmaceutically acceptable carrier; [A-28] A compound represented by formula (I) or a salt thereof according to the above [A-1], for use in the prevention and / or treatment of a KDM5-associated disease; [A-29] Use of the compound represented by general formula (I) or a salt thereof described in [A-1] above for the manufacture of an agent for the prophylaxis and / or treatment of KDM5-related diseases; or [A-30] Use of the compound represented by general formula (I) described in [A-1] above or a salt thereof for the manufacture of a pharmaceutical composition for the prevention and / or treatment of a KDM5-associated disease. [Effects of the Invention]

[0011] The compound represented by general formula (I) described herein or a salt thereof (hereinafter collectively referred to as the present compound) has KDM5 inhibitory activity. Therefore, a pharmaceutical composition containing the present compound is useful for 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 cirrhosis, and the like. The compound may be used as a preventive and / or therapeutic agent for diseases such as encephalopathy, pathological immune conditions associated with T cell 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 INVENTION

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

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

[0014] As used herein, "1 to 9 deuterated C1-4 alkyl" includes CH2D-, CHD2-, CD3-, CD3CD2-, CD3CD2CD2-, (CD3)2CD-, CD3CD2CD2CD2-, CD3CD2CD(CD3)-, (CD3)3C-, (CD3)2CDCD2-, 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, the term "C3-5 cycloalkane" includes, for example, cyclopropane, cyclobutane, and cyclopentane rings.

[0021] In the present specification, examples of the "C3-5 cycloalkane in which the carbon atoms of the 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 a 1,3-dioxolane ring.

[0022] In this 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 this 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 heterocycle containing 1 to 4 nitrogen atoms, 1 oxygen atom and / or 1 sulfur atom", etc. Examples of the "5-membered non-aromatic heterocycle containing 1 to 4 nitrogen atoms, 1 oxygen atom and / or 1 sulfur atom" include 2,3-dihydro-1,2,3-oxadiazole, 2,3-dihydro-1,2,3-thiadiazole, 2,3-dihydro-1,2,4-oxadiazole, 2,3-dihydro-1,2,4-thiadiazole, 2,3-dihydro-1,2,5-oxadiazole, 2,3-dihydro-1,2 ,5-thiadiazole, 2,3-dihydro-1,3,4-oxadiazole, 2,3-dihydro-1,3,4-thiadiazole, 2,3-dihydro-1,3,4-oxadiazole, 2,3-dihydro-1H-1,2,3-triazole, 2,3-dihydro-1H-1,2,4-triazole, 2,3-dihydro-1H-imidazole, 2,3-dihydro-1H-pyrazole, 2,3-dihydro-1H -pyrrole, 2,3-dihydro-1H-tetrazole, 2,3-dihydrofuran, 2,3-dihydroisothiazole, 2,3-dihydroisoxazole, 2,3-dihydrooxazole, 2,3-dihydrothiazole, 2,3-dihydrothiophene, 4,5-dihydro-1,2,3-oxadiazole, 4,5-dihydro-1,2,3-thiadiazole, 4,5-dihydro-1,2,4-thiadiazole, 4,5-dihydro-1H-1,2,3-triazole, 4,5-dihydro-1H-1,2,4-triazole, 4,5-dihydro-1H-imidazole, 4,5-dihydro-1H-pyrazole, 4,5-dihydro-1H-tetrazole, 4,5-dihydroisothiazole, 4,5-dihydroisoxazole, a 4,5-dihydrooxazole ring, and a 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, etc.

[0026] As used herein, examples of the "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 the "5- to 9-membered monocyclic or bicyclic heterocycle containing 1 to 4 nitrogen atoms, 1 to 2 oxygen atoms, and / or 1 sulfur atom" include pyrrole, imidazole, triazole, tetrazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, furan, pyran, thiophene, thiopyran, oxazole, isoxazole, thiazole, isothiazole, furazan, oxadiazole, oxazine, oxadiazine, thiadiazole, thiazine, thiadiazine, pyrroline, pyrrolidine, imidazoline, imidazolidine, triazoline, triazole, thiazole, thiadiazine, pyrroline, pyrrolidine, imidazoline, imidazolidine, triazole, thiadi ... 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, tetrahydrothiazolidine 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 out of 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., 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 clear to one skilled 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 contains, for example, 1 to 5 R 12 and more preferably, for example, a 5-membered non-aromatic heterocycle optionally substituted with 1 to 5 R 12 and 2,3-dihydro-1,2,5-oxadiazole, 2,3-dihydro-1,2,5-thiadiazole, 4,5-dihydro-1,2,3-oxadiazole, 4,5-dihydro-1,2,3-thiadiazole, 4,5-dihydro-1,2,4-oxadiazole, 4,5-dihydro-1,2,4-thiadiazole, 4,5-dihydro-1H-1,2,3-triazole, 4,5-dihydroisothiazole, or 4,5-dihydroisoxazole, each of which may be substituted with, for example, 1 to 5 R 12and 4,5-dihydro-1,2,4-oxadiazole or 4,5-dihydroisoxazole, optionally substituted with 1 to 5 R 12 and 4,5-dihydroisoxazole optionally substituted with

[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 attached, 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 attached, and particularly preferred is, for example, a C1-4 alkyl, or 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 attached.

[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 substituted with, for example, 1 to 5 R 13 and n is 1 or 2. The 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 and imidazole optionally 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) 1 to 3 R 16 or (4) C1-8 alkyl substituted with phenoxy, and more preferably, for example, (1) C1-8 alkyl or (2) C3-7 cycloalkyl optionally substituted with C1-4 alkyl.

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

[0037] In the present invention, R 15 is preferably, for example, (1) C alkyl, (2) C cycloalkyl optionally substituted with C alkyl, (3) 1 to 3 R 21 and C1-8 alkyl substituted with Cyc3 optionally substituted with C1-8 alkyl, 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 general formula (I) are preferably general formula (I-1A): [ka] (wherein all symbols have the same meanings as above).

[0040] In the present invention, the examples of general formula (I) are preferably 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; R 14 represents (1) C1-8 alkyl, (2) C3-7 cycloalkyl optionally substituted with C1-4 alkyl, or (5) C1-8 alkyl substituted with phenoxy; R 12-1 and R 12-2 each 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, C1-4 alkyl, halogen, or C1-4 alkoxy; R 15 represents (1) C1-8 alkyl, or (3) C1-8 haloalkyl; R 12-1 and R 12-2 independently represent 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 C alkyl, (3) a C cycloalkyl, (4) a C haloalkyl, (5) a C alkoxy, or (6) one to three R 17 (7) phenyl optionally substituted with C1-4 alkyl, (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) C alkyl, (3) C cycloalkyl, (4) C haloalkyl, (5) C alkoxy, (6) 1 to 3 R 17 (7) phenyl optionally substituted with C alkyl substituted with phenyl, (8) dimethylamino, (9) pyridyl, or (10) 1-(cyclopropylmethyl)pyrazol-3-yl (preferably, R 12H1 (2) C alkyl, (3) C cycloalkyl, (4) C haloalkyl, (6) 1 to 3 R 17 (7) phenyl optionally substituted with C1-4 alkyl, (9) pyridyl, or (10) 1-(cyclopropylmethyl)pyrazol-3-yl; R 12H2 is (1) a hydrogen atom, (2) a C alkyl, (3) a C cycloalkyl, (4) a C haloalkyl, (5) a C alkoxy, or (6) one to three R 17 (7) phenyl optionally substituted with 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 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) C alkyl, (3) C cycloalkyl, (4) C haloalkyl, (5) C alkoxy, (6) 1 to 3 R 17 (7) phenyl optionally substituted with C alkyl substituted with phenyl, (8) dimethylamino, (9) pyridyl, or (10) 1-(cyclopropylmethyl)pyrazol-3-yl (preferably, R 12H1 (2) C alkyl, (3) C cycloalkyl, (4) C haloalkyl, (6) 1 to 3 R 17 (7) phenyl optionally substituted with C1-4 alkyl, (9) pyridyl, or (10) 1-(cyclopropylmethyl)pyrazol-3-yl; R 12H2 is (1) a hydrogen atom, (2) a C alkyl, (3) a C cycloalkyl, (4) a C haloalkyl, (5) a C alkoxy, or (6) one to three R 17 (7) phenyl optionally substituted with 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) C alkyl, (3) C cycloalkyl, (4) C haloalkyl, (5) C alkoxy, (6) 1 to 3 R 17 (7) phenyl optionally substituted with C alkyl substituted with phenyl, (8) dimethylamino, (9) pyridyl, or (10) 1-(cyclopropylmethyl)pyrazol-3-yl (preferably, R 12H1 (2) C alkyl, (3) C cycloalkyl, (4) C haloalkyl, (6) 1 to 3 R 17(7) phenyl optionally substituted with C1-4 alkyl, (9) pyridyl, or (10) 1-(cyclopropylmethyl)pyrazol-3-yl; R 12H2 is (1) a hydrogen atom, (2) a C alkyl, (3) a C cycloalkyl, (4) a C haloalkyl, (5) a C alkoxy, or (6) one to three R 17 (7) phenyl optionally substituted with C alkyl, (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) C alkyl, (3) C cycloalkyl, (4) C haloalkyl, (5) C alkoxy, (6) 1 to 3 R 17 (7) phenyl optionally substituted with C alkyl substituted with phenyl, (8) dimethylamino, (9) pyridyl, or (10) 1-(cyclopropylmethyl)pyrazol-3-yl (preferably, R 12H1(2) C alkyl, (3) C cycloalkyl, (4) C haloalkyl, (6) 1 to 3 R 17 (7) phenyl optionally substituted with C1-4 alkyl, (9) pyridyl, or (10) 1-(cyclopropylmethyl)pyrazol-3-yl; R 12H2 is (1) a hydrogen atom, (2) a C alkyl, (3) a C cycloalkyl, (4) a C haloalkyl, (5) a C alkoxy, or (6) one to three R 17 (7) phenyl optionally substituted with 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 C alkyl, (3) a C cycloalkyl, (4) a C haloalkyl, (5) a C alkoxy, or (6) one to three R 17(7) phenyl optionally substituted with C alkyl, (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 C alkyl, (3) a C cycloalkyl, (4) a C haloalkyl, (5) a C alkoxy, or (6) one to three R 17 (7) phenyl optionally substituted with 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) C alkyl, (2) C cycloalkyl, (3) C haloalkyl, (4) C alkoxy, (5) 1 to 3 R 17 (6) C 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) C alkyl, (2) C cycloalkyl, (3) C haloalkyl, (4) C alkoxy, (5) 1 to 3 R 17(6) C 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) C alkyl, (2) C cycloalkyl, (3) C haloalkyl, (4) C alkoxy, (5) 1 to 3 R 17 (6) C 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) C alkyl, (2) C cycloalkyl, (3) C haloalkyl, (4) C 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, C1-4 alkyl, C1-4 alkoxy, or halogen, and 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) C alkyl, (3) C cycloalkyl, (4) C haloalkyl, (5) C alkoxy, (6) 1 to 3 R 17 (7) phenyl optionally substituted with C alkyl substituted with phenyl, (8) dimethylamino, (9) pyridyl, or (10) 1-(cyclopropylmethyl)pyrazol-3-yl (preferably, R 12H1 (2) C alkyl, (3) C cycloalkyl, (4) C haloalkyl, (6) 1 to 3 R 17 (7) phenyl optionally substituted with C1-4 alkyl, (9) pyridyl, or (10) 1-(cyclopropylmethyl)pyrazol-3-yl; R 12H2 is (1) a hydrogen atom, (2) a C alkyl, (3) a C cycloalkyl, (4) a C haloalkyl, (5) a C alkoxy, or (6) one to three R 17 (7) phenyl optionally substituted with 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) C alkyl, (3) C cycloalkyl, (4) C haloalkyl, (5) C 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) C alkyl, (3) C cycloalkyl, (4) C haloalkyl, (6) 1 to 3 R 17 (7) phenyl optionally substituted with C alkyl, (9) pyridyl, or (10) 1-(cyclopropylmethyl)pyrazol-3-yl; R 12H2 is (1) a hydrogen atom, (2) a C alkyl, (3) a C cycloalkyl, (4) a C haloalkyl, (5) a C alkoxy, or (6) one to three R 17 (7) phenyl optionally substituted with 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, C1-4 alkyl, halogen, or C1-4 alkoxy; R 14 represents (1) C1-8 alkyl, or (3) C1-8 haloalkyl; R 10 represents C alkyl or C 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, C1-4 alkyl, halogen, or C1-4 alkoxy; R 15 represents (1) C1-8 alkyl, or (3) C1-8 haloalkyl; R 10 represents C alkyl or C 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, examples of general formula (I) are preferably general formula (I-37): [ka] (wherein all symbols have the same meanings as above).

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

[0094] In the present invention, 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 configurations of the substituents corresponding to the substituent represented by the formula (I-37) are preferably in the same direction, as in the general formula (I-37).

[0096] In the present invention, or in the general formula (I) or (I-1), preferred compounds include, 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), preferred compounds include, 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), preferred compounds include, 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), preferred compounds include, 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 compounds include all isomers unless otherwise specified. For example, alkyl groups, alkoxy groups, etc. include straight-chain and branched-chain groups. Furthermore, the present compounds include double bond, ring, and fused ring isomers (E-, Z-, cis-, and trans-forms), asymmetric carbon atom isomers (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 (highly polar and less polar substances), equilibrium compounds, rotational isomers, mixtures of these in any proportions, and racemic mixtures. The present compounds also include tautomers. [Salts and solvates]

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

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

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

[0104] The N-oxide of the compound represented by general formula (I) refers to a compound in which the nitrogen atom of the compound represented by 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 general 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 salts may exist in a non-solvated form or in a solvated form with a pharmaceutically acceptable solvent such as water or ethanol. The solvate is preferably a hydrate. The compound represented by general formula (I) or its salts 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 pharmaceutically acceptable co-crystal former formed with a pharmaceutically 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. Co-crystals can be prepared according to known methods such as melt crystallization, recrystallization from a solvent, or physical grinding of the components. Suitable co-crystal formers include those disclosed in WO 2006 / 007448.

[0108] In the present invention, all references to the present 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., hydrate), N-oxide, or co-crystal of the compound represented by general formula (I), or a solvate (e.g., hydrate), N-oxide, or co-crystal of a salt of the compound represented by general formula (I).

[0110] [Prodrug] The prodrug of the compound represented by general formula (I) means a compound that is converted into the compound represented by general formula (I) by reaction with an enzyme, gastric acid, or the like in the living body. Examples of prodrugs of the compound represented by general formula (I) include, when the compound represented by general formula (I) has an amino group, compounds in which the amino group has been acylated, alkylated, or phosphorylated (for example, compounds 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); and, when the compound represented by general formula (I) has a hydroxyl group, compounds in which the hydroxyl group has been acylated, alkylated, phosphorylated, or converted to a borate (for example, compounds 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). Examples of prodrugs of the compound represented by general formula (I) include those that are converted into the compound represented by general formula (I) under physiological conditions as disclosed in "Drug Development," Vol. 7, "Molecular Design," 1990, Hirokawa Publishing, pp. 163-198. Prodrugs of the compound represented by general formula (I) can be produced by methods known per se. Like the compound represented by general formula (I), the prodrugs of the compound represented by general formula (I) may form salts such as acid addition salts, or may form solvates with water or alcoholic solvents (ethanol, etc.). [Labeled compound]

[0111] In the present invention, the compound represented by 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 manufacturing the present compound]

[0112] The compound represented by general formula (I) or a salt thereof 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 to the methods described in the Examples, or methods described in Comprehensive Organic Transformations: A Guide to Functional Group Preparations 2nd Edition (Richard C. Larock, John Wiley & Sons Inc., 1999), methods based on these, or combinations thereof. In the production methods described below, the starting 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-mediated synthesis (2) Method via mixed acid anhydride (3) Use of a condensing agent

[0115] These methods are described below. (1) The acyl halide-mediated method 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. 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 the presence or absence of a base (e.g., pyridine, triethylamine, dimethylaniline, or dimethylaminopyridine) in an organic solvent (e.g., chloroform, dichloromethane, dimethylformamide, diethyl ether, or tetrahydrofuran) or without a solvent 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)) at about 0°C to 40°C in the presence or absence of 1-hydroxybenzotriazole (HOBt).

[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 preferable results.

[0119] The compound represented by general formula (III) can be produced by subjecting the compound represented by 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] Deprotection reactions of amino-protecting groups are well known and are 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] 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 general formula (VII) can be produced by subjecting the compound represented by 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 general formula (VI) can be produced by subjecting the compound represented by general formula (V) to an oxime-forming reaction.

[0126] The oxime-forming 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] 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 amidation reaction of a compound represented by general formula (IX) and a compound represented by general formula (X).

[0129] The amidation can be carried out in the same manner as in the preparation of general formula (I) in Scheme I described above. The compound represented by general formula (II)-2 can be produced by alkylating a compound represented by general formula (XII) with a compound represented by general formula (XIII).

[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 temperatures between -78°C and 40°C.

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

[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] 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°C and 40°C. (2) DMSO oxidation can be carried out using dimethyl sulfoxide 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 general formula (XV) can be produced by an addition reaction between a compound represented by general formula (V) and a compound represented by general formula (XIV). M in general formula (XIV) 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 (eg, tetrahydrofuran) under an inert atmosphere (eg, dry nitrogen, or argon) at -78°C to 0°C.

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

[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 coupling reaction of a compound represented by general formula (XVII) with a compound represented by general formula (XVIII).

[0143] The coupling reaction is known, and for example, can be carried out 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)PdCl), tetrakis(triphenylphosphine)palladium (Pd(PPh 3)4), bis(triphenylphosphine)palladium dichloride (PdCl2(PPh3)2), palladium acetate (Pd(OAc)2), palladium black, 1,1'-bis(diphenylphosphinoferrocene)dichloropalladium (PdCl2(dppf)2), diallylpalladium dichloride (PdCl2(Allyl)2), iodophenylbis(triphenylphosphine)palladium (PhPdI(PPh3)2), etc.), at room temperature to 150°C using a base (e.g., sodium ethylate, sodium hydroxide, potassium hydroxide, triethylamine, sodium carbonate, sodium bicarbonate, potassium carbonate, cesium carbonate, thallium carbonate, tripotassium phosphate, cesium fluoride, barium hydroxide, tetrabutylammonium fluoride, etc.) or an aqueous solution thereof, or a mixture thereof.

[0144] The compound represented by general formula (XVII) can be produced by subjecting the compound represented by 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] 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] 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 (such as POCl3) at 80 to 120°C. The compound represented by general formula (XXII) can be produced by amidation reaction of a compound represented by general formula (XX) with a compound represented by general formula (XXI)-1 or (XXI)-2.

[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 general formula (XX) can be produced by subjecting the compound represented by 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) using an acidic catalyst (eg, TsOH) 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-forming reaction can be carried out using 1,1-dimethoxy-N,N-dimethylmethanamine in a solvent (eg, acetonitrile, DMF, etc.) at 100 to 120°C.

[0157] [ka] R in general formula (II) in Scheme I 1 teeth, [ka] 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 can be carried out using Tf2O and TMSN3 in a solvent (e.g., dichloromethane) at 0 to 30°C.

[0159] The compound represented by general formula (XXVI) can be produced by subjecting a compound represented by general formula (IX) and a compound represented by 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) at 100 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 general formula (XXVII) can be produced by subjecting the compound represented by 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 100 to 140°C.

[0164] The compound represented by general formula (XXX) can be produced by amidation reaction of a compound represented by general formula (IX) and a compound represented by general formula (XXIX). 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] General formula (II) can be expressed as general formula (II)-10 in scheme XI.

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

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

[0169] In the formula, the compounds represented by general formulas (IV), (VIII), (X), (XI), (XIII), (XIV), (XVI), (XVIII), (XIX), (XXI)-1, (XXI)-2, (XXIII), (XXV), (XXVII), (XXIX) and (XXXI) are commercially available. Alternatively, they 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).

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

[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 reaction of the ester can be carried out in a solvent (eg, THF, diethyl ether, or DME) using a reducing agent (eg, LiAlH4, DIBAL-H, Red-Al, etc.) at -20°C to 20°C.

[0175] The compound represented by general formula (XXXVII) can be produced by subjecting the compound represented by general formula (XXXVIII) to an imide reduction reaction. The imide reduction reaction can be carried out in a solvent (such as THF, diethyl ether, or DME) using a borane reducing agent (such as BH3THF complex, BH3Me2S complex, or B2H6) at 20 to 80°C.

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

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

[0178] The compounds represented by general formulas (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).

[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, a solid-phase supported reagent supported on a polymer (such as polystyrene, polyacrylamide, polypropylene, and polyethylene glycol) may be used, if necessary.

[0181] The products obtained by the reactions exemplified herein can be purified by conventional purification methods, such as atmospheric or reduced pressure distillation, 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 present compound has low toxicity, and therefore, pharmaceutical compositions containing the present compound can be safely used as pharmaceuticals. [Application to pharmaceuticals]

[0183] Since the present compound has KDM5 inhibitory activity, it can be used as an agent for preventing and / or treating KDM5-related diseases in mammals, particularly humans. The present invention provides pharmaceutical compositions containing the present compounds (hereinafter collectively referred to as the present pharmaceutical compositions), which can be used as an agent for preventing and / or treating KDM5-related diseases (in mammals, particularly humans).

[0184] Examples of such diseases include hyperproliferative disorders, 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 disorders, destructive bone disorders, proliferative disorders, 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 disorders, intellectual disabilities, post-traumatic stress disorder, and hepatitis.

[0185] In particular, the compound or pharmaceutical composition is 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 compound or pharmaceutical composition is particularly suitable for the prevention and / or treatment of cancer and Alzheimer's disease.

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

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

[0188] Mice (male C57BL / 6 mice, 16 to 23 months old, Charles River Japan) were used. The test substance and its vehicle were orally administered once daily for two weeks. Subsequently, cognitive function was assessed using a novel object recognition (NOR) test using a plastic cage equipped with a video camera (ECON cage, CL-0107, 345mm x 403mm x 177mm, CLEA Japan) as the experimental apparatus. The evaluation was performed in a dark room, with the light intensity adjusted to approximately 20 lux near the experimental apparatus. To allow the animals to acclimate to the evaluation environment, the mice were moved to the evaluation room at least one hour before the start of the test. This test was conducted over three days. On the first day, for acclimatization to the experimental apparatus, the mice were placed in a cage and allowed to move freely for 10 minutes. On the second day, for the acquisition trial, two identical objects (familiar objects) were placed on the cage in the same manner for 10 minutes. The two objects were placed apart on a line parallel to the long side of the cage. The distance between the object and the two adjacent inner walls 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 allowed to behave in the same way for 10 minutes. The test trial begins 24 hours after the acquisition trial (acceptable range: 23 to 25 hours). The exploration time for 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 for the familiar and novel objects using the following formula:

[0189] Total exploration time (seconds) = 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 after authentication. Cells are cultured for a maximum of 10–12 passages and then replaced with earlier-passage cells 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% CO2. They are passaged periodically by removing the DMEM, washing with PBS, and detaching the cells with an appropriate amount of trypsin / EDTA.

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

[0193] For cytotoxicity testing, Cell Counting Kit-8 (#CK04, DOJINDO) was used according to the manufacturer's instructions. MCF-7T47D or MDA-MB231 cell suspensions (5000 cells / 100 μL / well) were dispensed into 96-well plates. After 24 hours, compounds or DMSO were added to the growth medium and the cells were irradiated. 48 hours after irradiation, 10 μL of CCK-8 solution was added to each well of the plate and the cells were again cultured for 1 hour. The absorbance at 450 nm was 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 a 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 hours of incubation at 37°C, cells were switched to maintenance medium (Life Technologies) containing William's medium E supplemented with 0.5% penicillin / streptomycin, 6.25 pg / mL human recombinant insulin, 6.25 pg / mL human transferrin, 6.25 ng / mL selenite, 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, PHHs were infected with genotype D (AD38-derived) HBV at 500 genome equivalents per cell in maintenance medium supplemented with 4% PEG8000 (Promega). After 24 hours of incubation, cells were washed three times with William's medium E and fresh maintenance medium was added. Three days after infection, infected PHH cells were seeded at a concentration of 65,000 cells / well into collagen-precoated 96-well plates in a final volume of 125 μl of maintenance medium (Life Technologies) containing serially diluted compounds or DMSO (final concentration 1%). Compound-containing medium was replenished every 2 to 3 days. After 12 days of culture, HBsAg secreted into the supernatant was measured using a multiplex chemiluminescence (Mesoscale discovery, MSD) assay using an HBsAg-specific capture and detection antibody pair. EC50 values ​​were calculated by fitting the dose-response curve to a four-parameter equation.

[0196] An example of the test method for evaluating the pharmacological activity of the present compound is the evaluation system for improving depressive symptoms in a social defeat stress model.For example, the effectiveness of the present compound in a social defeat model can be evaluated using the following method.

[0197] Eight-week-old male DBA / 2 mice were used in the experiment. Social defeat stress was administered to the mice. The test mice were placed in a cage with highly aggressive CD-1 mice for five minutes. During this time, the CD-1 mice unilaterally attacked the test mice (physical stress). After five minutes, the CD-1 mice and the test mice were separated by a transparent acrylic board and maintained for 24 hours (psychological stress). This process was repeated for five consecutive days. Compounds or solvents were orally administered two hours before social defeat stress every day. Afterwards, social interaction tests and sucrose preference tests were performed.

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

[0199] In the sucrose preference test, a bottle containing a 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 in animals in an anhedonic state, which is a state of depression, sucrose preference is reduced.

[0200] When the present compound is used for pharmaceutical purposes, the present compound can be used as a single agent, or can be used as a combination agent with additional active ingredients such as those listed below, 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) alleviating 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 treatment agents, 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 2Aantagonists, 5-HT7 antagonists, 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 inhibitors), and EGFR-1 (upregulatory receptor inhibitors). epidermal growth factor receptor (EFR) inhibitors, FPRL-1 (formyl peptide-like receptor-1) ligands, GABA antagonists, and MICAL (molecules that interact 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 elimination and / or clearance, histone deacetylase inhibitors, 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, kynurenine 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 are 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-enhancing 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 (genetical recombination), etc.

[0203] In combination with an additional drug, the compound and the additional drug may be administered as a combined drug containing both ingredients in a single drug, or as separate preparations administered via the same or different administration routes. Separate preparations do not need to be administered simultaneously, and may be administered sequentially with a time lag. When administered sequentially, the order or method of administration is not particularly limited and can be appropriately adjusted to achieve the expected efficacy.

[0204] The dose of the additional drug used in combination with the present compound can be increased or decreased as appropriate depending on its clinical dose or similar drug. The ratio of the present compound to the additional drug can be adjusted as appropriate, taking into account the subject's age, body weight, administration method, administration time, target disease, pathological condition, etc. Typically, 1 part by weight of the present compound can be combined with 0.01 to 100 parts by weight of the other drug. Multiple other drugs may be used. In addition to the above drugs, the other drugs may have a mechanism of action similar to that of the above drugs. Such other drugs include not only known drugs but also drugs that will be discovered in the future.

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

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

[0207] When the pharmaceutical composition is used as a single agent or in combination with other drugs for the prevention and / or treatment of the above-mentioned diseases, the active ingredient, the compound, is typically formulated with pharmaceutically acceptable carriers such as various additives or solvents, and the resulting formulation is administered systemically or topically, orally or parenterally. Here, "pharmaceutically acceptable carrier" refers to a substance other than the active ingredient commonly used in pharmaceutical formulations. Pharmaceutically acceptable carriers preferably exhibit no pharmacological activity at the dosage of the formulation, are harmless, and do not interfere with the therapeutic effect of the active ingredient. Pharmaceutically acceptable carriers may be used to enhance the usefulness of the active ingredient and formulation, facilitate formulation, stabilize quality, or improve usability. Specifically, substances listed in the "Dictionary of Pharmaceutical Additives" (2000, Yakuji Nipposha, IPEC JAPAN edition) can be appropriately selected as needed.

[0208] The pharmaceutical composition containing the compound of the present invention can be formulated into various dosage forms. Examples of dosage forms include oral administration agents (e.g., tablets, capsules, granules, powders, oral liquids, syrups, oral jellies, etc.), oral preparations (e.g., oral tablets, oral sprays, oral semisolid preparations, oral gargles, etc.), injection preparations (e.g., injections, etc.), dialysis preparations (e.g., dialysis agents, etc.), inhalation agents (e.g., inhalation agents, etc.), ophthalmic preparations (e.g., eye drops, eye ointments, etc.), otorhinologic preparations (e.g., ear drops, etc.), nasal preparations (e.g., nasal drops, etc.), rectal preparations (e.g., suppositories, rectal semisolid preparations, enemas, etc.), vaginal preparations (e.g., vaginal tablets, vaginal suppositories, etc.), and dermatological preparations (e.g., solid topical preparations, liquid topical preparations, sprays, ointments, creams, gels, patches, etc.). [Oral administration]

[0209] Oral formulations include, for example, tablets, capsules, granules, powders, oral liquids, syrups, and oral jellies. Oral formulations are classified into rapidly disintegrating formulations, in which the release of the active ingredient from the formulation is not specifically controlled, and controlled-release formulations, such as enteric-coated and sustained-release formulations, in which the release is controlled according to the purpose by adjusting the formulation design and manufacturing method. Enteric-coated formulations are formulations designed to release the active ingredient primarily in the small intestine rather than in the stomach, with the aim of suppressing the degradation of the active ingredient in the stomach or reducing gastric irritation caused by the active ingredient. Enteric-coated formulations are generally manufactured by coating with an acid-insoluble enteric base. Sustained-release formulations are formulations in which the release rate, release time, and release site of the active ingredient are adjusted to reduce the frequency of administration or mitigate side effects. Sustained-release formulations are usually manufactured 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. to facilitate administration and to prevent decomposition of the active ingredient. (1) Tablets

[0210] Tablets are solid preparations for oral administration in a specific shape. Examples of tablets include plain tablets, film-coated tablets, sugar-coated tablets, multilayer tablets, dry-coated tablets, and other commonly known tablets, as well as orally disintegrating tablets, chewable tablets, effervescent tablets, dispersible tablets, and soluble tablets. Plain tablets can usually be manufactured by the following procedures (a), (b), or (c). (a) Add additives such as excipients, binders, disintegrants, etc. 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) Additives such as excipients, binders, disintegrants, etc. to the active ingredient and mix until homogeneous, then directly compress and mold, or add the active ingredient, lubricant, etc. to the granules to which the additives have been added and mix until homogeneous, then compress and mold. (c) The active ingredient is mixed with excipients, binders, and other additives to form a homogeneous mixture, then wet-kneaded with a solvent, molded into a specific shape, and dried by an appropriate method. Film-coated tablets are typically produced by applying a suitable thin film, such as a polymeric compound, to a plain tablet. Sugar-coated tablets are typically produced by applying a coating film containing a sugar or sugar alcohol to a plain tablet. Multilayer 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 using an appropriate known method. Tablets can be made into enteric-coated or sustained-release tablets using an appropriate known method. Orally disintegrating tablets, chewable tablets, effervescent tablets, dispersible tablets, and dissolving tablets are tablets with unique functions imparted by appropriately selecting excipients and can be produced according to the above-mentioned tablet manufacturing methods. Orally disintegrating tablets are tablets that rapidly dissolve or disintegrate in the mouth and are taken. Chewable tablets are tablets that are taken by chewing. Effervescent tablets are tablets that dissolve or disperse in water while rapidly effervescent. Dispersible tablets are tablets that are dispersed in water before being taken. Dissolving tablets are tablets that are dissolved in water before being taken. Effervescent tablets can be produced using additives such as suitable acidic substances, carbonates, and bicarbonates. (2) Capsules

[0211] Capsules are formulations in which an active ingredient is filled into 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 additives such as excipients to the active ingredient and blending them to form a homogeneous mixture, or by preparing granules or molded products using an appropriate method and then adding the granules or molded products directly or after appropriate molding to a 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, or the like, and molding the mixture into a specific shape. Capsules can be made into enteric-coated capsules or sustained-release capsules using appropriate known methods. Coloring agents, preservatives, etc. may be added to the capsule base. (3) Granules

[0212] Granules are granular preparations. Examples of granules include those commonly 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, binders, disintegrants and other additives to form a homogeneous mixture, and then granulated by an appropriate 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 form a homogeneous mixture, which is then granulated by an appropriate method. The granules may be coated with a film as needed, or may be made into enteric-coated 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 rapidly effervescent. Furthermore, they can be made into fine granules by adjusting the particle size. (4) Powder

[0213] Powders are powdered preparations 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 fluid viscous gels. Examples of liquids include those commonly referred to as oral solutions, as well as elixirs, suspensions, emulsions, and lemonades. Oral liquids are generally prepared by mixing the active ingredient with additives and purified water, dissolving, emulsifying, or suspending the active ingredient homogeneously, and filtering the formulation as needed. Elixirs are clear oral liquids containing ethanol and have a sweet, fragrant taste. Elixirs are typically prepared by dissolving a solid active ingredient or its extract in ethanol, purified water, flavorings, sucrose, sugars, or sweeteners, and then obtaining a clear liquid by filtration or other methods. Suspensions are oral liquids in which the active ingredient is finely and homogeneously suspended. Suspensions are typically prepared by suspending a solid active ingredient in purified water or oil with a suspending agent or additive, and then homogenizing the entire mixture using an appropriate method. Emulsions are 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 then emulsifying and homogenizing the whole by an appropriate method. Lemonade is a clear oral liquid that has a sweet and sour taste. (6) Syrup

[0215] Examples of formulations include syrups. Syrups are viscous liquid or solid formulations containing sugars or sweeteners. Examples include syrup preparations. Syrups are typically prepared by dissolving, mixing, suspending, or emulsifying the active ingredient in a solution of sucrose, other sugars, or sweeteners, or by using syrup alone, followed by boiling and filtration under heating if necessary. Syrup preparations are prepared by adding water to a granular or powdered formulation and are sometimes called dry syrups. Syrup preparations typically use sugars or sweeteners as additives and can be prepared in the same manner as granules or powders. (7) Oral jelly preparation

[0216] Oral jelly preparations are non-flowable, 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 mixture into a specific shape using an appropriate method. [Oral preparations] (1) Oral tablets

[0217] Oral tablets are preparations having a specific 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 using the same manufacturing method as tablets. Lozenges are oral tablets that gradually dissolve or disintegrate in the oral cavity and are applied locally to the oral cavity or pharynx. Sublingual tablets are oral tablets that rapidly dissolve under the tongue and allow the active ingredient to be absorbed through the oral mucosa. Buccal tablets are oral tablets that gradually dissolve between the molars and cheeks to allow the active ingredient to be absorbed through the oral mucosa. Adhesive tablets are oral tablets that adhere to the oral mucosa. Gum tablets are oral tablets that are 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 the active ingredient and additives in a solvent or the like, filtering the solution as needed, and filling it into a container together with liquefied gas or compressed gas, or by preparing a solution or suspension containing the active ingredient and additives and filling it into a container equipped with a spray pump. (3) Oral semi-solid preparations

[0219] Oral semi-solid preparations are preparations used on the oral mucosa. Examples of oral semi-solid preparations include creams, gels, and ointments. Oral semi-solid preparations are typically prepared by emulsifying an active ingredient and additives in an oily component such as purified water or petrolatum, or by mixing the active ingredient and additives with a base such as a polymer gel or fat to form a homogeneous mixture. Creams refer to semi-solid preparations of oil-in-water or water-in-oil emulsions, and lipophilic preparations of water-in-oil emulsions are also called oily creams. Creams are typically prepared by preparing an oil phase from petrolatum, a higher alcohol, 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 the active ingredient to the oil or aqueous phase, heating both phases, and mixing the oil and aqueous phases until homogeneous to obtain an emulsion. Gels refer to gel preparations, including, for example, aqueous gels and oily gels. Aqueous gels can be produced by dissolving or suspending an active ingredient in a polymer compound and additives such as purified water, and then crosslinking by heating and cooling, or by adding a gel-forming agent. Oily gels can be produced by mixing the active ingredient with a liquid oil base such as glycol or higher alcohol and additives. An ointment is a semi-solid preparation in which the active ingredient is dissolved or dispersed in a base. Examples of ointments include oleaginous ointments and water-soluble ointments. Oleaginous ointments are typically produced by melting an oleaginous base such as oils, waxes, or hydrocarbons including paraffin, heating, dissolving, or dispersing the active ingredient therein, and mixing and kneading to form a homogeneous mixture. Water-soluble ointments are typically produced by melting a water-soluble base such as macrogol, and then heating, mixing, and kneading the active ingredient therein to form a homogeneous mixture. (4) Mouthwash

[0220] Oral mouthwashes are liquid preparations for topical application to the oral cavity or pharynx, and may include solid preparations that dissolve upon use. Oral mouthwashes can usually be produced by homogeneously dissolving the active ingredient in a solvent and additives, and filtering as necessary. Solid preparations that dissolve upon use can usually be produced in accordance with the above-mentioned manufacturing methods for tablets and granules. [Injectable preparation] (1) Injectable

[0221] Injectables are solutions, suspensions, emulsions, or solid sterile preparations that are dissolved or suspended immediately before use and are administered subcutaneously, intramuscularly, or directly into bodily tissues and organs such as blood vessels. Examples include those generally referred to as injections, as well as freeze-dried injections, powder injections, pre-filled syringes, cartridges, infusion solutions, implantable injections, sustained-release injections, etc. Injectables can usually be manufactured by the following method (a) or (b): (a) The active ingredient or a mixture of the active ingredient and an additive is dissolved, suspended or emulsified in water for injection or other aqueous or non-aqueous solvent, filled into an injection container, and then sterilized; (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 sterile filtered or aseptically homogenized, filled into an injection container, and sealed. To produce a lyophilized injection, the active ingredient or an active ingredient together with additives such as a solvent is typically dissolved in water for injection, sterile filtered, and then 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 are typically produced by using sterile filtration and crystallization to obtain a powder, and then filling the powder directly or a mixture of the powder and sterile additives into an injection container. Prefilled syringes are typically 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 that is filled into a dedicated syringe. A drug solution-containing cartridge can typically be produced by filling a cartridge with the active ingredient or a solution, suspension, or emulsion of the active ingredient and additives. Infusions refer to injections, usually 100 mL or more, administered intravenously. Implantable injections are solid or gel-like injections administered subcutaneously or intramuscularly using implantable devices or through subcutaneous or intramuscular surgery to release the active ingredient over a prolonged period. Implantable injections are typically prepared by forming pellets, microspheres, or gels using biodegradable polymers. Sustained-release injections are injections administered intramuscularly to release the active ingredient over a prolonged period and are typically prepared by dissolving or suspending the active ingredient in vegetable oil or by forming a microsphere suspension using biodegradable polymers. [Dialysis preparations] (1) Dialysis agents

[0222] Dialysis agents are liquid or solid preparations used for peritoneal dialysis or hemodialysis that dissolve upon use. Examples include peritoneal dialysis agents and hemodialysis agents. Peritoneal dialysis agents refer to sterile dialysis agents used in peritoneal dialysis, and can usually be produced by filling a container with a solution of an active ingredient and additives dissolved in a certain amount of solvent, or a mixture of an active ingredient and additives, sealing the container, and sterilizing as needed. Solid preparations that dissolve upon use can usually be produced in a similar manner to the manufacturing methods for tablets and granules described above. Hemodialysis agents refer to dialysis agents used in hemodialysis, and can usually be produced by filling a container with a solution of an active ingredient and additives dissolved in a certain amount of solvent, or a mixture of an active ingredient and additives. Solid preparations that dissolve upon use can usually be produced in a similar manner to the manufacturing methods for tablets and granules described above. [Inhalation preparations] (1) Inhalants

[0223] Inhalants are preparations administered to the bronchi or lungs by inhaling an aerosol of the active ingredient. Examples include inhalable powders, inhalable liquids, and inhalable aerosols. Inhalable powders are preparations in which a predetermined amount of solid particles are inhaled in the form of an aerosol. They are typically produced by preparing fine particles of the active ingredient and mixing them with additives such as lactose as needed to make them homogeneous. Inhalable liquids are inhalable liquids administered using a nebulizer or the like. They are typically produced by dissolving or suspending the active ingredient homogeneously in a solvent, an appropriate tonicity agent, a pH adjuster, etc., and filtering as needed. Inhalable aerosols are metered-dose inhalable sprays in which a predetermined amount of the active ingredient filled in a container is sprayed 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 before use. Eye drops are usually produced by dissolving or suspending an active ingredient and additives in a certain amount of solvent or the like, or by filling a container with a mixture of the active ingredient and additives. (2) Eye ointment

[0225] Eye ointments are semi-solid sterile preparations that are administered to ocular 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 before use. Ear drops are usually prepared by dissolving or suspending the active ingredient and additives in a certain amount of solvent 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 include nasal powders and nasal liquids. Nasal powders are fine powder nasal drops administered to the nasal cavity and can usually be prepared by preparing the active ingredient as a suitable fine powder and mixing the active ingredient with additives as needed to form a homogeneous mixture. Nasal liquids are liquid or solid nasal drops that dissolve or suspend upon use and are administered to the nasal cavity. Nasal liquids can usually be prepared by dissolving or suspending the active ingredient in a solvent and additives, followed by filtration as needed. Examples of additives that can be used for nasal drops include tonicity agents, pH adjusters, etc. [Rectal preparation] (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 are usually 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, etc., filling a predetermined amount into a container, and solidifying / molding. Commonly used suppository bases include oily bases and hydrophilic bases. (2) Semi-solid preparation for rectal administration

[0229] Semi-solid preparations for rectal administration are preparations administered around or into the anus, and examples include rectal creams, rectal gels, and rectal ointments. Semi-solid preparations for rectal administration are typically prepared by emulsifying the active ingredient and additives in purified water and an oily component such as petrolatum, or by homogeneously mixing the active ingredient and additives with a base consisting of a polymer gel or oil. Rectal creams typically involve preparing an oil phase from petrolatum, 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 the active ingredient to the oil or aqueous phase, heating, and then homogenizing the oil and aqueous phases to form an emulsion. Rectal gels are gel preparations, and examples include aqueous gels and oily gels. Aqueous gels can be prepared by dissolving or suspending the active ingredient in additives such as a polymer compound or 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 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 are typically produced by heating, dissolving, or suspending the active ingredient in an oleaginous base such as oils, waxes, or hydrocarbons including paraffin, and then mixing and kneading the mixture to form a homogeneous mixture. Water-soluble ointments are generally produced by melting a water-soluble base such as macrogol by heating, and then mixing and kneading the active ingredient to form a homogeneous mixture. (3) Enema

[0230] Enema preparations are liquids or viscous gels administered via the anus. Enema preparations are typically prepared by dissolving or suspending the active ingredient in a specific amount of purified water or an appropriate aqueous solvent, and then filling the resulting solution into a container. 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 accordance with the manufacturing method for tablets described above.

[0232] Vaginal suppositories are semi-solid preparations with a specific shape that are administered into the vagina and release the active ingredient by melting at body temperature or gradually dissolving or dispersing in water. Vaginal suppositories can usually be manufactured in accordance with the manufacturing methods for rectal suppositories, etc. [Skin preparations] (1) Solid preparations for external use

[0233] Solid preparations for external use are solid preparations that are administered or applied to the skin, including the scalp or nails, and examples thereof include external powders. External powders refer to solid powder preparations for external use, and can usually be produced by mixing an active ingredient with additives such as a base to form a homogeneous mixture, and then powdering the mixture. (2) Topical liquid

[0234] Topical solutions are liquid preparations administered to the skin, including the scalp or nails, and examples include liniments and lotions. Topical solutions can typically be prepared by dissolving, emulsifying, or suspending the active ingredient in a solvent, additives, or the like, and then filtering as needed. Liniments refer to liquid or muddy topical solutions that are rubbed into the skin. Lotions refer to topical solutions in which the active ingredient is dissolved, emulsified, or finely dispersed in an aqueous liquid. Lotions can typically be prepared by preparing a solution, suspension, or emulsion of the active ingredient, additives, and purified water to form a homogeneous formulation. (3) Spray

[0235] Sprays are preparations in which an active ingredient is sprayed onto the skin in the form of a mist, powder, foam, or paste, and examples include topical aerosols and pump sprays. Sprays can typically be produced by preparing a solution or suspension of the active ingredient, filtering it as needed, and filling it into a container. Topical aerosols refer to sprays in which the active ingredient is sprayed together with a liquefied or compressed gas filled in a container. Topical aerosols can typically be produced by preparing a solution or suspension of the 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 optionally be added to topical aerosols. Pump sprays refer to sprays in which the active ingredient in a container is sprayed using a pump. Pump sprays can typically be produced by dissolving or suspending the active ingredient and additives and filling the solution into a container equipped with a pump. (4) Ointments

[0236] 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 oils, waxes, or hydrocarbons including paraffin by heating, dissolving, or suspending the active ingredient, and then 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 then mixing and kneading the active ingredient to form a homogeneous mixture. (5) Creams

[0237] Creams are semi-solid preparations in the form of oil-in-water or water-in-oil emulsions that are applied to the skin, and fat-soluble preparations of water-in-oil emulsions are also called oily creams. Creams are usually produced by preparing an oil phase from petrolatum, a higher alcohol, 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 homogeneous to form an emulsifier. (6) Gel

[0238] Gels are gels to be applied to the skin, and examples include aqueous gels and oily gels. Aqueous gels can usually be produced by dissolving or suspending an active ingredient in a polymer compound and additives such as purified water, and crosslinking the mixture by heating and cooling, or by adding a gelling agent. Oily gels can be produced by mixing the active ingredient with a liquid oil base such as glycol or higher alcohol and additives. (7) Patches

[0239] Patches are preparations to be applied to the skin, and examples include tapes and poultices. Patches can usually be produced by homogeneously mixing an active ingredient with a base, which is a polymer compound or a mixture thereof, and spreading the mixture on a support or liner (release material). Patches can also be made into transdermal absorption preparations using a controlled-release film. Additives such as adhesives or absorption enhancers may also be used in patches. Tapes refer to patches containing a base containing a small amount of water, and examples include bandages. Tapes usually use a water-insoluble natural or synthetic polymer compound, such as resin, plastic, or rubber, as the base, and can be produced by spreading a homogeneous mixture of the active ingredient or the active ingredient and additives on a cloth or a plastic film, which is then spread or enclosed and molded. Tapes can also be produced by incorporating a mixture of the active ingredient, base, or other additives into a release material consisting of a controlled-release 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 a water-absorbent polymer to make it homogeneous, and then spreading it on a cloth or the like to form it.

[0240] 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.

[0241] The contents of all patent and non-patent literature or references expressly cited herein are hereby incorporated by reference. [Example]

[0242] 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 system. Naming according to the IUPAC nomenclature system can be performed using, for example, ACD / Name (version 2019.2.0, Advanced Chemistry Development Inc.), ACD / Name Batch (version 12.02.45356, Advanced Chemistry Development Inc.), or ChemDraw Professional (version 17.1.0.105 or 18.0.0.231, available from PerkinElmer Inc.). In each of the following examples, the name of the target compound of the example is listed after the example number, and the compound may also be referred to as the "title compound." Analysis method

[0243] 1 H NMR spectra were recorded on a Bruker DRX-400 instrument and the residual undeuterated solvent ( 1 H NMR was calibrated using CHCl3, DMSO, and methanol at 7.26, 2.50, and 3.31 ppm, respectively. Chemical shifts (δ) are given in parts per million (ppm) and are designated in the numbered diagrams relative to the corresponding NMR solvent peak as s (singlet), d (doublet), t (triplet), q (quartet), combinations thereof (i.e., td denotes a triplet of doublets), or m (multiplet) and br s (broad singlet).

[0244] 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 of TFA - 4 L of water; Mobile phase (B): 0.75 mL of TFA-acetonitrile solution. Gradient: Gradient-Time Flow Rate mL / min %A %B 0.00 1.5 95 5 0.70 1.5 5 95 1.10 1.5 5 95 1.11 1.5 95 5 1.50 1.5 95 5 Detection: MS, 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 NH3-water-4L 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;

[0245] The high performance liquid chromatography (HPLC) used was as follows. General HPLC procedure Method 1 SHIMADZU 20A, 40℃ Ultimate C 18Equipped with a 3.0x50mm, 3um column. Mobile phase (A): 2.75mL TFA - 4L water; Mobile phase (B): 2.5mL 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 Equipped with a 3.0x50mm, 3um column. Mobile phase (A): 2.75mL TFA - 4L water; Mobile phase (B): 2.5mL 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 μm, 2.1 x 50 mm at 50 °C. Elution with A: 0.8 mL of NH₃·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 NH3-water-4L 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).

[0246] The chiral supercritical fluid chromatography (SFC) used was as follows: Chiral SFC procedure Method 1 Column: ChiralPak AD-3 150 x 4.6 mm I.D., 3 μm Mobile phase: A: CO2, B: IPA (0.05%DEA) Isocratic: 40%B Flow rate: 2.5 mL / min, column temperature: 40°C Back pressure: 100 bar Method 2 Column: Chiralcel OJ-3 150 x 4.6 mm I.D., 3 μm Mobile phase: A: CO2, B: EtOH (0.05%DEA) Gradient: 5% to 40% B for 5 minutes, 40% to 5% B for 0.5 minutes, hold at 5% B for 1.5 minutes Flow rate: 2.5mL / min Column temperature: 35°C ABPR: 1500 psi Method 3 Column: Chiralcel OD-3 150 x 4.6 mm I.D., 3 μm Mobile phase: A: CO2, B: EtOH (0.05%DEA) Gradient: 5% to 40% B for 5 minutes, 40% to 5% B for 0.5 minutes, hold at 5% B for 1.5 minutes Flow rate: 2.5mL / min Column temperature: 35°C ABPR: 1500 psi

[0247] 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.

[0248] 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) were added acetic acid (0.54 mL, 9.47 mmol, 1.0 eq) and potassium acetate (0.93 g, 9.47 mmol, 1.0 eq). 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 give a white suspension. The reaction mixture was poured into water (40 mL) and extracted with ethyl acetate (40 mL × 3). The combined organic layer was washed with brine (60 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to give 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).

[0249] tert-Butyl (1R,5S,6r)-6-[(Z)-chloro-(hydroxyimino)methyl]-3-azabicyclo[3.1.0]hexane-3-carboxylate To a solution of tert-butyl (1R,5S,6r)-6-[(E)-(hydroxyimino)methyl]-3-azabicyclo[3.1.0]hexane-3-carboxylate (2.2 g, 9.72 mmol) in DMF (18.4 mL) was added N-chlorosuccinimide (1363 mg, 10.21 mmol), and the mixture was stirred at 20 °C for 2 hours. The mixture was poured into water (90 mL) and extracted with ethyl acetate (50 mL × 3). The organic layer was washed with saturated brine (50 mL × 3), dried over anhydrous sodium sulfate, and concentrated to obtain the title compound as a white solid. LC-MS Method1 0.780 min, MS (m / z) 245.9 (M + H + ) 1 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).

[0250] tert-Butyl (1R,5S,6r)-6-(5,5-dimethyl-4,5-dihydro-1,2-oxazol-3-yl)-3-azabicyclo[3.1.0]hexane-3-carboxylate To a solution of tert-butyl (1R,5S,6r)-6-[(Z)-chloro(hydroxyimino)methyl]-3-azabicyclo[3.1.0]hexane-3-carboxylate (100 mg, 0.38 mmol) and triethylamine (0.19 mL, 1.15 mmol) in DMF (1.0 mL) was added 2-methylprop-1-ene (0.72 mL, 1.15 mmol) (15% solution in isopropyl ether), 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 give the title compound (100 mg, 0.356 mmol, 92.9% yield) 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).

[0251] (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 and 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).

[0252] [(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) was added HATU (194 mg, 0.51 mmol) 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 give a residue. The residue was purified by prep-HPLC (NH3) to give the title compound (4 mg, 0.012 mmol, 2.7% yield) as a white solid. 1 H NMR (400 MHz, CDCl3-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 + ].

[0253] 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) was added (1R,5S,6r)-6-(5,5-dimethyl-4,5-dihydro-1,2-oxazol-3-yl)-3-azabicyclo[3.1.0]hexane hydrochloride (91 mg, 0.42 mmol). The suspension was stirred at 20°C for 8 hours. The reaction mixture was concentrated under reduced pressure. The residue was purified by prep-HPLC (NH3) and lyophilized to give the title compound (17.45 mg, 21.8% yield) 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).

[0254] 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).

[0255] 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 hours. The residue was diluted with water (1 mL) and extracted with ethyl acetate (5 mL x 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).

[0256] [(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 and 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 h. The solution was purified by prep-HPLC (NH) 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).

[0257] 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) and cyclopropylboronic acid (681.15 mg, 7.93 mmol). The mixture was stirred at 70 °C under an oxygen atmosphere for 16 h. TLC (PE:ethyl acetate = 1:4) indicated the 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 using a 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).

[0258] 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 hours to give a white suspension. TLC (PE:ethyl acetate = 1:4) showed the reaction was complete (Rf = 0). The reaction mixture was directly concentrated. The residue was acidified with aqueous hydrochloric acid (1 M), and the resulting organic layer was lyophilized to give the title compound (120 mg, 0.7887 mmol, 93.618% yield) as a white solid.

[0259] (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 (hydrochloric acid). 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-d4) 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).

[0260] 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 hours at 50° C. The mixture was concentrated under reduced pressure, and 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 + ).

[0261] 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), indicating complete consumption of the reactant. The aqueous layer was washed with DCM (3 mL × 2) and acidified to pH = 2 with 1N aqueous hydrochloric acid. The remaining aqueous solution was lyophilized to afford the title compound (160 mg, 0.9628 mmol, 187.01% yield) as a pale yellow solid. 1 H NMR (400 MHz,D2O)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).

[0262] (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), and (1R,5S,6r)-6-(5,5-dimethyl-4,5-dihydro-1,2-oxazol-3-yl)-3-azabicyclo[3.1.0]hexane hydrochloride (97.36 mg, 0.5400 mmol) were added. The resulting mixture was stirred at 20°C for 4 hours. The reaction mixture was diluted with water (5 mL) and ethyl acetate (5 The resulting mixture was extracted with 2 mL of hexane (2 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure to give a crude oil. The crude oil was purified by prep-TLC (ethyl acetate / methanol = 10 / 1) followed by prep-HPLC (NH3) and lyophilized to give the title compound (12.15 mg, 0.0370 mmol, yield 6.8494%) as a pale yellow solid. LC-MS Method 1: 328.9 [M+H + ] 1 H NMR (400MHz, DMSO-d6) δ = 8.03 (d, J=1.3 Hz, 1H), 7.99 (s, 1H), 4.96 - 4.89 (m, 1H), 4.75 (br d, J=12.0 Hz, 1H), 4.12 (br d, J=12.3 Hz, 1H), 3.99 (br d, J=9.0 Hz, 1H), 3.66 (br s, 1H), 2.83 (s, 2H), 2.57 (t, J=8.7 Hz, 4H), 2.25 (br d, J=11.3 Hz, 1H), 2.17 (br s, 1H), 2.00 - 1.90 (m, 2H), 1.60 - 1.57 (m, 1H), 1.44 (s, 6H).

[0263] 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) were added bicyclo[1.1.1]pentan-1-amine (284.42 mg, 2.38 mmol) and triethylamine (0.58 mL, 4.46 mmol). The resulting mixture was heated at 76°C for 16 hours. The reaction mixture was diluted with water (5 mL) and extracted with ethyl acetate (5 mL x 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.

[0264] 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 mixture was stirred at 25°C for 16 hours. The aqueous layer was washed with DCM (3 mL x 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 product) as a pale yellow solid.

[0265] [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 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) was added HATU (137.86 mg, 0.3600 mmol), DIPEA (0.18 mL, 1.11 mmol), and (1R,5S,6r)-6-(5,5-dimethyl-4,5-dihydro-1,2-oxazol-3-yl)-3-azabicyclo[3.1.0]hexane hydrochloride (50 mg, 0.2800 mmol). The resulting mixture was stirred at 20 °C for 4 h. The reaction mixture 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 give a crude oil. The crude oil was purified by prep-HPLC (NH3) to give the title compound (2.4 mg, 0.0071 mmol, 2.5416% yield) as a yellow solid. 1 H NMR (400MHz, DMSO-d6) 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. 1.26 - 1.25 (m, 1H), 1.25 (s, 5H).

[0266] 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 hours. The mixture was concentrated under reduced pressure. The residue was purified by flash column chromatography (0-100% ethyl acetate, 0.5% aqueous ammonia in PE) 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 + ).

[0267] 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 x 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, D2O) 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).

[0268] (1-Cyclopentyl-1H-imidazol-4-yl)[((1R,5S,6r)-6-(5,5-dimethyl-4,5-dihydro-1,2-oxazol-3-yl)-3-azabicyclo[3.1.0]hex-3-yl]methanone To a solution of 1-cyclopentyl-1H-imidazole-4-carboxylic acid (60.38 mg, 0.2800 mmol) in DMF (0.50 mL) were added HATU (137.86 mg, 0.3600 mmol), DIPEA (0.18 mL, 1.11 mmol), and (1R,5S,6r)-6-(5,5-dimethyl-4,5-dihydro-1,2-oxazol-3-yl)-3-azabicyclo[3.1.0]hexane hydrochloride (50 mg, 0.2800 mmol). The mixture was stirred at 20 °C for 4 h. The reaction mixture 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 give a crude oil. The crude oil was purified by prep-TLC (ethyl acetate / methanol=10 / 1) and then by Prep-HPLC (NH 3 ) to give the title compound (11 mg, 0.0321 mmol, yield 4.6614%) as a white solid. 1 H NMR (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).

[0269] 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 hours. The mixture was concentrated under reduced pressure. The residue was purified by flash column chromatography (0-100% ethyl acetate, 0.5% aqueous ammonia in PE) 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 + ).

[0270] 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), indicating complete consumption of the reaction mixture. The aqueous layer was washed with DCM (3 mL × 2) and acidified to pH = 2 with 1N aqueous hydrochloric acid. 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-d4) 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).

[0271] (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 x 2). 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-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-d6) 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).

[0272] 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) was added n-butyllithium (1.43 mL, 3.57 mmol) at -78°C. After stirring at -78°C for 15 minutes, ethyl (2Z)-3-(dimethylamino)-2-isocyanoacrylate (200 mg, 1.19 mmol) was added. The mixture was heated to 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 chromatography (PE → 100% ethyl acetate in PE). The residue was purified by prep-TLC (ethyl acetate) to obtain the title compound (50 mg, 0.2117 mmol, 17.802% yield) as a brown oil.

[0273] 1-(1,1,1-trifluoropropan-2-yl)-1H-imidazole-4-carboxylic acid To a solution of ethyl 1-(1,1,1-trifluoropropan-2-yl)-1H-imidazole-4-carboxylate (50 mg, 0.2100 mmol) in THF (1.5 mL) and water (0.3 mL, 16.67 mmol) was added lithium hydroxide monohydrate (26.65 mg, 0.6400 mmol). The mixture was stirred at 20°C for 3 hours to give a black solution. LCMS indicated that starting material (50 mg, 0.2100 mmol) remained. The mixture was stirred at 40°C for 12 hours to give a black solution. The reaction mixture was directly concentrated. The resulting aqueous layer was acidified to pH 5-6 with 1N aqueous HCl. Lyophilization afforded the title compound (30 mg, 0.1441 mmol, 68.086% yield) as a brown solid.

[0274] [((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) were added HATU (66.12 mg, 0.1700 mmol) and DIPEA (0.12 mL, 0.7200 mmol). The mixture was stirred for 30 minutes. Then, (1R,5S,6r)-6-(5,5-dimethyl-4,5-dihydro-1,2-oxazol-3-yl)-3-azabicyclo[3.1.0]hexane hydrochloride (36.48 mg, 0.1400 mmol) was added. The mixture was stirred at 25°C for 3 hours to give a brown solution. The reaction mixture was directly concentrated. The residue was purified by Prep-HPLC (NH3) 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).

[0275] 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 To a solution of (R)-t-BuS(O)NH (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. The mixture was then filtered through Celite and concentrated under reduced pressure to give the title compound (8330 mg, 47.521 mmol, 68.535% yield) as a white solid. This was used directly in the next step. LC-MS Method1 0.825 min, MS (m / z) 176.2 (M + H + ).

[0276] (R)-2-Methyl-N-[(2S)-3-methyl-2-butanyl]-2-propanesulfinamide To a solution of (R)-2-methyl-N-[(1E)-2-methylpropylidene]-2-propanesulfinamide (2500 mg, 14.26 mmol) in THF (30 mL) cooled to -40 °C, methylmagnesium bromide (5.7 mL, 17.11 mmol) was added dropwise. The reaction mixture was stirred at -40 °C for 3 h and then gradually warmed to 20 °C over 13 h. TLC (DCM / ethyl acetate = 6 / 1, RF = 0.3) showed two new spots. Water (30 mL) was added, and the mixture was extracted with ethyl acetate (30 mL x 2). The organic layer was dried over sodium sulfate and concentrated under reduced pressure to 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).

[0277] (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.

[0278] Ethyl 1-[(2S)-3-methylbutan-2-yl]-1H-imidazole-4-carboxylate To a 5 mL microwave vial were added (2S)-3-methyl-2-butanamine (500 mg, 4.04 mmol), ethyl (2Z)-3-(dimethylamino)-2-isocyanoacrylate (680.27 mg, 4.04 mmol), 1-butanol (3 mL), and triethylamine (0.84 mL, 6.07 mmol). The reaction mixture was irradiated with microwaves at 130 °C for 1 hour to give a brown solution. Water (30 mL) was added and the mixture was extracted with ethyl acetate (30 mL x 2). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure to give a yellow oil. The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure to give a yellow oil. The crude product was purified by silica gel chromatography (PE / ethyl acetate = 10 / 1 → 3 / 2) to give the title compound (161 mg, 0.7657 mmol, 18.931% yield) as a brown oil. LC-MS Method1 0.691 min, MS(m / z)211.2(M+H + ).

[0279] 1-[(2S)-3-Methylbutan-2-yl]-1H-imidazole-4-carboxylic acid To a stirred solution of ethyl 1-[(2S)-3-methylbutan-2-yl]-1H-imidazole-4-carboxylate (150.0 mg, 0.7600 mmol) in 1,4-dioxane (3 mL) was added a solution of lithium hydroxide monohydrate (48.11 mg, 1.15 mmol). The mixture was stirred at 20 °C for 4 hours to give a yellow solution. Water (10 mL) was added, and the mixture was extracted with ethyl acetate (10 mL x 2). The mixture was lyophilized to give 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+).

[0280] [((1R,5S,6S)-6-(5,5-dimethyl-4,5-dihydro-1,2-oxazol-3-yl)-3-azabicyclo[3.1.0]hex-3-yl]{1-[(2S)-3-methylbutan-2-yl]-1H-imidazol-4-yl}methanone To a stirred solution of 1-[(2S)-3-methylbutan-2-yl]-1H-imidazole-4-carboxylic acid (1 mg, 0.5500 mmol) and HATU (251.76 mg, 0.6600 mmol) in DMF (3 mL) was added N-ethyl-N-isopropylpropan-2-amine (0.47 mg, 2.74 mmol). After stirring for 30 min, (1R,5S,6r)-6-(5,5-dimethyl-4,5-dihydro-1,2-oxazol-3-yl)-3-azabicyclo[3.1.0]hexane hydrochloride (138.94 mg, 0.5500 mmol) was added and the mixture was stirred at 20 °C for 16 h to give a yellow solution. Water (30 mL) was added and the mixture was extracted with ethyl acetate (30 mL x 2). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure to give a yellow oil. The crude product was purified by Prep-HPLC (NH3) and then lyophilized to give 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).

[0281] 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) detected 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 + ).

[0282] 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 mixture 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 had been consumed. The reaction mixture was diluted with water (15 mL) and extracted with ethyl acetate (8 mL x 5). The aqueous layer was acidified to pH 4 with 1N aqueous hydrochloric acid. The resulting 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.

[0283] {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). 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).

[0284] 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) detected a new spot (Rf = 0.2). The mixture was concentrated to give a residue. The residue was purified by flash column (PE:ethyl acetate = 1:0 → 1:4) to give the title compound (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 + ).

[0285] 1-[(2S)-butan-2-yl]-1H-imidazole-4-carboxylic acid To a mixture of ethyl 1-[(2S)-butan-2-yl]-1H-imidazole-4-carboxylate (160 mg, 0.8200 mmol) in THF (4 mL) and water (2 mL) was added lithium hydroxide monohydrate (0.07 mL, 1.22 mmol). The reaction mixture was stirred at 20°C for 16 hours to give a yellow mixture. The reaction mixture was diluted with water (15 mL) and extracted with ethyl acetate (8 mL x 5). The aqueous layer was acidified to pH 4 with aqueous hydrochloric acid (1N). The resulting aqueous layer was dried under reduced pressure to give the title compound (150 mg, 0.8918 mmol, yield 109.39%) (crude) as a yellow solid.

[0286] {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 indicated that the starting material had been consumed. The reaction mixture was filtered. The filtrate was purified by prep-HPLC (NH3). 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).

[0287] 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) and THF (10 mL) was added (R)-2-methylpropane-2-sulfinamide (1210.06 mg, 9.98 mmol) and titanium(IV) ethoxide (3414.54 mg, 14.98 mmol). The reaction mixture was stirred at 60°C for 2 hours to give 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 give a yellow suspension. The 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 (900 mg, 4.4261 mmol, 44.332% yield) as a colorless oil. LC-MS Method1 0.778 min, MS (m / z) 204.0 (M + H + ).

[0288] (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) and THF (9 mL) was added L-selectride (13.28 mL, 13.28 mmol) at 0 °C. The reaction mixture was stirred at 25 °C for 2 hours 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).

[0289] (2S)-4-Methyl-2-pentanamine hydrochloride (R)-2-Methyl-N-[(2S)-4-methylpentan-2-yl]-2-propanesulfinamide (610 mg, 2.97 mmol) in methanol / hydrochloric acid (10 mL, 2.97 mmol) was stirred at 25°C for 2 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.

[0290] 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) and 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 in a microwave oven at 130 °C for 1 hour 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 + ).

[0291] 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 1N aqueous hydrochloric acid and lyophilized to give the title compound (50 mg, 0.2548 mmol, 95.244% yield) as a yellow solid.

[0292] [(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) and pyridine (2.5 mL), EDCI (58.61 mg, 0.3100 mmol) was added. After stirring 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 (55.21 mg, 0.2500 mmol) was added. The mixture was stirred at 25°C for 16 hours to give a yellow mixture. LCMS indicated complete consumption of the starting material. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (NH3). 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).

[0293] 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 A round-bottom flask was charged with (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). 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 layers were 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 + ).

[0294] 1-[(1S)-1-Cyclopropylethyl]-1H-imidazole-4-carboxylic acid To a solution of ethyl 1-[(1S)-1-cyclopropylethyl]-1H-imidazole-4-carboxylate (150 mg, 0.7200 mmol) in water (0.50 mL), THF (0.50 mL), and methanol (0.50 mL) was added lithium hydroxide monohydrate (60.44 mg, 1.44 mmol). The resulting mixture was stirred at 20-25°C for 14 hours to give a white suspension. The reaction mixture was poured into water and extracted with ethyl acetate (20 mL x 4). The combined organic layers were washed with saturated brine (20 mL x 2), dried over sodium sulfate, filtered, and concentrated under reduced pressure to give the title compound (150 mg, crude product) as a yellow oil. LC-MS Method1 0.227 min, MS (m / z) 180.9 (M + H + ).

[0295] (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 give a yellow solution. The reaction mixture was poured into saturated aqueous ammonium chloride (50 mL) and extracted with ethyl acetate (50 mL × 4). The combined organic layers were washed with saturated brine (50 mL × 2), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by prep-HPLC (FA) to give 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).

[0296] Example 15 {1-[(1R)-1-Cyclopropylethyl]-1H-imidazol-4-yl}[(1R,5S,6r)-6-(5,5-dimethyl-4,5-dihydro-1,2-oxazol-3-yl)-3-azabicyclo[3.1.0]hex-3-yl]methanone Ethyl 1-[(1R)-1-cyclopropylethyl]-1H-imidazole-4-carboxylate To a solution of ethyl (2Z)-3-(dimethylamino)-2-isocyanoacrylate (500 mg, 2.97 mmol) in 1-butanol (1 mL) was added (1R)-1-cyclopropylethanamine (253.14 mg, 2.97 mmol) 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 saturated aqueous ammonium chloride solution (50 mL) and extracted with ethyl acetate (50 mL × 4). The combined organic layer was washed with saturated brine (50 mL × 2), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified using 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 + ).

[0297] 1-[(1R)-1-Cyclopropylethyl]-1H-imidazole-4-carboxylic acid To a solution of ethyl 1-[(1R)-1-cyclopropylethyl]-1H-imidazole-4-carboxylate (190 mg, 0.9100 mmol) in water (1.9 mL), THF (1.9 mL), and methanol (1.9 mL) was added lithium hydroxide monohydrate (76.56 mg, 1.82 mmol) at 20°C. The resulting mixture was stirred at 20-25°C for 2 hours to give 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 give 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 + ).

[0298] {1-[(1R)-1-Cyclopropylethyl]-1H-imidazol-4-yl}[(1R,5S,6r)-6-(5,5-dimethyl-4,5-dihydro-1,2-oxazol-3-yl)-3-azabicyclo[3.1.0]hex-3-yl]methanone To a solution of 1-[(1R)-1-cyclopropylethyl]-1H-imidazole-4-carboxylic acid (70 mg, 0.3900 mmol) in DMF (2 mL) was added HATU (193.06 mg, 0.5000 mmol) and N-ethyl-N-isopropylpropan-2-amine (0.33 mL, 1.94 mmol) at 20 °C. The reaction mixture was stirred for 30 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 give a yellow solution. The reaction mixture was poured into saturated aqueous ammonium chloride (50 mL) and extracted with ethyl acetate (50 mL × 4). The combined organic layers were washed with 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 give 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).

[0299] 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, yielding 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 mixture was diluted with ethyl acetate (40 mL). This mixture was added to water (10 mL) and stirred for 1 minute, yielding 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 give 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).

[0300] (R)-N-[(1S)-1-Cyclobutylethyl]-2-methyl-2-propanesulfinamide To a solution of (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 mixture was quenched with ammonium chloride (eq., 25 mL) and extracted with ethyl acetate (15 mL × 3). The combined organic layers were washed with brine (20 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified using a 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).

[0301] (1S)-1-Cyclobutylethanamine hydrochloride A solution of (R)-N-[(1S)-1-cyclobutylethyl]-2-methyl-2-propanesulfinamide (360 mg, 1.77 mmol) in methanol / hydrochloric acid (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.

[0302] 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 a microwave to give a brown mixture. LCMS showed complete consumption of the 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 = 6.8Hz, 3H), 1.39 (t, J = 6.8Hz, 3H).

[0303] 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 hours to give a brown mixture. TLC (PE:ethyl acetate = 1:1) showed complete consumption of the starting material. The reaction mixture 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-d6) 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).

[0304] (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 give a brown solution. The reaction mixture was directly concentrated. The residue was purified by prep-HPLC (NH3) to give 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).

[0305] 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) and ethyl (2Z)-3-(dimethylamino)-2-isocyanoacrylate (100 mg, 0.5900 mmol) in triethylamine (0.58 mL, 4.46 mmol) was added. The resulting mixture was stirred at 70 °C for 16 h to give a yellow mixture. TLC (PE:ethyl acetate = 1:1) detected 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 + ).

[0306] 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 hours to give a yellow mixture. TLC (PE:ethyl acetate = 1:1) showed complete consumption of the starting material. The reaction mixture was diluted with water (6 mL) and concentrated to remove most of the THF. The aqueous layer was acidified to pH = 5 with aqueous hydrochloric acid (1 N) and lyophilized to give the title compound (21 mg, 0.1081 mmol, 96.131% yield) as a yellow solid. LC-MS Method1 0.414 min, MS (m / z) 194.9 (M + H + ).

[0307] {1-[(1R)-1-Cyclobutylethyl]-1H-imidazol-4-yl}[(1R,5S,6r)-6-(5,5-dimethyl-4,5-dihydro-1,2-oxazol-3-yl)-3-azabicyclo[3.1.0]hex-3-yl]methanone To a mixture of 1-[(1R)-1-cyclobutylethyl]-1H-imidazole-4-carboxylic acid (21 mg, 0.1100 mmol) and DMF (0.50 mL), HATU (49.6 mg, 0.1300 mmol) and DIPEA (0.09 mL, 0.5400 mmol) were added. After stirring at 50°C for 30 minutes, (1R,5S,6r)-6-(5,5-dimethyl-4,5-dihydro-1,2-oxazol-3-yl)-3-azabicyclo[3.1.0]hexane hydrochloride (29.23 mg, 0.1600 mmol) was added. The mixture was stirred at 25°C for 16 hours, yielding a yellow mixture. The reaction mixture was purified by prep-HPLC (NH3). 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).

[0308] 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 by the same protocol as in Example 19, using (R)-2-methylpropane-2-sulfinamide instead of (S)-2-methylpropane-2-sulfinamide) in DMF (5 mL) was added HATU (137.68 mg, 0.3600 mmol) and triethylamine (0.12 mL, 0.9600 mmol). 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) and then lyophilized to give 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).

[0309] 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 and THF (20 mL), (S)-2-methylpropane-2-sulfinamide (2.47 g, 20.38 mmol) and titanium(IV) ethoxide (6.97 g, 30.57 mmol) were added. The suspension was stirred at 20 °C for 16 hours. The reaction mixture was diluted with ethyl acetate (60 mL). This was added to water (10 mL) and stirred for 1 minute to give a white suspension. The suspension was filtered. The filtrate was washed with water (30 mL x 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).

[0310] (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) and THF (20 mL), chloro(methyl)magnesium was added dropwise over 10 minutes at -40 °C under a nitrogen atmosphere. The suspension was stirred at 20 °C for 16 hours. The residue was diluted with aqueous ammonium chloride (15 mL), extracted with ethyl acetate (30 mL x 4), washed with saturated brine (30 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Purification by flash column (PE → 30% ethyl acetate in PE) 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).

[0311] (1R)-1-Cyclopentylethanamine hydrochloride To a mixture of (S)-N-[(1R)-1-cyclopentylethyl]-2-methyl-2-propanesulfinamide was added methanol / hydrochloric acid (5 mL). 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.

[0312] Ethyl 1-[(1R)-1-cyclopentylethyl]-1H-imidazole-4-carboxylate To a mixture of (1R)-1-cyclopentylethanamine hydrochloride (52.0 mg, 0.35 mmol) was added 1-butanol (0.5 mL). Ethyl (2Z)-3-(dimethylamino)-2-isocyanoacrylate (58.44 mg, 0.35 mmol) and triethylamine (52.64 mg, 0.52 mmol, 0.07 mL) were then added. The suspension was reacted in a microwave reactor (time: 1 hour, reaction temperature: 130 °C). The residue was concentrated under reduced pressure to give 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).

[0313] 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 x 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 + ).

[0314] {1-[(1R)-1-Cyclopentylethyl]-1H-imidazol-4-yl}[(1R,5S,6r)-6-(5,5-dimethyl-4,5-dihydro-1,2-oxazol-3-yl)-3-azabicyclo[3.1.0]hex-3-yl]methanone To a mixture of 1-[(1R)-1-cyclopentylethyl]-1H-imidazole-4-carboxylic acid (30.0 mg, 0.14 mmol) and pyridine (0.5 mL), EDCI (27.6 mg, 0.14 mmol) and (1R,5S,6r)-6-(5,5-dimethyl-4,5-dihydro-1,2-oxazol-3-yl)-3-azabicyclo[3.1.0]hexane hydrochloride (26.0 mg, 0.14 mmol) were added. The suspension was stirred at 20 °C for 16 hours. Water (10 mL) was added to the reaction mixture to quench the reaction. The residue was diluted with ethyl acetate (20 mL x 3), washed with saturated brine (5 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The solution was purified by prep-HPLC (NH3) and lyophilized to give the title compound (1.88 mg, yield 3.5%) as a white solid. LC-MS Method1: 3.486 min, MS (m / z): 371.3 (M + H + ). 1 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).

[0315] 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 mixture was heated at 60°C under a nitrogen atmosphere for 30 minutes 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 the mixture was stirred at 20°C for 5 minutes. The mixture was then filtered through Celite. 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 + ).

[0316] (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 mixture was stirred at the same temperature for 2 hours to give a yellow solution. Water (30 mL) was added, and the mixture was extracted with ethyl acetate (30 mL x 2). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure to give a yellow oil. The crude product was purified by silica gel chromatography (DCM / ethyl acetate = 3 / 1 → 1 / 1) to give the title compound (1700 mg, 7.2846 mmol, 52.772% yield) 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).

[0317] (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.

[0318] 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. Microwave irradiation at 130 °C for 1 hour gave a brown solution. Water (15 mL) was added, and the mixture was extracted with ethyl acetate (15 mL x 2). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure to give a yellow oil. The crude product was purified by silica gel chromatography (PE / ethyl acetate = 1 / 1 → 0 / 1) to give the title compound (135 mg, 0.5351 mmol, 22.481% yield) as a yellow oil. LC-MS Method1 0.638, MS (m / z) 253.2 (M + H + ).

[0319] 1-[(1S)-1-(tetrahydro-2H-pyran-4-yl)ethyl]-1H-imidazole-4-carboxylic acid A 100 mL round-bottom flask was charged with ethyl 1-[(1S)-1-(tetrahydro-2H-pyran-4-yl)ethyl]-1H-imidazole-4-carboxylate (130 mg, 0.5200 mmol), lithium hydroxide hydrate (43.24 mg, 1.03 mmol), and THF (3 mL). The mixture was stirred at 20 °C for 3 hours to give a yellow solution. Water (15 mL) was added, and the mixture was 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. This was used directly in the next step.

[0320] [(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) was added N-ethyl-N-isopropylpropan-2-amine (0.59 mL, 3.43 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 (384.3 mg, 0.7400 mmol) was added. Stirring continued for 16 h to give a yellow solution. Water (30 mL) was added, and the mixture was extracted with ethyl acetate (30 mL x 2). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure to give a yellow oil. The crude was purified by Prep-HPLC (NH3). The obtained fraction was concentrated in vacuo to remove most of the acetonitrile and lyophilized to give the title compound (9.57 mg, 0.0248 mmol, yield 5.0482%) 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).

[0321] 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 h. TLC (PE:ethyl acetate = 3:1) showed complete consumption of ethyl 2-isocyanoacetate (1.0 g, 8.84 mmol) (Rf = 0.6), with the detection of a new spot (Rf = 0.4). (S)-1-Phenylethanamine (4.5 mL, 35.36 mmol) was added. The resulting mixture was stirred at 50 °C for 16 h to give a brown mixture. TLC (PE:ethyl acetate = 1:1) showed the detection of 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, yield 43.06%) (PE:ethyl acetate=1:1, Rf=0.1) as a brown oil. LC-MS Method1 0.685 min, MS (m / z) 244.9 (M + H + ).

[0322] 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 complete consumption of the starting material. The reaction mixture was diluted with water (15 mL) and extracted with ethyl acetate (8 mL × 5). The aqueous layer was acidified to pH = 4 with aqueous hydrochloric acid (1N). The resulting aqueous layer was dried under reduced pressure to 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 + ).

[0323] [(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, yielding a brown mixture. TLC (DCM:methanol = 40:1 with 1 drop of triethylamine) showed one new spot (Rf = 0.5). The reaction mixture was diluted with water (10 mL). The resulting mixture was extracted with ethyl acetate (5 mL × 4). The combined organic layers were dried over anhydrous sodium sulfate, filtered, 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 (NH3). The resulting fractions were combined, concentrated to remove most of the acetonitrile, and lyophilized to obtain the title compound (3.85 mg, 0.0102 mmol, yield 1.8336%) 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).

[0324] 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 mixture was heated at 60 °C under a nitrogen atmosphere 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 the mixture was stirred at 20 °C for 5 min. The mixture was 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.

[0325] (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 the mixture was extracted with ethyl acetate (30 mL x 2). The organic layer was dried over sodium sulfate and concentrated under reduced pressure to give a yellow oil. The crude product was purified by silica gel chromatography (DCM / ethyl acetate = 10 / 1 → 3 / 1) to give the title compound (960 mg, 3.1553 mmol, 30.312% yield) 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).

[0326] (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 solvent was removed from the reaction mixture under reduced pressure to give the title compound (700 mg, 2.95 mmol, 100.04% yield) as a yellow oil, which was used directly in the next step. LC-MS Method1 0.592 min, MS (m / z) 202.1 (M + H + ).

[0327] Ethyl 1-[(1S)-1-(2-bromophenyl)ethyl]-1H-imidazole-4-carboxylate To an 8 mL microwave vial was added (1S)-1-(2-bromophenyl)ethanamine hydrochloride (780 mg, 3.3 mmol), ethyl (2Z)-3-(dimethylamino)-2-isocyanoacrylate (554.61 mg, 3.3 mmol), triethylamine (0.69 mL, 4.95 mmol), and 1-butanol (3 mL). The reaction mixture was irradiated in a microwave oven at 130 °C for 1 hour to give a brown-red solution. The reaction mixture was diluted with saturated aqueous sodium carbonate (10 mL) and extracted with ethyl acetate (20 mL × 2). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure to give a yellow oil. The crude product was purified by silica gel chromatography (DCM / ethyl acetate = 10 / 1 → 6 / 1) to give the title compound (230 mg, 0.7117 mmol, 21.581% yield) as a yellow oil. LC-MS Method1 0.726 min, MS (m / z) 324.9 (M + H + ).

[0328] 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 mixture was stirred at 120 °C for 16 hours to give a yellow solution. Water (15 mL) was added, and the mixture was extracted with ethyl acetate (20 mL x 2). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure to 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 directly in the next step.

[0329] 1-[(1S)-1-(2-cyanophenyl)ethyl]-1H-imidazole-4-carboxylic acid To a mixture of ethyl 1-[(1S)-1-(2-cyanophenyl)ethyl]-1H-imidazole-4-carboxylate (150 mg, 0.5600 mmol) in 1,4-dioxane (5 mL), a solution of lithium hydroxide monohydrate (46.74 mg, 1.11 mmol) in water (1.5 mL, 0.5600 mmol) was added. The mixture was reacted at 20 °C for 16 hours to give a yellow solution. The solvent was removed under reduced pressure to give 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 + ).

[0330] 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 the mixture was stirred for 16 h to give a black suspension. Water (30 mL) was added and the mixture was extracted with ethyl acetate (30 mL x 2). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure to give a yellow oil. The crude was purified by Prep-HPLC (NH3). The obtained fraction was concentrated in vacuo to remove most of the acetonitrile, and then lyophilized to obtain 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).

[0331] 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. This was used directly in the next step without further purification. LC-MS Method1 0.858 min, MS (m / z) 235.2 (M + H +).

[0332] (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) was added chloro(methyl)magnesium (4.69 mL, 14.08 mmol) at -48 °C. The resulting mixture was stirred at -40 °C for 14 hours to give a yellow solution. The reaction mixture was added to saturated aqueous ammonium chloride solution (30 mL) and extracted with ethyl acetate (30 mL × 4). The combined organic layer was washed with saturated brine (30 mL × 2), dried over sodium sulfate, filtered, and concentrated under reduced pressure to give 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 + ).

[0333] 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 give a yellow solution. The solvent of the reaction mixture was removed under reduced pressure to give the title compound (643 mg, crude product) as a yellow oil. LC-MS Method1 0.258 min, MS (m / z) 147. (M -HCl + H + ).

[0334] 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 give a yellow solution. The reaction mixture was poured into saturated aqueous ammonium chloride (30 mL) and extracted with ethyl acetate (30 mL × 2). The combined organic layers were washed with saturated brine (30 mL × 2), dried over sodium sulfate, filtered, and concentrated under reduced pressure to give the title compound (90 mg, 0.3342 mmol, 22.484% yield) as a yellow oil. LC-MS Method1 0.732 min, MS (m / z) 270.2 (M + H + ).

[0335] 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 hours to give a yellow solution. The reaction mixture was poured into water and extracted with ethyl acetate (20 mL × 4). The aqueous layer was concentrated and lyophilized to give the title compound (132 mg, crude product) as a white solid. LC-MS Method1 0.468 min, MS (m / z) 241.9 (M + H + ).

[0336] 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 to 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, resulting in a yellow solution. The reaction mixture was poured into saturated aqueous 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 give 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).

[0337] 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 give a yellow solution. Water (3 mL) was added dropwise and the mixture was stirred for 5 minutes. The solid was then removed by filtration through a pad of Celite, and the filtrate was concentrated under reduced pressure to give the title compound (8340 mg, 35.592 mmol, 93.345% yield) as a white solid. LC-MS Method1 0.858 min, MS (m / z) 234.8 (M + H + ).

[0338] (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) was added chloro(methyl)magnesium (4.99 mL, 14.98 mmol) at -48 °C. The resulting mixture was stirred at -40 °C for 14 hours to give a yellow solution. The mixture was quenched with aqueous ammonium chloride solution, and the aqueous layer was extracted with ethyl acetate (30 mL × 3). The combined organic layer was washed with saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The crude product was purified using 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 give the title compound (1310 mg, 5.2325 mmol, 52.396% yield) as a yellow solid. LC-MS Method1 0.732 min, MS (m / z) 250.9 (M + H+ ).

[0339] 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 hours 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 + ).

[0340] Ethyl 1-[(1S)-1-(4-cyanophenyl)ethyl]-1H-imidazole-4-carboxylate To a solution of ethyl (2Z)-3-(dimethylamino)-2-isocyanoacrylate (300 mg, 1.78 mmol) in 1-butanol (3 mL) were added triethylamine (0.38 mL, 2.68 mmol) and 4-[(1S)-1-aminoethyl]benzonitrile hydrochloride (300 mg, 1.78 mmol). The reaction mixture was irradiated with microwaves at 130 °C for 60 minutes to give a yellow solution. The reaction solution was poured into saturated aqueous ammonium chloride (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 the title compound (110 mg, 0.4085 mmol, 22.9% yield) as a yellow oil. LC-MS Method1 0.732 min, MS (m / z) 270.2 (M + H + ).

[0341] 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 give a yellow solution. The reaction mixture was poured into water and extracted with ethyl acetate (20 mL × 4). The aqueous layer was concentrated and lyophilized to give the title compound (130 mg, crude product) as a yellow solid. LC-MS Method1 0.443 min, MS (m / z) 241.9 (M + H + ).

[0342] 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) was added HATU (206.01 mg, 0.5400 mmol) and N-ethyl-N-isopropylpropan-2-amine (0.5 mL, 2.9 mmol) at 20 °C. The reaction mixture was stirred for 30 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 give a yellow solution. The reaction mixture was poured into saturated aqueous ammonium chloride (20 mL) and extracted with ethyl acetate (20 mL × 3). The crude product was purified by Prep-HPLC (FA) to give 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).

[0343] 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 give 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).

[0344] 1-[(1S)-1-(2-pyridinyl)ethyl]-1H-imidazole-4-carboxylic acid To a solution of ethyl 1-[(1S)-1-(2-pyridinyl)ethyl]-1H-imidazole-4-carboxylate (160 mg, 0.6500 mmol) in THF (5 mL) and water (1 mL, 55.56 mmol) was added lithium hydroxide monohydrate (0.11 mL, 1.96 mmol). The mixture was stirred at 20 °C for 12 hours to give a brown suspension. LCMS indicated that the starting material had been completely consumed. The reaction mixture was concentrated. The resulting aqueous layer was acidified with 1N aqueous hydrochloric acid to pH 5-7 and then lyophilized to give the title compound (130 mg, 0.5985 mmol, 91.746% yield) as a white solid.

[0345] [(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) was added HATU (274.55 mg, 0.7200 mmol), DIPEA (0.49 mL, 2.99 mmol), and (1R,5S,6r)-6-(5,5-dimethyl-4,5-dihydro-1,2-oxazol-3-yl)-3-azabicyclo[3.1.0]hexane hydrochloride (108 mg, 0.6000 mmol). The mixture was stirred at 30°C for 3 hours to give a brown solution. The reaction mixture was directly concentrated. The residue was purified by prep-HPLC (NH3), 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 (1H, 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).

[0346] 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 hours. 4-Methylbenzene-1-sulfonyl chloride (0.29 mL, 1.95 mmol) was added, and the mixture was stirred at 20°C to 25°C for 16 hours. 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).

[0347] 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) were added methyl 1H-imidazole-5-carboxylate (127.32 mg, 1.01 mmol) and cesium carbonate (164.47 mg, 0.50 mmol). 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 × 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, 11.993% yield) 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).

[0348] 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 mixture was directly concentrated. The reaction mixture was acidified with aqueous hydrochloric acid (1N) to pH = 6 and then lyophilized to give the title compound (40 mg, 0.1841 mmol, 85.167% yield) as a yellow oil. 1 H NMR (400MHz, DMSO-d6) 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=7.3Hz, 3H).

[0349] [(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) was added EDCI (26.48 mg, 0.14 mmol) and (1R,5S,6r)-6-(5,5-dimethyl-4,5-dihydro-1,2-oxazol-3-yl)-3-azabicyclo[3.1.0]hexane hydrochloride (19.95 mg, 0.0900 mmol). The resulting mixture was stirred at 20-25 °C for 16 h. The residue was purified by prep-HPLC (NH). The 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).

[0350] 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 To a solution of (1S)-1-(1,3-thiazol-2-yl)ethanamine (131.19 mg, 0.7800 mmol) in 1-butanol (1.4 mL) was added ethyl (2Z)-3-(dimethylamino)-2-isocyanoacrylate (100 mg, 0.7800 mmol) and triethylamine (0.16 mL, 1.17 mmol) at 25 °C. The resulting mixture was reacted in a microwave reactor (time: 1 h, temperature: 130 °C). The reaction mixture was poured into water (5 mL) and extracted with ethyl acetate (5 mL x 3). The combined organic layer was washed with saturated brine (10 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to obtain the 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.

[0351] 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.

[0352] [(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 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) was added EDCI (56.67 mg, 0.3000 mmol). The mixture was stirred at 25°C under a nitrogen atmosphere for 10 minutes. Then, (1R,5S,6r)-6-(5,5-dimethyl-4,5-dihydro-1,2-oxazol-3-yl)-3-azabicyclo[3.1.0]hexane hydrochloride (42.71 mg, 0.2000 mmol) was added. The resulting mixture was stirred at 25°C for 2 hours to give a yellow solution. The reaction mixture was poured into water (5 mL) and extracted with ethyl acetate (5 mL x 3). The combined organic layers were washed with saturated brine (20 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The crude product was purified by prep-HPLC (NH) to give 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).

[0353] 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). The mixture was stirred at 60 °C for 2 h to give a yellow mixture. TLC (PE:ethyl acetate = 2:1) showed complete consumption of the starting material, with one new spot (Rf = 0.5). The reaction mixture was diluted with ethyl acetate (30 mL). Water (10 mL) was added and the mixture was stirred for 1 min to give a yellow suspension. This suspension was filtered. The filtrate was washed with water (20 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the title compound (3.77 g, 17.428 mmol, 98.59% yield) as a yellow solid.

[0354] (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) and 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 complete consumption of the starting material, with one new spot (Rf = 0.3) detected. Ammonium chloride (60 mL) was added 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 give 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).

[0355] (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 hours 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) as a brown solid.

[0356] 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 oven to give a brown mixture. 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 (46 mg, 0.1830 mmol, 8.6116% yield) 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).

[0357] 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 x 3). The aqueous layer was acidified to pH 5 with 1N aqueous hydrochloric acid and lyophilized to give the title compound (40 mg, 0.1792 mmol, 97.882% yield) as a brown solid. 1 H NMR (400MHz, DMSO-d6) 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).

[0358] [(1R,5S,6S)-6-(5,5-dimethyl-4,5-dihydro-1,2-oxazol-3-yl)-3-azabicyclo[3.1.0]hex-3-yl]{1-[(1S)-1-(1,3-thiazol-5-yl)ethyl]-1H-imidazol-4-yl}methanone To a mixture of 1-[(1S)-1-(1,3-thiazol-5-yl)ethyl]-1H-imidazole-4-carboxylic acid (40 mg, 0.1800 mmol) and DMF (0.8286 mL), HATU (82.2 mg, 0.2200 mmol) and DIPEA (0.15 mL, 0.9000 mmol) were added. After stirring at 50°C for 30 minutes, (1R,5S,6r)-6-(5,5-dimethyl-4,5-dihydro-1,2-oxazol-3-yl)-3-azabicyclo[3.1.0]hexane hydrochloride (48.44 mg, 0.2700 mmol) was added. The mixture was stirred at 25°C for 16 hours, yielding a yellow mixture. The reaction mixture was purified by prep-HPLC (NH3). 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 + ] 1 H 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).

[0359] 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) were added triethylamine (0.45 mL, 3.23 mmol) and 4-methylbenzene-1-sulfonyl chloride (0.44 mL, 2.94 mmol). The reaction mixture 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 the mixture was extracted with DCM (30 mL x 2). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure to give a yellow oil. The crude product was purified by silica gel chromatography (PE / ethyl acetate = 1 / 0 → 10 / 1) to give the title compound (680 mg, 2.3418 mmol, 79.731% yield) as a white solid.

[0360] 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 the mixture was extracted with ethyl acetate (30 mL x 2). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure to give a yellow oil. The crude product was purified by silica gel chromatography (DCM / ethyl acetate = 10 / 1 → 3 / 1) to give the title compound (120 mg, 0.4912 mmol, 20.649% yield). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.61 (s, 1H), 7.35-7.15 (m, 5H), 6.95-6.85 (m, 2H), 4.45-4.35 (m, 1H), 3.88 (s, 3H), 3.10-2.90 (m, 2H), 1.56 (d, J = 6.8 Hz, 3H).

[0361] 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 mixture was stirred at 20 °C for 16 h to give a colorless oil. TLC (PE / ethyl acetate = 1 / 1, Rf = 0) showed a new spot. The reaction mixture was evaporated under reduced pressure and then lyophilized to give the title compound (110 mg, 0.4777 mmol, 97.252% yield) as a white solid.

[0362] [(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 the mixture was stirred at 20 °C for 16 h to give a yellow solution. Water (30 mL) was added and the mixture was extracted with ethyl acetate (30 mL x 2). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure to give a yellow oil. The crude was purified by Prep-HPLC (NH3). The obtained fraction was concentrated in vacuo to remove most of the acetonitrile, and then lyophilized to obtain the title compound (104.7 mg, 0.2668 mmol, yield 61.424%) 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).

[0363] 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 the mixture was 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 residue. The residue was purified by flash column chromatography (PE → 30% ethyl acetate in PE) to give 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 + ).

[0364] (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) and 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 hours to give a colorless mixture. TLC (PE:ethyl acetate = 2:1) showed one new spot (Rf = 0.3). The reaction mixture 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).

[0365] (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 give a yellow mixture, which was concentrated under reduced pressure to give the title compound (190 mg, 1.0232 mmol, yield 99.724%) (crude) as a yellow solid.

[0366] 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) and 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 + ).

[0367] 1-[(2S)-4-phenylbutan-2-yl]-1H-imidazole-4-carboxylic acid To a solution of ethyl 1-[(2S)-4-phenylbutan-2-yl]-1H-imidazole-4-carboxylate (40 mg, 0.1500 mmol) in THF (1.5 mL) and water (0.50 mL) was added lithium hydroxide monohydrate (0.01 mL, 0.2200 mmol). The reaction mixture was stirred at 40 °C for 16 h, resulting in a yellow mixture. TLC (PE:ethyl acetate = 1:1) showed complete consumption of the starting material. The reaction mixture was diluted with water (5 mL) and extracted with ethyl acetate (3 mL × 2). The aqueous layer was acidified to pH = 5 with 1N aqueous hydrochloric acid. 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 + ).

[0368] [(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) and pyridine (1.5 mL), EDCI (28.25 mg, 0.1500 mmol) was added. After stirring 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 indicated complete consumption of the starting material. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (NH3). 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).

[0369] 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). 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 the mixture was extracted with ethyl acetate (30 mL x 2). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure to 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.

[0370] (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 to hydrochloric acid / dioxane (5 mL, 20 mmol) and the reaction mixture was stirred at 20 °C for 3 h to give a colorless solution. LCMS showed a new peak in the desired MS region. 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 + ).

[0371] Ethyl 1-[(2S)-1-phenoxypropan-2-yl]-1H-imidazole-4-carboxylate A 5 mL microwave vial was charged with (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 mixture was microwaved at 130 °C for 1 hour to give a brown solution. LCMS showed a new peak in the desired MS region. The reaction mixture was diluted with saturated aqueous sodium carbonate (20 mL). Water (30 mL) was added, and the mixture was extracted with ethyl acetate (30 mL x 2). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure to 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 + ).

[0372] 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 (1 mL). Stirring at 20 °C for 16 h gave a yellow solution. LCMS showed a new peak in the MS spectrum. Water (30 mL) was added, and the mixture was extracted with ethyl acetate (30 mL). The aqueous layer was then acidified with 1 M 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 + ).

[0373] [(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 mL x 2). The organic layer was dried over sodium sulfate and concentrated under reduced pressure to give a yellow oil. The crude product was purified by prep-HPLC (NH3). The resulting fractions were 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).

[0374] 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 at 80° C. for 16 hours. The crude product was purified by flash column chromatography (PE:ethyl acetate=2:1) ​​to give the title compound (500 mg, 2.3779 mmol, 79.988% yield) as a brown oil.

[0375] 1-(pentan-3-yl)-1H-imidazole-4-carboxylic acid To a solution of ethyl 1-(pentan-3-yl)-1H-imidazole-4-carboxylate and water (5 mL) in THF (15 mL) was added lithium hydroxide monohydrate (0.41 mL, 7.13 mmol). The mixture was stirred 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 (0.5 M). The solution was then lyophilized to give the title compound as a yellow solid.

[0376] [(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 To a solution of 1-(pentan-3-yl)-1H-imidazole-4-carboxylic acid (50 mg, 0.2700 mmol) in DMF (5 mL), HATU (157.35 mg, 0.4100 mmol) and triethylamine (0.14 mL, 1.1 mmol) were added and stirred at 25 °C for 15 min. (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 then added. The resulting mixture was stirred at 25 °C for 2 h 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 (NH3) 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).

[0377] 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) was added 1-methylcyclopropanamine (300 mg, 2.79 mmol) and triethylamine (0.54 mL, 4.18 mmol). 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 mixture was directly concentrated. 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).

[0378] 1-(1-methylcyclopropyl)-1H-imidazole-4-carboxylic acid To a solution of ethyl 1-(1-methylcyclopropyl)-1H-imidazole-4-carboxylate (118 mg, 0.61 mmol) in THF (1.5 mL) and water (0.50 mL) was added lithium hydroxide monohydrate (0.05 mL, 0.79 mmol). The resulting mixture was stirred at 20-25°C for 2 hours. The reaction mixture was directly concentrated. The residue was acidified with aqueous hydrochloric acid (1M) to pH = 6. Lyophilization afforded the desired compound (100 mg, 0.6018 mmol, 99.05% yield) as a yellow solid. 1H NMR (400MHz, DMSO-d6) 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).

[0379] [(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 then (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 mixture was stirred at 20-25 °C for 1 h. LCMS showed the desired MS (as a major peak). The residue was purified by prep-HPLC (NH3). 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 + ].

[0380] 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 h. The reaction mixture was diluted with water (5 mL) and extracted with ethyl acetate (5 mL × 3). The combined organic layers were washed with brine (10 mL), dried over sodium sulfate, and concentrated under reduced pressure to 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 + ).

[0381] 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 hours. The aqueous layer was washed with DCM (3 mL x 2) and acidified with 1N aqueous hydrochloric acid to pH = 2. The aqueous solution was lyophilized to afford the title compound (50 mg, 0.2775 mmol, 115.57% yield) as a pale yellow solid.

[0382] [(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) was added HATU (137.86 mg, 0.3600 mmol), DIPEA (0.18 mL, 1.11 mmol), and (1R,5S,6r)-6-(5,5-dimethyl-4,5-dihydro-1,2-oxazol-3-yl)-3-azabicyclo[3.1.0]hexane hydrochloride (40 mg, 0.2200 mmol). The resulting mixture was stirred at 20 °C for 4 h. The reaction mixture was diluted with water (5 mL), extracted with ethyl acetate (5 mL × 2), and washed with brine (8 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure to give a crude oil. The crude oil was purified by prep-HPLC (NH3) and then lyophilized to give the title compound (3 mg, 0.0088 mmol, yield 3.9478%) as a pale yellow solid. 1 H NMR (400MHz, CD3OD) δ = 7.74 (s, 1H), 7.67 (s, 1H), 4.41 (br d, J=12.0 Hz, 1H), 4.09 (br d, J=12.3 Hz, 1H), 3.93 (br dd, J=3.8, 11.8 Hz, 1H), 3.59 (br dd, J=3.9, 12.4 Hz, 1H), 2.71 (s, 2H), 2.63 - 2.52 (m, 2H), 2.30 (tt, J=3.0, 8.9 Hz, 2H), 2.14 - 2.08 (m, 1H), 2.07 - 1.92 (m, 3H), 1.68 (s, 3H), 1.48 (t, J=3.4 Hz, 1H), 1.32 (s, 6H).

[0383] 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. The mixture was stirred at 130 °C for 6 h 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 (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).

[0384] 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 mixture was stirred at 40 °C for 12 h. The reaction mixture was diluted with water and extracted with DCM. The aqueous layer was acidified to pH = 5 with aqueous hydrochloric acid (1 N). 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. 1H NMR (400 MHz, DMSO-d6) 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).

[0385] [(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 the mixture was stirred at 20 °C for 16 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 under reduced pressure 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).

[0386] Example 36 [(1R,5S,6r)-6-(5,5-dimethyl-4,5-dihydro-1,2-oxazol-3-yl)-3-azabicyclo[3.1.0]hex-3-yl](1-isobutyl-1H-imidazol-4-yl)methanone Ethyl 1-isobutyl-1H-imidazole-4-carboxylate To a solution of ethyl (2Z)-3-(dimethylamino)-2-isocyanoacrylate (1.50 g, 8.92 mmol) in 1-butanol (17.8 mL, 0.5 M) was added 2-methylpropan-1-amine (1.0 mL, 9.8 mmol, 1.1 eq) and triethylamine (0.74 mL, 5.35 mmol, 0.6 eq). The mixture was stirred at 130 °C for 6 h 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).

[0387] 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 (1 N). 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-d6) 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).

[0388] [(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 the mixture was 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 under reduced pressure 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).

[0389] 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) were added 1-propene (4.6 mL, 2.3 mmol) and triethylamine (0.38 mL, 2.3 mmol). The resulting mixture was stirred at 20 °C for 16 hours to give a pale yellow mixture. The reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (10 mL × 2). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure to give the title compound (130 mg, crude) as a pale yellow oil. LC-MS Method1 0.825 min, MS (m / z) 267.0 (M + H + ).

[0390] (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 mixture was stirred at 0 °C for 30 minutes to give a pale yellow mixture. The reaction mixture was directly concentrated to dryness to give the title compound (90 mg, crude).

[0391] (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 complete consumption of 1-isopropylimidazole-4-carboxylic acid (46.38 mg, 0.30 mmol). 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 (NH3) to give the title compound (5 mg, 0.0165 mmol, yield 5.4972%) as a white solid. 1 H NMR (400MHz, CH3OH) 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, 16.9Hz, 1H), 2.13 - 1.95 (m, 2H), 1.42 (d, J=6.6 Hz, 6H), 1.18 (d, J=6.3 Hz, 3H).

[0392] 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 mixture was stirred at 0 °C for 16 h to give a yellow solution. LCMS showed a new peak in the MS region of interest. The reaction mixture was diluted with water (30 mL) and extracted with ethyl acetate (30 mL × 2). The combined organic layers were dried over sodium sulfate and concentrated to 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 + ).

[0393] 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 hours to give a yellow solution. LCMS showed a new peak in the MS spectrum. The solvent from 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, which was used in the next step. LC-MS Method1 0.178 min, MS (m / z) 179.1 (M + H + ).

[0394] (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 A 100 mL round-bottom flask was charged with 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 reactant and the desired product. The reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (30 mL x 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 fractions were concentrated in vacuo to remove most of the acetonitrile and lyophilized to give the title compound (14.67 mg, 0.0467 mmol, 5.0137% yield) 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).

[0395] 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) was added methylenecyclobutane (78.4 mg, 1.15 mmol). The resulting 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 (20 mL x 3), washed with saturated brine (5 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the title compound (46 mg, crude) as a yellow powder. LC-MS Method1: 0.818 min, MS (m / z): 237.0 (M-56 + H + ).

[0396] 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) and 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 + ).

[0397] (1-Isopropyl-1H-imidazol-4-yl)[(1R,5S,6r)-6-(5-oxa-6-azaspiro[3.4]oct-6-en-7-yl)-3-azabicyclo[3.1.0]hex-3-yl]methanone To a mixture of 7-[(1R,5S,6r)-3-azabicyclo[3.1.0]hex-6-yl]-5-oxa-6-azaspiro[3.4]oct-6-ene trifluoroacetate (30.0 mg, 0.16 mmol) in pyridine (0.5 mL) was added EDCI (29.9 mg, 0.16 mmol) and 1-isopropylimidazole-4-carboxylic acid (24.1 mg, 0.16 mmol). The suspension was stirred at 20 °C for 16 h. Water (10 mL) was added to quench the reaction. The residue was diluted with ethyl acetate (20 mL x 3), washed with saturated brine (5 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Purification by prep-HPLC (NH3) and lyophilization afforded 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).

[0398] 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) was added triethylamine (0.22 mL, 1.53 mmol). The reaction mixture was stirred at 20 °C for 12 hours to give a pale yellow solution. The reaction mixture was diluted with ethyl acetate (15 mL), saturated aqueous sodium bicarbonate (10 mL) was added, and the mixture was stirred for 5 minutes. The aqueous layer was extracted with ethyl acetate (10 mL × 2). The combined DCM layers were dried over sodium sulfate and concentrated under reduced pressure to give the title compound (240 mg, 0.7683 mmol, crude) as a pale brown oil.

[0399] tert-Butyl (1R,5S,6r)-6-[5-(difluoromethyl)-5-methyl-4,5-dihydro-1,2-oxazol-3-yl]-3-azabicyclo[3.1.0]hexane-3-carboxylate To a solution of tert-butyl (1R,5S,6r)-6-[5-(dihydroxymethyl)-5-methyl-4,5-dihydro-1,2-oxazol-3-yl]-3-azabicyclo[3.1.0]hexane-3-carboxylate (240 mg, 0.77 mmol) in DCM (10 mL) was added DAST (371.11 mg, 2.31 mmol) at -78 °C. The reaction mixture was warmed to 20 °C and stirred for an additional 12 h to give a light brown solution. The reaction mixture was cooled to 0 °C, 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 give a crude oil, which was purified by prep-HPLC (HCl). The eluent was washed with saturated aqueous sodium bicarbonate (2 mL) and concentrated to remove acetonitrile. The residue was extracted with ethyl acetate (10 mL × 2). The combined ethyl acetate layers were dried over sodium sulfate and concentrated 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).

[0400] {(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, resulting in 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, resulting in a yellow mixture. The reaction mixture was concentrated and purified by prep-HPLC (NH3). 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).

[0401] 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 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), 2-methylbut-1-ene (403.48 mg, 5.75 mmol) and triethylamine (116.4 mg, 1.15 mmol, 0.16 mL) were added and stirred at 20 °C for 16 h. Water (10 mL) was added to the reaction mixture to quench the reaction. The residue was extracted with ethyl acetate (20 mL × 3). The combined organic layers were washed with saturated brine (5 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by prep-TLC (PE:ethyl acetate = 2:1, Rf = 0.5) to give the title compound (76 mg, crude) as a yellow powder. LC-MS Method1: 0.833 min, MS (m / z): 239.0 (M-56 + H + ).

[0402] (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 + ).

[0403] [(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 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) were added EDCI (49.3 mg, 0.26 mmol) and 1-isopropylimidazole-4-carboxylic acid (39.7 mg, 0.26 mmol). The suspension was stirred at 20 °C for 16 h. Water (10 mL) was added to quench the reaction. The residue was extracted with ethyl acetate (20 mL × 3), washed with saturated brine (5 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by prep-HPLC (NH3) and lyophilized to afford the title compound (5.77 mg, 6.8% yield) 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).

[0404] 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 production process of Example 41, respectively. The final step of Example 41, {(1R,5S,6r)-6-[(5R)-5-ethyl-5-methyl-4,5-dihydro-1,2-oxazol-3-yl]-3-azabicyclo[3.1.0]hex-3-yl}(1-isopropyl-1H-imidazol-4-yl)methanone (63.41 mg, 0.19 mmol, 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), were isolated by SFC purification as 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).

[0405] 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. 2,5-Dioxopyrrolidin-1-yl(2-(trimethylsilyl)ethyl)carbonate (4.06 g, 15.65 mmol) in DCM (20.27 mL) was then 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 mixture was directly concentrated. The crude product was purified by flash column chromatography (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).

[0406] 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 chromatography (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).

[0407] 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) was added DMP (2.97 g, 6.99 mmol) and sodium bicarbonate (979.14 mg, 11.66 mmol) at 0 °C and stirred at 30 °C for 2 h. 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 × 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).

[0408] 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 to water (40 mL) and extracted with ethyl aceta...

Claims

1. General formula (I): 【Chemical 1】 (In the formula, R １ is Cyc1, -CO-Cyc2 or -CONR １０ R １１ represents; Cyc1 has 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) C alkyl, (2) C cycloalkyl, (3) C haloalkyl, (4) C 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 may form a C3-5 cycloalkane together with the atom to which it is attached, and the carbon atoms of the C3-5 cycloalkane 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 C3-12 mono- or bi-carbocyclic ring or 5-9-membered mono- or bi-heterocyclic ring 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 imidazole optionally substituted with 1 to 3 R １５ represents pyrazole optionally substituted by 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 Cyc3, which may be substituted with (Cyc3), or (6) 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 Cyc4, which may be substituted with (Cyc4), or (6) 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]hexane-3-yl]methanone, [(1S,5R)-6-(2,2-dimethylpyrrolidine-1-carbonyl)-3-azabicyclo[3.1.0]hexane-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, and a pharmaceutical composition comprising a pharmaceutically acceptable carrier.

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

3. 3. The pharmaceutical composition according to claim 2, wherein the 5-membered non-aromatic heterocycle is 4,5-dihydroisoxazole or 4,5-dihydro-1,2,4-oxadiazole.

4. R ９ But 1 to 3 R １４ The pharmaceutical composition according to any one of claims 1 to 3, wherein the imidazole is optionally substituted with:

5. The compound represented by general formula (I) or a salt thereof is represented by 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, and R １４－１ represents C1-4 alkyl or C3-5 cycloalkyl optionally substituted by C1-4 alkyl, and other symbols have the same meanings as defined in claim 1), or a salt thereof.

6. The compound represented by formula (I) or a salt thereof (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, and (9) The pharmaceutical composition according to any one of claims 1 to 5, which is a compound selected from the group consisting of [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 pharmaceutical composition according to any one of claims 1 to 3, wherein the compound represents an optionally substituted pyrazole.

8. The compound represented by general formula (I) or a salt thereof is represented by general formula (I-2): 【Chemistry 4】 (wherein all symbols have the same meanings as defined in claim 1 or claim 5), or a salt thereof.

9. The compound represented by formula (I) or a salt thereof (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, and (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. The pharmaceutical composition according to any one of claims 1 to 3, 7 and 8.

10. R １ Ga-CONR １０ R １１ 2. The pharmaceutical composition of claim 1, wherein

11. R １０ The pharmaceutical composition of claim 10, wherein represents isopropyl, tert-butyl, 1,1,1-trifluoro-2-methylpropan-2-yl, 1-methylcyclopropyl, 1-(trifluoromethyl)cyclopropyl, or 1-cyanocyclopropyl.

12. R ９ But 1 to 3 R １４ 12. The pharmaceutical composition according to claim 10 or 11, wherein the imidazole is optionally substituted with:

13. The compound represented by general formula (I) or a salt thereof is represented by general formula (I-3) 【Chemistry 5】 (In the formula, R １０－１ The pharmaceutical composition according to any one of claims 1 and 10 to 12, which is a compound represented by the following formula (I) or a salt thereof:

14. The compound represented by formula (I) or a salt thereof (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, and (4) The pharmaceutical composition according to any one of claims 1 and 10 to 13, which is a compound selected from the group consisting of (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 pharmaceutical composition according to claim 10 or 11, wherein the compound represents an optionally substituted pyrazole.

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

17. The compound represented by formula (I) or a salt thereof (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, and (4) The pharmaceutical composition according to any one of claims 1, 10, 11, 15 and 16, which is a compound selected from the group consisting of (1R,5S,6r)-N-methyl-N-(1-methylcyclopropyl)-3-[5-(propan-2-yl)-1H-pyrazole-3-carbonyl]-3-azabicyclo[3.1.0]hexane-6-carboxamide or a salt thereof.

18. 18. The pharmaceutical composition of any one of claims 1 to 17, which is a KDM5 inhibitor.

19. The pharmaceutical composition according to any one of claims 1 to 18, which is an agent for preventing and / or treating a KDM5-related disease.

20. The pharmaceutical composition according to claim 19, wherein the KDM5-related disease is cancer or Alzheimer's disease.

21. 10. A preventive and / or therapeutic agent for KDM5-related diseases, comprising the compound represented by general formula (I) according to claim 1 or a salt thereof as an active ingredient.

22. A pharmaceutical composition comprising [(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 or a salt thereof and a pharmaceutically acceptable carrier.

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